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Okay, now I’m kinda regretting that I even pointed that out, but that “wordsmith” section from the 10-K bothered me when I originally read it, and then you inadvertently brought it up in this post that I replied to. (which was an excellent rebuttal to ex by the way)
As for disclosing the analysis plan in their top line PR... are you joking? Remember, they've indicated it was phone book sized... how on earth could they disclose the SAP in their PR? They've already disclosed the endpoints in the last Q
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164974255
Did Northwest Bio actually disclose the endpoints? Where does it say what the new endpoints are?
This was under the risk factors in the 10-K:
Quote:
We may not receive regulatory approvals for our product candidates or there may be a delay in obtaining such approvals.
Our products and our ongoing development activities are subject to regulation by regulatory authorities in the countries in which we and our collaborators and distributors wish to test, manufacture or market our products. For instance, the FDA will regulate our product in the U.S. and equivalent authorities, such as the MHRA and EMA will regulate in Europe and other jurisdictions. Regulatory approval by these authorities will be subject to the evaluation of data relating to the quality, efficacy and safety of the product for its proposed use, and there can be no assurance that the regulatory authorities will find our data sufficient to support product approval of DCVax-L or DCVax-Direct. In addition, the endpoint against which the data is measured must be acceptable to the regulatory authorities, and the statistical analysis plan for how the data will be evaluated must also be acceptable to the regulatory authorities. The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the “crossover” provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence). The statistical analysis plan uses external control patients rather than within-study controls. There can be no assurance that regulatory authorities will allow a product approval to be based upon this approach.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=164976734
I doubt anybody in science would ever consider -L results to apply to Direct just because they share a similar name. Very unrelated.
Why did "Method B" vanish when they had later results?
Ha ha. I’m not sure who else is on the list, but you will definitely be invited to the NWBO celebration party! Somehow, I don't think it would be the same without you.
Perhaps it’s headlines like these for example? Pretty easy to find similar headlines for Merck’s Keytruda.
Bristol Myers Seeks Redeeming Combination for Struggling Checkpoint Inhibitor
Published: Jul 27, 2021 By Vanessa Doctor, RN
https://www.biospace.com/article/bridgebio-bristol-myers-squibb-start-clinical-trial-to-treat-advanced-solid-tumors-with-kras-mutations/
Bristol Myers pulls lymphoma indication for Istodax after confirmatory trial falls flat
August 2, 2021 05:05 PM EDT Kyle Blankenship
https://endpts.com/bristol-myers-pulls-lymphoma-indication-for-istodax-after-confirmatory-trial-falls-flat/
Both of these BP’s have or had combo trials with DCVax set up, so they certainly know of Northwest Bio . . . . but then you probably knew that.
Autologous Dendritic Cells Pulsed With Tumor Lysate Antigen Vaccine and Nivolumab in Treating Patients With Recurrent Glioblastoma
https://clinicaltrials.gov/ct2/show/NCT03014804?term=NCT03014804
Pembrolizumab and a Vaccine (ATL-DC) for the Treatment of Surgically Accessible Recurrent Glioblastoma
https://clinicaltrials.gov/ct2/show/NCT04201873?term=NCT04201873
And Merck exec’s have said that they are particularly interested in immunotherapies which show efficacy as a monotherapy . . . .
Drugmakers struggle to find immunotherapy combinations for cancer
David Crow in New York MAY 30, 2018
Roger Perlmutter, Merck’s top scientist, said the company would focus its future efforts on combinations where each of the drugs has been proven to work separately as a “monotherapy” before testing them together. “I’d prefer to combine mechanisms where both parts of the combination have activity by themselves,” he said.
https://www.ft.com/content/d39afa5e-6066-11e8-9334-2218e7146b04
My thought was that when Sawston is certified and Advent initially begins production for compassionate use there, they will be using the same expensive, manual process by highly-skilled technicians that was transferred from the CCGTT, so the existing contract would apply. But obviously Advent's operating costs will be different, so that makes more sense.
If it’s so clear, then why do you have it so wrong? Northwest Bio has not shut down any programs nor has it made any payments for it.
Cognate was contracted to manufacture for the clinical trials, so understandably, the focus in the SEC filings was on them. The current focus is on preparations for commercial production at Sawston, and Advent has been contracted to perform that task, so the focus in the SEC documents is on them. I believe that Northwest Bio will use both contract manufacturers for commercial production, but is waiting to sign commercial manufacturing contracts until the comparability studies on the Flaskworks’ equipment has produced actionable results.
I think Advent will manufacture for the UK & EU from Sawston since it will have plenty of capacity for both markets for the next few years at least, and the lowest operating costs. Beyond that, I agree it’s fluid, and there’s a distinct possibility that Charles Rivers Labs could acquire Advent Bioservices at some point.
Thanks ATLnsider, yes I think that’s the simple explanation.
Sorry I missed that discussion. I do think they will use Charles Rivers Labs for manufacturing in the US, so it could be posturing for those negotiations, but the key factor may be the Flaskworks’ equipment.
I thought it was clear that I was making an observation and speculating, but thanks for clarifying if that was not clear.
