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xoma, thanks for reposting that. That’s one of the interesting discussions by Linda Powers that I was thinking of, and it always makes me wonder how many other combination discussions have not been made public. It’s a bit outdated though because that UCLA trial in recurrent Glioblastoma is now in combination with Merck and Keytruda, and no longer with Bristol Myers and Opdivo.
abeta, it means that about 23 out of every 100 patients treated with DCVax, would be expected to be alive at their 5-year milestone anniversary. For those patients that didn’t receive DCVax, and only received the standard of care, according to comparable historical trials, only about 7 out of 100 patients would be expected to reach their 5-year anniversary.
It does not mean that once a patient reaches their 5-year anniversary, that the chance of survival beyond that is 23%, if that is what you’re asking. The curve is nearly flat at that point, and there is anecdotal evidence with DCVax and other immunotherapies to suggest that once a patient lives beyond a certain point, usually around 3 or 4 years, the chance of continuing to survive is very high.
spartex, the topic is very relevant to the potential value of the DCVax platform and Northwest Bio’s share of that $200B market that article discusses.
spartex, yes Linda Liau, Linda Powers, Dr. Bosch, and many other experts have all discussed combining DCVax with other immunotherapies including Keytruda, to treat many types of cancer. And yes, I believe that the label could be expanded rapidly with the appropriate resources, exactly as Merck has done with Keytruda. I believe that is exactly Linda Powers’ intention, both as single agent monotherapy, and also in combination with other immunotherapies including Keytruda.
Here is a study of 188 distinct indications of 107 cancer drugs which shows that using surrogate endpoints of tumor response rate can reduce the average study time to 25 months, and as little as 11 months: https://pubmed.ncbi.nlm.nih.gov/30933235/
Keytruda has been approved in over 20 indications in less than 6 years from the first approval.
https://www.drugs.com/history/keytruda.html
Development Timeline for Keytruda
Jun 29, 2020 FDA Approves Merck’s Keytruda (pembrolizumab) for First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer
Jun 24, 2020 FDA Approves Merck’s Keytruda (pembrolizumab) for the Treatment of Patients with Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (cSCC) that is Not Curable by Surgery or Radiation
Jun 17, 2020 FDA Approves Second Biomarker-Based Indication for Merck’s Keytruda (pembrolizumab), Regardless of Tumor Type
Apr 28, 2020 FDA Approves Merck’s Keytruda (pembrolizumab) for Use at an Additional Recommended Dose of 400 mg Every Six Weeks for All Approved Adult Indications
Jan 8, 2020 FDA Approves Keytruda (pembrolizumab) for Patients With BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer
Sep 17, 2019 FDA Approves Keytruda (pembrolizumab) plus Lenvima (lenvatinib) Combination Treatment for Patients with Certain Types of Endometrial Carcinoma
Jul 31, 2019 FDA Approves Keytruda (pembrolizumab) for Recurrent Locally Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus
Jun 18, 2019 FDA Approves Keytruda (pembrolizumab) for the Treatment of Metastatic Small Cell Lung Cancer (SCLC)
Jun 11, 2019 FDA Approves Keytruda (pembrolizumab) for First-Line Treatment of Head and Neck Squamous Cell Carcinoma
Apr 22, 2019 FDA Approves Keytruda (pembrolizumab) in Combination With Inlyta (axitinib) as First-Line Treatment for Patients With Advanced Renal Cell Carcinoma (RCC)
Apr 11, 2019 FDA Approves Expanded Monotherapy Label for Merck’s Keytruda (pembrolizumab) for First-Line Treatment of NSCLC
Feb 19, 2018 FDA Approves Keytruda (pembrolizumab) for the Adjuvant Treatment of Patients with Melanoma with Involvement of Lymph Node(s) Following Complete Resection
Dec 19, 2018 FDA Approves Keytruda (pembrolizumab) for the Treatment of Patients with Recurrent Locally Advanced or Metastatic Merkel Cell Carcinoma
Nov 9, 2018 FDA Approves Keytruda (pembrolizumab) for the Treatment of Patients with Hepatocellular Carcinoma (HCC) Who Have Been Previously Treated with Sorafenib
Oct 30, 2018 FDA Approves Keytruda (pembrolizumab) in Combination with Carboplatin and Either Paclitaxel or Nab-Paclitaxel for the First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)
Aug 21, 2018 FDA Approves Expanded Label for Merck’s Keytruda (pembrolizumab) in Patients with Metastatic Nonsquamous NSCLC with No EGFR or ALK Genomic Tumor Aberrations
Jun 13, 2018 FDA Approves Keytruda (pembrolizumab) for Treatment of Refractory or Relapsed Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
Jun 12, 2018 FDA Approves Keytruda (pembrolizumab) for Previously Treated Patients with Recurrent or Metastatic Cervical Cancer Whose Tumors Express PD-L1
Sep 22, 2017 FDA Approves Merck’s Keytruda (pembrolizumab) for Previously Treated Patients with Recurrent Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer Whose Tumors Express PD-L1
May 13, 2017 FDA Approves Keytruda (pembrolizumab) as First Cancer Treatment for any Solid Tumor with a Specific Genetic Feature
May 18, 2017 FDA Approves Merck’s Keytruda (pembrolizumab) for Certain Patients with Locally Advanced or Metastatic Urothelial Carcinoma
May 10, 2017 FDA Approves Merck’s Keytruda (pembrolizumab) as First-Line Combination Therapy for Patients with Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC), Irrespective of PD-L1 Expression
Mar 15, 2017 FDA Approves Merck’s Keytruda (pembrolizumab) for Classical Hodgkin Lymphoma (cHL)
Oct 24, 2016 FDA Approves Merck’s Keytruda (pembrolizumab) for First-Line Treatment of Certain Patients with Metastatic Non-Small Cell Lung Cancer
Aug 5, 2016 FDA Approves Merck’s Keytruda (pembrolizumab) for Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
Dec 18, 2015 FDA Approves Expanded Indication for Keytruda (pembrolizumab) for the Treatment of Patients with Advanced Melanoma
Oct 2, 2015 FDA Approves Keytruda (pembrolizumab) for Advanced Non-Small Cell Lung Cancer
Sep 4, 2014 FDA Approves Keytruda (pembrolizumab) for Advanced Melanoma
abeta, those percentages are estimates for the treatment arm (232 patients). So if a patient with GBM receives the current standard of care plus DCVax, that would be their chances of living that long. It would be a huge advancement from the current standard of care, and may provide some hope for Glioblastoma patients. I think Northwest Bio is attempting to identify who is likely to benefit from this treatment, and will also combine DCVax with other immunotherapies, which should improve those percentages in the future. (and potentially eliminate toxic chemotherapy)
As longfellow said, the current alive number is a bit irrelevant to this percentage since this trial has been going on for 13 years and some of those early patients whose lives may have been extended by 3, 4, 5 or more years, could have passed by now.
