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thanks senti, but that’s what I said. I believe that Linda Powers approached Dr. Shashi Murthy back in 2017 to help her solve Northwest Bio’s need for a closed, automated, dendritic cell manufacturing system. I believe Dr. Murthy created (or founded) Flaskworks for that purpose. He didn’t have the manufacturing capabilities for this project, so he collaborated with Corning to develop the system. I posted links earlier today to show that Flaskworks was funded by grants from the NIH that I speculate Linda Powers was either behind, or certainly aware of.
I highlighted this part from the interview and would ask: What other company was attempting to commercialize a dendritic cell therapy back in 2017?
Hint: It wasn’t Dendreon
You recently started working with dendritic cell therapy. How did you become interested in this?
My lab has worked on technologies for cell processing and separation for over 12 years now. It was on the basis of this work that we were approached by a collaborator who highlighted the problem of dendritic cell culture and that’s when I started working with dendritic cells.
I think it goes deeper than that biosect. I believe today’s announcement has been in the works for several years. My research has led me to believe that Flaskworks was actually created by Shashi Murthy, at the request of Northwest Biotherapeutics. I have a couple more pieces somewhere, but here is a big one:
Automated Manufacturing of Dendritic Cell Therapies: Progress & Challenges
Cell Gene Therapy Insights 2017; 3(8), 603-606.
10.18609/cgti.2017.061
PUBLISHED: 27 OCTOBER 2017
https://www.insights.bio/immuno-oncology-insights/journal/article/383/automated-manufacturing-of-dendritic-cell-therapies-progress-challenges
INTERVIEW
Shashi Murthy
Shashi Murthy is a Professor of Chemical Engineering and the Founding Director of the Michael J and Ann Sherman Center for Engineering Entrepreneurship Education at Northeastern University. He is an expert in the areas of cell separation and automated cell culture and current projects in his lab focus on patient-specific dendritic cell generation and dendritic cell-mediated T-cell expansion for therapeutic use. Prof. Murthy obtained his PhD from the Massachusetts Institute of Technology (MIT) and BSc from Johns Hopkins University. He joined Northeastern in 2005 following a postdoctoral fellowship at the Harvard Medical School and Massachusetts General Hospital. Prof. Murthy is the recipient of the National Science Foundation’s Faculty Early Career Development (CAREER) Award and the Søren Buus Award for Outstanding Research in Engineering at Northeastern University and was elected Fellow of the American Institute for Medical and Biological Engineering (AIMBE) in 2015. He has co-authored over 70 publications and is an inventor on seven issued or pending patents. He co-founded Quad Technologies, which commercialized hydrogels as releasable magnetic beads for cell separation and reagents for cell activation. More recently, Prof. Murthy founded Flaskworks, which is commercializing automated systems for the manufacturing of patient-specific dendritic cells and dendritic cell-stimulated therapeutic T cells.
You recently started working with dendritic cell therapy. How did you become interested in this?
My lab has worked on technologies for cell processing and separation for over 12 years now. It was on the basis of this work that we were approached by a collaborator who highlighted the problem of dendritic cell culture and that’s when I started working with dendritic cells.
Dendritic cell (DC) therapy against cancer has been studied extensively over the past two decades. DC is the most powerful antigen-presenting cell in the immune system and it has been a popular choice as a basis for personalized cellular immunotherapies.
Typically, in DC-based cancer immunotherapy, DCs derived from the patient is armed with appropriate tumor-associated antigens, followed by DC stimulation and reintroduction into patients. It has been shown to reactivate tumor-specific T cells in both preclinical and clinical settings. There is also considerable interest in using these cells in combination with other immunotherapies to fight cancer.
Provenge was the first DC-based immunotherapy to be approved. It had limited success not only because of its efficacy, but also significantly because of the manufacturing challenges. However, even despite its challenges, Provenge is still being used to treat around 4,000 patients a year, highlighting the potential of dendritic cells and specifying the need to address the manufacturing issues.
Culturing DCs is a standard process in which DCs are typically obtained from monocytes and peripheral blood. The process of turning them into DCs is a 20-year-old protocol and it’s well established and effective. However, automating the protocol is challenging due to a number of reasons and that’s what brought us into the field.
What are the barriers to advancing DC therapy to the clinic?
As I alluded to, manufacturing is one of the main barriers in advancing DC therapy to the clinic. The tricky part with DCs is that you start out with an adherent cell type, monocytes, and then they turn into larger, non-adherent cells. Therefore, any automation platform must be able to accommodate both adherent and non-adherent cells.
The other barrier has been the science behind DC therapy, which has been steadily advancing, although perhaps not receiving enough credit as it should be as a field. Provenge was a therapy that had essentially a single target in terms of its capability and modification. Whereas the DC therapies that are under investigation and in early clinical trials now have broad range of targets targeting various patient-specific mutations. Therefore, I think the therapies have grown more complex and powerful, but it is a slow process.
One reason why automated platforms for DCs have not received much attention thus far is the number of patients treated. The market size tends to be relatively small and therefore the major players have not devoted resources to the development of a customized DC therapy manufacturing system.
What progress has been made in automating the autologous DC manufacturing process?
This falls into two parts. On one hand, we have the more conventional and familiar process of large-scale cell manufacturing where cell culture is done in bags. With dendritic cells, however, culturing in bags is challenging and the yields are not as high with respect to the amount of end product you get using the given amount of starting material.
On the other hand is the fact that DCs can be generated with pretty high yields in flat cell culture plastic ware like T-flasks or well plates. These combination of cell attachment properties and surface area are optimal for DCs. We still have a large number of researchers and early clinical trial experts performing their work with T-flasks. However, these culture systems are not scalable.
Therefore, the challenge with automating the cell culture process is that on one hand you have something that is scalable but low yield, and on the other hand something else that is high yield but not scalable. Our work in this area aims to find a way to address these twin challenges.
Your group has received funding to develop an automated method of DC generation for clinical application. Could you elaborate on this?
Our funding in this area is for the development of an automated platform that can generate DCs with high yield in a fully automated and scalable manner. Right now we are able to generate DCs with high yield, a yield that matches or exceeds that of the planar T-flasks. We are working now on scaling up to achieve enough numbers of DCs for clinical applications. Additionally, we are trying to incorporate multiple steps involved in manufacturing of DC therapy, which include the maturation and pulsing of those cells with tumor specific antigens. The workflow is very different from that of, for instance, CAR-T manufacturing and that’s part of the challenge. It requires instrumentation and automated systems that are customized exclusively for DCs.
What advantage could this method offer compared to already existing automated approaches? Could the automated system be used as a platform for other cell types?
The existing automated approaches were not specifically designed for DCs. The peculiarity of DC cultures, namely the adherent and non-adherent combination, makes it very difficult to adapt those platforms for DC manufacturing. The expectation is that our system will combine the high yield of planar plasticware with the scalability of bag-based culture system and that’s what we’re driving towards.
