Replies to post #34510 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

Very true Senti. It is ironic that the case M.K. tried to make against NWBO instead ultimately demonstrated the theoretical basis proving NWBO's platform is superior once follow up data was provided by Linda Powers, and the research group to demonstrate the huge variation in somatic mutations throughout the GBM population in 2013, disproved the interpretation MK tried to glean from their prior work he cited in 2008.

And LP did not stop there, she also refuted one of his other comments questioning DCVax-L's phase III trial design.

So four months difference is all we have to show in the phase three trial, and if we show that much of a difference, we will have a very strong p-value of .02. The trial is also powered for the secondary endpoint of overall survival, and as you see here, multiple subgroup analyses were prospectively included. There are a number of subgroups, certainly MGMT status is one of them; there are several others. In fact, MGMT status, which is a gene that effects chemo therapy sensitivity… that’s part of standard of care… to the chemotherapy, is included in the actual randomization of the patients. So it’s taken into account in the formula under which patients are randomized. So they’re even randomized for these factors. Again, that trial is due to finish around the summer of next year to reach the primary endpoint, and we are certainly looking forward to that. -- LP

I just recently posted about that point a few messages back.

IMHO, the market has yet to reflect that MGMT status was also randomized into the DCVax-L phase III trial.

In fact, MGMT status, which is a gene that effects chemo therapy sensitivity… that’s part of standard of care… to the chemotherapy, is included in the actual randomization of the patients. So it’s taken into account in the formula under which patients are randomized. So they’re even randomized for these factors. -- Linda Powers

Methylated MGMT maintains a very significant efficacy correlation with chemoradiation and most cancer therapy interventions. The fact that this status was randomized into the DCVax-L phase III trial means that the control group is unlikely to perform beyond historical expectation, but that's not all.

Many people, myself included, focused somewhat on the pseudopreogression arm (which we now know is 32 people, and as Pyrr thought, outside the 348 patients in the main trial.) The missing emphasis, at least on my part, was now that we know this, what impact will it have on the control group?

I re-reviewed some studies and found that indeed, pseudo-progression highly correlates with long time survival in chemoradiation patients. But that is not all, add methylated MGMT to pseudo-progression status, and chemoradiation effects are found to be best in that group. (Methylated G-cimp is also highly correlated with survival, but not as prevalent).

With pseudo-progression limited to the pseudo arm -- and it's clear doctor Bosch thinks pseudo progressives do very well on DCVax-L, "of course," -- the main trial takes away most/all advantages to chemoradiation and places the focus on non-"outliers". It kind of looks like this.

1. The pseudo-arm of just 32 patients should get something like 15 months pfs (ballpark) in the control arm, but the treatment arm may get somewhere near 30 months pfs (ballpark) because mesenchymal also respond well with DCVax-L, and many pseudos should be mesenchymal because mesenchymal are inflammatory.

2. The rapid/indeterminate info arm has already been disclosed.

3. The main arm, devoid of rapid recurrence (which helps placebo and control, and balanced/randomized with MGMT methylation status (which levels the playing field), will tell us something the further we keep going without reaching 149 events. That is, because the outliers have been either placed in separate arms or balanced/randomized within the trial, the further we go without reaching a triggering event, the better DCVax-L is doing and not the control. Why is that? Because controlling the outlier effect, the control group is akin to a time clock set at a predictable number of months.

So, we know that there were about 66 events in December, 2013, and near 190 enrollment (according to Pyrr's old protocol) around the 1st quarter of 2014.

Consider Immunocellular. It reached full enrollment (it's press release was inaccurate regarding number but later corrected when results were released) of 124 patients by September 5, 2012. By December 11, 2013, they already had 103 events out of 124 patients over 14 months time. The immunocellular trial did not allow patients with recurrence (However, the CEO recently disclosed they did not screen out early progressors from their phase II trial), and they randomized after chemoradiation. 103/124 = 83% over fourteen months.

Because rapid progressors (which likely hurts results) and pseudoprogressors (which likely helps results) were excluded in the NWBO trial but not the IMUC trial, comparing ICT-107 phase II and DCVax-L phase III is not an apples to apples comparison; However, now, conservatively consider that with approximately 190 patients enrolled by March 2014, NWBO apparently has not had its first interim analysis by May 9, 2015. That is 17 months. 149/190 = 78.4% (if we did not add to enrollment since then, which of course we have in reality added many patients.) IMHO, if these numbers and assumptions are accurate, the entire patient population in the NWBO trial is already easily demonstrating it is eventing more slowly than the entire patient population in the IMUC trial did over a shorter period of time. I also did not include the patients added to the DCVax-L trial since approximately March 2014, which I can't speculate on because NWBO has held it's enrollment numbers close to the vest. Had I added them, the advantage to DVax-L would be even far greater.

Regardless, back to the original premise of this post, and that is I don't think the market has yet taken into consideration what LP announced last week regarding that randomization of MGMT status was included in the phase III trial -- especially when it is combined with the fact pseudo-progression is also analyzed separately. That is, as the time for the first interim analysis continues not to arrive, it is likely due to the treatment group and not the control group extending eventing. It's not something one puts in a PR, but I have little doubt more and more institutions will recognize it. IMHO

[Ready4bluesky]

He nailed it when he said "The fact that Linda refutes my argument by citing the 2013 Cell paper by the TCGA Research Network and their 21,540 figure indicates that either 1) she misunderstood my argument or 2) she is presenting a straw man argument to avoid addressing the real issue."

Note, this isn't the first time we've seen straw man arguments to avoid discussing the real issues.

What I found the most interesting, was the exchange between someone with a close personal experience with DCVAX in a fight against cancer and the author:

" My sincere apologies Mark. As we've been able to speak offline I've gotten a chance to understand your viewpoints and the opportunity to present the data that you've accumulated in your own research to share with others. I hope in the future I will be more open to welcoming opposing views as iron certainly sharpens iron. The more we learn, the more we realize how much we don't know.

Best wishes to you."

Ben demonstrates integrity and a very open minded approach that we should all try to emulate. Of course some here would rather try to discredit anyone with personal attacks if/when their statements don't fit an eternally bullish perspective of NWBO and all things related. Okay, head back in the sand. Carry on..