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Smokey, I don’t think it has to do with Flaskworks per se, but is consistent with a commercial process. GMP for an investigational product only requires final-product testing, and initially, it appears that Advent outsourced their final-product sterility testing, which normally takes a couple of weeks. This would make economical sense in the limited quantities they were sending out, but would make less sense for larger quantities of a commercial operation. In-house sterility testing would also be important for in-process testing that is required for the validated commercial process.
I would agree with that dmb, but I don't have any direct experience or knowledge of the MHRA process either.
Changes were made to the methods and processes for health technology evaluations in the UK. Evaluations that were started prior to February 1, 2022 will be evaluated using the oder methods. However, new evaluations will benefit from the use of the updated and more flexible process. Perhaps Northwest Bio would prefer to begin a new evaluation so that DCVax-L is evaluated using the updated methods and processes?
Thanks wavelenthy! You beat Lykiri to it :)
thanks for the additional info Roman. The job openings I was discussing were in September, and I believe they’ve been filled. (I thought I had a list but can’t find it) Also, this guidance document may be relevant:
EudraLex The Rules Governing Medicinal Products in the European Union
Volume 4
Good Manufacturing Practice
Medicinal Products for Human and Veterinary Use
Annex 11: Computerised Systems
https://health.ec.europa.eu/system/files/2016-11/annex11_01-2011_en_0.pdf
meirluc, NFL football fans may know that when a new rule is implemented for a new season, very often during the preseason, that rule is the focus of the referees attention and they will call the penalty excessively in order to get the attention of the teams about the new rule.
Similarly, some regulators/inspectors will do the same, and focus their attention on certain elements during an inspection, (like computerized systems) and a new system like Flaskworks, will receive extra scrutiny. This potential additional validation was pure speculation on my part. I’m very familiar with a small company like Advent, with limited resources and experience, and I think it’s possible that Advent anticipated that the inspectors would find some issues that were insufficient, and allowed the inspectors to pinpoint exactly what they were looking for, and then Advent addressed the specific issues. If there was going to be an excessive delay, I think Northwest Bio would inform shareholders. So far this hasn’t occurred, so I’m optimistic for an update by the end of the year as well.
antihama, there are three primary processes the Flaskworks’ Eden system must go through before it can be used in the commercial production of DCVax: qualification, validation, and comparability. I believe the first two may have been accomplished based on the ASCO presentation, and they are both necessary to be included in the automated process used for the commercial license application. I’ve posted previously about this here
The comparability study itself (what Dave was discussing) may not have been conducted yet, and Advent may be waiting until the commercial license is approved using the automated process. The Comparability Protocol (CP) takes months to prepare, and it’s usually submitted to the regulator for feedback which could take up to sixty days. The planning and preparation generally take longer than the actual study, which only requires 3 batches for analysis, so there’s still sufficient time to conduct the study, analyze the results, and prepare the documentation before marketing approval is granted and commercialization begins. If the CP is not available when the final marketing application is submitted (and marketing approval given), it can be submitted afterward as a Post Approval Supplement (PAS).
The first inspection may have looked at the IT infrastructure for the facility and immersed systems, such as the control panels for the various processes and systems, the Laboratory Information Management System (LIMS), Document Management System (DMS), Manufacturing Execution System (MES) etc., however, for this commercial inspection, the inspectors would likely be looking more closely at the Process Analytical Technology (PAT), which the FDA defines as, “System for designing, analyzing and controlling manufacturing through timely measurements of critical quality attributes and performance for raw and process materials and processes in order to ensure final product quality.” They are based on the principle that the quality of a product must be from the design. This will include the validation of the automated equipment, which should comply with Good Automatic Manufacturing Practices (GAMP). Most of the automated commercial equipment available from vendors will come with a validation package (including its computer system), however, the Flaskworks’ Eden is a bespoke system which does not, so its validation (including its software/firmware code) will call for closer scrutiny. This (and the software/validation job openings) is what leads me to believe (if there was an issue) there may have been more validation work to do on the Flaskworks system.