At this time we are focusing exclusively on DCs; however, there are likely other cell types that could benefit from the features of our system.
In terms of automating DC manufacturing, how do you see the field progressing in the next 3–5 years?
I don’t expect there to be a single dominant type of cell therapy. My view is that we will see a broad range of cell therapies, and a range of combinations where the cell therapies are combined with biologics to address a broad range of indications. Within this broad range I think that DCs will likely play a significant role.
Affiliation
Shashi Murthy
Department of Chemical Engineering, Northeastern University, MA, USA.
Excellent research Lykiri, thank you. This announcement is extremely positive. Through this acquisition, not only was Northwest able to buy the necessary technology to close and automate production, (and throw up some roadblocks to potential competition) they were able to find some very knowledgeable and talented personnel.
I did some research on Flaskworks and their MicroDEN system last year. It was born from a grant from the NIH and part of the Small Business Innovation Research Project:
NIH/NCI 397 - Manufacturing Innovation for the Production of Cell- Based Cancer Immunotherapies
https://sbir.cancer.gov/funding/contracts/397
Fast track proposals will be accepted.
Direct-to-Phase II proposals will not be accepted.
Number of anticipated awards: 2-4
Budget (total costs, per award):
Phase I: up to $400,000 for up to 9 months
Phase II: up to $2,000,000 for up to 2 years
PROPOSALS THAT EXCEED THE BUDGET OR PROJECT DURATION LISTED ABOVE MAY NOT BE FUNDED.
Summary
Cancer immunotherapy is a therapeutic approach that directs a patient’s own immune system to eradicate their tumor cells. Past and current NCI investments in adoptive T cells, CAR-T cells, NK cells, and other cell-based cancer immunotherapies have resulted in the translation of many lab-specific approaches into early clinical trials. Importantly, reproducible and robust production methods are critical to ensure that advances in basic research result in successful translation of cell-based therapies. Clinical development of such therapies requires multi-center, randomized clinical trials that must be supported with high quality, consistent, and reproducible cell-based products. Patient-specific autologous or allogeneic lots must be adequately characterized to ensure that similar products are given to all patients. For non-patient specific cell-based therapies, large-scale and reproducible manufacturing technologies are needed to produce high-quality products with uniform identity and potency. Current limitations in cell manufacturing can increase both the cost and time required to bring a therapy to market and can result in missed opportunities to evaluate promising new cell-based therapies. Product failures can be attributed to poor product design and characterization, as well as inadequate scale-up and manufacturing processes; therefore, further investments are needed to develop state-of-the art manufacturing technologies and processes to advance cell-based cancer immunotherapies at the commercial-scale. Effective use of science and engineering principles during the early development phase of a cell-based therapy can improve both the efficiency and reliability of the manufacturing process and the quality of the final product. Moreover, it is anticipated that standardized approaches to manufacturing, process analytics, release testing, and product characterization will result in more rapid, cost-effective product development and a higher level of regulatory success. Achieving the desired level of standardization for current and future cell-based cancer immunotherapy products will require both pragmatic research to establish consistent manufacturing processes, as well as the development of new innovations and technologies.
Project Goals
The overall goal of this contract topic is to facilitate the development of innovative methods and technologies capable of improving and modernizing product manufacturing processes for cell-based cancer immunotherapies. This includes the use of autologous, allogeneic, or pluripotent cells. Offerors submitting proposals under this solicitation are strongly encouraged to establish collaborative relationships with clinical product development companies focused on the development of specific cell-based products. In all cases, it is expected that offerors will demonstrate the utility of their innovation(s) in the context of at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies.
Examples of manufacturing innovations/advancements might include, but are not limited to:
* Automated closed systems for cell separation, genetic modification, differentiation, and/or expansion;
* Low-cost, high-efficiency methods for genetic modification to support cell engineering;
* Standardized assays and/or surrogates to evaluate cell attributes that ensure lot-to-lot consistency in terms of phenotype, functionality, quality, and potency;
* Real-time, non-destructive test methods with sensors and/or imaging technologies to assess critical quality attributes (e.g., contamination); and/or
* Process analytics capable of feedback control in response to real-time changes in critical attributes of the cell product.
It is expected that Phase I proposals will focus on novel inventions related to innovations or improvements in cell manufacturing processes, including in-line or on-line (i.e., continuous) process analytics to support product consistency and safety, as well as GMP production of a particular class of cell therapies. Phase II proposals should demonstrate the scalability and validation of the production platform or process improvements developed in Phase I. Engineering and process solutions must be capable of regulatory compliance with FDA Guidelines. The long-term goal of this initiative is to provide the tools necessary for efficient, high-quality manufacturing of novel products in the emerging field of cell-based cancer immunotherapies.
Phase I Activities and Deliverables
* Develop a device/technology/process to support commercially-relevant manufacturing advancements or improvements for the production of a specific class of cell-based cancer immunotherapies (e.g., CAR-T cells, adoptive T-cells, NK cells)
* Establish defined specifications, assays and/or metrics to interpret scientific data supporting the feasibility of the device/technology/process, with respect to reproducible product manufacturing, process analytics, and/or process controls
* Demonstrate the suitability of the device/technology/process to improve relevant manufacturing metrics (e.g., product uniformity, quality, efficiency, cost-effectiveness) for at least one cell-based product, which is representative of a particular class of cell-based cancer immunotherapies
* Provide proof of collaboration or partnership with an entity that is developing a representative cell-based therapeutic agent OR otherwise demonstrate access to a representative cell-based therapeutic agent through other means (e.g., internal drug development program), that can be used for validation of the device/technology/process
* Demonstrate pilot-scale beta-testing of the production process to demonstrate reproducible performance within appropriate specifications for identity, purity, potency, and/or other relevant metric for the chosen cell-based immunotherapy product
Phase II Activities and Deliverables
* Generate scientific data demonstrating the proposed scalability (e.g. scale-up, scale-out, point-of-use) of the production platform, process analytics and/or process controls
* Develop an at-scale prototype of the device/technology/process with detailed specifications for hardware/software that supports the production platform or process analytics/process controls improvements
* Validate the production innovation and/or process improvements, including standards for calibrating any novel process analytics or process controls that monitor production
Receipt date: October 23, 2019, 5:00 p.m. Eastern Daylight Time
Apply for this topic on the Contract Proposal Submission (eCPS) website.
For full PHS2020-1 Contract Solicitation, CLICK HERE.
