Replies to post #219795 on NorthWest Biotherapeutics Inc (NWBO)

[flipper44]

If you were in NWBO's decision making shoes, and you knew PFS was going to improve (or at minimum be confirmed) once more accurate (better tech/assessment techniques) adjudication (rereview) occurred, you would also choose not to give out interim blinded data on PFS that would be fluid and only ultimately cause confusion.

[Smokey21]

Great post Umibe!

You know, on #6 (the helmet), you mention it is effective, but lacks the long tail that DCVax appears to have. Yes, I think that comes down to MOA. The helmet interferes with the cell division process, slowing the cancer's progression. Once you stop using the helmet, there is no immune memory or active killer cells in place to continue doing the job. That could explain why no long-tail in the helmet. People don't want to wear that the rest of their life; or they can't afford to.

[longfellow95]

Umibe. Thanks for a thoughtful post.
I am, perhaps less confident of approval 'first time round', not because I fear that the data will disappoint, but rather because of my cynicism about the FDA, and whether they actually apply objectivity and a level playing field. We know of the rather insidious links between BP and the FDA, and how the FDA could be viewed almost as client organisation for BP. The associations run deep. It almost goes without saying that each new commissioner has a background of connections and remunerative links with BP, and such links tend to permeate much of the organisation.
I fear that the new 'flexibilities' at the FDA are only applied selectively.

Of course I hope my cynicism is misplaced.

I think many on the Board are being rather optimistic about timelines to unblinding and topline.
The revamping of the SAP is indeed a formidable task.
I'm inclined to think that they are holding on to PFS, as at least the nominal primary endpoint, but instead of co-primaries, where if the primary falls so does the secondary, I think they have or will promote OS to a position where it is powered completely separately (as suggested by Dr Bosch comment at ASCO).
That requires a division of 'alpha spend' to control for the multiple endpoints (two). In turn, as I understand it, that means a higher bar for each. We would be talking about a target 'p value' of 0.025 instead of 0.05, if each endpoint was equally weighted.
If they were intending removing PFS, and relying solely on OS, I think they would have done so by now, and would probably have needed to get specific consent from the FDA and to have PR'd it.

That was certainly the process for Halozyme in their pancreatic cancer trial, when they recently did just this; removing PFS and relying on OS.
It's an interesting case example if nothing else:-

https://seekingalpha.com/article/4225195-halozyme-explaining-change-trial-design


Anyway, they certainly need to nail their colors to the mast with the new SAP. I have my doubts as to whether it has even been submitted to the various regulators just yet. They will probably want to know how many PFS dates were 'amended' by the PFS panel, before finalizing their SAP. That can be done without compromising the blind. When that has happened, only then can they submit the SAP, and then they have to wait for agreement to the revamp.
All of this needs to happen before unblinding.

And topline necessarily doesn't come until after unblinding..

I have no doubt that following approval, DCVaxL will be quickly adopted as a mainstay of GBM treatment. Frankly, the results and outcomes will speak for themselves with an ever louder voice.
There really is no downside to electing DCVax treatment. It adds no toxicity into the mix, and as you suggest, may even ameliorate toxicities from other treatments. That is in stark contrast to other treatments. For sure, BP is trying to make inroads with Keytruda and Nivo, but even if they can match (real) response rates, it comes at the price of a high likelihood of severe toxicity and 'synergistic toxicity' when used alongside SOC.
Only the other day, I read on a patient forum of a GBM patient who was left paralysed after Keytruda treatment due to transverse myelitis, which developed some months after the ICI treatment.

A downside to electing to use Optune that is not often mentioned, is that it bars you from the majority of trials for other treatments, unless it happens to be a trial using Optune as an element of a combo.

I'm sure NWBO are expediting all this as fast as they can, but I have my doubts about any unblinded results by ASCO.

I have no doubt that the eventual BLA (or equivalent elsewhere) will state the case for approval for the whole GBM population.
For sure, the benefit to unmeth is smaller in absolute terms. But in relative terms, the survival benefit is probably proportionately about the same.
The fact that patients older than the median in the trial are amazingly doing almost as well as their younger counterparts is particularly encouraging.
NICE always ask the question as to whether evidence from a trial population actually reflects the real world population with the disease. 'Real world' patients tend to be older (GBM median onset around 65) with more co-morbidities. I think the interim results on the older patients are really quite encouraging in this respect.

As regards the phenotypes, I think this will indeed not be a factor. I don't think the trial subjects were tested for phenotype anyway, and I doubt any reference will be made to phenotype in either SAP or BLA. Genomic profiling is moving on at such a pace that hundreds of different genes are now being studied as to their predictive and prognostic relevance in GBM. The phenotypes will I think come to be considered as just loose groupings.
As an example, IDH mutation which is a huge positive prognostic factor, is very closely associated with pro-neural. But going forward, the marker that people are interested in is IDH status, not whether it is a pro-neural GBM.

I really have no idea what all this means for the share price, other than suspecting it will stay in the doldrums, relatively speaking, for the time being...
I think it is currently priced as if it had 'already failed'. As you say, Wall Street are really disregarding this stock, other than the bravest shorts still trying to squeeze a bit more juice out of this.
So the upside surely has to be huge, at least to Novocure size market cap, if approval is achieved, with a diverse program of Direct trials under way. Positive topline would do wonders, but approval is all that matters in the long term.
The other side of that coin is that I don't expect any sort of precipitous decline from here on in, even if we are without meaningful news post ASCO.

I prefer to think of NWBO working assiduously and methodically towards the target, rather than them being 'in no rush'. Though, it might appear that way to some, as the months go by.



Just my opinions.

[iwasadiver]

I am a rather unsophisticated(as compared to others on this board and, of course, experts in the field) simple thinker when it comes to things bio-technica

From the rest of your post, especially the concluding remarks, you hardly appear unsophisticated. Not sure why you'd try to "dumb it down" for your own understanding, it appears you have quite a good grasp.

However, from your take on why PFS is important to Wall Street (I'm going from this post and the one later regarding silence on NWBO's part regarding PFS) I understand your concern but I also don't share it. While I agree Wall Street are followers and not the cutting edge of investment I believe the story of NWBO will be told well by the data and from that data there will be a land swell of press. Patients will tell this story better than anyone in my opinion and physicians will also. This will explode. Wall Street will be scurrying because of their arrogant ignorance and this will rocket the share price. PFS will most likely be very good, but it won't matter one way or another, this is much bigger than the stupid investment community.