And just to clarify, I’m not suggesting that a buyout is the reason for Northwest Bio’s absence from the Glioblastoma Drug Development Summit, but merely pointing out that I would think that the first company to release successful results in a Glioblastoma trial (in over 400!) would want to share their successful, unique immunotherapy approach with their peers, perhaps network and seek funding opportunities with potential collaboration partners at a conference that is dedicated to developing treatments for Glioblastoma, and it’s a conference they’ve always attended.
It’s not until March, so there’s still time, but in previous years, Dr. Bosch and Dr. Liau were scheduled to speak months in advance. This seems to be a company that’s still in a quiet period, for whatever reason.
(and yes, it may be that they already have a collaboration partner(s) selected)
dmb, I’m hopeful that we may get some clarification about the commercialization pathway and progress at the shareholder meeting. I agree that the commercial licensing of Sawston is likely a lynchpin event, and also doubt there’s a major issue. As I’ve posted previously here, and here, my hunch is that it may have to do with the computer validation of Flaskworks, and potentially other automated equipment. I recall that the initial license of Sawston was anticipated by the end of the 3rd quarter last year, but wasn’t received until the end of the 4th, so I anticipated there could be some delays with the commercial license as well - sometimes it’s just a matter of slotting into a busy regulator’s schedule after addressing issues that were raised during the inspection.
Happy Holidays and New Year to you as well
Thanks for sharing this Lykiri. I hope they receive all the funding and support they need, it’s truly heartbreaking.
Does anyone else think it’s odd that Northwest Bio, the company that just announced unprecedented survival results of their phase III trial in Glioblastoma, that some experts are calling the greatest advancement in the treatment of Glioblastoma in decades, is somehow not represented at the Glioblastoma Development Summit March 14-16 in Boston, for the first time in its existence?
thanks Lykiri, that’s right Northwest Bio’s trial is going to be the new benchmark, but there we go again with the cherrypicking implication.
At first glance this was also interesting:
My opinion is that Roger Stupp may be financially conflicted, and is more concerned with his ego and outdated protocol, than what’s best for Glioblastoma patients. It’s disappointing that a doctor of his stature is unwilling to even acknowledge that Dr. Liau and DCVax has actually produced unprecedented survival results, but even worse, he knowingly made a poorly written and false critique of a trial that passed very strict peer review in JAMA Oncology. To me, that shows a real lack of professional integrity. That anyone would echo and support that type of behavior is unfortunate, but not surprising.
Agree Enoch, Michael Lewis would be the perfect author to tell the Northwest Bio story! He is one of my favorite authors, and this would be right in his wheel house. I think Linda Liau even said her favorite book was “The Big Short” authored by Michael Lewis. I know he has a folder of potential books that he’s thinking about writing, but I wish someone would send him an intriguing synopsis to get him interested.
Completely agree Fireman; Les basically said the trap was set years ago, but I think many forgot. It should be clear to everyone now, why May 10th went down the way it did:
Remember the 2018 Annual Shareholder Meeting when Les almost gave it away? It was clear that Northwest Bio knew their stock was being manipulated and developed a plan to gather the electronic forensic evidence. It doesn’t sound to me like they plan to settle, and I think the lawsuit is bigger than some realize . . .
Thanks for the kind words Bright Boy, but I’m far from it.
I know, I nearly spit out my coffee yesterday morning when I read that. The audacity! How dare little Northwest Bio sue us when we were caught red handed manipulating their stock! After all, this is how we keep order in the market!
Bright Boy, in the combination trial at UCLA, Keytruda is administered by IV infusion, while DCVax is administered by intradermal injection. If at some point, Merck can administer Keytruda by subcutaneous injection, the two treatments would still be given separately, because the timing of each treatment, and the injection method are different. (additionally, they cannot be manufactured together) So no, I don’t think anything Northwest Bio brings to the combination will improve the administration method for Merck. But you bring up a good point; that DCVax may help solve at least one important problem for Keytruda, and other checkpoint inhibitors: toxicity.
I’m sure that one of the major problems Merck is attempting to overcome with reformulating Keytruda for subcutaneous injection, is not increasing the toxicity of an already toxic treatment. It seems likely that they would need to increase the dosage, which could potentially increase the toxicity along with it.