Reefrad, Branko adjusted the DCVax curve back a few months to account for the difference in comparator curves. You can read about some of the assumptions he used on his earlier models, and the questions and answers about them on his old blog here: https://askthebranko.blogspot.com/?m=1
For anyone who doesn’t know about Branko’s model, it’s here: https://twitter.com/KrstevskiBranko/status/1315989744644321280/photo/1
I believe his milestone survival estimates will prove to be pretty accurate.
1 year - 91%
2 year - 51%
3 year - 32%
4 year - 25%
5 year - 23%
6 year - 20% (my estimate)
anders, both you and ex are wrong. Again. Trials to expand the label for other indications can be done in less than a year, but average about two years based on a surrogate endpoint such as tumor response rate. I’m not saying that Northwest Bio is capable of doing this at present, but if the trials were being run by Merck for example, in their own labs by their clinicians, it might.
And by the way, it doesn’t appear that you read the information that I provided about biomarkers. It doesn’t work the way you say.
Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials
Abstract
Importance: Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life.
Objective: To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS).
Design, setting, and participants: This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018.
Main outcomes and measures: The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS.
Results: In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months).
Conclusions and relevance: From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Prasad reported receiving royalties from his book Ending Medical Reversal; funding from the Laura and John Arnold Foundation; honoraria for grand rounds or lectures from several universities, medical centers, and professional societies; and payments for contributions to Medscape. Dr Prasad hosts the podcast Plenary Session, which has Patreon backers. No other disclosures were reported.
https://pubmed.ncbi.nlm.nih.gov/30933235/
This from the guy who tells others to “know what you own.” Sorry, but that is not an “offer that can’t be refused.” You might think that the market does not value DCVax-Direct, but you can bet that Linda does.
I have to point out that the PlusOne posts are probably the best I’ve seen for a long time. Another thank you to those posters and to countless others who continue to share and make this the best board on ihub. There are some here who can see the big picture by connecting the dots, but it seems there are quite a few others who can’t seem to see it until the dots have been drawn for them. That picture just got noticeably clearer this week. I’ve said this before, but it deserves repeating. Underestimate Linda Powers at your own peril!
Ssshhh. It's a secret.
Northwest Bio may be looking at simultaneous approval in all four jurisdictions.
Did you not know that the UK is now part of Project Orbis? (as of Jan 1) And possibly the EU could join?
Brexit deal to fast-track drugs will SAVE LIVES: UK now breaking free from EU red tape
EXCLUSIVE: BREXIT will help save lives by allowing new wonder drugs to be approved more quickly.
By SAM LISTER, DEPUTY POLITICAL EDITOR
PUBLISHED: 07:00, Mon, Oct 5, 2020 | UPDATED: 07:48, Mon, Oct 5, 2020
Health Secretary Matt Hancock revealed Britain will join forces with the best medical regulators in the world to speed up medicine licensing. The international team will focus on authorising innovative cancer treatments swiftly and safely. Britain will be free of European Union medical red tape from January 1.
Mr Hancock said: “This means that one of the benefits of Brexit will be faster access to life-saving treatments on the NHS.”
Britain is currently bound by European Medicines Agency (EMA) rules but stops being a member of the organisation when Brexit transition arrangements end in December.
The government has informally joined Project Orbis, set up to allow medical regulators to work together to fasttrack treatments, and will officially become a member from January 1. It means the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) will work with its counterparts in the United States, Canada, Australia, Singapore and Switzerland on assessing new treatments.
Mr Hancock said the government is determined not to “lose sight” of the benefits of Brexit. “As a member of the EMA we were constrained to operate within the European rules which are slower,” he said. “The MHRA was our regulator within the European system and was always at the cutting-edge of the European system and now we’ll work with similar regulators around the world.”
Pharmaceutical companies can submit pioneering treatments through Project Orbis to be reviewed by several countries at the same time, speeding up the process. But the MHRA will still have independence to make the final authorisation decision for the UK.
“We are teaming up with the fastest regulators in the world to get safe licences as fast as the science allows,” Mr Hancock said. “You have all the safety standards but you run different trials in parallel rather than one after the other and that means people can get life-saving treatments faster.
As a member of the EMA we were constrained to operate within the European rules which are slower. “Teaming up with Project Orbis means that we will be able to share the understanding between some of the world’s best medical regulators. “In the first instance the focus of Project Orbis will be on life-saving cutting-edge cancer drugs. “I feel incredibly proud that Britain’s amazing medical science and our world leading regulator are going to be able to save lives by doing what is right for Britain and right by the science in the most dynamic group of medical regulators in the world.”
Since Project Orbis was set up in May 2019 lifesaving treatments have already been approved for breast, lung, liver and endometrial cancer as well as chronic lymphocytic leukemia. Scientific research is using the latest technology and genomic research, which Britain is a “global leader” in, Mr Hancock said.
The Daily Express has been the leading champion for patients struggling to access medical innovations. Mr Hancock hailed our crusade to secure wonder drug Orkambi for patients with cystic fibrosis as “incredibly powerful”.
But the Cabinet minister warned that coronavirus is making some illnesses “harder to treat”. He was sent a letter by a group of GPs warning the action being taken to suppress the virus now "outweighs the benefits" because it is causing a rise in other types of death.
Mr Hancock said he had read the message but insisted the government’s response was the right one. “We’ve got to remember that there are some things that are harder to treat when the virus is at large,” he said. “When there’s a lot of virus cases, it’s harder to treat cancer. “Treating other conditions is easier for the NHS when the number of cases is low. “If Covid is out of control, that hits the NHS’s ability to treat other things like cancer. So to save lives from cancer as well as from Covid, we need to keep the virus under control. “I’m absolutely emphatic that the best way to keep people safe from other diseases is to keep coronavirus under control.”
Mr Hancock also warned GPs that they must offer all patients appointments in person if they want one, despite the shift towards online consultations.“GPs have Covid secure arrangements and every GP surgery should be accepting face to face visits as well as providing tele-medicine for people who want to see them from home,” he said.
The Health Secretary, who was struck down by Covid 19 at the start of the crisis, told how the coronavirus crisis has affected him. “My view is I get out of bed in the morning and I work as hard as I can and make the best judgments I can and then I go to bed. “I feel the weight of the responsibility on my shoulders to try to get as many decisions right as possible. “I don’t get all the calls right, nobody ever does. But I feel a very strong sense of duty to do the best I can.”
