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Well ATLnsider, it seems to me that the best way to handle the logistical issues with a cell therapy is to first remove any time constraints by cryopreserving the leukapheresis material, which I’m pretty sure will be the case. I’ve posted before that I think it makes sense to have regional manufacturing regardless, so when the time comes for commercial manufacturing, I believe Northwest Bio will contract with Advent at Sawston to manufacture for the UK and EU, while Charles Rivers Labs will manufacture for the US and Canada. The closest model that I know of for the commercialization of a cell therapy is KITE/Gilead, and that’s exactly what they did (regional manufacturing) even with cryopreserved leukapheresis material.
I’m not sure if anyone else noticed this language in the latest Q:
Wow, impressive!...but how did you ever get the name BigAl?
During the approval process for new marketing applications, the FDA conducts inspections and assessments of all facilities (worldwide) wherever a drug is manufactured, processed, and packaged to determine a drug manufacturers’ compliance with CGMPs, applicable laws and regulations, and to determine whether the firm has the necessary facilities, equipment, and ability to manufacture the drug it intends to market. There are Mutual Recognition Agreements (MRAs) between the FDA and foreign regulatory authorities which allow drug inspectors to rely upon information from drug inspections conducted within each other’s borders, however, Advanced Therapy Medicinal Products (ATMPs) are excluded from the scope.
Facts About the Current Good Manufacturing Practices (CGMPs)
https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmps
Northwest Bio has said that the monocytes should arrive at their manufacturing facility within 24 hours to remain viable for the manufacturing of DCVax, but generally fresh monocytes remain viable for 24 to 48 hours. I posted about this not too long ago:
Okay Doc, we'll see.
Thanks for the clarification iwasadiver.
ski, it might be a good idea to take the time to read the published study by the Flaskworks’ technical team, and peruse their patents to inform your speculations. I’ve already replied to you in another post that in both the published study, and in the patents, the Flaskworks’ system was placed in a conventional incubator on a bench top during the maturation process to control temperature and CO2 levels. I’m not sure if this is the currently designed system though, and while I don’t ever recall reading anything about the system being stackable, perhaps it could be. However, it’s completely unnecessary and makes no sense to stack them, so most often the simplest and proven solution is the one that is used. In my opinion, the point is irrelevant, so speculate away.
Northwest Biotherapeutics has an ancillary services agreement with Advent Bioservices to oversee the construction and development of the Sawston manufacturing facility, which includes testing the Flaskworks system and developing an automated process. Milestones in the Flaskworks Purchase Agreement require that the Flaskworks’ technical team assist Advent Bioservices for the deployment and comparability studies of the Flaskworks’ system, as well as the preparation of the necessary documentation for submission to the regulatory agencies in the UK, US, Canada and EU. Nowhere in this agreement does it state that Cognate, Charles Rivers Labs, or UCLA will be conducting any validation activities with the Flaskworks’ system, and I’m not sure why so many posters on this board continue to perpetuate this notion.
You have got to be kidding, right? No offense to skitahoe, but just about everything in that post you’re replying to is wrong.
- The current manual production process is “open” which means there can not be more than one patient’s cells in a clean room at a time.
- There are not “cell lines.” This is a personalized cell therapy, so there is only a single patient’s cells.
- There are no robots!!!!!!
- DCVax-Direct has it own patented process that uses a bagged culture system, not the flask culture system used in the Flaskworks’ system. It likely requires this bagged system for the delayed maturation process.
- The Flaskworks’s system cannot be stacked.
- Elon Musk is not developing robots to service multiple Flaskworks devices!!!!! (this has to be a joke)
—————————————
Why do you think there were other companies that wanted the Flaskworks’ technology? It’s specialized to close and automate the culturing process strictly for dendritic cells, which makes it a pretty small group of companies that would even be interested. It seemed like a pretty routine acquisition according to the filing, and no mention of a bidding war.
Are you saying that you think Charles Rivers Labs is working with the Flaskworks’ equipment? And you’re guaranteeing this?