I would think that Cognate would have run the equivalency studies for cryopreserved leukapheresis material during the trial, but keeping that language in the annual reports long after the trial was completed made me think otherwise. It’s encouraging that Northwest Bio finally addressed the need for automated manufacturing with the Flaskworks’ purchase (NEARLY A YEAR AGO) but the speed with which they operate is frustrating, and this does make me wonder if their limited resources have prevented them from addressing other manufacturing issues in a timely manner. I’m quite confident that they will eventually receive regulatory approval and begin commercial manufacturing, but I’ve begun to think it may be later rather than sooner.
BTW - Do you (or anyone else) have an explanation for the language change from this:
2019 10-K
Our intention is for the U.K. facility to manufacture DCVax products for the whole European region.
2020 10-K
Our intention is for the U.K. facility to manufacture DCVax products for both the UK and other regions.
I’ve noticed the language regarding regional manufacturing and the mention of Cognate has changed in the 10K’s over the last couple of years. It was necessary to have regional manufacturing during the trial because the PBMC’s collected from leukapheresis were shipped from the hospital fresh (not frozen) to Cognate’s manufacturing facility, but I doubt that this will be feasible for commercial manufacturing, and it may be part of the reason for the language change.
With fresh monocytes, there’s a limited window (24-48 hours) in which manufacturing should take place because cell viability decreases after that time. Therefore, manufacturing timeslots have to be reserved for each patient prior to undergoing leukapheresis. This presents logistical challenges if there are shipping delays, or if sick patients miss their leukapheresis appointment, which can cause cancelled manufacturing slots and rescheduling backlogs. During the trial, there were only a few hundred patients treated over many years, so these issues could be overcome fairly easily. But this becomes a nightmare for commercial manufacturing when hundreds of patients a month from all over the country are being scheduled. The solution is to cryopreserve the leukapheresis material, which not only provides scheduling flexibility, but also allows centralized manufacturing from a greater distance. Unfortunately, this requires comparability studies to show the equivalence of cryopreserved cells to fresh cells. The question is: who will perform the comparability studies, and when? By the way, Kite performed the comparability studies early in the development of Yescarta, and used cryopreserved leukapheresis material during their clinical trials so they were well prepared for commercialization.
I’ve said that I believe manufacturing has been the major hold up, and there are still so many issues that have yet to be worked out for commercialization. How can they sign commercial manufacturing contracts when they haven’t even worked out the commercial process, or know if the automated equipment they intend to use will even function properly?
To me, the talk of fast-track status and rapid Project Orbis approvals seems a bit premature if manufacturing isn’t ready. And yes, I’ve been guilty of it too, but that was before the March 16th reality check. I believe there’s a reason that Northwest Bio is currently projecting not just monthly production of 40-45 patients, but an annual figure based on that number . . .
2017 10-K
Cognate BioServices’ manufacturing facility for clinical-grade cell products is located in Memphis, Tennessee. Cognate BioServices' facility is approximately 80,000 square feet and contains substantial buildout expansion space in addition to the portions currently built out and in use. The current manufacturing facilities are sufficient to produce DCVax for at least several thousand patients per year. The expansion space will allow us to procure significantly increasing capacity when needed for commercial readiness. We are also developing a facility for manufacturing in the U.K. for the European market. It is necessary for us to have manufacturing operations in Europe to meet the logistical requirements for European patients relating to the collection, delivery and processing of the patient’s blood draw containing the immune cells (for which the time window is too limited to reach the US manufacturing facility).
2018 10-K
Cognate BioServices’ manufacturing facility for clinical-grade cell products is located in Memphis, Tennessee. Cognate BioServices' facility is approximately 80,000 square feet and contains substantial buildout expansion space in addition to the portions currently built out and in use. The current manufacturing facilities are sufficient to produce DCVax for at least several thousand patients per year. The expansion space could allow us to procure significantly increasing capacity when needed for commercial readiness. We are also developing facilities for manufacturing in the U.K. for the European market. It is necessary for us to have manufacturing operations in Europe to meet the logistical requirements for European patients relating to the collection, delivery and processing of the patient’s blood draw containing the immune cells (for which the time window is too limited to reach the US manufacturing facility).
Our intention is for the U.K. facility to manufacture DCVax products for the whole European region. With the impending exit of the U.K. from the European Union (Brexit), it is unclear whether it will be feasible for U.K.-based manufacturing to supply DCVax products throughout Europe. It could be years before the full legal and regulatory rules and requirements become clear. We anticipate that the manufacturing facilities in the U.K. will eventually obtain the necessary approvals, and will be able to supply DCVax products, for clinical trials or otherwise, anywhere in Europe; however, this may not turn out to be feasible, for regulatory, operational and/or logistical reasons.
2019 10-K
Our intention is for the U.K. facility to manufacture DCVax products for the whole European region. With the recent exit of the U.K. from the European Union (Brexit), it is unclear whether it will be feasible for U.K.-based manufacturing to supply DCVax products throughout Europe. It could be years before the full legal and regulatory rules and requirements become clear. We anticipate that the manufacturing facilities in the U.K. will eventually obtain the necessary approvals for Europe, and will be able to supply DCVax products, for clinical trials or otherwise, anywhere in Europe; however, this may not turn out to be feasible, for regulatory, operational and/or logistical reasons.
2020 10-K
Our intention is for the U.K. facility to manufacture DCVax products for both the UK and other regions. However, this may not turn out to be feasible, for regulatory, operational and/or logistical reasons. It is also unclear whether or how Brexit will affect or interfere with these plans in regard to Europe.