Mr Hancock said he was inspired by the millions of Britons who are “doing their bit”. “Fighting a pandemic is a team effort and the whole country is on the same side.”
The Health Secretary has come under pressure over his tough approach to imposing new rules after a surge in the virus. MPs overwhelmingly backed the renewal of emergency powers last week despite a threatened rebellion by some senior figures in his own party. He said the result “sums up the very significant majority for the strategy we are pursuing”. “I know that’s reflected in the country,” he added. “I also know how difficult the measures are. “But I think that the alternative of letting it rip would lead to more misery and death and I’m absolutely sure that that would be the wrong approach.”
https://www.express.co.uk/news/politics/1343604/Brexit-latest-cancer-wonder-drugs-matt-hancock-project-Orbis
Regulators discuss accelerated approvals, Project Orbis at DIA
Posted 16 June 2020 | By Michael Mezher
Regulators from the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Health Canada gave their perspectives on different issues related to accelerated approval pathways in their respective jurisdictions at the DIA Global Annual Meeting.
All three regulators offer their own form of accelerated approval based on less comprehensive clinical data than a traditional marketing approval would require. In the US, that pathway is dubbed accelerated approval (AA), while the EU version is called conditional marketing authorization (CMA) and in Canada it is referred to as notice of compliance with conditions (NOC/c). . .
Project Orbis
The regulators also discussed FDA’s recent collaborative review effort for oncology products that includes Australia’s Therapeutic Goods Administration (TGA), Health Canada, Singapore’s Health Sciences Authority (HSA) and Swissmedic.
When asked how products are identified for participation in Project Orbis, Keegan said, “We don’t have a formalized process, typically the review team will, in their discussions before the application comes in, ask about the timing of submission of an application to other agencies … and invite the sponsor to consider participation in Orbis, but there’s no reason that the sponsor couldn’t bring it up as well.”
Kegan said that the timing of submissions internationally is “a major issue,” as companies often target a handful of jurisdictions, such as the US and EU, for their initial submissions.
On Health Canada’s participation in Project Orbis, Robinson said, “it’s an opportunity … for new indications or new products to come to Canada sooner than they otherwise would,” adding that the initiative also gives reviewers from the different agencies more opportunities to interact.
Falk, when asked whether EMA would ever participate in Project Orbis, said he couldn’t comment, but emphasized that EMA has bilateral discussions with FDA related to ongoing submissions, “maybe on a daily basis.”
https://www.raps.org/news-and-articles/news-articles/2020/6/regulators-discuss-accelerated-approvals-project-o
Project Orbis
https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis
WOW!! THANKS ATLnsider. This is really huge news!! There will not be any ambiguity in the results, which was my biggest concern. I’m not really surprised by this news, as I’ve said that I think the primary endpoint would be changed to OS, but having this confirmation before TLD is VERY VERY good to know.
right kabunushi, we don’t know the details of the Advent services agreement. I posted that to show that the SOW’s for “activities related to the development of the Sawston facility and the compassionate use activities in the UK,” was not completed as expected by July, and it was actually extended on August 7th for an additional 12 months. That tells me that although there is a mid October completion date for phase 1 at Sawston, the facility will not be ready for manufacturing until well into next year. You’re probably aware that there were additional disclosures in the 10-Q that no compassionate use manufacturing occurred during Q2 due to lockdowns, travel restrictions, and personnel under lockdown, and this could be halted again if they’ve been restarted during Q3 and Q4. I suspect that the cell characterization and optimization work that needs to be done to produce DCVax on the MicroDEN system can’t be started until the phase 1 construction has been completed, but Advent personnel may have to prioritize the backlog of compassionate use cases over this work. What do you think?
flip, you caught my attention with that headline. The pharmaceutical cold-chain logistics business is an area I’m invested in, so the potential Covid-19 vaccines are of interest. Unfortunately, I doubt that Cognate or the cryogenic storage at Sawston will get any of the covid-19 vaccine business. In the past five years, there has been many partnerships and consolidation in the pharmaceutical distribution and cold-chain logistics business segment, and the new Covid-19 vaccine business will be handled by these major companies.
As a side note to investors praying for a buyout of NWBO: be careful what you wish for. That cryogenic logistics company, Cryoport (CYRX) may have some similarities to Northwest Bio because it had many long-time investors who were forced to endure declining stock prices and reverse stock splits over the years, and who were praying for a miracle buyout at $20 a share. Well that little company went from about $2 in 2017 to $60 last month!
Here’s a couple articles about Covid-19 vaccines cold-chain logistics if interested:
Logistics providers are getting ready for a Covid-19 vaccine surge
September 14, 2020
https://pharmaceuticalcommerce.com/cold-chain-focus/logistics-providers-are-getting-ready-for-a-covid-19-vaccine-surge/
Today’s pharma cold chain is going cryogenic
September 25, 2020 | Updated: September 29, 2020
https://pharmaceuticalcommerce.com/cold-chain-focus/todays-pharma-cold-chain-is-going-cryogenic/
ex, it’s clear that the Sawston facility is at least six months behind, at least partially due to COVID. You know guidance wasn’t given, but there was a clue in the last 10-Q:
Lykiri, the EDEN isn’t gen 2, and is actually a very important part of the MicroDEN system. It’s the enclosed fluidic system for culturing the dendrite cells, which replaces the expensive manual process of culturing in well plates or T-flasks that requires numerous interventions by highly trained technicians to replace the depleted differentiation medium during the five-day process, which increases the potential for contamination, and is performed under a laminar hood or in a biosafety cabinet surrounded by an expensive B-class cleanroom.
Been away awhile. Did I miss anything? :)
Interesting. So ex quietly concedes that DCVax will be in commercial production. So now it’s not that it won’t be, but simply WHEN. I think that WHEN, is likely to be considerably less than two years, but it’s still speculation. As usual though, I think you have mischaracterized the process. As iwasadiver suggests, Northwest Bio has already developed assays to identify and demonstrate the critical quality attributes of DCVax. Yes, they will need to fine tune and document the process to produce Northwest’s product to specification, but the only signing off by RA’s is done during the approval process. I understand the OP was discussing Sawston and the UK, but in the US, Cognate has had a couple years to fine tune the process, and I’m pretty sure that they are more than ready for commercial production.
Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
Guidance for Industry JANUARY 2020
https://www.fda.gov/media/113760/download
Some relevant sections here:
It may be crucial to establish CQAs as early as possible particularly when you plan to make manufacturing changes during product development because well-established CQAs are generally necessary for demonstrating product comparability by analytical methods. For additional information regarding establishing CQAs, please see FDA’s Guidance for Industry: “Q8(R2) Pharmaceutical Development” (Ref. 6), and “Q11 Development and Manufacture of Drug Substances” (Ref. 8). Information to support a CQA and results from specific studies or published literature may be included in Module 3 of the CTD in the “Manufacturing Process Development (3.2.S.2.6)” section or the “Pharmaceutical Development (3.2.P.2)” section (see Ref. 1) depending on whether the attribute pertains to a DS or a DP. Information may also be linked to the relevant nonclinical or clinical sections of the application in the CTD.
f. Manufacturing Process Development (3.2.S.2.6)
You should provide a description and discussion of the developmental history of the manufacturing process as described in the “Description of Manufacturing Process and Process Controls (3.2.S.2.2)” section of the CTD.
For early stage INDs, there may be differences between the manufacturing and testing of the toxicology lots and the material you plan to use in the clinical studies. For later stage INDs, there may be changes to the manufacturing process as part of process development, optimization, or under certain conditions there may be reprocessing step(s). In both situations, we recommend that you describe how manufacturing differences are expected to impact product safety and activity and to provide batch analysis information in the “Batch Analysis (3.2.S.4.4)” section of the CTD.
If you make significant manufacturing changes, then comparability studies may be necessary to determine the impact of these changes on the identity, purity, potency, and safety of the product. The extent of comparability testing would depend on the manufacturing change, the ability of analytical methods to detect changes in the product, and the stage of clinical development. For first-in-human studies, any differences between toxicology lots and clinical lots should be assessed for their impact on product safety. For later phase studies, especially those designed to measure product efficacy, differences in clinical lots should be assessed for their impact on product safety and activity.
Please note that it is important to retain samples of the DS and manufacturing intermediates, when possible, in the event that comparability studies are requested during future product development or after licensure of the investigational DP.
d. Batch Analysis (3.2.S.4.4)
You should include a table with test results for batches (or lots) of the DS that you have manufactured. For early stage INDs, this may include toxicology lots, developmental batches, engineering runs, or a single manufacturing run for clinical grade material. We recommend that you gain adequate experience with a new clinical manufacturing processes prior to making clinical material. This is especially critical following technology transfer to a new manufacturing facility, when manufacturing changes occur during development, and when multiple manufacturing facilities will be utilized. Please note that batches manufactured in different ways should be clearly identified in the submission. Information regarding process development of these materials should be outlined in the “Manufacturing Process Development (3.2.S.2.6)” section of the CTD. We recommend that you annually update this section of your IND as new batches are produced. You should indicate any batches that fail to meet release specifications and any action taken to investigate the failure according to your Quality Unit procedures (for Quality Unit information please see section V.C.1., “Appendices – Facilities and Equipment (3.2.A.1),” of this guidance). We recommend that you retain samples of production lots for use in future assay development, validation, or comparability studies.
I see restricted mean survival time (RMST) being used in immunotherapy trials, and think it could be used in this one.
Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time
Background
In recent years, immunotherapy has emerged as an alternative to chemotherapy and has been commonly viewed as a “game changer” for its potential to improve survival in a small proportion of patients.1–4 Randomized controlled trials often report measures of absolute survival benefit as differences in median survival times or differences in survival rates at specific times on Kaplan-Meier (KM) curves, whereas measures of relative survival benefit are reported as hazard ratios (HRs). However, reporting survival benefits of immunotherapy using these measures is potentially challenging.
For example, differences in median survival times are not estimable when the median survival time has not been reached in at least one of the trial arms.5 Although median survival time is an absolute survival measure of central tendency, it ignores the rest of the shape of the survival curve and treats long-term survivors as outliers (in contrast to mean survival), especially in cases in which the survival curves diverge after the median times. For relative survival benefit measures, HRs rely on the proportional hazards assumption, which depends on the number of observed events and not directly on exposure times or sample size of the study.6 HRs also may vary with time and thus violate the proportional hazards assumption.7,8 When the proportional hazards assumption is violated, the HR estimate may not be a statistically valid measurement of the treatment effect and becomes difficult to interpret clinically.
Immunotherapy trials sometimes exhibit nonproportional hazards, often because of late postprogression benefit (ie, after median survival times) or nonuniform divergence of the survival curves with potential plateau of the immunotherapy arm, with some trials even exhibiting crossing of survival curves.9–13 Median survival time also does not account for the “tail of the curve,” where the benefit of immunotherapy is more pronounced. Conventional measures of survival benefit have clinical limitations that were previously overlooked in immunotherapy trials.7
An interpretable and robust measure of clinical efficacy in survival analyses is critical to capture the full context of the benefits of oncology drugs and to make more informed decisions about the cost versus benefit of treatment options. With various studies showing a steady increase in the cost and variety of novel oncology drugs, the benefits associated with these drugs are not necessarily following the same upward trend.14–16
Restricted mean survival time (RMST) is increasingly being recognized as a robust and clinically interpretable summary measure alternative to HR and median survival time because it directly quantifies information of the entire observed survival curve.7,17 RMST is defined as the area under the KM curve up to a specific time point (t), which is the follow-up time of the study.18,19 Because this measure takes the average (ie, mean, not median) to summarize the entire survival profile, it does not rely on the proportional hazards assumption and captures the benefit across the entire trial.6,19 RMST difference is the difference between the area under the KM curve of the treatment arm and the control arm, and has been proposed as a measure of absolute survival benefit as an alternative to median survival time.6 RMST ratio is the ratio of the RMSTs between the treatment arm and the control arm.7 An RMST ratio >1 shows an improvement in survival in the treatment arm. Unlike the HR, which is a ratio of the rates of death,20 RMST ratio is a ratio of survival, which is arguably clinically more meaningful. For example, if survival associated with a control arm were high, a “good” HR (such as 0.5) would still represent little relative survival gained (RMST ratio may be only 1.2 rather than 2.0 as one may incorrectly expect) (supplemental eFigure 1, available with this article at JNCCN.org). It has been shown that HR is a relative measure of the rate of death and tends to overestimate the relative survival benefit.4,8,21 Comparability of treatment effects of immunotherapy drugs between RMST ratios and HR estimates has also been shown to be in general agreement.21 It has been suggested that it may be useful to report RMST in immunotherapy trials, in which the benefit typically is at the tail of the curve.3,21,22
Because RMST methods seem to be a reasonable alternative approach to measure survival benefits to overcome limitations of conventional measures, our study aimed to quantify the magnitude of survival benefit in oncology drugs recently approved by the FDA, using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit) in a meta-analysis. We further aimed to compare whether immunotherapy drugs provide a greater survival benefit than nonimmunotherapy drugs. . . .
https://jnccn.org/view/journals/jnccn/18/3/article-p278.xml
Dynamic RMST curves for survival analysis in clinical trials
Background
The data from immuno-oncology (IO) therapy trials often show delayed effects, cure rate, crossing hazards, or some mixture of these phenomena. Thus, the proportional hazards (PH) assumption is often violated such that the commonly used log-rank test can be very underpowered. In these trials, the conventional hazard ratio for describing the treatment effect may not be a good estimand due to the lack of an easily understandable interpretation. To overcome this challenge, restricted mean survival time (RMST) has been strongly recommended for survival analysis in clinical literature due to its independence of the PH assumption as well as a more clinically meaningful interpretation. The RMST also aligns well with the estimand associated with the analysis from the recommendation in ICH E-9 (R1), and the test/estimation coherency. Currently, the Kaplan Meier (KM) curve is commonly applied to RMST related analyses. Due to some drawbacks of the KM approach such as the limitation in extrapolating to time points beyond the follow-up time, and the large variance at time points with small numbers of events, the RMST may be hindered.