Posted Date:
July 10, 2019
SBIR Phase I: Automated Closed Systems for Manufacturing Autologous Dendritic Cell Therapies
https://www.sbir.gov/sbirsearch/detail/1521705
Award Information
Agency:
National Science Foundation
Branch:
N/A
Contract:
1819306
Agency Tracking Number:
1819306
Amount:
$225,000.00
Phase:
Phase I
Program:
SBIR
Solicitation Topic Code:
BT
Solicitation Number:
N/A
Timeline
Solicitation Year:
2017
Award Year:
2018
Award Start Date (Proposal Award Date):
2018-07-01
Award End Date (Contract End Date):
2018-12-31
Small Business Information
FLASKWORKS, LLC
165 Waltham Street, Newton, MA, 02465
DUNS:
080172813
HUBZone Owned:
N
Woman Owned:
N
Socially and Economically Disadvantaged:
N
Principal Investigator
Name: Jennifer Rossi
Phone: () -
Email: jennifer.m.rossi@flaskworks.com
Business Contact
Name: Jennifer Rossi
Phone: (617) 767-3363
Email: jennifer.m.rossi@flaskworks.com
Research Institution
N/A
Abstract
The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is in the development of new technologies to manufacture personalized therapies for cancer and other diseases that are based on a patient's own cells. Such therapies have shown remarkable success in recent years, however, manufacturing these therapies is challenging because mass production techniques cannot be employed when each patient receives a unique therapy. Indeed, for therapies based on dendritic cells, which are an important part of the human immune system, there are no manufacturing systems currently available that can perform all of the required steps. This project will address this major unmet need by leveraging advanced concepts in engineering and biology to design an integrated system for cost-effective manufacturing of dendritic cell therapies. Given the large number of personalized cell-based therapies currently in clinical trials, and recently approved therapies, such a system is expected to address a major societal need and have significant commercial potential. This SBIR Phase I project proposes to develop a manufacturing system to cover the steps involved in the manufacturing of autologous dendritic cell therapies. Because of the low abundance of these cells in blood, dendritic cells are typically generated from blood-derived monocytes. Following differentiation of monocytes into dendritic cells, these cells are then matured and stimulated with tumor-specific antigens. These steps represent discrete unit operations that require a system capable of handling both adherent and non-adherent cell types, different reagents for each step, and the ability to transition from one step to another with minimal loss of cells. Further, all steps must be performed in a disposable single-use enclosure. In order to achieve automation and integration of these steps, the proposed system will leverage innovations in perfusion-based dendritic cell culture and novel and cost-effective bioreactor design strategies. A combination of computational modeling and rapid-prototyping techniques will be employed for rapid iteration of prototypes and testing with potential users involved in therapeutic development. Successful completion of this project will result in feasibility demonstration of an integrated manufacturing system developed with significant end user feedback. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
SBIR Phase II: Automated Closed Systems for Manufacturing Autologous Dendritic Cell Therapies
https://www.sbir.gov/sbirsearch/detail/1644527
Award Information
Agency:
National Science Foundation
Branch:
N/A
Contract:
1926967
Agency Tracking Number:
1926967
Amount:
$749,998.00
Phase:
Phase II
Program:
SBIR
Solicitation Topic Code:
BT
Solicitation Number:
N/A
Timeline
Solicitation Year:
2017
Award Year:
2019
Award Start Date (Proposal Award Date):
2019-09-01
Award End Date (Contract End Date):
2021-08-31
Small Business Information
FLASKWORKS, LLC
38 Wareham Street, 3rd Floor, Boston, MA, 02118
DUNS:
080172813
HUBZone Owned:
N
Woman Owned:
N
Socially and Economically Disadvantaged:
N
Principal Investigator
Name: Jennifer Rossi
Phone: (617) 488-9086
Email: jennifer.m.rossi@flaskworks.com
Business Contact
Name: Jennifer Rossi
Phone: (617) 488-9086
Email: jennifer.m.rossi@flaskworks.com
Research Institution
N/A
Abstract
The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is in the development of new technologies to manufacture personalized therapies for cancer and other diseases, based on a patient's own cells. Such therapies have shown tremendous potential in the treatment of previously intractable cancers. However, challenges in manufacturing these completely personalized therapies are a significant impediment to the ability to realize their full societal potential both in terms of therapeutic efficacy and cost. This project aims to remove major manufacturing barriers for therapies based on dendritic cells, which are an important part of the human immune system and can be modified to target specific diseases. No manufacturing systems currently available can perform all the required steps of manufacturing personalized dendritic cell therapies. This project will address this major unmet need by leveraging advanced concepts in engineering and biology to design an integrated system for cost-effective dendritic cell therapy manufacturing. Given the large number of personalized cell-based therapies currently in clinical trials and recently approved, such a system is expected to address a major societal need and have significant commercial potential. This SBIR Phase II project will advance to commercialization an advanced bioreactor system for closed-system manufacturing of autologous dendritic cell therapies. Multiple technological challenges must be overcome to automate and integrate the unit operations associated with the manufacturing of these therapies. Because of their low abundance in blood and tissue, dendritic cells are typically generated from leukapheresis-derived monocytes. Adherent monocytes must first be converted into nonadherent immature dendritic cells via incubation inIL4 and GM-CSF, prior to maturation and stimulation with tumor specific antigens. In order to achieve automation and integration of these steps on a single platform, the proposed system will build on successful Phase I work in perfusion-based dendritic cell culture that enables reduction of process steps associated with cytokine infusion and achievement of perfusion in a simple and cost-effective single-use bioreactor design. In addition, an agile product development methodology will be utilized in conjunction with computational modeling to rapidly and iteratively create prototypes and test them in the hands of potential customers. Feedback obtained from these users will be incorporated into the assembly of a pre-production beta system to be launched commercially at the end of Phase II. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
Haha senti. Sounds like you know your Dr. S
“And their whole world was saved by the smallest of ALL!”
Hmmm Dr. Liau? :)
I agree ski, it’s not the PR that we wanted right now, but I would think if data lock was anticipated in the next couple of days, they would have just waited to announce this news along with it. And yes, good news but we already knew from the 10-Q that they were slowed by Covid-19 and were working double shifts to mitigate the delay. We’ve also known much longer about the facilities at Sawston from the Advent website, so this wasn’t new either. And why mention the air change rate for class c cleanrooms?
So basically, the news is they received a “loan for £1.35 ($1.77M) from the Department for Business, Energy & Industrial Strategy and the Company currently anticipates the Phase I buildout will finish by mid-October of 2020.” It makes me wonder when they actually started working double shifts, and how long it would have taken them to finish had they not accelerated the buildout.
actually drugrunner, exwannabe ranks 4th on NWBO board:
https://investorshub.advfn.com/boards/boardposters.aspx?boardid=3441
Cclr0007, you can request to be added to the PR list by contacting NW Bio here:
https://nwbio.com/contact-us-general/
Right there with you senti - it's like you read my mind. Thanks.
