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doingmybest, we might be able to chat during the board happy hour on Friday sometime, but my guess is that we haven’t crossed paths, as I keep a pretty low profile, and I think you were in larger operations. Hope we do have a chance to meet up one day - Sawston would be epic.
I appreciate your posts as well, and wish I had more time to respond to some of them. You wrote one yesterday with the scenario of a commercial license in conjunction with a marketing application, which is what I think is likely, but I don’t have time to fully flesh out a response.
Regarding validation, I had some lingering questions about Advent which have been put to rest. They’ve proven to be quite capable, and have actually demonstrated an ability to meet timelines. I've been impressed.
What? You don’t believe me? Agree, that idea would be better than speculation . . . if he could answer.
Doc, without full knowledge of the actual protocols, I think Mike Scott would be the one to ask.
Generally, the time to remove undesired cells or other contaminants is during cell selection in the first step. What you’re discussing is the end product, and at that point, I think it’s just final release viability and sterility testing; the undesired cells at that point are dead or unactivated. I don’t think there’s currently a way to separate and remove those, but they don’t need to if at least 80% are viable. I think Novartis proved that point.
For Kymriah, Novartis was only achieving the commercial specifications the FDA set of 80% viable cells in ~75% of their batches. They were unable to remove the unviable cells, so they had to give away those treatments for free that couldn’t meet spec. I think later Novartis did a study which showed those patient who received those free treatments achieved similar results to those patients whose treatment did meet the commercial specs, so Novartis lobbied the FDA (I think unsuccessfully) to lower the specs to the clinical specification of 70% cell viability.
ski, you’re right that the Flaskworks system uses single-use disposables, but GMP rules are very explicit, and every facility will have documented procedures for regularly scheduled cleaning, sanitizing, inspecting, and maintaining of each piece of equipment and all work areas. The cleaning procedures will detail the type of cleaning agent, the pH, the strength, contact time for sanitizing the surface, what agent to clean off the sanitizing agent, etc. Detailed records will be kept of all these activities which report, not only proof of what cleaning took place, but who, when, and the outcome.
Because it adds up to the stated seven.
And they would need 5 for a weekly production cycle:
Each day for 5 days, Advent separates a single patient’s monocytes, then loads them in the EDEN system. Each EDEN system would have 5 days of incubation, and on day 6 of the production cycle, Advent introduces the lysate antigens and matures a half day. Then day 7 is washing and harvesting the cells, then cleaning the EDEN system for the next patient’s cells.
(and no offense taken)
Ah yeah, those were the days Laser. I’m still holding a good chunk of my original CYRX shares (and BLFS for that matter). It’s certainly taken NWBO longer than either of us expected, but I’m pretty sure the rewards will be even sweeter. One good thing about that, is that’s it’s given us a chance to accumulate plenty of shares.
You’ve known me longer than anyone here, so I appreciate you having my back. I don’t mind flying against the wind, which tends to ruffle some feathers. Best wishes to you too.
Right laser, I’m definitely not a trader. It’s not really for me to characterize my own posts as far as pumping, but I will admit that I’m generally unbiased to positive about NWBO. Some may be confused because hyperopia has “hype” in it, but it actually means far-sighted. I bought my first shares in NWBO in October 2017 for 17 cents, and my last shares in April 2020 for 17 cents. I did a little swing trading back in 2018-2019 to accumulate shares, and I’m now a tier 3 investor.
These are the tiers my associates use:
Tier 1} > 10 million
Tier 2 } 3 million - 10 million
Tier 3 } 1 million - 3 million
Tier 4 } 500,000 - 1 million
Tier 5 } 300,000 - 500,000
Tier 6 } 100,000 - 300,000
Tier 7 } 50,000 - 100,000
Tier 8 } 20,000 - 50,000
Tier 9 } < 20,000
The aforementioned initial automated Flaskworks production line could potentially consist of:
1 Gibco CTS Rotea cell processing system
5 Flaskworks’ EDEN systems
1 Aseptic Technologies Pure M1 Isolated Fill and Finish Unit
note: It appears (to me) that the EDEN system pictured in the ASCO presentation was in an incubator, which is to be expected for the culturing process, but I doubt incubators are included in the seven pieces
What do you think were the seven pieces of equipment?
flipper, I don’t think it is, or ever was the plan to use the manual process for commercial production for the reasons I’ve explained. But just because I’m convinced, doesn’t mean it’s right. Anyone can think or argue otherwise. It’s possible that the initial plan was to use the Flaskworks system for investigational use at Sawston as an interim step while it was being developed and validated for commercial use. But if that ever was the plan, I think it was probably scrapped when the initial license at Sawston was delayed. That delay was when my thinking about Flaskworks changed to Advent developing and validating the entire automated commercial process.