Methods
The dynamic RMST curve using a mixture model is proposed in this paper to fully enhance the RMST method for survival analysis in clinical trials. It is constructed that the RMST difference or ratio is computed over a range of values to the restriction time t which traces out an evolving treatment effect profile over time.
Results
This new dynamic RMST curve overcomes the drawbacks from the KM approach. The good performance of this proposal is illustrated through three real examples.
Conclusions
The RMST provides a clinically meaningful and easily interpretable measure for survival clinical trials. The proposed dynamic RMST approach provides a useful tool for assessing treatment effect over different time frames for survival clinical trials. This dynamic RMST curve also allows ones for checking whether the follow-up time for a study is long enough to demonstrate a treatment difference. The prediction feature of the dynamic RMST analysis may be used for determining an appropriate time point for an interim analysis, and the data monitoring committee (DMC) can use this evaluation tool for study recommendation. . . .
https://bmcmedresmethodol.biomedcentral.com/articles/10.1186/s12874-020-01098-5
That might not have been the only hint. After that Aug 27th PR, I questioned why Northwest Bio bothered to mentioned the air change rates as it seemed strange, but now after the news of the Flaskworks purchase, I think they may have been hinting that they will mostly be operating in a class C cleanroom with the MicroDEN equipment because it’s a closed, automated system. About 80% of the energy used by a cleanroom is consumed by the HVAC system, and since the air in a B-class cleanroom is 100 times cleaner, the requirements for the HVAC system are much greater, so the cost difference between operating in a (EU/UK classification) class B cleanroom and a class C cleanroom is quite significant. While some work may need to be performed in a Biosafety Cabinet surrounded by a class B cleanroom, the closed system operation will lower cleanroom costs considerably.
Connecting the dots . . . this might explain the double shifts at Sawston.
Week 6-9: Under the RTOR program, the applicant would officially submit the following items to their marketing application as a pre-submission as soon as they become available:
1. User fee, if applicable
2. Complete SDTM dataset package
3. Top line efficacy/safety tables/figures
4. Complete ADaM datasets for key efficacy and safety tables/figures for pivotal study (see OOD data specifications for requested format of safety datasets)
5. Key results, analysis, and datasets for other disciplines, if applicable.
6. Final study reports of all pharmacology and toxicology studies
7. Summary of data supporting dose and dosing regimen selection
8. The protocol and amendments (a list of major changes for each amendment), SAP, and DMC charter and DMC minutes
9. SAS programs
10. Proposed labeling
11. CRFs as required by regulation
12. All CMC information including list of all manufacturing, testing and critical intermediate facilities with addresses and FEI numbers other than stability data for registration batches (if not available) for drug substance(s), drug product.
13. Completed AAid.
Real-Time Oncology Review Pilot Program Timeline
Week 0-3: At the time of top-line results of a pivotal trial, an applicant can apply for the RTOR pilot by submitting a request via email to the appropriate application RPM. The clinical division director/deputy director, the review team (including reviewers, team leaders, and management from all relevant review disciplines, and CDRH as applicable) and OCE management will jointly decide whether the application can be selected for the RTOR pilot program. This decision will generally be made in approximately 15 business days of the receipt of notification through the appropriate division RPM.
Week 3-6: Once an application is selected, a teleconference with the applicant will be arranged in approximately 15 business days. The clinical division director/deputy director, the review team, and OCE staff will participate in this meeting. If the drug product is co-developed with a companion diagnostic, the diagnostic partner and CDRH should also be on the teleconference. If the applicant or the Agency determines that RTOR is not appropriate, a routine review procedure will be followed. Otherwise, FDA and the applicant will discuss the plan for RTOR in detail, reach tentative agreement on responsibilities, and proposed pre-submission timelines. The final SAP/protocol should be submitted as soon as possible. If the drug product is co-developed with a companion diagnostic, the applicant should outline timelines with the diagnostic partner and with CDRH.
Week 6-9: Under the RTOR program, the applicant would officially submit the following items to their marketing application as a pre-submission as soon as they become available:
1. User fee, if applicable
2. Complete SDTM dataset package
3. Top line efficacy/safety tables/figures
4. Complete ADaM datasets for key efficacy and safety tables/figures for pivotal study (see OOD data specifications for requested format of safety datasets)
5. Key results, analysis, and datasets for other disciplines, if applicable.
6. Final study reports of all pharmacology and toxicology studies
7. Summary of data supporting dose and dosing regimen selection
8. The protocol and amendments (a list of major changes for each amendment), SAP, and DMC charter and DMC minutes
9. SAS programs
10. Proposed labeling
11. CRFs as required by regulation
12. All CMC information including list of all manufacturing, testing and critical intermediate facilities with addresses and FEI numbers other than stability data for registration batches (if not available) for drug substance(s), drug product.
13. Completed AAid.
Week 10-16: Pre-submission meeting: In addition to responding to the applicant’s questions in the meeting package, FDA may share with the applicant preliminary key review questions or issues and critical analyses needed. If FDA requests additional analyses, the applicant may submit them before or at the time of submission of the marketing application. In some cases, the applicant may submit the requested additional analyses after the marketing application is submitted.?These discussions may be documented in the meeting minutes under the section, “Agreement of a Complete Application” for NMEs or original BLAs, under a new “Additional Items discussed” which can be added by the RPM for other applications or under specific questions as appropriate.
Week 16-22: The applicant submits the complete marketing application. Once FDA receives the completed application, the review clock will start. The complete application will include any remaining components previously not submitted in the presubmission.
https://www.fda.gov/about-fda/oncology-center-excellence/real-time-oncology-review-pilot-program
Regulatory Background
Typically, the FDA takes between 8 and 12 months to review a new drug application (NDA) or biologics license application (BLA). The speed of a review depends on if the product is given standard review (10 months, plus 2 months of administrative time) or priority review (6 months, plus 2 months of administrative time). Typically the FDA prioritizes the review of drugs and biologics for high-need conditions that are life-threatening or debilitating.