Right antihama, modern pharmaceutical supply chains are highly decentralized, with APIs manufactured in one region of the world, formulated in another, and packaged in a third. There are considerable risks inherent in this process, and current verification methods don’t provide the level of control needed throughout the supply chain, so product integrity can be compromised. In 2013 the FDA established the Drug Supply Chain Security Act (DSCSA) to identify suspect or illegitimate products in the supply chain. It mandates that companies serialize products and implement a track and trace system to track their product throughout the entire supply chain, among other requirements. There are several stages, with full implementation required by 2023, which is why blockchain has become attractive.
And yes, the supply chain is far more critical for personalized advanced therapy products, which require cryopreservation. Every shipment is monitored in real time, and each shipping container has data loggers that report not only location, but all conditions like internal temperature, external temperature, orientation, light, humidity, and pressure, which are part of the chain of condition. The name of the courier and all personnel who handle the shipment at each point of contact are recorded, and are part of the chain of custody. Other documentation includes all patient data, the date, time, and GMP facility where the batch was manufactured, product labeling, the registered medical doctor and treatment center information, etc., so yes, I think the chain of compliance basically certifies that the advanced therapy product is authentic, meets regulatory and quality requirements, and complies with good distribution practices. Due to the complexity, personalization, and novel nature of some advanced therapies, it isn’t even possible to directly compare batches of the final product in the same ways that are used for conventional biologics. I haven’t really dug into the import/export regulations to know if there are additional requirements though.
antihama, the logistics companies that Northwest Bio’s manufacturers work with provide customs documentation and compliance with the import/export regulations. Cognate currently contracts with Cryoport (CYRX) who also handles the logistics supply chain for Yescarta and Kymriah. For personalized medicine, the entire logistics supply chain is part of the manufacturing process and is written in the CMC section of the BLA. The logistics companies integrate the patient data, manufacturing batch data, and all logistical transportation data from blood draw, to manufacturing, to treatment of the patient. This is known as the Chain of Identity, Chain of Custody, Chain of Condition, and Chain of Compliance. Personalized Therapy Management (PTM) Platforms like Autolomous that Mark Lowdell just started up in the UK are involved in the software side of this, but the entire pharmaceutical supply chain is beginning to implement blockchain and I’m sure personalized medicine will as well.
CHAIN OF COMPLIANCE®
Navigating customs and shipping regulations and GDP compliance
https://www.cryoport.com/why-cryoport/chain-of-compliance
CherryTree, yes there are several statistical methods to mitigate crossover effect, but none are really ideal for this trial. The most common method I’ve seen used in oncology trials is the rank-preserving structural failure time (RPSFT). The RPSFT model
The RPSFT model allows a direct comparison of randomization groups by adjusting the OS of patients who cross over so that it reflects the OS had they not received the investigational treatment. The method is related to the accelerated failure time model in OS analysis in which prognostic variables measured on the individual level are assumed to act multiplicatively on the time scale, for example, affecting the rate of progression. . .
The RPSFT model is rank preserving because a constant factor is used for adjusting the time to event for each patient. Thus, if two patients are on the same treatment (either control or crossover), and patient i fails (dies) before patient j, before adjustment, patient i will also always fail before patient j after adjustment: the ranking in failure times is preserved. The model is structural (causal) in the sense that it assumes a defined relationship between the observed event time and the event time that would have been observed if crossover had not occurred.
A key assumption of the RPSFT model is that the investigational treatment causes a constant reduction in time to death, assumed equal for all patients before and after progression. This may be a reasonable assumption in some cases but not in others, which may restrict the use of the method to cases in which a constant proportional reduction in the time to event is biologically plausible
Analyzing Overall Survival in Randomized Controlled Trials with Crossover and Implications for Economic Evaluation
https://www.sciencedirect.com/science/article/pii/S1098301514018907#ab0005
Linda Liau is speaking at the 2nd Annual Glioblastoma Drug Development Summit on December 9th
Linda Liau
Chair of Neurosurgery
UCLA
Day One
Wednesday, December 09, 2020
10:00 am | Optimize the Role of Immunotherapy for Treatment of Glioblastoma
Synopsis
* Outline the historical and current understanding of the mechanisms of
* immune responses against glioblastoma
* Discuss the common challenges of designing and evaluating clinical
* trials of immunotherapy for glioblastoma
* Elucidate the considerations of timing, sequence, and tumor/patient
* heterogeneity in developing combination immunotherapy/vaccine trials
* for glioblastoma
Day Two
Thursday, December 10, 2020
11:00 am | PANEL DISCUSSION: Recognize the Financial Difficulty of Developing Glioblastoma Treatments and Moving Drugs to the Next Phase
* James Garner ?Chief Executive Officer & Managing Director, Kazia Therapeutics Limited
* Petra Hamerlik? Associate Research Director/Bioscience, AstraZeneca
* Ranjit S. Bindra? Associate Professor of Therapeutic Radiology, Yale School of Medicine
* Linda Liau? Chair of Neurosurgery, UCLA
Synopsis
* Explore the challenges of funding development
* How can drug developers inspire and attract companies to invest in their novel preclinical glioblastoma development and pipeline?
* How can the industry come together to overcome the paucity of funding?
https://glioblastoma-drugdevelopment.com/about/speakers/
Sorry if this is a repeat, I haven’t been keeping up.
thermoo, it was very encouraging to hear that a settlement was reached with Cognate in May of last year, and production of DCVax-Direct would be restarted, and then, days later at ASCO, that “multiple new clinical trials have been in preparation - the first 2 of these trials are anticipated to start in the coming months.” The brain mets trial had been cleared by the FDA and the DIPG and SHGG trial had been submitted and was waiting for FDA approval. So what happened? They were certainly capable of running multiple trials before, so that wasn’t it. The Sawston profits evaporated? I’m not buying the “scarce capital” excuse. What about grants? There’s dozens of government agencies funding medical research - the NIH alone gives away $32B a year, and there are literally dozens of private grants for billions more. But even if they didn’t go the grant route, the trials were relatively small, (a dozen patients to start) so they wouldn’t need to raise anywhere near $50M, and in the bigger picture, getting DCVax-Direct developed could actually create value for the company. I even speculated at one point last year that maybe the holdup was due to another entity (Merck?) being interested in DCVax and wanting to be in control of designing and running all the trials in their own labs, but this was obviously a stretch. There’s so much promise with Direct, and so much was learned during the Phase I trials and improved upon, so it never made sense to me why they wouldn’t they do everything they could to get Direct going. But I think I get it now. In Northwest Bio time, a year delay is really nothing.
ex, cell therapy and manufacturing go hand in hand, and finding available cell therapy manufacturing capacity around the world is getting increasingly difficult. It’s pretty clear that Linda understands this, and is guaranteeing access to manufacturing, and attempting to lower production costs. It’s likely that reimbursement will be lower in the UK and EU than the US, and by owning the building and equipment at Sawston, and simply contracting Advent to perform the manufacturing, Northwest should still be able to earn a considerable profit.
ex, not a big deal, but some of that equipment is listed under “Construction in Progress” which is about $1.5M. Contrary to what you say, it appears that Northwest Bio will own the equipment, not Advent. Either the project is a total farce, or Advent owns the equipment. And nobody knows what the terms are. Advent will be making product for other companies (just like Cognate does). Do they get to use NWBO's physical facility for free to do this? Do they pay rent?