Nope, they could not have had TLD in September 2020, because the data lock and distribution to statisticians did not occur until October 2020.
BETHESDA, Md., October 5, 2020 – Northwest Biotherapeutics (OTCQB: NWBO) (“NW Bio”), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today announced that the database for the Phase III trial of DCVax®-L for Gliobastoma has been locked.
https://nwbio.com/northwest-biotherapeutics-announces-data-lock-of-phase-iii-trial/
I choose to believe they were not lying in August and September 2020 without further information, so I think it is logical an external (outside the trial and company) event/agent led to the change of course.
When the Company receives the initial results, it will review the data and results with its Scientific Advisory Board, the Trial Steering Committee, and other key advisors. During this process, any questions or comments from the experts will be addressed as part of the preparation of the results for public reporting. The Company anticipates that these very important discussions with experts could take several weeks, especially with the significant logistical challenges due to COVID-related restrictions (which may be further increasing as the COVID resurgence grows).
In light of the significant progress reported here, together with the next steps in the process and the operational and logistical challenges, the Company currently anticipates that Trial results will be ready for reporting approximately sometime after Labor Day in the month of September. The Company will be consulting with its Principal Investigator and experts on the appropriate venue and manner of presenting the Trial results.
https://nwbio.com/northwest-biotherapeutics-announces-completion-of-phase-3-trial-sites-databases/
ski, the 2019 ASCO presentation discussed the DCVax-Direct manufacturing process, which of course is personalized, uses tangential flow filtration, and a bagged culture system vs the Flaskworks’ flask culture system. There’s a picture/illustration of the manufacturing system in the slideshow presentation, which you can download here:
https://nwbio.com/program-update-presentation-by-dr-marnix-bosch-at-asco-2019/
The Flaskworks’ system doesn’t eliminate the need for a cleanroom, they will likely be installed in a C-class cleanroom, which is still over 5 times cheaper to operate than a B-class cleanroom. The current Flaskworks’ MicroDen system is designed to be operated inside a conventional incubator, which may be required to control some environmental conditions. The patents state this, and the published study from Northeastern University showed pictures of the system placed inside an incubator.
And by the way, it’s common to have bench-top manufacturing stations set up in a cleanroom, even Kite’s commercial CAR-T manufacturing plant in El Segundo has hundreds of automated systems similar to this:
Large-scale cell manufacturing – The CliniMACS Cell Factory
I have no idea how things remain individual and are automated beyond the FlaskWork device, other than having robots actually handling the FlaskWork cassettes rather than humans. I don't see how anything that's common to many batches of the vaccine can keep each batch completely separate and unique.
I'm of the belief that a decade or so from now many personalized products will be approved and far more effective than mass produced therapeutics. I'm hoping that the FlaskWork devices are actually capable of producing many of them. The day may come when such devices are located at most hospitals, or perhaps even in Doctor's offices, and personalized products will be made in short periods of time after patients leave the appropriate sample to make it from.
No prob senti. I thought maybe you saw it somewhere in the filings that I missed. I just found it curious that they revealed all that info without actually disclosing the new endpoints.
Thanks ae, but maybe you missed my point. (Northwest Bio didn’t actually disclose the new endpoints - it was disclosed by the clinical trials registry)
So you think I should visit your pay website rather than the actual source? (Eudra https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB )
Some good points longfellow, always enjoy your thoughtful posts.
As you know, the “combo is best” mantra is so prevalent because there hasn’t been a monotherapy that’s been able to increase survival in a large percentage of cancer patients, and of course, the influence of Big Pharma pushing this idea to increase their sales. Finding the right combination of toxic agents is proving difficult as they mostly tend to increase the toxicity without increasing efficacy. I think this will likely change though as the less toxic, personalized cell therapies that are coming through the pipeline now, are added to the market. (DC’s and NK’s for example)
I’m aware of your disdain of checkpoints, and I agree . . . to a point. They are clearly effective for some patients, and I think there is a place for them in cancer treatment, (certainly not the oversized role they now enjoy though) but there should be a far-greater effort to understand and minimize the hyperprogression and other adverse events. Unfortunately, to date, there hasn’t been a big enough incentive. Perhaps if competition from a more effective and less-toxic therapy comes along . . .
Interesting hypothesis. Do you think that if Dr. Liau believed as you do, that Prins would be able convince her? (that’s rhetorical) There’s some research (not just UCLA’s) to suggest the combination with DC’s may be more effective than either monotherapy, and it’s certainly worth testing with DCVax. (I suspect there is a subset of patients the combo may work for) In the case of rGBM, (or other terminal cancers) if the combo can add a few months of survival, even with the added risk of adverse events, I think it should be another option available for the patient to decide if it’s worth the risk. I’m guessing that for many it would be.
ski, I think the comparability studies will be completed by next year, (which may coincide with a commercial marketing approval in the UK) but regardless, I don’t think Northwest Bio would begin commercial production until the closed, automated process using the Flaskworks’ equipment is approved. I believe that when that time comes, there will be more than sufficient capacity since the space at Sawston can be built out modularly as the need increases, and I also think it will be a slow ramp. Cell therapies are difficult to scale up quickly since there will be logistical issues to iron out, hospital procedures to establish and certify, and insurance reimbursement to negotiate, just to name a few of the hurdles that will slow the initial roll out.
