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pgsd, it’s beyond uncomfortable for me. I don’t think that two-bit show is worthy of the science or this company. In my opinion, i’s humiliating and demeaning, and so difficult to watch, that I only watched the very first one, the one where Les had that bright pink makeup on his cheeks like a clown. I honestly can’t watch it. To me, it’s like an entertainer who was once at the top of their game, a headline act who once performed in the biggest venues, but has fallen on hard times, and is forced to perform in broken-down, cheap clubs to pay the bills. The company is now associated with this cheap lounge act. I’m normally a positive person and attempt to look for the bright side, but I fail to understand why Les would think this is a good idea, and I can only guess that he’s a promoter (cheap salesman?) and he’s trying to attract new retail investors. I’m not a fan of Jim Cramer or his show, but at least his show has a tiny bit of professionalism. But going on the Big Biz Show . . . it honestly make me question his judgement.
Outstanding posts senti, thanks for digging this up. I was pretty sure about Northwest Bio’s biomarker development, but this discovery would sure seem to confirm it. This is why Linda Powers continues to declare that DCVax is applicable to all solid tumors, and that she intends to prove it. Also interesting that all these years later, the FoundationOne CDx test is the companion diagnostic to identify patients with solid tumors that are TMB-H for this new Keytruda approval.
I posted an interview with Dr. Steven Brem, who is a professor and Chief of Neurosurgical Oncology at the University of Pennsylvania and also a Northwest Bio SAB member. According to him, Northwest Bio is looking at radiological markers as well. These will likely identify the tumor response rate, so that future trials can be ended more rapidly. This is all obviously important for the appropriate valuation of the DCVax platform and may be why some posters here want to create the impression that it will take a long time for multiple new trials for each new indication, which is simply not true.
anders, you have repeatedly asserted that it will be necessary to run trials for every organ-specific cancer, and that is completely outdated and WRONG. The FDA has approved, and will approve a treatment for cancer in ANY location in the body based on genetic or other type of biomarker that the treatment has been proven to work for in clinical trials. This first occurred with Keytruda back in 2017, and Keytruda was just approved again this June based on another biomarker.
This latest approval was very significant as it relates to Northwest Bio because DCVax has proven to be particularly effective based upon that same biomarker - ALL cancers with a high Tumor Mutational Burden (TMB). TMB is a measure of the number of gene mutations inside the cancer cells, which can be determined by a lab test. Cells that have many gene mutations (a high TMB) might be more likely to be recognized as abnormal and attacked by the body’s immune system. It’s very likely that this trial in Glioblastoma will identify other biomarkers in the long-lived patients in the survival tail, which will be used to expand the label to ALL cancers in the body with this biomarker.
Biomarkers at FDA
Biomarkers are a key medical product development tool capable of facilitating development of medical products and spurring innovation. When used in the right context, biomarkers have the potential to help expedite patient access to safe and effective treatments by reducing the time and cost of clinical trials while maintaining patient protections.
FDA is working to help speed the development of promising new therapeutics by developing regulatory science standards, reference libraries, research methods, and tools that are needed for integrating biomarker information into medical product development and clinical decision-making. . . .
https://www.fda.gov/science-research/about-science-research-fda/biomarkers-fda
FDA Approves Pembrolizumab for Tumors with Specific Genetic Features
https://www.cancer.gov/news-events/cancer-currents-blog/2017/fda-pembrolizumab-genetic-features
FDA Approves Second Biomarker-Based Indication for Merck’s KEYTRUDA® (pembrolizumab), Regardless of Tumor Type
https://finance.yahoo.com/news/fda-approves-second-biomarker-based-104500734.html
Longfellow, I agree and have also said that I think the Power’s Plan is to remain independent and take an unconventional path just as you suggest. But I could point to a half dozen comments from Merck’s management that leads me to believe that they would be interested in DCVax. The question I’ve always had is: will they (or any BP) be willing to make an offer that can’t be refused? Anyway, here’s some recent comments from Merck”s ASCO 2020 presentation:
Q&A
Seamus Fernandez – Guggenheim Securities
Roger, just hoping you could comment on what feels like a couple of gaps in your internal development pool, and you’ve been accessing that by buying companies like ArQule. We’re seeing a lot of encouraging early data with point mutation kinase inhibitors. Just hoping you could give us a general sense of the Merck philosophy around kinase inhibitors development there and the ability or Merck’s interest in potentially building out that space. . .