Construction in Progress
In connection with the Company’s manufacturing facility in U.K, the Company has incurred and is incurring costs with certain vendors to design and build out the initial stage of the facility. Additionally, the Company purchased certain manufacturing equipment that will be installed in connection with the buildout. These costs were all capitalized and recorded as part of construction in progress as of June 30, 2020. Upon completion of the buildout, all costs associated with the buildout will be recorded as manufacturing equipment or leasehold improvement and amortized over the estimated useful life of the facility.
nice post longfellow, I think you nailed it.
ex, I don’t think it is particularly valuable at this point. I was just answering the question. I agree the focus is on the Specials Program, which does produce (modest) revenue.
incline, yes good news - they are trying to mitigate (lessen the delay) by working 2 shifts likely due to social distancing issues.
Hi H2R. Yes the PIM designation is still valid. Unlike the Hospital Exmeption which expires after 5 years, the PIM designation does not expire. It’s likely why Les is under the impression (and has apparently told various investors) that Northwest Bio may be able to get an expedited approval there.
Promising Innovative Medicine (PIM) Designation - Step I of Early Access to Medicines Scheme (EAMS)
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/375327/PIM_designation_guidance.pdf
Do designation opinions expire?
No, the designation is a statement at one point in time, that the product shows promise in a particular patient setting and is suitable for future application to the EAMS scientific opinion step.
More about EAMS timeline here:
https://www.gov.uk/guidance/apply-for-the-early-access-to-medicines-scheme-eams
Doc, the buildout at Sawston has been delayed. It was in the 10-Q:
The COVID-19 situation, and related restrictions and lockdowns, have adversely affected the Company’s programs and may continue to adversely affect them. However, the Company is continuing to make progress in its programs despite these difficulties, with a primary focus on reaching data lock, unblinding and reporting the results of the Company’s Phase 3 clinical trial of DCVax-L for Glioblastoma brain cancer. Examples of effects of the COVID-19 situation include the following: the process for completion of the final data collection from trial sites for the Phase 3 trial has been materially slowed by the limited availability or capacity of independent service firms responsible for collecting and confirming the data, by the inability to perform in-person monitoring and other visits to trial sites, by very limited availability of investigators and staff at trial sites (many of whom have been reassigned to treating COVID-19 patients), and substantially longer timeframes for Institutional Review Board or Ethics Committee meetings and regulatory processes for matters other than COVID-19. The Company has been unable to undertake compassionate use cases during part of March and during Q2, due to lockdowns, travel restrictions and hospitals focusing most of their personnel and resources on COVID-19 patients. In addition, manufacturing of DCVax products is impeded by personnel being under lockdown, and the buildout of the Sawston facility was delayed in starting due to the construction sector shutdown and restrictions, and the duration of the work will be substantially longer due to the contractors having to operate under social distancing arrangements. The Company anticipates that such effects of the COVID-19 situation may continue for an extended period of time. However, the Company has been able to mitigate some of these effects. For example, for the Sawston facility buildout the Company is paying increased costs to have the contractors operate on two shifts daily rather than the normal one shift.
9
Construction in Progress
In connection with the Company’s manufacturing facility in U.K, the Company has incurred and is incurring costs with certain vendors to design and build out the initial stage of the facility. Additionally, the Company purchased certain manufacturing equipment that will be installed in connection with the buildout. These costs were all capitalized and recorded as part of construction in progress as of June 30, 2020. Upon completion of the buildout, all costs associated with the buildout will be recorded as manufacturing equipment or leasehold improvement and amortized over the estimated useful life of the facility.
14
Advent BioServices Agreement
The Company has a Manufacturing Services Agreement with Advent BioServices for manufacture of DCVax-L products at an existing facility in London, as previously reported. The Company also has an Ancillary Services Agreement with Advent, which establishes a structure under which Advent will submit Statements of Work (“SOWs”) for activities related to the development of the Sawston facility and the compassionate use activities in the UK, as previously reported. To date, Advent has not yet submitted SOWs and the Company has not yet made any payments for these Ancillary Services. The Ancillary Services Agreement had an original term of 8 months, ended in July 2020. On August 7, 2020, the Company extended the term by 12 months, and did not make any other changes.
Or in preparation for a commercial launch.
Thanks for sharing Truthfan. I’m familiar with Tim Moore, he’s also a board member of another company I’m invested in, and he brings key commercial experience.
Tim has over three decades of leadership experience in biopharmaceutical manufacturing and operations. Prior to joining PACT, he served as Executive Vice President, Technical Operations at Kite, a Gilead Company, since March of 2016. During this time Mr. Moore was responsible for overseeing the process development, manufacturing, quality and supply chain for the launch of Yescarta®, one of the first CAR T therapies to be developed, manufactured and commercialized, as well as advancement of the Kite pipeline. . . Prior to Kite, Mr. Moore served as the Senior Vice President, Head of Global Technical Operations – Biologics of Genentech, Inc.
I’m surprised that they didn’t just wait (until next week?) to announce data lock, but I guess Dave understood investor’s frustration with missed deadlines, and was compelled to announce any progress. Did anyone notice that they have said multiple times “The Company anticipates that the statisticians' work will take several weeks,” but todays presser said “As previously reported, the statisticians' work is estimated to take a couple of weeks.” Makes you wonder if they are even aware of the inconsistency or consider that a week or so doesn’t really matter.
The LBA deadline for ESMO has passed, so it looks like the likely venue will be SNO, which was probably the plan for a while now anyway.
Evaluate, obviously it’s just speculation, but that’s all we’re left with. It probably made sense at some point last year to just wait for the results of this trial since so much is going to be learned about DCVax from this trial. The composition of the survival tail will be of great interest, and analysis of the various subgroups of patients that make up the tail will help to identify patients that best respond to this treatment, and these biomarkers will likely be used in future trials to select patients. In addition, I think surrogate endpoints based on tumor response will be used to demonstrate efficacy, (which should be very rapid) which should also help to speed them up.
