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dstock07734
Re: None
Saturday, July 20, 2024 11:34:16 AM
Post#
707229
of 707235
NCI researchers along with Dr. Liau and her colleagues did genetic profiling analysis on tissue samples from the p3 trial. In February the same group of NCI researchers just published a paper on long-term GBM survivors. The interesting part is that in the paper published in February NCI scientists defined long-term survivor as those who lived over three years while in the analysis which involves the p3 trial they chose those who lived over five years as long-term survivors. It is obvious that NCI set a higher bar to evaluate the results on the p3 trial.
Glioblastoma Molecular Characteristics and Immune Microenvironment Associated with Survival Outcomes in Patients Treated with Dendritic Cell Vaccination
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE249282
Long-term survivors of glioblastoma: Tumor molecular, clinical, and imaging findings
https://academic.oup.com/noa/article/6/1/vdae019/7603818
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Member Level
Re: theorysuit post# 707223
Saturday, July 20, 2024 11:40:20 AM
Post#
707232
of 707233
There are very good reasons for breaking out the cost of building a CDMO and not having it a part of the company developing the drug and that goes to risk and what happened to Dendreon, in this exact same space. Their burn rate is relatively low in this period for that reason. Their deal with the regional development authority allows the facility to be somewhat self-sustaining while they seek approval, yet they still control it and can develop it in stages. Meanwhile, their facility is funded as if it is an accelerator for similar companies in the region, by the regional development authority. The regional development authority saw no problem here. Neither do I.
The fact is, the CDMO is a contract relationship. It owns NO IP. It is not valuable without that contract. It's simply a took for isolating risk and costs and managing a process with lots of expertise that is needed for key moments and a key stage. Later, when funds are not an issue, it can all be brought in house either by ending the contract or buying the employment contracts of those people out. But the reality is, the value of the CDMO is simply a measure of the costs of making the drug, with 10% on top. And the contract is cancelable at will.
The other reality is, if they did not do it this way, they would be paying many multiples of what they are paying now, to pay for another companies complete facility and likely a much higher built in profit given that that other company would depreciate all of the assets paid for and have them for any other project they took on. The reality is, small companies like this virtually ALWAYS use CDMOs, with this kind of cell based manufacturing, and this company not only has the CDMO working on its subsidized facility, but it has space to develop its own technology for automating the process, which it owns outright and which it will deploy on commercialization. At that stage, the CDMO might help to deploy and resource such a facility, but also the company can then also likely do all kinds of arrangements including set-up to manufacture itself.
The reality is, the flaskworks technology is where all the innovation and IP will originate going forward, and the efficiencies, not in hand made craft work creating the vaccines, but in closed-end, automated manufacturing of these cell based vaccines. So hiring in this manner is very efficient and well thought out and ensures they scale only when they are ready to scale, and they might decide to create a very modular corporate structure in the long run as well. We'll have to see. But they have all the tools to be very flexible and that is the best way to be when you're dealing with the kinds of potential costs and challenges that such new biotech companies face.
Bullish
BULLISH
flipper44
Member Level
Re: Red_Right_Hand post# 707004
Saturday, July 20, 2024 9:12:31 AM
Post#
707167
of 707182
My guess is the Court already drafted its decision. Perhaps a vacation here or there delayed all relevant personnel review. I assume a decision will come out this week.
Re: GoodGuyBill post# 707105
Friday, July 19, 2024 7:31:22 PM
Post#
707106
of 707131
This is a single arm, Phase 1 trial. Nothing to see here. Enjoy your weekend. 😀
Bullish
BULLISH
This is a PSA to all manipulative and collusive Market Makers, Hedge Funds and Short Sellers:
GoodGuyBill
Re: None
Friday, July 19, 2024 7:27:55 PM
Post#
707105
of 707129
How can this be?!?!?!?! NWBO doesn't have dendritic cells on lock-down after all? Did NWBO/LP fuck around and let someone else beat them to the finish line? Did NWBO make an error by not applying to the FDA?!?!?! WTF is going on!
NWBO doesn't have fast track status:
"The time required to obtain regulatory approval varies between countries. In the U.S., for products without "Fast Track" status, it can take up to eighteen (18) months after submission of an application for product approval to receive the FDA's decision. Even with Fast Track status, FDA review and decision can take up to twelve (12) months. At present, we do not have Fast Track status for our lead product, DCVax-L for GBM. We plan to apply for Fast Track status, but there can be no assurance that FDA will grant us such status for DCVax-L".
https://www.onclive.com/view/fda-grants-fast-track-designation-to-doc1021-for-glioblastoma
FDA Grants Fast Track Designation to DOC1021 for Glioblastoma
Author(s):
Ashling Wahner
The FDA has granted a fast track designation to the dendritic cell vaccine DOC1021 for use as a potential therapeutic option in patients with glioblastoma multiforme.
The designation is based on preliminary safety and efficacy findings from a phase 1 trial (NCT04552886).
DOC1021, which was developed at the Texas Medical Center in Houston, mimics a viral infection with the patient’s cancer markers and harnesses the body’s ability to find and kill infected cells. The vaccine uses a “double-loading” technique that stimulates a novel viral recognition and response pathway. DOC1021 uses patients’ dendritic cells to load unique cancer markers internally and externally into the immune cells, as would occur in a viral infection.
Patients’ individualized DOC1021 treatments are prepared and administered through 3 injections that target the deep cervical lymph node chains. This treatment leads to immune responses that target the central nervous system directly.
“The FDA’s decision acknowledges the potential of this new treatment approach for a very challenging disease,” Mike Wicks, chief executive officer of Diakonos, stated in a news release. “Our protocol represents a first for cancer immunotherapy and could be viable for many types of cancers beyond glioblastoma multiforme.”
“The vaccine's mechanism of action and its unique route of administration showcase the potential of harnessing the body's immune system to combat glioblastoma,” Joseph Georges, DO, PhD, assistant professor of neurosurgery at the University of Arizona College of Medicine — Phoenix, added in the press release.
The single-arm, open-label, first-in-human phase 1 trial is evaluating the safety and feasibility of delivering DOC1021 in 9 to 24 adult patients with glioblastoma who have undergone neurosurgical tumor resection and in whom a neuropathological diagnosis has been established.2 Eligible patients include those with potentially resectable glioblastoma who are deemed good candidates for adjuvant chemotherapy and radiation therapy, including those with tumors deemed suitable for gross total resection or partial resection. Patients must have adequate liver, kidney, immune, and bone marrow function and have an ECOG performance status of 2 or lower.
Patients will be excluded if they have locally advanced tumors deemed unresectable and/or recurrent tumors after prior vaccination; used a nonstandard adjuvant treatment regimen of chemoradiation and temozolomide (Temodar); have any uncontrolled or severe condition that could affect study participation, including hyperthyroidism, hypothyroidism, systemic autoimmune disorders, untreated viral hepatitis, or autoimmune hepatitis; need or are expected need for concurrent therapy with corticosteroids during the trial’s vaccination phase; received prior treatment with another investigational drug or intervention beyond the prespecified standard of care for glioblastoma; or have active HIV.
The phase 1 trial planned to treat 3 to 6 patients with a starting dose of 3.5 x 106 of DOC1021. If this dose was associated with unacceptable adverse effects (AEs), no further patients would be enrolled at this dose, and a de-escalation cohort of 3 to 6 patients would receive the vaccine at a dose of 1.75 x 106 cells. If the starting dose was not associated with unacceptable AEs, a dose-escalation cohort of 3 to 6 patients would receive a dose of 7.0 x 106 cells. If no unacceptable AEs were associated with the vaccine at 7.0 x 106 cells, a second dose-escalation cohort of 3 to 6 patients would receive a dose of 1.4 x 107 cells.
The primary end point of this trial is the safety and potential toxicity of DOC1021. Secondary end points include overall survival and progression-free survival.
“Because phase 1 clinical trials are generally not statistically powered to demonstrate efficacy, detection of a statistically significant efficacy signal is very promising,” William Decker, PhD, an associate professor of immunology at Baylor College of Medicine and the inventor of the DOC1021 technology, stated in the press release.1
The phase 1 trial is ongoing at the MD Anderson Cancer Center at Cooper University Health Care in Camden, New Jersey, and at the University of Texas Health Science Center, and it is expected to complete in 2023.
“Historically, glioblastoma outcomes have been notoriously challenging to improve upon,” Georges said in the press release. “From a clinical and scientific standpoint, the results we are observing with DOC1021 are encouraging.”
“When bad men combine, the good must associate; else they will fall one by one, an unpitied sacrifice in a contemptible struggle.”
~Edmund Burke
dstock07734: I have a family member who had an operation for colorectal cancer about four weeks ago. I understand she starts 3 months of chemo next week. Some spread to the lymph nodes was noted. If she can be admitted to the trial you have described below, please email the instructions to jhpratt@alphavestcapital.com . I can email you back my cell pne number , so we can talk about the case, if you like. A.E.K.
Re: None
Friday, July 19, 2024 2:07:23 PM
Post#
707068
of 707072
If the collaboration trial with Merck is real, according to the latest rule, it seems like the trial has to be registered in a public accessible website if the trial is to be continued beyond January 30, 2025.
A multi-center, Phase II clinical trial evaluating DCVax-L (autologous dendritic cells pulsed with tumor lysate antigen) and pembrolizumab (an anti–PD-1 monoclonal antibody) for subjects with liver metastases of primary colorectal carcinoma
https://www.rlp-forschung.de/public/facilities/2807/research_projects/22146
Any EU/EEA trial with a foreseen Last patient last visit* after 30 January 2025 is required to transition to the Clinical Trials Information System to comply with Regulation (EU) 536/2014. This needs to be done as soon as possible, since this deadline includes the time necessary for completion of the Member State(s) procedure, which can take up to 3 months. More information here.
If your trial is expected to continue after 30 January 2025: see CTIS: how to get started and how to transition a trial. In case of a multi-country trial, sponsors should ensure the harmonisation of their clinical trial under the Directive through EudraCT, prior to transitioning their trial to CTIS: see Guidance for the Transition of clinical trials.
*This applies to all trials having at least one active site in the EU/EEA ('Active site' in the context of transition trials means that the last visit of the last subject, or other trial-specific interventions with the subject specified in the protocol) as well as to any EudraCT trial for which an additional member state application needs to be submitted.
https://eudract.ema.europa.eu/
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dstock07734
Re: None
Friday, May 03, 2024 10:59:29 PM
Post#
688907
of 707073
In the PR in 2016 on the collaboration trial between Merck and NWBO, LP said the trial took more than 2 years of planning and work. The PI of the collaboration trial was Markus Moehler. I went through some of his publications between 2013 and 2023 to see if he had been in contact with Merck. I suspect if there are still some people who claimed that this trial never happened. The collaboration between Markus Moehler and Merck reminds me of the interaction between Vivek Subbiah and NWBO.
Linda Powers, CEO of NW Bio, noted that, “More than 2 years of planning and work have gone into developing this Phase II trial program. We are excited to work with a leading team to test the potential synergies of combining broad spectrum DCVax-L and targeted Pembrolizumab to treat a heterogeneous and challenging disease such as metastatic colorectal cancer.”
https://nwbio.com/nw-bio-announces-phase-ii-clinical-trial-program-combining-dcvax-l-and-pembrolizumab-keytruda-for-colorectal-cancer/
2023
The Oncology Biomarker Discovery framework reveals cetuximab and bevacizumab response patterns in metastatic colorectal cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10477267/
M.M. received honoraria for advisory boards or talks by Amgen, BMS, Roche, Merck KGaA, MSD Sharp & Dohme, Lilly Oncology, Servier, Pierre Fabre, Taiho Sanofi and Bayer Pharmaceuticals and serves as officer for the European Organisation on Research and Treatment of Cancer (EORTC), and Arbeitsgemeinschaft internistische Onkologie (AIO).
Standard diametric versus volumetric early tumor shrinkage as a predictor of survival in metastatic colorectal cancer: subgroup findings of the randomized, open-label phase III trial FIRE-3 / AIO KRK-0306
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9889429/
M.M. has received grants and non-financial support from EORTC, grants and non-financial support from AIO, grants and non-financial support from German Cancer Aid, and grants and non-financial support from BMBF, during the conduct of the study; personal fees from Falk Foundation; personal fees from Lilly; grants and personal fees from MSD; personal fees from Roche; grants and personal fees from Pfizer; grants, personal fees, and non-financial support from Amgen; grants, personal fees, and non-financial support from Bristol-Myers Squibb; grants and personal fees from Merck Serono; personal fees from MCI Group; and personal fees from Taiho, outside the submitted work.
2022
Survival after secondary liver resection in metastatic colorectal cancer: Comparing data of three prospective randomized European trials (LICC, CELIM, FIRE-3)
https://onlinelibrary.wiley.com/doi/10.1002/ijc.33881
Markus Moehler: Honoraria or consulting or advisory role: Falk, Nordic Amgen, AstraZeneca, mcI, Frankfurt, Lilly, MSD, MerckSerono, BMS, Pfizer, Roche; Research funding: Amgen, BMS, MSD, Merck Serono, EORTC; Travel, accommodations, expenses: Merck Serono, BMS, Roche, MSD, Amgen.
Early weight loss is an independent risk factor for shorter survival and increased side effects in patients with metastatic colorectal cancer undergoing first-line treatment within the randomized Phase III trial FIRE-3 (AIO KRK-0306)
https://onlinelibrary.wiley.com/doi/10.1002/ijc.33775
Markus Moehler reports potential conflict of interest from Merck Germany, MSD, BMS, Servier, Pierre-Fabre Pharma, Lilly Deutschland, Dragonfly.
2021
Early-Onset Colorectal Adenocarcinoma in the IDEA Database: Treatment Adherence, Toxicities, and Outcomes With 3 and 6 Months of Adjuvant Fluoropyrimidine and Oxaliplatin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8677996/
Markus Moehler
Honoraria: Amgen, Roche/Genentech, Merck Serono, MSD Oncology, Bristol Myers Squibb, AstraZeneca/MedImmune, Servier, Pierre Fabre, Sanofi
Consulting or Advisory Role: Bayer, MSD, Merck Serono, Amgen, Taiho Pharmaceutical, Pfizer, Roche, Lilly, Servier, BeiGene, BMS
Research Funding: Amgen (Inst), Leap Therapeutics (Inst), Merck Serono (Inst), AstraZeneca (Inst), MSD (Inst)
Travel, Accommodations, Expenses: Amgen, Merck Serono, Roche, Bayer, ASCO, German Cancer Society, MSD, ESMO
Cancer gene related characterization of patterns and point of recurrence after resection of colorectal liver metastases
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506541/
MM reports grants and non-financial support from EORTC, grants and non-financial support from AIO, grants and non-financial support from German Cancer Aid, grants and non-financial support from BMBF, during the conduct of the study; personal fees from Falk Foundation, personal fees from Lilly, grants and personal fees from MSD, personal fees from Roche, grants and personal fees from Pfizer, grants, personal fees and non-financial support from Amgen, grants, personal fees and non-financial support from Bristol-Myers Squibb, grants and personal fees from Merck Serono, personal fees from MCI Group, personal fees from Taiho, outside the submitted work.
2020
Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials
https://aacrjournals.org/clincancerres/article/26/24/6559/83059/Amphiregulin-Expression-Is-a-Predictive-Biomarker
M. Moehler reports personal fees and nonfinancial support from Roche and Servier; grants and personal fees form MSD; grants, personal fees, and nonfinancial support from Merck Serono, BMS, and Bayer during the conduct of the study.
Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573695/
Dr Moehler reported receiving grants from Merck Serono during the conduct of the study and receiving personal fees from MerckSerono and Roche outside the submitted work.
2019
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927316/
MM: got honoraria for presentations and advisory board role from: AMGEN, BMS, MSD, Merck-Serono, Lilly, Falk, Pfizer, Roche; DPM: got honoraria for presentations and advisory board role from: Merck-Serono, Roche, Servier, Sirtex, BMS, MSD, Bayer, Boehringer-Ingelheim, Lilly
Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors: Rationale and Current State
https://pubmed.ncbi.nlm.nih.gov/31535338/
Markus Moehler reports a consulting/advisory role for Amgen, Bayer, Bristol-Myers Squibb, Eli Lilly, Merck, Merck Sharpe & Dohme, Onyx, Pfizer, and Roche; research funding from AIO-Studien-gGmbH, Amgen, Bristol-Myers Squibb, European Organisation for Research and Treatment of Cancer, Merck, Merck Sharp & Dohme, Roche, Taiho Pharmaceutical, and Transgene; and honoraria from American Society of Clinical Oncology, Amgen, Bristol-Myers Squibb, Eli Lilly, European Society for Medical Oncology, Falk, Merck, Nordic, and Pfizer.
2018
Immuno-oncology in GI tumours: Clinical evidence and emerging trials of PD-1/PD-L1 antagonists
https://pubmed.ncbi.nlm.nih.gov/30196908/
MM: Advisory role: Lilly, Onyx, Roche, Bristol-Myers Squibb, MSD, Amgen, Merck, Pfizer; Honoraria: Falk, Nordic, Amgen, mci, Lilly, MSD, Bristol-Myers Squibb, Merck, Pfizer; Research grants: Merck, Amgen, Bristol-Myers Squibb, Taiho, Roche, MSD, Transgene
2017
Relevance of liver-limited disease in metastatic colorectal cancer: Subgroup findings of the FIRE-3/AIO KRK0306 trial
https://onlinelibrary.wiley.com/doi/10.1002/ijc.31114
M.M. has received honoraria from Falk, Nordic, Amgen, mci, Lilly, MSD, Merck, Pfizer, BMS, ESMO, ASCO and travel support from Merck KgaA, Amgen, Roche. He served on advisory boards for Lilly, Onyx, Roche, BMS, MSD, Amgen, Merck, Pfizer.
Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306)
https://pubmed.ncbi.nlm.nih.gov/28843184/
MM received honoraria/travel support from Lilly, Amgen, Roche, Merck, MSD, BMS, Pfizer and AstraZeneca.
2016
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial
https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30269-8/abstract
MM reports personal fees and non-financial support from Pfizer, Merck, Roche, and Medac.
Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives
https://pubmed.ncbi.nlm.nih.gov/27039171/
MM’s institution received research support from Amgen, Boehringer, Bayer and Merck Serono. MM advised or lectured to Amgen, AstraZeneca, Bayer, BTG, MSD, Merck Serono, Biontech, Lilly, Nordic, Roche and Taiho.
2015
Inclusion of targeted therapies in the standard of care for metastatic colorectal cancer patients in a German cancer center: the more the better
https://pubmed.ncbi.nlm.nih.gov/25230900/
M Moehler received honoraria for presentations in satellite symposia by Merck and Roche.
Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study
https://pubmed.ncbi.nlm.nih.gov/26527776/
Marcus Möehler
No relationship to disclose
2014
Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial
https://pubmed.ncbi.nlm.nih.gov/25272957/
Competing interests
The authors declare that they have no competing interests.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial
https://pubmed.ncbi.nlm.nih.gov/25088940/
MM has received honoraria for lectures or presentations from Merck and Roche.
2013
Single-agent therapy with sorafenib or 5-FU is equally effective in human colorectal cancer xenograft—no benefit of combination therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587684/
Disclaimer
Carl Schimanski received research funding; Markus Moehler, speech honoraria; and Peter R. Galle, consulting and speech honoraria
Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776974/
AH has received research support from Novartis; DA, RH and UTH have received research sponsorship from Roche; DA has received speaker’s honoraria from Roche and Sanofi-Aventis; RH and UTH have received speaker’s honoraria from Roche. The remaining authors declare no conflict of interest.
@peter_brit
Obviously we are waiting for notification of MAA Approval however, important to note we are also closing in on some important dates in both combo trials:
https://clinicaltrials.gov/study/NCT01204684
Dendritic Cell Vaccine for Patients With Brain Tumors
Primary Completion (Estimated)
2025-01-31
Study Completion (Estimated)
2026-01-31
https://clinicaltrials.gov/study/NCT04201873?tab=history&a=1&b=2&compareMode=sideBySide#StudyPageTop
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma:
Primary Completion
2024-08-01 [Estimated]
Study Completion
2025-08-01 [Estimated]
https://nature.com/articles/s41467-024-48073-y.pdfFDA issues final guidance user fees for combination products
📷Regulatory News | 16 July 2024 |
The US Food and Drug Administration (FDA) on Tuesday finalized guidance for sponsors explaining how it assesses user fees for combination products and the different programs available to sponsors for requesting user fee waivers under the Prescription Drug User Fee Act (PDUFA) and the Medical Device User Fee Amendments (MDUFA) programs.
The update replaces a final guidance issued in April 2005 to make it more consistent with current user fee programs and to reflect combination product provisions in section 503(g) of the Federal Food and Drug Cosmetic Act (FD&C Act).
The question-and-answer guidance includes background information on combination products, how the agency determines user fees for single applications and two applications, and information on requesting user fee waivers or reductions of user fees.
FDA states that a combination product is assigned to an agency center that will have primary jurisdiction for its premarket review and regulation. “Under section 503(g)(1) of the FD&C Act (21 U.S.C. 353(g)(1)), the assignment to a lead center is based upon a determination of the primary mode of action (PMOA) of the combination product. For example, if the PMOA of a combination product is that of a biological product, then the combination product would be assigned to the Agency center responsible for premarket review of that biological product.”
FDA said combination products may be reviewed in a single application or in separate applications for its constituent parts.
For most combination products, one application is appropriate, yet noted there are circumstances in which an applicant may choose to submit two applications. In these situations, “the applications may fall under the same or different user fee programs. In such cases, FDA would evaluate each application user fee independently under the relevant user fee statute, as if it were a stand-alone application, and two application fees would be assessed (i.e., one fee for each application).”
In situations where applicants must file MDUFA and PDUFA applications, FDA may grant some user fee relief to sponsors. For these applicants, FDA will waive the PDUFA fee if the product protects the public health, and the sponsor has limited resources.
The agency will also waive the PDUFA user fee for innovative products for applicants that have limited resources. Eligible product must demonstrate “new, progressive methods and forward-thinking in the treatment or diagnosis of disease or is at the forefront of new medical technology” and “there are no comparable alternatives for treatment, prevention, or diagnosis available in the U.S. market.”
Besides these waiver programs, other PDUFA waiver programs include the small business waiver, the exception for orphan designated products, and the state or federal government entity exemption.
Under MDUFA, waiver programs include the humanitarian device exemption (HDE) program and the pediatric conditions of use program if the proposed condition for use is solely for the pediatric populations.
This guidance should be used in conjunction with the guidance for industry Prescription Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products and the appropriate MDUFA guidance documents.
https://raps.org/News-and-Articles/News-Articles/2024/7/FDA-issues-final-guidance-user-fees-for-combinatio
@ARPA_H
"A 'superpower' of the agency is our ability to fund internationally and have quite a bit of flexibility in how we connect with the research community globally – patients, researchers, international organizations, other funders, technologists, entrepreneurs." -Megan Frisk
Q: What is the ARPA-H model?
A: We take on those really challenging health problems in pursuit of those high-impact solutions. We’re modeled off of the business model pioneered by DARPA. If you think of [a] valley in between basic biomedical research, and on other end of this valley being industry, where you have commercial products and services that have a viable pathway to market, we really sit in that middle space that I like to call the ‘Valley of Opportunity.’ We’re bridging basic biomedical research and industry development.”
Q: Is all the collaboration just in the U.S.?
A: “An emerging superpower of the agency is our ability to fund internationally and to really have quite a bit of flexibility in how we connect with the research community globally – patients, researchers, international organizations, other funders, technologists, entrepreneurs.
Q: What are the mission areas of the agency:
A: “We are disease agnostic. We don’t have a dedicated line in cancer, immunology, or allergy, or others. Instead, we focus on mission areas. We have four mission areas. One is on the future of health science. That is the really cool novel technology and technology platforms. The next area is resilient systems—thinking of what’s not working in our [healthcare] system. This could be data sharing, this could be cybersecurity, this could be issues with reimbursement or care models. But also: how are those cool new technologies being integrated into our system? The third area is scalable solutions—how are we going to scale these new platforms, approaches, [and] technologies up and out? This is where you start thinking about things like biomanufacturing, like supply chains. And then the last [mission area] is on proactive health – our preventative medicine office. This is keeping people from becoming patients.”
Since its establishment in 2022, the Advanced Research Projects Agency for Health (ARPA-H) has been working to accelerate better health outcomes for everyone by supporting “big bets” in the health arena: time-limited, high-risk, high-reward projects aimed at achieving major breakthroughs in health. Megan Frisk, PhD, director for International Affairs at ARPA-H, joined us for a conversation on how ARPA-H is working to find high-impact, novel solutions to society's most challenging health problems and how they engage internationally.
America Alliance Discussion with Megan Frisk, International Affairs Director at ARPA-H:
(With full transcript)
https://youtube.com/watch?v=fuqqzYsYjyU
Excellent post by Doc Logic
One of the most interesting data points from the Phase 3 trial was that those who crossed over after progression but did not have a second surgery did better than those who did. This totally kills the bear arguments that those who are resected most or best live the longest. Vaccine was not produced from tumor removed from second surgery, only the first, so this needs to be taken into consideration for those storing their tumors now or in the near future. Obviously the best option would be to make vaccine from the second resection but for those unable to have one there is still benefit from that first resection vaccine to be had in many cases.
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3:30 AM · Jul 19, 2024
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492
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@d_stock07734
FDA granted Amgen approval on one t-cell engager based on phase 2 trial. The words used by the media really surprise me. Have they seen something better? Words like "game-changing" and "watershed" should be saved for DCVax-L.
Again the target loaded on the t-cell engager is the overexpressed gene called DLL3 which can be found from the data uploaded by Dr. Liau. Again DCVax-L in combination with poly-iclc can fixed this mutated gene. For those who worry about phase 3 trial for DCVax-L, I would say your worry is completely unnecessary. I speculate that FDA would grant approval for the combination adopted in the current combo trial should Merck or NWBO file for approval.
A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301)
https://clinicaltrials.gov/study/NCT05060016
Amgen’s game-changing lung cancer treatment gains FDA approval
https://pacbiztimes.com/2024/05/22/amgens-game-changing-lung-cancer-treatment-gains-fda-approval/
Amgen's 'watershed' lung cancer drug nabs FDA nod in deadly, tough-to-treat form of the disease
https://fiercepharma.com/pharma/fda-nod-amgens-watershed-lung-cancer-drug-could-make-it-rain
FDA APPROVES IMDELLTRA™ (TARLATAMAB-DLLE), THE FIRST AND ONLY T-CELL ENGAGER THERAPY FOR THE TREATMENT OF EXTENSIVE-STAGE SMALL CELL LUNG CANCER
https://amgen.com/newsroom/press-releases/2024/05/fda-approves-imdelltra-tarlatamabdlle-the-first-and-only-tcell-engager-therapy-for-the-treatment-of-extensivestage-small-cell-lung-cancer
https://multivu.com/players/English/9246451-fda-approves-imdelltra-tarlatamab-dlle-the-first-and-only-t-cell-engager-therapy-for-the-treatment-of-extensive-stage-small-cell-lung-cancer/
Merck CEO says Keytruda is ‘not a repeatable model’
https://endpts.com/merck-ceo-says-keytruda-is-not-a-repeatable-model/
The immunotherapy drug will mark the 10-year anniversary of its first approval in September. It’s since been approved for a total of 39 indications across 17 different tumor types. Davis said Merck has spent about $46 billion to date developing the treatment and will spend almost another $20 billion by 2030 as it tests the drug in a wide range of combination studies.
“The future is less monolithic Keytruda,” Davis said. “It’s going to be a lot of smaller, precision-based therapies aimed at specific tumors or indications.”
“Very Exciting” Future for Cancer Research, Bradway Says at “Business of Biotech” Conference
https://amgen.com/stories/2024/03/very-exciting-future-for-cancer-research-bradway-says-at-business-of-biotech-conference
How is Amgen using human genetic data to improve drug discovery and design?
Bradway observed that Amgen is the largest company using human genetic data to inform drug development, thanks in large part to our deCODE genetics subsidiary. He explained the importance of this data by noting that even when candidate medicines show promise in preclinical research with non-human animals, those models don't always replicate how drugs work in the human body, leading sometimes to failures in later-stage human clinical trials. By using human genetic data to inform target identification, we can "tilt the odds in our favor" and improve our ability to identify drugs that will work in humans.
Roche
https://roche.com/stories/roche-in-cancer-immunotherapy
In the future, we hope that a patient with cancer will be able to walk into a doctor’s office, have a piece of their tumour biopsied, so that we can understand what’s wrong with their immune response, and then receive a therapy tailored specifically for them.
Either way, we’re on the threshold of a new era for cancer treatment. After years of downplaying the possibility, researchers are even starting to talk about the potential of cure.
"Well, the more interesting part is that those mutated genes currently loaded on ADCs for other types of cancers can also be found overexpressed on GBM cancer cells which indicates DCVax-L as a platform can identify a bunch of targets commonly overexpressed in various types of solid tumors"
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174769775
9:58 AM · Jul 18, 2024
·
2,769
Views
https://x.com/shitscaredmum/status/1813928800281121129
Excellent posts by
@d_stock07734
dstock07734
07/18/24 2:47 PM
Post #706891 on NorthWest Biotherapeutics Inc (NWBO)
NCI was so serious about the genetic profiling analysis of the tissue samples from the p3 trial. We can see two chiefs from two different NCI sectors were involved in the analysis. For each sample tissue, two different mass units were adopted. To keep the objectivity of the analysis, no formal employees from NWBO participated in the analysis. Would NCI apply the same magnitude of seriousness to the current combo trial? How could NCI would not? Was NCI involved in the trial design? Did NCI profiling analysis show that for the most life-threatening subtype GBM DCVax-L has the most significant efficacy?
Here is the NIH procurement record in the first quarter 2021. By simply taking a look the procurement record around the same time the combo trial was started, we can have a sense about whether NCI was serious about the current combo trial.
https://nih.gov/sites/default/files/institutes/foia/procurements-specified-q1-2021.xlsx
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174774616
https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE249282
https://clinicaltrials.gov/study/NCT04201873
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174776729
SIO Capital Management's largest holding is Labcorp Holdings Inc. with shares held of 225,902
Revolutionizing cancer drug development: Harnessing the potential of basket trials
https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.35085
Vivek Subbiah reports ...... personal consultancy/advisory fees from Bayer Healthcare Pharmaceuticals Inc., F. Hoffman-La Roche AG, Incyte Corporation, Jazz Pharmaceuticals, LabCorp (a.k.a. Lab Corporation), LOXO Oncology/Eli Lilly, QED Pharma, and Regeneron Pharmaceuticals Inc.;
The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer
https://link.springer.com/content/pdf/10.1007/s40487-024-00270-x.pdf
The evolving landscape of tissue-agnostic therapies in precision oncology
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21844
Vivek Subbiah reports ...... personal/consulting fees from AbbVie, Bayer HealthCare Pharmaceuticals Inc., F. Hoffmann-La Roche AG, Illumina, Incyte Corporation, Jazz Pharmaceuticals Inc., LabCorp (aka Lab Corporation), Regeneron Pharmaceuticals, Inc., and Relay Therapeutics;
Pearls and pitfalls of ChatGPT in medical oncology
https://sciencedirect.com/science/article/abs/pii/S2405803323001097
V.S. is on the advisory board of Illumina, Labcorp, Relay Therapeutics, Bayer, Jazz Pharmaceuticals, and Aadi Biosciences.