I said in another post that it was difficult to tell exactly where Advent was with automation, even after the ASCO presentation, and that may have been intentional. Looking back, now that we know the application for a commercial license has been submitted, I’m recalling a tweet in early April “Sawston hiring a 2nd shift. Flaskworks installing a production line for certification.” (likely leaked from Loose Lips Les) So I think the comparability study was probably done in April, which would allow enough time to analyze the data and prepare the regulatory documentation. Also, in that ASCO presentation, they did describe the automated process as the future, but then at the end said “The Future is Now.’ That seemed odd when I first watched it, and I remember wondering what that meant, but it seems more clear to me now. Regarding “the work done in the course of the last month,” I will just note Mike Scott’s comment, “Our Team has put in an extraordinary effort to meet our self-imposed, end of Q2 deadline to submit the MIA application.“
Haha. Good one Chiu.
When I said the Flaskworks’ system is ready for commercial production, I meant that the system has completed the validation processes and comparability study, and can now consistently meet commercial standards. The automated process using the Flaskworks system will still need to be approved by the MHRA.
The entire reason Northwest Bio acquired Flaskworks in the first place is because it’s necessary to automate the culturing process to commercialize DCVax. The manufacturing process must be automated and digitized for several reasons: to improve consistency and reduce risk to meet higher commercial regulatory requirements, to lower manufacturing costs, and to scale production for commercial volumes that are not possible with manual production. Flaskworks/Advent has spent the past two years upgrading and developing the system from a clinical device to a commercial device, testing, validating, and optimizing it for commercial use at Sawston, and incorporating it into an automated process to manufacture DCVax.
Shashi Murthy’s ASCO presentation explained the automated manufacturing process: first, the monocytes are isolated in the Gibco CTS Rotea cell processing system, next culturing, lysate pulsing, maturation, and washing in the Flaskworks system, and finally filling the final doses into cryovials in the new automated fill and finish system. The most critical component of that automated manufacturing work flow is the Flaskworks’ system.
As I’ve previously posted and the PR states, the GMP for a commercial product are far more stringent than for an investigational product. Quality is designed and built into the commercial manufacturing process at every step. Risk assessment/process validation studies must be performed on each process to provide evidence that every process will operate in a state of control, which ensures a consistent and high quality product.
Advent has not spent the past year validating an obsolete, inefficient, manual culture process which requires 15 expensive man hours, is subject to potential contamination risk, and requires an expensive high grade cleanroom.
It’s crystal clear to me that Advent intends to use the automated process that includes the Flaskworks system to apply for the commercial license at Sawston. I have zero doubt.
And by the way, for anyone that says this commercial license has nothing to do with Northwest Bio, that is ridiculous and completely false. This commercial license has everything to do with Northwest Bio. Advent has to demonstrate their ability to manufacture, store, and distribute in compliance with GMP for a commercial product. That commercial product is Northwest Bio’s DCVax-L.
This PR is pretty big news, so don’t be fooled by the supposed “market” reaction. Commercial GMP regulations are extremely stringent, and licensing the Sawston facility for commercial manufacturing would be a significant achievement for an experienced Big Pharma company, let alone for Advent, a relatively small and inexperienced CDMO. To me, it makes this milestone all the more impressive, especially in light of the mentioned shortage of GMP experts in cell manufacturing, and equipment shortages and delays.
So we now know that all of the additional commercial GMP SOP’s and documentation required for cleaning, packaging, distribution, etc., have already been drafted, and all of the required qualification, validation and comparability work for all of the equipment used in the commercial process has been accomplished. Yes, this means that Flaskworks system is now ready for commercial production.
