Replies to post #132987 on NorthWest Biotherapeutics Inc (NWBO)

[Hiawatha16]

Senti,

Great post, great DD. Thanks for this info and insight. I'm going to do some digging now.

[Extremist223]

Excellent job Sentiment. I would never have found this because I use adblock plus plugin, in all my browsers including my phone. As of typing this, I am unable to replicate your results even without the plugin and using search tools past 24hrs on both laptop and android. Mozilla firefox and internet explorer respectively.

Nonetheless, this is an awesome, awesome find. I'll be looking into the rest of the links now.

Go NWBO! :)

[Sub Atomic master]

Cool senti, thx

[hankmanhub]

Very interesting post Senti. I do not have enough knowledge to comment on the main substance, but I do do have one minor nitpick. Are you sure that the cost to the dna is $10 per click - sounds rather high! Perhaps the cost is $10 per 100 or 1000 clicks or some such?

[flipper44]

Great detective work. Seriously, this is fantastic....and in one day no less. One point, mesenchymal is thought to make up 49% of GBM, so what you found was probably a percentage for overall brain gliomas.

Dr. Liau and Dr. Prins have been the champions of the mesenchymal connection with DCVax-L since at least 2011.

Many on the board havel emphasized it at times, but it seems you found a possible missing link here.

This looks to be right on the money:

During the drug development
process, a pharmaceutical
company may engage directly with
the FDA to reach agreement on
the value of a particular biomarker
in a given drug’s development
program and the biomarker can
be accepted through the drug
approval process (in an IND/
NDA/BLA submission). While this
pathway may be efficient for drug
developers, it has limitations. The
CONFIDENTIAL discussions between
the FDA and the drug developer do
not allow for input from the larger
scientific community, because the
information about the biomarker
may not be publicly available. This
process also puts the entire burden
of developing a biomarker on a
single pharmaceutical company

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/UCM552881.pdf

Wow. This is far more relevant now that Keytruda just was approved for a biomarker found (albeit in low percentages) across all cancer types. That's the first time that's ever happened in cancer treatment....ever.

TAKING THIS BACK TO SARCOMA FOR DIRECT, it is a mesenchymal cancer, and you'll recall that DCVax-Direct outperformed survival expectation in seven of eight patients in the DCVax-Direct trial.

MOVING RIGHT ALONG TO COLORECTAL CANCER:

Nature Medicine 21, 1350–1356 (2015) doi:10.1038/nm.3967
Received 06 March 2015 Accepted 06 September 2015 Published online 12 October 2015

Abstract

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression–based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor–ß activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC—with clear biological interpretability—and the basis for future clinical stratification and subtype-based targeted interventions.

In short, mesenchymal and the other subclasses in colorectal cancer are highly mutated, and Dr. Prins has pointed out these are perfect targets for DCVax.

It used to be oncologists bemoaned their ability to treat smokers and sunbathers, but they so highly mutate their cells that their cancer cells are like a giant blinking neon sign to DCVax's therapeutic method of action.

Merck needs to find something less toxic but more targeted than simply using CIs. So does BMY.

MOVING ON TO RECURRENT GBM: As has been pointed out on the board from time to time, GBM tends to trend more mesenchymal over time, so of course bringing this back to DCVax-L, one might think, ah ha, that means there is crossover confoundment in the phase III nGBM trial where there is recurrent mesenchymal. This may be true to a degree, but it is likely washed out considerably by the fact that recurrent is often inoperable, the treatment is delayed in the DCVax-L trial until after long term chemotherapy may have reduced lymphocyte count to an insufficient level. Moreover, some mesenchymal did not cross-over.

That is likely why NWBO went back to high resection and lymphocyte standards in the recurrent trial similar to the DCVax-L phase III newly diagnosed. Moreover, the recurrent trial monotherapy with DCVax-L seems to exclude chemotherapy use. This may have been determined during the phase III trial, because it may have become obvious long term chemotherapy use provided diminishing returns, whereas shortened chemotherapy may have allowed DCVax-L to utilize its method of action even in recurrent patients. I'm convinced they saw a very clear signal there. IMHO

FINALLY, ALL THE OTHER CANCERS DIRECT MAY TREAT. Dr. Bosch stated they did not have to start a new IND, they basically just start a new trial for each indication, which might mean they are targeting cancers with a very important biomarker across perhaps all cancer indications (a certain percentage in each). Like Merck did with I think microsattelite instability.

Does any of this reflect upon the Phase III trial? Well, perhaps there will be some crossover confoundment for OS, but likewise, there may be some reinitiating DCVax-L after recurrence in the original treatment group, and for the other reasons I raised above, confoundment might not rise to a significant level.

[biosectinvestor]

Great post Sentiment! Very interesting. I've published and used Google Adwords extensively as well. What you've posited makes perfect sense.