Building a Better Silver Bullet: New Tests Improve Cancer Treatment
https://insideprecisionmedicine.com/topics/oncology/building-a-better-silver-bullet-new-tests-improve-cancer-treatment/
That study came out in The Lancet Oncology last September. “These findings are a testament to the power of precision medicine,” Subbiah said.
LabCorp senior vice president and oncology head Prasanth Reddy adds that diagnostic testing is keeping up with this shift.
“There are molecular alterations now associated with treatments that are approved for use regardless of tumor histologic type or site of origin. These biomarkers include microsatellite instability[-high] (MSI-H), high tumor mutation burden (TMB-H), NTRK and RET fusions, and BRAF V600E mutations,” he says.
@sharpie510
Among the 232 ndGBM and 64 rGBM patients, the median OS was notably longer than the matched external cohort (22.4 months vs 16.5 months for ndGBM; 13.2 months vs 7.8 months for rGBM).
💪
$nwbo #dcvax #glioblastoma #gbm #ForAllSolidTumors #CancerMoonshotExcellent post by Doc Logic
One of the most interesting data points from the Phase 3 trial was that those who crossed over after progression but did not have a second surgery did better than those who did. This totally kills the bear arguments that those who are resected most or best live the longest. Vaccine was not produced from tumor removed from second surgery, only the first, so this needs to be taken into consideration for those storing their tumors now or in the near future. Obviously the best option would be to make vaccine from the second resection but for those unable to have one there is still benefit from that first resection vaccine to be had in many cases.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174776791
@peter_brit
#dcvax $nwbo #gbm
FDA unveils rare disease innovation hub, plans public meeting this fall
📷Regulatory News | 18 July 2024
The US Food and Drug Administration (US) announced the creation of a Rare Disease Innovation Hub to speed development of new treatments, integrate regulation of drugs and biologics, and engage patient advocacy communities.
The Rare Disease Innovation Hub, or “the Hub”, will focus on diseases that are not fully understood and where development of treatments is “particularly challenging”, the agency explained. It will be co-led by Center for Biologics Evaluation and Research Director Peter Marks and Center for Drugs Evaluation and Research (CDER) Director Patrizia Cavazzoni.
The agency is also recruiting for a new senior leader – Associate Director for Rare Disease Strategy – who will serve as a single contact point of communication and engagement with rare diseases stakeholder groups. The leader will oversee a new joint, integrated CBER/CDER model “to accelerate development of treatments across modalities, including drugs, cell, gene therapies and other biologics”. As part of the job, they will create a rare disease strategic agenda action plan driven by the needs of patient communities.
“In developing such a plan, they will work closely with the CBER and CDER Center Directors, leadership of the CDER Accelerating Rare disease Cures (ARC) program, and comparable CBER programs initiatives to assure appropriate integration and alignment across each center,” FDA explained.
The agency plans to issue a public docket and hold an open meeting this fall to get feedback on the Hub plans and “help shape priorities and initiatives.”
Progress, but persistent unmet need
An estimated 30 million people in the US have rare diseases and over half the new drugs and biologics approved in 2023 were aimed at treatments for small populations, but more needs to be done, according to FDA. (RELATED: New Systems Needed for bringing rare disease treatments, at home devices to market, Regulatory Focus 15 February 2024).
“Many rare diseases lack treatment options and therefore many patients have high unmet medical needs,” FDA noted. “This requires new approaches to expedite development and approval of safe and effective drugs and biologics.”
The new integrated model has three main functions:
“Serve as a single point of connection and engagement with the rare disease community, including patient and caregiver groups, trade organizations, and scientific/academic organizations, for matters that intersect CDER and CBER.”
“Enhance intercenter collaboration to address common scientific, clinical and policy issues related to rare disease product development, including relevant cross-disciplinary approaches related to product review, and promote consistency across offices and Centers.”
“Advance regulatory science with dedicated workstreams for consideration of novel endpoints, biomarker development and assays, innovative trial design, real world evidence, and statistical methods.”
Stakeholders give thumbs up
FDA’s announcement did not come as a surprise to stakeholders, as FDA’s Marks had publicly discussed the idea for a rare disease hub at the Drug Information Association (DIA) meeting in June. The National Organization for Rare Disorders (NORD) and other stakeholders reacted positively to FDA’s formal announcement in July.
“BIG congratulations to
@US_FDA
on the #FDA Rare Disease Innovation Hub, an exciting milestone for millions of Americans in the #RareDisease community!’ NORD wrote on X. “NORD is thrilled to see the Hub take flight and is excited to support it.”
The nonprofit EveryLife Foundation for Rare Diseases had submitted a letter signed by more than 100 patient advocacy organizations to Congress asking for the creation of a Rare Disease Center of Excellence to integrate and streamline processes for treatment development in the 2025 Appropriations Bill. Scientific and policy leaders, with rare disease community members have had an impact, the EveryLife Foundation wrote in a July 17 statement about the Hub news.
“This is a positive and meaningful step forward in addressing the regulatory science challenges unique to rare disease therapy development and we look forward to working with the Agency and stakeholders to ensure that the Innovation Hub is sustained over time,” EveryLife wrote.
https://raps.org/News-and-Articles/News-Articles/2024/7/FDA-unveils-rare-disease-innovation-hub,-plans-pub
https://aacrjournals.org/cancerimmunolres/article/9/7/735/666151/Host-IL11-Signaling-Suppresses-CD4-T-cell-Mediated
Transfecting cancer cells with interleukin-11 receptor alpha results in immunologically mediated tumor regression
It would be so exciting to combine lysates of transfected tumor cells with $NWBO Dendritic Cell Technology
$NWBO is very exciting !
https://sciencedirect.com/science/article/abs/pii/S1567576924007239?via%3Dihub
@d_stock07734
Doc,
I think now with DCVax-L as the platform BPs can have a very efficient way of identifying the targets that they can load on their ADCs and t-cell engagers to have the so-called precision medicines. That's why I suspect that the reason that all the BPs have ADC and t-cell engager programs is because of DCVax-L.
In the poly-iclc trial, Dr. Liau measured the variation of 38614 genes before and after the DCVax-L treatment.
https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE237562
Anytime I see targets from current ADCs or t-cell engagers, I search them in the database that Dr. Liau uploaded to Gene Expression Omnibus. I think different solid tumors should have different mutated genes. But from all the search I did, I found that the highly overexpressed genes that those ADCs or t-cell engagers were loaded to treat other types of solid tumors also exist in GBM.
I even think what AMGEN said in the following might have connection with DCVax-L as a platform. But it is just speculation.
Bradway observed that Amgen is the largest company using human genetic data to inform drug development, thanks in large part to our deCODE genetics subsidiary. He explained the importance of this data by noting that even when candidate medicines show promise in preclinical research with non-human animals, those models don't always replicate how drugs work in the human body, leading sometimes to failures in later-stage human clinical trials. By using human genetic data to inform target identification, we can "tilt the odds in our favor" and improve our ability to identify drugs that will work in humans.
Justin Keister MS DABR
@justinkeister5
·
Jul 18
I’m on the record saying Merck’s CEO is wrong. Tumor heterogeneity requires a broad spectrum of antigen/neoantugen target, not specific receptor targets. Specific receptor targeting is a losing battle in tumors that can look vastly different from one side to the other. $NWBO
Quote
Peter Davis
@peter_brit
·
Jul 18
#dcvax $nwbo #gbm
Excellent posts by @d_stock07734
FDA granted Amgen approval on one t-cell engager based on phase 2 trial. The words used by the media really surprise me. Have they seen something better? Words like "game-changing" and "watershed" should be saved for DCVax-L.
Show more
d_stock
@d_stock07734
·
21h
I suspect there are some solid tumors that Merck's approach should be working. Any solid tumors that BPs cannot treat will be covered by DCVax-L.
Justin Keister MS DABR
@justinkeister5
·
21h
More homogeneous tumors should be treatable with Merck’s singular target approach. But we have a long way to go to find the best targets. Until then, a broad spectrum approach is necessary and available now.
d_stock
@d_stock07734
Doc,
I think now with DCVax-L as the platform BPs can have a very efficient way of identifying the targets that they can load on their ADCs and t-cell engagers to have the so-called precision medicines. That's why I suspect that the reason that all the BPs have ADC and t-cell engager programs is because of DCVax-L.
In the poly-iclc trial, Dr. Liau measured the variation of 38614 genes before and after the DCVax-L treatment.
https://ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE237562
Anytime I see targets from current ADCs or t-cell engagers, I search them in the database that Dr. Liau uploaded to Gene Expression Omnibus. I think different solid tumors should have different mutated genes. But from all the search I did, I found that the highly overexpressed genes that those ADCs or t-cell engagers were loaded to treat other types of solid tumors also exist in GBM.
I even think what AMGEN said in the following might have connection with DCVax-L as a platform. But it is just speculation.
Bradway observed that Amgen is the largest company using human genetic data to inform drug development, thanks in large part to our deCODE genetics subsidiary. He explained the importance of this data by noting that even when candidate medicines show promise in preclinical research with non-human animals, those models don't always replicate how drugs work in the human body, leading sometimes to failures in later-stage human clinical trials. By using human genetic data to inform target identification, we can "tilt the odds in our favor" and improve our ability to identify drugs that will work in humans.
Peter Davis
@peter_brit
#dcvax $nwbo #gbm
@MHRAgovuk
@NICEComms
@US_FDA
@YorkshireBTC
@OuthouseThought
@NBTStweets
@ourbrainbank
@brainstrust
@theIBTA
@NIHBrainTumor
@braintumourrsch
@NIH
@brainstrust_nth
@CancerResrch
Northwest Biotherapeutics, Inc is a clinical stage biotechnology company focused on the development of personalized cancer vaccines designed to treat a broad range of solid tumor cancers.
DCVax® - personalized immune therapies for solid tumor cancers.
DCVax® - "The benign safety profile observed can enable treatment of patients vulnerable to adverse events. Furthermore, it avoids the need (and cost) for other treatments…
Patients treated with DCVax-L showed a clinically meaningful and statistically significant extension of survival… …in both newly diagnosed and recurrent GBM, …with an excellent safety profile, and …noteworthy long tails of survival
First Phase 3 trial of a systemic treatment in 17 years to show a significant extension of mOS in nGBM.
?
First Phase 3 trial of any type of treatment in 27 years to show a significant extension of mOS in rGBM.
One of the first, if not the first, Phase 3 trial to show meaningful increases in the long-term tails of the survival curves in both nGBM and rGBM
https://virtualtrials.org/dcvax/dcvax.pdf
Red_Right_Hand
Friday, July 19, 2024 10:41:01 AM
Today is 5 weeks since the briefing package was complete. Last R&R was issued on a Friday around 1:30 pm, 6 weeks and 3 days after the briefing package was complete.
Red_Right_Hand
Re: XMaster2023 post# 703184
Tuesday, July 02, 2024 7:59:49 AM
Post#
703212
of 707017
The last R&R was issued roughly six weeks after the last briefing package was complete (including oral arguments). This time around, the briefing package is focused on one issue (loss causation) and the court has indicated it doesn't need oral argument to probe the written briefing documents and render its decision. Plus, the next R&R is essentially written, except for updates needed to the loss causation section. So depending on what other dockets are occupying the court's time and attention, there's a reasonably good chance the next R&R will be issued in less than six weeks from when the briefing package was complete on 6/14. So we're two+ weeks in and have less than four weeks to go?
combo patent:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174633920
Red_Right_Hand
Re: StonkMaster post# 700035
Friday, June 21, 2024 9:25:08 AM
Post#
700041
of 707012
EP Allowed Claim 1. A therapeutic agent in combination with an agent that is a checkpoint inhibitor for use in a method of treating a glioma or initiating, enhancing, or prolonging an anti-glioma response in a subject in need thereof comprising administering to the subject the therapeutic agent in combination with the agent that is a checkpoint inhibitor, wherein the therapeutic agent is a glioma lysate-pulsed dendritic cell vaccine, and wherein the checkpoint inhibitor is selected from the group consisting of a monoclonal antibody, a humanized antibody and a fully human antibody or a combination thereof and inhibits a checkpoint protein selected from the group consisting of PD-1 and PDL1 or a combination thereof.
AT THE BOTTOM OF THIS TWITTER POST:
STEVE BANNON: The Apes Are in ‘Holy War’ Against Corrupt Wall Street
— Wall Street Apes (@WallStreetApes) June 18, 2023
“This is not about economics, this is not about finance,” Bannon said on War Room. “This is about power.”
Ron DeSantis’ MEGADONOR is Ken Griffin of Citadel the worst market manipulating criminal on earth. Ken… pic.twitter.com/3bOcLYeZcS
Considering that the Citadel algorithms have “set" the price of nwbo for at least 10 years (see Ken Griffin link below), it will take the MAA approval and/or the dismissal of the MTD to break that grip. For years, retail and institutional investors have been scared away from $nwbo’s Griffin manipulated trading on the OTC market . And it’s that same grip on 1000s of American stocks that earns Ken Griffin -Citadel $ 10 billion annually . Judge Woods surely appreciates that the nwbo lawsuit is a landmark case.And it's Griffin's s $200 million in annual on campaign contributions to Congressman and Senators that keeps securities regulators (SEC, Finra, DOJ) from enforcing laws already on the books. But this David-Goliath war(see @Charles Payne link below) can be turned in David’s favor by the huge cash that can be generated by Judge Woods dismissing the MTD and the MAA approval allowing the start of the commercial sale of DC VAX L. NWBO’s combination trial data has shown MOS extension from 16.5 months with current SOC to 10 years with the Liau combination formulas (see Allen Turner links below). Because of this 5x life extension, demand will be huge.
Impressive LCM strategy before initial approval! #dcvax $nwbo
— Allen Turner (@AllenTurner206) February 15, 2023
DCVax-L + Poly-ICLC. Est primary completion Jan 2024. Unpublished interim results: ~50% survival at >8 YEARS.
DCVax-L + PD-1. Est primary completion Aug 2024. Unpublished interim results: ~65% survival at >26 mos. pic.twitter.com/T0jAwH65Uo
☑️Long-term survivors have now been followed for over 10 years
— Allen Turner (@AllenTurner206) May 8, 2024
☑️OS (placebo: 7.7 months, poly-ICLC: 52.5 months, and resiquimod: 16.7 months)
☑️PFS (placebo: 5.5 months, poly-ICLC: 31.4 months and resiquimod: 8.1 months)#DCVax #Mercidencel $NWBO https://t.co/ef3TaWGUFH
Ken Griffin (12/22/23) and Citadel tell us that he sets the prices of all stocks. Maybe ...Fuhrer of the U.S. stock market as he has total dictatorial control.His $200 million in annual " campaign contributions" ...https://t.co/RE1PVazt9u @alphavestcap $nwbo
— alphavestcapital.com (@alphavestcap) December 23, 2023
https://t.co/7xTa3gXvaP $nwbo @alphavestcap
— alphavestcapital.com (@alphavestcap) July 18, 2024
does the mhra discourage conferencing with the enemy ?
file:///Users/josephhprattii/Desktop/BNOS%202024%20Programme.pdf
https://bnosconference.co.uk/bnos-conference/
file:///Users/josephhprattii/Desktop/BNOS%202024%20Programme.pdf
file:///Users/josephhprattii/Desktop/BNOS%202024%20Sponsorship%20Prospectus%20(1).pdf
@HenryMuney
Marnix Bosch CTO @NorthwestBio at #BNOS2024 on Wednesday, July 17, 2024. @BNOSofficial
https://bnosconference.co.uk/bnos-conference/programme/
November 30, 2022
The need to report as-planned analyses and the weakness of historical controls
Matt Williams, MbChB FRCR PHD | Imperial College Hospitals NHS Trust
We would like to congratulate the authors on conducting a large, multi-centre, international study in patients with Glioblastoma (GBM). However, due to the methodology used it is difficult to conclude that the experimental arm, addition of autologous tumour lysate-pulsed dendritic cell vaccine (DCVax), improves the outcome beyond standard of care in newly diagnosed Glioblastoma.
Our main concern with the methodology is the change in comparison arm. In the original version of the protocol provided, the primary and secondary endpoints were specified as PFS and OS, compared between the treatment cohort and the placebo cohort. The published study compared treated cohort with external controls. This change in comparator partway through the trial is not highlighted in the methods section of the final publication. The explanation given in the paper about PFS being confounded by immune-mediated effects does not explain the switch from comparing the randomised arms to using external controls. Although one possible reason could be to account for the number of patients in the control arm crossed-over to active treatment, we are not aware of any treatment, for any solid tumour, where treatment at relapse produces comparable survival to use in the upfront setting.
This is particularly problematic because the trial mandated exclusion of patients with significant residual disease, bilateral disease or early disease progression. In fact out of 1599 patients screened, 1268 were excluded for a range of reasons including disease progression and early clinical deterioration (Liau JTM 2018). While the matched cohort included some trials that excluded early progression, not all did, and since these were different trials, patients may have been excluded using different definitions of early progression from that used in this trial. In addition, there is evidence of general improvement in OS in patients with GBM enrolled in trials: for example, the median OS in the control studies for patients with MGMT methylated GBM receiving chemo-radiotherapy with Temozolomide is quoted as being 21.3 months; we note that the recent NOA-09 study had a median OS of 31 months in that same group of patients, emphasising the importance of using data from contemperaneous randomised controls. The general effect is these would be to increase the survival rate in the trial arm, irrespective of the effect of DCVax.
It is particularly interesting that the greatest benefit may be in the older age group, and confined to the subtotally resected (OS 17.5mo vs 14.2mo in subtotally resected historical controls), rather than completely resected (20.3mo vs 20.4mo). Furthermore it is interesting to note the benefit reported in the second line setting against externally matched controls. This hypothesis generating data does warrant further exploration.
We recognise the benefits of novel trial designs to accelerate advances. For example, the flexible nature of the multi arm multi stage design has been successfully used in other cancers. (SydesTrials 2012). However, as per the GBM AGILE platform study, it important to retain a contemporaneous control arm (Alexander Clin Can Res 2018).
We recommend an addendum clarifying the change in trial design, and reporting the results as specified in the initial protocol.
Dr. Matt Williams, London
Dr. Paul Sanghera, Birmingham
Prof. Susan Short, Leeds
Dr. Anup Vinayan, London
Dr. Juliet Brock, Oxford
Dr. Chris Herbert, Bristol
Dr. Joanne Lewis, Newcastle
Dr. Shaveta Mehta, Liverpool
(All UK Cancer Centres; truncated for length)
CONFLICT OF INTEREST: None Reported
April 11, 2023
Authors' Response
Marnix Bosch, BS, MBA, PhD | Northwest Biotherapeutics, Inc
We appreciate the comments made by Dr. Matt Williams and colleagues, and their recognition that novel trial designs can accelerate advances. They acknowledge our rationale for moving away from a progression free survival (PFS) endpoint which is confounded by immune mediated effects, while they question why external controls were needed for the overall survival (OS) endpoint. As explained in our paper, the reasons included substantial depletion of the control arm due to the crossover trial design allowing control patients to receive DCVax-L following recurrence. The rationale did not require that patients crossing over from placebo achieve any treatment effect, as erroneously implied by Williams, because receiving DCVax-L at any time point automatically disqualified these patients from being true controls for a survival endpoint.
Regarding in-/exclusion of patients, as previously reported, the screening process began before the initial surgical resection, and the largest exclusion of patients was because they were found not to have glioblastoma, and the next largest exclusion was because the patient’s tumor was too small to provide sufficient tumor protein to meet eligibility criteria. Additionally, although there was an intent for near gross total resection at screening, we still included patients if this goal was not met (i.e., patients with significant residual disease after surgery).
Williams observes that not all the comparator trials excluded patients with early progression. As explained in our paper, we too noted this and checked for bias by conducting sensitivity analyses specifically on this factor. These analyses found that the hazard ratio remained the same with those trials excluded, and the OS benefit of DCVax-L remained statistically significant.
We agree with Williams that it is important for comparison data to be contemporaneous. This was an express factor in the selection of the external controls for our trial by independent experts.
Williams suggests that the NOA-09 study with an mOS of 31 months in MGMT methylated patients may be a more appropriate comparator than the mOS of 21.3 months seen in the 5 large contemporaneous trials we used as comparators for our study. However, the NOA-09 trial enrolled only a selected subset of MGMT methylated patients, and is not representative given the chosen cutoff in the MGMT assays. As the authors of the report on the NOA-09 trial themselves recognize: “Median overall survival in the temozolomide group [i.e., control group] of our trial was greater than that of comparable historical groups of patients with tumors with methylated MGMT …”. So far, the NOA-09 trial has proven to be an outlier, and it is therefore a less appropriate comparison for our trial than the 5 large contemporaneous trials we used.
We agree that the DCVax-L trial results include some interesting (and clinically useful) observations, such as the greater relative benefit seen in older patients and in patients with subtotal resections, in addition to the encouraging overall results. We look forward to further exploring these findings.
Linda M. Liau, MD, PhD, University of California, Los Angeles, USA
Keyoumars Ashkan, MD, FRCP, FRCS, Kings College Hospital, London, UK
Marnix L. Bosch, PhD, Northwest Biotherapeutics, Inc
Dr Liau reported serving on the board of directors of ClearPoint Neuro outside the submitted work and having a patent pending for combinations of inhibitors with dendric cell vaccines to treat cancer. Dr Ashkan reported receiving grants from Northwest Biotherapeutics during the study conduct.
CONFLICT OF INTEREST: Dr Bosch reported being an employee of and owning shares in Northwest Biotherapeutics, Inc. and reported having patent 13/492693 pending.
dstock07734
Re: Doc logic post# 706764
Thursday, July 18, 2024 12:15:47 AM
Post#
706765
of 706775
Doc logic,
I think the new patent with controllable chain length of poly-iclc was developed with the funding from NCI with two employees from Curia Global listed as inventors. The thing I found interesting is that Oncovir didn't file the new patent in the US. We saw the filing of combination patent in the US from NWBO was abandoned too. I was wondering if this means that the new version of poly-iclc is not protected in the US.
Scalable production of polyribonucleotides of controlled size
https://patents.google.com/patent/WO2022031314A2/en
Combinations of checkpoint inhibitors and therapeutics to treat cancer
https://patents.google.com/patent/US20150202291A1/en
dstock07734
Re: None
Wednesday, July 17, 2024 6:08:55 PM
Post#
706722
of 706773
FDA granted Amgen approval on one t-cell engager based on phase 2 trial. The words used by the media really surprise me. Have they seen something better? Words like "game-changing" and "watershed" should be saved for DCVax-L.
Again the target loaded on the t-cell engager is the overexpressed gene called DLL3 which can be found from the data uploaded by Dr. Liau. Again DCVax-L in combination with poly-iclc can fixed this mutated gene. For those who worry about phase 3 trial for DCVax-L, I would say your worry is completely unnecessary. I speculate that FDA would grant approval for the combination adopted in the current combo trial should Merck or NWBO file for approval.
A Phase 2 Study of Tarlatamab in Patients With Small Cell Lung Cancer (SCLC) (DeLLphi-301)
https://clinicaltrials.gov/study/NCT05060016
Amgen’s game-changing lung cancer treatment gains FDA approval
https://www.pacbiztimes.com/2024/05/22/amgens-game-changing-lung-cancer-treatment-gains-fda-approval/
Amgen's 'watershed' lung cancer drug nabs FDA nod in deadly, tough-to-treat form of the disease
https://www.fiercepharma.com/pharma/fda-nod-amgens-watershed-lung-cancer-drug-could-make-it-rain
FDA APPROVES IMDELLTRA™ (TARLATAMAB-DLLE), THE FIRST AND ONLY T-CELL ENGAGER THERAPY FOR THE TREATMENT OF EXTENSIVE-STAGE SMALL CELL LUNG CANCER
https://www.amgen.com/newsroom/press-releases/2024/05/fda-approves-imdelltra-tarlatamabdlle-the-first-and-only-tcell-engager-therapy-for-the-treatment-of-extensivestage-small-cell-lung-cancer
https://www.multivu.com/players/English/9246451-fda-approves-imdelltra-tarlatamab-dlle-the-first-and-only-t-cell-engager-therapy-for-the-treatment-of-extensive-stage-small-cell-lung-cancer/
Merck CEO says Keytruda is ‘not a repeatable model’
https://endpts.com/merck-ceo-says-keytruda-is-not-a-repeatable-model/
The immunotherapy drug will mark the 10-year anniversary of its first approval in September. It’s since been approved for a total of 39 indications across 17 different tumor types. Davis said Merck has spent about $46 billion to date developing the treatment and will spend almost another $20 billion by 2030 as it tests the drug in a wide range of combination studies.
“The future is less monolithic Keytruda,” Davis said. “It’s going to be a lot of smaller, precision-based therapies aimed at specific tumors or indications.”
“Very Exciting” Future for Cancer Research, Bradway Says at “Business of Biotech” Conference
https://www.amgen.com/stories/2024/03/very-exciting-future-for-cancer-research-bradway-says-at-business-of-biotech-conference
How is Amgen using human genetic data to improve drug discovery and design?
Bradway observed that Amgen is the largest company using human genetic data to inform drug development, thanks in large part to our deCODE genetics subsidiary. He explained the importance of this data by noting that even when candidate medicines show promise in preclinical research with non-human animals, those models don't always replicate how drugs work in the human body, leading sometimes to failures in later-stage human clinical trials. By using human genetic data to inform target identification, we can "tilt the odds in our favor" and improve our ability to identify drugs that will work in humans.
Roche
https://www.roche.com/stories/roche-in-cancer-immunotherapy
In the future, we hope that a patient with cancer will be able to walk into a doctor’s office, have a piece of their tumour biopsied, so that we can understand what’s wrong with their immune response, and then receive a therapy tailored specifically for them.
Either way, we’re on the threshold of a new era for cancer treatment. After years of downplaying the possibility, researchers are even starting to talk about the potential of cure.
See new posts
Conversation
Peter Davis
@peter_brit
#dcvax $nwbo #gbm
Obviously we are waiting for notification of MAA Approval however, important to note we are also closing in on some important dates in both combo trials:
https://clinicaltrials.gov/study/NCT01204684
Dendritic Cell Vaccine for Patients With Brain Tumors
Primary Completion (Estimated)
2025-01-31
Study Completion (Estimated)
2026-01-31
https://clinicaltrials.gov/study/NCT04201873?tab=history&a=1&b=2&compareMode=sideBySide#StudyPageTop
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma:
Primary Completion
2024-08-01 [Estimated]
Study Completion
2025-08-01 [Estimated]
https://nature.com/articles/s41467-024-48073-y.pdf
Patients with fifteen types of solid tumors received DCVax-L treatment. "Most of them blockbuster drugs".
You are talking about pumping? Do you have common sense?
See the following? The last time Timothy Cloughesy had a meeting with Merck was March 22, 2021. The same day Merck executive joined Ontada as CEO and President. Tell if it was just a coincidence.
newman2021
Re: None
Wednesday, July 17, 2024 1:20:08 PM
Post#
706651
of 706664
Judge Stein's second and final R&R recommending MTD denial to Judge Woods is going to hit the PACER any day, imo
what % of the mhra maa processing group is on vacation in August?
https://assets.publishing.service.gov.uk/media/64df8877c8dee400127f1ebe/Marketing_authorisations_granted_1_August_to_14_August_2023.pdf
https://assets.publishing.service.gov.uk/media/64f9ab409ee0f2000fb7c03a/Marketing_authorisations_granted_15_August_to_31_August_2023.pdf
hyperopia : Wondering if there is a way to get a transcription of what dr. bosch says 6/17/24 at BNOC?
Re: sentiment_stocks post# 703881
Friday, July 05, 2024 11:44:45 AM
Post#
703931
of 706475
No problem senti. I also use transcription software assisted by AI, which puts in punctuation, and paragraph breaks, but yes, it still requires considerable corrections, or “scrubbing.” One really nice thing, is that it removes all the “uh’s.” If you’ve ever transcribed one of Linda Liau’s presentations, (which I’m pretty sure you have) you know what a time saver that is!
$nwbo @alphavestcap @metacollectiveG @BrianEgolf2 @SmithOnStocks1 @ATLnsider @glen_bwrhr42 @TiltMyBrain @hoffmann6383
— alphavestcapital.com (@alphavestcap) July 16, 2024
“First a recommendation from Judge Stein, likely end of July - end of Aug, then a ruling shortly after “
N.B. If the seven MMs are enjoined from making a…
Red_Right_Hand :
Do you think Judge Woods might be inclined to enjoin the seven market makers from trading $nwbo?
Re: exwannabe post# 706352
Tuesday, July 16, 2024 9:44:16 AM
Post#
706353
of 706445
After discovery defendants will move for a summary judgement
The timing depends a lot on what there is to discover. Defendants know that, and can value that, better than anyone.
"Unlike TRO, temporary injunctions are slightly more enduring in effect than TRO, and requires a court proceeding and usually requires a notice to the opposing party. In determining whether to grant or deny a preliminary injunctive relief, the courts generally look to several of the factors including: (1) the plaintiff's likelihood of prevailing on the merits;(2) a showing of irreparable injury to plaintiff if relief is not granted; (3) the threatened injury to the movant is demonstrated to outweigh whatever damage the proposed injunction may cause the opposing party; and (4) the balancing of equities."
District Court Decisions
Smith v. Commc'ns Works of Am. (CWA) District 2, No. 8:12-cv-00027-AW, 2012 U.S. Dist. LEXIS 181810 (S.D. Md. Dec. 26, 2012) (Williams, J.). Holding: Granting EEOC's motion to dismiss. The court determines that if the plaintiff's complaint was construed as one for injunctive relief, it would fail because the "EEOC complied with Plaintiff's request to release a copy of his charge file, making only mild redactions for deliberative process information."
Landmark Legal Found. v. EPA, No. 12-1726, 2012 WL 6644362 (D.D.C. Dec. 21, 2012) (Lamberth, J.). Holding: Denying motion for preliminary injunction. The court denies plaintiff's request for injunctive relief ordering expedited processing of its request. First, the court holds that plaintiff has not shown that there is a substantial likelihood of success on the merits because plaintiff has not shown that it is entitled to expedited processing. Second, plaintiff has also not demonstrated that it will suffer irreparable injury if the court does not order release of the records on an expedited basis. The court notes that given that the "agency has stated that it will complete processing of the request by the end of next month," it is difficult to see how denial of the injunction motion will cause irreparable harm. Additionally, even "f the EPA did, for political reasons, delay a controversial proposed rule until after the presidential election, the Court fails to see how receiving this information in January will irreparably harm [plaintiff]." Plaintiff could still "publicize the information" and "launch legal challenges." Furthermore, even if the court ordered production, many of the records "could fall under exemptions to the FOIA and thus be withheld or redacted." Third, the court agrees that there would be no substantial injury to other interested parties, but concludes that this is insufficient to overcome the other prongs of the injunctive relief analysis. Fourth and finally, the court determines that the public interest would not be furthered by requiring EPA to disclose the records within three days. "The EPA has already stated that Landmark's request is 'at the top of the FOIA processing queue,' and that it 'anticipates completing the response to this request on or before January 31, 2012.'"