I doubt they are doing parallel equivalency runs with the Flaskworks’ system yet. The current production is in London, so these can’t be started until after Sawston is certified. You’ll notice Northwest has stated that initial practice runs and optimization of the Flaskworks system MAY begin this summer, and then a regulatory validation process will occur after sufficient practice runs have been completed. This is a major process change that will require an extensive equivalency study, which unfortunately won’t be “quick.”
I didn’t think you agreed with me senti, and it’s not about being right or wrong, but I wanted to know if you understood how everyone in the financial world does the calculation. The quarterly filing is a factual snapshot of the financial situation of the company at that particular point in time, and why I prefer to use those numbers, even if somewhat dated. As I’ve said, there’s a lot of financial activities occurring during the quarter, so you could certainly be correct about their current situation.
Agree Hbpainter, that 17 acres could be one of those rabbits, but I’m afraid that it might be stuck in the hat! Are you still keeping an eye on the rezoning permits? Seems so long ago. And yeah, I thought it was just Northwest Bio that was slow . . .
Thanks Gus, appreciate the confirmation and your insights. In the first half of the year, I think ~5 million shares were issued for debt conversions, so it’s definitely something to keep an eye on as available shares dwindle, but probably not a major issue yet. I suspect the current number available is higher than 20 million because they suspended almost 4 million additional options in July, and I assume they’ll continue to suspend more in the coming months. I think your views tend to be more pessimistic than mine, and certainly more than the eternal optimist senti’s. :)
Of course I read the terms of the recently issued four-month notes with great interest, and I think it does indicate that data release is likely to occur before November. And yes, I think it’s safe to assume that Les has been working the phones in anticipation of a private placement among the small stable of accredited investors that have continually supported the company, but guessing that it’s just to gage interest right now. I don’t agree with your characterization of these financings as “toxic,” but, I know what you’re saying. Although it’s not ideal, at this point there’s already been massive dilution, and since a placement and smaller follow-on will occur after the data release, it will be at a higher price, whatever that is. If a small group of investors, who have continued to provide funding to keep the company afloat, are able to get a favorable price, so be it.
I was thinking the private placement and folllow-on offering would catch the company up with creditors and (along with warrant exercises) provide a little breathing room until the company could hold a special shareholder meeting early next year to propose an increase in authorized shares and/or a reverse split, and then file a new shelf. I didn’t think they had to wait until next spring’s annual meeting for this as long as the Q3 filing in November is on time, but I’m not sure.
No problem senti, but now I’m curious. Can we at least agree that as of June 30, they were 25,256,000 shares under the authorized limit? (since this is a fact)
857,230 Common Stock Outstanding
312,035 Warrants Outstanding
+305,779 Stock Options Outstanding
————
1,475,044 Total Common Stock, Warrants, and Options Outstanding
- 300,300 Total Warrants and Options suspended - (241.5 million options + 58.8 million warrants)
————
1,174,744 Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options
———————————————
———————————————
1,200,000 Share Authorization Limit
- 1,174,744 Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options
—————
25,256 Shares Available
Thank you sharpie - excellent news!
Hi senti, I double checked, and the numbers in my post below, as of June 30, were accurately transposed directly from the tables in the Q. It’s not necessary to perform any calculations, as the numbers are given under each heading. (i.e. common stock, warrants, and options) The only calculation necessary is adding them up, and then subtracting the suspended warrants and options, as I have done.
My numbers subsequent to the end of the quarter were indeed off. I didn’t notice that the 15.2 million shares of common stock issued during July and August were issued upon warrant exercises, so that probably did not affect the authorized limit. (unless some was cashless) However, the additional 3.7 million options that were suspended in July, should be added to the 25.25 million shares available, so best guess, they are currently approximately 29 million shares under the authorized limit.
I didn’t see your previous post senti, since I’m pretty far behind, but our numbers are way off. I was not the most dedicated student at the University of Hawaii, which itself is not exactly known as a bastion of higher education, so you could be right. :) But, I’ve never seen it calculated the way you did. That 1.174 figure that I got was as of June 30, from the tables in the Q, so that should be pretty close. Just glancing at your numbers, I can see your warrant figure is way different than what was listed in the table of the Q.