In years past, Northwest Bio was paying Cognate for dedicated manufacturing capacity, but I’m not sure this is still the case. Any mention of development activities or payments in news releases or SEC filings have only related to Advent at Sawston. There’s been no mention of Northwest Bio’s development activities at Cognate/Charles Rivers, or even an updated manufacturing agreement, so I doubt Charles Rivers Labs is conducting any comparability studies with the Flaskworks’ equipment at this time. My guess is that Advent will conduct the comparability studies and develop the automated process, and then transfer that approved process to Charles Rivers. (or whoever is their manufacturing partner in the US) Charles Rivers Labs will then have to install the Flaskworks’ equipment, develop an automated workflow process, and run their own comparability study in their GMP manufacturing facility before production can begin in the US.
As far as DCVax-Direct, it has it’s own proprietary, closed, automated process that’s been optimized, and approved by regulators, so I doubt that they would completely upend that process to use the Flaskworks’ equipment for that product, but who knows. When funds become available, Charles Rivers could immediately begin production for future trials in the US & Canada since they manufactured DCVax-Direct for previous trials from Cognate’s Memphis facility. I think Advent would have to conduct more comparability studies to transfer that established process to the Sawston facility before they could begin manufacturing DCVax-Direct for trials in the UK/EU though.
I don’t think the large-scale manufacturing that you’re really talking about, will happen as fast as you might think. The Flaskworks’ equipment can potentially manufacture enough batches for thousands of patients annually, and will be used for the Glioblastoma indication, and likely future clinical trials for DCVax-L, but I think by the time that label is expanded for multiple other cancers, a more efficient, industrialized process using the Eden culturing system, may be developed. There’s a reason that cell and gene therapies have been primarily developed for rare diseases. (small patient numbers & lack of large-scale manufacturing ability)
As a reference, Kite/Gilead’s personalized CAR-T cell therepy, Yescarta, was approved about 4 years ago, and their last quarter’s worldwide sales ($191M) were from about 500 patients. The CAR-T’s have had a slow roll out partly due to massive competition between the two commercial companies (Gilead & Novartis) and all the CAR-T clinical trials recruiting their potential patients. I do think DCVax (or whatever the commercial name will be) will ramp multiple times faster though.
Yescarta sales over time
https://www.loncarblog.com/yescarta-sales
Thanks Lykiri, I missed this. It’s a very sad reminder how devastating it is for the patient to lose their brain functions, and for everyone involved. Glioblastoma is truly a horrible disease.
Did Northwest Bio actually disclose the endpoints? Where does it say what the new endpoints are?
This was under the risk factors in the 10-K:
We may not receive regulatory approvals for our product candidates or there may be a delay in obtaining such approvals.
Our products and our ongoing development activities are subject to regulation by regulatory authorities in the countries in which we and our collaborators and distributors wish to test, manufacture or market our products. For instance, the FDA will regulate our product in the U.S. and equivalent authorities, such as the MHRA and EMA will regulate in Europe and other jurisdictions. Regulatory approval by these authorities will be subject to the evaluation of data relating to the quality, efficacy and safety of the product for its proposed use, and there can be no assurance that the regulatory authorities will find our data sufficient to support product approval of DCVax-L or DCVax-Direct. In addition, the endpoint against which the data is measured must be acceptable to the regulatory authorities, and the statistical analysis plan for how the data will be evaluated must also be acceptable to the regulatory authorities. The statistical analysis plan that we submitted to regulators for the Phase III trial embodies a different primary endpoint and secondary endpoint than did the original Protocol for the trial. Under the Protocol the primary endpoint was progression free survival, or PFS, and the secondary endpoint was overall survival, or OS. Both of these endpoints were confounded: the PFS endpoint by pseudo-progression, and the OS endpoint by the “crossover” provision in the trial design, which allowed all of the patients in the trial to cross over to DCVax-L treatment after tumor recurrence (while remaining blinded as to which treatment they received before tumor recurrence). The statistical analysis plan uses external control patients rather than within-study controls. There can be no assurance that regulatory authorities will allow a product approval to be based upon this approach.
Yes, the GMP certification will allow Advent to begin production of DCVax for compassionate use (Specials) at Sawston using the established manual process that has been used in the clinical trials and transferred from Advent’s facility at the Royal Free Hospital. Of course they can’t produce a commercial product since they haven’t even filed a BLA or MAA to receive regulatory approval. Northwest Bio could seek regulatory approval using this well-documented, established manual manufacturing process, while Advent performs the comparability studies. It’s a major manufacturing change that will require substantial documentation of the comparability of the automated process, (as I posted) but it is preferred and even expected by all the regulatory authorities that any cell therapy manufacturer would close and automate the manufacturing process for commercial production. Perhaps I missed the part where it says that additional clinical trials are necessary. Could you post that? Or was that just more FUD? And who is LP’s UK pal? Mark Lowdell?
All equipment used in a GMP manufacturing facility must go through the qualification stages that Northwest Bio mentioned in their March 16th press release: Design Qualification (DQ), Installation Qualification (IQ), Operations Qualification (OQ), and Performance Qualification (PQ). The Flaskworks Agreement required the newly-sourced EDEN prototype to be ready for testing at Advent Bioservices within 90 days of of the close (Aug 28th), which is why I believe the Flaskworks’ equipment was likely installed at the Sawston facility last fall, and was part of that qualification process, which would allow Advent to perform the comparability studies this summer. At this late stage of development, (post phase II and prior to commercialization) the studies will be quite extensive and are required not only for the new automated commercial process using Flaskworks’ equipment, but also for the manual process transferred from the CCGTT at the Royal Free Hospital to the new Sawston facility.