This PR also confirmed that Advent has installed, and will be using an automated fill and finish system, so all of the major manufacturing processes can be done in the same low-level cleanroom environment, which should lower cleanroom and personnel costs right from the start.
This manufacturing readiness also means that all the the manufacturing information that is needed for a marketing application should now be available. (except possibly some stability data, which can be submitted later)
I believe the MHRA has a policy to process the application in 90 working days, but as we’ve seen, it can take longer if there are backlogs. I also recall reading somewhere that this inspection could be processed more rapidly if it’s in conjunction with a marketing application though. (as in a pre-approval inspection)
That's exactly right hankman. (take note of the "to date")
I think a rolling review is highly likely.
jabadencel? suckonthatadamdencel?
Insights from the ASCO presentation:
For reference: Manufacturing of DCVax-L Past, Present and Future
presented by Dr. Marnix L. Bosch, MBA, PhD, Chief Technical Officer of NW Bio at ASCO on June 4, 2022
bio, I’m not presuming anything. I’ve stated that the Flaskworks culturing system could be approved for investigational use as an interim step, but it’s unclear if this is the plan, or if further validation studies are being done for the automated commercial process.
I don’t think manufacturing is standing in the way of approval either, and I agree that regulatory approval can be given based on manual production. In fact I wrote in another post that a post-approval supplement can be submitted for the change from manual processes to automated.
That really is next level, thanks for sharing flipper. Despite what some suggest, Northwest Bio is definitely not sitting on their hands.
Although it’s difficult to tell exactly where they are with automated production, I personally doubt the ASCO presentation intended to mislead viewers. I think it’s still a ways away. And no, I don’t think Charles Rivers Labs is about to step in to speed thing along. Advent will develop the automated process, and once that process has been approved, it can be transferred to other manufacturing locations.
Right, and as you say “not fully commercial” makes sense. That’s why I suggested the “conditional approval” as a potential option. One of the other other issues the MHRA would have for approval based on manual production is supply vs demand. If Advent can only produce 40 - 45 treatments per month manually, why create a large demand that couldn’t be fulfilled until automated manufacturing is ready? All that is needed right now is the funding to provide the treatment to patients that will match the current supply capability.
I think your question whether the MHRA would approve DCVax based on manual production was strictly from a manufacturing perspective, but in my mind there was a question of NICE’s cost analysis based on manual manufacturing that would then change considerably once automated manufacturing was approved. Now I think we have an answer how this can be accomplished: The Cancer Drugs Fund/Innovative Medicines Fund can fund the treatments until a final (long-term) cost assessment can be made based on automated manufacturing.
Right. Linda Powers’ hat is full of rabbits.
Thank you Lykiri. This is HUGE! This document that you posted provides the details on how the new Innovative Medicines Fund will operate. I thought Northwest Bio might be able to access this new funding to provide early access to DCVax for Glioblastoma patients in the UK, but after reading through this, I’m now convinced that this is the plan to fund DCVax for compassionate use until the Flaskworks automated process development work is completed and approved.
flip, since the MHRA has already approved DCVax-L for compassionate use, all they would need to do is provide the funding for the patients to receive the treatment. There are new pathways in the UK if the MHRA is receptive. Here's a couple:
Conditional Marketing Authorization Applications
The MHRA has introduced a national conditional marketing authorization (CMA) scheme for new medicinal products in UK effective from 1 January 2021. Eligibility criteria for this scheme, as that of the EU scheme, is intended for medicinal products that fill an unmet medical need and for serious and life-threatening diseases where no satisfactory treatment methods are available, or where the product offers a major therapeutic advantage.
The MHRA determines eligibility for a CMA at the time of MAA assessment. The MHRA does not have a specific application route for a CMA. e sponsor needs to file the MAA dossier for a full marketing authorization. At the completion of the MAA dossier assessment, the MHRA will determine whether to approve the application and grant a conditional MA or whether the benefit-risk ratio is negative and reject the application. e CMA may be granted where comprehensive clinical data is not yet complete and available. e sponsor must provide justification for a CMA, including the ongoing clinical studies’ status and timing of the availability of comprehensive clinical data. CMAs are valid for one year and can be renewed annually.