I generally don’t dig too deep into subsequent financing actions as they’re often on-going and changing during the current quarter. I merely glanced at the subsequent actions and notes to get the 15 million shares issued and the 4M additional warrant suspensions to calculate the 13-14M current figure, so that could certainly be off. If it was the result of warrant exercise, then that would reduce that liability.
Anyway, I don’t have time to double check right now, but I might tomorrow. I do think you’re correct about the friendlies who own many of those warrants helping Northwest Bio if they can, but I haven’t had time lately to verify the expiration dates of the warrants. Is that what Bigger’s comment the other day on Twitter was about? Was this discussed?
hank, approximately 25 million shares under the authorized limit, as of June 30, or between 13-14 million shares under the cap currently, by my calculations:
Common Stock Outstanding as of June 30 - 857,230
Warrants Outstanding as of June 30 - 312,035
Stock Options Outstanding as of June 30 - 305,779
Total Common Stock, Warrants, and Options Outstanding - 1,475,044
Total Warrants and Options suspended - 300,300 (At June 30, 2021, approximately a total of 241.5 million options and 58.8 million in underlying warrants were under block or suspension agreements)
Total Common Stock, Warrants, and Options Outstanding excluding suspended Warrants and Options - 1,174,744
Share Authorization Limit - 1,200,000
Note: during July and August, just over15 million shares of common stock were issued, and almost 4 million additional options were suspended.
Haha. Good to know.
belated thanks flipper!
Thanks for the reminder longfellow, it’s been a while since I’ve looked at that. The full question from my initial post was “We all know that the administration, source of antigen, (lysate vs. tumor tissue in vivo) activation method, and maturity of the cells are different, but what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?” So yes, I’m aware of many of the basic differences required for injection into a tumor’s hostile microenvironment vs. intradermal, as well as the delayed activation (method B) used in that -Direct trial. But that's a good point about the process being the product
So you think Dr. Bosch is the one to ask instead of ex?
That still didn’t answer the question of “what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?” but I appreciate the extra effort, and no further bumbling around is necessary. We’ve all seen behind the curtain now, and it’s pretty clear that you have no business telling Dr Bala or anyone else about “a lack of understanding of the basic science.” If Linda Powers says that the therapeutic cells of DCVax-L and DCVax-Direct are essentially “the same” based upon their experience and testing with sophisticated assays, then I believe it. I still think -Direct will have its own label, but it may have an accelerated pathway after -L is proven.
That’s what I thought ex. Your claim was that -L and -Direct are different, and I would like to know exactly what makes them different, but you go on about other companies dendritic cells, and again make the very same claim (without proof) that they are very different agents. Maybe you didn’t answer my question, but you certainly revealed a lot in your answer. Thank you for your time.
By the way, if anyone can answer this question, I would seriously like to know.
ex, since you seem to have a deep understanding of the basic science, then perhaps you can explain what exactly separates the dendritic cells of -L and -Direct. As someone who clearly doesn’t possess your superior knowledge of the basic science, I’ve wondered about that myself. We all know that the administration, source of antigen, (lysate vs. tumor tissue in vivo) activation method, and maturity of the cells are different, but what specifically in the cell characteristics and critical quality attributes of the actual dendritic cells are different?
Please feel free to use these examples and claims made in Northwest Bio’s patents for their assays:
Right Doc, optimally activated DC’s are injected at the periphery of the tumor where they are exposed to the dead and dying tumor cell’s antigens. And yes, as jondoeuk likes to note, the tumor microenvironment is very difficult for immunotherapies to overcome, which is why “method B” is so critical. As the Phase I proved, delayed activation circumvents the tumor’s defenses.
And speaking of “method B, ” I’m reminded why the Flaskworks’ equipment likely won’t be used to produce DCVax-Direct. This delayed activation isn’t possible with the flask culture system and may be the reason why DCVax-Direct uses a bagged culture process.
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)
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 . . . .
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:
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.
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
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 )