Here’s some relevant parts of a good article which details some of the comparability requirements:
Comparability considerations for Advanced Therapy Medicinal Products (ATMP)
Introduction
CHMP scientific advice questions are often related to the suitability of comparability proposals following changes to ATMP manufacturing processes or due to introduction of additional manufacturing sites. Manufacturing process changes may encompass improvements/change in equipment, raw materials and critical starting materials such as the cells or the vector or their suppliers, manufacturing process scale or product stability. Such changes are frequent, especially in the early stages of development of ATMPs.
Every change in manufacture should be done in accordance with GMP. The criticality of the changes and the estimation of their impact on the characteristics of the product should determine the amount of comparability data needed. Where applicable, the Variation Regulation1 (for authorised ATMPs) or the clinical trial framework (for investigational ATMPs) should be followed.
A suitable comparability program is required to support the introduction of changes during the development stages of an ATMP. The acceptable level of flexibility is progressively reduced from the non-clinical stage to the pivotal clinical use. Comparability is also an important tool to support changes after marketing authorisation where the process and the product are expected to be well defined and appropriately controlled by quality specifications and characterisation tools.
Cell-based advanced therapy medicinal products are complex in terms of composition and dynamic nature (e.g. different function, different differentiation stage, presentation in 3-dimensional forms). Also, the manufacturing process often depends on the combination of multiple biologically active reagents and manufacturing conditions that require careful consideration to ensure that the product remains the same for all patients treated. Changes are often necessary and include renewal of cell lots for production, modifications in the manufacturing process, changes of process scale, change of a raw material supplier, or proposals for additional manufacturing sites sharing the same manufacturing process. In all such cases the comparability exercise becomes a relevant tool to demonstrate that safety and efficacy data with a given preparation is also applicable after the change was introduced. The comparability program for these complex products cannot be based solely on the characterisation of the phenotypic markers related to purity confirming a heterogeneity profile. The dynamic nature of the product reflecting its metabolism, differentiation stage, structural organisation and interactions should be part of the comparability assessment. Functional / biological properties of the product are key to define the level of comparability attained as well as to define the extent of non-clinical and/or clinical data to be generated.
Q1: What do “comparability” and “comparability exercise” stand for?
A: Comparability is the conclusion of the comparability exercise demonstrating that no adverse impact on the quality, efficacy and/or safety profile of a product has occurred when a manufacturing process change/transfer is introduced for the drug substance/product. Comparability is not a demonstration of similarity as for a biosimilar approach.
The comparability exercise is a set of activities including both the generation and analysis of data in the context of a study/studies suitably designed and conducted with identified batches and analytical tools at the quality level. Additional study/studies at the non-clinical and clinical level may be needed to investigate comparability of the batches pre- and post-change/transfer of the manufacturing process.
Demonstration of comparability through a suitable exercise is a fundamental part of the evolving manufacturing process to ensure that the safety and/or efficacy data gathered as well as the benefit/risk balance of a product is valid throughout development, for marketing authorisation and beyond.
Overall, the general principles of ICH Q5E can be applied to ATMPs:
* The comparability exercise should be conducted stepwise, starting with the physico-chemical and biological properties of the product. This will be based on analytical testing e.g., routine batch analysis, in-process controls, process validation/evaluation data, characterization and stability studies, as applicable. ?
* Theinvestigationshouldfocusonthemanufacturingprocessstepsmostappropriatetodetect a change. This may require an evaluation on all critical steps/in-process controls/materials of the manufacturing process downstream of the change. ?
* Analytical methods should be suitable for purpose and sufficiently sensitive to ensure the detection of differences/modifications. Any observed analytical difference should be evaluated in relation to its impact on the product quality, safety and efficacy. ?
Q4: How should process comparability be addressed?
A: A comparability exercise should not only cover evaluation of equivalency of manufactured products but should include also comparison of processes themselves, if relevant. Comparison of processes is particularly important when a new manufacturing site is introduced. Data from process parameters and results of in-process controls should be evaluated to understand better the impact of any introduced changes. Especially for some attributes, it is more suitable to monitor them at a specific step during the manufacturing process than at the level of drug substance or drug product. These are for example expansion profiles during the cultivation phase, yields of individual steps, monitoring of product or process related impurities etc. The specific strategy should be established based on knowledge gained during the process development.
Q7: What is the preferred approach for demonstrating comparability?
A: In general, there are two main approaches for comparability study:
a) Side-by-side testing of products in the same analytical run. Due to the complexity of ATMPs, it is very important to focus on the effect of the introduced change(s). To reduce the source of variability, it is also advisable that both the pre- and post-change processes should be performed with the same batch of raw materials.
Furthermore, to eliminate the effect of variability of a cell starting material a split-based approach is highly recommended. This is important especially for patient-based (e.g. autologous) cell-based products where the intrinsic patient to patient variability can represent a confounding aspect for the demonstration of comparability.
b) Comparison of post-change data to historical data obtained from pre-change process. This approach is not recommended but it can be acceptable if a side-by-side study is not possible. In this case, potential impact of all variable parameters (analytical methods, personnel, used equipment and materials, ...) need to be evaluated.