This is also a major issue when combining treatments that are toxic by themselves; they tend to be even more toxic in combination. The extremely safe profile of DCVax is one of the huge attractions for companies like Merck and Bristol Myers who are looking for combinations with their toxic checkpoint inhibitors. Dendritic cell therapy in combination with checkpoint inhibitors is known to improve immune response to killing cancer cells, but also one of the primary outcome measures that Merck and many others are anxiously awaiting, is to determine if the combination actually lessens the adverse effects of Keytruda, or at a minimum doesn’t increase adverse events.
Bright Boy, that article is simply about Merck reformulating Keytruda to allow for subcutaneous (below the skin) injection just like Pfizer, Roche, and many others have been working on for years, partly (or mostly) in an attempt to extend the patents.
Biologics (like Keytruda) are commonly administered by IV infusion because of the need to deliver safe concentrations, maintain stability, avoid aggregation and undesirable viscosity properties, and limit degradation in the digestive tract due to short half-life.
Biologics can be difficult to formulate for subcutaneous or intramuscular delivery as these typically involve injection of small volumes of highly concentrated drug solutions. Biologics that need to be given in high doses and/or have limited solubility can be particularly challenging and lead to loss of biological properties. Changes to the route of administration can also impact the dose and dose frequency, e.g., small volume subcutaneous or intramuscular injections of a biologic will likely need to be administered more frequently and/or at a higher dose compared to the same dose administered by infusion.
Of course they will have the votes dennisdave. Every time there is a shareholder vote, there’s always a chorus of “vote no” on this message board, but guess what? These critical votes always pass. Northwest Bio may have thousands of novice retail shareholders, but their largest investors are quite savvy, and will certainly support the company at this critical stage. I would bet on it.
Northwest Bio has FINALLY delivered the goods, and I think the pace of events of the past few years is about to accelerate. Those entities that have been fighting against Northwest Bio and have been able to keep the share price depressed, are fighting a losing battle, and their time is running out. These big fish in the little pond are going to discover that there are much, much larger fish out there . . . one might even say whales.
antihama, the initial inspections for the first two licenses at Sawston were important for the facility in general, (i.e. the HVAC, storage, water, quality systems, etc.), however, the inspection for a commercial license will be more rigorous for the production, labeling/packaging, storage, and distribution processes than for an investigational product. For example inspectors will look at in-process controls, validation and risk analysis plans, computer systems and data integration, for the automated equipment and manufacturing process that wouldn’t have been required for the initial license. I’m confident that Advent will obtain the commercial license for Sawston reasonably soon, but it’s not uncommon for there to be gaps to fill in for newly written procedures, or missing updates to established procedures for additional equipment, validation documentation, or other requirements, even though Advent would have conducted their own internal audit prior to applying. Delays beyond the 90-working-day time frame to correct some issues identified by the inspectors wouldn’t surprise me at all, especially considering that Advent is a relatively small (but capable) CDMO without all the experience and resources of much larger CDMOs, and they may have to re-slot into the timetable of a busy government agency for a final inspection.
I wonder how many on this message board really understand the magnitude of the all tasks that Advent is undertaking with qualifying, validating, and conducting the comparability study for the Flaskworks system, developing and validating all the automated processes for the commercial license, managing and overseeing the buildout at Sawston, as well as preparing the “Quality” module for the MAA. Each project is extremely detailed, highly complex, and they ALL must comply with very strict regulations.