The review process focuses on a substantial amount of data, including pre-clinical data (such as toxicology testing or testing in animals), top-line clinical results (such as whether the product was shown to work), and the raw clinical trial data associated with each trial participant. The evaluation of this data is extremely time-consuming, and the review process is intended to identify potential problems with the application, identify safety signals, and determine if a product should be approved and, if so, for which indications of use.
The FDA will also review supplemental NDAs and BLAs, which are used to support the approval of a new indication of use for a drug. The review of an sNDA or sBLA can be somewhat abbreviated, since the FDA and sponsor already know a significant amount about a product.
However, the review still generally takes the standard amount of time since the FDA must review new data within a new clinical context. Some diseases may alter the effects of a drug, for example.
In recent years, the FDA has been pushed to accelerate the review of medications for patients with high levels of clinical need, and in particular those with conditions requiring rapid access to new innovations. One notable area in which this need is most evident is cancer.
In 2018, the FDA’s Oncology Center of Excellence established a pilot program known as Real-Time Oncology Review (RTOR). The goal of the program is to efficiently review applications for approval “to ensure that safe and effective treatments are available to patients as early as possible.”
A key feature of the program is the “real time” review element. Under a standard review, the FDA typically waits for an applicant to formally submit an application before it begins to review the company’s data. Under the RTOR program, the FDA will begin reviewing a prospective applicant’s data even before an application for approval is officially submitted. By communicating with a sponsor throughout the development process, the FDA is able to more efficiently and quickly review an application for approval once it is submitted.
This allows for any deficiency to be communicated to the sponsor early-on. By the time the application is submitted for review in its entirety, sponsors are presenting data that is analyzed and organized based on the reviewer’s initial analysis of the raw data. Additionally, during the pre-review period, the FDA is able to analyze safety and efficacy data, thereby shortening the entire review time.
According to former FDA commissioner Scott Gottlieb, the RTOR program could potentially save between 10% and 30% of the reviewer’s time.
For now, participation in the RTOR pilot criteria is limited to applications that have straightforward trial designs with easy-to-interpret endpoints, and therapies that demonstrate substantial improvement over available therapy. Though the pilot program was initially geared towards sNDAs and sBLAs, it has expanded to some new molecular entities (NMEs) submitted under an NDA or BLA as well.
Several products have been approved under the RTOR program. The first approval was an sNDA filed for Kisqali (ribociclib) in mid-2018. The review was completed in 20 days once the completed sNDA was submitted. Since then, multiple sNDAs and sBLAs have been approved under the RTOR program. In 2019, the first new molecular entity (NME) NDA was approved three months earlier than the approval goal date under the RTOR program.
I’ve yet to see anyone refute Carlo Rago’s Report on DCVax. Have you? Can you? No. Didn’t think so. So until it is, or can be refuted, then I think most intelligent people would support it.
https://www.scribd.com/document/411229128/A-Dendritic-Cell-Cancer-Vaccine-Shines-Brighter-for-Glioblastoma-Patients
yes, I noticed that too. Some significant volume in larger blocks this month since the acquisition announcement. Perhaps some larger players have joined the party. I’m not a big believer in the whole naked short squeeze theory on NWBO. I believe it was heavily shorted and attacked back in 2015, but think the perps have long since moved on. Having said that, the move to suspend the warrants and the continual accumulation of shares by longer-term investors may have taken quite a few tradable shares out of the float, and this may cause some interesting moves in the near future if fantastic news is released and big investors want to initiate substantial positions . . .
Meanwhile, Merck & Co (USA) is sitting on $11.1B in cash, (as of June 30) will receive a dividend of $8-9B from a spinoff in the beginning of 2021, and “remains highly focused on strategic business development.” There might be a clue as to what the “focus” is from their comments at ASCO 2020 during the Q & A:
Seamus Fernandez – Guggenheim Securities
Roger, just hoping you could comment on what feels like a couple of gaps in your internal development pool, and you’ve been accessing that by buying companies like ArQule. We’re seeing a lot of encouraging early data with point mutation kinase inhibitors. Just hoping you could give us a general sense of the Merck philosophy around kinase inhibitors development there and the ability or Merck’s interest in potentially building out that space. . .
Roger Perlmutter (President of Research)
Right. Thanks, Seamus. I think, first of all, the idea of looking at kinase inhibitors, of course, we are interested in them potentially in our using LENVIMA as a way to probe the protein tyrosine kinase inhibitor field. So field, of course, that I know extremely well and been involved in it for the better part of 40 years. So I have a lot of experience in looking at these molecules. I have to say that the – a lot of our attention has been drawn, of course, to immuno-oncology mechanisms because of what we found with KEYTRUDA. And we’ve naturally gone and asked, well, okay. What can you do to improve KEYTRUDA responses to get beyond where we are? Because we want to do better. And what we’ve learned some things about that, we’ve certainly shown that combinations in a variety of different settings can be helpful.
And that includes a lot of things that just kill tumor cells. So chemotherapy, working cytotoxic agents, traditional chemotherapy, radiotherapy, and, of course, signal transaction targeting agents. And all of them, I think, have similar kinds of effects. We’re interested in them. And what we’re trying to do is improve the benefit risk profile. So where we can find more selective compounds at a fewer adverse effects, in general, my guess is that those things will pair pretty well with KEYTRUDA, and we are interested in those. And we have tried to address them principally by taking advantage of the very large number of companies out there, small and large, that have pursued such things.
So that’s that. I don’t think the answer’s very different for the antibody drug conjugates. Of course, we’ve been doing experiments with these, particularly the EV data that you’ve seen in urothelial cancer is working with Seattle Genetics. And we’re looking at a number of other programs. We set up at the beginning, as you know, a mechanism, and Roy set this up, whereby we can provide KEYTRUDA to lots of people who are doing studies to get an early look at which sorts of things work in combination with KEYTRUDA. And that’s been very helpful to us in terms of targeting licensing opportunities and acquisitions. That’s the general approach we’re taking. And at the high level, I would say, it appears that things that kill malignant cells, maybe because they have a pro-inflammatory effect, perhaps for other reasons, tend to work pretty well in combination with KEYTRUDA.
https://seekingalpha.com/article/4351618-mercks-mrk-management-presents-oncology-event-asco-2020-conference-transcript
Right flip, that’s exactly what Gilead wisely decided to do with their Kite acquisition:
Kite gets freedom to fly after separation from Gilead
08-May-2019 By Vassia Barba
Gilead’s new CEO unties Kite as an independent business unit to give Yescarta’s manufacturer more autonomy in the biotech sky. During a first-quarter earnings conference call, Daniel O’Day, former Roche Pharmaceuticals CEO who took Gilead’s helm in March, announced the plan to separate Kite Pharma, which Gilead acquired in 2017 for $11,9bn . . .
https://www.biopharma-reporter.com/Article/2019/05/08/Gilead-separates-Kite-Pharma
Oddly enough, you’re not far off quackmastee. Most experts think the future of cell manufacturing will move from the current centralized manufacturing model, to a decentralized model, when the manufacturing technology advances further. If you want to understand this better, look at what Lonza, the largest Contract Development and Manufacturing Organization (CDMO) in the world is doing with their automated cell therapy manufacturing platform, Cocoon, and their recent collaboration with IsoPlexis. It’s quite amazing.