It is advised that historical data ranges or different statistical approaches (e.g., for control of attributes with a recognised impact) that are utilized for comparability assessment, should be thoroughly selected and justified. In this context, comparability acceptance criteria should always be clearly provided and justified to assure product consistency and therefore comparable efficacy and safety. It should also be considered that acceptance criteria depend on the available data and on the statistical approach/methodology chosen, e.g., a proper interval based on historical data if the approach is based on ranges for post-change individuals/mean, a p-value if the approach is based on inference statistics, etc.
For further statistical aspects, see Question 11.
In case comparability studies are performed using stored (starting) materials, drug substance, or final product, the impact of storage should be considered.
In the comparability exercise at the time of the MAA, comparability acceptance criteria should always be reported along with the results of the comparability exercise runs.
In both approaches, historical data, if representative, can be used to provide insight into potential “drifts” in quality attributes with possible impact on safety and/or efficacy.
Q10: Is there a minimum number of batches that should be included in a comparability exercise?
A: There is no ‘one size fits all’. For considering the required level of comparability demonstration, the intrinsic variability of the product needs to be evaluated and taken into account.
Depending on the type of change introduced, while a small number of batches can serve to demonstrate comparability for a given analytical method where intrinsic variability is minimal and precision and sensitivity is high, other methods such as biological characterisation methods may require more extensive testing of significant numbers of samples as the inherent variability is high. The number of batches included in the comparability exercise needs to be evaluated case by case, and the approach taken requires careful consideration and justification based on the type of change, product and manufacturing process understanding, overall control strategy, sensitivity of the methods and the level of risk.
The higher the variability between batches, the higher the number of batches required to conclude the comparability exercise.
Q12: What is the comparability exercise needed when a new manufacturing site is added to an existing authorisation?
A: When several manufacturing sites are introduced under the same authorisation procedure, a high degree of comparability is expected to be demonstrated. The comparability of the product manufactured at different sites should be comprehensively substantiated. The first step should be to perform a comparability assessment of the manufacturing process and equivalence of the analytical methods on both sites by evaluation of process parameters and in-process control, to validate the process transfer. Secondly, the comparability of the product itself through release and suitable characterisation testing should be demonstrated. (See also Questions 4, 6 and 9)
https://www.ema.europa.eu/en/documents/other/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp_en.pdf
I'm not aware of anything to suggest that L is less effective with other high grade gliomas. It's just that there hasn't been a formal trial.
Nice post longfellow. This landmark trial should set a new standard, and I think part of the reason for the collection of the IDH mutation data is that future trials in Glioblastoma will now be compared to this new standard. This is from the last time the WHO reclassified brain tumors in 2016, but is still relevant:
World Health Organization Reclassification of Brain Tumors Overview & Frequently Asked Questions (FAQ)
1. Why are these changes happening now?
?The World Health Organization sets international standards for how tumors are classified, and in conjunction with leaders in each field, periodically review their classifications to ensure that the latest science is guiding how tumors are defined. Recent findings from brain tumor research studies in the past few years have provided new information on the distinct molecular make-up of many brain tumor types, as well as how some types that look different under a microscope may actually be driven by the same mutations, and thus behave the same way...or, conversely, that two current types look the same under a microscope, but have very different genetic alterations, and thus should be treated differently.
2. Why does it matter how tumors are defined? Why does re-classification matter?
How tumors are classified – or defined, or characterized – has an impact on many different and important aspects of individual, as well as population, health in any given disease area. This includes:
* Care of individual patients – more accurate diagnosis, estimating prognosis, guiding therapy
* Conduct and interpretation of clinical trials – ensure that patients participating in clinical trials are comparable within and across trials
* Stratification for future clinical trials – matching patients by their molecular signatures with target therapies most likely to benefit them
* Getting the right results from scientific experiments – more accurate analysis and understanding of experimental studies in the lab
* Disease epidemiology- better interpretation of population-based disease trends that may help identify causes and risk factors
* Research funding- allocation of resources by governments and health insurers to support health care based on areas of greatest need
http://braintumor.org/wp-content/assets/WHO-Re-Classification-2016_FINAL.pdf
ATLnsider, that was the same language used in the Journal of Translational Medicine
Conclusions
The addition of DCVax-L autologous dendritic cell vaccine to SOC is feasible and safe. Collectively, the blinded interim survival data suggest that the patients in this Phase 3 trial are living longer than expected. These findings warrant further follow up and analyses.
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6
I suppose if Northwest Bio were to choose Charles Rivers Labs as their commercial partner, then old pals will be reacquainted. The timing of the Cellero and Cognate acquisitions are certainly interesting.
Speaking of Northwest Bio’s connection with Charles Rivers . . . it’s been posted here that last year Charles Rivers acquired Cellero, (formerly Astarte), where Anne Lodge was Chief Science Officer. Not sure if this was posted though . . . Do you know who was VP of Research & Technology at Cellero? This might be a familiar name . . . Benjamin A. Tjoa. Hmmmm, small world.
Anne Lodge, Ph.D.
Chief Science and Innovation Officer
Anne Lodge received her Ph.D. in Cell and Molecular Biology from the University of Vermont. Her thesis work examined the activation of CD4+ and CD8+ T cells by vascular endothelium and revealed the importance of endothelial cells in triggering organ rejection.
