NorthWest Biotherapeutics Inc (NWBO)

[hyperopia]

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

I wrote a post a few month ago here and speculated that Advent was translating the three major manual manufacturing processes into automated processes. Some of this speculation turned out to be true, and some was wrong, so this is an update now that I’ve had a chance to watch the presentation for a second time, and know a little more.

I thought that the first manufacturing step, isolation/enrichment of PBMC’s from the leukapheresis material, would be closed and automated using Northwest Bio’s patented Tangential Flow Filtration system. However, the ASCO presentation made clear that this first step will not use TFF, but instead will use a commercially available cell processing system. Although the brand name was blurred, I’m almost certain that it’s this Gibco CTS Rotea cell processing system here.Tangential flow filtration is actually an old technology, and this CTS Rotea system is superior. It performs more functions such as cell separation, concentration, washing, buffer exchange, and cryopreservation. It’s GMP compliant, has programmable software/firmware (compatible with Autolomous’ Manufacturing Execution System software), it’s highly efficient, and more gentle on the cells. It’s been proven by the Car-T manufacturers that the better the starting material, the better the end product. This system may be why Dr. Bosch was able to brag about achieving 98% purity (meaning 98% dendritic cells, and only 2% other white blood cells), which is a very impressive accomplishment, and way above what commercial regulations require.

It was confirmed that the last major step of the manufacturing process, fill & finish (filling each dose into individual vials) will be automated, but not by the Finia system that I thought. The system Advent is actually using is this Aseptic Technologies, Crystal M1 automated filling system here. This system is actually manually operated so it’s only semi-automated, and it’s not in an isolation cabinet, so it requires a higher grade clean room and is installed in a Biosafety Cabinet. This system will be fine for smaller volumes during the initial ramp up, but it can be easily upgraded to an isolated and fully automated system when volumes increase.

I speculated that the original version of the Flaskworks Eden system (which was intended for clinical use) had been further developed for commercialization in the time period since the acquisition, and this also was proven to be true. Some may have noticed that slide 25 displayed a picture of the latest version of the Eden system which had significantly more wires and tubes than the original version. I believe they are in-process sensors/bio analyzers that monitor and maintain optimal culturing conditions. They are critical to accurately measure and maintain tight control of the culture process parameters and allow early detection of any deviation, and minimize user interference. Although it’s unclear what this system’s capabilities are, other systems can provide real-time, in-process QC data on cell count, cell viability, cell size, acidity, dissolved oxygen, temperature, and levels of metabolites and nutrients, and generate important data and documentation for the electronic batch record for each patient. The FDA has stressed the importance of Quality by Design (QbD) approach to process development and validation, and in-process controls are now an integral part of commercial GMP regulations.

It was very reassuring for me to see Northwest Bio’s assay development work, particularly the “next generation potency assay” developed by Shashi Murthy et al. at Flaskworks/NW Bio. Approved biological products are required to be accompanied by analytical tests to demonstrate safety, purity, and potency. Product testing strategies are at the heart of product specifications, process development, and provide part of the evidence required to ensure a consistent quality product, and demonstrate comparability for any proposed process changes. Potency and mode of action assays are often the most complex, but are the most critical. As I stated in another post, in 2020 alone, the FDA issued Complete Response Letters to over a half a dozen gene and cell therapy companies, denying their marketing applications due to manufacturing issues, frequently siting inadequate potency assay development.

To me, this presentation confirmed what I suspected month ago. That a relatively simple comparability protocol to approve the Flaskworks system for investigational use as an interim step wasn’t the plan. The development work that has been done on the critical assays and on the Flaskworks system, as well as the digitization and automation of the manual manufacturing processes, indicates that the plan was actually to prepare for commercialization all along. The good news is that it now appears that most of the development work and process validation studies have been accomplished, and Advent is well prepared to conduct the comparability study.

A quick note:
Shashi Murthy confirmed that Saint Gobain is the new supplier of the single-use plastic disposables.

Okay now for some speculation . . . . according to this part of the Q1 10-Q:

Subsequent Events

In total, the Company received $8.3 million from exercises of warrants and issuance of common stock between April 1, 2022 and May 6, 2022.

During April 2022, 7.7 million shares of common stock were issued upon warrant exercises for proceeds of approximately $2.0 million.

During April and May 2022, the Company received $6.3 million from issuance of 8.5 million shares of common stock to various investors. Approximately 1.7 million shares of common stock are pending to be issued.

During April 2022, the Company entered into a Statement of Work #6 (“SOW 6”) with Advent that will be incorporated into the Ancillary Services Agreement that was originally entered into dated November 8, 2019 and was extended on July 8, 2021. SOW 6 is for baseline costs and conditional milestone costs related to product and clinical trial matters during the period April 1, 2022 through the end of September 2022. The parties anticipate entering into a separate agreement, as an extension of SOW 5, for work by Advent related to the Sawston facility during Q2 and Q3 of this year, but this work is still in the process of being determined. The total costs under the SOW 6 include estimated baseline costs in the range of $3.2 million to $3.9 million and milestone costs ranging between $1.5 and $8.0 million in cash and 1.5 to 12.5 million in shares, depending upon what milestones are achieved.

it appears the company received $8.3M in April and May that may be used to conduct the comparability study, (probably in the development labs) and potentially to begin construction on the next phase of the Sawston buildout, which may occur over the next couple of quarters. This may be a fairly large area (similar to the size of the first phase or perhaps a little larger) that would be a lower level controlled environment, (C-class) and this space will be used for the first two major steps (separating the monocytes from leukapheresis material, and Flaskworks culturing) of the closed automated manufacturing process, while the fill & finish step may be conducted in one of the finished high grade clean rooms. I don’t think this initial scale up will be for the 1000 per month capability suggested in the presentation though, but rather it may be for a smaller number, perhaps 100-200 per month. The funding for the equipment required for this initial commercial scale up may be raised later this summer. If all the foregoing goes well and doesn’t meet with any delays, I think Sawston could potentially achieve commercial readiness in the 4th quarter this year.