I posted this recently about the requirements for the “Quality” module for the MAA:
ISPE Introduction to CMC Regulatory Affairs
https://www.ispeboston.org/download/educational_presentations/2016/2016-11-10-Regulatory-Symposium-BMamidipudi.pdf
Here is an example of requirements to change a piece of equipment in a GMP facility, just to give an idea about the scope of that type of project, and issues that could be overlooked:
Equipment and Utility Change Control for GMP Production Facilities
https://easconsultinggroup.com/equipment-and-utility-change-control-for-gmp-production-facilities/
Sorry to hear this DanishDude. Hang in there and be the strong support your friend needs right now, and please continue your valuable contributions. This is deeply personal for many of us, and it’s truly unfortunate that some would prioritize their own personal greed over dying cancer patients, and attempt to delay and undermine the most promising treatment in decades. But I’m encouraged because it appears that Northwest Bio has FINALLY won the war, and there only remains a few trivial naysayers who refuse to face that fact.
thermo, perhaps you misunderstand. I don’t think “Advent is expanding from 2 suites to a total of 7.” Advent currently has 2 suites which contain 7 cleanrooms (2 Grade B, 3 Grade C, 2 Grade D). This additional cleanroom capacity in Q2, 2023 may be timed to coincide with marketing approval in the UK.
I disagree that the additional capacity will be used for the manual production process though (which requires high grade B cleanrooms). Instead I think the cleanrooms will be grade C and D (lower level and much less expensive to operate) for the commercial automated manufacturing production lines that include the Flaskworks’ Eden system, which I believe has been qualified and validated over the past year and a half, and is part of the seven new pieces of automated equipment that were installed at Sawston and are being utilized for the commercial license application.
That was a report from a manufacturing survey likely conducted over the summer. There is more information about the manufacturing reports here:
https://ct.catapult.org.uk/resources/manufacturing-surveys
I think it’s likely that Sawston was inspected a couple months ago. My hunch (and this is only a guess) is that Advent is addressing some issues that were raised during the inspection.
MHRA inspector (to Mike Scott): Okay so we’ve met with the QP, QA, and now we’d like to meet with the CSVS.
Mike Scott: Errr, the what now?
MHRA inspector: you know, the computer systems validation specialist
Mike Scott (picks up the phone to HR): add a computer systems validation specialist to the hiring list
Okay that was a joke, but some hiring back in September could be a clue. According to An Analysis Of MHRA’s Latest Annual GMP Inspection Deficiencies Report "Quality Systems" continues to be the most frequently cited reason for inspection deficiencies, however, “Computerized Systems, Annex 11, remains in the top 10 for both critical and major deficiencies, reinforcing the importance of this area to data integrity and the regulator’s focus on the control and management of electronic data.”
The Cell and Gene Therapy Catapult recently published its ninth annual UK cell and gene therapy Good Manufacturing Practice (GMP) manufacturing report, which mentions Advent Bioservices:
I’m also in the partnership first camp. I don’t think there’s really a question that a deal is forthcoming; with about a dozen employees, and this close to the marketing approval stage, it seems unlikely that Northwest Bio will begin commercialization on their own. The question is whether it’s a partnership, multiple partnerships, or a buyout.
There are many ways to value an asset, platform, or company, and both sides of the deal will have their own financial analysts who will use various methods and assumptions to calculate the value of the asset to show why it’s worth what they say. (depending on the assumptions used in their models, they can make the final number come up to whatever number they desire) Big Pharma would likely attempt to value it in comparison to the previous CAR-T cell therapy companies and highlight that there are currently no revenues, high start-up commercialization and marketing costs, and give little value to the undeveloped pipeline (DCVax-Direct), while Northwest Bio will highlight that DCVax is a platform which may treat all solid tumor cancers both operable and inoperable, (and potentially other immunological diseases) has a patented low-cost automated manufacturing process, and has synergistic combination attributes with a multitude of other agents.
Right now at this stage though, I wonder if a Big Pharma company will be prepared to make an offer that Linda Powers and Les Goldman would find acceptable for a platform that one day could be worth hundreds of billions, but so far has only proven efficacy in one phase III trial for brain cancer. So at this stage, a partnership rather than a buyout seems to make more sense until the broader applications to other solid tumor cancers and DCVax-Direct can be proven, which would greatly increase the value, but also lower the risk for an acquirer.
One caveat though: if there are multiple BP’s that understand the potential value of the platform and covet this type of asset, and are willing to take the risk, then this could end up in a bidding war, and then all bets are off, and there could be some sky-high valuations.
