Replies to post #23993 on NorthWest Biotherapeutics Inc (NWBO)

[Dan_P]

Thank you for this very helpful information. Excellent

[Chiugray]

Flipper, An echoing "wow" compliment comes from me to you. Thanks for breaking down and summarizing the complexities of 4 different immunotherapy technologies that I could never have done on my own. Also your analysis of the competitive advantages and potential synergies or not of each relative to NWBO was nice.

[sentiment_stocks]

This now has it's own spot in the intro board.

Now all I need to do is print it out and read it - looking forward to it!

If you update this or want to replace them with newer versions, just let me know.

[inveterate]

Thanks so much for the time that you have put into this précis. It certainly helps me to understand more clearly the advantages of each different vaccine. Much appreciated!

[beachlifeisfun]

Flipper,

That is a very informative post. I truly appreciate all of your (and Steven's) DD that you willingly share with this board. IMHO most Big Pharma companies have stayed away from NWBO because of what happened to DNDN...the tech definitely works, but it still seems somewhat gold-plated with very little profit margin.

I would debunk this by the obvious amount of $$ that NWBO has invested in the manufacturing process...but more importantly I would suggest that Direct will likely be much less expensive than DCVax-L. Both have already been shown to be outright efficacious, but I think that Direct's profit margin will be considerably higher as it should be much less expensive to make (tumor preservation, transport, storage, lysate preparation, etc all goes away)...AND it should also be more potent because *debated hotly here* each injected tumor represents a new vaccine, thus minimizing the tumor's ability to "hide" from the active immune system.

Additionally, while not explicitly identified, the lysate process for -L is pretty brutal...it most assuredly destroys all of the tertiary and quaternary structure of the antigen(s), and likely some of the more fragile primary and secondary structure as well...Direct will allow phagocytosis in situ, meaning much of these structures will be preserved...again likely making Direct a more potent treatment.

Ultimately Big Pharma have been chasing the profit margin, which is why they overlooked the DC-lysate tech, but NWBO seem to be on a mission to do some serious damage to the disease itself (here, here, it's about time) despite the lower profit margin...and in doing so learned the trick, through Direct, to making the therapy very profitable while still effectively treating/curing a good chunk of cancer types.

[Rkmatters]

Thanks Flip. As you know, a keeper. :)

[Ready4bluesky]

Good info. Thanks!

[longusa]

Flip, good stuff. The other consideration for all the treatments is manufacturing and the impact on TTM (time to market). CLDX I believe has their own manufacturing, so if Rindo gets AA for EGFR rGBM, CLDX could see a quick TTM.

IMUC on the other hand, does not have its own manufacturing, and does not have a long term deal with a contract manufacturer, such as NW has w/ Cognate. So the IMUC has yet another hurdle for ICT-107 TTM.

[sentiment_stocks]

Had a chance to read through this last night - it was very helpful and very informative. I thought it was very easy to read and very organized. It also made me feel significantly better about how Rindopepimut and DCVax-L might fit into the future of GBM SOC. I don't see Celldex as a threat anymore, but possibly a compliment to the overall SOC picture.

I also found this section particularly interesting:

due to the fact that soley EGFRVIII targeted tumors ultimately escape Rindopepimut therapy once this mutation is eliminated (as cited above)

I also appreciated the explanation of the EGFRIII variant as I frankly hadn't known what it was.

EGFRvIII has not been detected at a significant level in normal tissues, but it has been identified in glioblastoma; therefore, targeting this tumor-specific molecule is not likely to impact healthy tissues. EGFRvIII can turn normal cells into malignant cells by way of its oncogenic properties, providing a constant growth signal to tumor cells which express it. Consequently, cells producing EGFRvIII have an enhanced capacity for unregulated growth and are associated with more aggressive disease and worse prognosis."

On that note, it would be helpful to understand better what the HLA-A2 positive unmethylated MGMT patients exactly means. I know it's mentioned quite a bit; a bit more explanation of that would only enhance this really useful work you've done here.

Thanks so much for assembling this great DD for us - and for making it comprehensible at the same time.

[flipper44]

As some background to the GBM trial announcement by Merck with Agenus today, here is something I wrote back in November 2014, IMHO.

C. Prophage Series G-100

i. Potential Niche for Prophage series G-100

Agenus own the rights to Prophage series G-100. Prophage is a protein peptide complex consisting of a 96 kDa heat shock protein (Hsp), gp96, and an array of gp96-associated cellular peptides. The response to Prophage seems to be more pronounced in those patients with less expression of the checkpoint ligand PDL-1 on the white blood cells, suggesting that combinations of Prophage with checkpoint modulators like PD-antagonists might make Prophage even more effective in a greater percentage of patients with GBM.
PDL-1 is expressed in approximately 25% of the GBM patient population.

Conclusion:
Theoretically, Prophage vaccines can target all cancers, however, no approved products are on the near horizon. Prophage is also currently being studied against melanoma in a phase I trial. Consequently Prophage's only niche appears to target GBM perhaps with some focus on tumors not expressing PD-L1.

ii. Potential Competition.

Unlike the previous two therapies discussed, prophage is not designed to target any preset tumor antigen(s). Instead, the proprietary process selects specific antigens in a patient’s specific tumor(s) increase expression when cells are exposed to elevated temperatures or other stresses.

This process ultimately uses more antigens than Rindpopepimut and ICT-107, and is personalized to the particular patient’s tumor(s); however, unlike DCVAX, Prophage does not potentially use all the antigens from the tumor, and the personalized selection/activation process is not accomplished by the dendritic cell, instead the antigens are selected by through a man made proprietary process.

The results in the July phase II open label trial demonstrated 9 month overall survival advantage over historical controls, and PFS surpassed historical comparisons by 10 months. (Notice, again, as we move up the chain from 1, 6 and now many tumor antigens the overall results and durability improve). Pragmatically, it is hard to imagine that Prophage will perform at this level in a phase III controlled trial. Moreover, DCVax-L (which utilizes all the tumor antigens) Phase 2 trials results demonstrated 21 months OS advantage against the same historical control in their phase II trial, and PFS surpassed the above historical comparison by 17 months. (Notice DC-Vax uses all the antigens and returns selection control and expression to the dendritic cell

A phase III GBM trial has not been initiated Prophage.

While this therapy actually offers a more straight forward head to head comparison, it appears DCVax-L is superior.

iii. Potential Collaboration

IMHO, the two antigen targeting selection processes are incompatible. -- 11/2014