NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Reefrad said:

In any case, here is my question. We know that the Germans are supposed to contribute 80 patients to the PIII. It seems like their decision to offer the Tx and reimburse for it basically sabotages the recruitment of these patients. In fact it would be unethical to enroll a patient in to the trial and give them placebo while the country has already agreed to fund the drug.

I also find it hard to believe that the PEI would announce this without understanding the ramifications on the future of the trial in Germany.

How do we reconcile this? -- Reefrad

Maybe it would be good to attempt to place the German exemption in its proper historical narrative.

Prior to this decision, in the fall of last year, we had Germany announcing that they were ready to proceed with the phase three trial. Since then, we were made aware by excellent expert analysis, that the German hospital exemption, when it came to pass, would cause a sharp upturn in the stock price. This is a milestone the company was very much looking forward to, and upon its passage, NWBO was certainly pleased that it occurred.

So why would Germany, NWBO and expert analysts desire something that would jeopardize the trial?

Answer: They would not sabotage their own trial for German hospital exemption.

Then what is happening here?

Again, historical context might help. As many here pointed out, including you Reefrad, Germany has been working toward this Hospital exemption "for a long time." This also means, from everything we know, NWBO fully supported and sought this German hospital exemption.

The approval of the Hospital Exemption for DCVax-L is the culmination of nearly two years of regulatory processes and scrutiny, starting with a Scientific Advice process during 2012, and followed by an application for Hospital Exemption in December, 2012. The evaluation of NW Bio’s application by the German regulatory authorities included comprehensive and detailed scrutiny of all aspects of the DCVax-L technology, all DCVax-L clinical data to date, all manufacturing processes, all product characteristics (including potency, composition, sterility and other aspects), all frozen storage of DCVax-L and frozen shelf life, and all distribution and handling of the DCVax-L products.

Although Section 4b of the German Drug law for Hospital Exemptions was implemented in July 2011, the approval for DCVax-L is the first such approval granted by the German regulatory authorities in multiple key ways. Only two prior approvals have been given in the more than 2-1/2 years since the law was put in place, and those were for two German companies with tissue engineered products which had already been on the market commercially under prior laws and were grandfathered for regulatory purposes, and which did not have pharmacological (i.e., drug-like) effects in the patient’s body.

In contrast, DCVax-L is the first product of its kind to receive Hospital Exemption approval from the German regulators, in the following key ways:

the first immunotherapy;
the first product which exerts pharmacological (i.e., drug-like) effects in the patient’s body;
the first product that has never previously been on the market commercially;
the first product developed by a non-German company, not previously under the German regulators’ oversight; and
the first “somatic” cell therapy product (a somatic cell is any cell of the body other than a reproductive or embryonic cell). -- NWBIO Press release

Clearly, this German Hospital Exemption for a foreign company is extremely important. So why did Germany wait to announce it, and why did analysts believe about a month ago that the announcement would come when it did?

Certainly Germany long held all the other information it needed to make this decision back on December 09, 2013; or did it?

So finally, somehow, the PEI now apparently has the information they needed to allow this monumental exemption sought out by NWBO and Germany.

Germany already stated back in the fall that it was not going to contribute pseudo-progression patients into the phase three trial. Let me flatly state that unless the PEI brain trust flatlined, they already knew from years of data that it would be cruel to give a pseudo progression patient a placebo pill, because pseudo progression patients clearly benefit from DCVAX-L, and moreover, that certainty of benefit is recognized earlier than all other potential responders because of the unique radiological signature after chemoradiation. Well, the PEI brain trust did not flat line. (Interestingly, perhaps to preserve the trial, this was not the reason Germany gave for excluding German contribution of pseudo progression enrollees.)

Let's return to the NWBO trial. What remains outstanding (aka: pending) from the first interim analysis? That's correct, the efficacy analysis. By now all of you know my speculation regarding the reason this remains outstanding is because the pseudo progression group has not reached their minimal event number. If I had been a NWBO researcher, FDA or PEI professional, I certainly would have anticipated this waiting period would come. Why? Simply because chemoradiation (and DCVAX-L) work so predictably well on this subgroup, and the subgroup, once identified, is akin to an atomic clock.

So let's review.

The German hospital exemption was anticipated and held off until three months after the 66th event.
The 1st interim efficacy decision is not in yet, and for the sake of argument, accept that my reason for that is correct.

What things did Germany and NWBO believe would likely have a chance to materialize during this waiting period before the DMC decision comes down?

1. Price negotiations.
2. Glimpses of the DCVAX-Direct trial.


Ah yes….the DCVAX direct trial.

Remember, Germany has seen all clinical trial data to date??? Well as everyone, including myself, was speculating about whether the Germans saw DCVAX-L phase three data, and what that would mean for the blinding effect in the trial, most or dare I say all of us forgot just how damn important the open label DCVAX-Direct trial data might be to the Germans.

I'm certain there are some here who will doubt Germany would get this information, but we have painstakingly looked at the regulations that might allow this information sharing for an ongoing blinded trial; therefore, while I accept there may be lingering doubt for some whether this occurred, I do not believe there should be any reasonable doubt the Germans know what is going on in the DCVAX-Direct trial.

If you have been following this company for a long time, or at least studied the history of the company with extreme due diligence, you should know what a disrupting technology DCVAX-Direct will be -- dare I say -- even to DCVAX-L. If it works as many of us expect, it is as close to a cure for all solid tumors for 80-100% of patients, as one can possibly conceive. GBM is a solid tumor.

It's hard to keep all this timing in perspective. It's hard to connect all the dots. I expect most people will find some snag to hang their hat upon, but I strongly suggest that DCVAX-L is ultimately an effective treatment and will act as a place holder until the ultimate treatment can take its place, and remember, with tumor reduction as the yardstick, orphan status and blazingly fast enrollment, this relatively brief window in which we all find ourselves will begin to make sense very soon.

So, finally, let's consider the ability to obtain fast enrollment for DCVAX-Direct. Let me suggest that the next phase 2b/3 trial would fill up so fast it will make your head spin. And the results? They will come very quickly. The only time delay beyond that will be the time it takes to get FDA and EMA approval. That takes about a year. What countries during that time will be able to provide a hospital exemption for DCVAX-Direct? I guarantee you one thing Germany will be the first but by that time its template will be used throughout the world, so that it is not the only country that will make Direct available during the NDA waiting period.

So to address the last part of your question, yes, I believe Germany and NWBO understand the "ramifications" on the future of the phase 3 DCVAX-L trial in Germany. I think they understand them far better than any one of us.