And yes, I took note of that language in the 10Q as well, but there was also this:
Our operating costs also include the costs of preparations for the launch of new or expanded clinical trial programs, such as our planned Phase II clinical trials. The preparation costs include payments to regulatory consultants, lawyers, statisticians, sites and others, evaluation of potential investigators, the clinical trial sites and the CROs managing the trials and other service providers, and expenses related to institutional approvals, clinical trial agreements (business contracts with sites), training of medical and other site personnel, trial supplies and other. Additional substantial costs relate to the maintenance and substantial expansion of manufacturing capacity, for both the US and Europe. Our operating costs also include significant legal and accounting costs in operating the Company.
There’s a more recent interview of Dr. Brem by Al Musella from a few months ago. He discusses advances in brain mapping, emerging imaging technologies, and various on-going trials and treatments including immunotherapies, but doesn’t mention DCVax until the Q & A at the end. (~32:20 minute mark) But really nothing new.
Presented 5/3/2020 as part of the Musella Foundation Brain Tumor Awareness Month Webinar Series:
Innovations in Brain Tumor Treatments by Stephen Brem
Agreed Doc. It seemed to me that the company had a SAP that simply needed finalizing in the fall of 2018, but may have gotten wind of (or had something to do with) the new FDA Guidance that came out last year and then apparently decided to completely rewrite the SAP. I suspect that Dr. Duffy was heavily involved in that process. So the Direct trials were put on hold to redesign and update the protocols and endpoints, and while this appears to be a backstep, it may actually end up being many steps forward in the long run.
Thanks for your thoughts Doc. I was thinking more along the lines of trial milestones myself, so I was thinking topline, venue of full data presentation, and potentially filing a BLA or MAA, but you may be right that Advent manufacturing readiness could be considered a key milestone. I’m not prepared to go as far as you on the other potential milestones though, as something seemed to be holding up additional Direct trials, and now we may know why. Not sure if this has been discussed, but this language in the 10-Q looks new:
The Company’s primary focus at present is on its DCVax-L program and completion of the Phase 3 trial of DCVax-L for Glioblastoma brain cancer. Our second product, DCVax®-Direct, is designed to treat inoperable solid tumors. A 40-patient Phase I trial has been completed, and included treatment of a diverse range of cancers. As resources permit, the Company is working on preparations for Phase II trials of DCVax-Direct including discussions with key institutions in regard to trial design and trial preparations. The Company has stopped the DCVax-Direct contract manufacturing preparation activities at present, while the trial design activities and preparations with the trial sites continue.
ae, there are two “approved” dendritic cell vaccines: Provenge, which China’s Sanpower Group bough from Valeant Pharmaceuticals who acquired Dendreon in bankruptcy, and of course Apceden made by APAC in India that ex is so enamored with. How well either of those actually kill tumors though, is debatable.
I’m getting a bit fatigued by all the feigning outrage these days, but this one by ex made me laugh. He has a good sense of humor.
Conflicts of interest; seems the esteemed doctor “forgot” to disclose them before . . .
FDA bars own expert from evaluating risks of painkillers
Jeanne Lenzer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC529357/
The US Food and Drug Administration has barred one of its own experts from serving on the panel considering the safety of cyclo-oxygenase-2 (COX 2) inhibitors after he made remarks indicating that valdecoxib (Bextra) may—like rofecoxib (Vioxx), which was recently withdrawn from the market by Merck—cause heart attacks and strokes.
Dr Curt Furberg, a member of the FDA's drug safety advisory committee and a prominent authority on drug safety, was told his invitation to participate in FDA hearings on the safety of COX 2 inhibitors had been rescinded. This followed his being quoted in the New York Times on 10 November as saying that a study that he and his colleague performed “showed that Bextra is no different than Vioxx, and Pfizer is trying to suppress that information.”
Larry Sasich, research associate with the US consumer association Public Citizen in Washington, told the BMJ that “Dr Furberg has an unimpeachable record as a scientist” and that his experience as a cardiovascular researcher and the lead investigator of the largest clinical trial on hypertension in the United States put him in a unique position to evaluate risks of drugs. “I don't understand the [FDA] claiming an intellectual conflict of interest in Dr Furberg's case when the reproductive drugs advisory committee has an adamant pro-life advocate, Dr [W David] Hagar.”
Dr Hagar, known for his opposition to birth control for unmarried women and his writings suggesting that women with menstrual cramps should read the Bible, was appointed to the committee by President George W Bush.
Victoria Kao, spokesperson for the FDA, told the BMJ that Dr Furberg's removal was the result of a routine review of all panel members for “financial and intellectual conflicts of interest.” When asked about the timing of Dr Furberg's removal, only days after his interview with the New York Times but months before the panel is to meet in February 2005, Ms Kao said that was because “it takes a long time” to do all the reviews.
According to a September 2001 report by USA Today, 55% of all FDA advisory panellists had financial interests in the drugs they reviewed. A transcript of the most recent arthritis advisory panel meeting in June 2004 shows that seven of the 14 panellists, including the panel's chairperson, received waivers for financial conflicts of interest. Several of the arthritis panellists have written favourable reports on COX 2 inhibitors. When asked how the FDA reaches a decision to remove a panellist who has no financial conflicts while giving waivers to panellists who do have financial conflicts, Ms Kao said, “Each case is individual.”
Dr Furberg's contention that Pfizer suppressed negative data has been publicly denied by Pfizer. Pfizer's spokeswoman, Susan Bro, told the BMJ that the company issued a news release on 15 October in which it warned about potential risks to patients having cardiac bypass surgery. When the BMJ first called Pfizer, on 14 October, however, Ms Bro denied that valdecoxib posed any cardiac risk. When asked about the negative outcomes seen in the two cardiac bypass studies, Ms Bro instead asked, “Who gave you that information?” and added, “We haven't talked about that.”
Ms Bro said that other studies of valdecoxib, including a trial of over 8000 patients with osteoarthritis and rheumatoid arthritis, showed no increase in cardiovascular risk.
I agree senti, that sentence indicates to me that they do intend to announce data lock, since it is considered a “key milestone.” But it also raises other questions for me. For example, will they report data lock in a simple announcement when it actually happens, or sometime afterward, along with other “progress,” perhaps in a 10-Q? And since it is plural, exactly what other milestones does Northwest Bio consider “key?”
hi longfellow, back atcha. I don’t think I’ve seen anything more definitive than that, but I can certainly understand your skepticism. I have a different take because it seems to me that things have changed in the last five years since the hold was initiated, and there is not only more of an acceptance of personalized medicine, but an understanding that cell and gene therapies are the future, and the regulators have taken a more supportive and collaborative approach. That’s not to say that Northwest doesn’t need to have all their ducks in a row as this is a highly regulated industry and the regulations are evolving, but I’m fairly optimistic going forward.
BTW - Here’s what the regulators are looking at coming down the pipeline: http://www.summit-re.com/blog/2020/6/12/are-you-ready-preparing-for-gene-and-cell-therapies-coming-down-the-pipeline
I know there has been much debate here about the reasons for the partial hold, but I first invested almost a year after the hold was lifted, so I’ve avoided going down that rabbit hole myself. But since you asked . . . Rk's theory seems reasonable to me:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=132792356
It would significantly lower the cost of production, likely by 30%-50%, and equally as important is the consistency and purity of the product, and reduction in the risk of contamination.
and if it has to do with L.
Longfellow, I think the shelf-life has been validated up to five years. Maybe you don’t remember this presentation at Phacilitate Immunotherapy World, January 26, 2015:
Sometimes I feel like a jackass. I see the carrot. It’s right in front of me. I want that carrot. That carrot is very close. I’ll just walk a little further to get that carrot. Oh that carrot is close now. I keep walking but that carrot is just out of my reach. Wow, look how fast my foals have grown up. Okay, just a little more. Yes, I think it’s closer now. That carrot is so close I can almost taste it . . . to be continued
Did you see AF’s tweet the other day?
@adamfeuerstein Jul 15
If $CVM digs another 50 meters or so, it will find the $NWBO data.
Haha. I’m obviously not a fan, but I have to admit that was pretty funny.
cfoofme, heartbreaking to hear this. FYI - Ziopharm just dosed the first DIPG patient in a Phase 1/2 trial for pediatric brain tumors two days ago. https://clinicaltrials.gov/ct2/show/NCT03330197
Unfortunately the trial is not recruiting but it may be worth contacting UCSF about it. This is a gene therapy that is injected into the tumor and it inserts a gene that is activated by an oral drug which produces IL-12, an immune enhancer. Too much IL-12 causes severe problems so it is controlled by the oral drug which can turn off the gene by stopping the oral drug. It has been used on over 175 patients in other cancers including glioblastoma with decent results.
Ziopharm Oncology Doses First DIPG Patient in Phase 1/2 Trial of Controlled IL-12 for the Treatment of Pediatric Brain Tumors
BOSTON, July 08, 2020 (GLOBE NEWSWIRE) -- Ziopharm Oncology, Inc. (“Ziopharm” or “the Company”) (Nasdaq:ZIOP) today announced that the first patient with diffuse intrinsic pontine glioma (DIPG) has been dosed in its phase 1/2 study of Ad-RTS-hIL-12 with veledimex (Controlled IL-12) for the treatment of pediatric brain tumors.
“We are pleased to report that this young child has tolerated the dosing regimen well,” said Laurence Cooper, M.D., Ph.D., Chief Executive Officer of Ziopharm. “Working with our colleagues at Northwestern University and Lurie Children’s Hospital, we continue to monitor this patient’s progress and are evaluating additional patients for enrollment in Chicago and at the other trial sites. For Ziopharm, this trial represents an additional clinical path for of Controlled IL-12, beyond the ongoing studies in recurrent glioblastoma (rGBM).”
Stewart Goldman, M.D., Division Head Hematology-Oncology, Neuro-Oncology & Stem Cell Transplantation at Lurie Children's and investigator in the study, added, “One of the hallmark characteristics of DIPG is that immune cells cannot access the tumor, yet the microenvironment is not immunosuppressive. Therefore, driving T cells into this tumor could change the outcome for children with this lethal disease. Ziopharm’s data evaluating Controlled IL-12 in rGBM demonstrates that there is a sustained infiltration of activated T cells, turning “cold” tumors “hot” for months after veledimex dosing is finished. Extensive experience, as well as encouraging survival data associated with treating rGBM in adults, underscores our desire to evaluate Controlled IL-12 in children with gliomas, who currently lack viable treatment options.”
The phase 1/2 trial (NCT03330197) is designed to evaluate the safety and tolerability of a single intratumoral injection of Ad-RTS-hIL-12 given with up to 14 days of oral veledimex in children with gliomas. Up to 12 patients may be enrolled in phase 1 of the study, which is being conducted at leading pediatric cancer centers across the United States, including the Dana-Farber Cancer Institute in Boston and the University of California in San Francisco.
About DIPG
In children, the incidence of brain cancer is approximately 4.84 per 100,000, according to the National Cancer Institute. Glioma in the pontine region of the brain, or DIPG, accounts for approximately 10-15 percent of all cases of pediatric brain tumors, with about 150-300 new diagnoses per year in the United States.1 Median survival ranges from 8-11 months.2 There are no curative options.
About Controlled IL-12 (Ad-RTS-hIL-12 plus veledimex)
Ziopharm’s Controlled IL-12 platform is an investigational gene therapy designed to induce and control the production of human interleukin 12 (hIL-12), a master-regulator of the immune system. The Company has treated more than 175 patients, including more than 125 patients with rGBM, with Ad-RTS-hIL-12 plus veledimex and administered more than 1,300 doses of veledimex across three types of solid tumors, building a significant safety profile, mechanistic dataset and evidence of anti-tumor effects.
About Ziopharm Oncology, Inc.?Ziopharm is developing non-viral and cytokine-driven cell and gene therapies that weaponize the body’s immune system to treat the millions of people globally diagnosed with a solid tumor each year. With its multiplatform approach, Ziopharm is at the forefront of immuno-oncology with a goal to treat any type of solid tumor. Ziopharm’s pipeline is built for commercially scalable, cost effective T-cell receptor T-cell therapies based on its non-viral Sleeping Beauty gene transfer platform, a precisely controlled IL-12 gene therapy, and rapidly manufactured Sleeping Beauty-enabled CD19-specific CAR-T program. The Company has clinical and strategic partnerships with the National Cancer Institute, The University of Texas MD Anderson Cancer Center and others.
For more information, please visit www.ziopharm.com.
I’ve read that about the IDH mutation testing being “decided at a late stage” here before, and it’s not really accurate. It appears that it was decided a long time ago that it would be collected at the end of the trial during final data collection, and used for label extension. This is from the article in the Journal of Translational Medicine published in May 2018, but written in the summer/fall of 2017, so almost three years ago.
The mutation status of the IDH1 gene has not yet been investigated for this trial, as this factor was not included in trial designs a decade ago when this trial began. It will be collected and analyzed later, but is unlikely to explain the overall survival results, as the mutation associated with prolonged survival occurs in less than 10% of newly diagnosed glioblastoma patients.
I guess I misunderstood you hank. I actually do think the announcement will mention the statistical significance one way or the other, as that is what “topline” basically means. I thought you were saying that if the trial doesn’t reach statistical significance, that would be the “kiss of death” like others who have stated that the price would go to zero and bankrupt the company. I don’t believe this is true, and those who believe that probably haven’t been paying attention. It appears to me that Linda Powers is preparing for all of the potential outcomes. After they receive the statistical analysis and review it with their SAB, it’s possible that Northwest Bio will meet with the FDA (virtually) to discuss the data and potential pathways to approval, prior to the public announcement, to ensure that the announcement will be well received.