Exceptional Circumstances Marketing Authorizations
From 1 January 2021, the MHRA’s existing scheme for applications under exceptional circumstances will continue to be available for medicines where a comprehensive data package cannot be provided because the condition to be treated is rare or because the collection of full information is not possible or is unethical. This scheme has the same eligibility criteria as the EU scheme (see Chapter 2). designation of a product as being eligible for an exceptional circumstances scheme by EMA or another jurisdiction may be taken into account by the MHRA, but the final decision on eligibility of the product for the GB scheme will rest with MHRA.
And perhaps this will help:
marzan, I know the capacity of Sawston has been a question for many here, but there was far more high-level manufacturing questions addressed in that presentation that few on this board will understand, but some in attendance will certainly appreciate.
For example, what has actually been more of a concern to me is that a number of other gene and cell therapy companies like Bluebird, Mesoblast, Sarepta, BioMarin, Voyager, Astellas, and others, have been held up for approval by the regulators (mostly the FDA) due to various manufacturing issues, most frequently from inadequate assay development. Approved biological products are required to be accompanied by analytical tests to demonstrate safety, purity, and potency. This additional scrutiny may have been prompted because not enough attention was paid to manufacturing controls during the rapid approvals of the early gene and cell therapies, a couple of which have had subsequent manufacturing issues. (Novartis)
So it was very reassuring for me to see slides 9-15 which showed Northwest Bio’s assay development work, particularly the “next generation potency assay” developed by Shashi Murthy et al. at Flaskworks/NW Bio.
As I said, in that presentation, Northwest Bio addressed the significant manufacturing challenges encountered by other cell therapy developers, and it’s clear to me that they’re well prepared.
Good to hear that some oncologists came away with the impression that manufacturing won’t be a problem. That was likely the gist of what Northwest Bio wanted to convey.
I imagine that some of those assay slides caused a yawn or two though.
Initial thoughts on IET presentation:
Northwest Bio has traditionally been very patient focused, and has been actively engaged with patient advocacy groups and even allowed them to speak about the trial data lately while Northwest Bio has been silent, so I was initially surprised that NW Bio did not bring DCVax-treated patients and their patient voice to ASCO, and instead discussed manufacturing details. Generally, the oncologist attendees want to learn more about the various treatments and the patient and clinical information, rather than the manufacturing details.
So it’s clear that Northwest Bio was speaking to a different audience today; investors, industry analysts, and other Pharma companies. And not only did Northwest Bio’s presentation say that they expect this treatment will be approved, but they answered the analysts next question: Okay, so if the treatment gets approved, is Northwest Bio capable of actually manufacturing it to meet commercial specifications, and in sufficient quantities? Both those questions were answered with an emphatic, YES and YES.
Since I haven’t seen the presentation yet, and I’m only going off the posted slides, I won’t go into detail, but the information that was presented today should indicate to industry professionals that Northwest Bio has a documented manufacturing development strategy, understands what is necessary, and seems well prepared for the common challenges faced in commercial cell-therapy manufacturing. I can’t wait to see the presentation.
The tumor response rate is the most commonly used surrogate endpoint in early cancer trials since it allows an early determination of anti-tumor activity, which may correlate to extended survival. Some immune checkpoint inhibitors were even approved on the basis of tumor response end points in nonrandomized trials.
In an interview a couple years ago with Al Musella, Stephen Brem said, “They’re looking at radiological markers. We do need a better biomarker that would really make all these trials to be more meaningful and be able to stop an effective trial, be able to accelerate effective when we see effective.” ( I transcribed the relevant part of the interview here)
So yes, if Northwest Bio can identify biomarkers that show that tumor response can predict longer survival, and is a meaningful endpoint, that would be huge, not only for this trial, but all future trials.
Excellent Flaskworks patent news hmuney, thanks. That “Dendritic Cell Generating Apparatus” is the one currently undergoing process validation by Advent Bioservices to automate the culture process for DCVax-L, which will be necessary for commercial production. This patent is a very big deal; Northwest Bio continues to throw up roadblocks for the competition beyond just their trial data, which alone is a very high hurdle. Since “the process is the product,” Northwest Bio has now effectively patented their cell therapy treatment!