After completing her graduate work, Dr. Lodge received a postdoctoral fellowship from the Multiple Sclerosis Society. The fellowship supported her work at Vanderbilt University in the laboratory of Dr. Subramaniam Sriram. She studied T cells from patients with MS to determine their role in the disease process.
Dr. Lodge then accepted a position with Northwest Biotherapeutics, Inc. in Seattle. She had a number of different roles at the company and contributed to the Investigational New Drug filings for the company’s dendritic cell vaccine. Her expertise in cell-based therapeutics and broad background in immunology led to her founding Astarte Biologics in 2004 to provide immune cell products for research.
Patents
Smith J.P.; Lipsky P. E.; Lodge A. Human T cell line assay for evaluating the immunologic identity of glatiramer acetate preparations. Application Number 14/522,521. Filed October 23, 2014.
Shankar G.; Lodge, P.A.; Brunelle, A.N. Quality assays for antigen presenting cells. Application Number 60/379,126. Filed June 14, 2012.
Bosch M. L.; Harris P. C.; Monahan S. J.; Turner A.; Boynton A. L.; Lodge P. A. Tangential flow filtration devices and methods for leukocyte enrichment. Application Number 12/759,552. Patent Number 8,518.636. Filed April 13, 2010.
Bosch M. L.; Lodge P. A.; McEarchern J. A.; Boynton A. L.; Hugenholtz P. G. Tangential flow filtration devices and methods for stem cell enrichment. Application Number 10/992,154. Patent Number 7,790,039. Filed November 18, 2004.
Bosch M. L.; Harris P. C.; Monahan S. J.; Turner A.; Boynton A. L.; Lodge P. A. Tangential flow filtration devices and methods for leukocyte enrichment. Patent Number 7,695,627. Filed June 19, 2003.
Benjamin A. Tjoa, Ph.D.
Vice President, Research & Technology
Benjamin Tjoa received his Ph.D. in Biochemistry/Immunology from the University of Illinois at Urbana-Champaign. With over 20 years of experience, Dr. Tjoa has held various positions in R&D, product development, and translational research.
As a Senior Scientists at Northwest Biotherapeutics, Dr. Tjoa studied human dendritic cell basic biology, in vitro generation, antigen-loading, maturation, pre-clinical dendritic cell-based cancer vaccine studies, and assay developments. He published over 20 scientific articles and earned two patents.
Before joining Astarte Biologics, Dr. Tjoa also held VP of R&D and Lead Scientist positions at Sangretech Biomedical and Bostwick Therapeutics where he led research teams in the development of “second generation” dendritic cell-based vaccines for solid tumors and conducted process development and qualification for a GMP production of a cellular cancer vaccine for clinical testing.
As one of the first scientists to develop dendritic cells for use in cell-based vaccines, Dr. Tjoa has traveled internationally to set up laboratories for dendritic cell-based therapies.
Patents
Murphy G.P.; Boynton A.L.; Tjoa B.A. Isolation and/or preservation of dendritic cells for prostate cancer immunotherapy. Application Number US5788963. Filed July 31, 1995.
Tjoa B.A.; Bosch M.L. Generation of dendritic cells from monocytic dendritic precursor cells with GM-CSF in the absence of additional cytokines. Application Number: US8389278. Filed February 27, 2004.
That’s the million dollar (pound?) question isn’t it? Why issue that definitive timeline and lead everyone to believe that topline was imminent last fall, only to leave us hanging? And don’t forget, there was also Linda Powers' presentation at the 2020 American Brain Tumor Association’s National Conference on September 12th, where she said this:
in the next couple weeks, later this month of September, we will be expecting to unblind, unveil, and announce, finally, the results of our thirteen-year-long phase III trial of DCVax for Glioblastoma brain cancer. And we think this study is going to be a major contribution to the field in terms of data, and we certainly hope to be able to bring a new treatment option to patients. So please stay tuned to see those clinical trial results in just a few weeks.
Okay, thanks. Yes, there are a couple interesting ties to Charles Rivers.
Manufacturing. Manufacturing. Manufacturing. What was announced in between that PR and the data lock announcement on OCT 5?
hint:
21 AUG 2020 Northwest Biotherapeutics Announces $5 Million Financing: Non-Dilutive Debt; No Amortization For 7 Months; Maturity of 21 Months
27 AUG 2020 NW Bio Accelerating Sawston Plant Phase I Buildout: Construction Crews Working Double Shifts To Accelerate Completion Despite COVID Effects
01 SEP 2020 Northwest Biotherapeutics Acquires Flaskworks: Breakthrough Automation Technology For Cell Therapy Products To Enable Scale-Up of Production Volumes and Reduction of Production Costs
and since:
16 MAR 2021 Northwest Biotherapeutics Announces Development Completed for Initial Production Capacity of Sawston, UK Facility
12 MAY 2021 UK Manufacturing Facility & Phase III Trial Updates From Northwest Biotherapeutics
They’re getting close . . .
Huh? Is this the same exwannabe who wrote this only a few months ago?
No way.
I doubt they will be certified this year. They are still about 6 to 8 weeks (LP time) away from having an application in (LP time). And I am guessing the UK has a serious backlog in the GMP inspection process right now, which is never fast to begin with.