The court also denies plaintiff's request for injunctive relief "compelling preservation of responsive information." The court notes that plaintiff has not shown a likelihood of success on the merits. The court concludes that this case "does not demonstrate the need for an order compelling preservation of records." The court notes that "there is no indication that the EPA has or will destroy any records related to this request." The court also comments that "the mere 'potential of destruction' is not sufficient to demonstrate the need for such an order" and that "the EPA is already barred from destroying many records which would be responsive, for example, under the Federal Records Act." Second, plaintiff has not shown there would be irreparable injury because there is no indication that EPA will destroy the responsive records. Third, while there is no risk of substantial injury to other interested parties, this prong has little impact because plaintiff fails to meet the other factors. Finally, an injunction would not further the public interest because there is no indication that EPA may destroy records. Indeed, "EPA has submitted a sworn declaration from the employee overseeing the response to this FOIA request in which he states that there is a litigation hold requiring the preservation of records and that he will comply, to the best of his ability, with the obligation to preserve records."
Hajro v. U.S. Citizenship & Immigration Servs., No. 08-1350, 2011 U.S. Dist. LEXIS 117964 (N.D. Cal. Oct. 12, 2011) (Grewal,Mag.). Holding: Dismissing FOIA claims brought against individual defendants; holding that party who did not submit FOIA request at issue has standing to assert a "pattern or practice" claim under FOIA; granting declaratory relief that defendant engaged in pattern or practice of failing to abide by FOIA; granting plaintiffs' request for injunctive relief; concluding that defendant is required to release certain non-exempt information previously withheld pursuant to Exemption 5; concluding defendant's FOIA processing policy violates a previous settlement agreement as well as the terms of the Administrative Procedure Act (APA) and the FOIA; dismissing a claim brought under APA; and granting partial summary judgment to defendants on plaintiffs' equal protection claims. The court awards summary judgment to plaintiffs on the basis that they have "establish[ed] a pattern or practice of FOIA violations" by USCIS's actions in repeatedly exceeding the twenty-day response time for requests. The court finds that "[d]efendants have not offered evidence to the contrary, pointed out inconsistencies in the record that would suggest a genuine issue of fact for trial, or come forward with even assertions that USCIS is in compliance with the timing requirements of FOIA." With respect to plaintiffs' request for a permanent injunction, the court notes that such relief is available "in order to remedy a pattern and practice of FOIA violations by an agency where there is 'a probability that alleged illegal conduct will recur in the future.'" Here, the court finds that injunctive relief is warranted based on the "repeated occurrence of the delays and lack of any indication by Defendants of efforts to cease such violations in the future," "the history of past violations by USCIS and its predecessor agency," and the fact that "the effect on the public of disclosure or nondisclosure is substantial where the information sought is not available through any other means." Based on these findings, the court grants plaintiffs' request for injunctive relief and "require[es] USCIS to: 1) provide a copy of the requestor's file within the twenty-day time limit mandated by 5 U.S.C. §552(a)(6)(A); and 2) give the written notice mandated by 5 U.S.C. §552 (a)(6)(B) if an extension of time is needed due to 'unusual circumstances.'"
U.S. Department of Justice - 950 Pennsylvania Avenue, NW, Washington DC 20530-0001
Justice.gov
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An injunction is a court order requiring a person to do or cease doing a specific action. There are three types of injunctions: Permanent injunctions, Temporary restraining orders and preliminary injunctions. Temporary restraining orders (TRO) and preliminary injunctions are equitable in nature. They can be issued by the judge early in a lawsuit to stop the defendant from continuing their allegedly harmful actions. Choosing whether to grant temporary injunctive relief is up to the discretion of the court. Permanent injunctions are issued as a final judgment in a case, where monetary damages will not suffice. Failure to comply with an injunction may result in being held in contempt of court, which in turn may result in either criminal or civil liability. See, e.g., Roe v. Wade 410 US 113 (1973).
Injunctions: An Overview
An injunction is a court order requiring an individual to do or omit doing a specific action. It is an extraordinary remedy that courts utilize in special cases to alter or maintain the status quo, depending on the circumstances, particularly where the defendant must stop its course of action to prevent possible injustice and irreparable harm to the plaintiff. Injunctive relief is a discretionary power of the court, in which the court balances the irreparability of harm and inadequacy of damages if an injunction were not granted against the damages that would result if an injunction was granted. An individual who has been given adequate notice of an injunction but fails to follow the court's orders may be punished for contempt of court.
An injunction is an equitable remedy, and is therefore available only in cases of in-personam jurisdiction, and not in in-rem or quasi-in-rem jurisdiction. Rule 65 of the Federal Rules of Civil Procedure explains what temporary injunctions TRO are, and establishes the rules regarding them. Rule 65, however, only addresses the collateral requirements of notice, form, and scope of the temporary injunctions, but does not prescribe the standards for issuance of the injunctions. Therefore, the standards have been judicially developed by the courts, and thus the exact standards and balancing test vary across jurisdictions.
Temporary Restraining Order (TRO):
A temporary restraining order is a short-term measure in effect until the court is able to issue something more enduring, such as a preliminary injunction. For example, a temporary restraining order can be issued without notice by a federal court, but cannot exceed ten days without additional court proceedings. Temporary restraining orders may be issued without a court hearing and without informing the opposing party. Temporary restraining orders are often issued by state and local courts to prevent contact between parties, where the defendants’ actions could seriously harm the plaintiffs. For example, in 1981, a federal court, issued a temporary restraining order against the Los Angeles Unified School District in an effort to stop the school district’s plans to dismantle an organized busing plan, fearing that the school district’s plans would harm the students.
Temporary Injunctions:
Unlike TRO, temporary injunctions are slightly more enduring in effect than TRO, and requires a court proceeding and usually requires a notice to the opposing party. In determining whether to grant or deny a preliminary injunctive relief, the courts generally look to several of the factors including: (1) the plaintiff's likelihood of prevailing on the merits;(2) a showing of irreparable injury to plaintiff if relief is not granted; (3) the threatened injury to the movant is demonstrated to outweigh whatever damage the proposed injunction may cause the opposing party; and (4) the balancing of equities.
Other circuits have alternatively looked to a different criteria, consisting of a showing of (1) probable success and the possibility of irreparable injury; or (2) serious questions on the merits and a balance of hardships. See e.g., W.W. Williams Co. v. Google, Inc., 2013 WL 3812079 (S.D. Ohio 2013).
Permanent Injunctions:
There is a balancing test that courts typically employ in determining whether to issue an injunction. To seek a permanent injunction, the plaintiff must pass the four-step test: (1) that the plaintiff has suffered an irreparable injury; (2) that remedies available at law, such as monetary damages, are inadequate to compensate for the injury; (3) that the remedy in equity is warranted upon consideration of the balance of hardships between the plaintiff and defendant; and (4) that the permanent injunction being sought would not hurt public interest. See, e.g., Weinberger v. Romero—Barcelo, 456 U.S. 305, 311–313, 102 S.Ct. 1798, 72 L.Ed.2d 91 (1982); Amoco Production Co. v. Gambell, 480 U.S. 531, 542, 107 S.Ct. 1396, 94 L.Ed.2d 542 (1987). The decision to grant or deny permanent injunctive relief is an act of equitable discretion by the district court, reviewable on appeal for abuse of discretion. See: eBay Inc. v. MercExchange, L.L.C., 547 U.S. 388, 391, 126 S. Ct. 1837, 1839, 164 L. Ed. 2d 641 (2006).
In balancing the damages to the plaintiff and the defendant and the public interest, the courts balance the relative harm and benefit to both the defendant and the plaintiff if the injunction is granted. A leading decision, Boomer v. Atlantic Cement Co., ruled against a permanent injunction against the cement company in a nuisance claim by the homeowners in the neighborhood. In reaching the decision, the court factored in the factory’s apparent inability to develop improved abatement methods, and the defendant’s 45 million dollar capital investment in the factory, both of which are factors by which the defendant would be significantly hurt by the injunction.
Also, in some jurisdictions, courts take into consideration the good faith of the parties. If it seems that the defendant is acting in good faith, by doing all that it can to abate the nuisance, the court may reflect those efforts in the terms of its order. In contrast, if the court believes the defendant is acting in bad faith, the court will show little sympathy and rule in favor of permanent injunction. See, e.g., Penland v. Redwood Sanitary Sewer Serv. Dist., 965 P.2d 433, 440 (Or. Ct. App.1998).
Federal Material
U.S. Constitution and Federal Statutes
U.S. Code:
5 U.S.C. § 703 - Judicial Review of Agency Actions
5 U.S.C. § 552b - Section f, Injunctive Relief Against Federal Agencies
7 U.S.C. § 228a - Authority of Secretary to request temporary injunction or restraining order
7 U.S.C. § 2159 - Authority to apply for injunctions
15 U.S.C. § 1116 - Trademarks
15 U.S.C. § 1195 - Injunction and condemnation proceedings
28 U.S.C. - Judiciary and Judicial Procedure
29 U.S.C. - Labor - § 107 - Issuance of injunctions in labor disputes; hearing; findings of court; notice to affected persons; temporary restraining order; undertakings
29 U.S.C. - Labor - § 662 - Injunction proceedings
47 U.S.C. - Telecommunications - § 401 - Enforcement provisions
49 U.S.C. - Transportation - § 60120 - Enforcement
CFR:
49 CFR Transportation § 386.71 - Injunctions
Federal Rules
Federal Rules of Civil Procedure:
Rule 52(a)
Rule 62(a), (c), and (g)
Rule 65
[Last updated in March of 2023 by the Wex Definitions Team]
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Abstract
The law of preliminary injunctions has evolved, in many instances, away from its roots in equity and towards a more rigid and formalistic approach that raises the bar for when a preliminary injunction may be granted. This evolution is rooted in hostility held by the Supreme Court toward certain types of rights, such as abortion, voting, public health, and environmental protection, to name a few. In the aftermath of the Supreme Court’s 2009 decision in Winter v. Natural Resources Defense Council, a few circuits adopted a strict, literal reading of some dicta from Winter and dramatically reshaped decades of circuit court precedent on preliminary injunctions. Specifically, that minority of courts has abandoned a more flexible approach to preliminary injunctions that allows a “sliding scale” to consider all relevant factors, in favor of raising the bar on assessing the likelihood of success on the merits. The courts have further erred by treating the factors, traditionally balanced all together, as elements that must be established individually. This mistake should not spread any further to circuits that have not yet decided the issue, and the Supreme Court should correct this mistake at its earliest opportunity.
Although preliminary injunctions are important in all cases, this Article focuses on public law. These cases typically involve a challenge to government action. Preliminary injunctions are often critical in ensuring that full judicial review of those actions is even possible because if an election passes or a forest is cut down while the litigation plays out over many years, then the claims likely become moot. However, injunctions should not automatically be issued in these cases just because the government has a strong interest in acting without delay to solve problems facing society. Faced with this dilemma, courts are best empowered to use a flexible balancing approach, which has historically been the hallmark of equity jurisprudence. This Article demonstrates why the minority of circuits have badly erred on this issue, lays out the doctrinal and policy reasons supporting a flexible approach, and responds to the arguments in favor of the rigid, inflexible approach coming down from the Supreme Court.
I. Introduction
In an era when federal court litigation typically spans many years, a preliminary injunction is often the only means by which courts can preserve the status quo while the litigation plays out. Although this relief is not granted as a matter of course in every case, it is an important and necessary tool for courts to balance the equities before them, where failure to preserve the status quo would cause irreparable harm to one party. Preliminary injunctions are of particular importance in public law cases, which often involve either broad questions of public policy or intense private interests being affected by laws or administrative regulations. Courts have long employed a flexible approach to granting forms of equitable relief, such as preliminary injunctions; however, more recently, the U.S. Supreme Court has imposed more rigid, formulaic approaches to equitable relief—finding fault with how lower courts balanced competing interests in the cases before them. Most notably for this Article is the 2008 decision in Winter v. NRDC, where the Court refused to allow a preliminary injunction to be issued based upon a showing of the mere possibility of irreparable harm, rather than a likelihood of such harm.[1] Although this case focused on the consideration of irreparable harm, it contained sweeping language regarding other traditional factors that courts look to in balancing the equities in preliminary injunction cases, such as the likelihood of success on the merits.[2] This broad language has led some lower courts to adopt similarly rigid approaches, and some circuits have jettisoned their traditional flexible approaches to assessing the merits, while others have retained that flexibility by taking a narrow reading of Winter. The circuits employing a newly rigid test have gotten it wrong and should reverse course to return to the equitable balancing approaches used by other circuits to assess the merits of a case at its early stages. If the Supreme Court truly meant to take such a dramatic and ill-conceived approach to assess the merits of a preliminary injunction, it should say so clearly and explain itself while grappling with the arguments in favor of a flexible approach to equity head-on. This issue is of particular importance in public law cases where the public interest is of greatest import and needs to be incorporated into the balance along with private interests raised during litigation. Private law cases are outside the scope of this Article, although historically, they have also benefitted from the traditional flexible approach to preliminary injunctions.
A preliminary injunction is the name given to an order when a party, usually the plaintiff, asks the court to enjoin another party from taking some action (or perhaps to require some action be taken, a mandatory injunction) during the pendency of the litigation. This request is made of the trial court, which is typically a federal district court.[3] However, similar requests can be made at different stages of litigation. If the request is made in a rushed fashion, such that a decision is needed quickly, it is called a temporary restraining order.[4] This is typically of short duration, not to exceed fourteen days, but it may provide time to allow for further briefing on a preliminary injunction.[5] If the request is made after a trial court decides a motion for a preliminary injunction, the relief is referred to as a stay or an injunction pending appeal, depending on whether the preliminary injunction was granted or denied, respectively.[6] This Article focuses on preliminary injunctions, although similar issues are raised in these related contexts, and the law has evolved on each front. An injunction that is issued after the merits have been decided is called a permanent injunction, although the issues raised by those are quite different because the merits have been resolved at that point (at least by one court).[7]
Why, then, does the standard for assessing the merits of a preliminary injunction matter? Consider, for example, the following scenario, which illustrates some of the problems associated with setting the bar too high when analyzing the likelihood of success on the merits. Suppose an environmental organization files suit in federal court to challenge a decision by the U.S. Forest Service to authorize a timber sale in a national forest. The merits of the case will turn on the agency’s compliance with the approved management plan for that national forest, or the adequacy of an environmental impact statement prepared for the project. Yet these cases will be reviewed based on an administrative record that is before the agency, which will often include behind-the-scenes e-mails among staff for the agency, outside contractors, and potentially interested industry participants. These e-mails sometimes include “smoking gun” information that shows the agency was aware of serious deficiencies in its analysis or problematic conflicts with the existing management plan. However, this information is not necessarily available to the plaintiff until many months into the litigation. Even if the information is available, the case may raise a novel legal issue of first impression, such that it is challenging for a single district court to accurately assess whether the plaintiff will prevail. This may be the first, and only, case regarding a national forest that this judge has presided over, for example. Either way, without guidance to the contrary, timber companies may still enter the land and cut down the forest, even though the activity might later be deemed unlawful by the court. If the court does not issue a preliminary injunction, it is too late because the harm cannot be undone.
Another example may more starkly demonstrate the importance of preliminary injunctions. In a recent case challenging whether the methods used to conduct federal executions violated the Eighth Amendment’s prohibition on cruel and unusual punishment, death-row prisoners faced the most irreparable harm of all: being put to death by the state.[8] Although the district court granted a preliminary injunction to pause four planned executions, the Supreme Court vacated the injunction and allowed the executions to proceed.[9] Two dissenting opinions lamented the rush to judgment that inevitably foreclosed any judicial review of these claims.[10] Any serious questions raised by these individuals can no longer be addressed by the courts, whether or not they turn out to have merit in the courts’ eyes. By setting the bar too high in assessing the merits related to a preliminary injunction, courts will expand the category of cases in which meaningful relief is not possible and promote injustice in at least a subset of those cases.
A series of recent high-profile decisions relating to Texas’ anti-abortion law SB-8 further show how imposing impossible burdens on parties seeking a preliminary injunction will cause harm. This case involves a Texas bill signed into law on May 19, 2021, which “bans abortion after approximately six weeks of pregnancy,” at a time when many women do not even know they are pregnant.[11] Although this law blatantly violated Supreme Court precedent, such as Roe v. Wade, it attempted to game the system by circumventing any state official role in enforcement, and instead delegating enforcement to private parties and offering a bounty for successful litigants.[12] Although the law was promptly challenged, and the district court scheduled oral argument on a request for a preliminary injunction before the law took effect on September 1, 2021, the appellate court decided to intervene in a highly unusual manner and prevent the issuance of an injunction.[13] Although the health clinics challenging the law then requested that the Supreme Court intervene, the Court did not act before the law took effect.[14] Instead, only after the law took effect—leading to much chaos in Texas—did the Supreme Court bother to explain why it did not act.[15] The Court noted the “serious questions regarding the constitutionality of the Texas law at issue” but nevertheless declined to intervene because the health clinics did not meet their “burden of making a ‘strong showing’ that [they are] ‘likely to succeed on the merits.’”[16] Several strongly-worded dissents went even further, describing SB-8 as “a flagrantly unconstitutional law engineered to prohibit women from exercising their constitutional rights and evade judicial scrutiny”[17] or as a “patently unconstitutional law banning most abortions.”[18] Here, the distinction between “serious questions” and a higher “likely to succeed on the merits” test has critical consequences—many women in Texas lost their constitutional right to abortion during the course of the litigation. A clear statement affirming the serious questions test for preliminary injunctions, which seemingly all nine justices would agree was met in this case, would have allowed the preservation of the status quo while any tricky issues related to the novel enforcement scheme could be carefully and deliberately resolved in the lower courts.[19]
Of course, a preliminary injunction should also not be issued automatically in any case where a party claims irreparable harm. There are often real concerns about issuing a preliminary injunction. But those concerns are better addressed under the “balance of equities” and “public interest” factors, rather than raising the bar on the merits too high. The litigation surrounding COVID vaccine requirements provides a good example of this. Although courts are right to reject preliminary injunctions in those cases where the plaintiff has no chance of succeeding,[20] in cases where at least serious questions are raised regarding the merits, a more cautious approach is warranted. However, even serious questions are not sufficient to support an injunction when the balance of equities and public interest weighs against the issuance of an injunction, such as cases where unvaccinated individuals might threaten the group vaccination dynamics of their communities.
Flexible standards of equity necessarily and heavily rely on the discretion of judges. As a result, judges reach conclusions in balancing these factors that will inevitably spark disagreement between reasonable observers. But the response to such cases should not be to raise the standard required for a preliminary injunction. Egregious outliers can be corrected on appeal through abuse-of-discretion review.[21] Although the temptation is understandable, appellate courts, including the U.S. Supreme Court, should not wade into every dispute to correct perceived errors, particularly when the intervention will foreclose meaningful and deliberate judicial review of the merits of the claims presented.[22]
This issue is not only percolating in the courts, but there is a current legislative proposal regarding a stay on so-called “high-impact” rules under the Administrative Procedure Act.[23] This proposal would amend 5 U.S.C. § 705 to require agencies to postpone the effective date of such rules until the final dispositions of all actions seeking judicial review of the rule.[24] Although limited only to a subject of rules issued by federal agencies, this proposal represents the opposite extreme of staying all rules, no matter how urgent or important they may be, during the course of litigation. This is the flip side of a preliminary injunction standard where the merits factors are set too high, and it would not allow for urgent action on important issues. Fortunately, this legislation seems unlikely to be enacted given the political dynamics in Congress.
As stated previously, this Article is concerned with the standard for granting or denying preliminary injunctions in public law cases. Public law is the “body of law dealing with the relations between private individuals and the government, and with the structure and operation of the government itself . . . .”[25] Public law thus includes issues of constitutional law, criminal law and procedure, elections law, environmental law, administrative law, public health law, and more.[26] Public law does not include private law cases, which “deal[ ] with private persons and their property and relationships.”[27] Although private cases are undoubtedly important, oftentimes they involve disputes where the harm is not irreparable because of the increased availability and sufficiency of monetary damages for private law claims. Public law cases, in contrast, present a myriad of situations where harm will truly be irreparable. A prisoner cannot be brought back to life after execution. A forest cannot be put back after it is cut down for timber. The decision to terminate a pregnancy cannot be exercised after a woman is forced to carry a pregnancy to term. A voter cannot turn back time and submit a valid ballot after being prevented from participating in an election. When—and under what circumstances—those harms will be prevented depends on the standard for a preliminary injunction, especially the standard for assessing the likelihood of success on the merits.
The issues presented by public law cases call for a flexible approach in deciding preliminary injunctions, especially regarding early, and often rushed, assessments of the merits of the case. Over the years, most circuits have developed an array of flexible formulations for how to weed out the meritless cases from those deserving of a closer review. These tests are described as “sliding scale” approaches where the equities related to harm and the public interest can compensate for uncertainty about the merits. One leading formulation is that there need only be “serious questions” going to the merits, rather than a near certainty that the plaintiff will prevail. Abandoning this flexible approach to require a showing that the plaintiff is likely to succeed (which is identical to the ultimate burden in a civil case such as this) sets the bar too high. As a result, the forest may be cut down even though important environmental protections were not complied with, such as those that ensure the forest will regenerate over time. At least, it may be cut down in the Tenth Circuit, which has abandoned its historical flexible standard, but it would likely be protected in the Ninth Circuit, which has retained this approach. Thus, a national forest in Utah is less protected than one just across the border in Arizona.[28]
As the Supreme Court has imposed more rigid standards for equitable relief on lower courts, the courts of appeals have fallen generally into two camps. First, those that have retained their flexible standards and have engaged in thoughtful decision-making with their reasoning clearly explained in writing as to why they retained their standards even after Winter. On the other side, courts, such as the Tenth and Fourth Circuits, have taken broad language from Winter out of context, finding that the court overturned decades of practice and experience without any kind of analysis, and ignored the different outcomes reached by their sister circuits. This shoddy and overly simplistic judicial decision-making has hamstrung the ability of lower courts to reach equitable and just results accounting for the totality of circumstances in individual cases, and it should be resolved. Although the Supreme Court has the power to correct this misstep, the appellate courts could also fix the problem themselves. If that does not happen, the Federal Rules of Civil Procedure should be updated to help courts better balance competing interests in preliminary injunction cases.
This Article proceeds in four parts. Part II provides an overview of the preliminary injunction standard, both its historical treatment in the lower courts and the turn towards a sequential, multi-factor test in recent Supreme Court cases, especially in Winter. Part III examines the scholarly literature on preliminary injunctions and related equitable remedies. Part IV argues that the circuit split should be resolved and provides several reasons why the resolution should restore the flexible approach in assessing the merits of preliminary injunctions across all circuits. Part V responds to arguments that critics of flexible equity have made or are expected to raise in objection to this proposal.
II. The Preliminary Injunction Standard Over Time
The preliminary injunction is a remedy with a long history in equity, including in federal courts in the United States. The hallmark of preliminary injunctions, as with other equitable principles, has always been the flexibility for the court to fashion a remedy that is appropriate under the circumstances. However, in recent years, the Supreme Court has taken steps to limit and focus that flexibility, not just for preliminary injunctions but also for related equitable remedies, such as permanent injunctions, stays, and injunctions pending appeal.
Flexibility has consistently been acknowledged as the core of equity. The Supreme Court has long recognized, for example, that “[t]he essence of equity jurisdiction has been . . . [f]lexibility rather than rigidity . . . .”[29] Furthermore, “[e]quity eschews mechanical rules; it depends on flexibility.”[30] The Court has further noted that “equity has been characterized by a practical flexibility . . . .”[31]
The unification of law and equity culminated in the creation of the Federal Rules of Civil Procedure.[32] Under this regime, preliminary injunctions are authorized by Rule 65; the rule merely requires notice to the adverse party and a security to cover the costs of any party later found to have been wrongly enjoined.[33] The rule also (at least theoretically) requires that every order granting an injunction “state the reasons why it issued[,] . . . state its terms specifically[,] and describe in reasonable detail . . . the act or acts restrained or required.”[34] However, the rule does not state the factors to be used in deciding whether to issue a preliminary injunction, and thus, court decisions lay out the standard to provide the necessary guidance.[35]
Despite the historical flexibility accorded to this area of the law by federal courts, in recent cases, the Supreme Court has turned away from flexibility in favor of more rigid tests to guide lower courts in exercising their equity discretion. This change is described as the “New Equity” by Professor Bray[36] and discussed by other scholars as well, most of whom are critical of it.[37] One of those cases is Winter: the most prominent case by which the Court introduced changes to courts’ consideration of preliminary injunctions.
A. Flexible Standards Developed in the Circuits
1. Historical Treatment of Preliminary Injunctions
The well-known Wright & Miller treatise on civil procedure notes the “bewildering variety of formulations of the need for showing some likelihood of success.”[38] Although divining true differences from the various statements on the likelihood of success on the merits may not be possible, a background discussion of the older cases that lay out the flexible approach to equity will help set the stage for the more recent emphasis on rigid rules and strict tests.
In an early case decided by the U.S. Supreme Court, an injunction was issued to prevent irreparable injury—with the only harm to the opposing party being “a short delay”—and to allow “a fair investigation and determination upon” the claim raised by the State of Georgia.[39] About a century later, the Eighth Circuit held that “[w]hen the questions to be ultimately decided are serious and doubtful, the legal discretion of the judge in granting the writ should be influenced largely by” the balance of harms.[40] In Ohio Oil Co. v. Conway, the Supreme Court dealt with a factual dispute relating to the effect of a state tax on oil revenues on the plaintiff, which had to ‘‘be resolved before the constitutional validity of [a] statute [could] be determined.’’[41] Faced with this situation, the Court instructed that ‘’[w]here the questions presented by an application for an interlocutory injunction are grave, and the injury to the moving party [in the absence of such an injunction] will be certain and irreparable . . . the injunction will usually be granted.‘’[42] A short time later, the Court declared “[t]he essence of equity jurisdiction has been the power of the Chancellor to do equity and to mould each decree to the necessities of the particular case. Flexibility rather than rigidity has distinguished it.”[43] When both the “plaintiff and defendant present competing claims of injury, the traditional function of equity has been to arrive at a ‘nice adjustment and reconciliation’ between the competing claims.”[44] “[T]he basis for injunctive relief . . . has always been irreparable injury and the inadequacy of legal remedies.”[45]
Although the “traditional test” for preliminary injunctions laid out four factors that courts would weigh together, for many decades numerous federal courts have adopted a sliding scale test. The traditional test consists of (1) the likelihood of success on the merits; (2) irreparable harm absent an injunction; (3) the balance of hardships or equities; and (4) the public interest.[46] The alternative formulation of the “sliding scale” allowed a preliminary injunction to be issued when there were “[serious] questions going to the merits” as long as “the balance of hardships tip[ped] decidedly toward the [moving party].”[47]
To justify a temporary injunction it is not necessary that the plaintiff’s right to a final decision, after a trial, be absolutely certain, wholly without doubt; if the other elements are present (i.e., the balance of hardships tips decidedly toward[s] [the] plaintiff), it will ordinarily be enough that the plaintiff has raised questions going to the merits so serious, substantial, difficult and doubtful, as to make them a fair ground for litigation and thus for more deliberate investigation.[48]
Under this test, proof of irreparable harm is still necessary because it is a “fundamental and traditional requirement of all preliminary injunctive relief.”[49] The Ninth Circuit took a similar but slightly different test, allowing for a sliding scale approach but describing it not as separate from the traditional test but instead “the outer reaches ‘of a single continuum.’”[50]
Many other circuits adopted similar, flexible approaches along the lines of the sliding scale tests adopted in the Second and Ninth Circuits. The Tenth Circuit explained that, in addition to the traditional test,
f the plaintiff can establish that the latter three requirements tip strongly in his favor, the test is modified, and the plaintiff may meet the requirement for showing success on the merits by showing “that questions going to the merits are so serious, substantial, difficult, and doubtful as to make the issue ripe for litigation and deserving of more deliberate investigation.”[51]
A version of this serious questions test was also used by the Fourth,[52] Sixth,[53] and D.C. Circuits.[54] Similar tests using slightly different wording were used by the Third,[55] Fifth,[56] Seventh,[57] Eighth,[58] and Federal Circuits.[59] Thus, before the Supreme Court decided Winter, the flexible approach of the lower courts included some version of a sliding scale test that would allow an injunction to be issued, even when the moving party did not prove it was certain to prevail on the merits.
B. Winter
Before it decided to impose a more rigid test for preliminary injunctions, the Court had taken a similar approach to the related issue of permanent injunctions.[60] For permanent injunctions, the case has already been decided on the merits, and so the test replaces the likelihood of success on the merits factor with one asking whether “th[e] remedies available at law, such as monetary damages, are inadequate to compensate for that injury.”[61] Key to this case was that the Court reaffirmed that its pronouncements regarding the standard for injunctive relief were trans-substantive and rejected arguments that disputes arising under the Patent Act should have a different standard.[62]
In Winter, the Court extended the “traditional doctrine” approach from eBay to the context of preliminary injunctions. The test was slightly different because it included a factor assessing the merits of the case because preliminary injunctions are issued before a final decision on the merits, as opposed to permanent injunctions, which are issued after a final decision. Thus, the Court established four factors for a preliminary injunction—not as considerations to balance in equity, but as individual requirements to be met.[63] Those four factors were: (1) irreparable harm absent an injunction; (2) likelihood of success on the merits; (3) balance of harms between the parties; and (4) the public interest.[64] This restatement (or transformation) of the test was not necessary to the resolution of the case, which was focused on the burden concerning irreparable harm carried by the movant.[65] The Court ultimately rejected the “possibility” of irreparable harm standard from the Ninth Circuit that had been applied by the lower courts.[66] However, a strict reading of Winter[67] arguably upset the longstanding practice of the lower courts, which had developed more detailed, flexible approaches in deciding preliminary injunctions. The circuit split over how to read Winter, and how it should be resolved, is the primary focus of this Article.
In its prior term, the Court issued a related decision in Munaf v. Geren.[68] In this case, a lower court granted a preliminary injunction with regard to a habeas petition submitted by two American citizens who traveled to Iraq and allegedly committed crimes there.[69] The Supreme Court faulted the lower court for failing to consider the likelihood of success on the merits at all, instead focusing on the difficult and substantial questions of jurisdiction posed by the habeas petition.[70] The Court did not question the “serious questions” formulation but instead focused only on the jurisdictional versus merits distinction.
There is a related group of cases focusing not on the principles that guide equity decisions, but rather on the boundaries of what courts may do when issuing equitable relief. In Grupo Mexicano, for example, Justice Scalia authored a 5-4 opinion that split along ideological lines, holding that equitable relief was limited to the types of relief that had been issued before 1789.[71] Justice Ginsburg wrote the dissent and reiterated the view that equity was adaptable, dynamic, and flexible.[72] Although the focus there was not on the principles or tests to be applied in deciding equitable remedies, it illustrated the same tension between a narrow view of history in conflict with the flexible approach to equity.
C. Post-Winter Development of a Circuit Split
1. Circuits Retaining Serious Questions Test
Most circuits that have considered the question have decided that Winter did not alter their long-established tests for deciding whether to grant preliminary injunctions, specifically where they have a flexible approach to the merits prong.