ASCO Journals can coordinate simultaneous publication with ASCO Conference. Here’s one:
Real, live, DCVax-treated patients at ASCO could also be powerful and create a buzz. It certainly was in 2018. It would be beneficial for oncologists to interact with these patients at Northwest Bio’s very large booth to learn about their personal experiences with the treatment as well.
Oh and by the way, the MHRA is quite interested in treatments that have taken a patient-centered approach like Northwest Bio has:
Interesting that Dr Ashkan will be at ASCO if true. As most know, he’s not only a lead investigator in the trial, but he’s also been treating patients for compassionate use under the UK “Specials” programme. I believe some manufacturing improvements have been implemented outside of the trial in the UK, so this data could be extremely beneficial in confirming a real-world clinical benefit of DCVax. I believe this data will be used to support a marketing application, but would he be able to present some Real World Data at ASCO if patients consented?
Kings College has participated in NHS research using digital health records:
Reefrad, I haven’t kept up with with board so I appreciate you sharing your conversation, and I apologize if I wasn’t very clear. I agree with your characterization of Dave as genuine and honest, and I think he is extremely knowledgable about the industry and markets, which is why I find it curious that he said that “the clinical trials update is a nothing burger and meaningless.“
I personally think that updating the clinical trials registry is a pretty big deal, and I believe it’s a prerequisite for the journal article, so I’m not sure why he is saying that it’s not related and is downplaying the significance. The timing of the update occurred when it did for a reason, and I don’t believe that it was just some afterthought to clear things up. Northwest Bio has been slow and deliberative in their actions and disclosures. So whether it’s for regulatory reasons, or they are gathering evidence for an investigation, or something else, I think there are likely valid reasons for the way things have played out this past week, but it appears Dave and Northwest Bio are not able to disclose this right now, and perhaps don’t want to draw attention to it.
Yeah right. Nothing to see here, move along.
Biotech M&A, despite big expectations, has yet to pick back up. Here are the latest deals.
Dealmaking is essential to the business of drug development. Keep track of M&A as it happens with this database.
Updated April 13, 2022 • By Jacob Bell
In the business of drug development, deals can be just as important as scientific breakthroughs. Many of today’s most influential medicines, from the life-saving cancer treatment Keytruda to the anti-inflammatory agent Humira, might not have become so without mergers and acquisitions.
Over the last few years, pharmaceutical M&A hit record highs as larger companies turned again and again to young biotechs for innovation. Often, these deals focused on cancer, rare diseases and immune system disorders — areas of drug research that were seeing major victories in clinical trials and huge profits for treatments that made it to market.
These deals haven’t come cheap, however. Biotech companies have had an easy time raising huge sums of money from private investors and, until recently, the public markets. That funding can make them less receptive to a buyout offer and force would-be acquirers to offer more to lock down deals. Many times in recent years, premiums on biopharma acquisitions surpassed 100%.
While M&A was plentiful in 2018 and 2019, and even held up during a year gripped by the coronavirus pandemic, 2021 was much quieter. In fact, the second quarter hit a five-year low in both the value and number of biopharma transactions. This year, too, has seen only a small amount of activity thus far, though analysts believe a resurgence is likely. Whether this down trend in M&A activity continues, or reverts back to pre-pandemic levels, will have a significant effect on which drug programs get funded and advanced.
BioPharma Dive is tracking these deals below. The database, which shows drugmaker acquisitions that happened since 2018 and were valued at $50 million or more in upfront consideration, will be regularly updated.
Click on an acquiring company to pull up more information, and scroll to the bottom of the page to read how this information was collected and organized. If there’s anything we’ve missed, or any additional information you’d like to see, please reach out and let us know.
https://www.biopharmadive.com/news/biotech-pharma-deals-merger-acquisitions-tracker/604262/
dmb, it’s interesting that we can all read the same thing and each come away with different ideas of what is said based upon our own point of view and experience. I wouldn’t have thought that consumables leaching would be an issue until the professor raised it, but it seems likely that some assurances would be a part of the new supplier agreement. I think you’re right, and it makes sense that it would simply be a perfunctory task, particularly if Saint Gobain is the new supplier, since they’re as established as Corning in plastic lab supplies. (note: Saint Gobain supplied the consumable bags for the DCVax-direct trial) This testing would probably be more of an issue for a lesser-known supplier, or if they were selling Flaskworks as a medical device, which the professor didn’t know.