No hank it’s not the kiss of death. I think its important to remember that Glioblastoma is a severely debilitating, rare disease, and one of the deadliest, and most difficult to treat cancers, with very limited treatment options and mortality rates little changed in the past 20 years, when many other cancers have seen huge advances. The naysayers here want everyone to believe that this is the same old rigid FDA of years past, but it is not. The FDA understands that gene and cell therapies represent a new medical treatment paradigm that requires new methods for trials and new ways to evaluate them. The FDA’s really wants to approve more treatment options for rare diseases like GBM, and there is growing political pressure to do so. One of the primary concerns of the FDA when making a Benefit Risk Assessment during the approval process of a new molecular entity, is safety. Well guess what? DCVax is extremely safe, and especially so when compared to chemotherapy, or even other immunotherapies like the checkpoint inhibitors, or the hot CAR-T’s, which the FDA has been falling over to approve.
Have you read the Congressional Glioblastoma Awareness Day Resolution? Here’s the highlights:
https://mast.house.gov/_cache/files/b/7/b75c3380-6809-495c-b634-340e9e51cdfa/047DE2899DD53E6E51082C01FBE9C238.glioblastoma-awareness-resolution.pdf
Whereas there is a need for greater public awareness of glioblastoma, including awareness of both—
1) the urgent unmet medical needs of glioblastoma patients; and
(2) the opportunities for research and treatment advances for glioblastoma: Now, therefore, be it
Resolved, That the House of Representatives—?(1) supports the designation of ‘‘Glioblastoma Awareness Day’’;
?(2) encourages increased public awareness of glioblastoma;
?(3) honors the individuals who have lost their lives to glioblastoma, a devastating disease, or are currently living with it;
(4) supports efforts to develop better treatments for glioblastoma that will improve the long- term prognosis of individuals diagnosed with glioblastoma;
(5) expresses its support for the individuals who are battling brain tumors, as well as the families, friends, and caregivers of those individuals; and
(6) urges a collaborative approach to brain tumor research, which is a promising means of advancing the understanding and treatment of glioblastoma.
More importantly, have your read the FDA’s most recent guidance on Demonstrating Substantial Evidence Of Effectiveness? Here is an especially critical part:
https://www.fda.gov/media/133660/download
EXAMPLES OF CLINICAL CIRCUMSTANCES WHERE ADDITIONAL FLEXIBILITY MAY BE WARRANTED:
A. When the disease is life-threatening or severely debilitating with an unmet medical need
Subpart E regulations promulgated in 1988 call for FDA to exercise its broad scientific judgment in applying the evidentiary approval standards to drugs for life-threatening and severely debilitating diseases, especially where there is no satisfactory alternative therapy. . . Below are considerations for drugs developed for life-threatening and severely debilitating diseases. ?
1. Trial design
2. Trial endpoints
3. Number of trials
4. Statistical considerations
. A typical criterion for concluding that a trial is positive (showed an effect) is a p value of < 0.05 (two sided). A lower p value, for example, would often be expected for reliance on a single trial. For a serious disease with no available therapy or a rare disease where sample size might be limited, as discussed further below, a somewhat higher p value – if prespecified and appropriately justified – might be acceptable.
B. When the disease is rare
By statutory definition, a rare disease – including a genetically defined subset of a disease – affects fewer than 200,000 people in the U.S.; . . . In addition, many rare disorders are life-threatening or severely debilitating diseases with no approved treatments, leaving substantial unmet medical needs for patients. ?
Do you remember Linda Powers’ comments on this document regarding statistical considerations? Here’s a little reminder:
“In regard to p value… professional statisticians and other professionals involved in data modeling and evaluation have been calling for years for the drug approval process to stop using a rigid cutoff of p ≤ 0.05 for determination of statistical significance. A group of 800 such statisticians and professions published a paper making compelling case as to why such a rigid cutoff is inappropriate and fails to give an accurate picture of the real efficacy (or lack of efficacy) of a new medicine. See, e.g., https://www.nature.com/articles/d41586-019-00857-9?utm_source=twt_nnc&utm_medium=social&utm_campaign=naturenews&sf209700813=1 Other similar papers have been published by professional statisticians as well.
It is not fair to patients for a potentially helpful new medicine to be blocked from approval by the rigid application of p value measures that even professional statisticians oppose. In addition – as with the rejection of sub-groups – the rigid application of p values to refuse product approvals is something that the healthcare system simply cannot afford. Each time a new medicine is rejected on this basis, it adds enormous development costs. It also prevents new competition by the new medicine. All of these factors are leading to the skyrocketing drug prices.
Accordingly, we urge that the Agency add to the Draft Guidance express flexibility in regard to p values, along the lines proposed by such a large number of professional statisticians.”
No one (except maybe ex or AVII) knows the shortcomings of this trial better than Linda Powers, or the best ways to overcome them. I probably don’t need to remind anyone that it took nearly eleven months of “the most labor-intensive work with independent statisticians” (and 1 PhD from Merck) to complete the draft SAP. It’s clear that it was not simply “finalizing the SAP” as they indicated in November 2018, but instead, composing a completely new “phonebook size” SAP that spells out multiple pathways to approval, and is based on the most optimal methods of analyzing an immunotherapy with a potential delayed vaccine effect, crossover, and a long survival tail, and incorporating feedback from the very regulators who want to approve a new (safe) treatment. It wouldn’t surprise me at all if the endpoints were modified, or alpha adjusted if it would benefit the OS endpoint to achieve statistical significance.
senti, I agree that much will depend on the data, but if it is as good as I think, you may be underestimating not only the total available market, but also the potential annual revenue. I think the brain tumor market alone could be worth over $3B annually.
I believe that Northwest Bio will initially attempt to obtain the broadest label possible, which would include ALL gliomas, both newly diagnosed, AND recurrent. Even if many people here have forgotten that the PEI approved a hospital exemption for DCVax for this broad label, I’m pretty sure that Linda has not. And even if it was initially only able to cover all nd gliomas (which make up over 80% of malignant brain tumors) that would add another 10k to 15k patients to that total available market.
With your numbers, you appear to be estimating the pricing to be around $150k? Is that the wholesale acquisition cost (WAC)? I have thought that Northwest Bio would try to keep the price as low as possible, say between $150k - $200k, but they may have to price it even higher than that to account for discounting and insurance reimbursement. For example, Optune is priced at $22k per month but CMS (Medicare) coverage is only around $13.5k. (40% discounts are common)
Perhaps you were just being conservative, but I’m curious why you think DCVax usage will only be 1/3. I believe (if approved) that usage may be over 2/3 because DCVax will be added to the standard of care for GBM. This was formerly called “the Stupp Protocol” but with DCVax added, I predict that it will become known as “the Liau Protocol.” That has a nice ring to it . . . the Liau Protocol.