I'd imagine that they have certain policies they want to promote and get attention for and adwords is the cheapest, most direct and easiest route to do that PR work. It suggests to me, something must be happening in the background, clearly to promote the biomarkers program and somehow DCVax-L has been targeted as a keyword to get that attention. Inductively, one might consider that this could mean that news is ahead. We can't know, but certainly tempting to consider, given what you've discovered.

[tencoin]

Sent, excuse me, maybe you missed reading the phrase indicated before the circle highlighted in red ... It is not $ 10 for every click ...

Average monthly searches: 100 - 1 k = $ 10


The problem is to understand why the FDA pays!

You can see that for every click, the FDA would pay about $10

[doingmybest]

Thx for this work. I am not the scientist input you are seeking, but:

- if you start with the groupings looking something like neural = 10%; proneural = 20%; classical = 35%; mesenchymal = 35%,

and then assume the order of effectivity strength of SOC is approx. mesenchymal at the bottom followed by classical by neural by proneural at the top,

and then assume 25% of the 35% of the mesenchymal pts flip from the bottom to the top priority, there is the potential of a nice change in the medians of both PFS and OS if you can move the median out of the SOC treatment bottom dwelling sets of mesenchymal and then classical and progress into the neural sub-type when determining DCVax-L therapy medians. This is why FDA wants to see a biomarker to understand who is responding and who is benefitting.

I think the complicating factor in understanding sub-type correlations in GBM is the heterogeneity of the tumors, which seems to show that there are combinations of phenotype sub-types in each tumor, which then means the accuracy of any test needs extensive work to validate and rules of composition to make clear determinations have to be developed,... there is more but I will hold up, such as speed and cause of mutation and whether certain sub-types are dominant in behavior,... I wonder about the accuracy of the early tests on pt tumors and how dependable those determinations were as knowledge grew about the heterogeneity of GBM tumors. It does not appear to be so black and white until more work is done to track tumor composition and the changes to that composition over time and over time in relation to therapy, which can change the course of the mutation. I don't think the more accurate single point in time tumor composition tests that are discussed now were always in existence nor in general use. Maybe UCLA was involved in the test development but I don't put too much weight on the accuracy of the body of knowledge of GBM tumor compositions to date, but, rather it is directionally usable. I would like to see more data on the complete composition of some tumors. That would take the saving of complete resected tumor tissue and testing of all the tissue as much as possible throughout the entire tumor, not just using small tissue samples. This is a great example of why work such as this can take decades and not just years. Complications of tissue sample availability, test method development, new learnings about the test capabilities given the samples are live tissue,... All this just to understand what one is trying to solve, then on to designing, developing and proving the solution. It is easy to see why all the steps have to be conducted concurrently. And, easy to see clinical trials are not as easy as performing tests on pts and collecting results.

I agree with you this is an area of collaboration with FDA by NWBO and a necessary area of work particularly if an immune response is seen in a limited number of pts. If a good to a very good response is seen in these pts the work is absolutely worthwhile to try to ring fence the correct pt population. If there are little safety concerns involved the ring fence can be somewhat broader than if there were safety concerns. Generally speaking if a treatment does not help everyone or at least elicit a positive response in most pts the FDA will want to know who it helps so all pts are not subject to it with a good percentage having little chance of being helped. This is considered more heavily when a treatment is additive to SOC and not an alternative treatment. But, keep in mind DCVax-L has virtually no negative QOL effects, another reason why I think FDA would tend to be very careful about restricting the treatment too tightly. And, there may be other longer term benefits from early treatment with DCVax-L, TBD shortly.

So, given the relative inaccuracy that would be possible and necessary for such testing for a DCVax-L pt population and the potentially significant benefit that could result for the pts a relatively accurate testing would probably suffice. And, the testing may not restrict the application of the therapy to a subset of pts but rather serve to continually grow the field of knowledge of tumor composition and their respective response to the therapy. The use of a biomarker as of a point in time may suffice for treatment applicability decisions, assuming it accurately reflects at least the general or majority tumor composition. When one pauses to consider the depth and breadth of what is needed to present to FDA in a BLA, it is quite remarkable such a small company can undertake the work. This is more the concern I have than the effectivity of the treatment. FDA will want a deep understanding of the treatment's MOA and other effects in addition to its effectivity vs GBM tumors. It can lead to significant gains in knowledge for treatment evolution. Once a treatment has been approved the use of it to learn is geometric given the chance to collect so much more data. BP's are so much better equipped to perform all development work and to capitalize post approval. Folks who think a company such as NWBO can do it alone are just not privy to what occurs behind the industry. Since DCVax-L has demonstrated little safety and QOL effects to worry about I am hopeful the benefits demonstrated will carry the day until NWBO partners with a BP soon.

[Astavakra]

Incredible work, Senti! Part serendipity and part tenacity. One part I want to ask for clarification on, though. When you mention 'the past 24 hours' as a search criteria, are you saying that this adwords buy of DCVax by FDA became active in the past 24 hours?
TIA