Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
sorry georgebailey, I hadn’t read the board or posted for a while and missed this. The term “semi-automated” did not refer to Eden. It referred to the manufacturing process that I believe Advent used to apply for the commercial manufacturing license. That process employed the use of some automated cell processing and fill & finish equipment, along with a manual culturing process, making it partially (or semi) automated.
I don't think Eden is being utilized in the "Specials" Program. But to clarify: Eden is a fully automated system. I don't think there is any such thing as a semi-automated Flaskworks system. So when the comparability testing is/was conducted, it is/was fully automated.
Oh okay, then disregard my previous post.
Right flipper, great minds . . . :)
Regulators present? Nah, I think the odds are probably better that some spies were in attendance though.
I had the same thought ATLnsider. It seems Northwest Bio may be researching potential tissue-agnostic biomarkers and laying the groundwork for future trials/approvals.
By the way, while a few of the Immune Checkpoint Inhibitors have received tissue agnostic approvals using genetic sequencing to discover common molecular targets, there may be another way using proteomics. (I’m not saying they will - just that it’s impressive how far technology has come)
antihama, even the intro of that FDA guidance states that when companies are applying for marketing approval, they are not only required to include the clinical trial data that proves that their drug or treatment is safe and effective, but they must also include supporting, non-clinical data from animal or in vitro studies that prove that the treatment performs in the patient, or has the pharmacological effects or mechanism of action, the way that the company claims:
The FDA just released draft guidance on GASK in applications for drug and biological products. Northwest Bio has clearly been in discussions with the regulators, and I don’t think it’s a coincidence that this new MOA information was provided in their ASCO presentation this year. I think it’s likely that this non-clinical information was one of the prerequisites that Linda discussed. Yep, I think they're close.
Generally Accepted Scientific Knowledge in Applications for Drug and Biological Products: Nonclinical Information
https://www.fda.gov/media/168408/download
Very impressive ASCO presentation from a medical/scientific perspective. It certainly appears that Northwest Bio has (by far) the most advanced Dendritic Cell Therapeutic ever produced, as well as the knowledge and understanding of its mechanisms of action.
I sincerely hope Northwest Bio posts the full recording on their website.
No Doc, not Eden related. Fun fact though; blue horseshoe crab blood (which is blue/green) contains a unique clotting agent (it coagulates around and encases gram-negative bacteria, which produce harmful endotoxins) that is used to make an important test reagent, Limulus Amoebocyte Lysate (LAL). LAL has been used to detect endotoxins in vaccines, injectable medicines, and medical devices for decades.
Charles River Labs is one of the few companies that has a license to harvest blue horseshoe crabs from US public waters to produce LAL, which is a huge competitive advantage, so they have been reluctant to develop or change to a more eco-friendly test, despite greatly declining horseshoe crab populations, (most die from having their blood drained) and lawsuits from environmental groups.
Supply chain disruptions caused by the pandemic, along with vastly increased covid-vaccine testing, has forced Charles River to begin using alternative testing methods, [recombinant factor C (rFC)] which was developed a decade ago by a competitor, Lonza.
Thanks Lykiri, you saved me the time to look up the transcript.
Thanks ATLnsider, sounds reasonable.
Yes of course London was using the exact manual process that was used during the trial - it was the the legacy process established by Cognate that was used to manufacture for compassionate use in the UK. That manual process was then transferred to Sawston for the initial investigational license there.
I can’r recall if London has a commercial license. If it’s only an investigational license, then Advent could manufacture for the pediatric trial or another small trial there. That’s the only reason I can think of to keep the facility open using an obsolete, less efficient, manual process. I think it’s likely the new established semi-automated process will be transferred to London and used to apply for a commercial license if it doesn’t already have one, and then the facility could be used for extra commercial capacity, or for small clinical trials.
Well Doc, since I don’t believe that Eden is a prerequisite for marketing approval, or currently a part of the marketing application, I think that “comparability” could mean the semi-automated process that was used to apply for the commercial license at Sawston, and will be used in the marketing application. This would be the comparability protocol to establish “comparability” of the new process using the automated cell processing and fill & finish equipment, to the former manual processes, so I believe that one has already been completed.
Thanks senti. My understanding is that patients still need to fly to the UK for the leukapheresis procedure.
Sure biosectinvestor, you said the same thing a couple years ago, (without providing any evidence) that the comparability studies were previously done. And yet, the most recent confirmation (in January) that the PBMCs are not frozen, was by Dr. Toms, when he stated at the Lifespan WPRI news conference, that the tumor lysate could be shipped from the US, but the leukapheresis procedure would have to be performed in the UK. This would be consistent with using fresh, not frozen, leukapheresis material, as Northwest Bio has always done. If the comparability studies had already been done, and the monocytes were frozen, then it wouldn’t be necessary to perform the leukapheresis in the UK, they could be shipped from the US, just like the tumor tissue.
I’ve stated multiple times that the logistics for cell therapy products are considered a part of the manufacturing process, and will be a part of the marketing application, so of course this has been discussed with regulators. For marketing approval in the UK, performing the leukapheresis locally and using fresh monocytes is perfectly acceptable. However, to ship in commercial volumes globally, the leukapheresis material will absolutely need to be frozen. This is why I raised the issue years ago, not because I think it’s some insurmountable task; it’s not, the procedures are well established. Both Kite and Novartis conducted comparability studies on frozen leukapheresis material well before CAR-T's commercialization. There certainly has been sufficient time for Advent to conduct the comparability studies, but Northwest Bio has been rather elusive on the details about this for some reason, which is curious.
Yes, but my old question remains: Has Advent conducted comparability studies for the cryopreservation of the leukapheresis material? (which would allow shipping from the US) Or are patients still required to fly to the UK for the leukapheresis procedure?
For reference:
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=170890424
Is this the first time the workstreams are listed from the Statement of Work #6? Seems to be a little more detail in this Q than I remember about this, and as of the end of March, nine of the ten milestones that were prerequisites for regulatory approval, were completed:
10 reasons why DCVax will be approved worldwide:
1. The DCVax phase III clinical trial met its primary and secondary endpoint with high statistical significance.
2. The positive phase III clinical trial results are confirmed by real world compassionate-use data.
3. The positive phase III clinical trial results are confirmed by early clinical trial data.
4. DCVax can be manufactured to commercial standards.
5. DCVax is extremely safe.
6. DCVax treats a rare and deadly disease for which there are no other or very limited treatment options.
7. The clinical trial results passed peer review in JAMA, one of the world’s top 3 medical journals.
8. Regulatory agencies are modernizing and creating new accelerated approval pathways for treatments exactly like DCVax.
9. The world’s top Neuro-Oncologists support DCVax approval.
10. Brain tumor patients and brain tumor charity groups are advocating for DCVax approval.
DCVax is going to be approved worldwide whether the handful of naysayers like it or not. They would be wise to start coming to terms with that.
Thanks Estevito. Yeah Dave is full of . . . useful information.
rkawong, the company has not announced whether Advent’s commercial license included Flaskworks or not, so we can only speculate about it. Flaskworks’ Eden is a pretty big deal, and if it was included in the commercial license, I would think that it would have been announced. Right? Since it wasn’t, my post was about the reasons why Eden might not have been included in the commercial license. If it wasn’t completely qualified and validated, then I don’t think it would have been included, which is why I don’t think it was.
The Flaskworks system was originally designed and commercially sold as a clinical device (to be used for clinical trials). The GMP regulations for this type of investigational product only requires that the final product be tested to meet the pre-defined final-release specifications. However, to produce a commercial product, the GMP regulations require in-process controls and the ability to test, monitor, and maintain the quality of the product throughout each manufacturing process, to ensure a consistent and high quality final product.
Therefore, in order to be used in the commercial manufacturing process, the Flaskworks system had to be modified and enhanced with a way to monitor and maintain, or adjust the conditions during the culture process. This is accomplished with the use of biosensors which measure and analyze the critical conditions in a culture vessel. They provide real-time, in-process quality control data on measures like cell count, cell viability, cell size, acidity, dissolved oxygen, temperature, and level of metabolites and nutrients. Based on this continual feedback information, adjustment can be made to the different culturing parameters to maintain the optimum culturing conditions to induce differentiation of the patient's monocytes into dendritic cells.
This is just one of the many tasks the Flaskworks' team/Advent has been working on for the past couple of years in order to get the Flaskworks system ready for the comparability studies (along with the qualification of the system and process validation) to prove that it can produce a similar product as the manual method. As far as I can tell, this wasn’t accomplished prior to the filing of the application for the commercial manufacturing license.
Thanks for your thoughts and comments dmb. I understand what you’re saying, and agree that the MAA could include Flaskworks, and if it was in fact included, then that could be a reason the MAA application has taken so long. However, my thinking is that Northwest Bio only needs the Flaskworks system for commercial scale up, but not necessarily to gain marketing approval, so they may not want to include the Flaskworks process, which could potentially complicate and/or delay receiving marking approval, which could also delay other (financial?) plans. I think a less risky and preferred approach, (even if it takes a bit longer) would be to add the Comparability Protocol (CP) for the Flaskworks’ process after the marketing application has been approved, as a Post Approval Supplement (PAS). I’ve always maintained that this was a possibility, and now I think it may be likely, given what we know.
I agree with your validation concerns. Shashi Murthy commented at the ASCO presentation in June, that more validation work needed to be done, and that language “integrating technology for monitoring cell culture to ensure reliability” sounds like validation work, so this is why I believe that Flaskworks’ Eden was left out of the initial commercial licensing process, and likely, the final MAA as well.
It makes sense (to me) that Advent would do it step by step; file a CP for the initial change to a semi-automated manufacturing process (which had all been validated) for the general commercial license, excluding the Flaskworks system; so basically automated cell selection, manual culturing, and automated fill & finish. The idea is to get the initial commercial manufacturing license approved, and then use that approved semi-automated commercial manufacturing method in the marketing application without further complication.
Meanwhile, in the intervening period since the ASCO presentation, the Flaskworks’ team has been working to get the Eden system fully validated including in-process controls. Then, once validation has been completed, Advent will plug the Flaskworks system into that established approved process, run the comparability study using the Flaskworks automated process to show equivalence to the established semi-automated process, and then submit the CP to regulators as a PAS . . . and hopefully within 60 days, it will be approved. Simple as that!
By the way, I’m not trying to convince anyone of this, or even saying that this is correct, but just saying that this is what makes the most sense to me at the moment.
Good to know, thanks Lykiri.
Actually dmb2, I wasn’t being pragmatic. As you may know, after the ASCO manufacturing presentation last year, I was convinced that the Flaskworks’ Eden system had been qualified and was completing validation, and I thought it had been included in the automated process that Advent used for the commercial license. However, last fall, I was told by an associate (who talks to management) that Flaskworks wasn’t included because its development wasn’t completed by July, when Advent applied for the commercial license for Sawston.
When I saw the biosensors on the prototype system on the slides of the ASCO presentation, (after nearly 2 years of development time) I assumed that it was completely functional, (and mostly validated) but maybe it wasn’t. Flaskworks and Advent both hired some key personnel in September which appeared (to me) to be related to Flaskworks’ development. (Flaskworks hired for product development engineers whose responsibilities included “Identifying design improvements and integrating technology for monitoring cell culture to ensure reliability” and Advent hired for multiple computer validation, and software/firmware script writing positions) So, as of last fall, Flaskworks/Advent may still have been working to control the biosensors for the culturing/feedback parameters of the automated culture process, and the software integration with the Autolomous Manufacturing Execution System software at Sawston to control the Flaskworks system, and/or validation work on the biosensor controls. Perhaps a sense of urgency finally occurred last fall for the proper resources to get the Flaskworks system ready for the comparability study, so that it could be approved in time for commercial production by the end of this year.
I think marketing approval in the UK can be much faster than the comparable timeframe in the US that you’re referencing. In the UK, DCVax has been designated as a Promising and Innovative Medicine (PIM) for a rare and deadly disease with limited treatment options, so it qualifies for an accelerated review process. Many of us believe that it could already be in a rolling review, which allows modules of the eCTD dossier to be submitted incrementally for pre-assessment by the MHRA, rather than as part of a consolidated full dossier, and it also allows enhanced regulatory interaction and advice to reduce the risk of failure, and “the final decision on approvability reached by Day 100.”
I anticipate that Northwest Bio will announce the MAA filing when the final submission has been accepted by the MHRA. Northwest Bio is likely interacting with a very busy, and back-logged regulatory agency, and potentially may be working out a schedule, so that once the completed final MAA has been submitted, it can be assessed and approved within the MHRA’s 100-day window.
.
If that is true, then I would anticipate regulatory approval within about 3 months of the filing announcement, but potentially up to 5 months, if there are issues that require follow up information. And by the way, that previously mentioned associate also thinks that approval in the UK will be very rapid.
Also Doc, “Approval of L changes everything” because it puts the naysayer’s primary false narrative (that the clinical trial failed, and DCVax won’t be approved) to death.
MHRA approval is important because it’s the first major step that allows a chain of events to occur. It lowers the risk of FDA approval, which also significantly lowers the risk of investment in Northwest Bio, which is necessary to: attract large risk adverse institutional investors, attract large industry partners, uplist to a major stock exchange, and attract large-scale media attention, which all should lead to a significantly increased stock price. (hopefully even a short squeeze somewhere in there)
I second that opinion flipper. In the UK, during the Rolling Review, the pre-assessment process includes consultation with the Commission on Human Medicines (CHM), so it shouldn’t require that fixed date schedule.
senti, just to follow up and clarify the question I asked you: why the HTA license wasn’t updated to show “export”?
I received an answer from the HTA to my question: Does the export of an Advanced Therapy Medicinal Product (ATMP) from the UK to the European Economic Area (EEA) or elsewhere, require an export license from the HTA?
The answer is no, because the final product (ATMP) is regulated by the MHRA. So of course, you were right!
Sometimes it takes public outcry to move politicians to act, and I like the idea of calling it an emergency and crisis. Hopefully this will help speed the approval (and reimbursement) of DCVax/Murcidencel:
Poor Man, sorry I don’t know where Northwest Bio was in the filing process at the time of the regulatory change, nor the level of revision that would be required to update the quality module. I have personally anticipated an announcement of the MAA filing a couple months after the MIA was received, and that hasn’t changed.
Hi dmb2, yes Autolomous’ software can accommodate manual processes, like cell culturing. I currently don’t think the MAA will include the Flaskworks system, but I believe it will be included as a post approval supplement shortly after.
yes ATLnsider, Advent’s relationship with Autolomous is obvious, and I thought it was known amongst the more senior members here. It’s been posted about by Lykiri, me, and a few others over the years. I realize that many here don’t understand the importance of what they do, though. Thanks for highlighting it better for others, and all that you do here.
Poor Man, the supply chan and logistics for an advanced therapy product are considered a part of the manufacturing process, and are included in the quality (CMC) module of the MAA. Any regulatory updates from last year would need to be updated in the MAA.
Thanks senti, you may be right. I know they need a HTA export license for the export of human tissue and cells for starting materials, so I would think it would be necessary for the finished product as well. Either way, I’m sure that Advent knows and will obtain the required export licenses.
flipper, one of the major manufacturing bottlenecks in the UK, is that every single batch must be checked by the Qualified Person (QP) and have a QP declaration before the final product can be released. Batch records for cell therapy products can be several hundred pages long, so if batch records are paper, it requires the Qualified Person to be on site, and it could take several hours or more per batch for evaluation. Data recorded manually, can sometimes be prone to human error and reported incorrectly, documentation may be missing or stored elsewhere, or signatures may be missing, etc. If there are errors or deviations, it could potentially take days to certify a batch. To make matters worse, there’s a shortage of Qualified Persons in the UK; as of a couple years ago, there were estimated to be less than two dozen QP’s performing certification activities of CGT products in the UK. This bottleneck alone highlights the need for the digitization of the manufacturing process, and it is why Autolomous was founded. A digital manufacturing process, and an electronic batch record are clearly essential for scaling at volume for a commercial cell therapy product.
I think what Linda was alluding to at the ASM, is Autolomous’ digital batch verification technology, known as AutoloMATE Assist, which is the third module from Autolomous’ digital platform AutoloMATE. The AutoloMATE Assist project began in April 2021, and was expected to last 24 months. (doing the math?)
The first two AutoloMATE modules were AutoloMATE-eBMR, which digitizes batch manufacturing records, and AutoloMATE-CLOCK which provides scheduling of all critical manufacturing processes and variables, from scheduling leukapheresis, to final administration of the finished product to the patient.
According to Autolomous, it will be the first first digital batch verification solution available to the market that will be fully integrated with both an electronic batch manufacturing record and also have scheduling capability. It allows everything in the manufacturing process (including the logistics) to be monitored, captured, traced, and logged in realtime, and the data is secured using blockchain ledger technology. So when it comes to the batch verification and final release of the product, each responsible department, Quality Control, Quality Assurance, and Qualified Person, can easily and quickly evaluate each manufacturing record, (even remotely) which vastly streamlines product release. It’s a pretty big deal in my opinion.
https://autolomous.com/autolomate/
I think I posted this Mark Lowdell’s investment pitch before which includes a development timeline for Autolomous going back the several years that Linda was discussing:
https://atmpmanufacture.org/wp-content/uploads/2019/11/autolomous-mark-lowdell.pdf
PoorMan, in case you didn’t see it, senti posted the export guidance update which occurred In October last year:
Thanks senti for the links to the MHRA guidance update. That’s what I thought, but didn’t see it.
BTW - for the second question that wasn’t answered; I think the Human Tissue Authority (HTA) license will be updated to show “export” after another inspection in conjunction with a marketing authorization for DCVax-L/Murcidencel in the UK, and Advent obtains a wholesale dealer license (wholesale distribution authorisation) (WDA) for Sawston.
I know the world revolves around Northwest Bio, but it’s not a big deal, it’s just an annual reporting requirement that will now exempt single patient cell and gene therapy products because they have a highly controlled supply chain, the information is actually already reported so it would be redundant, and it’s not necessary to protect the public health. The FDA actually spells this out:
Do you know that Cohen Milstein is representing plaintiffs in a class action against six of those biggest megabanks? For guess what?
You know why Zardiw. Check your DDAmanda Chart; most think NWBO is going to revisit (and pass) that all time high. . . . or perhaps it’s the brilliant posters and fascinating discourse here.