Lanza Brings Cell Therapies From Three Industries Into Cocoons
10-Mar-2020 By Vassia Barba
HTTPS://WWW.BIOPHARMA-REPORTER.COM/ARTICLE/2020/03/10/LONZA-PARTNERS-WITH-THREE-INSTITUTES-ON-COCOON-SYSTEM
IsoPlexis and Lonza Collaborate on Cell Therapy Manufacturing
August 20, 2020
https://www.genengnews.com/topics/bioprocessing/isoplexis-and-lonza-collaborate-on-cell-therapy-manufacturing/
IsoLight® automated proteomics platform will be used for functional quality analytics for products produced on Lonza’s Cocoon® automated cell manufacturing system.
IsoPlexis, which markets single-cell functional proteomics products, is collaborating with Lonza, a CDMO, to use IsoPlexis’ IsoLight platform for cell and gene therapy manufacturing. The IsoLight will provide quality analytics for cell therapy products generated on Lonza’s Cocoon, an automated, highly flexible cell therapy manufacturing platform, according to Sean Mackay, CEO of IsoPlexis.
The Cocoon allows for centralized and decentralized manufacturing of novel cell therapies, and the IsoLight provides a solution for the functional characterization of the cell therapy product, to ensure correlative functional potency of the manufactured cell product, continues Mackay.
Officials at both companies emphasize that improved end-to-end automation on the Cocoon minimizes the need for human involvement in numerous steps, and IsoPlexis’ systems provide functional phenotyping to characterize the cell therapy product from heterogeneous cell populations better.
“This collaboration between Lonza and IsoPlexis highlights the evolution of cell therapy manufacturing,” notes Matthew Hewitt, PhD, Head of Clinical Development and Personalized Medicine at Lonza. “As we continue to scale the manufacturing of cell therapies, it will be critical to characterize the quality and performance of these products with technologies such as IsoPlexis’ IsoLight.”
“We are excited to collaborate with Lonza to shape the future of cell therapy manufacturing and quality analytics,” adds Mackay. “As cell therapies continue to grow in therapeutic importance, manufacturing processes will require more precision relating to potency and performance. Alongside Lonza’s novel platform, the IsoLight will play a key role in enabling that increased level of precision and insight into cell product performance.”
IsoPlexis’ functional phenotyping has been published with a variety of CAR-T and cell therapy biopharma companies and academic institutions in areas ranging from research to process development and clinical biomarkers.
“In understanding that cell therapy manufacturing requires more precision regarding potency and performance two things come into play. You not only need to measure cytokines because that’s how cells communicate but you also need to measure each cell because all the cells act differently,” explains Mackay. “A single cell platform can measure all the cytokines and the functions from each cell. And that’s what we do. It turns out that small subsets of immune cells produce all the cytokines. We call them superhero cells and that’s what we capture.”
Patients who have these superhero cells in their cell product end up doing well in therapy because those superhero cells are driving almost all the response in the patients by themselves, he points out.
By using the Cocoon platform’s automated programming and on-board, real-time analytics, the collaboration will seek to significantly improve the biological understanding of starting material, process, and product analytics to enable more efficient manufacturing and higher quality cell therapies.
“We know that cell therapies work,” says Mackay. “They do so in blood cancers and they’re starting to show positive data in NK cell therapies and other cancers. You’re beginning to see good preclinical evidence in liver cancers.”
Bottom line, according to Mackay, is that there are going to be a lot of different patients who could be receiving cell therapies. Question is how to do you scale up these therapies around the globe?
“For that to happen manufacturing must have a couple of things take place: it has to be scalable and modular worldwide,” continues Mackay. “You also must have an understanding of the product as it relates to patient performance. That involves an aspect of precision medicine. You need to create reproducible metrics and manufacturing processes. The Cocoon and the IsoLight are trying to address that by bringing scalable, modular self-contained performance workflows that can be used anywhere.”
In the end? That seems just a little short sighted. We’re not there yet.
Yes, when you are fighting for your very survival, nothing else matters, and shareholders will not be well served if the company goes bankrupt. Linda Powers has done whatever is necessary, and has adapted and overcame whatever obstacles were in her path to approval for DCVax. If DCVax is approved, investors will be rewarded. Did it happen in the timeframe that some investors would prefer? For most, the answer is probably no. But successful investing is often about timing and patience. For some, that is a difficult lesson to learn.
excellent post highwayman. I think this is exactly what Linda was saying. So much will be learned from this trial, and knowledge gained from early trials will be confirmed in this trial, that Northwest Bio (and Linda Liau) will be responsible for making huge advances in the treatment of brain tumors. Finally, a new treatment paradigm, and hope for patients!
pgsd, it’s beyond uncomfortable for me. I don’t think that two-bit show is worthy of the science or this company. In my opinion, i’s humiliating and demeaning, and so difficult to watch, that I only watched the very first one, the one where Les had that bright pink makeup on his cheeks like a clown. I honestly can’t watch it. To me, it’s like an entertainer who was once at the top of their game, a headline act who once performed in the biggest venues, but has fallen on hard times, and is forced to perform in broken-down, cheap clubs to pay the bills. The company is now associated with this cheap lounge act. I’m normally a positive person and attempt to look for the bright side, but I fail to understand why Les would think this is a good idea, and I can only guess that he’s a promoter (cheap salesman?) and he’s trying to attract new retail investors. I’m not a fan of Jim Cramer or his show, but at least his show has a tiny bit of professionalism. But going on the Big Biz Show . . . it honestly make me question his judgement.
Outstanding posts senti, thanks for digging this up. I was pretty sure about Northwest Bio’s biomarker development, but this discovery would sure seem to confirm it. This is why Linda Powers continues to declare that DCVax is applicable to all solid tumors, and that she intends to prove it. Also interesting that all these years later, the FoundationOne CDx test is the companion diagnostic to identify patients with solid tumors that are TMB-H for this new Keytruda approval.