The Second Circuit faced this question of the continuing viability of its serious questions test in a case involving a dispute between financial firms over credit default swaps.[73] The court examined not just Winter but also the Munaf and Nken cases to see whether the serious questions test remained valid—and concluded that it did.[74] The Second Circuit framed the question as to whether Winter and its companion cases require a showing that the movant “is more likely than not to succeed on its underlying claims,” but rejected that as too broad a reading.[75] The court upheld its prior statement of the test, which requires a showing of either “likelihood of success on the merits or . . . sufficiently serious questions going to the merits to make them a fair ground for litigation and a balance of hardships tipping decidedly toward the party requesting preliminary relief.”[76] The court praised the flexibility of its serious questions approach, which allowed it to avoid confining relief to cases that are simple or easy.[77]
The Third Circuit has not addressed the question in the context of a preliminary injunction, but has upheld its “‘sliding scale’ approach” for the merits for a stay pending appeal.[78] The court explicitly noted that Winter changed the standard for irreparable harm, but it retained a broad reading of what constituted likely success on the merits.[79] The court noted the wide variance in formulations of the “degree of likelihood of success” required to obtain equitable relief, including “more likely to succeed than fail,” “substantial possibility, although less than a likelihood of success,” or “a reasonable chance, or probability, of winning.”[80] Although stays pending appeal are not the same as preliminary injunctions, the similarities are such that the same reasoning should apply with equal force to a preliminary injunction, especially since the court explicitly noted Winter’s impact on the irreparable harm requirement.
The Seventh Circuit faced this issue in a business dispute where one party claimed it faced bankruptcy, which would cause irreparable harm.[81] After citing Winter for the preliminary injunction factors, the court went on to explain that in the Seventh Circuit, “[h]ow strong a claim on the merits is enough depends on the balance of harms: the more net harm an injunction can prevent, the weaker the plaintiff’s claim[s] on the merits can be while still supporting some preliminary relief.”[82] In this case, the claims had “enough punch to justify interlocutory relief” given the harm avoided by an injunction.[83] The court later noted numerous uncertainties about how the case would come out and held that “[a]ll of these uncertainties collectively support the district court’s conclusion that Hoosier Energy has some prospect of prevailing on the merits.”[84]
The Ninth Circuit decided that its sliding scale test survived Winter in a case challenging logging and timber sales in a National Forest.[85] The court described its approach to preliminary injunctions as “a stronger showing of irreparable harm to plaintiff might offset a lesser showing of likelihood of success on the merits” or specifically allowing an injunction when “serious questions going to the merits were raised and the balance of hardships tips sharply in [plaintiff’s] favor.”[86] The court noted that an injunction could not be issued simply based on serious questions and strong irreparable harm, but also requires all four prongs identified in Winter to have some showing for a successful preliminary injunction.[87]
The D.C. Circuit reaffirmed the sliding scale in an employment law case brought by a group of pilots.[88] The court did not go into great depth but noted that, although a broad reading of Winter might change the sliding scale approach, it continued to apply; however, the issue was unnecessary to its decision because the pilots involved in the litigation could not succeed even under the sliding scale approach.[89] It should be noted that then-Judge Kavanaugh filed a concurring opinion in this case, stating his belief that the four prongs of Winter were each independent requirements for a preliminary injunction, and thus, a movant must show “both a likelihood of success and a likelihood of irreparable harm . . . .”[90] Thus, he might be expected to push for a further reduction in flexibility given to lower courts if presented with the question at the Supreme Court.[91] Additionally, some district court judges in the District of D.C. have recently questioned whether the sliding scale approach survived Winter.[92]
The reasons for retaining these flexible standards are discussed in more detail later,[93] but the courts gave several reasons for why they did not take a broad reading of Winter. One reason was the longstanding practice of applying the flexible standard.[94] Another reason was the belief that existing precedent should not lightly be overruled absent explicit direction from the Supreme Court.[95] Some found support for retaining a flexible merits standard in Winter and noted the relevance of other factors, such as the balance of harms in assessing the merits.[96] Thus, the movant must show a “better than negligible” chance of success but need not show it is “more likely than not” to succeed.[97] Another reason is that the serious questions formulation requires an “overall burden [that] is no lighter than . . . the ‘likelihood of success’ standard.”[98]
2. The Fourth Circuit Rejected Its More Lenient Test After Winter
In contrast to most circuits, the Fourth Circuit was an early outlier in finding that Winter had tightened the merits prong in addition to the irreparable harm inquiry. In Real Truth About Obama, Inc. v. FEC, the court found that Winter required it to abandon its more lenient standard for assessing the merits on preliminary injunctions.[99] This case was later vacated by the Supreme Court,[100] but the Fourth Circuit affirmed in a later case that Winter compelled a change in how it decided preliminary injunctions.[101] Notably, the previous Fourth Circuit standard required a lessened overall burden and also allowed courts to disregard some of the four preliminary injunction factors identified in Winter, so the court found it to be inconsistent.[102] However, the court did not consider whether it should have adopted any of the sliding scale standards from sister circuits rather than take a strict, simplistic reading of the dicta from Winter.
3. The Tenth Circuit Rejected Serious Questions but Even Has an Intra-Circuit Split
In the immediate aftermath of the Winter decision, the Tenth Circuit, at first, seemed to reaffirm the serious questions test. The court later issued two decisions in 2013 that followed the same standard as applied in RoDa Drilling, one of which specifically upheld a preliminary injunction issued under the serious questions standard.[103] These cases led scholarly observers, including the Author, to describe the Tenth Circuit as taking a narrow reading of Winter and preserving the serious questions test.[104] However, the Tenth Circuit eventually reversed course.
When faced with the question for the fourth time, a divided panel of the Tenth Circuit held that although Winter “dealt with a different prong of the preliminary injunction” standard, the rationale of that decision meant that “any modified test which relaxes one of the prongs for preliminary relief and thus deviates from the standard test is impermissible.”[105] The case dealt with oil and gas leases on public lands and whether new developments in fracking technology required an assessment of the environmental impacts under the National Environmental Policy Act.[106] The panel majority did not cite RoDa Drilling—or the other Tenth Circuit decisions that had reached the opposite conclusion—or discuss the other circuits which had considered this question, instead relying only on its broad reading of Winter.[107] Judge Lucero, in dissent, disagreed “that the Supreme Court has sub silentio reversed a decades-old standard used by a majority of circuits.”[108] Judge Lucero went on to go through the history of the serious questions test in the Tenth Circuit and also canvassed the approaches taken by other circuits.[109]
Due to the limited attention given to this critical issue by the majority, and Judge Lucero’s strong dissent, an en banc hearing was sought by the petitioner, supported by a large number of amici who were environmental nonprofits regularly engaged in litigation in the Tenth Circuit.[110] However, the court failed to take up the en banc petition, and thus, did not resolve the intra-circuit split or give more complete and thorough attention to the split with other circuits.[111] As a result, the Tenth Circuit has joined the Fourth in the minority of circuits, that have rejected their more flexible approaches to assessing the merits in preliminary injunction cases, in favor of a broad reading of Winter.
4. The First Circuit Avoids the Issue in 2021
The First Circuit was the most recent to consider this issue, although ultimately, it avoided deciding whether a relaxed standard for the merits survived Winter. Several environmental groups were denied a preliminary injunction in the district court in an attempt to halt the construction of an electric power transmission corridor running from Quebec, Canada to Massachusetts.[112] The environmental groups had argued in the lower court, and on appeal, for the serious questions test to be used regarding the merits prong.[113] The court did issue an injunction pending appeal while it considered the appeal on an expedited basis, so that it could preserve the status quo while the litigation played out, although it did not lay out the factors it considered in granting this request.[114] The case even attracted amicus briefs from environmental law clinic directors who laid out the implications of the issue for the court.[115] Ultimately, though, the First Circuit avoided the issue because it decided that the environmental groups would not succeed even under the serious questions test.[116] Thus, this Article will be particularly timely if the First Circuit (or another) is presented with the issue in another case soon.
5. The U.S. Supreme Court Has Reaffirmed a Flexible Approach to the Merits Prong
Although it is not a preliminary injunction case, the U.S. Supreme Court did reaffirm a flexible approach to assessing the merits of a case that involved a requested stay of a district court order, which is like a preliminary injunction and often involves similar factors to consider. In Hollingsworth v. Perry, the Court considered whether to grant a stay that would prevent the broadcast of a trial determining the constitutionality of Proposition 8, which banned gay marriage in California.[117] The Court stated that all that was required regarding the merits factor was “a reasonable probability that four Justices will consider the issue sufficiently meritorious to grant certiorari.”[118] This is the same degree of probability as required under the serious questions test in numerous circuits.[119] Thus, later Supreme Court precedent supports the idea that the Court did not intend to impose too high of a bar regarding merits before equitable relief (such as a stay or preliminary injunction) could be granted.
III. Theoretical Approaches to Preliminary Injunction Standards
A. Early Views of Preliminary Injunctions
Earlier generations of scholars recognized the variety of formulations that courts used to weigh the equities when deciding whether to grant a preliminary injunction. John Leubsdorf, for example, provided an early scholarly look at preliminary injunctions in the 1970s.[120] In his article, Professor Leubsdorf catalogued the great variety of formulations that had been used by courts, provided a coherent rationale to explain this variety, and highlighted the common elements.[121] However, the article did not anticipate the sharp turn towards rigid factor tests that the Supreme Court would take in the 2000s. Drawing on Leubsdorf’s work, the Seventh Circuit even adopted the sliding scale test and applied an algebraic formula to preliminary injunctions.[122] Other scholars who looked at preliminary injunctions were primarily focused on the public interest prong, which they noted functioned often as a judicial Rorschach test, allowing a judge to use highly subjective views of the public interest to tip the scales on a preliminary injunction.[123] Orin Lewis characterizes the public interest factor as an amorphous factor that simply reflects the court’s estimation of the likely success on the merits in a majority of cases.[124]
In contrast to the view of preliminary injunctions that favors preserving the status quo, one author found that judicial flexibility in deciding whether to grant preliminary injunctions had its genesis in the court’s role protecting economic efficiency at the expense of environmental interests.[125] Goldstein highlighted judicial flexibility as a hallmark of the court’s power to protect the interests of industry while denying relief to less favorable environmental interests.[126]
B. Scholarly Reaction to Winter
Professor Sarah Morath conducted an interesting empirical study of the effect of Winter on environmental cases.[127] This study found that most trial courts continued to look to circuit court precedent on preliminary injunctions, and only the Fourth Circuit had modified its test at that time. Thus, the study found that the effects of Winter were mild in environmental cases in the years following the decision.[128] However, now that the Tenth Circuit has also rejected its sliding scale test, perhaps the effect will be more pronounced.[129] Morath notes that post-Winter, courts are also making more of an effort to analyze the public interest factor.[130] Another outcome might be that environmental plaintiffs may be less likely to seek preliminary injunctions in circuits that have rejected the sliding scale test.
Additionally, several insightful student notes were published in the first few years after Winter was decided.[131] The first of these was published in 2011, and it examined the different approaches circuit courts were taking in applying Winter to their sliding scale tests for preliminary injunctions.[132] This note called for greater uniformity among the circuits by applying a variation of the sliding scale test.[133] Another interesting student note from 2012 looked at the developing state of the circuit split on preliminary injunctions in the immediate aftermath of Winter.[134] Even at this early stage the potential circuit split was evident, as the Fourth Circuit had already indicated it thought its test did not survive Winter. Although that decision was ultimately vacated on other grounds, the Fourth Circuit did later reaffirm that decision with respect to its preliminary injunction standard. The note also identified the D.C. Circuit and Tenth Circuit as not yet having addressed the issue,[135] although in part that is because the note was published before the Tenth Circuit decided Diné CARE v. Jewell.[136] The note proposed that the Supreme Court should resolve the circuit split by adopting “a sequential preliminary injunction test” with a narrow exception allowing a showing of serious questions going to the merits when the balance of hardships tips sharply in favor of an injunction.[137] Overall though, this note concluded that “the disadvantages of sliding[ ]scale tests outweigh the advantage of flexibility.”[138] This conclusion was premised on the assumption that federal judges are able to accurately predict the likely success on the merits at an early stage,[139] an assumption that is not proven and one that this Author disagrees with based on personal litigation experience. The introduction to this Article, sets out the complications facing a judge who is presiding over a case involving a national forest for the first time. With novel or complex litigation, a judge may not be able to accurately predict the success on the merits at an early stage of litigation. Even in areas where the judge has more experience, accurate predictions of the merits are not always possible at early stages.
Professor Jean Love has also written an article about whether Winter precludes a sliding scale test for preliminary injunctions.[140] She concludes that Winter does not necessarily foreclose all iterations of the sliding scale test and that circuits might continue to employ these more flexible approaches, at least under certain constraints.[141] Professor Love’s approach praises the Ninth Circuit’s retention of the serious questions test in Alliance for the Wild Rockies,[142] and I believe that her approach is also consistent with my call for the circuit split to be resolved in favor of retaining the flexible, serious questions standard.
Earlier, this Article focused on a related issue associated with assessing the merits at the early stages of litigation for a preliminary injunction: the potential for cognitive bias in the form of lock-in.[143] The lock-in effect is of particular concern where a party can show significant irreparable harm, but cannot demonstrate a sufficient likelihood of success on the merits.[144] In such cases, a court will deny a preliminary injunction, and if the plaintiff was correct, then the irreparable harm will occur during the course of the litigation. If the party continues to pursue the claim, because it is not moot and there is potential for further harm still, then the judge will have a strong incentive to rationalize any additional evidence that comes to light or any change in position on the merits that might result from further reflection and fuller development of the issues by the parties.[145] Although this does not mean that a judge might never change her mind, the lock-in effect can be expected to bias the ultimate resolution of the merits against a party who sought but did not obtain a preliminary injunction.[146] This issue highlights the importance of not setting the bar too high regarding likely success on the merits so as not to risk bias on the ultimate merits decision.
Another interesting reaction to Winter focused on the conflict of equitable balancing in federal statutory cases with the principle of separation of powers.[147] That author argues that equitable balancing in federal statutory cases should be abandoned in favor of traditional principles of statutory interpretation because of a conflict with the separation of powers. Of some concern is that equitable balancing in cases involving competing federal polices “requires, that judges pick which federal policy they consider most important.”[148] The author further argues that this level of judicial decision-making is an aggrandizing action of the judicial branch and is best resolved by the traditional principles of statutory interpretation or left to the political branches to decide.[149]
C. Related Areas in the Literature
1. Permanent Injunctions
The area of permanent injunctions has a clear relationship to preliminary injunctions, although the differences are critical for the focus of this Article, which is the assessment of the likelihood of success on the merits. The major difference between a preliminary injunction and a permanent injunction is when it is granted during litigation. A preliminary injunction would be granted before the final resolution of the case on the merits, while a permanent injunction is part of the final relief granted by the court after trial or other resolution of the merits (such as summary judgment or the resolution of appeal-style Administrative Procedure Act challenges). Thus, the “likelihood of success on the merits” is critical for a preliminary injunction but is not even considered for a permanent injunction because the plaintiff has necessarily already prevailed on the merits.
However, despite these differences and the absence of the “likelihood of success on the merits” factor, scholars have traced a direct line from earlier cases imposing more rigid requirements on permanent injunctions to Winter, which applied similar constraints on preliminary injunctions. For example, the Supreme Court issued its decision in eBay in 2006,[150] just a few years before its Winter decision. This led Professor Bray to describe the Supreme Court’s evolving case law on equitable relief—such as permanent and preliminary injunctions—as “the New Equity.”[151] The hallmark of these new equity cases is a focus on the distinction between legal and equitable remedies and an entrenchment of the “‘no adequate remedy at law’ requirement for equitable relief.”[152]
In similar fashion to the unclear decision in Winter, Bray calls the test instituted by the Supreme Court in eBay surprising in how accidental it seems to have been.[153] The Court’s announcement of a traditional test for permanent injunctions was a surprise because prior to eBay, remedies scholars had never heard of a traditional, four-factor test for permanent injunctions.[154] The appeal to a historical standard for permanent injunctions by the Court mirrors the later Winter decision.
2. Stays, Injunctions Pending Appeal, and Similar Procedures
As explained above, preliminary injunctions are not the only time when courts must decide whether to preserve the status quo while litigation plays out. Stays and injunctions pending appeal are two such areas, and courts have historically applied very similar standards to the preliminary injunction standard in those areas. The hallmark of all, of course, has been equitable balancing. Although these are treated as distinct remedies by courts,[155] they typically employ similar, perhaps even identical, language to help them weigh the equitable issues presented by the request for relief.[156]
The leading scholar in the area of stays is Professor Portia Pedro.[157] She defines a stay pending appeal as when “a court determines whether to prevent the enforcement of a final order or judgment until an appellate court issues an opinion.”[158] Stays are ostensibly decided based on the same four factors as preliminary injunctions at the circuit court or Supreme Court levels.[159] However, the standard for stays pending certiorari is notably lenient regarding the merits: “a fair prospect that a majority of the Court will vote to reverse the judgment below.”[160] In contrast, the standard typically applied to the merits of stays pending appeal in the circuit courts is often “a strong showing” rather than a “mere possibility” or “better than negligible” chance of success.[161] Despite the similarities to preliminary injunctions, there are, of course, meaningful differences—most notably in the context of litigation. Thus, Professor Pedro proposes a presumption in favor of stays for guaranteed-review appeals, and a presumption against stays pending appeal for discretionary appeals, unless the movant demonstrates that the court is likely to grant appellate review.[162] She also proposes a number of critical reforms that would greatly benefit this area of the law, such as asking courts to write more to explain their decisions and several improvements to the procedures used in deciding stay requests from parties.[163] Pedro’s proposal to ask courts to write more could be applied to great effect in denials of preliminary injunctions to lessen the impact of the lock-in effect and provide a clearer picture for litigants to understand why an injunction is granted.[164]
Pedro also highlights the inconsistent application of the stay factors courts apply.[165] When they do write opinions on stays, courts are split on the application of the factors.[166] The Fourth Circuit applies a balance-of-hardships approach that only considers the likelihood of success after a balancing of the hardships and applies the serious questions standard to the issues presented for litigation.[167] Some courts, however, apply a sliding scale approach which allows for a stronger showing of likelihood of success to excuse a weaker showing of irreparable injury.[168] Some courts even use a distinct serious questions test that allows for a less than likely success on the merits to be excused by a strong showing of the other three stay factors.[169] Pedro notes that the decision in Winter has forced some reconciliation of the standard for stays, but also notes that “some courts have not yet determined whether the sliding scale or serious-questions approaches, as applied in determining stays pending appeal, survive Winter.”[170]
IV. Remedying the Preliminary Injunction Standard
A. Is the Circuit Split a Problem?
Of course, the mere presence of a circuit split is not necessarily a problem. In fact, one could easily argue that a circuit split existed before Winter, as the circuits have each developed their own versions of the considerations for granting a preliminary injunction. Many of these have notable similarities, of course, but some of the differences have proven meaningful. For example, the Fourth Circuit’s lesser standard on the merits arguably did not require a heightened showing for the other factors, and this may explain why the fourth was the first circuit to apply a strict reading of Winter to the merits factor.[171]
So, is the growing circuit split a problem? I would argue that it is, for several main reasons. First, the stricter standard in the Fourth and Tenth Circuits can be expected to discourage litigants from seeking preliminary injunctions because of the increased burden. Or when they do seek injunctions, they will prevail less frequently. As a practical matter, this means that effective, meaningful relief will be precluded to some portion of litigants in those circuits. These impacts can be expected to be concentrated in areas where establishing likely success on the merits is difficult without first engaging in discovery,[172] or where review depends on an administrative record that may not be available or complete.[173]
Second, a higher standard for preliminary injunctions, specifically related to the merits factor, can be expected to introduce bias into the system due to the lock-in effect of courts denying an injunction based on failure to show likely success on the merits.[174] In such a case, where irreparable harm is demonstrated and then eventually occurs, the court will be biased towards denying relief to the plaintiff, even if subsequent developments in the case should lead the plaintiff to succeed.
Third, and finally, the Supreme Court’s attempts to impose rigidity on courts deciding whether to issue a preliminary injunction, or to make equitable remedies such as preliminary injunctions even more “extraordinary,” should be resisted by the lower courts and halted or abandoned by the Supreme Court. Although federal courts love to refer to preliminary injunctions as an “extraordinary remedy”[175] there are many circumstances where they are justified and necessary. Attempts to put a thumb on the scale thus harm plaintiffs and favor entrenched interests and those with political power. Additionally, as numerous scholars have noted,[176] the Court has been wrong to embark on its effort, intentional or not, to reduce the flexibility of lower courts by cabining their discretion using mandatory factor standards.
These reasons suggest that the circuit split should be resolved. The following section will explain in more detail reasons why the strict interpretation of Winter, requiring an early showing of likely success on the merits, should be rejected or limited whenever the chance arises.
B. Reasons Not to Extend a Strict Interpretation of Winter
There are many strong reasons why the strict interpretation of Winter should not extend to the merits factor, especially in public law cases. Winter should not be read to overturn decades of practice without clear intent. Such an approach would move the doctrine of preliminary injunctions significantly away from the flexible approach that has always been the hallmark of equity. Additionally, the information asymmetries are often particularly pronounced in public law cases, many of which are decided based on an administrative record that has not even been prepared at the time a decision on a preliminary injunction is reached. A rigid approach in this area will also lead to significant irreparable harm occurring over the objection of the plaintiff. As a result, judges will likely be subjected to cognitive bias when ultimately reaching a decision on the merits, inappropriately skewing the results against plaintiffs who unsuccessfully seek a preliminary injunction. A flexible approach to equity also comports with judicial humility, recognizing that the judges asked to assess the merits at the early stages of litigation would often get the question wrong, thereby depriving deserving plaintiffs of relief from illegal government action. Thus, although courts love to state that a preliminary injunction is an extraordinary remedy, that does not necessarily mean it should be a rare remedy in public law cases; otherwise, much illegal conduct would no longer be accountable to judicial review.
1. Winter Should Not Overturn Decades of Practice Without Thought/Sub Silentio.
If Winter really was intended to overturn decades of precedent and experience of the lower courts applying the flexible sliding scale approach to preliminary injunctions, including the evaluation of the merits, then it should have clearly done so. But at best, Winter simply includes a broad statement of four preliminary injunction factors, including likely success on the merits.[177] The decision does not cite any of the circuit court precedent applying the sliding scale or serious questions approaches to evaluating the likelihood of success on the merits.[178] This is perhaps unsurprising, given that the merits factor was not at issue in Winter, where the plaintiff had demonstrated likely success on its underlying claims.[179] Thus, lower courts should resist mechanical extrapolations of the broad language from Winter and push back on any claim that Winter sub silentio overturned their decades of practice and precedent with respect to early and incomplete evaluation of the merits in preliminary injunction cases.
The Supreme Court itself has cautioned against changes to equity tradition, stating that “a major departure from the long tradition of equity practice should not be lightly implied.”[180] Following this principle, it would not be proper for lower courts to read into Winter such a radical departure from decades of equity practice without some kind of clear statement from the Court that it intended to effect this radical change. This would also be consistent with Justice Ginsburg’s dissent in Winter, stating that the court did not reject the sliding scale formulation.[181] Notably, Chief Justice Roberts, in the opinion for the Court in Winter, did not object to this statement from Justice Ginsburg even though he did respond to other points made in the concurrence and dissent.[182] Thus, lower courts are wrong to read too much into statements from Winter taken out of context, especially when they would use those statements to overturn decades of settled equity tradition.
As the Second Circuit noted in Citigroup, if the Supreme Court wanted to “abrogate the more flexible standard[s], one would expect some reference to the considerable history of the flexible standards applied in various circuits and the Supreme Court.”[183]
In direct contravention of the preceding points, the Tenth Circuit decision in Diné CARE v. Jewell is a poor example of judicial reasoning and decision-making,[184] highlighting the pitfalls of taking a simplistic reading of broad language from Winter out of context, and refusing even to minimally engage with contrary precedent from other circuits and even prior decisions of the Tenth Circuit that applied the sliding scale test even in the aftermath of the Winter decision. When abandoning decades of precedent applying the flexible sliding scale standard, the court had an obligation to engage in thoughtful and reasoned decision-making. It failed badly in that regard. Even more perplexing, and frustrating, was the failure of the full court to hear the case en banc to address not only the circuit split but also the unexamined break from precedent, which effectively overruled prior cases without even citing, let alone discussing, why a change in course was necessary.[185]
One must concede, of course, that the Supreme Court has exhibited a clear hostility in recent years towards the flexible standards that once were the hallmark of equity, instead favoring the application of supposedly clear, but certainly more rigid, rules and factor-based tests.[186] Thus, it is not crazy to think that the Supreme Court, were it to consider whether the serious questions test should continue to be applied, might take the rigid and restrictive approach that the Fourth and Tenth Circuits have read into Winter. But if it wants to make such a dramatic change in the law, the Supreme Court should do so clearly and explicitly, after weighing the arguments on both sides and considering the impacts such a change would have on the lower courts.
2. Flexibility Rather Than Rigidity
Flexibility used to be the hallmark of equity: no longer. Each incremental step from the Supreme Court has had the effect, intentional or not, of restricting the flexibility of lower courts. Perhaps some of this can be explained by the adage, “bad facts make bad law.” Who is surprised that the Supreme Court, when faced with dire claims by the military opposed to protections for whales in the Winter case, decided that lower courts (especially those in the Ninth Circuit) cannot be trusted to exercise their discretion appropriately and must be reined in? The Court, of course, has never repudiated its often-repeated language that flexibility is the hallmark of equity. Instead, it chooses to focus on other language in tension with that, that equitable relief such as injunctions are “an extraordinary remedy” and therefore should be granted only in rare circumstances.[187] And to ensure that preliminary injunctions are granted less frequently, it has created ever more hurdles whenever faced with lower courts that granted injunctive relief when the Court would have disagreed.[188] At the same time, the Supreme Court itself is part of a worrying trend in federal courts where the courts will not explain themselves when deciding whether to grant equitable relief.[189] The Court grants stays of lower court orders with regularity, even though that form of equitable relief is also supposedly extraordinary.[190] This situation leaves lawyers and litigants to wonder what the test really is, other than a convenient means for appellate courts to second-guess the discretion of lower courts without applying the proper abuse of discretion standard.
3. Information Asymmetries/Administrative Record Issues
One of the biggest reasons why the merits prong should be treated differently from irreparable harm comes down to information asymmetries between the parties as well as other difficulties in accurately assessing the merits at the early stage of litigation. Irreparable harm is all about the harm to the party seeking an injunction. While there are often difficulties in establishing harm, especially when asked to predict events in the future, at least the difficulty is not due to a lack of access to information that would prove such harm. Instead, the party seeking an injunction usually has access to all the information it needs to demonstrate the likelihood of irreparable harm. Any failure to demonstrate irreparable harm would then be due to bad facts or failure to provide sufficient convincing evidence, perhaps expert testimony, that would demonstrate irreparable harm.
In stark contrast, assessment of the merits at the early stage of litigation will often run up against the barriers of information asymmetries. Specifically, while the plaintiff may have enough evidence to state a claim for relief, oftentimes the evidence needed to prove success on the merits is in the possession of the defendant. This is the entire purpose of discovery in our adversarial system. Thus, when a preliminary injunction is sought before discovery has been completed, or especially before any discovery is allowed, asking the court to assess the merits with any accuracy is problematic. A lower standard for the merits, such as serious questions, still allows courts to weed out cases that are particularly weak on the merits, while not presenting an insurmountable barrier.
Many cases where preliminary injunctions are sought against government defendants raise related but different concerns. One of the main ways to sue the federal government is through the Administrative Procedure Act, which is processed like an appeal based on an administrative record.[191] Although the administrative record was theoretically prepared at the time the agency made a decision subject to judicial review under the APA, in practice, it often takes many months for the government to produce the administrative record to the court. Although plaintiffs can sometimes identify documents that will be part of the administrative record and submit them to the court early, they do not always have access to the full record and may not know about a “smoking gun” e-mail or another document in the record that will significantly bolster their chances of success. Thus, just as in cases where an injunction is sought before discovery has concluded, it is unfair and unrealistic to require courts to assess the merits of a case where the full administrative record has not yet been produced to the court.
4. Practical Effects: Preserving the Status Quo During Judicial Review/Lock In
The principal reason for courts to issue a preliminary injunction is to preserve the status quo while the litigation plays out. Unique circumstances might justify deciding the case on an expedited timeframe so that any delay imposed by the injunction is of limited duration. However, justice is not served by courts abdicating their duty to resolve disputes or by rushing judgment in a manner likely to increase errors by the courts. A preliminary injunction that preserves the status quo thus allows for deliberate consideration of the issues, which can be properly presented after the adversarial system plays out to fairly resolve disputed facts.
In contrast, denial of preliminary injunctions in the face of substantial irreparable harm is likely to significantly skew or bias the outcome of litigation. First, if irreparable harms are allowed to occur, then plaintiffs’ claims might become moot, and no relief would ever be possible. Even if claims are not mooted, however, a judge who allows significant irreparable harm to occur is going to face cognitive pressure to later justify an initial finding that the plaintiff was not likely to succeed on the merits. Otherwise, the judge would be faced with the stress of cognitive dissonance where a plaintiff ultimately demonstrates she should prevail on the merits, but the court previously found otherwise and allowed significant illegal and irreparable harm to be inflicted upon her. Maintaining a flexible approach to lock-in, thus, is a much better approach in that it preserves the status quo and allows for careful and deliberate consideration of serious issues raised in litigation.
In addition to the lock-in effect for those cases where irreparable harm is easy to prove but success on the merits is not, it is worth paying attention to the probable effects that a more stringent preliminary injunction standard will have in the real world. For example, in the environmental context, fewer preliminary injunctions favor development at the expense of the environment because projects that would have been enjoined under the more lenient standard can now proceed—often more quickly than judicial review can occur.[192] In the business context, raising the standard for preliminary injunctions will provide incentives for defendants to drag litigation out, thus unfairly favoring businesses with greater resources to spend on litigation. In fields, such as employment law—particularly in employment discrimination—the plaintiffs are primarily employees, and thus this change will shift power to employers.[193] In more general suits against the government, which is rife with corruption and the influence of lobbyists, fewer injunctions means that changes sought by the powerful interests in society will be able to proceed without facing effective judicial review. While counterexamples can be imagined,[194] this change in procedural requirements will have a meaningful impact on substantive rights in this country, with power skewing ever further in favor of the rich and powerful.
5. Judicial Humility
This point may seem simple, but it is worth making. Judges are human beings. They make mistakes. They do not have perfect foresight. We should not expect these people, flawed like the rest of us, to accurately predict the merits of a case on a rushed timeline, at an early stage of litigation where the facts and legal issues have not been fully developed, and without the benefit of normal briefing in the case. Thus, taking a flexible approach in assessing the merits allows time for more deliberate investigation. Crafting a standard that assumes perfect prescience on the part of trial court judges is unrealistic at best, and perhaps lacks humility. Courts should thus return to the flexible approach of equity and acknowledge the limitations necessarily involved in early assessments of the merits.
