NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

This post is about biomarkers in GBM - and I think some of you may find it interesting.
Bear with me here.


I was looking up “DCVax-L” on my phone this morning…

(so it was a mobile search)

and when I used the “search tools” option,

(if you don't know how to do this, and you have an i-phone, slide the menu bar to the left - menu bar starts with “All” - and you’ll see “search tools to the far right)

an FDA google adwords ad came up for the FDA’s

“Biomarker Qualification - FDA CDER Program.”

So what does this mean?
It means is that the FDA is paying to use “dcvax-l” as a keyword in a google adwords campaign for this program.

First… see my phone screen shot below which shows exactly what it looked like on my phone.



Now some of you may know exactly what I mean by this. For those who don’t, it means that for some reason, the FDA is paying for the key word or phrase to bring their ad up when someone searches for DCVax-L.

It doesn’t come up for me, however, UNLESS I put in the “past 24 hours” provision - AND it’s on a mobile device. When someone plans a google adwords campaign, one can also indicate whether they want to pay for mobile or desktop searches as well - it's possible this campaign is concentrating on those using mobile devices.

Now for those who don’t understand what I’m writing, I’ve provided another screen shot below that shows what this might cost the FDA when someone clicks on their ad. Mind you, the cost only kicks in if someone clicks on the ad. There is not a link to this as I used a google adwords account of mine to determine what someone would pay for the keyword "dcvax-l".



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

Some of you may have done searches before for “dcvax-l” and seen google adword ads come up for Keytruda, or Opdivo, or Dana Farber, or any number of other treatments or facilities. That is because these facilities want to direct you to them when you are looking up dcvcx.

So the question is…

Why is the FDA paying $10 to direct - let’s assume “patients” and not investors - to their new “Biomarker Qualification Program” by using the dcvax-l keyword?

The first question that comes to my mind is does it have anything to do with the “mesenchymal” subtype?

Most long investors here know that from various sources such as Linda Liau and Dr. Prins that mesenchymal GBM patients do particularly well on DCVax-L. Additionally, this subtype is a particularly large subtype - ranging from 30% to 50% of all GBM patients.

Now the FDA offers a lot of interesting sources to review when looking at this Biomarker Qualification Program.

Below is a link to a page of quick videos that the FDA has assembled to explain the program, what biomarkers are, and what their role is in the treatment of conditions. You’ll find there are additionally many more on youtube.

https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm558083.htm

So some may want to watch a few or all of these FDA videos on biomarkers if you want to learn more about them and their role in the drug development whole process.

One of the Biomarker Qualification Program videos from the FDA was narrated by Dr. Chris Leptak in which he discusses several sources of biomarker information that can impact drug development and potentially facilitate a drug approval.

Pleasehttps://www.youtube.com/watch?v=j3Xwb6Fk7Lw" rel="nofollow" target="_blank" >click here for his video, and https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm543159.htm" rel="nofollow" target="_blank" >click here for the transcript if you’d like to read along.

In this video, Dr. Leptak speaks about using the drug approval process as part of the development of a specific drug or biologic, and he makes note that establishing EGFR status as biomarker for lung cancer is an example.

He says,

The specific drug approval process involves the use of a biomarker as part of the development of a specific investigational new drug or a biologic. Regulatory acceptance of biomarkers through this development process is intended for biomarkers that will be used for a specific candidate drug.

The information for a given drug program can be used by other drug companies if the biomarker ultimately proves to have more generalized applicability. An example of a biomarker accepted through this pathway is the EGFR status, which is a predictive biomarker for EGFR-targeted therapy in lung cancer.

The FDA also provided a fictionalized FDA Case Study to help readers understand what the process of Biomarker Qualification entails.

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

On page 4 under “Two Pathways for Biomarker Integration in Drug Development through CDER, FDA”, I thought this paragraph very interesting as I thought it read like what might be happening with NWBO and their trials (perhaps Direct as well).

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.

So this process…

- requires confidential discussions with the FDA

- involves no input from the larger scientific community

- means biomarkers can be accepted through the drug approval process

- places the burden to develop the biomarker on the single pharmaceutical company

In the end, I wonder if NWBO has been working directly with the FDA
on establishing
or further establishing
or somehow establishing
a biomarker, or biomarkers for mesenchymal status in a clinical trial (like the phase 3 trial), as well establishing biomarkers for other GBM subtypes. This would, as one can read in the above linked case study, have to be kept secret, and be quite a cumbersome and long-term project.

So after stumbling across this google adwords ad where the FDA is literally using dcvax-l as a key word for an ad campaign they are doing for this biomarker program, I again do wonder for what reason is the FDA doing this? As I've indicated, if someone clicks on the ad, the FDA is charged for that click by google.

NWBO’s own website states that the "DCVax technology targets the full set of biomarkers on a patient’s tumor." And Longfellow recently reminded us that it can be predicted with reasonable accuracy whether a patient carries the biomarkers for the mesenchymal subtype. It seems like a fairly easy process - they use the volume of contrast enhancement, volume of central necrosis, combined volume of contrast enhancement and central necrosis, and I guess the ratio of T2/FLAIR to contrast enhancement and necrosis is shown to be significantly lower when comparing the MES to the non-MES GBM phenotypes.

https://www.ncbi.nlm.nih.gov/pubmed/23444259

And I’d like to further remind longs, which Dr. Prins has also stated in a March 2016 presentation, and Dr. Liau stated in her now removed December 2016 video (and found in the above linked abstract) that in GBM,

the mesenchymal (MES) GBM subtype, (which) has the worst patient prognosis.

So if the subgroup of mesenchymal does as well as some longs suspect it will with DCVax-L, just think what that would do to the median OS of 14.6 that has been the long standing median GBM patients have had to face. With 30% or more GBM patients being the subtype of mesenchymal, and they have the worst prognosis, you’d know that subtype has been dragging that median OS down to its current 14.6 mOS.

If suddenly there is a treatment by which a large number of the patients who typically die first are suddenly living the longest, think of what that would do to the current SOC median OS.
Why it would raise it up.
The median OS could suddenly catapult significantly higher - maybe in the mid to high 20s, or possibly even more.

There is no way the good people at the FDA would, or could, ignore that.

So back to biomarkers… according to this 2013 study below, EGFR, MGMT, DNA Methylation and several other biomarkers were considered “emerging” as established biomarkers for GBM. However, mesenchymal, proneural, classical and neural were considered more to be sub-types as opposed to biomarkers. So I’m wondering if perhaps NWBO is working closely with the FDA to establish additional biomarkers for these subgroups, and then by doing so, subsequently demonstrating how DCVax-L can work with these various subgroups. And in doing so, perhaps living longer when one or more of these biomarkers are present can become a sort of surrogate endpoint for DCVax-L?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795381/

I would appreciate if others on the board with a scientific background (which I do not have) can offer up some of their own clarity or opinions on on this.