I posted an interview with Dr. Steven Brem, who is a professor and Chief of Neurosurgical Oncology at the University of Pennsylvania and also a Northwest Bio SAB member. According to him, Northwest Bio is looking at radiological markers as well. These will likely identify the tumor response rate, so that future trials can be ended more rapidly. This is all obviously important for the appropriate valuation of the DCVax platform and may be why some posters here want to create the impression that it will take a long time for multiple new trials for each new indication, which is simply not true.
anders, you have repeatedly asserted that it will be necessary to run trials for every organ-specific cancer, and that is completely outdated and WRONG. The FDA has approved, and will approve a treatment for cancer in ANY location in the body based on genetic or other type of biomarker that the treatment has been proven to work for in clinical trials. This first occurred with Keytruda back in 2017, and Keytruda was just approved again this June based on another biomarker.
This latest approval was very significant as it relates to Northwest Bio because DCVax has proven to be particularly effective based upon that same biomarker - ALL cancers with a high Tumor Mutational Burden (TMB). TMB is a measure of the number of gene mutations inside the cancer cells, which can be determined by a lab test. Cells that have many gene mutations (a high TMB) might be more likely to be recognized as abnormal and attacked by the body’s immune system. It’s very likely that this trial in Glioblastoma will identify other biomarkers in the long-lived patients in the survival tail, which will be used to expand the label to ALL cancers in the body with this biomarker.
Biomarkers at FDA
Biomarkers are a key medical product development tool capable of facilitating development of medical products and spurring innovation. When used in the right context, biomarkers have the potential to help expedite patient access to safe and effective treatments by reducing the time and cost of clinical trials while maintaining patient protections.
FDA is working to help speed the development of promising new therapeutics by developing regulatory science standards, reference libraries, research methods, and tools that are needed for integrating biomarker information into medical product development and clinical decision-making. . . .
https://www.fda.gov/science-research/about-science-research-fda/biomarkers-fda
FDA Approves Pembrolizumab for Tumors with Specific Genetic Features
https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-pembrolizumab-genetic-features
FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type
https://finance.yahoo.com/news/fda-approves-second-biomarker-based-104500734.html
Longfellow, I agree and have also said that I think the Power’s Plan is to remain independent and take an unconventional path just as you suggest. But I could point to a half dozen comments from Merck’s management that leads me to believe that they would be interested in DCVax. The question I’ve always had is: will they (or any BP) be willing to make an offer that can’t be refused? Anyway, here’s some recent comments from Merck”s ASCO 2020 presentation:
Q&A
Seamus Fernandez – Guggenheim Securities
Roger, just hoping you could comment on what feels like a couple of gaps in your internal development pool, and you’ve been accessing that by buying companies like ArQule. We’re seeing a lot of encouraging early data with point mutation kinase inhibitors. Just hoping you could give us a general sense of the Merck philosophy around kinase inhibitors development there and the ability or Merck’s interest in potentially building out that space. . .
Roger Perlmutter (President of Research)
Right. Thanks, Seamus. I think, first of all, the idea of looking at kinase inhibitors, of course, we are interested in them potentially in our using LENVIMA as a way to probe the protein tyrosine kinase inhibitor field. So field, of course, that I know extremely well and been involved in it for the better part of 40 years. So I have a lot of experience in looking at these molecules. I have to say that the – a lot of our attention has been drawn, of course, to immuno-oncology mechanisms because of what we found with KEYTRUDA. And we’ve naturally gone and asked, well, okay. What can you do to improve KEYTRUDA responses to get beyond where we are? Because we want to do better. And what we’ve learned some things about that, we’ve certainly shown that combinations in a variety of different settings can be helpful.
And that includes a lot of things that just kill tumor cells. So chemotherapy, working cytotoxic agents, traditional chemotherapy, radiotherapy, and, of course, signal transaction targeting agents. And all of them, I think, have similar kinds of effects. We’re interested in them. And what we’re trying to do is improve the benefit risk profile. So where we can find more selective compounds at a fewer adverse effects, in general, my guess is that those things will pair pretty well with KEYTRUDA, and we are interested in those. And we have tried to address them principally by taking advantage of the very large number of companies out there, small and large, that have pursued such things.
So that’s that. I don’t think the answer’s very different for the antibody drug conjugates. Of course, we’ve been doing experiments with these, particularly the EV data that you’ve seen in urothelial cancer is working with Seattle Genetics. And we’re looking at a number of other programs. We set up at the beginning, as you know, a mechanism, and Roy set this up, whereby we can provide KEYTRUDA to lots of people who are doing studies to get an early look at which sorts of things work in combination with KEYTRUDA. And that’s been very helpful to us in terms of targeting licensing opportunities and acquisitions. That’s the general approach we’re taking. And at the high level, I would say, it appears that things that kill malignant cells, maybe because they have a pro-inflammatory effect, perhaps for other reasons, tend to work pretty well in combination with KEYTRUDA.
https://seekingalpha.com/article/4351618-mercks-mrk-management-presents-oncology-event-asco-2020-conference-transcript
WOW nice find ATL, thanks for posting. I thought that's where they'd present, but I'm surprised it's out already.
I doubt the market is very large for this MicroDEN product right now because, for the most part, the only need for dendritic cells are from clinical trials, with only minimal units required for each. Corning was probably willing to do the deal with Northwest Bio because they will now have a commercial market for their consumables business, and it would eliminate their sales and marketing budget. Well that, and the thought of owning some NWBO stock from the deal probably had them as giddy as schoolgirls. :)
For Corning, I think their deal with Flaskworks may be similar to the printer and ink business model. Flaskworks manufactures the MicroDEN unit, and Corning manufactures all the disposable consumables, and is responsible for sales, marketing, and support. (revenue shared accordingly) When I checked with a distributor last year, the MicoDEN unit was priced at $15k, and all the consumables were ~$800.
I agree ATLnsider, I think attending that conference is all about exposure. Thanks for posting that BTW.
Interesting idea abeta, but it sounds far more complicated, and less efficient than DCVax.
Well on that point, we agree. :) For some, it may be difficult to see the bigger picture. There are ethical reasons for crossover in cancer trials. Prior to this trial, a GBM diagnosis meant that patient was very likely to die very shortly. The GBM patients who enrolled in this clinical trial were simply hoping to live a little longer, and perhaps with fewer debilitating symptoms. (and many have)
Hi All. Been a while. I got a message today that CYRX hit my price target, but I think I'll just let it ride. This board was dead for so long, that I forgot about it. Nice to see some of you are still around.
agreed senti, I didn’t write that very clearly. I guess I thought we were of the same mind since I seem to agree with everything you write. :)