For example, the Supreme Court issued a rushed decision in 2020 regarding the administration of Wisconsin’s election in light of the COVID pandemic.[195] The Wisconsin governor sought to delay the election in light of the stay-at-home order issued by the state due to the pandemic, which was then in its early and uncertain stages.[196] But the state legislature, controlled by the Republican party, refused to comply.[197] A district court judge in Wisconsin, and then the Seventh Circuit, had granted the request for a preliminary injunction to allow more time for absentee ballots to be properly counted due to administrative challenges resulting from a dramatically higher use of absentee ballots because of the dangers associated with in-person voting.[198] The Supreme Court, took it upon itself to wade into this partisan fight, ultimately siding with the Republicans on the eve of the election—ironically, leaning on the principle that federal courts should not make last-minute changes in state elections.[199] Rather than deferring to the lower courts, which had considered the issue in more detail and under less time-pressure, the Court decided to step in and substitute its judgment for that of the lower courts.[200] Unsurprisingly, the Court messed up a key fact in this case when it described the relief requested by the plaintiffs compared to the relief granted by the district court.[201] As a result, unknown numbers of absentee ballots were not counted in the election.[202] It should be too obvious to state, but courts should not rush to issue decisions, but rather, should take actions to preserve the status quo and take the necessary time to properly weigh the merits of claims presented to them.
6. Should Preliminary Injunctions Really Be Extraordinary?
In some fields, preliminary injunctions are commonly necessary to preserve the status quo. Environmental law is one of those areas. Although preliminary actions may not be the norm in all fields, in some fields they should be more common. This is not to suggest that preliminary injunctions should be granted willy-nilly, but instead, that courts should not continually harp on the supposed extraordinary nature of preliminary injunctions. Although they may not formally mean that extraordinary means rare, if they think about it, the unexamined repetition of the word extraordinary has a risk of giving the impression that it is a remedy that should rarely be granted.
Many injunction cases will distinguish between mandatory and prohibitory injunctions. A mandatory injunction requires the non-moving party to affirmatively do something and are often said to be disfavored. On the other hand, a prohibitory injunction simply enjoins a party from carrying out a project, enforcing a law, or otherwise taking some action that the other party is hoping to forestall to preserve the status quo. Prohibitory injunctions—though they should not always be granted—pose less of a concern and should be less extraordinary than mandatory injunctions.
Professor Bray has noted that although preliminary injunctions are exceptional, that does not mean they are rare or unusual, and the courts have not said that they are.[203] Instead, when noting that preliminary injunctions and other equitable relief are extraordinary, the court means that they are a departure from a norm of granting legal relief after resolving the merits of a case. And thus, the departure from a norm “demands [a] justification.”[204]
C. Paths Forward
Assuming that the relevant constituencies are convinced now that the flexible approach to preliminary injunctions is preferable, how can that best be accomplished? The three clearest ways to resolve the issue include a clear, on-point decision from the Supreme Court; the circuits resolving the split themselves; or amendments to the rules of procedure in the district and circuit courts, specifically Federal Rule of Civil Procedure 65 and Federal Rule of Appellate Procedure 8.
The Supreme Court is the obvious entity that can resolve the circuit split. Indeed, Supreme Court practice often involves letting issues percolate in the lower courts until there is a circuit split, and then stepping in to resolve the issue. Thus far, the Supreme Court has not taken up a case that clearly presents the issue of whether the serious questions test survived Winter. However, the development of the circuit split has made it increasingly likely that the Supreme Court will take up the issue in a future case.[205] This approach is also the riskiest approach, however, at least from the perspective that a flexible approach to preliminary injunctions is important. The majority in Winter, of course, displayed great distrust in the ability of lower courts to weigh the equities in any given case to reach the appropriate outcome, and thus imposed a bright-line rule for irreparable harm. Unless the case is presented carefully to the Court, it can be expected to continue imposing rigid factor-based tests in this area of the law.[206]
Another approach to resolving the circuit split is less obvious, but the circuits could resolve the split themselves if they so choose by moving past the doctrine of the “law of the circuit” to allow later panels, or even the full circuits en banc, to reevaluate their decisions considering the conflict with other circuits. This is the approach detailed by Professor Wyatt Sassman in his recent article.[207] The general idea is that “courts of appeals should relax the law of the circuit doctrine when a prior panel opinion has subsequently resulted in a conflict with another circuit.”[208] This approach would work particularly well for the Fourth Circuit, where the initial strict reading of Winter made in Real Truth About Obama occurred before other circuits had made their conflicting interpretations of Winter. The Fourth Circuit should also consider whether, even if its more lenient standard was precluded by Winter, it should instead adopt the sliding scale or serious questions tests used by other circuits, which place the same overall burden on the party seeking a preliminary injunction. This approach would not be as simple to apply to the Tenth Circuit, where the panel in Diné CARE made its decision after those of other circuits, but simply failed to consider those conflicting decisions.[209] However, the Tenth Circuit could still take an appropriate opportunity to correct these deficiencies in a future case by aligning itself with its sister circuits that have retained a flexible approach to assessing the merits in preliminary injunction cases.
Finally, the circuit split could also be resolved through amendments to the federal rules of procedure, particularly Federal Rule of Civil Procedure 65[210] and Federal Rule of Appellate Procedure 8.[211] Specifically, Federal Rule of Civil Procedure 65(a) could be amended to explicitly allow an injunction to be issued based on serious questions going to the merits, or on a sliding scale approach. Federal Rule of Appellate Procedure 8 could similarly be amended to allow injunctions pending appeal upon a showing of serious questions or a sliding scale approach to the merits, at least where the lower court denied a preliminary injunction before discovery was complete or before the full administrative record was presented to the court.
V. Responding to Anticipated Objections
A. Winter Is Clear
This is the argument accepted by the Fourth Circuit and Tenth Circuit. While this argument may seem terrible on its face, it has somehow prevailed in those two circuits. Thus, it is worth addressing this argument fully head-on. Several courts have already done so, and their reasoning is persuasive.
First, the statements relied upon were not necessary to the decision in the case, and therefore may appropriately be described as dicta. While sometimes we make too much of the nebulous dicta/holding distinction, in this case it helps to avoid cherry-picking a statement out of context in a way that upends decades of circuit precedent. It is important to keep in mind that the Supreme Court in Winter did not claim to modify the test for likelihood of success on the merits at all.
Second, as Justice Ginsburg pointed out in her dissent, and the opinion for the Court did not contest, the Court did not intend to upend decades of doctrine regarding the sliding scale tests in the lower courts. Instead, the case was focused on what it found to be an improper “possibility of irreparable harm” test.
Finally, good reasons exist to treat the merits factor and harm factors differently. Irreparable harm is something that the plaintiff knows a lot about. The harm must be to the plaintiff itself, and it is likely what motivated the plaintiff to sue in the first place. Thus, setting a higher bar for irreparable harm can be justified more than a higher bar for the merits. Relatedly, the harm must be shown to be irreparable in the sense that damages at law would be inadequate to remedy the harm, as it is explicitly part of the standard for a permanent injunction. The merits, in contrast, are often covered in a fog of litigation at the outset of a case. There is great uncertainty in how the case will play out (otherwise the parties would have strong incentives to settle). Important facts may not be fully developed yet, and thorny legal issues will not have had time for full briefing and deliberate consideration by the court. Thus, a more flexible standard on the merits will allow closer cases to proceed, where the absence of a preliminary injunction might make the claims moot. This is why courts have stated that “[l]imiting the preliminary injunction to cases that do not present significant difficulties would deprive the remedy of much of its utility.”[212]
B. Injunctions Are Too Commonly Issued
The push to tighten preliminary injunction standards often reflects the view that such injunctions are issued too frequently, and inappropriately. The Supreme Court has apparently tasted the porridge left by the lower courts and found it to be “too hot.” But whether courts are currently finding the Goldilocks zone of preliminary injunctions is entirely in the eye of the beholder, and it is difficult to conceive of any objective standard for making this judgment. Yet the Supreme Court has arguably decided to tighten the standard for assessing the merits related to preliminary injunctions—apparently without any realization of what it was doing.
However, if it is correct that the burden on movants is the same under serious questions as it is under likely to succeed on the merits, then one can question whether differential outcomes should turn solely on a judge’s preliminary assessment of the merits. If the burden is set at the appropriate threshold, then the number of preliminary injunctions issued should be “just right.” However, by taking away the flexibility to weigh all the competing considerations, a strict reading of the Winter factors means that courts are “too cold” in issuing injunctions.
One argument noted by many circuit courts that have rejected a literal reading of Winter is that the serious questions or other flexible standards for assessing the merits are not a relaxation of the traditional test at all. With this view, shared by this Author, any decreased burden on likelihood of success on the merits is offset by an increase in the other factors, especially the requirement that the balance of equities tips strongly in favor of an injunction. Under the traditional test, the balance of equities need only favor an injunction, instead of strongly favoring one. This is why, for example, the Second Circuit describes its approach to preliminary injunctions not as two separate tests with one lower than the other, but instead as variations on the same test that elaborate how the factors are to be weighed collectively.[213] Thus, those who argue that the serious questions test is a lower bar and therefore impermissible have simply misunderstood the serious questions formulation.
C. Plaintiffs Should Be Able to Prove They Will Succeed
Another potential argument against a lower threshold on the merits is that the party seeking an injunction should be able to prove it will prevail in the litigation. In an ideal world, where all parties have perfect knowledge of the facts, this argument would be very convincing. However, that is not the world we live in. As discussed previously, the litigation process, and discovery in particular, is designed to address, among other things, the information asymmetries that are known to exist. There is no reason, and courts have not identified any, why parties who lack information are less deserving of having their legal interests protected by the courts. Or why defendants with great informational advantages (like the government or large corporations) should be shielded from liability more than other defendants who lack those advantages. This is why equity developed such a flexible framework over time—to deal with the unique issues raised by each case.[214] When judges are not trusted to use their discretion but are instead hamstrung to reduce preliminary injunctions, fairness and equity in our judicial system suffer.
This is not to say that preliminary injunctions should be issued as a matter of course. The requirement for irreparable harm still imposes a significant limit on the availability of a preliminary injunction as a remedy. And requiring serious questions as to the merits weeds out cases that have no merit, and then some. Judges still retain the flexibility to craft an appropriate remedy. Thus, if there is significant irreparable harm to the defendant caused by an injunction, the injunction may be time limited. This could allow for narrow, targeted discovery to occur, which may shed light on whether the injunction should be continued or perhaps even lead to a settlement or faster judicial resolution of the case.
D. Delays Harm Defendants and the Public
Delays in resolving litigation cause obvious harm to plaintiffs, of course. Justice delayed is justice denied, as the saying goes. However, when preliminary injunctions are removed as a practical, available remedy, then defendants have every incentive to delay litigation and carry on with the plans which the plaintiff hopes to enjoin. If they wait long enough, the product might be sold, the forest cut down, or the pipeline built. Irreparable harm, by its very definition, cannot simply be undone or compensated for with monetary damages.
But is adding even more incentives for the delay in our litigation system good for the system as a whole? Delay also harms defendants who face longer uncertainty over the legality of their actions and perhaps damages they owe (in many cases, there is reparable harm along with irreparable). By engaging in delay tactics, defendants also increase their own legal expenses. Delay harms the public as well by prolonging uncertainty, dragging out bitter fights among competing interest groups, and imposing greater transaction costs on society. The delay also harms courts, whose dockets remain more crowded than before, and that often must referee the attempts at delay. Thus, by making preliminary injunctions even more extraordinary than they were before, courts risk imposing greater costs on society.
E. “Serious Questions” and Other Limiting Principles
This proposal does not mean that preliminary injunctions will be issued as a matter of course in nearly every case. Several key limiting principles will give courts all the tools they need to equitably consider the totality of circumstances when considering preliminary injunctions. Mainly, of course, serious questions about the merits will weed out cases with a low likelihood of success, or none at all.[215] But in addition, the remaining equitable factors and the requirement from Winter that irreparable harm be shown to be probable will ensure that preliminary injunctions do not become a commonplace means of bogging down the machinery of government and other important actions that are challenged in public law cases.
Regarding serious questions, this test is still a bar that must be passed. The idea here is that courts can recognize when there are really important issues deserving of litigation, even though they cannot say with any certainty whether the plaintiff will prevail or not. Thus, open questions that have not been decided but could plausibly prevail should meet this test. Arguments for a change in the law likely would not. Cases where only a minor distinguishing fact would not be enough to escape negative precedent would not pass this bar. But close cases—where the law is being extended into new territory or where the existing law is not determinative of outcomes—would be the types of cases that would raise serious questions, even if they are not probable to succeed.
Bright Boy
Re: CaptainObvious post# 706320
Tuesday, July 16, 2024 10:28:03 AM
Post#
706371
of 706380
Not sure, but I'll check with my securities lawyer this afternoon.
Cheers,
BBCaptainObvious
Re: Bright Boy post# 706302
Tuesday, July 16, 2024 12:41:29 AM
Post#
706320
of 706379
Errors and Omissions are covered by insurance, but is purposeful criminal behaviour?Bright Boy
Re: XMaster2023 post# 706306
Tuesday, 07/16/2024 12:19:03 AM
Settle the case and risk a waterfall of copycat lawsuits or buy the company and dismiss the lawsuit!! OR settle the case before the ruling on the MTD and no one will ever know if the judge thinks there is a case either way!!!
Cheers,
BB
Bright Boy
Re: Red_Right_Hand post# 706230
Monday, July 15, 2024 9:33:14 PM
Insurance companies won't allow discovery. Potentially catastrophic claims/settlements.
Cheers,
BB
Red_Right_Hand
Re: manibiotech post# 706225
Monday, July 15, 2024 3:22:58 PM
Post#
706230
of 706307
MTD denied will have an impact. MTD denied means discovery (->trial) or settlement.
Red_Right_Hand
Re: manibiotech post# 706264
Monday, July 15, 2024 6:27:51 PM
Post#
706270
of 706308
It may take months and months to reach a settlement or the conclusion of the trial, but the knowledge that they're heading to trial but for a settlement will be known on the day the MTD is denied.
There is due diligence and then there is
@d_stock07734
who takes due diligence to another level, and then some!
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@peter_brit
Amgen, BMS and Merck have the most exposure as Big Pharma eyes $183B patent cliff: analyst
Jul 15, 2024
It’s no surprise that Merck is on the list, with 56% of its revenue exposed to patent expirations. Most of that comes from mega-blockbuster cancer drug Keytruda, which generated $25 billion in sales last year, accounting for 42% of the company’s total haul. Keytruda is set to lose its exclusivity in 2029.
"Merck continues to have the combination of need to offset the Keytruda LOE and meaningful balance sheet capacity," the Morgan Stanley analysts wrote. "AbbVie, BMS and Pfizer have all recently transacted, so we see these companies as more likely to be acquirers over the medium term."
While patent cliffs are looming for many of biopharma’s top-selling products, the industry has enormous capacity to respond as “conditions for M&A are favorable,” according to a research note from Morgan Stanley.
In the July 11 report, the analysts calculate that products losing exclusivity through 2030 are generating a combined $183.5 billion in annual sales, with Amgen, Bristol Myers Squibb and Merck facing the most exposure of their revenue.
Meanwhile—citing company financial reports and data from Visible Alpha and FactSet—Morgan Stanley estimates that Big Pharma has $383.1 billion of firepower available for dealmaking. The companies sitting on the most dry powder are Johnson & Johnson, Merck and Novo Nordisk, the analysts said.
"We continue to see the conditions as generally favorable for bolt-on M&A as large-cap pharma companies have balance sheet capacity and a need to acquire outer-year revenue," the Morgan Stanley team, led by Terence Flynn, Ph.D., wrote.
Per Morgan Stanley’s metrics, J&J is in excellent shape as just 33% of its revenue is exposed to patent expirations through 2030, compared to an industry average of 38%. Other biopharma companies in good positions regarding their patent cliffs are Vertex (6%), Gilead (24%), AbbVie (29%), Eli Lilly (31%) and Pfizer (33%).
At the other end of the list, Amgen has the most revenue at risk at 67%, with its top four products on the clock. Bone cancer drugs Prolia and Xgeva, which combined for sales of $6.1 billion last year, are due for patent expirations over the next two years. Enbrel ($3.7 billion) and Otezla ($2.2 billion) also are set to lose exclusivity by the end of the decade.
Amgen, of course, has already taken a major step in addressing the patent cliff with its $27.8 billion acquisition of Horizon, which was completed in October and brought potential blockbusters in Tepezza for thyroid eye disease, Krystexxa for gout and Uplizna for a rare neurologic disorder.
Next on the patent cliff exposure list is BMS, with 63% of its revenue at risk. Blood thinner Eliquis, which generated $12.2 billion last year, and cancer drug Opdivo ($9 billion) are on the clock in the next few years while another cancer treatment, Revlimid ($6.1 billion), has already lost its U.S. exclusivity.
BMS also has addressed its cliff, acquiring Karuna, Mirati and RayzeBio in a three-month splurge at the end of 2023. Last month, BMS CEO Chris Boerner said that the company’s still scouting out deals.
"Despite these transactions, there remains significant LOE exposures for many of these companies," the analysts wrote. "Further, uncertainty related to the FTC's approach to pharma transactions, which we believe may have impacted deal appetites in the 2022-2023 period, seems to have largely subsided at this point following the closure of larger transactions in recent months."
It’s no surprise that Merck is on the list, with 56% of its revenue exposed to patent expirations. Most of that comes from mega-blockbuster cancer drug Keytruda, which generated $25 billion in sales last year, accounting for 42% of the company’s total haul. Keytruda is set to lose its exclusivity in 2029.
"Merck continues to have the combination of need to offset the Keytruda LOE and meaningful balance sheet capacity," the Morgan Stanley analysts wrote. "AbbVie, BMS and Pfizer have all recently transacted, so we see these companies as more likely to be acquirers over the medium term."
https://x.com/d_stock07734/status/1813036011435229425
https://fiercepharma.com/pharma/firepower-aplenty-and-patent-cliffs-ahead-time-right-ma-activity-report
#dcvax $nwbo #gbm
Hot off the press: our pick of real-world evidence articles published in June 2024
8 JUL 2024
Why is target trial emulation not being used in health technology assessment real-world data submissions?
Authors: Alejandra Castanon, Stephen Duffield, Sreeram Ramagopalan & Robert Reynolds
Publication: Journal of Comparative Effectiveness Research
DOI: https://doi.org/10.57264/cer-2024-0091
Building on their session from ISPOR 2024, the authors delve into the application of target trial emulation (TTE) in RWD submissions for HTA. Despite increasing endorsements from HTA agencies, they explore why widespread adoption of TTE by the industry remains limited.
Key takeaway:
“Ultimately, the key to successful RWE submissions lies in transparently documenting the rationale for decisions made in data source selection and analysis, which TTE supports. Broadly, there appears to be a need in the health economics and outcomes research community to develop expertise in this area, something which stakeholders should collaboratively seek to address.”
Assessing real-world data from electronic health records for health technology assessment: The SUITABILITY Checklist: A Good Practices Report of an ISPOR Task Force
Authors: Rachael L Fleurence, Seamus Kent, Blythe Adamson, James Tcheng, Ran Balicer, Joseph S. Ross, Kevin Haynes, Patrick Muller, Jon Campbell, Elsa Bouée-Benhamiche, Sebastián García Martí & Scott Ramsey
Publication: Value in Health
DOI: https://doi.org/10.1016/j.jval.2024.01.019
While electronic health record (EHR) data can address evidence gaps and enhance decision-making, they come with significant limitations that can impact their validity and relevance. This ISPOR Good Practices report presents a framework for evaluating the suitability of EHR data in HTA and introduces the ISPOR SUITABILITY Checklist. The report outlines the challenges in extracting and transforming both structured and unstructured information into a reliable format for analysis.
Key takeaway:
“EHR-derived data use in RWE evaluations are relatively modest today but are expected to expand greatly over the next few years. To ensure that the use of the EHR realizes its full potential for HTAs, the task force provides recommendations for HTA agencies and policy makers for establishing procedures and processes to improve the use of EHR-derived data over time.”
The potential role of real-world evidence in Centers for Medicare & Medicaid Services’ future price negotiations: Recommendations for a robust framework
Authors: Ashley Jaksa & Patrick J Arena
Publication: Journal of Managed Care & Specialty Pharmacy
DOI: https://doi.org/10.18553/jmcp.2024.30.6.604
This Letter explores the role of RWE in Centers for Medicare & Medicaid Service (CMS)’s drug price negotiations. The authors recommend that CMS commit to using high-quality RWE, develop clear evaluation processes, and invest in robust data infrastructure to ensure evidence-based pricing decisions.
Key takeaway:
“The use of RWE to inform CMS’ decision-making will be particularly significant, given that negotiations apply only to drugs that have been approved by the US FDA and marketed for at least 7 years before the start of price negotiations, a condition that allows RWD adequate time to accumulate. RWE is also critical for the types of evidence CMS must evaluate under the statute (e.g., unmet need, effectiveness compared with therapeutic alternatives, and effectiveness of drugs in special patient populations.) Consequently, a growing list of US policy experts have called for the use of RWE in price setting (e.g., Duke Margolis Institute for Health Policy). Given the potentially significant role RWE may play in CMS negotiations, as well as the novelty of the program in the US, it is important to explore what CMS can learn from the successes and struggles of HTA agencies’ use of RWE.”
Price benchmarks of drugs selected for Medicare price negotiation and their therapeutic alternatives
Authors: Inmaculada Hernandez, Emma M Cousin, Olivier J Wouters, Nico Gabriel, Teresa Cameron & Sean D Sullivan
Publication: Journal of Managed Care & Specialty Pharmacy
DOI: https://doi.org/10.18553/jmcp.2024.24153
This paper outlines the key prices CMS will use to negotiate the first 10 selected drugs, including current post-discount prices paid by health plans. The findings indicate significant variation in Medicare’s potential savings across different drug products.
Key takeaway:
“Our analyses inform managed care professionals on the key elements that will be involved in the derivation of the initial price offer for each product selected for the Medicare Drug Price Negotiation Program. Our results suggest that the ability to achieve savings varies greatly across drugs based on existing rebates and the statutorily defined ceiling price. Our analyses help improve transparency in the Medicare negotiation process.”
A targeted review of worldwide indirect treatment comparison (ITC) guidelines and best practices
Authors: Shiro Tanaka, Ataru Igarashi, Raf De Moor, Nan Li, Mariko Hirozane, Li Wen Hong, David Bin-Chia Wu, Dae Young Yu, Mahmoud Hashim, Brian Hutton, EVERSANA Group, Krista Tantakoun Imtiaz A. Samjoo & Chris Cameron
Publication: Value in Health
DOI: https://doi.org/10.1016/j.jval.2024.05.015
Direct comparisons of medical treatments through randomized trials often present significant challenges. To address these difficulties, indirect treatment comparisons (ITCs), such as network meta-analyses and matching adjusted indirect comparisons, offer valuable insights into the clinical effectiveness and safety of healthcare interventions to assist regulatory and reimbursement agencies in decision-making. This review identifies and compares the landscape of ITC guidance and highlights the global acceptance of various ITC techniques as a source of comparative evidence.
Key takeaway:
“The findings from this review suggest that ITCs are accepted and recognized by authorities across Europe, North America, and Asia-Pacific, and aligned with observations that ITC methods are increasingly used. Most guidelines explicitly mention that ITCs are particularly valuable when direct evidence is not available to provide key evidence regarding the relative benefits and harms of competing therapies. However, to reliably inform healthcare decision-making, an ITC must consider the relevant comparators in each market and be tailored to the specific requirements and preferences of the given region and the respective expert body.”
ROBVALU: a tool for assessing risk of bias in studies about people’s values, utilities, or importance of health outcomes
Authors: Samer G Karam, Yuan Zhang, Hector Pardo-Hernandez, Uwe Siebert, Laura Koopman, Jane Noyes, Jean-Eric Tarride, Adrienne L Stevens, Vivian Welch, Zuleika Saz-Parkinson, Brendalynn Ens, Tahira Devji, Feng Xie, Glen Hazlewood, Lawrence Mbuagbaw, Pablo Alonso-Coello, Jan L Brozek & Holger J Schünemann
Publication: BMJ
DOI: https://doi.org/10.1136/bmj-2024-079890
ROBVALU is a tool designed to assess bias in quantitative studies measuring values, utilities, or outcome importance, crucial for determining the certainty of evidence in systematic reviews and guideline development. Developed using a sequential mixed methods approach involving GRADE-based signaling questions and a modified Delphi method for refinement, the tool has demonstrated strong validity and reliability in assessing bias across four key subdomains.
Key takeaway:
“ROBVALU can be used to assess risk of bias in studies included in systematic reviews and health guidelines. It also can support health research assessments, where the risk of bias of input variables determines the certainty in model outputs. These assessments include, for example, decision analysis and cost utility or cost effectiveness analysis for health technology assessment, health policy, and reimbursement decision making.”
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We have now published an illustrative case on dendritic cell vaccine:
"Tumor regression following autologous tumor lysate-loaded dendritic cell vaccination immunotherapy" published on @TheJNS Case Lessons.
Read more: https://doi.org/10.3171/CASE24112
👏👏@naomi_sibtain , Prof Ashkan
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Amgen, BMS and Merck have the most exposure as Big Pharma eyes $183B patent cliff: analyst
Jul 15, 2024
It’s no surprise that Merck is on the list, with 56% of its revenue exposed to patent expirations. Most of that comes from mega-blockbuster cancer drug Keytruda, which generated $25 billion in sales last year, accounting for 42% of the company’s total haul. Keytruda is set to lose its exclusivity in 2029.
"Merck continues to have the combination of need to offset the Keytruda LOE and meaningful balance sheet capacity," the Morgan Stanley analysts wrote. "AbbVie, BMS and Pfizer have all recently transacted, so we see these companies as more likely to be acquirers over the medium term."
While patent cliffs are looming for many of biopharma’s top-selling products, the industry has enormous capacity to respond as “conditions for M&A are favorable,” according to a research note from Morgan Stanley.
In the July 11 report, the analysts calculate that products losing exclusivity through 2030 are generating a combined $183.5 billion in annual sales, with Amgen, Bristol Myers Squibb and Merck facing the most exposure of their revenue.
Meanwhile—citing company financial reports and data from Visible Alpha and FactSet—Morgan Stanley estimates that Big Pharma has $383.1 billion of firepower available for dealmaking. The companies sitting on the most dry powder are Johnson & Johnson, Merck and Novo Nordisk, the analysts said.
"We continue to see the conditions as generally favorable for bolt-on M&A as large-cap pharma companies have balance sheet capacity and a need to acquire outer-year revenue," the Morgan Stanley team, led by Terence Flynn, Ph.D., wrote.
Per Morgan Stanley’s metrics, J&J is in excellent shape as just 33% of its revenue is exposed to patent expirations through 2030, compared to an industry average of 38%. Other biopharma companies in good positions regarding their patent cliffs are Vertex (6%), Gilead (24%), AbbVie (29%), Eli Lilly (31%) and Pfizer (33%).
At the other end of the list, Amgen has the most revenue at risk at 67%, with its top four products on the clock. Bone cancer drugs Prolia and Xgeva, which combined for sales of $6.1 billion last year, are due for patent expirations over the next two years. Enbrel ($3.7 billion) and Otezla ($2.2 billion) also are set to lose exclusivity by the end of the decade.
Amgen, of course, has already taken a major step in addressing the patent cliff with its $27.8 billion acquisition of Horizon, which was completed in October and brought potential blockbusters in Tepezza for thyroid eye disease, Krystexxa for gout and Uplizna for a rare neurologic disorder.
Next on the patent cliff exposure list is BMS, with 63% of its revenue at risk. Blood thinner Eliquis, which generated $12.2 billion last year, and cancer drug Opdivo ($9 billion) are on the clock in the next few years while another cancer treatment, Revlimid ($6.1 billion), has already lost its U.S. exclusivity.
BMS also has addressed its cliff, acquiring Karuna, Mirati and RayzeBio in a three-month splurge at the end of 2023. Last month, BMS CEO Chris Boerner said that the company’s still scouting out deals.
"Despite these transactions, there remains significant LOE exposures for many of these companies," the analysts wrote. "Further, uncertainty related to the FTC's approach to pharma transactions, which we believe may have impacted deal appetites in the 2022-2023 period, seems to have largely subsided at this point following the closure of larger transactions in recent months."
It’s no surprise that Merck is on the list, with 56% of its revenue exposed to patent expirations. Most of that comes from mega-blockbuster cancer drug Keytruda, which generated $25 billion in sales last year, accounting for 42% of the company’s total haul. Keytruda is set to lose its exclusivity in 2029.
"Merck continues to have the combination of need to offset the Keytruda LOE and meaningful balance sheet capacity," the Morgan Stanley analysts wrote. "AbbVie, BMS and Pfizer have all recently transacted, so we see these companies as more likely to be acquirers over the medium term."
https://x.com/d_stock07734/status/1813036011435229425
https://fiercepharma.com/pharma/firepower-aplenty-and-patent-cliffs-ahead-time-right-ma-activity-report
$NWBO investor, the following items to help you understand
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174742998
2. Journal AmerMedAssoc article showing efficacy pub on 11/2022: https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847?resultClick=1
3. Nature elucidating the method of DCVax action: https://nature.com/articles/s41420-023-01782-7
https://nwbio.com
learningcurve2020
Re: None
Monday, July 15, 2024 6:24:07 PM
Post#
706269
of 706361
Fantastic read. This is the kind of article that somehow forever eluded DCVAX.
>>The patent for June’s CAR-T therapy for leukemia is owned by Novartis, and the median cost for the treatment is $620,000. Even if drug companies don’t try to profit from these therapies, the process is inherently labor-intensive: T cells have to be removed from the patient’s own blood, genetically altered, then reinfused. It’s difficult to determine where economies of scale might kick in.
>>McNally has gone through an exhaustive list of treatments trying to improve on the standard of care, including a personalized cancer vaccine. “If someone told me scorpion poison would kill it, I’d probably take it,” he said. “I’m a giant mouse; let’s go. Let’s do it.” He won’t be able, however, to enroll in Maus’s trial. Because they want to ensure that any positive outcome can be attributed to the CAR-T regime alone, the exclusion criteria rule out anyone who has been treated with “any prior gene-therapy or gene-modified cellular therapy.”
>>Researchers are looking at ways to use a virus to genetically modify T cells inside a patient’s body, effectively eliminating half of the steps Maus walked me through in her lab. Others are experimenting with vaccines that can teach the immune system to target the same kind of antigens that the CAR-T cells bind to.
>>Maus and Choi have already refined the protocol for their glioblastoma trial. Patients will now have a short run of chemotherapy before the infusion to limit the number of CAR-T cells killed or inactivated by the innate immune system, allowing more of them to remain active at the tumor site for longer.
>>Tom suffered a cascade of complications: atrial fibrillation, mysterious infections, a punishing fever. The nurses swaddled him in blanket after blanket, but still he shook uncontrollably. Debbie kept watch 12 hours a day. Choi tried to reassure them that the effects were a sign that the treatment was working.
https://nymag.com/intelligencer/article/cancer-treatment-immunotherapy-oncology-tcells-brain-tumor.html
https://www.amgen.com/stories/2024/03/very-exciting-future-for-cancer-research-bradway-says-at-business-of-biotech-conference
HEALTH JULY 15, 2024
Immunotherapy Is Changing Cancer Treatment Forever His brain tumor was a hopeless case. Then an experimental medicine made it melt away.
By Christopher Cox, a features editor at New York Magazine
Tom Fraser in June. Photo: Bobby Doherty
This article was featured in One Great Story, New York’s reading recommendation newsletter. Sign up here to get it nightly.