I think Tobira holds the record for buyout premium. Its market cap was about $90M when Allergan paid $534M cash plus CVR’s totaling $1.7B. (and that was in spite of a failed phase II trial)
Allergan sparks a second liver disease craze
https://www.evaluate.com/vantage/articles/news/allergan-sparks-second-liver-disease-craze
muee88, as of September 30, 2022, there were approximately 948 million shares of common stock outstanding, 885,155 shares of convertible preferred, approximately 305 million options, and 145 million warrants outstanding. Since the end of the 3rd quarter, some financing actives have occurred, (i.e. stock was sold, warrants converted etc.) and as of November 8, 2022, the total number of shares of common stock outstanding was 1,052,853,970, so yes, TD Ameritrade is correct. The market cap is often used as the current value of the company, which is the number of shares of common stock outstanding multiplied by the stock price, which is currently about 1.05B x $1.15 = $1.2B.
However, in the case of a buyout, the remaining warrants and options would also be considered outstanding, and the C-series preferred would be converted to common, so the buyout price should be divided by the total number of shares of outstanding common stock, warrants, and options, which currently are approximately 1.5 billion in total. So for example, if the buyout offer was $22 billion, the buyout offer would be divided by 1.5B, so the buyout price per share would be $14.66.
Hmmmm, I didn’t realize that so I checked, and you’re right; that’s when it was first reported. Interesting timing. Do you believe in coincidence?
Merck's Buyout Of Seagen Hits Speed Braker Over Price Agreement: Report
August 26, 2022
https://www.benzinga.com/general/biotech/22/08/28646856/mercks-buyout-of-seagen-hits-speed-braker-over-price-agreement-report
Pricing Debate Stalls Merck-Seagen Acquisition Deal
Published: Aug 26, 2022
https://www.biospace.com/article/merck-seagen-hit-impasse-on-acquisition-deal-due-to-pricing/
Merck’s Stalled Seagen Deal Shows Valuing Cancer Drugs Is Tough
August 31, 2022
https://www.bloomberg.com/news/articles/2022-08-31/merck-s-stalled-seagen-deal-shows-valuing-cancer-drugs-is-tough
JAMA accepted the article on August 27th, but didn’t publish until November 17th. The median time from acceptance to online publication is 15 days, so it does appear that it was held back. The question is why? It seems likely that it was to coordinate with Dr. Liau’s SNO presentation, but it’s possible there could be other reasons as some have suggested. (on-going partnership/buyout negotiations)
Article Information
Accepted for Publication: August 27, 2022.
Published Online: November 17, 2022. doi:10.1001/jamaoncol.2022.5370
https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847
Acceptance to online publication, median, d 15
https://jamanetwork.com/journals/jama/fullarticle/2789674
Apparently it was good enough for JAMA, ex. Sounds like you’re just looking for a shred of consolation. Something. Anything. Yeah, Northwest Bio cheated! And yet, somehow, it got past peer review in JAMA, for all the world to see. Boo hoo hoo
Huh? The Guardian says JAMA? Thanks Jack!
hank, IBorrow Desk is a reasonably accurate free source.
Never thought I’d say this but; exwannabe the pumper?
You mean his reasoning. Columbine Capital Services appears to be based in the residential home of John Brush, the sole proprietor.
okay, murci beaucoup, :) that's what I thought.
I agree that it’s likely that Northwest Bio will announce the final submission of the application. Where are you getting this information about 29 or so modules? I think there are 5 modules in a Market Authorization Application:
Modules of a MAA
1. Administrative and Prescribing Information
* Application form
* Brief overview of Product characteristics
* Labeling text and mock-ups
* Experts’ information
* Risk assessments related to the environment
* Orphan market exclusivity information
* Description of the pharmacovigilance system
* Risk management plan
2. High Level Summaries
* Quality
* Non-clinical overview
* Non-clinical summary
* Clinical overview
* Clinical summary
3. Quality Documentation
* References
* Body of data
4. Non-Clinical Documentation
* Reports of conducted studies
* References
5. Clinical Documentation
* Tabular listing of conducted studies
* References
They are normally submitted in a Common Technical Document: