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senti, I missed those conversations, but it doesn’t surprise me that this has been discussed before, or that there were naysayers suggesting that it couldn’t be used for DCVax-L.
I don’t know if it was actually validated for DCVax-L, but the patent was announced close the the mid-point of enrollment of the DCVax-L trial. I think it was originally designed during the manufacturing development work for DCVax-Direct, and it was obviously used in the production of DCVax-Direct for that clinical trial, but it was FDA approved, and I have always assumed that it could also be used for DCVax-L, partly because NW Bio said it could be used in DCVax trials, and products.
Tangential flow filtration is a common method to isolate or separate cells. It uses pressure and counter flow to push the desired or undesired cells through ultrafiltration membranes with highly defined pores. The system that Northwest Bio has patented, is a self-contained, closed automated system that separates the desired monocytes (precursors to dendritic cells) from the undesired blood constituents like lymphocytes, erythrocytes, platelets etc., from the patient’s leukapheresis material. This is the first step in the manufacturing process for both DCVax-L and DCVax-Direct. The system has disposable sets where I assume the monocytes are collected so they can be transferred to the next process step. (culturing)
There are a number of commercially available automated cell processing systems that could be used for the cell separation step, (remember Flodesign Sonics?) but I’m assuming that Advent will use Northwest Bio’s patented technologies for the two most critical processes.
NW Bio's Patent Portfolio Further Expanded With Manufacturing Automation Patent
BETHESDA, Md., Sept. 10, 2013 /PRNewswire/ -- Northwest Biotherapeutics (NASDAQ: NWBO) (NW Bio), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, announced today that it has been issued another key U.S. patent (#8,518,636) covering a next generation process for manufacturing lower cost human dendritic cells of both a higher quality and higher reliability.
This next generation system has already been cleared by FDA for use in the manufacturing for NW Bio's clinical trials. These systems are now in use producing the vaccines which already have been injected into the tumors of DCVax-Direct patients.
This next generation process automates certain crucial stages of the manufacturing process within a self-contained system. Automating some or all of the production process within such a system can eliminate the need for today's extremely expensive "GMP" clean rooms (with, for example, special air handling to maintain sterile air in an entire building). Eliminating the special costs for such clean rooms will further enhance product economics, allowing wider margins and pricing flexibility.
At the heart of this next generation manufacturing advance are Tangential Flow Filtration machines, or TFF for short. These machines and associated disposable sets provide an automated, closed system for the crucial stages of the manufacturing process isolating the particular immune cells that become the dendritic cells in the Company's DCVax products.
Most significantly, the dendritic cells produced through this next generation system, are manufactured using procedures which are more closely related to what one finds in nature. The result is increased potency of the dendritic cells (which are the active agent in the DCVax products).
As such, full implementation of the TFF can be another major step forward in advancing immune therapies, and help to position the manufacturing of DCVax products for potential commercial scale-up when the time comes.
"Ongoing development of our technologies for cost reduction and simultaneous enhancements in quality continues to strengthen our competitive position," commented Linda Powers, CEO of NW Bio. "The TFF system provides major advantages in this regard, and the issuance of this latest patent is a significant addition to our portfolio of over 180 issued and pending patents worldwide."
Dr. Marnix Bosch, one of the inventors on this line of patents, says: "We have approached the issues of dendritic cell manufacturing from a process-improvement perspective, and the material covered in these issued patents takes advantage of the natural biology of dendritic cells and their precursors, thereby allowing us to produce more potent dendritic cells in a more efficient and automated system."
https://www.prnewswire.com/news-releases/nw-bios-patent-portfolio-further-expanded-with-manufacturing-automation-patent-223111161.html
Ha right. I won’t hold my breath. Did you know that Kite invited investors to the grand opening of their state-of-the-art CAR-T manufacturing plant in El Segundo back in 2016? It was a pretty big deal at the time since no cell therapy (besides Provenge) had yet been approved. Lots of Michael Bigger types and biotech analysts were asking detailed, sophisticated questions, but the Kite reps were pretty tight lipped and didn’t reveal much there, or on the tour. Some pretty good discussions among the investors and analysts though.
There’s a lot of focus on the validation of the Flaslworks system, which is certainly a critical piece of equipment and where the cells spend 90% of the manufacturing time, but as the saying goes, “the process is the product.” What the regulators will actually be approving is an entirely new commercial process, which incorporates the new automated equipment. The Flaskworks bioequivalence study is part of a larger (phonebook sized) Comparability Protocol (CP) which is a detailed plan for assessing the risks and effects of the proposed manufacturing change(s) on the identity, purity, potency, and quality of a product. The comparability protocol likely took months to prepare and was probably submitted to a regulator to incorporate their feedback on the proposed changes and assessment methods. The CP can be preemptively submitted in the CMC section of the original MAA or BLA, while the results and data analysis can be submitted later when completed in a post approval supplement. Or the MAA or BLA can be submitted based on the manufacturing method of the clinical trials, and the entire Post Approval Change Management Protocol (PACMP) with data analysis, can be submitted separately later, as a post approval supplement.
I believe that Advent has developed an automated (digitized) workflow using multiple pieces of equipment to close and automate most of these processes for the commercial production of DCVax. The lot release specifications required for a commercial product are much more stringent than for clinical trials, so it’s necessary to eliminate technician variability, and contamination risk by closing and automating the open manual processes. (recall that Novartis was forced to give away over 25% of Kymriah batches for free because they could not meet commercial specs) Part of process optimization also involves reducing high cleanroom and labor costs, and eliminating potential time-sensitive bottlenecks due to manual processes. (there’s no sense in automating and speeding up certain processes, only to be backed up later by a lengthy manual step following it)
I believe the first manufacturing step, isolation/enrichment of PBMC’s from the leukapheresis material, has already been closed and automated with Tangential Flow Filtration, and the culturing, maturation, lysate pulsing,and washing will be automated and closed within the Flaskworks system. The final, “fill and finish” step is currently open and manual, which brings inherent technician-dependent variability, potential contamination risk, high labor and cleanroom costs, and a potential bottleneck in higher volumes, so I believe it will also be closed and automated for commercial production. I’m guessing that Advent may use a commercially available fill and finish system like the “Finia,” which is capable of filling individual doses into cryovials. Although it shows cryobags instead of vials, there’s a video which compares this automated system to the manual method here
Advent has been working on a monumental task that not only includes building out and certifying Sawston, but also developing a new automated manufacturing protocol based on the previous manual protocols, and incorporating that with Autolomous’s manufacturing execution system (MES,) a comprehensive, dynamic software system that monitors, tracks, documents, and controls the process of manufacturing goods from raw materials to finished products. Some of this work has been done, but a good part could not even begin until production was started at Sawson, so anyone who thinks this will be completed by the first or second quarter is probably underestimating the task.
ski, the requirements for the marketing applications, applicant information, pre-clinical studies, clinical studies, product/manufacturing information, and labeling (the Common Technical Documents) are essentially the same in both jurisdictions, but the UK seems more willing to make exceptions and cut through the bureaucracy for approval, under certain circumstances, to speed an innovative treatment to patients with unmet medical needs. Maybe there’s less political and Big Pharma influence on the regulatory process and insurance reimbursement in the UK.
So now that Northwest Bio has an approved GMP facility in the UK with the ability to produce DCVax (in limited quantities), and since DCVAx meets the criterial for some of the new accelerated pathways in the UK, and holds a Promising Innovative Medicine designation by the MHRA, it makes sense (to me at least) to seek a marketing approval in the UK first.
Huh? Flaskworks certified? Seriously? You’re using the words of wordsmiths to deduce this? Can you please explain how this was accomplished?
Thanks Lykiri for the new Linda Liau presentation. Your DD is unmatched, and much appreciated.
It looks like the same information that she presented last summer. Is there anything new or different here?
Interesting flipper, I talked to someone from Northwest Bio about a year ago, and he said they were all very excited about the new approval pathways in the UK. I mentioned the 150-day assessment and the rolling review and he said “yes, those . . . aaaand others.”
It wouldn’t surprise me if Northwest Bio attempts one of these pathways:
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. e 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). e 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.
Orphan Medicine Designation, Orphan Medicine Development/ Marketing Authorization Application
In the UK, no premarketing authorization orphan designation process exists, and if a medicinal product has been designated an orphan in the EU under Regulation (EC) 141/2000, an MAA can be submitted for the orphan medicine designation under regulation 50G of the Human Medicines Regulation 2012 (as amended). An orphan medicine designation application and the associated MAA (submitted together) in the UK can only be considered in the absence of an active EU orphan medicine designation.
The orphan designation criteria mirror those in the EU. Medicines need to fulfill the following criteria to qualify for orphan designation in an orphan condition:
* It must be intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating.
*the prevalence of the condition in the UK must not be more than five in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development.
* No satisfactory method of diagnosis, prevention, or treatment of the condition concerned exists in the UK, or, if such a method exists, the medicine must be of significant bene t to those affected by the condition.
* Satisfactory methods may include authorized medicinal products, medical devices, or other methods of diagnosis, prevention, or treatment used in the UK.
To obtain the designation, the sponsor needs to submit an orphan medicine designation application form along with the MAA. e MHRA makes the decision on orphan status at the time it decides whether to approve the marketing application.
This approach differs from EMA, which includes a process for granting the orphan medicine designation in advance of the MAA submission and offers orphan fee incentives and other benefits for sponsors of orphan medicines during development. The MHRA’s advisory committee, the Commission on Human Medicines (CHM), will examine the application for orphan designation concurrently with the MAA under review. Medicines with an orphan marketing authorization will be listed on the UK Orphan Register.
In the UK, no orphan designation is issued separately from the MA. Therefore, if a change of ownership application is submitted, the orphan designation will automatically transfer to the new marketing authorization holder.
It is assumed that the MAA requirements for approval will be similar to EU requirements. ere might be a risk if the MHRA requirements differ, and additional work or evaluation of a new parameter during development is requested. Also, there may be difficulties navigating differences between MHRA and EMA opinions on protocol design or development plans.
Scope of Orphan Medicine Exclusive Approval
Once a medicinal product receives MA with orphan designation in the UK, it benefits from 10 years of market exclusivity. e market exclusivity period begins on the date of the first approval of the product.
The UK also will recognize remaining market exclusivity for centrally authorized medicines (granted prior to 1 January 2021) in the EU that are converted to UK marketing authorizations. Unlike the EU, it is not necessary to submit orphan maintenance reports to the MHRA, but they can be submitted as additional information.
Market Access
The following three Health Technology Assessment (HTA) agencies have adopted special assessment criteria for orphan medicinal products (OMPs) in the UK:
1. The National Institute for Health and Care Excellence (NICE) includes a program for ultra-orphan medicine (highly specialized technologies [HST]).
2. The Scottish Medicine Consortium (SMC) includes orphan and ultra-orphan modi er criteria.
3. The Welsh agency, All Wales Medicines Strategy Group (AWMSG), includes additional criteria to consider the severity and unmet need.
A nominative prescription of the OMP from a National Health Service (NHS) doctor automatically provides the right to reimbursement to the patient.
https://www.raps.org/RAPS/media/Publications-Resources/Sample-Chapter/Orphan-Drug-Development-for-Rare-Diseases-Sample-Chapter.pdf
Thanks Basin. This is a very significant milestone achievement, and I’m glad it was announced. Start the clock . . .
Viking, cell therapy and its manufacturing is in its infancy so I would agree with your friend that yes, over time, cell therapy treatments will likely be produced in specialized hospital labs. The first version of the Flaskworks’ system is only capable of automating part of the manufacturing process, (culturing, maturation, lysate pulsing, and washing) but there’s several other steps in the manufacturing process that currently require highly skilled technicians and expensive cleanrooms. I believe that Advent is developing an automated workflow using multiple pieces of equipment to close and automate most of these processes for the commercial production of DCVax, but it will be many years down the road before DCVax can be manufactured in hospital labs using the Flaskworks’ system. I think the plan is to follow the established central manufacturing model of the CAR-T’s, and have regional manufacturing facilities while manufacturing is further developed and optimized.
There are other completely closed and automated cell therapy manufacturing systems that are capable of manufacturing cell therapies start to finish like the CliniMACS Prodigy, Cocoon, and Cell Shuttle that I think are likely to be used in a hospital setting far earlier than Flaskworks. I answered a similar question a while ago and provided links to some of these more advanced systems here
Thanks ATLnsider, nothing really new but good publicity.
Agree senti, Advent Bioservices’ price list for “Specials” treatment in the UK, that TiltMyBrain posted on Twitter a while back, confirms an extended payment schedule. I believe the commercial price and payment schedule will be similar, despite a significantly lower automated cost of production using the Flaskworks’ system.
$NWBO looks like Advent is getting ready to ramp up production at Sawton pic.twitter.com/pqpjVZnVLr
— TiltMyBrain (@TiltMyBrain) April 16, 2021
Yes, that’s my read. In the past, NICE attempted to review all treatments within 90 days after licensing by the MHRA, but in order to speed access to patients, NICE is attempting to review and collaborate with the MHRA during the licensing assessment stage to have a decision as soon as a drug or treatment receives a license. This Parliament discussion reveals that due to bureaucracy and other issues, NICE is not actually working with the MHRA as intended, and the NICE review in some cases, is not keeping up with the faster timelines.
Thanks flipper, I’ve seen this in a few instances. (AstraZeneca’s Tagrisso for one) I think it’s through the Cancer Drugs Fund (CDF) which funds certain promising cancer drugs for a short period until NICE publishes the final approval.
I agree senti, but a NICE decision may take longer than some here suggest. NICE still hasn’t caught up with the new expedited licensing routes in the UK, and if this recent debate is any indication, it does not appear that the situation will improve anytime soon:
UK Parliament Debate on Cancer Drugs: Licensing and Approval
Volume 815: debated on Monday 8 November 2021
https://hansard.parliament.uk/lords/2021-11-08/debates/0A9856B1-F71E-4FAA-A708-0949118BB93F/CancerDrugsLicensingAndApproval
Nice timeline Dude. Factually, data lock occurred on October 4, 2020, but was announced on October 5:
Overview
The Company is focused on developing personalized immune therapies for cancer. We have developed a platform technology, DCVax®, which uses activated dendritic cells to mobilize a patient's own immune system to attack their cancer.
Our lead product, DCVax®-L, is designed to treat solid tumor cancers that can be surgically removed. We recently completed our 331-patient international Phase III trial of DCVax-L for newly diagnosed Glioblastome multiforme (GBM).
As previously reported, the data collection and confirmation process was completed by the independent contract research organization (CRO) who managed the trial and by other independent service firms, and we reached Data Lock for the Phase III trial on October 4, 2020. As explained in our prior announcements, following Data Lock the independent statisticians conduct analyses of the raw data and Trial results for review by the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, in preparation for scientific publication and for public announcement. During this process, any questions or comments from the experts will be addressed as part of the preparation of the results for publication and public reporting.
https://sec.report/Document/0001104659-21-004396/
Well done senti.
Advanced Therapies Week January 25th - 28th 2022 (formerly Phacilitate Leaders World)
A Who’s Who in the advanced therapy industry, where literally anyone who has anything even tangentially related to an advanced therapy, is present in some form. Apparently Northwest Bio is too busy. (Kwok Pang, COO of Autolomous is remotely related)
Sponsors and Exhibitors
https://advancedtherapiesweek.phacilitate.com/sponsors-partners/
Speakers
https://advancedtherapiesweek.phacilitate.com/advanced-therapies-speakers/
BTW - I’m not sure if anyone else was notified (I’ve been contacted 3 times by phone from London) but the 3rd Glioblastoma Drug Development Summit has been changed to an all-digital event (Dr. Bosch still speaking):
https://glioblastoma-drugdevelopment.com
Happy Holidays Everyone!
No way ex. Either you can’t count, or you conveniently can’t remember. You didn’t think I would let you forget about this estimate, did you?
No way.
I doubt they will be certified this year. They are still about 6 to 8 weeks (LP time) away from having an application in (LP time). And I am guessing the UK has a serious backlog in the GMP inspection process right now, which is never fast to begin with.
I would take June or July 2022 as a better guess.
https://investorshub.advfn.com/boards/read_msg.aspx?message_id=162678792
I think you’re probably right senti, not only the visibility given in the UK, but also the due diligence on this board! I know it was just authorized today, but surely the MHRA notifies the company (or at least Advent) prior to posting.
Thanks Lykiri, great news! It figures that you would be the one to find it, but I'm a little surprised that this wasn't announced by Northwest Bio.
Thanks flipper, this patent is for Flaskworks’ BATON system, not the MicroDEN system that will be used for DCVax-L. The BATON system cultures two types of cells using two different culturing methods; dendritic cells in an adherent container, and T-cells in suspension. It was developed by Shashi Murthy to manufacture Neon Therapeutics’ neoantigen immunotherapy with his first grant from the National Science Foundation in 2016.
I’ve wondered if this system will be tailored and further developed to produce DCVax-Direct, which cultures the dendritic cells in suspension. I think I read somewhere that the company intends to develop the Flaskworks’ technology for DCVax-Direct, after development for DCVax-L has been completed.
BTW - This is the system that Shashi Murthy was making presentations about dendritic cell manufacturing systems at conferences like Phacilitate, where I believe he caught the attention of Linda Powers, who potentially encouraged the development of the MicroDEN system.
Shashi Murthy Wins NSF Grant for Cell Therapy Manufacturing with Neon Therapeutics
Via Northeastern | September 2, 2016
Chemical Engineering Professor Shashi Murthy has received funding from the National Science Foundation to develop novel manufacturing technologies for cell-based cancer therapies. This project will be a collaborative effort with Cambridge, MA-based Neon Therapeutics which is developing neo-antigen-based therapeutic vaccines and cell-based therapies for cancer. Cell-based therapies represent the next major frontier in the treatment of cancer and their personalized nature presents unique challenges in manufacturing. This project brings together an interdisciplinary team of engineers and immunologists to design innovative automated bioreactors that can be optimized for biological function. This grant provides $300,000 in funding over a two year period to be shared equally by Northeastern and Neon Therapeutics.
https://aimbe.org/college-of-fellows/COF-2015/
National Science Foundation
Award Abstract # 1645205
EAGER: Biomanufacturing: BATON: Bioreactor System for Autologous T-Cell Stimulation
https://nsf.gov/awardsearch/showAward?AWD_ID=1645205&HistoricalAwards=false
Thanks Lykiri, excellent details!
flipper, it’s general knowledge in the industry. But a while back I did post a document from the EMA intended to clarify guidance around the comparability issue, which confirms what I’m saying. Some of the new “manufacturing experts” on the board may also benefit from reading it:
Comparability considerations for Advanced Therapy Medicinal Products (ATMP)
Q12: What is the comparability exercise needed when a new manufacturing site is added to an existing authorisation?
A: When several manufacturing sites are introduced under the same authorisation procedure, a high degree of comparability is expected to be demonstrated. The comparability of the product manufactured at different sites should be comprehensively substantiated. The first step should be to perform a comparability assessment of the manufacturing process and equivalence of the analytical methods on both sites by evaluation of process parameters and in-process control, to validate the process transfer. Secondly, the comparability of the product itself through release and suitable characterisation testing should be demonstrated. (See also Questions 4, 6 and 9)
https://www.ema.europa.eu/en/documents/other/questions-answers-comparability-considerations-advanced-therapy-medicinal-products-atmp_en.pdf
meirluc, the Flaskworks’ comparability study cannot be initiated in one manufacturing facility (London) and then completed in another facility (Sawston). The entire study (start to finish) will be conducted in one facility (Sawston). There are a multitude of variations between labs (personnel, equipment, media, etc.) which can have an effect on a product, so any change in a manufacturing site is considered a change in manufacturing, and will require its own comparability study. The level of a comparability exercise that needs to be conducted should be commensurate with the degree and timing of the change.
In my conversations with DI, what I have deduced, and caution this is MY personal opinion on what I heard, is that they are already testing Flaskworks on their own; in a parallel stream to vaccine creation testing/training via standard clean room technology. I believe they are targeting end of Q1, early Q2 2022 completion for Flaskworks certification.
Cell culture systems are configured with interchangeable cartridges, allowing versatility and scalability. Systems are configured to have multiple connected cell culture chambers, which allows parallel processing. . .
Certain aspects of the invention are directed to methods of determining a cell culture protocol. The methods comprise receiving data associated with cells to be cultured; connecting to one or more databases to receive data about cell culture protocols; and determining a cell culture protocol for the cells to be cultured.
In some embodiments of the invention, methods further comprise updating the cell culture protocol based on feedback during cell culture. The feedback is from one or more sensors disposed on a cell culture apparatus and communicatively coupled with a controller. In some embodiments, the feedback is associated with at least one of pH, glucose concentration, lactate concentration, dissolved oxygen, total biomass, cell diameter, temperature, cell type, media type, and fluid flow rate.
Thanks for the details Jack. So Les told you . . . yes, that would explain it. Of course I believe you, and I appreciate your perspective.
Yes, I think that 40-45 patient number is the production capacity using the current manual process. The last paragraph of that PR discussed the Flaskworks system:
As previously reported, the Company has also been moving forward on optimization of the Flaskworks system for manufacturing of dendritic cell vaccines. The buildout of the Sawston facility is purposefully being done in phases, both for efficiency in the timing of capital costs and to allow flexibility in operations and usage. It is anticipated that implementation of the Flaskworks system will enable the buildout of some or all of the rest of the 88,345 square foot facility, beyond the initial manufacturing suites, to be simplified and streamlined at reduced cost.
https://nwbio.com/northwest-biotherapeutics-announces-development-completed-for-initial-production-capacity-of-sawston-uk-facility/
Maverick, I actually agree with your previous sentiment that they may not reach 40 “specials” patients a month. I know that several posters have been throwing around that 45 patients per month number, but it may be time to remind everyone what that PR actually said:
The Sawston facility contains a total of 88,345 square feet on two floors. The initial production capacity comprises two manufacturing suites, occupying approximately 4,400 square feet on the ground floor. These two suites, together with some additional support and storage space, have a potential production capacity of dendritic cell vaccines for about 40 to 45 patients per month, or approximately 450 to 500 patients annually, subject to regulatory approval.
https://nwbio.com/northwest-biotherapeutics-announces-development-completed-for-initial-production-capacity-of-sawston-uk-facility/
I’ll share a story with you Maverick since you’re new here. My grandfather was diagnosed with Glioblastoma and his oncologist gave him about a year to live. The Optune “helmet” was recommended after standard of care as the only “treatment” available that might extend his life. It cost $20k a month and it wasn’t covered by Medicare at the time. He was not wealthy but his house was paid for and he had some savings. He didn’t want to spend the money because he wanted to leave it for my grandmother to have a comfortable life. My grandmother begged and pleaded with him to pay for it because she was terrified of losing him and being alone since he had always taken care of her. He could never say no to my grandmother. I’ll spare you the ugly details, but he battled one of the worst cancers you can imagine for ten months, and it cost his entire life savings. You might not understand what people are willing to do to live a little longer until you’ve been there.
Thanks Biosect. The board, and you in particular, are usually pretty good about challenging the flood of false narratives and misinformation. The posts I’ve seen that project minimal revenue and no profit during the initial phase of Sawston production, were from posters that have little credibility with me, so I wanted to give Jack a chance to show if there is a factual basis for it.
My thinking is; if the production in London was performed at cost, then the savings achieved from manufacturing at higher production volume in Northwest Bio’s own facility, could be kept as profit by Northwest Bio.
Jack, I asked if you can provide a link to prove that your information is fact, but you only repeated it. I posted the regulations and guidance around the issue of unlicensed medicinal products for “specials,” and it does not state that a profit cannot be made. However, you are correct that it does state that these products cannot be advertised. Price lists are allowed though.
Is that a fact Jack? Or is it simply your understanding that companies supplying unlicensed medicines (specials) can’t make a profit? If it is a fact, can you post a link?
Yes they can charge cost but not profit at all from it. It’s modest direct costs only….
UNLICENSED MEDICINAL PRODUCTS IN THE UK
CHARGING FOR SUPPLY
The 2012 Regulations do not place any restrictions on companies charging for the supply of unlicensed medicinal products, and historically there were no other restrictions on pricing or pharmacies’ ability to seek reimbursement for unlicensed medicinal products under the NHS.
However, concerns that some pharmacies were making excess margins on unlicensed medicinal products led to the introduction of a new Part VIII B of the Drug Tariff (see NHS: Electronic Drug Tariff: Arrangements for payment for Specials and Imported Unlicensed Medicines). As at August 2016 this set limits on prices of 250 high-cost, high-volume unlicensed medicinal products prescribed commonly and supplied on NHS prescription, using sales and volume data from suppliers (see NHS: Part VIIIB: August 2016).
https://www.arnoldporter.com/~/media/files/perspectives/publications/2017/02/unlicensed-medicinal-products-in-the-uk.pdf
Thanks, but that’s not indicative of MM’s loading. It looks like Moloney Securities Asset Management already held around 160,000 shares and increased it by 5%, which is a little over 8,000 shares over an entire quarter . . . and they’re not a market maker in NWBO.
They are still managing the authorized share limit, and can continue to survive hand to mouth for a while. Not sure if this was posted, but there was some disagreement on the number of shares available under the authorized limit back in August.
At September 30, 2021, approximately 30,882,000 shares were technically available under the authorized share limit, however, an addition 3.4 million shares should have been issued by September 30 but were not, so a more accurate number may be 27.42M shares available: (BTW - What warrant/option agreement wasn’t finalized? Linda’s?)
The Company also received approximate $0.8 million cash proceeds from investors prior to September 30, 2021, for which the corresponding exercise agreement was not finalized and thus, common stock totaling 3.4 million was not issued as of September 30, 2021. Accordingly, such amounts are included in Investor advances in the accompanying condensed consolidated balance sheet as of September 30, 2021.
Subsequent Events
In total, the Company received $8.2 million from exercises of warrants and issuance of notes between October 1, 2021 and November 12, 2021.
During October and November 2021, 34.8 million shares of common stock were issued upon warrant exercises of $6.9 million. Approximately 0.9 million shares of common stock are pending to be issued.
During October 2021, the Company entered into multiple four-month note agreements (the “Notes”) with various individual lenders (the “Holders”) with an aggregate principal amount of $1.14 million for net proceeds of $1.1 million. The Notes contain a conditional piggy-back right to independently purchase shares from the Company, which provides a right for the Holders, contingent on the release of clinical trial data and the next private placement offering (“Next Offering”) after this release, to (a) purchase shares from the Company within seven days following such Next Offering at a 12% discount from the share price of the Next Offering for a variable number of shares equal to an amount up to 50% of the principal amount of the loan and (b) exchange some or all of the outstanding loan amount for a variable number of shares, within seven days after the Next Offering at a 12% discount, resulting in a reduced cash amount repayable under the loan agreement.
In October 2021, the Company entered into multiple note extension agreements whereby the maturity date of the notes was extended for additional 2-4 months.
Yes Northwest Bio has stated their intention to file for accelerated approval and should qualify for RMAT designation, so I think it’s highly likely that it has been considered, and may be used eventually. But why haven’t they applied or announced it yet? My point was that the reason may be that they are considering another accelerated approval route first.
DCVax should meet the criteria for an Innovation Passport but it may be too late in development. This is the relevant section of the guidance:
When to enter the pathway
The ILAP enables multiple entry points depending on:
* the stage of development of the product
* the data available
* the ambition of the applicant to engage with UK stakeholders
* the applicant’s appetite for new innovative ways of working
Therefore, the pathway will allow entry very early, based on non-clinical data, where all the tools described below might be options, as well as catering for products with mid-development ‘global’ dossiers. However, to maximise the benefits, applicants are encouraged to apply early in the development of their products. Products that are towards the end of their development programme are generally not suitable for the ILAP unless there are one or more indications still under active investigation.
The ILAP does not replace the Early Access to Medicines Scheme (EAMS), which remains an important flexibility for earlier patient access towards the end of the development programme in areas of unmet medical need and where major advantage over existing therapies can be demonstrated. The ILAP is broader in scope and is open to all innovative products.
Early pipeline discussions with developers are encouraged. These can be conducted with the MHRA and partners in the context of broader scope meetings, for example.
Thanks Lykiri, it’s good to hear that they wouldn't provide that information since they state:
Data sharing and confidentially
Any information shared during the ILAP is considered as confidential. It will be held on a secure shared digital platform for access by the ILAP partners, as agreed by the applicant. In order to maximise the benefits of collaborative working with multiple UK stakeholders, the current and future sharing of relevant data is highly recommended. The partners will adhere to relevant institutional confidentiality and non-disclosure agreements.
I suspect that Northwest Bio will first take advantage of a more favorable route in the UK, and may have applied for the Innovation Passport, which is the entry point for the Innovative Licensing and Access Pathway (ILAP). Nineteen applications were filed in only the first few months of the year, yet to date, only about a half dozen have been publicly announced. (some may have been denied)
Les has stated privately to a number of investors of their intention to apply for approval first in the UK, and Dave Innes talked enthusiastically about the various new regulatory pathways in the UK, and continues to state that getting DCVax to market is the primary goal. Compared to the FDA, the MHRA (post-Brexit) seems far more eager to bring new and innovative treatments to patients as rapidly as possible, and is also very willing to assist companies through the regulatory process.
RECOMMENDED READING:
MHRA Innovation Office
The MHRA Innovation Office is open to ideas for innovative medicines, medical devices and manufacturing processes. It provides free and confidential expert regulatory information, advice and guidance to organisations of all backgrounds and sizes based nationally or internationally. Call our customer services team on 0203 080 6000.
https://www.gov.uk/government/groups/mhra-innovation-office
Innovative Licensing and Access Pathway
A new pathway supporting innovative approaches to the safe, timely and efficient development of medicines to improve patient access.
https://www.gov.uk/guidance/innovative-licensing-and-access-pathway
The Target Development Profile Toolkit
This toolkit is for Innovation Passport holders following the Innovative Licensing and Access Pathway (ILAP) and provides activities to support the design and development of medicines.
SOME HIGHLIGHTS:
Certifications
Building on the Agency’s scientific advice approach, the Certification tool provides developers with an enhanced official regulatory review of packages of Common Technical Document (CTD) data (including Module 1). The process will provide applicants with specific and actionable feedback on the expectations for marketing authorisation and the regulatory requirements, highlighting potential deficiencies and where there are key issues to address.
This tool is not part of a formal marketing authorisation application but provides expert advice on how ‘regulatory ready’ a particular part of the development is.
How it works
You must confirm in the TDP which aspects of the CTD you are interested in having certified. We would expect this to be within Module 1, Module 3, Module 4 or Module 5, not necessarily a full module.
You can apply to have packages of CTD data assessed by an MHRA multi-disciplinary team including licensing, pharmacovigilance and inspectorate colleagues who will review the submission against marketing authorisation requirements and expectations for regulatory compliance.
Packages of CTD data might include quality, non-clinical or clinical and pharmacovigilance aspects. Early engagement on the acceptability of the submission will provide the developer with the opportunity to make timely changes to their programme in advance of a formal marketing authorisation application.
For biological medicines, such as vaccines, blood products and other immunological biotherapeutics, you will be able to engage early on with the National Institute for Biological Standards and Control (NIBSC) scientists. Interactions will facilitate the rapid establishment of the relevant tests and make sure that, where possible, legally mandated batch testing can be performed in parallel to manufacturer’s in-house testing, ensuring no delays in access to these medicines.
Certification may be considered for the whole of one module or a subsection or across modules if agreed. You can request more than one certification over time for different modules.
Following the submission, the team will assess the modules against the regulatory framework and standards. The outcome of the certification will be a letter summarising the regulatory view of the data, the parts that are satisfactory and the major deficiencies if they exist and opportunities for further scientific advice as needed.
Delivery partners
If you use the Certifications tool you will work with experts from the MHRA divisions and centres.
Related tools
The Certification tool could be used alongside rolling review in the Innovative and Flexible Licensing tool and Adaptive Inspections tool.
Innovative and Flexible Licensing Routes
The tool is intended to provide support and guidance in the choice of routes for products in the ILAP. Some of these routes may be available as options to companies with products outside of ILAP.
The Innovative and Flexible Licensing Routes tool can provide expedited timelines for review, pragmatic approaches to evidence requirements and international options where appropriate and available.
Regulatory licensing flexibilities can be used to expedite the approval process once a product or new indication has sufficient data for regulatory review. Independent laboratory testing can also support authorisations based on reduced data packages through the generation, post-licensure, of data supporting batch-to-batch consistency.
The routes are:
* Accelerated assessment
* Rolling review
* Approval with conditions
* Conditional Marketing Authorisations
* Approval under exceptional circumstances
* Project Orbis
* Access Consortium
Accelerated Assessment
An accelerated assessment procedure will reach opinion on approvability of a marketing authorisation application within 150 days of submission of a valid application. This option is available for good quality marketing authorisation applications for both new and existing active substances.
Eligibility will also include those applications seeking an orphan MA approval in Great Britain and those submitted for conditional and full marketing authorisations as well as those submitted for approval under exceptional circumstances.
Rolling Review
The Rolling Review is a new route for marketing authorisation application intended to enhance development of novel medicines. It does this by offering ongoing regulatory input and feedback. The process is envisaged as a phased, modular, iterative approach to evaluation of marketing authorisation applications.
The quality, non-clinical and clinical parts may be submitted singly or in combinations depending on the individual circumstances as data becomes available. It is expected that each module will be near completion to avoid multiple iterations of assessment of the same module. Each assessment phase will progress independently permitting early identification of issues.
Each assessment cycle with points of clarification raised will offer the applicant the opportunity and time for a comprehensive update of the modules prior to final submission. The final phase will involve submission of a complete application including the remaining module together with updated versions of the modules evaluated previously.
Approval with Conditions
Conditions are obligations that are imposed at the time that the marketing authorisation is granted. Conditions include PASS/ PAES that can be used to provide reassurance that gaps in the evidence generation will be filled appropriately.
Conditional Marketing Authorisation
In order to meet unmet medical needs of patients and in the interest of public health, it may be possible to grant marketing authorisations on the basis of less complete data than is normally required. In such cases, the granting of a marketing authorisation is subject to certain specific obligations to be reviewed annually.
These medicines are for the treatment, the prevention or the medical diagnosis of seriously debilitating diseases or life-threatening diseases, medicinal products to be used in emergency situations, in response to public threats and medicinal products for rare diseases. Conditional marketing authorisation will allow medicines to reach patients with unmet medical needs earlier than might otherwise be the case and will ensure that additional data on a product are generated, submitted, assessed and acted upon.
Approval under exceptional circumstances
For licensing under exceptional circumstances, the applicant must demonstrate that they are unable to provide comprehensive data on the efficacy and safety under normal conditions of use. This may be because:
* the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence or
* in the present state of scientific knowledge, comprehensive information cannot be provided or
* it would be contrary to generally accepted principles of medical ethics to collect such information
Under these circumstances an authorisation may be granted with a reduced clinical data package than would ordinarily be required.
Project Orbis
Project Orbis is an initiative of the Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) that provides a framework for concurrent submission and review of oncology products among international partners including the UK.
Access Consortium
The Access Consortium is a collaborative initiative of medium-sized regulatory authorities between Australia’s Therapeutic Goods Administration (TGA), Health Canada (HC), Singapore’s Health Sciences Authority (HSA), the Swiss Agency for Therapeutic Products (Swissmedic) of Switzerland and MHRA. The purpose of the consortium is to build synergies and share knowledge amongst the regulatory authorities thereby enhancing the efficiency of regulatory systems.
How it works
The TDP will recommend the most suitable routes to market based on the product and patient population to treat in the context of the ongoing development programme.
Regulatory licensing flexibilities can be used to expedite the approval process once a product or new indication has sufficient data for regulatory review. Independent laboratory testing can also support authorisations based on reduced data packages through the generation, post-licensure, of data supporting batch-to-batch consistency.
Early engagement with NIBSC will enable the rapid establishment of the relevant tests to make sure that, where possible, legally mandated batch testing can be performed in parallel to manufacturer’s in-house testing, ensuring no delays in access to these medicines.
Novel methodology and innovative clinical trial design
The Novel Methodology and Innovative Clinical Trial Design tool, co-developed by MHRA, NICE and SMC, is designed to establish a system and culture that is receptive and supportive of novel methodologies in both the clinical and pre-clinical space to develop new medicines or new indications. This includes innovative clinical trial designs, manufacturing, and endpoint development. We will also demonstrate that innovative methodologies are acceptable to all stakeholders, for example by issuing an opinion on the proposed methodology or technology.
The tool has the potential to significantly accelerate development and bring safe, effective medicines to patients faster, balancing the risks and benefits of any novel approaches, with a strong patient focus.
Novel trial designs with virtual and decentralised elements will increase patient-centricity in trials and reduce the burden of taking part, improving recruitment and retention. Qualification and multi-stakeholder regulatory acceptance of novel methodologies will de-risk and reduce the costs of development. The tool will encourage and facilitate the proactive use of novel trial designs for evidence generation – including master protocols – to ensure a flexible regulatory approach that can react to emerging data with a focussed, efficient use of resources.
How it works
According to the individual requirements of the applicant, key outputs from the tool include:
* securing multi-stakeholder agreement for novel and innovative approaches to evidence generation
* qualification of the new methodologies and support via (joint) scientific advice procedures (e.g. with NICE) offered during the ILAP, including targeted inspections of novel technologies
* guideline documents on topics of interest
* encouragement and facilitation of the use of novel trial designs, including master protocols, to ensure a flexible regulatory approach that can react to emerging data with a focussed use of resources
* regulatory assurance on the requirements and acceptability of virtual, AI and decentralised elements in trial conduct
* regulatory assurance on new e-systems technologies that may be used to support any such novel trial designs
You should expect regulatory assurance on the requirements and acceptability of, for example, use of Artificial Intelligence (AI), virtual and decentralised elements in trial conduct, and e-systems technologies used to support such novel trial designs. Developers will also see use of new approaches for qualification of new methodologies, technologies, use of modelling and simulation, and novel endpoints.
https://www.gov.uk/guidance/the-target-development-profile-toolkit
Amgen’s timeline for Sotorasib using RTOR and Project Orbis: (which seems typical of BP's)
October 5, 2020 - Amgen announces positive topline phase 2 results for investigational KRAS G12C inhibitor sotorasib in advanced non-small cell lung cancer.
https://www.prnewswire.com/news-releases/amgen-announces-positive-topline-phase-2-results-for-investigational-kras-g12c-inhibitor-sotorasib-in-advanced-non-small-cell-lung-cancer-301145947.html
December 16, 2020 - Amgen Submits Sotorasib New Drug Application To U.S. FDA for its use in patients with KRAS G12C–mutant locally advanced or metastatic NSCLC
https://www.amgen.com/newsroom/press-releases/2020/12/amgen-submits-sotorasib-new-drug-application-to-u-s--fda-for-advanced-or-metastatic-non-small-cell-lung-cancer-with-kras-g12c-mutation (Reviewed under RTOR Pilot Program)
December 24, 2020 - Amgen submit sotorasib marketing authorization application to the European Medicines Agency.
http://pharmabiz.com/NewsDetails.aspx?aid=134343&sid=2
May 28, 2021 - FDA Approves sotorasib the First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy
https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug
June 24, 2021 - Abstract published in NEJM
https://www.nejm.org/doi/full/10.1056/NEJMoa2103695
September 13, 2021 - UK’s MHRA approves Amgen’s sotorasib for non-small cell lung cancer (MHRA’s 2nd approval using Project Orbis)
https://www.pharmaceutical-business-review.com/news/uks-mhra-sotorasib-lung-cancer/
Still waiting for approval by EMA????
Well, precise isn’t a word that I would use to describe Linda speak. But I agree that she definitely covered her bases there by throwing in “hope” and “around” which does allow a stretch into October.
Actually, Linda DID say “by around the end of the third quarter this year” at the ASM according to the transcript provided by IkeEsq:
5. Sawston
"The next category of subject matter that was asked about was the Sawston, UK facility. I think probably a number of the questions came before our announcement, our press release last week which was on this subject. And I hope everybody had a chance to see our press release last week. Because it was announcing that a quite important milestone was reached. The milestone was the completion and the submission to the UK regulatory authority, the FDA of the UK, of the whole application package for the initial licensing of the Sawston facility. I think everyone knows, but just to provide the background, all facilities that produce medical products for human patients are required to be licensed by the regulator in that country. Every facility has to go through this. And the application that was submitted and that we announced last week as we said in the announcement, was the culmination of more than two years of work by a large team and a whole lot of expert consultants. So that was a quite important step, a quite important milestone. Looking ahead, looking forward, we are hopeful that the process, the next steps are for the regulatory authority to make an on-site inspection, in person of the facility. There’s some lead-time for scheduling that, there’s some time involved in the regulatory authority writing up the results after the inspection and if there is anything to address then having that be addressed. So we are hopeful that that process those steps will proceed quickly over the coming months. And we hope to have the initial license for the Sawston facility by around the end of the third quarter this year. Something in that time frame. Once we have the initial license, then we expect to begin producing vaccine products for our existing programs as we’ve been doing at the small facility in London that we’ve been using up ‘til now. So that’s the update on the Sawston facility and the discussion related to the questions we got on that."
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