One morning at the end of April 2023, Marcela Maus, a cancer researcher at Mass General in Boston, got a call from her colleague Bryan Choi. “He called me, and he’s like, ‘Oh my God, oh my God, oh my God!’ And I’m like, ‘What is going on?’” Maus said. Choi, a neurosurgeon with the languid demeanor of a surfer, was not given to outbursts. Maus hung up the phone and hurried over to his office.
The day before, Choi and Maus had treated their first patient in a clinical trial for an aggressive brain cancer called glioblastoma, infusing genetically modified white blood cells directly into the fluid surrounding the brain. They had been up all night worrying, especially after the patient, a 74-year-old man, developed a fever. Choi had ordered an MRI. “We were not looking for the results,” he said. “We were trying to make sure that our patient was okay.”
When Maus got to Choi’s office, images from the MRI were loading on his screen. They stared in wonder: The patient’s tumor, which a few days before had shown up on the scan as a bright blob the size of a strawberry, had almost entirely disappeared. No one had heard of that kind of regression in glioblastoma, especially not overnight. “My first instinct was that there was something wrong with the MRI scanner,” Choi said. But then the follow-up scans looked even better.
Several weeks later, they treated a second patient, a civil engineer from upstate New York named Tom Fraser, and the process repeated itself: the infusion, the fever, and the rapid regression of the tumor. “It was almost like clockwork,” Maus said, still sounding astonished months later. After a third patient had a similar response, she paused the trial and wrote up her results.
Glioblastoma is the most common type of malignant brain cancer. It can strike at any age, and it’s uniformly fatal. Patients are often diagnosed in the emergency room after the tumor causes some somatic catastrophe, such as seizure, sudden loss of speech, or an inability to control the limbs on one side of the body. The median time from diagnosis to death is just over a year.
The first step in treating the disease hasn’t changed in decades: “maximal safe resection,” a surgery to remove as much of the tumor as possible while preserving neurological function. Because glioblastoma is so adept at infiltrating the brain, the surgeon almost always leaves cancer behind, which quickly starts growing again. Some patients respond to radiation or the chemotherapy drug temozolomide, but even that adds months rather than years to the average survival time. Roger Stupp, an expert in glioblastoma (he wrote the paper that made temozolomide “standard of care”), told me the disease had proved to be “a graveyard of ideas.” Decades of research have gone nowhere.
Within the past 20 years, however, a once unfashionable field called immunotherapy has upended all expectations in oncology. It proceeds from a simple premise: The human immune system is very good at attacking anything it registers as disease. If it could be turned against cancer, it could eliminate a tumor more thoroughly than a surgeon’s knife and more durably than the poison of chemotherapy.
Maus and Choi thought they’d found a way to do just that using the immune system’s all-purpose killer: the T cell, which the body sends to neutralize pathogens of all sorts, including bacteria, viruses, and parasites, but not (usually) cancer. By extracting T?cells from a patient’s blood, editing the cells’ DNA in a lab, and reintroducing them at the site of the tumor, they had gotten the body to react to cancer as it would to a virus and destroy it. It was the culmination of years of research in immunotherapy labs like the one Maus runs at Mass General.
Fraser remembers that on the day of his infusion, the room was crowded with doctors, nurses, and scientists. There was a sense, he said, that history was being made. “I felt a little poke when the needle was inserted,” he wrote me in an email, “but it was a very quick process.” Twenty-four days later, he walked out of the hospital, weak and exhausted but with his tumor in near-total remission.
“There’s been a revolution in understanding cancer and the tools to tackle it,” Daniel Haber, the director of the Mass General Cancer Center, told me. Immunotherapy, paired with our greater understanding of the genetics of cancer cells, has produced breakthroughs for previously untreatable forms of the disease, especially in liquid tumors like leukemia and lymphoma and skin cancers like melanoma. Death sentences have been commuted; hopeless cases have been cured.
Until recently, the biggest exception to this parade of good news has been in solid tumors like pancreatic cancer and glioblastoma, which have resisted almost all efforts to check them. So Fraser had it right. If these early results from Boston held, it would make history. If we can treat glioblastoma — perhaps the hardest case in a field made up of hard cases — there’s not a cancer that would seem to be out of reach.
After Choi and Maus published their results in the New England Journal of Medicine in March, they heard from oncologists all over the world. “They’re desperate, and they say, ‘We want to offer something because there’s just nothing out there,’” Choi told me. The status quo, Choi knew from his own patients, was miserable.
This spring, I got to witness the kind of brain surgery that’s standard of care for glioblastoma but may one day become obsolete. It was both simple and high-tech. Five figures in blue scrubs stood around the patient, and there were screens on every wall stacked like amps at a death-metal show. I was led around the operating table, ducking between machines until I arrived at the patient’s head, where the surgeon showed me how he could insert a stereotactic probe and see on the monitor exactly where in the brain he was working.
A square of scalp on the patient’s head was peeled back to reveal the skull underneath. A smaller area of skull, about the size of an eye patch, had been removed, and the brain itself sat exposed, pulsing with each heartbeat, as if it were breathing. And it was: The engine of cognition, the seat of human consciousness, the anthropocentric core of the universe lay before us, and it was alive, fragile and yet somehow bursting with vitality, like it wanted nothing more than to leap free of the vessel that contained it.
On a screen on the far wall, I could see a hole where the tumor had been, an almost perfectly round miniature planet. I switched my gaze to look at the brain directly. The hole was darker than I would have imagined. I tried to stare all the way into its bottom but could see only black.
Patients with glioblastoma are often sent to surgery within days of their diagnosis. The urgency comes both from the aggressiveness of the disease and the unique nature of the brain itself. Trapped inside the skull, there’s nowhere for it to go when a tumor begins growing. As normal tissue is pushed aside, the neurological effects can multiply quickly. Cancer elsewhere in the body can be debilitating, but it’s unlikely to suddenly take away your ability to speak, to move, to think.
A vial containing 10 million of Tom Fraser’s CAR-T cells. Photo: Faith Ninivaggi
Maus and her team started enrolling new trial participants in May. Hundreds of people with glioblastoma have written to or called Mass General about the study, but Maus had room for only 18?more. I asked her whether they had already filled the remaining spots. She said they couldn’t: Until recently, her team could treat only one patient at a time, and the disease progresses too quickly to look more than a few months into the future. “It’s heartbreaking,” Maus said about having to turn people away. “You get a lot of stories.”
Not long ago, I spoke with Katie McKay, whose husband, Kevin, was diagnosed with a brain tumor in 2016. That summer, Katie and Kevin were driving down for a vacation in Myrtle Beach with their two children, ages 3 and?5. They had made good time from their home in Annapolis, so Kevin phoned the hotel and asked if they could check in early. Shortly after he hung up, he began convulsing and moaning. The kids were watching cartoons in the back seat, “and they thought he was playing a joke on them, like being like a monster, and I?thought so too,” Katie said. “I grabbed his arm, and I realized his eyes were in the back of his head.”
Katie pulled to the side of the road and Kevin’s head fell in her lap. He was out for several minutes, during which he soiled himself. When he woke up, Katie was standing outside the passenger side of the car checking his pulse. “He’s like, ‘Katie, what are you doing?’ And I?said, ‘Nothing, everything’s fine. Something seems a little off with you.’”
At the hospital in Myrtle Beach, doctors saw two lesions on his brain. Kevin had his first surgery on August 2, at Johns Hopkins, and began radiation and chemotherapy. When Katie recounts the months that followed, her voice falters as she remembers how difficult their lives became. She kept spreadsheets of appointments and medications and leads to follow for novel treatments. “I?started researching because I remember in the beginning going to a lot of the appointments and not knowing the lingo,” she said. “And I?didn’t want to waste any more time asking somebody, ‘Can you tell me what they were talking about?’”
Katie and Kevin were college sweethearts. They met at the University of Maryland and married in 2010. He was so lovable, Katie said. He liked to play little pranks on the family: dropping habanero in Katie’s drink when she wasn’t watching or waking his mother-in-law up with a leaf blower. He was 32 when he was diagnosed.
Kevin remained optimistic even as the disease progressed, while Katie remained, in her words, the worrywart. “In the beginning,” she said, “I would cry and be so sad and have so much anxiety about it, worrying about his fate, and he would be like, ‘Hey, Katie, if not us, it would be somebody else.’” Eventually, he had to step back from his job as an engineer, and Katie had to drive him everywhere while trying to manage the kids’ schedules. She enrolled him in a trial at Johns Hopkins, but it didn’t seem to have much of an effect. He lost the ability to sense his left side. Soon, he could no longer speak.
Kevin died in July 2018, two years after his first seizure. As the tumor spread throughout his brain, he qualified for a trial at MD Anderson Cancer Center, but Katie decided against it: “He was already in a wheelchair. He was in a diaper at that point, and I could not feasibly get him there.” She said she’d rather spend her final weeks with him at home than subject him to a treatment that likely would not work.
The vial on ice at Mass General Cancer Center in Boston. Photo: Faith Ninivaggi
When Maus started her Ph.D. in immunology a little more than 25 years ago, the idea that it could one day make brain tumors like Kevin’s disappear was laughable. “I was told that it was career suicide,” Maus said. “People had been trying for a hundred years to get the immune system to recognize cancer, and it was a dead end.”
Maus is short and has an eager smile and dark, expressive eyebrows. When I met her at her lab at Mass General in a building one block from Boston Harbor, I got a sense of how she might have stuck it out despite the warnings from her colleagues. She was friendly but didn’t let me get away with being wrong, a practice seemingly honed from years of supervising Ph.D. students and postdocs. “Let me tweak that,” she would say back to me when I fumbled through a question about cellular biology. Her attraction to immunotherapy was simple: Because it should work, she was determined to make it work.
Maus knew that though cancer has long confounded efforts to kill it, it has a vulnerability. Cancerous tissue can be a pinpoint or a swarm, but it is always made up of cells. And those cells have to be at least somewhat different from the other cells in the body, or they wouldn’t be cancer. If you could train the immune system’s T cells to recognize that difference, that would be the end of the disease.
Efforts to attain that goal have already reshaped oncology. Researchers have developed drugs that selectively bind to proteins in cancer cells, inactivating them (targeted therapies); they’ve discovered ways to attack tumors by modulating the body’s immune response (immune checkpoint inhibitors); and they’ve gotten good at growing white blood cells outside the body and reinfusing them to overwhelm a tumor.
Some of these approaches, while powerful, were a bit like flooding your house to get rid of the rats. What if we could hire an exterminator instead? Immunologists zeroed in on the T?cell, learning how to manipulate its genetic code to prompt it to hunt for specific proteins on the surface of cancer cells; other changes made the T cells more active. This engineered T?cell has a special name: a CAR-T cell. (car stands for “chimeric antigen receptor.” The receptor is what binds a T cell to a protein on a cell’s surface. Antigen is another name for that protein. And the chimera, in this case, is the hybrid between the T cell’s normal receptor and its genetically modified components.)
A decade ago, when Maus was at the University of Pennsylvania, her mentor, the immunologist Carl June, developed an astonishingly effective CAR-T therapy for leukemia. In some forms of the disease, a class of white blood cells called B?cells begins to divide rapidly. June and his team programmed their CAR-T cells to target a protein on the B cells’ surface called CD19.
The CAR-T cells did their job quickly and thoroughly, binding to CD19, eliminating the B cells, and curing the leukemia. Almost overnight, CAR-T cells became the most exciting technology in cancer. Today, more than 34,000 leukemia patients have received some form of CAR-T therapy, and there are some 1,100 different CAR-T trials underway around the world. Everyone working in June’s lab became cancer-world famous. (At a recent conference, a scientist who got up to speak after June told the audience he felt like he was “standing up to play the ukulele after the Rolling Stones.”)
The biggest question in oncology today is whether this approach could also be used for solid tumors. Maus was one of dozens of specialists in immunotherapy who began looking for a suitable cancer for a new CAR-T trial. “I’m not an expert in any disease right now,” she told me, “but I think a lot about how to get T cells to do what we want them to do. The T cell is my hammer, and I’m on the lookout for nails.”
Glioblastoma, she knew, had a promising nail for the T-cell hammer: an antigen called epidermal-growth-factor-receptor variant III (EGFRvIII), which isn’t found in healthy brain tissue. In a clinical trial she began before moving to Mass General, she and a neurosurgeon at Penn named Donald O’Rourke gave patients intravenous injections of T cells engineered to target EGFRvIII.
The experiment was a failure. Some of the CAR-T cells made it to the patients’ brains, but they didn’t seem to have any effect on the tumor. By the time Maus set up her lab at Mass General in 2015, she had two ideas for how to improve the treatment, “one big one and one medium one.” The medium one was to infuse the T cells directly into the fluid surrounding the brain, which would, she hoped, allow more of them to reach the tumor.
The big idea was meant to address a separate problem. Glioblastoma, like most solid tumors, is heterogeneous. Different parts of the tumor have different proteins on the surface of their cells, which makes eliminating them by going after EGFRvIII alone impossible. Maus’s new CAR-T cell was engineered to secrete a molecule called a bispecific T-cell engager, which acted like a bit of double-sided tape, making it easier for T cells to bind to a second protein called wild-type EGFR. The approach, Maus said, was “as fine-tuned as I can possibly imagine.”
Maus and Haber were at dinner when she showed him scans from the first patient. “The world stopped,” he said. The possibilities were immediately clear. “If it’s really working in glioblastoma,” he said, “does that open up the whole bandwidth of solid tumors?”
Maus was quick to point out the limits of what this first phase of the trial has proved. The modified T cells were remarkably effective, but they also eventually disappeared, probably killed by the body’s own immune system. Of the three patients, one died from a perforated bowel, an adverse reaction to a medication he was taking. The second had a recurrence within months of the tumor vanishing. And even Fraser, who had the longest-lasting response, has recently seen signs that his cancer is starting to grow again. “I feel like this was a double or a triple,” Maus told me. “It’s not a home run.”
June’s assessment was more sanguine. He compared Maus’s experiment to his celebrated work with leukemia. It took just five years to get from their first promising results to FDA approval; today, thousands of patients have been effectively cured. “I think by 2029, we’re going to have FDA approval of CAR-T cells for glioblastoma,” he said. “It’s going to be a huge thing, and 2024 is going to be looked at as the breakthrough year.”
Photo: Bobby Doherty
Cancer researchers are fluent in the language of failure. The past century, divided in half by Richard Nixon’s declaration of a war on cancer in 1971, has been marked by frustrations and setbacks, approaches that should have worked but didn’t. Oncologists once thought they were treating a single disease. Now they know that no two types of cancer are alike. Indeed, the same cancer in two individuals can be wildly different. “Cancer,” Haber told me, “is as complicated as medicine.”
For all the promise of immunotherapy, there are formidable obstacles. The first of these is cost. At Maus’s lab, every device and every person represents tightly coiled helixes of time and money. There are PCR machines, biosafety cabinets, ELISA readers, autoclaves, freezers, cell counters, incubators, and centrifuges. The proliferation of white, boxy machines makes the space look like an open-floor-plan office with an unusual number of personal mini-fridges.
When I visited, many of the researchers on the floor (there are dozens of them — young, a mix of genders and races) were staring at computers. Others were busy at what we’d recognizably call lab work, transferring liquids from one container to another, moving things in and out of freezers, placing things under a microscope or removing them. The lab itself carries Maus’s affect: friendly but solemn, collegial but not disposed to gossip or chitchat. Nearly everyone has an M.D., a Ph.D., or both.
Maus walked me through some of the steps needed to create CAR-T cells for the trial. We started with the room where the DNA instructions that are added to the T cell’s genome are written. (“I ran my first restriction digest on a DNA plasmid the summer after eighth grade,” Maus told me. “I was so excited. I didn’t sleep for two days afterward.”) We went on to the lentiviral-production room, where technicians create viral vectors carrying this DNA. From there, we moved to the tissue-culture room, where the vector is mixed with normal T cells to create the CAR-T. Finally, we visited the immune-monitoring part of the lab, where lab techs assay blood draws and other samples from patients, looking for proof that the CAR-T cells have made it to their targets.
Maus calls the lab “as whole shebang as you can get.” The only part missing are the mice they use for testing; those are upstairs. Maus says she’s glad of that — she’s allergic to mice. It takes this whole apparatus, working together, weeks to create enough T?cells for one infusion.
Jennifer Wargo, a professor of genomic medicine at MD?Anderson, referred to the cost of immunotherapy treatments as “financial toxicity.” The patent for June’s CAR-T therapy for leukemia is owned by Novartis, and the median cost for the treatment is $620,000. Even if drug companies don’t try to profit from these therapies, the process is inherently labor-intensive: T cells have to be removed from the patient’s own blood, genetically altered, then reinfused. It’s difficult to determine where economies of scale might kick in.
The complicated process of producing CAR-T cells also limits the number of people who can be treated. For an emerging therapy like CAR-T for glioblastoma, the restrictions are even greater. Over the past few months, I spoke with several patients searching for a trial that would take them on. ??Michael McNally was diagnosed last summer, after he noticed a slight droop on the left side of his face. He went to Mass General, suspecting a mild stroke. After an MRI, the doctor told him he had a tumor in his right frontal lobe. “I said, ‘Look, we’re changing the rules here at Mass General,’” McNally said. If a doctor delivered news like that, “you better have a Redbreast whiskey in your right hand.” He had surgery two days later.
McNally has gone through an exhaustive list of treatments trying to improve on the standard of care, including a personalized cancer vaccine. “If someone told me scorpion poison would kill it, I’d probably take it,” he said. “I’m a giant mouse; let’s go. Let’s do it.” He won’t be able, however, to enroll in Maus’s trial. Because they want to ensure that any positive outcome can be attributed to the CAR-T regime alone, the exclusion criteria rule out anyone who has been treated with “any prior gene-therapy or gene-modified cellular therapy.”
Timing can be difficult for patients and their families to manage. After her father, Yuriy, was diagnosed with glioblastoma, Yelena Tsyrlin tried to enroll him in an immunotherapy trial right away, but she still missed the eligibility window. (She has since started the process to secure a spot in O’Rourke’s follow-up study to the one he conducted with Maus, which has also shown promising results.) Another caregiver wrote that her mother kept getting rejected from trials because she was still on hormone therapy for breast cancer, which she’d had more than five years earlier. “I understand the reasoning and the science behind these decisions,” she wrote, “but when you’re facing this as a patient or a family member, it feels cruel.”
None of the oncologists I spoke with thought that immunotherapy would completely supplant proven approaches. Some cancers will still be best treated by surgery, others by radiation or chemotherapy. CAR-T therapy may be reserved for the most stubborn cancers.
As more CAR-T treatments get FDA approval, however, cost and efficiency may improve. “You’re on the incipient curve of discovery,” Haber said, “but science builds on itself, and sometimes things that are incredibly complicated, expensive, and dangerous open the door to things that become much more democratic, affordable, and standard.” Researchers are looking at ways to use a virus to genetically modify T cells inside a patient’s body, effectively eliminating half of the steps Maus walked me through in her lab. Others are experimenting with vaccines that can teach the immune system to target the same kind of antigens that the CAR-T cells bind to.
Maus and Choi have already refined the protocol for their glioblastoma trial. Patients will now have a short run of chemotherapy before the infusion to limit the number of CAR-T cells killed or inactivated by the innate immune system, allowing more of them to remain active at the tumor site for longer.
In our first conversation, I asked Maus if Mass General hired her because of the incredible results from the CAR-T therapies developed at Penn. She said they weren’t hiring a CAR-T specialist; they were hiring a T-cell specialist. The difference was meaningful. The CAR-T cell, as complicated as it is, is one expression of a much deeper knowledge. That may be how we ultimately reduce costs: The better we understand the immune system, the easier it will be to find ways to make it do what we want.
Tom and Debbie Fraser at home 11 months after his car-T-cell therapy. Photo: Bobby Doherty
On the first day of summer, I went to visit Tom Fraser, participant No. 2 in the trial, at his home outside Rochester. I had been warned that the cancer had made speaking difficult for him, and all my phone communications to that point had been with his wife, Debbie. After spending months talking to patients with glioblastoma and their families, I?feared the worst. So it was a pleasant surprise to be greeted at the door by a tall, sturdy man with a shock of salt-and-pepper hair. “Welcome,” he said, shaking my hand. “I’m Tom Fraser.” He led me to his tidy kitchen, where we sat and talked for nearly two hours. The sun outside was almost unbearably bright.
Before he retired, Tom led a forensic engineering firm. After some catastrophe, he’d be called in to determine its causes. When a Bethlehem Steel warehouse near Buffalo caught fire a few years ago, sending up a plume of smoke so large 300 households and several schools had to be evacuated, Tom determined that the culprit was an improperly installed lighting system that had thrown sparks onto flammable materials below.
He takes the same methodical approach to discussing the course of his disease, consulting a timeline he’s marked out on a legal pad. “I put some dates down here just so I can remember,” he told me. Sometimes Debbie, voluble where Tom was laconic, with a neatly trimmed gray bob, would interject. Tom would pause to listen, then return to his outline.
In August 2021, they were staying at their cottage in the Thousand Islands — a little white house perched on a rock in the Saint Lawrence River — when Tom first knew something was wrong. “I got up in the morning,” he said, “and I couldn’t read.” It took him a month to schedule an MRI, but once he did, the diagnosis arrived quickly. He’d never heard of glioblastoma, but his doctor was direct with him: Without treatment, he could die within six months. He and Debbie told their family — four daughters and eight grandchildren — the news over Zoom.
One of Tom’s daughters works as a physician’s assistant at Mass General, and she encouraged him to travel there to get his tumor resected. His surgeon, Brian Nahed, needed nearly five hours to complete the operation. Tom showed me the scar, a horseshoe on the left side of his head. “It’s okay as long as I?can comb my hair over it,” he said.
After the surgery, he started radiation and chemotherapy, then underwent treatment by Optune, a device that uses electric fields to try to disrupt cell division. Nahed was frank about the likelihood of any of these approaches keeping the cancer in remission for long. “He said, ‘That’ll work until it doesn’t work,’” Debbie told me. “‘This is what happens. This heterogeneous cancer figures out ways. That’s what makes it so aggressive and so difficult to treat.’” Even so, when the cancer recurred after 20 months, the Frasers felt blindsided.
It was Nahed who suggested Tom enroll in the trial being run by his colleagues at Mass General, calling the Frasers at dinner on a Sunday night in the spring of 2023. His message was one of both caution and hope: There was no guarantee this treatment would work, but there was also no more promising trial anywhere in the world.
On the day of the infusion in July 2023, 30 people crowded into the room with Tom and Debbie to watch. For all the time and money and innovation that went into producing that moment, the scene was oddly humble: a normal hospital room, Tom sitting up in his bed as a doctor wearing gloves pushed the plunger on a syringe.
The next month was difficult. Even though the scans showed the tumor shrinking, matching the dramatic results from the first patient, the doctors were reluctant to read too much into them. “They really were very careful not to give us information, even though we were asking all the time,” Debbie said. In the weeks that followed, Tom suffered a cascade of complications: atrial fibrillation, mysterious infections, a punishing fever. The nurses swaddled him in blanket after blanket, but still he shook uncontrollably. Debbie kept watch 12 hours a day. Choi tried to reassure them that the effects were a sign that the treatment was working.
“By the time I left,” Tom said, “I could hardly walk.” Debbie showed me a picture from that day. Tom looked feeble and miserable, “not himself,” in her words. “Let me see that,” Tom said, and Debbie turned the picture to him. “Oh,” he said. “That is not myself.” When they arrived back in New York, the grandchildren greeted them with a WELCOME HOME poster, a hand-drawn rainbow floating near the bottom.
That fall, Tom felt strong enough to return to the family’s cottage in the Thousand Islands. He wanted to help power-wash the house, but Debbie overruled him. They knew nothing about participants Nos. 1 and 3 in the trial and precious little about Tom’s own prognosis. “We knew that things were stable, but we did not know the profound results,” Debbie said. That all changed when Maus and her team published the paper in the New England Journal of Medicine.
If CAR-T therapy for glioblastoma eventually becomes standard of care — if Maus and others can reproduce and improve on the results she got for Tom Fraser — his name will forever be tied with the birth of this treatment. “I shouldn’t say it, but I’m a little proud of myself,” Tom said. “There were three of us in the group, the first three to ever have it and try it. And I?was the No.?2 guy.”
Hope can be a shot of adrenaline or the steady drip of an IV, but it’s always strong medicine. The intense days of those first incredible scans are long behind the Frasers; they have settled into a different rhythm recently, something approximating the way they were before the diagnosis. Tom has also shifted the way he talks about his disease. For years, he spoke about beating glioblastoma — finding a cure for himself. Now he’s more likely to refer to the patients who come after him, who will undoubtedly live longer because of what we’ve learned from his response to the CAR-T therapy. This spring, he packed up his library of engineering reference books and donated them to Clarkson College, his alma mater.
He might not be done with his fight yet, however. After a scan in February showed signs of recurrence, a new set of images taken in June showed just the opposite. The tumor had seemingly shrunk again. “I said, ‘Holy crap, I’m going to do a dance,’” Tom said. Now, according to Debbie, he’s in better shape than he’s been in months. Was it a temporary effect or a sign that the T cells were still active in his brain? We may only know years from now, and then only by implication, if a strong enough signal emerges from future CAR-T trials.
Tom’s next scan is not till August. In the meantime, he told me about a trip he and Debbie were planning: “I’ve never visited Chicago in my life. I said, ‘This is nuts. I?want to see this place — so let’s go.’” That morning, they had been to their youngest grandson’s fifth-grade graduation. It was a hot day, and they sat sweating in the parking lot. It had been almost three years since he’d been told he might have six months to live.
Want more stories like this one? Subscribe now to support our journalism and get unlimited access to our coverage. If you prefer to read in print, you can also find this article in the July 15, 2024, issue of New York Magazine.
Bright Boy
Re: XMaster2023 post# 706306
Tuesday, 07/16/2024 12:19:03 AM
Settle the case and risk a waterfall of copycat lawsuits or buy the company and dismiss the lawsuit!! OR settle the case before the ruling on the MTD and no one will ever know if the judge thinks there is a case either way!!!
Cheers,
BB
Bright Boy
Re: Red_Right_Hand post# 706230
Monday, July 15, 2024 9:33:14 PM
Insurance companies won't allow discovery. Potentially catastrophic claims/settlements.
Cheers,
BB
Red_Right_Hand
Re: manibiotech post# 706225
Monday, July 15, 2024 3:22:58 PM
Post#
706230
of 706307
MTD denied will have an impact. MTD denied means discovery (->trial) or settlement.
Red_Right_Hand
Re: manibiotech post# 706264
Monday, July 15, 2024 6:27:51 PM
Post#
706270
of 706308
It may take months and months to reach a settlement or the conclusion of the trial, but the knowledge that they're heading to trial but for a settlement will be known on the day the MTD is denied.
Bright Boy
Re: Red_Right_Hand post# 706230
Monday, July 15, 2024 9:33:14 PM
Insurance companies won't allow discovery. Potentially catastrophic claims/settlements.
Cheers,
BB
Red_Right_Hand
Re: manibiotech post# 706225
Monday, July 15, 2024 3:22:58 PM
Post#
706230
of 706307
MTD denied will have an impact. MTD denied means discovery (->trial) or settlement.
Red_Right_Hand
Re: manibiotech post# 706264
Monday, July 15, 2024 6:27:51 PM
Post#
706270
of 706308
It may take months and months to reach a settlement or the conclusion of the trial, but the knowledge that they're heading to trial but for a settlement will be known on the day the MTD is denied.
TTsr
Re: ilovetech post# 706210
Monday, July 15, 2024 2:38:55 PM
Post#
706216
of 706218
This PUB MED link is discussing the same data/patient! Enjoy
https://pubmed.ncbi.nlm.nih.gov/38976918/ae kusterer
https://pubmed.ncbi.nlm.nih.gov/38976918/
Re: None
Friday, July 12, 2024 10:08:46 AM
Post#
705598
of 706212
dstock07734
Re: None
Friday, July 12, 2024 10:03:28 AM
Post#
705595
of 705597
Doc logic had a great point.
While you worry about one or two CDMOs maybe you might want to consider that it would take about 1,000 Advents to treat every new cancer patient in the world each year let alone those with ongoing states of cancer. Maybe try to wrap your head around who might be able to help ramp up with that, the transition to Direct that eliminates the need for surgery and then other disease states.
Did LP mention Corning at ASM? Take a look at those companies which have been collaborating with Corning. The writing is on the wall!
Curia Collaborates with Corning to Advance Biopharmaceutical Continuous-Flow Development and Manufacturing Programs
https://curiaglobal.com/news/curia-collaborates-with-corning-to-advance-biopharmaceutical-continuous-flow-development-and-manufacturing-programs/
Curia reveals continuous-flow collaboration with Corning
https://manufacturingchemist.com/news/article_page/Curia_reveals_continuous-flow_collaboration_with_Corning/207778
West, Corning Collaborate to Enable Advanced Pharmaceutical Injectable Drug Delivery
https://www.contractpharma.com/contents/view_breaking-news/2022-01-25/west-corning-collaborate-to-enable-advanced-pharmaceutical-injectable-drug-delivery/
West Introduces Daikyo Crystal Zenith® (CZ) Ready-to-Use Nested Vials in Tub at the International Society for Cell and Gene Therapy
https://www.prnewswire.com/news-releases/west-introduces-daikyo-crystal-zenith-cz-ready-to-use-nested-vials-in-tub-at-the-international-society-for-cell-and-gene-therapy-302157350.html
Stay “Closed” or “Open” Up: Finding the right balance for cell therapy manufacturing
https://www.westpharma.com/es-es/blog/2023/december/enhancing-cell-therapies-packaging-strategies
Packaging Containment Solutions for Cell and Gene Therapies
https://www.westpharma.com/blog/2020/july/packaging-containment-solutions-for-cell-and-gene-therapies
Vial Containment Systems for Gene and Cell Therapies
https://www.westpharma.com/blog/2023/november/vial-stopper-seal-containment-systems-cell-gene-therapies
Corning launches Corning MicroDEN automated system for generating dendritic cells
https://www.selectscience.net/article/corning-launches-corning-microden-automated-system-for-generating-dendritic-cells
Perfusion-Based Dendritic Cell Culture Platform
https://www.science.org/doi/10.1126/science.367.6478.704
Manufacturing Dendritic Cells for Immunotherapy: Monocyte Enrichment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005329/
https://andelynbio.com/content/uploads/2021/08/AndelynBiosciences_ANewCDMOwithRootsInGeneTherapy_August2021.pdf
dstock07734
Re: None
Monday, July 15, 2024 10:50:21 AM
Post#
706135
of 706210
Here is the part from NWBO's PR on the challenge of isolating adherent dendritic cells without damage.
The special difficulty involved in developing the Flaskworks machine was that, unlike other cell types, the dendritic cells tightly adhere to the surface of the culture vessel (similar to barnacles). Extracting them from inside the culture vessel without damaging the cells or reducing the yield of doses was extremely challenging. Other cells (including T cells) are generally cultured suspended in liquid in a bag, which makes it much easier to move them through processes. Many companies have developed or are developing machines to handle such other cell types – but not adherent cells.