I would take June or July 2022 as a better guess.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=162678792
Sorry flipper, maybe I’m missing the significance of this. For decades, Charles River Labs has been (primarily) a pre-clinical CRO specializing in laboratory support services (which includes assay development and testing services) for hundreds of companies. Doesn’t every CDMO have this capability?
In order to receive regulatory approval, a cell therapy program is required to determine the critical quality attributes (CQA's) of their cells, or the characteristics which define their product, (characterization) and to develop analytic methods (assays) to analyze each batch for potency, purity, sterility, viability, and stability. This is essential for quality control, GMP product release, and comparability testing. I believe UCLA would have developed some of the assays to test DCVax for safety and identity in preclinical and phase I trials, and then further characterization and assay development was done by Cognate and Fraunhofer. DCVax should have been fully characterized, and all the required assays developed, qualified, optimized, and validated many years ago.
(This is how Linda Liau was able to tell senti that the ATL-DC vaccine that UCLA is using in the combination trial with Pembro for rGBM, is essentially the same vaccine as DCVax-L)
C’mon jondoe, Roger Perlmutter told you why Merck is providing Keytruda for that trial in bold and red type. You're right, we don’t know how many mild or moderate events there were, but there were zero major adverse events reported, which indicates to me that there was none grade 3 or higher. I’m quite sure that Merck took notice of that. Have you seen the toxic effects of a combination of Keytruda and Yervoy in a recent study? Ouch!!
Merck’s Keytruda Proves Better Alone in Combination Trial With BMS’ Yervoy
Published: Feb. 1, 2021 By Mark Terry
Less than a year ago, Bristol Myers Squibb’s Yervoy received approval for previously untreated non-small cell lung cancer in a combination of Opdivo and Yervoy. Today, Merck released first-time data from the Phase III KEYNOTE-598 trial of Keytruda in combination with Yervoy (ipilimumab) compared to Keytruda alone as first-line therapy for metastatic non-small cell lung cancer (NSCLC) without EGFR or ALK genomic tumor aberrations and whose tumors express PD-L1. Adding Yervoy to the therapy did not improve overall survival (OS) or progression-free survival (PFS) but did add toxicity to Keytruda monotherapy.
In the study, median OS was 21.4 months in the Keytruda-Yervoy group compared to 21.9 months for the Keytruda only group. Also, the median PFS was 8.2 months in the combination cohort compared to 8.4 months for patients receiving Keytruda alone.
The trial enrolled 568 patients randomized 1:1 to receive Keytruda 200 mg intravenously on Day 1 of each three-week cycle for up to 35 cycles in combination with 1 mg/kg IV on Day 1 of each six-week cycle for up to 18 cycles of Yervoy, or Keytruda alone. There were no new safety signals for the Keytruda monotherapy arm, but in the combination arm, 76.2% reported treatment-related adverse events (TRAEs) compared to 68.3% of the Keytruda monotherapy arm. Of the TRAEs, 35.1% versus 19.6% were Grade 3-5, 27.7% versus 13.9% were serious, and 6.0% versus 3.2% led to discontinuation of Yervoy or placebo, and 19.1% versus 7.5% led to discontinuation of both drugs, while 2.5% versus 0.0% led to death. There were also immune-mediated adverse events and infusion reactions in 44.7% of patients receiving the combination compared to 32.4% received Keytruda alone. . . .
It has been hypothesized that by adding a CTLA-4-targeted antibody to a PD-1 checkpoint inhibitor would create more benefits in some cancers, but this is the first well-designed comparison trial. And it completely undercuts the hypothesis. “The results are clear,” said Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “The combination did not add clinical benefit but did add toxicity.”
https://www.pharmalive.com/keytruda-proves-better-alone-in-combination-trial-with-yervoy/
Yes, it was the Thorlund slide that senti posted, and in the discussion that followed, I posted the Medicenna trail for rGBM that will use that model with two-thirds matched external control arm. This type of hybrid control design was blessed or actually recommended by the FDA to Medicenna according to their announcement on October 15th, 10 days after NW Bio announced the database was locked. So clearly the FDA bought into that type of matched external control arm. Was that timing just coincidence? And then Dr. Liau talking about it several months later?
Right jondoe, and why do you think Merck is providing Keytruda for this combination? Did you happen to notice the number of adverse events? Do you remember these 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
thanks GGB. I recall that now. So much to remember . . .
Dendream, if you follow that thread back a couple of posts, senti posted a slide on external control arms that was shared by Dr. Liau during her (Utah?) talk in April. While it appears that Dr. Liau favors the scientific design using only one third of control patients within the trial group along with two thirds matched external controls, that is not what the Eudra clinical trial registry states Northwest Bio will use. It simply states “control patients from comparable, contemporaneous trials.”
The primary objective of this study is to compare overall survival (OS) between patients randomized to DCVax-L and control patients from comparable, contemporaneous trials who received standard of care therapy only, in patients with newly diagnosed glioblastoma. This endpoint will be assessed using 3 different analyses.
https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-001977-13/GB
Doc, I thought the same thing, and believe this is like a generic version of DCVax-D, which may be why it didn’t have a better response. I have wondered the same thing about UCLA’s version of DCVax-L for the combination trial in rGBM. If NW Bio were running these trials with their optimized versions and know-how, would the results be the same? And does this hurt their value in BP's eyes? (not asking you, but wondering to myself)
Good to know you read it to the end.