Roger Perlmutter (President of Research)
Right. Thanks, Seamus. I think, first of all, the idea of looking at kinase inhibitors, of course, we are interested in them potentially in our using LENVIMA as a way to probe the protein tyrosine kinase inhibitor field. So field, of course, that I know extremely well and been involved in it for the better part of 40 years. So I have a lot of experience in looking at these molecules. I have to say that the – a lot of our attention has been drawn, of course, to immuno-oncology mechanisms because of what we found with KEYTRUDA. And we’ve naturally gone and asked, well, okay. What can you do to improve KEYTRUDA responses to get beyond where we are? Because we want to do better. And what we’ve learned some things about that, we’ve certainly shown that combinations in a variety of different settings can be helpful.
And that includes a lot of things that just kill tumor cells. So chemotherapy, working cytotoxic agents, traditional chemotherapy, radiotherapy, and, of course, signal transaction targeting agents. And all of them, I think, have similar kinds of effects. We’re interested in them. And what we’re trying to do is improve the benefit risk profile. So where we can find more selective compounds at a fewer adverse effects, in general, my guess is that those things will pair pretty well with KEYTRUDA, and we are interested in those. And we have tried to address them principally by taking advantage of the very large number of companies out there, small and large, that have pursued such things.
So that’s that. I don’t think the answer’s very different for the antibody drug conjugates. Of course, we’ve been doing experiments with these, particularly the EV data that you’ve seen in urothelial cancer is working with Seattle Genetics. And we’re looking at a number of other programs. We set up at the beginning, as you know, a mechanism, and Roy set this up, whereby we can provide KEYTRUDA to lots of people who are doing studies to get an early look at which sorts of things work in combination with KEYTRUDA. And that’s been very helpful to us in terms of targeting licensing opportunities and acquisitions. That’s the general approach we’re taking. And at the high level, I would say, it appears that things that kill malignant cells, maybe because they have a pro-inflammatory effect, perhaps for other reasons, tend to work pretty well in combination with KEYTRUDA.
https://seekingalpha.com/article/4351618-mercks-mrk-management-presents-oncology-event-asco-2020-conference-transcript
WOW nice find ATL, thanks for posting. I thought that's where they'd present, but I'm surprised it's out already.
I doubt the market is very large for this MicroDEN product right now because, for the most part, the only need for dendritic cells are from clinical trials, with only minimal units required for each. Corning was probably willing to do the deal with Northwest Bio because they will now have a commercial market for their consumables business, and it would eliminate their sales and marketing budget. Well that, and the thought of owning some NWBO stock from the deal probably had them as giddy as schoolgirls. :)
For Corning, I think their deal with Flaskworks may be similar to the printer and ink business model. Flaskworks manufactures the MicroDEN unit, and Corning manufactures all the disposable consumables, and is responsible for sales, marketing, and support. (revenue shared accordingly) When I checked with a distributor last year, the MicoDEN unit was priced at $15k, and all the consumables were ~$800.
“The Corning MicroDEN system is composed of the MicroDEN unit manufactured by Flaskworks, and closed-system consumables manufactured by Corning, such as tissue culture-treated polystyrene flasks, storage bottles, and tubing. The Corning MicroDEN system is jointly branded with Flaskworks and will be marketed, sold, and supported globally by Corning.”
https://www.selectscience.net/product-news/corning-launches-corning-microden-automated-system-for-generating-dendritic-cells/?artID=50630
I agree ATLnsider, I think attending that conference is all about exposure. Thanks for posting that BTW.
Interesting idea abeta, but it sounds far more complicated, and less efficient than DCVax.
I don’t really know anything.
Well on that point, we agree. :) For some, it may be difficult to see the bigger picture. There are ethical reasons for crossover in cancer trials. Prior to this trial, a GBM diagnosis meant that patient was very likely to die very shortly. The GBM patients who enrolled in this clinical trial were simply hoping to live a little longer, and perhaps with fewer debilitating symptoms. (and many have)
Hi All. Been a while. I got a message today that CYRX hit my price target, but I think I'll just let it ride. This board was dead for so long, that I forgot about it. Nice to see some of you are still around.
agreed senti, I didn’t write that very clearly. I guess I thought we were of the same mind since I seem to agree with everything you write. :)
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.