The tight adherence of dendritic cells is essential for 3 main reasons: (a) to isolate the specific desired cell population and remove others, (b) to assess the health of the patient’s immune cells (if the cells do not adhere tightly, they are likely not healthy) and (c) to start the activation of the dendritic cells (the adherence triggers the start of activation).
https://nwbio.com/northwest-biotherapeutics-moves-from-optimization-of-flaskworks-prototype-to-fabrication-of-gmp-compliant-units-for-installation-validation-and-final-testing-prior-to-regulatory-certification/
It seems like Corning has the type of technology of manufacturing adherent cells.
Improve Scale-up of Adherent Cells for Bioproduction
A major challenge for manufacturing adherent cells for advanced therapies is producing the large quantities of cells needed in a cost-effective manner. To address the need for a more efficient solution, Corning developed the novel Ascent FBR System, a fixed bed bioreactor system designed to combine the benefits of adherent bioproduction platforms with the scale and automation of suspension manufacturing systems.
https://www.corning.com/in/en/products/life-sciences/products/bioprocess/ascent-fbr-system.html
Corning Announces Collaboration with NIBRT To Help Accelerate Cell Therapy Development
https://www.corning.com/worldwide/en/about-us/news-events/news-releases/2024/06/corning-announces-collaboration-with-nibrt-to-help-accelerate-cell-therapy-development.html
From ChatGPT about adherent cells
Adherent cells are a type of immune cell that tend to stick to surfaces or to each other in a culture environment. This adherence property is often used to differentiate and study various immune cell types. Common types of adherent immune cells include:
Macrophages: These are large phagocytic cells that engulf and digest cellular debris, foreign substances, microbes, and cancer cells. They are key players in the immune response and are derived from monocytes in the bloodstream.
Dendritic Cells: These cells act as antigen-presenting cells (APCs). They process antigen material and present it on their surface to T-cells, thus initiating an adaptive immune response. They are also derived from monocytes.
Monocytes: These are a type of white blood cell that circulates in the bloodstream and migrates into tissues to become macrophages or dendritic cells.
In a laboratory setting, these cells can be isolated based on their ability to adhere to plastic surfaces, a common method used in immunology research to study their function and behavior.
dstock07734
I wouldn't worry about mRNA. As a matter of fact, if the combo results were published officially last year, the funding could not have been awarded to the two researchers. I suspect at the time the grant was awarded, ARPA-H should know about the preliminary results on the combo trial. NWBO has the technology to prime dendritic cells so that they can command t-cells to attack tumor cells even the tumor cells in the most privileged organ in human body. I see no point why they want to give mRNA a shot. But you know it is a complex world. We know this fact simply by taking a look at which company won the Best Therapeutic Vaccine Award at the World Vaccine Congress 2024.
https://www.terrapinn.com/awards/vaccine-industry-excellence/2024-Winners.stm
Best Therapeutic Vaccine Award
Merck / Moderna INT (Cancer)
Highly Commended Award : BioNTech
Here is PFS figure from the collaboration trial on melanoma between Merck and Moderna. It may seem impressive before we make a comparison with the results from the trial of neoadjuvant Nivolumab and Ipilimumab sponsored by BMS. If I am not mistaken, neoadjuvant treatment delivered better results. Keep in mind melanoma is hot tumor. When mRNA can deliver impressive results on cold tumors, we can start to worry.
We watched Les' video before. He said for 15 types of solid tumors, DCVax-L are blockbuster drugs for most of them (10:23).
Re: MarkoMD post# 705751
Saturday, July 13, 2024 12:10:29 PM
Post#
705802
of 705931
MarkoMD, Thanks for your reply. I am not a doctor, so if my logic is wrong, any feedback would be appreciated.
My assumption is:
- today's cancer drugs are typically limited to treating malignant tumors
- most patients with benign tumors are treated with surgery, radiation, and or monitoring (wait and see)
- the reason is, drugs with risk for high toxicity have restrictive labeling for use only in malignant tumors
- much easier for a doctor to off-label a non-toxic vaccine than a toxic drug
- if the patient with a benign tumor is doing surgery to remove it anyway, why not use DCVax-L
- given DCVax-L is non-toxic, generates an immune response, and leaves behind immune memory, there is no downside
- DCVax would be prophylactic
My conclusions:
- Patients would ask for and doctors would strongly consider providing DCVax to patients with benign cancer
- DCVax penetrates the benign tumor therapy market where other cancer drugs have not been able to.
Chiugray
Re: dstock07734 post# 705688
Friday, July 12, 2024 5:39:44 PM
Post#
705713
of 705782
Dstock, Agree every big investor in NWBO has their own internal value assessment, on a look forward basis.
Even me, as a retail small investor, I have mine. Of course, all are my personal opinions.
Short term: asymmetric risk-reward opportunity
Binary event: MHRA decision for DCVax-L
Probability: 99% approval, 1% refusal
Stock price scenario (within 3 months post-decision):
- Approval means price goes up 1,000% to 5,000% (from $0.40/sh to the $4-$20 range) (approval will create a domino effect of cascading positive events, all will add to positive momentum for stock price, including potential for a major short squeeze, but there is much range in possibility there over such a short period)
- Refusal means price goes down 50%
Asymmetric investment: A $10K investment today has a 99% upside chance of becoming $100K - $500K and a 1% downside chance of becoming $5K within 3 mos post-MHRA decision.
Long term: unicorn company revenues and growth
DCVax’s non-toxic profile makes it applicable to the larger benign cancer market, as a prophylactic vaccine to prevent it from getting worse or from metastasizing.
- My understanding is today’s cancer drugs are typically limited to treating malignant tumors only. Their toxicity profile is the primary reason for a narrow drug labeling. It is this same reason that, for benign tumors, doctors will often choose less toxic treatments like surgery, radiation, and or monitoring (wait-and-see) first.
- But with DCVax that can all change.
- In terms of revenue potential and market size, patients with benign is a much larger group than malignant.
- For example: There are 94K newly diagnosed brain tumors in the USA per year. Of that, 26K are malignant and 68K benign. Benign is 2.6X larger than malignant. But that’s not all. There is an additional 1M people in the USA living with brain tumors (which is benign by definition, another 38X equivalent). That is just one example.
https://braintumor.org/brain-tumors/about-brain-tumors/brain-tumor-facts/
The world of business is now a "winner takes most" of the revenues
- DCVax not only is a cancer killing therapy, it also develops immune memory against recurrence and metastases.
- Because other drugs do not, I can only imagine that most, if not all, cancer patients will want to use DCVax.
- No downside. The DCVax tech platform is unique in that it can be combined with other drugs, like a modular therapy model (DCVax as the base layer, adjuvants and other cancer drugs are added on top of it).dstock07734
dstock07734
Friday, July 12, 2024 3:29:56 PM
How could you know big investors haven't valued the company? IMO, they value a lot. The simple fact is that you can sense it.
Let me ask you a simple question? Do you think Teresa Bitetti, President, Global Oncology Business Unit at Takeda knew about DCVax-L? Of course, she knew. BMS must do some DDs before striking a collaboration trial deal with NWBO which was taken away by Merck later. Is it coincident that Takeda has the aspiration to cure cancer after Teresa Bitetti joined the company? There is no coincidence in biotech.
Now you can take a break.
https://www.takedaoncology.com/about/our-leadership-team/teresa-bitetti/
https://clinicaltrials.gov/study/NCT03014804
https://www.takedaoncology.com/news/our-viewpoints/better-together-our-aspiration-to-cure-cancer/
Chiugray
Re: ilovetech post# 705739
Saturday, July 13, 2024 2:56:06 AM
Post#
705741
of 705784
Ilovetech, Speculating, but I believe monetizing the platform will be what the Franchise model does. Possibly the franchisees will be oncologists and BPs, who all want access to DCVax for their cancer patients. Doctors get support for off-label use. BPs get access to DCVax for combination therapies and clinical trials. And NWBO gets access to more cancer patients and cancer types, or rather gives cancer patients access to DCVax.
My opinion is a licensing structure for a large upfront payment and royalty, say 15%, is a less preferable way to monetize. That is equivalent to selling 85% of the business (future revenues). I prefer to keep 100% of the product sales, be a product company. That is the path towards being a Big Pharma. The reward will be a valuation multiple applied against a larger sales number.
Chiugray
Re: ilovetech post# 705739
Saturday, July 13, 2024 2:56:06 AM
Post#
705741
of 705775
Ilovetech, Speculating, but I believe monetizing the platform will be what the Franchise model does. Possibly the franchisees will be oncologists and BPs, who all want access to DCVax for their cancer patients. Doctors get support for off-label use. BPs get access to DCVax for combination therapies and clinical trials. And NWBO gets access to more cancer patients and cancer types, or rather gives cancer patients access to DCVax.
My opinion is a licensing structure for a large upfront payment and royalty, say 15%, is a less preferable way to monetize. That is equivalent to selling 85% of the business (future revenues). I prefer to keep 100% of the product sales, be a product company. That is the path towards being a Big Pharma. The reward will be a valuation multiple applied against a larger sales number.
dstock07734
Re: newman2021 post# 705670
Friday, July 12, 2024 3:13:45 PM
Post#
705679
of 705711
Congrats! Hopefully this July is an exciting month for you.
The longs will be the winner. The only question is how big our win is going to be. My bet is our win is going to be enormous.
Here is a tool developed by a Harvard professor to uncovering high-dimensional structure in single-cell gene expression data. The variations of the same genes from p3 tissue sample were also analyzed by NCI researchers. Can we imagine what it will look like if NWBO can generate these type of data from hundreds or thousands of patients? Dendritic cell trained by NWBO technology can spot mutated genes highly efficiently and fix these mutated genes.
Glioblastoma Molecular Characteristics and Immune Microenvironment Associated with Survival Outcomes in Patients Treated with Dendritic Cell Vaccination
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE249282
https://kleintools.hms.harvard.edu/tools/springViewer_1_5_dev.html?cgi-bin/client_datasets/nacho_springplot/allMerged
https://kleintools.hms.harvard.edu/tools/spring.html
dstock07734
Re: None
Friday, July 12, 2024 10:03:28 AM
Post#
705595
of 705597
Doc logic had a great point.
While you worry about one or two CDMOs maybe you might want to consider that it would take about 1,000 Advents to treat every new cancer patient in the world each year let alone those with ongoing states of cancer. Maybe try to wrap your head around who might be able to help ramp up with that, the transition to Direct that eliminates the need for surgery and then other disease states.
Did LP mention Corning at ASM? Take a look at those companies which have been collaborating with Corning. The writing is on the wall!
Curia Collaborates with Corning to Advance Biopharmaceutical Continuous-Flow Development and Manufacturing Programs
https://curiaglobal.com/news/curia-collaborates-with-corning-to-advance-biopharmaceutical-continuous-flow-development-and-manufacturing-programs/
Curia reveals continuous-flow collaboration with Corning
https://manufacturingchemist.com/news/article_page/Curia_reveals_continuous-flow_collaboration_with_Corning/207778
West, Corning Collaborate to Enable Advanced Pharmaceutical Injectable Drug Delivery
https://www.contractpharma.com/contents/view_breaking-news/2022-01-25/west-corning-collaborate-to-enable-advanced-pharmaceutical-injectable-drug-delivery/
West Introduces Daikyo Crystal Zenith® (CZ) Ready-to-Use Nested Vials in Tub at the International Society for Cell and Gene Therapy
https://www.prnewswire.com/news-releases/west-introduces-daikyo-crystal-zenith-cz-ready-to-use-nested-vials-in-tub-at-the-international-society-for-cell-and-gene-therapy-302157350.html
Stay “Closed” or “Open” Up: Finding the right balance for cell therapy manufacturing
https://www.westpharma.com/es-es/blog/2023/december/enhancing-cell-therapies-packaging-strategies
Packaging Containment Solutions for Cell and Gene Therapies
https://www.westpharma.com/blog/2020/july/packaging-containment-solutions-for-cell-and-gene-therapies
Vial Containment Systems for Gene and Cell Therapies
https://www.westpharma.com/blog/2023/november/vial-stopper-seal-containment-systems-cell-gene-therapies
Corning launches Corning MicroDEN automated system for generating dendritic cells
https://www.selectscience.net/article/corning-launches-corning-microden-automated-system-for-generating-dendritic-cells
Perfusion-Based Dendritic Cell Culture Platform
https://www.science.org/doi/10.1126/science.367.6478.704
Manufacturing Dendritic Cells for Immunotherapy: Monocyte Enrichment
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005329/
https://andelynbio.com/content/uploads/2021/08/AndelynBiosciences_ANewCDMOwithRootsInGeneTherapy_August2021.pdf
dstock: As in the case of Asco, I am sure its a big fee cost to attend, but still slides and a video of Bosch's presentation were made availavble by nwbo to its website.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174741280
dstock: any suggestion on how to tap into BNOC, 7/17? My emails have reached silence. A British holdover from (https://en.wikipedia.org/wiki/Blackout_(wartime)#:~:text=Blackout%20regulations%20were%20imposed%20on,that%20might%20aid%20enemy%20aircraft.) ? A.E.K.
No reply from BNOC on how to get the transcript and slides.https://t.co/LRWzO12ina$nwbo @alphavestcap
— alphavestcapital.com (@alphavestcap) July 12, 2024
dstock07734
Re: RobotDroid post# 705531
Thursday, July 11, 2024 7:17:23 PM
Post#
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of 705546
You do care what Les said, don't you?
Here is the part you should pay attention.
Les said in last August the number of patients who received DCVax-L treatment is about 800. Patients of 15 types of solid tumors received the treatment through compassionate program. "most of them blockbuster drugs".
See this webpage created on May 24.
https://cdmrp.health.mil/gbmrp/default
There are $10m that need to be allocated before the end of this fiscal year. The combo trial is going to be completed on August 1. You don't think this fund should be awarded to UCLA which has been licensing technology from NWBO?
Let's see what will happen next Wednesday. When will the present start? Is it 14:45pm UK time? That's 9:45am ET.
I'll make sure my champagne ready.
ATLnsider
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174740309
Re: A deleted message
Thursday, July 11, 2024 2:24:51 PM
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of 705523
You’d be surprised at what I know. 😀
This is a PSA to all manipulative and collusive Market Makers, Hedge Funds and Short Sellers:
newman2021
Re: ATLnsider post# 705472
Thursday, July 11, 2024 2:43:24 PM
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of 705525
ATLnsider, the Fire Works starts next Wednesday from the Symposium I guess.
Re: newman2021 post# 705476
Thursday, July 11, 2024 2:48:27 PM
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of 705525
Possible, but what I know for sure is that DCVax-L will be approved in the UK by the MHRA SOON. 😀
Traders and FUDsters are yapping a lot now, trying to discourage, dissuade, distract and frustrate NWBO longs.
Bullish
BULLISH
This is a PSA to all manipulative and collusive Market Makers, Hedge Funds and Short Sellers:
Member Level
Re: Nemesis18 post# 705439
Thursday, July 11, 2024 3:06:31 PM
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You're being silly... this company has operated on very low funds for years and years, and can continue to do so, given their large supply of angel investors. And upon an MHRA approval, they'll be able to fulfill their role as a reliable supply partner to NHS.
Additionally, as far as your suppliers code of conduct, they haven't hired any children, they don't use forced labor, they comply with the UK laws re: hours, wages, benefits, health, safety and environmental codes, they don't discriminate, are prepared for disruptions of business due to natural disasters, etc., and haven't bribed anyone.
https://wwwmedia.supplychain.nhs.uk/media/supplier_conduct_code.pdf
beachhyena
Followers 28
Posts 677
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Alias Born 07/26/2017
beachhyena
Re: slicknick617 post# 705346
Thursday, July 11, 2024 9:30:19 AM
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of 705428
Dendritic cell technology will encompass all future advancements towards cures in all disease that afflicts mankind and it starts with cancer. The United Kingdom want to be the central hub for biologics aka the Cambridge Triangle. The decline in chemical drugs will begin as dendritic cell technology starts to advance. The world is on the cusp of a monumental shift away from chemo towards bio and NWBO has cornered the Dendritic Cell technology that will lead the way towards a complete change in how we as humans are treated in the future. There is a reason why NWBO has been so maligned by the markets and why it has had to go to the courts and that reason is that it is a disruptive technology that will change the status quo of so many BP’s their Hedge Funds allies who have been clinging onto their mass produced extremely profitable poisonous chemo drugs that do nothing for our health. This has been the battleground and will continue to be so until finally NWBO receives true validation. We are hoping that day comes soon. IMO.
evanstony
Re: beachhyena post# 705360
Thursday, July 11, 2024 10:05:36 AM
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705378
of 705429
The United Kingdom wants to be the central hub for biologics aka the Cambridge Triangle.
This (NWBO) is a huge win for the UK. High paying jobs are growing fast in this region and will explode with even greater opportunities after approval.
Manufacturing Manufacturing Manufacturing.... as DL says = high paying JOBS JOBS and more JOBS!!!!
1)https://www.nature.com/articles/s41591-024-03084-6
2)I believe the rationale presented by
@d_stock07734
underscores why big pharma can’t afford to buy out $NWBO #DCVAX. This company has achieved something remarkable: they have patented a platform technology and its manufacturing process with #Flaskworks that harnesses billions of years of evolutionary refinement. By leveraging the body’s innate immune system to precisely target specific cancers and diseases, #DCVAX represents a groundbreaking advancement that will revolutionize treatment paradigms hence #Franchising 💯 https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174566808
Northwest Biotherapeutics: CEO Linda Powers’ In-depth Company Overview at the Annual Meeting
POSTED by LARRY SMITH on JUL 8, 2024 • (0)
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174706145
Glossary of Key Acronyms Used in this Report
MHRA Medicines and Healthcare products Regulatory Agency is the United Kingdom regulatory counterpart to FDA. The two agencies have a close, collegial working relationship. Approval of DCVax-L by MHRA would carry great weight in the FDA’s decision making.
MAA Marketing Authorization Application is the document that must be submitted to the MHRA by companies seeking approval for a drug. The MIA is an integral part of this submission. Approval of the MAA allows commercialization.
MIA Manufacturer's Importation Authorization is required by the MHRA before a company can manufacture, import or export drugs. To qualify, a manufacturer needs to demonstrate to MHRA that it complies with good manufacturing practices and can pass regular GMP inspections of its manufacturing site.
GMP Good Manufacturing Practice is a system required by regulatory agencies for ensuring that drugs are consistently manufactured according to carefully defined quality standards. Guidelines address issues such as process validation, quality assurance assays, record keeping, personnel qualifications, sanitation, cleanliness, equipment verification and others.
NICE National Institute for Clinical Excellence plays a crucial role in determining reimbursement for new pharmaceutical products and treatments in the UK's National Health Service (NHS). It is considered to be the gatekeeper to reimbursement by the NHS. A positive recommendation from NICE typically obliges the NHS to make funding available for a product or treatment, usually within three months
Introduction
It has been over a year since CEO Linda Powers has spoken about her strategic vision for Northwest Biotherapeutics; during this time there has been some remarkable progress. At the annual shareholder meeting on June 29th, 2024 CEO Powers provided a comprehensive, hour long overview of what has been accomplished over the last 18 months and her key priorities for the coming year. In this report I have largely reproduced a verbatim transcript of her talk which contains a wealth of information. I have summarized what I consider to be the key points, but I would urge you to read the whole report in order to understand the amazing job that NWBO has done with the development of DCVax-L in the face of an egregious stock manipulation scheme that has had an extremely negative impact on the stock price and blocked ready access to capital.
The transcript of her talk is over 18 pages. Speaking is not always as precise as writing which makes reading the transcript challenging. I have tried to edit and organize the subject matter to give a more user friendly format. My purpose is to organize and edit but not to inject my own thoughts. Her presentation focused on issues relating to:
MAA submission for DCVax-L in the UK,
Manufacturing accomplishments at Sawston with special emphasis on Flask Works,
Broad, industry leading portfolio of intellectual property covering dendritic cell technology that has been assembled.
Groundbreaking lawsuit against the market makers who have been manipulating the stock price and continue to do so,
Key accomplishments in the past 18 months and
Priorities for the coming year.
My Key Takeaways
I would urge you to take the time to read this full report. However, if you just want a quick summary here are my key takeaways.
The MHRA is actively reviewing the MAA for DCVax-L for the treatment of newly diagnosed and recurrent glioblastoma multiforme (GBM). The regulatory agency has not issued and will not issue guidance on when their review process will be completed. Most analysts who closely cover the company, me included, are estimating UK approval in the September-October of 2024 time frame.
NWBO has done an awesome job in building a world class personal cell manufacturing capability at its Sawston, UK facility to support the commercial launch. MIA approval was obtained in March 2023.
Before launching DCVax-L in the UK, NWBO will need to get a favorable reimbursement recommendation from NICE. Ms. Powers reported that there have been ongoing interactions with NICE over years that have been quite encouraging and there is reason to hope that a positive reimbursement recommendation will follow swiftly on the approval of the MAA.
The manufacturing capacity at launch is expected to be 1,000+ patients per year using grade B clean labs. However, the implementation of the Flask Works grade C lab technology could expand capacity to 15,000 in the not too distant future.
NWBO has assembled an industry leading, dominant package of intellectual property covering dendritic cell technology which was recently bolstered substantially by the acquisition of a very important IP package from Roswell Park whose scientists have spent 24 years developing a cutting edge dendritic cell technologies and arguably are the leading group worldwide in this field.
Along with the IP acquired from Roswell, NWBO also gained control of two phase 2 trials that are being conducted by independent investigators that are fully funded by grants. NWBO will not be required to fund these trials or to provide any support until a phase 3 begins (if warranted). This gives an immediate jump start to the medium term pipeline.
NWBO has been the target of a long term stock manipulation scheme that has had a devastating impact on the stock price. The company filed a lawsuit against seven market makers in December 2022 to block this. I believe that the defendants motion to dismiss the lawsuit will be denied in a month or two and allow NWBO to go forward to discovery. This could lead to stopping the manipulation and ultimately the awarding of substantial damages, possibly meaningfully above $1 billion.
Market makers through illegal naked shorting can create a limitless number of counterfeit shares. The exact number can only be known after discovery allows NWBO to subpoena trading records from market makers and DTCC. However, based on what I have seen with other companies that have been victimized by this scheme, I hypothsize that there may be more than 1 billion counterfeit shares circulating in the market alongside legally issued shares.
Discussions are underway to begin combination trials of DCVax-L with other drugs such as checkpoint inhibitors, targeted therapies and chemotherapies. We may hear more by year end. Phase 2 trials of DCVax-L combined with checkpoint inhibitors and other drugs have produced very exciting results in GBM.
The company is in a number of discussions involving partnering parts of its technology platform. We may hear more by year end.
NWBO is in the process of restarting trials of DCVax Direct. This product takes a different approach from DCVax-L in that it addresses the treatment of metastatic cancers in which the tumor cannot be surgically removed. This is a huge unmet need. DCVax-L addresses cancers that are surgically resectable.
The major weakness of NWBO is an extremely strained balance sheet. Approval of the MAA and denial of the motion to dismiss in the lawsuit could provide access to the substantial low cost capital needed to implement the Company’s plans. Ms. Powers did not directly address this in her remarks.
The company chose to file for regulatory approval in the UK because the process is much faster than for other regulatory agencies and because it us highly respected will carry great weight in future decisions by other regulatory agencies. It is preparing to file for approval in the US, European Union and elsewhere following UK approval.
The MAA Submission to the MHRA
Prerequisites to Filing the MAA
The MAA was filed on December 20, 2023 seeking approval for both newly diagnosed and recurrent glioblastoma multiforme. In addition to the clinical trial results from the DCVax-L phase three trial, there were significant prerequisites that had to be completed before MHRA would accept the submission.
On March 20, 2023 NWBO announced that an MIA license had been approved and issued by the MHRA for commercial manufacturing of cell therapy products at the GMP facility in Sawston, U.K. Under this license, cell therapy products manufactured in the Sawston facility may be exported globally. Products (e.g., immune cells) may also be imported into the U.K. for production or release of cell therapy products under the facility’s licenses. This license was obtained by Advent
A human tissue authority license is a regulatory requirement for organizations that use and store human tissue. This was also obtained by Advent.
A Pediatric Investigation Plan (PIP) for clinical trials of DCVax-L in children had to be submitted to and approved by the MHRA; beginning the trial is not a requirement for approval of the MAA for DCVax-L. This work was largely done by NWBO.
Ms. Powers said that the interactions with MHRA have so far been wonderful. They gave NWBO quicker than expected turnarounds on each of these prerequisites.
Trial Master File Submitted with the MAA Is an Enormous Document
This phase three trial was one of the largest clinical trials of a cell therapy product (particularly a personalized cell therapy product) that has ever been conducted. This resulted in an enormous Trial Master File (TMF) which is a comprehensive collection of documents that provide evidence of how a clinical trial was conducted and managed. It also contains essential documents that demonstrate compliance with regulatory requirements and Good Clinical Practice. It allows monitors, auditors, and regulators to evaluate the conduct of a trial and the quality of data produced.
Pulling together all of the contents of the TMF, was an enormous organizational exercise. The drafting in combination with medical writers began in the fall of 2022. If the digital file were reproduced on paper, it would create a stack of paper 200 feet tall. There cannot be any gaps in the file and all data must be easily accessible. For example, if inspectors want to see lab tests for patient X at clinical trial site Y, the regulator must be able to immediately access that data.
Preparing for MHRA Inspections as Part of the MAA Review
An enormous amount of work is required to prepare for MHRA field inspections. NWBO as the sponsor is going to be inspected as are the contract research organization that conducted the trial, the independent database company that held the database and certain hospital trial sites. Each organization has to have everything ship shape and NWBO has been working diligently with teams of consultants to prepare them. MHRA typically sends a team of inspectors who may stay for a week or more. NWBO hired people who previously worked as inspectors for regulatory agencies and now act as consultants, to conduct audits and mock inspections. They try to anticipate what kind of questions MHRA will ask and what kind of supporting information might be required.
Demonstrating Mechanism of Action
The MHRA will also have questions on the proposed mechanism of action of DCVax-L. Over the last 18 months, NWBO completed and then presented results from mechanism of action studies which studied the underlying biology of how DCVax-L is believed to work. Chief Technical Officer, Dr. Marnix Bosch, presented that information in a company presentation at ASCO last year. It is tremendously important because it strongly supports the underlying biology hypothesized for DCVax that results in its broad spectrum of activity.
It was shown that the dendritic cells on which DCVax-L is based are picking up a very broad range antigens from the tumor tissue sample (the lysate). Studies showed that over 600 different tumor antigen targets were displayed to T-cells. This is the basis for its broad spectrum of activity. Those studies were extremely important to add scientific underpinning that supports the clinical trial results that have been seen. Proteomics technologies that study the activity of proteins that have only recently been developed and were used in this study.
Data from the Compassionate Use Program Supplements the MAA
They continue to follow patients still alive from the phase 3 trial; the exact number wasn’t specified. With standard of care, the five year survival rate is about 5%. There are still a meaningful number of patients alive from the trial in which the last patient was enrolled in November of 2015. This means that each of these patients has survived at the very least about nine years. NWBO has gleaned important information about these long-term survivors.
There has been a long running, well over a decade, compassionate use program that has provided valuable, real world experience. In a clinical trial, the goal is to replicate in cookie cutter fashion the treatment of each patient. However, this is not how it works in the real world. For example, there are patients whose tumor tissue sample wasn't in the condition that it was supposed to be. It may not have been frozen quite the right way or was frozen several years ago or the patients were way outside the age range. They have had patients in their 80s. And so the compassionate use program has been valuable in gaining a tremendous amount of real world experience, basically practicing for what will happen when they go commercial. Recent activity has slowed because of the preoccupation with the MAA.
Activities At Sawston, Commercial Preparation and Flask Works
Sawston Has Received a License for Commercial Production of DCVax-L
Another huge area of activity over the past 18 months has been in the development of the Sawston facility allowing for the MIA and TIA licenses. To put this in perspective, Ms. Powers provided some history. The very first manufacture of DC-VAX-L for a patient in Sawston was in February of 2022. GMP allowing for the MIA in Sawston was obtained less than two and a half years from the time this first product was made; there has been enormous progress. Phase 1 grade A and grade B lab build outs that will be used for initial commercial production which were the basis for the MIA approval. Specialized architects and engineers are at work to design the grade C labs under development with Flask Works technology that will be ultimately used in production. Advent is working on commercial readiness.
Grade B Labs Will Be the Basis for Initial Manufacturing, But Grade C Labs Based on Flask Works Are the Future
NWBO highlighted in a March 2024 press release progress made in the Flask Works system which ultimately will be used for all production at Sawston. Before discussing Flask Works, Ms. Powers addressed the traditional type of clean rooms involved in a GMP (good manufacturing practice), clinical grade manufacturing facility. The regulatory requirement is to have labs with no particulates in the air. Europeans call these grade B labs; in the US they are referred to as a class 10,000 lab. They are high level sterility facilities that perform a complete air change of the whole suite once every minute. They are manned by technicians wearing spacesuits. Facilities require special water and environmental systems.
The traditional Class B facilities must be perfectly sterile and are very expensive. The objective of Flask Works system is to enable NWBO to transition first to being a closed system for most manufacturing steps and then to automate the process in a grade C lab which will ultimately be the basis for all commercial manufacturing at Sawston.
Manufacturing Capacity Will Be Significantly Increased in a Grade C Lab
In the most rigorous, sterile grade B labs, only one product for one patient can be produced at a time. Then the whole suite has to be cleaned before the next product can be produced because the procedure is partially open. In the grade C lab, everything is closed allowing for the manufacture of product for multiple patients at the same time in the same suite. This has been a huge focus for NWBO. It's not simple to change planning from grade B labs to grade C labs, because not only is the size and the configuration different, even the load on the building is different. There has been tremendous progress over the last 18 months.
In terms of initial capacity, the current anticipation for the class B lab is estimated to be about 1,000 or 1,100 DCVax-L patient treatments per year. Sawston is very large with close to 88,000 square feet on two floors. When the building is fully built out with C labs, it is anticipated that each of the grade C labs operating with two shifts should be able to provide product for 15,000 patients a year. That is an enormous amount, especially for personalized cell therapies. The big companies who brought the CAR T cell technologies to the market in their first years of commercial operations were only able to produce 50 patient treatments per year. Having the eventual capacity to make product for up to 15,000 patients would be an absolutely enormous manufacturing achievement.
Additional Nuts and Bolt Preparations for Commercialization
There have also have been a lot of preparations for the more nuts and bolts things that are needed for commercial operations beyond the physical aspects of building out the facility. One example is that NWBO has established controlled clinical-grade cryogenic storage for three million dosage vials. Also, readouts from the environmental monitoring system must be able to make sure that the number of particles in the air in the suite during the entire seven-day process stays below the maximum allowed.
An important focus is that after manufacturing is completed the product has to go through product release. This requires quality control tests using assays or tests or analyses that have been approved by the MHRA to test and assure the sterility, purity, potency and composition of the product. These are regulatory requirements.
The manual way of doing product release is for a certified quality person (QP) to manually review all records which can take up to 30 person hours. It’s one thing if a batch of product is made up a million tablets, but entirely different if a batch is a personalized therapy for one patient. The development of the manufacturing process was started five years ago by their Advent. It essentially automates the product release process and removes it as a bottleneck.