I believe closing and automating processes is more commonly done in conjunction with a marketing application or post approval, but Northwest Bio seems to blaze their own (slower) path, so if I had to guess, right now I would say that Flaskworks approval for investigational products will come before marketing approval, but I agree that it will be interesting to watch how this is unfolds.
Lykiri, of course I agree with you “that the changes to the manufacturing of the ATMP must be supported by the data generated in a comparability exercise.“ However when you say “IMO, this is valid for both investigational ATMPs and authorised ATMPs,” are you saying that you think that only a comparability exercise for the Flaskworks system is all that’s needed for commercialization? If so, you’re probably in good company, but I think we may be reading into some information differently.
The way that I read the quote that you highlighted from the Arnold and Porter Blog is that it’s saying that the data from a comparability exercise for an investigational product should show evidence that the post-change investigational product is equivalent to the pre-change investigational product, and the data from the comparability study for a commercial product should show evidence that the post-change commercial product is equivalent to the pre-change commercial product. There are different GMP for investigational products than for commercial products, so the comparability exercise for each type of product should comply with the GMP for that type of product.
I don’t think a comparability study alone will provide sufficient evidence for regulators to conclude that an investigational product is equivalent to a commercial product, and it will require additional process validation and development documentation, which may or may not be occurring simultaneously. It makes sense to me to do this all at the same time for expediency, but there’s always unknown factors that may make expediency less of a priority.
dmb, I agree that surely Flaskworks possesses all of the relevant development documentation for their systems. However, I think the professor was just giving a general answer to a general question, and it does not appear to me to be specifically discussing the Flaskworks’ system, which was previously sold commercially by Corning.
Most of the new closed automated manufacturing systems use single-use consumables, and I think the testing that he discussed was to ensure that no chemical substances leached from the plastic consumables, which is a well-known potential issue. Corning obviously would have done this testing prior to selling their consumables for the Flaskworks system, but it’s unknown if the new supplier (Saint Gobain) can provide the same assurances, or test results, so it’s a good point.
https://www.eppendorf.com/product-media/doc/en/146279/Consumables_White-Paper_026_Consumables_Leachables-Minimizing-Influence-Plastic-Consumables-Laboratory-Workflows.pdf
Thanks for sharing Lykiri. He was a good person to ask, and I would think he knows about the system and process you were describing but because of the vague way the questions were asked, his answers were more general and less specifically helpful, so this is my two cents:
To the first question: Advent is changing a part of the manufacturing process with the Flaskworks system, so they will need to prepare a Comparability Protocol (CP) which s a comprehensive plan that describes the specific tests and validation studies and acceptable limits to be achieved to demonstrate the lack of adverse effects that the Flaskworks system has on the identity, strength, quality, purity, or potency of the final product. So the Regulatory Authorities will approve the manufacturing process changes using the Flaskworks system rather than actually certifying the system itself. If the current process is for an investigational or clinical product, then then the system will only need to comply with the Good Manufacturing Practices for an investigational product.
To the second question: For the CP, the Regulatory Agencies require data from a minimum of 3 runs (in a row) post process change for comparison, and this is the most common number submitted. However, I would guess that Advent has likely run between 20 to 30 tests prior to the study for Performance Qualification, and to “dial in” the system for Northwest Bio’s product.
To the third question: Often a CP is submitted as part of the MAA or BLA in the CMC section, or later as a post-approval supplement. Irregardless of where Northwest Bio is in the marketing application process, the CP could be submitted on its own, and I believe the Regulatory Agencies have a 60-day window to approve it, but this could be delayed due to Covid backlogs or other more critical issues. The professor raises an issue about the testing of the new EDEN consumables from Saint. Gobain. A comparability study may be required for the new plastic consumables as part of the second Flaskworks’ milestone. This may be why Northwest Bio has not reported the second milestone in the 10-K, as this consumables comparability study may be part of the larger CP, and it would likely be submitted all together, so the second, third, and fourth Flaskworks’ milestones may be recognized together when the CP is approved.