More on Flask Works
Before the acquisition by NWBO, Flask Works had developed only one approach for its system. It was a good approach and part of the reason why NWBO acquired it from Corning. Still, it wasn't as optimized as NWBO wanted. So over the last 18 months since the acquisition, Advent and NWBO have developed two additional, fundamentally different approaches to the automation and the closing of the manufacturing process. Extensive comparative testing between the two evaluated how cells did with one approach or another looking at parameters such as the yield and the stress on the cells.
They first developed an optimized non-GMP, non-clean room version of the machine and then adapted it for the clean room. This required the use of different materials and different mechanics. The adaptation work for GMP was recently finished. There are a couple of improvements that are being done to streamline the machine for which units are about to be ordered.
Advent’s Contributions Have Been Critical
Most of the work at Sawston has been carried out by Advent which provides a range of contract services to Northwest that are critical. Advent people on the ground in the UK do things like:
Manage the operation and development of this Sawston facility,
Draft all the manufacturing related sections of the MAA,
Conduct on-site detailed science,
Oversee the functionality and the actual work done on the Compassionate Treatment Program.
This is all done under contract and in collaboration with NWBO.
Advent is owned by the Toucan Investment Fund which is managed by Linda Powers and this makes it a related entity. Working with Advent is far less costly than would be the case if NWBO were using a third-party provider with whom it did not have a close relationship. It makes a lot of operational sense and has produced a great working relationship.
NWBO monitors Advent inputs and costs very carefully. A large chunk of what is paid to Advent is just pass-through for costs of the work that they're doing with their personnel and the various contractors that they bring in to work on Sawston. Advent is compensated with a pass-through of costs plus a 15% fee on top. Payment is based on meeting contractual milestones, e.g. receiving the MAA or getting the facility going for the next phase of designing the grade C lab. Advent is extremely valuable to NWBO not only in its manufacturing capabilities, but also on experimentation and the work that has to be done on the science side.
NWBO Has Assembled an Industry Leading Portfolio of Intellectual Property
Dendritic Cell Technology Is in Its Early Stages of Development
Acquisition of dendritic cell technology intellectual property has been a significant area of activity and has been very productive. From a big picture standpoint, the goal is to build a to build the industry leading platform. The mainstream biopharma thundering herd are always a followers on innovative technologies such as monoclonal antibodies and CAR-T.
The herd hasn't yet fully recognized the special capabilities of dendritic cells, but it's beginning. For example, when the federal government created a new agency modeled on DARPA (Defense Advanced Research Projects Agency) which is called ARPA-H (Advanced Research Projects Agency for Health). The very first grant that this elite “technologies of the future” agency awarded was a large $25 million grant for dendritic cell technologies to an academic setting. Increasingly people are beginning to recognize the special capabilities of dendritic cells. NWBO has been aggressively building a dominant franchise before the thundering herd recognizes the promise of dendritic cell technologies.
In its regulatory filings, NWBO has been quietly reporting on the in-licensing of technologies that they believe will be valuable in building this franchise. NWBO just recently announced a consequential agreement that was the in-licensing of IP from Roswell Park Comprehensive Cancer Center. It covered the IP package developed by a world leading group of dendritic cell scientists based on seven years of work at Roswell. However, NWBO previously completed an in-license of a package of the original, older foundational work which that group had spent 17 years developing at another institution.
Synergy of Acquired Intellectual Property and Technologies with the DCVax Platform
NWBO stayed in stealth mode while it was putting all the IP pieces together. The two packages just described have some wonderful things in them. They include enhanced versions of dendritic cells. They also include technologies that are complementary to use with dendritic cells such as immune system boosters for use in combination trials. This collection of new tools and technologies provides a wealth of growth opportunities that complement the existing DCVax platform of which there are two versions. DCVax-L is for operable tumors and DCVax Direct for inoperable tumors. NWBO hasn’t said much about DCVax Direct lately, but Advent is finishing up requirements that will allow a restart of the DCVax Direct program
The in-licensed IP also can be used with drugs of other companies. For example, there is a conditioning regimen meant to condition the patient to have a stronger response to immune therapies; this is referred to as reprograming the tumor microenvironment. This is synergistic with any type of agent and would allow NWBO to partner with companies who have biologics or targeted therapies or checkpoint inhibitors which might or might not be promising combinations with the DCVax platforms.
One of the really important aspects of the in-licensed package from Roswell is that NWBO gained two phase two trials currently underway. They are fully funded by grants and are being fully carried out by independent investigators. NWBO isn’t required to provide funding or any other type of support. If they produce encouraging results, NWBO will then have the right to take them into phase three. Roswell is a very prestigious, top tier cancer center. They have done a marvelous job of developing dendritic cell technologies at the research stage and at the early clinical trial stage and even now into the mid stage clinical trials. NWBO is really gratified that they were chosen to carry the baton to take these assets forward into late stage clinical trials and hopefully into commercialization.
These are some of the intellectual property, that NWBO has been quietly in-licensing. They provide quite a number of different pieces of technology that they feel will be useful building blocks. NWBO has also been putting some collaborations in place which haven’t yet been announced; those will be something that will be coming along.
Lawsuit Against Citadel, Virtu, Canaccord Genuity, G1 Execution, GTS, Instinet and Lime Trading-in the United States District Court, Southern District of New York.
Status of the Lawsuit
NWBO filed a lawsuit in December 2022 that alleges that seven market makers illegally manipulated its stock price. Management and investors are unbelievably frustrated that the share price is not reflecting the value that has been and is being built because of this. NWBO believes this scheme has been going on for many years. Management was very anxious to try to take some action to do something about it, but had to bide its time and meticulously collect evidence as the bar for success in this type of lawsuit is extremely high. The degree of detail required to be put in a complaint is hard to even describe. NWBO did bide its time until it could put together a very strong case.
Since the lawsuit was filed, it has gone through a lot of back and forth skirmishes, all of them relating to the defendants’ effort to have the case dismissed by filing a motion to dismiss. NWBO is encouraged that the magistrate and the court have found that the pleadings in the complaint have been sufficient on all but one of the elements that they need to plead in order to deny the motion to dismiss and proceed to discovery and then to trial or settlement.
NWBO Has Successfully Pled that the Market Makers Purposely Manipulated Its Stock
The magistrate and district court have found already that NWBO’s pleadings are sufficient to show that the defendants engaged in manipulation of the stock through spoofing and that they did so with scienter (intent to damage Northwest). This is at the pleading stage so the court has only said that they have adequately pled this; it has to be proven in a trial. However, this is a very, very big deal. This is a widespread scheme and there are many, many cases in which the companies who've been the victims or targets of this alleged criminal enterprise have not been able to get anywhere close to trying to seek redress.
This is because the plaintiff must articulate all the minute details of the transactions that are alleged in the manipulation before getting to discovery. However this data is controlled by the market makers and DTCC and not readily available. This is a catch 22 in which the data that is necessary to proceed to discovery isn’t available unless they get to discovery. Hence for years and years, victim companies have been unable to get over that bar. Ms. Powers encourages investors to read the complaint in which the result of a special investigative technique allowed them to get details for thousands of transactions down to the millisecond. NWBO is very proud of this and a lot of work thar went into it over the years that NWBO has been vigorously pursuing this case.
The Court found based on NWBO pleadings that the market maker defendants had spoofed the stock. Spoofing is a trading strategy where traders manipulate market prices by pretending to have interest in buying or selling assets without the intention to execute those trades. In the U.S., spoofing was explicitly made illegal by the Dodd-Frank Wall Street Reform and Consumer Protection Act of 2010. In addition to spoofing, NWBO had to demonstrate three other acts in its pleading. Two of these were reliance which essentially means that the trading data used in the pleading is valid and scienter which means that the defendants knowingly spoofed the stock with the intent to damage NWBO. The magistrate ruled in NWBO’s favor on reliance and scienter as well as spoofing.
Successfully Pleading Loss Causation is Key to Having the Motion to Dismiss Denied
The fourth and final element of the case is loss causation. This must establish that the illegal spoofing did cause financial damage to NWBO. It needs to be shown that that there is a connection between the defendants bad behavior and the damage it caused. The magistrate and the court said that NWBO hadn't pled sufficiently this element which is referred to as loss causation. The court was asking if they did manipulate the stock with the intention to harm, in what time frame and to what extent did this occur? Was it the same day? Was it within 24 hours? Was there a lingering effect that lasts for much longer-weeks, months or years? Encouragingly, the court and the magistrate specifically gave NWBO permission to amend its complaint to strengthen the pleading claims on loss causation.
An amended filing that only deals with loss causation has been submitted. There is no need to reargue reliance, spoofing or scienter. The defendants made their objections to the filing as it pertains to loss causation and NWBO replied. The company is now waiting for the magistrate to evaluate this and give his report and recommendation, which the court will then act on. It has been a long time ( a year and a half) since the complaint was filed. They have tried to press the schedule as much as they can but defendants went to great lengths to slow the process. Still, this is a pretty good pace from what they understand. It's in line with other cases of this type and may actually be a little bit faster. It's just that the wheels of justice grind slowly.
Strong Reasons to Believe Defendants Motion to Dismiss Will Be Denied
There are no guarantees, but they are optimistic about what the ultimate decision will be about the motion to dismiss, namely, that the motion to dismiss will be denied and the case will be allowed to go forward to discovery. They believe the case is meritorious and strong and that there will be an opportunity to recoup damages and to get the manipulation to stop.
Looking Forward
To this point, the presentation focused on accomplishments reached in the last 18 months. The next part of the presentation dealt with potential milestones in the next 18 months or so. CEO Powers laid out priorities, grouping them into three categories: top priorities, second priorities and then feasible priorities.
Top Tier Priorities
MAA Approval for DCVax-L in the UK
Needless to say the top priority on which they are laser focused is to complete the process and hopefully obtain the first commercial approval of DCVax-L in the UK. NWBO believes that the MHRA is following the hundred and fifty day process that they have but do not have confirmation and don't have a way to be sure. They believe that the hundred and fifty day process involves approximately three stages and the time frame of each stage is approximate. The first stage is approximately 80 days of initial review of the application. The second is approximately a 60 day clock stop when the agency delivers a list of questions to the sponsoring company. It's not just that they deliver questions; they may also ask for supplementary information. After the 60 days or however long the clock stop turns out to be, there is a third stage of approximately 70 days in which MHRA may seek additional information. NWBO is trying to guess what they might ask and to prepare to provide all the answers and for additional information in the third stage.
In the US, the FDA gives a target date for reaching a decision. There is not an equivalent thing in the UK. The approximate timeframes of the three stages also depend also on MHRA's workload and backlog. CEO Powers also emphasized that during this approximate 150 day process there will be numerous inspections that will have to be completed before an MAA decision can be rendered. NWBO as is typical for biopharma companies will not provide information on interim steps or questions asked and answered. They will just release the result when the MAA reaches its decision.
Preparing for the Commercial Launch
Another top priority is preparation for commercial launch. They have been working on this for years, but there is still a lot to do. They anticipate beginning commercialization using the existing grade B labs while pursuing . the buildout process for the grade C labs. As a part of this preparation for commercialization, they will be finishing the process previously described for the Flask Works machine to establish a grade C lab. The design work has been done. Advent will need to conduct a large number of engineering or practice runs. They will need to collect all the data and compare it with the data from the DCVax-L products produced by the existing manual process.
NWBO will have to demonstrate to regulators that the Flask Works machine operates properly and doesn’t shed particles into the clean room air. They also have to show that it produces a product that's the same or acceptably close to the same. They will collect all the data and do equivalency studies and collect the data from that. These will be submitted to the regulator for approval.
These are all things going on in parallel as the MAA process and inspections are taking place. They also need to do some more mundane things like expanding operating arrangements. One example is expanding contractual arrangements for leukapheresis blood draw slots. They have to contract for those and they have to pay for them so it's such a little bit of chicken and egg calibration. They want to have enough slots but don't want to get too far ahead of needs and needlessly increase the burn rate. So they will be calibrating contract arrangements for more of those slots. They will certainly need to expand the staff who will handle logistics. As part of the preparation for commercialization, they will need to determine what the pricing model is going to be for DCVax-L. That's something on which they are working with expert advisors and it will be important obviously and again all these tracks are going on in parallel.
Applying for Reimbursement
Following MAA approval, they will need to go through the process of applying for reimbursement. In the UK, the gatekeeper is NICE. CEO Powers says that NICE has been absolutely supportive in their dealings with NWBO and she cannot say enough wonderful things about the relationship so far. They have been reaching out to NWBO every couple of months to check on the status of things. She couldn't imagine a government agency that's been as supportive as they have been. NWBO will need to do a health economics model that justifies the cost benefits of the DCVax-L treatment. NWBO has engaged specialized consultants to develop that model. This is certainly one of top priorities over the coming 18 month period.
Filing for Approval in Other Countries
NWBO is planning to submit applications for approval in other countries. They are very happy to be going through the first approval process in the UK because they have a very fast process; probably the fastest in the world. In submissions to other counties, they have an important head start because one big components of the application anywhere is data comparable to the trial master file combined with the 20 years of efficacy and safety data from every program that's ever been done with DCVax-L This includes use with cancers other than GBM.
Expanding the Management Team
The management team needs to be substantially expanded. Core members of the senior team have been wearing multiple hats fulfilling multiple roles. In many cases these normally would require a separate senior management person. They need to ramp up, but want to be highly selective as they expand the management team.
Vigorously Pursuing the Lawsuit
The last item in the grouping of top priority is to continue to vigorously pursue the lawsuit in New York against the parties that they believe have been and are continuing to manipulate the stock.
Second Grouping of Priorities
Pediatric Trial of DCVax-L in the UK
NWBO is planning to initiate a pediatric glioma trial with DCVax-L in the UK as a requirement by MHRA. CEO Powers emphasized that completing the trial itself is not a specific requirement for obtaining approval for the adult GBM indication. What was in fact a prerequisite in order to file the MAA was that they had an approved plan. This was a long process in the UK that involved a year and a half of discussions with pediatric neurosurgeons and oncologists before reaching conceptual agreement. NWBO is going to proceed with just one of the two planned pediatric trials first and the second one will be sequential rather than simultaneous. This is actually a good thing as it will reduce the bandwidth and resource requirement.
Restarting the DCVax Direct Program
NWBO has been eager to restart the DCVax Direct program. The first requirement is to restart manufacturing which requires a technology transfer to Sawston. This is necessary because the product was only produced in the US by parties who are no longer operational. This requires the drafting of a whole new set of standard operating procedure, regulatory documents.
Usually a technology transfer, especially for a cell therapy, is a minimum of at least six months of work. There have been two major challenges that have been faced and hopefully will soon be behind NWBO. One related to the machine that is used for the first stage of the process and the other to some key ingredients in the process. Restarting the manufacturing process is a significant priority. There will be a press release once manufacturing is restarted
Once manufacturing is restarted NWBO is very eager to get the clinical trials underway. The early stage trial was a phase one trial which was conducted at MD Anderson. It treated 13 different types of very diverse, inoperable solid tumors-pancreatic, breast, lung colorectal, et al. There were very encouraging survival extensions in metastatic patients who had failed all other treatments. DCVax Direct was really encouraging in this extremely difficult to treat patient group. Today with all the billions that have been spent by the pharma and biotech industry on cancer development, there is not very much that can be done with patients who have inoperable, metastatic solid tumors.
DCVax Direct is a very promising technology because it is directly injected into the tumor. In many cases, the tumor can't be surgically removed because there are too many metastases or because of where it is located. With image guidance physicians can reach almost any location in the body and inject DCVax directly into the tumor. Ms. Powers said that she’s not aware of any treatment that has had the kind of encouraging results shown in phase one trial at MD Anderson.
Starting Combination Trials
In all of its public presentations about the trial results in the phase 3 trial, NWBO has emphasized the survival extensions with DCVax L when used as a monotherapy in combination with standard of care. This is version 1.0 of the DCVax L technology platform. They are eager to build on that by combining DCVax-L with drugs having different mechanisms of action. Its benign safety profile and broad spectrum lends itself to combination therapies. It is eminently combinable with treatments such as checkpoint inhibitors (Keytruda and Opdivo), targeted therapies, chemotherapies and indeed almost any variety of therapy. They have received considerable interest from various companies. NWBO has some collaboration discussions underway and one of their priorities is to do one or more of those combination trials in the not too distant future.
The DCVax-L phase 3 trial was one of the biggest and without question the longest trial ever done in glioblastoma. NWBO believes that it will be a major landmark study in the field. However, they now want to do future trials more focused and using faster path tumor shrinkage endpoints. They want to focus particularly on clinical trials where tumor response (meaning tumor shrinkage) can be the endpoint as opposed to overall survival. Tumor shrinkage can be seen in a matter of months while survival takes years. They have so many opportunities that the challenge is choosing the right one.
Partnering
NWBO has had questions from shareholders as to whether they are open to partnering. Ms. Powers cited a couple of examples of potential partnering deals especially now that they have this this tool chest of new technologies and intellectual property. They are looking for deals that have either strategic or financial value. This could be a regional partnering. They have emphasized filing and maintaining their IP in a wide range of countries. They would also consider partnering for a specific application.
Listing on a National Exchange
Shareholders have also asking about up listing to a national exchange from the OTC. The company realizes that some investors are experiencing difficulties with some brokers with share management and purchases. They will be looking to up list when the time is right.
Conclusion
Ms. Powers in her concluding comments said that she had tried in this presentation to give an overview of a lot of different areas without going into great detail. She feels they have made tremendous progress in the last 18 months and are a different and much stronger company. While there are no guarantees, she believes they are well positioned to get their first product approval and begin commercialization with DCVax-L in the UK. They believe that the infrastructure and the systems that they have been working on for years are in order to build for the day that's now arriving. They have the physical facilities, operating systems and strategies that can facilitate commercialization
She believes that through in-licensing they have built a tool chest that provides tremendous growth opportunities. She is painfully aware that the share price does not currently reflect the progress that has been made. She believes that they can continue making progress in building intrinsic value if they can continue taking action against parties that they believe are artificially manipulating and holding the shares down. They also will work to attract institutional investors. Ms. Powers thinks that the combination of building intrinsic value and fighting back against manipulation will ultimately lead the market to recognize the value.
© 2024, EXPERT FINANCIAL ANALYSIS AND REPORTING | SMITH ON STOCKS + WORDPRESS/AGREGADO | TERMS OF USEwhat other possible deals are mentioned in the forward looking 6/29/24 ASM transcript ?
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2)Excellent post by Chiugray 5/8/24
TiltMyBrain, DCVax is about to give a knockout 1-2 punch against brain tumors and will mark a historic moment to the joy of cancer patients and oncologists.
1. Regulatory approvals (first UK, then globally) DCVax-L for stage 4 brain tumors/GBM
(replaces standard of care, generates robust immune memory, potential for cure, non-toxic)
2. Validation for off-label to add Poly-ICLC (adjuvant to DCVax-L therapy) for stage 3 brain tumors
(UCLA phase 2 clinical trial results, Nature scientific publication)
Excerpts from this Nature publication on the UCLA Phase 2 clinical trial:
- "results support the conclusion that DC vaccination with poly-ICLC induces Type I and Type II IFN responses more effectively than with adjuvant resiquimod or a dendritic cell vaccine alone"
- "combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses"
- "placebo: 7.7 months, poly-ICLC: 52.5 months"
- "for the IDH mutant/Grade III cohort, all four patients that received ATL-DC + poly-ICLC treatment are still alive at the cutoff date (three of the patients have survival >120 months and one > 112 months), and they have significantly longer OS and PFS compared to... ATL-DC + resiquimod or ATL-DC alone"
Off-label drug use is common in cancer treatment because
- many cancer drugs are effective against more than one type of cancer
- cancer treatment often involves the use of combination chemotherapy
...
The FDA usually does not approve combinations of chemotherapy. There are so many of them that it would not be practical to approve each combination.
Health insurance coverage of off-label drugs in cancer treatment
Medicare and many insurance companies pay for off-label drugs for cancer treatment, as long as the off-label uses are listed in an approved compendium. A compendium is a collection of drug summaries put together by experts who have reviewed data about the drug’s use in patients.
https://cancer.gov/about-cancer/treatment/drugs/off-label
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3)what other possible deals are mentioned in the forward looking 6/29/24 ASM transcript ?
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174706145
1) MANUFACTURING PARTNERSHIP:
What we are transitioning to now, and we're able to do this because of the FlaskWorks system, is we're transitioning to grade C labs, which would roughly be more like class 100, 000 in the US. In other words, it's a lower level of rigor and sterility, and you can only do that when you have your whole manufacturing process is done in a closed way. The word closed is a magic word in the world of medical manufacturing. Right?
So you can start to see, even if we get part of the way towards 15,000 a year, that is an enormous amount of patients, especially for personalized cell therapies. My understanding is, for example, big company, the big companies who bought the CAR T cell technologies, in their first years of commercial operations, made 50 patient products. Right? So, you know, having the eventual capacity to make up to 15,000 patients would be absolutely enormous.
2)PARTNERING TO EXPLOIT ROSWELL TECHNOLOGY:
Now just recently, we announced one that was particularly big. I mean, ginormous. And that's the arrangement, the in-licensing package that we did from Roswell Park. But if you noticed, even in that announcement, we explained that that package from Roswell covered 7 years of work by this leading research group on dendritic cell technologies. But we had also completed last year, an in-license of a package of the original older foundational work, that that group had spent 17 years developing, at another institution. And we have in-licensed both of those packages. And we purposely stayed in stealth mode while we put all the pieces together, because we believe, in our own analysis, that the whole, the sum is greater than the parts.
And those two packages together have some just wonderful things in them. They include enhanced versions of dendritic cells. They also include technologies that are complementary to, to use with dendritic cells. For example, a combination treatment regimen, in a trial, or agents to just be immune booster agents, that kind of thing. And if you think about it, interestingly, this collection of new tools or technologies, gives us a lot of growth opportunities, which we can use together with our existing DCVax platforms, which as you know, we have two versions of the platform, DCVax-L for operable tumors, DCVax-Direct that you haven't heard much about recently, but which will be coming up again, now I'm happy to say, for inoperable tumors. We can use these complementary technologies with our own DCVax platforms.
3) PARTNERSHIP FOR TWO ROSWELL PHASE 2 TRIALS:
So we start to have a pipeline that has complementary things, but has many permutations and combinations that we can can do. And, obviously, one of the really nice things about the package, and I was, we were surprised because people, maybe it didn't quite register. But as we said in our announcement, there are two phase 2 trials currently underway with these technologies that we in licensed. Okay? And these two clinical trials are fully funded by grants, and they're being fully carried out by the investigators.
So we don't pay anything, and we don't do anything. But these are the results of technologies that we now have. So those will be going along in the background in parallel, while we're busily working on the MAA, and all of that. And if they produce positive encouraging results, we will then take them on into phase 3. And, we we think Roswell, which is an absolutely top tier. If you don't know, it's a very prestigious institution, very top tier cancer center. We think they've done a marvelous job of developing the technologies at the research stage ,and then the early clinical trial stage, and even now into the mid stage clinical trials.
And we're really gratified that they chose us to pass the baton to, to take it forward, for late stage clinical trial ,and hopefully, eventually, the commercialization. So, these are some of the, intellectual property, but we've been quietly in-licensing quite a number of different pieces of technology that we feel will be useful building blocks in building our, our franchise. And we've also, been putting some collaborations in place. So we haven't announced those yet, but, those will be, something that will be coming along. Okay.
4)PEDIATRIC GLIOMA PARTNERSHIP:
Okay, second grouping of priorities for this going forward period: we plan to initiate the pediatric glioma trial. Just so everybody understands, that conducting the trial itself, is not specifically a requirement connected to our obtaining approval for our adult medicine. What was a requirement, it was in fact a prerequisite, and it was a requirement in order to, for our application to be validated, which it has been as we publicly reported. We had to have an approved plan. We don't have to have completed the trial. So we're going to be pursuing that.
5)DC VAX DIRECT PARTNERSHIP FOR 13 SOLID TUMORS:
We treated 13 different types of solid tumors, very diverse, pancreatic, breast, sarcoma, lung, colorectal. I mean, very diverse solid tumors, with very encouraging survival extensions in patients who were metastatic, and had failed every other treatment, and were pretty, pretty broken. DCVax-Direct. So that was really encouraging in the phase 1 trial. And even today, with all the billions that have been spent by the whole pharma and biotech industry on cancer treatments, when you have metastatic solid tumors today, there's not very much for you, as a patient.
6)COMBO TRIAL PARTNERSHIPS:
You can imagine combining it with checkpoint inhibitor drugs, with targeted therapies, with chemotherapies, any variety of type of therapy. So we, we have some collaboration discussions underway, and at the appropriate time, because we only announce things when they're significant, and they're done. Right? We don't say, and that you know, giving our forward perspective, is quite unusual for us. But, anyway, again, these are forward looking statements. Everybody knows that. Right? Just reminding you again.
But we have said in every presentation, we are eager to combine DCVax-L with these other combinations. And so one of our many priorities, for the going forward period, is to do one or more of those combinations. And we've received considerable interest from various parties for that. So, we are looking forward to that. One thing I will say about our general approach, as we look forward on further clinical trials, is this: We want to focus particularly on clinical trials where tumor response, meaning tumor shrinkage, can be the endpoint as opposed to overall survival being the endpoint.
Why? Because, if you're going to see tumor shrinkage from a treatment, you can typically, potentially see it in a matter of months . . . and survival takes years and years. And we've just got done conducting one of the biggest, one of the longest, one of, you know, a real a major landmark in the field, in our opinion. But we would now like to do some more focused, faster path, tumor shrinkage endpoint trials. So we are, as we evaluate, I mean, we have so many opportunities in front of us now. Really, the challenge is choosing. Right? And so we we gotta steer ourselves, to the extent we can, towards that direction, to more shrinkage endpoints.
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ae kusterer
Re: None
Sunday, July 07, 2024 9:22:11 AM
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what other possible deals are mentioned in the forward looking 6/29/24 transcript ?
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=174706145
1) MANUFACTURING PARTNERSHIP:
What we are transitioning to now, and we're able to do this because of the FlaskWorks system, is we're transitioning to grade C labs, which would roughly be more like class 100, 000 in the US. In other words, it's a lower level of rigor and sterility, and you can only do that when you have your whole manufacturing process is done in a closed way. The word closed is a magic word in the world of medical manufacturing. Right?
So you can start to see, even if we get part of the way towards 15,000 a year, that is an enormous amount of patients, especially for personalized cell therapies. My understanding is, for example, big company, the big companies who bought the CAR T cell technologies, in their first years of commercial operations, made 50 patient products. Right? So, you know, having the eventual capacity to make up to 15,000 patients would be absolutely enormous.
2)PARTNERING TO EXPLOIT ROSWELL TECHNOLOGY:
Now just recently, we announced one that was particularly big. I mean, ginormous. And that's the arrangement, the in-licensing package that we did from Roswell Park. But if you noticed, even in that announcement, we explained that that package from Roswell covered 7 years of work by this leading research group on dendritic cell technologies. But we had also completed last year, an in-license of a package of the original older foundational work, that that group had spent 17 years developing, at another institution. And we have in-licensed both of those packages. And we purposely stayed in stealth mode while we put all the pieces together, because we believe, in our own analysis, that the whole, the sum is greater than the parts.
And those two packages together have some just wonderful things in them. They include enhanced versions of dendritic cells. They also include technologies that are complementary to, to use with dendritic cells. For example, a combination treatment regimen, in a trial, or agents to just be immune booster agents, that kind of thing. And if you think about it, interestingly, this collection of new tools or technologies, gives us a lot of growth opportunities, which we can use together with our existing DCVax platforms, which as you know, we have two versions of the platform, DCVax-L for operable tumors, DCVax-Direct that you haven't heard much about recently, but which will be coming up again, now I'm happy to say, for inoperable tumors. We can use these complementary technologies with our own DCVax platforms.
3) PARTNERSHIP FOR TWO ROSWELL PHASE 2 TRIALS:
So we start to have a pipeline that has complementary things, but has many permutations and combinations that we can can do. And, obviously, one of the really nice things about the package, and I was, we were surprised because people, maybe it didn't quite register. But as we said in our announcement, there are two phase 2 trials currently underway with these technologies that we in licensed. Okay? And these two clinical trials are fully funded by grants, and they're being fully carried out by the investigators.
So we don't pay anything, and we don't do anything. But these are the results of technologies that we now have. So those will be going along in the background in parallel, while we're busily working on the MAA, and all of that. And if they produce positive encouraging results, we will then take them on into phase 3. And, we we think Roswell, which is an absolutely top tier. If you don't know, it's a very prestigious institution, very top tier cancer center. We think they've done a marvelous job of developing the technologies at the research stage ,and then the early clinical trial stage, and even now into the mid stage clinical trials.
And we're really gratified that they chose us to pass the baton to, to take it forward, for late stage clinical trial ,and hopefully, eventually, the commercialization. So, these are some of the, intellectual property, but we've been quietly in-licensing quite a number of different pieces of technology that we feel will be useful building blocks in building our, our franchise. And we've also, been putting some collaborations in place. So we haven't announced those yet, but, those will be, something that will be coming along. Okay.
4)PEDIATRIC GLIOMA PARTNERSHIP:
Okay, second grouping of priorities for this going forward period: we plan to initiate the pediatric glioma trial. Just so everybody understands, that conducting the trial itself, is not specifically a requirement connected to our obtaining approval for our adult medicine. What was a requirement, it was in fact a prerequisite, and it was a requirement in order to, for our application to be validated, which it has been as we publicly reported. We had to have an approved plan. We don't have to have completed the trial. So we're going to be pursuing that.
5)DC VAX DIRECT PARTNERSHIP FOR 13 SOLID TUMORS:
We treated 13 different types of solid tumors, very diverse, pancreatic, breast, sarcoma, lung, colorectal. I mean, very diverse solid tumors, with very encouraging survival extensions in patients who were metastatic, and had failed every other treatment, and were pretty, pretty broken. DCVax-Direct. So that was really encouraging in the phase 1 trial. And even today, with all the billions that have been spent by the whole pharma and biotech industry on cancer treatments, when you have metastatic solid tumors today, there's not very much for you, as a patient.
6)COMBO TRIAL PARTNERSHIPS:
You can imagine combining it with checkpoint inhibitor drugs, with targeted therapies, with chemotherapies, any variety of type of therapy. So we, we have some collaboration discussions underway, and at the appropriate time, because we only announce things when they're significant, and they're done. Right? We don't say, and that you know, giving our forward perspective, is quite unusual for us. But, anyway, again, these are forward looking statements. Everybody knows that. Right? Just reminding you again.
But we have said in every presentation, we are eager to combine DCVax-L with these other combinations. And so one of our many priorities, for the going forward period, is to do one or more of those combinations. And we've received considerable interest from various parties for that. So, we are looking forward to that. One thing I will say about our general approach, as we look forward on further clinical trials, is this: We want to focus particularly on clinical trials where tumor response, meaning tumor shrinkage, can be the endpoint as opposed to overall survival being the endpoint.
Why? Because, if you're going to see tumor shrinkage from a treatment, you can typically, potentially see it in a matter of months . . . and survival takes years and years. And we've just got done conducting one of the biggest, one of the longest, one of, you know, a real a major landmark in the field, in our opinion. But we would now like to do some more focused, faster path, tumor shrinkage endpoint trials. So we are, as we evaluate, I mean, we have so many opportunities in front of us now. Really, the challenge is choosing. Right? And so we we gotta steer ourselves, to the extent we can, towards that direction, to more shrinkage endpoints.