Replies to post #273234 on NorthWest Biotherapeutics Inc (NWBO)

[sukus]

Excellent post.

[Sojourner55]

As usual, I appreciate your well reasoned, logical and articulate post.

[Survivor2012]

Umibe5690,
Great summary/narrative! Please send to FDA!!

[Doc logic]

Umibe5690,

Very well thought out post and I am in agreement. The problem is that this supporting thought process was not shared by NWBO with investors before submitting their comment which is why my posts on this topic seem a bit more terse and less apologetic than normal especially in light of current circumstances. I know everyone at NWBO is focused on finishing strong and not much on investor sentiment but there is a seeming lack of awareness and or sensitivity at times to the impact that their communications and actions can have on some of their long term investors and I am not talking about me. The amount of detail you gave in your opinion of the situation would not have been equally matched but an approximation would have been nice. Best wishes.

[kabunushi]

Hey Umibe san, nice analysis! As usual, you seem to have a good grasp of what this is all about. You are quite right that Linda has not been communicating to the market so far. Can that change going forward? I think it has to but DI for example certainly did not come into the job with the idea that he would have much leverage to get Linda to change. She is CEO and seems to be really dictatorial. That's more or less how she is supposed to be in such a tiny company.

If what has happened in the last 4-5 years didn't make her try to communicate more with shareholders, I have to wonder if that will change at all even after they get the P3 data out. It's imperative for her to move the market to where there is strong enough interest that the shares sell at least a bit higher. At least it is from the pov of us longs. I'm not sure if anybody is going to have the chance to raise this with her at the ASM. Whatever is 'interesting', I believe the stock will do better the more clearly she can explain the deeper significance and how they plan to take dc-vax forward.

[highwayman4life]

Umibe~

IMO you are spot on and I appreciate you spelling it out in a way that the common shareholder understands. I view the "letter" to the FDA exactly as you do. It is more about a public record and I am quite certain all this has already been discussed repeatedly in the ongoing dialogue between NWBO and the FDA pertaining to the SAP.

As to:

I do not mean to harp on Mr. Inness but I would have hoped he would have brought at least a modicum of "perception supervision" to the company. Perhaps he has tried but has not been as successful as investors would like and expect. Linda and Les, both being lawyers, are hard-line debaters and it is not easy to get in a word edge-wise. I know....I have tried many times.

I talk with DI regularly and have found his approach and input refreshing compared to having to deal with LG. DI certainly understands perception but as you stated so precisely, he is dealing with two lawyers. One of which is a bit of a loose cannon and lets his mouth write checks that his *ss can't cash. The other as we know, is a do it my way or the highway (hence the "go it alone" mantra) and is hell bent on absolutely no one stopping her in spite of devaluing that which she has fought so hard to achieve and preserve.

From an investors perspective, I have let go of the Volkswagen/Short position scenario that at one point I believed might be in play. I have gone against many of my own strategies/rules with NWBO and in short term (last 4+ yrs) the pain has been at times overbearing. But, with that said, something in my gut has told me to not only hold on but to accumulate. This is a longer play than I had initially anticipated and I personally think that true value won't be recognized for another 2-3 yrs and possibly more. So, I have had to adjust my thinking and let go of emotion that simply was not serving me at all. Many here are still stuck in that emotional side of the investment and I get it...a screenplay could be written off this one and perhaps one day we will all have a better understanding as to what truly "went down."

Anyway, I just wanted to thank you for your perspective. I always find your posts well balanced and informative!

GLTA

[JRIII]

This is a failed trial. They just admitted it in the letter to the FDA. There are no "ifs" about it. They wouldn't be asking the question otherwise, and no amount of quixotic denials will change the fact that if this trial had been successful they would have told us five or more years ago. But they didn't, and now, five years later, we have this letter to the FDA and people still want to make excuses and deny, deny, deny.

They've been living a lie for five years, and screwing shareholders in the process with their secrecy and silence while pocketing millions of dollars. It's just crazy that there are some people who still cannot see this.

[flipper44]

The blinded information paints a different story regarding crossover.

For instance, the very long lived are primarily non-eventers. This suggests any impact from cross-over in that LTS group was negligible, at best. This may be partially due to the dearth of second surgeries amongst those who stayed on trial; and logically, the inferential impact of DCVAx-l.

I’d also take exception to your certainty that the FDA provided comments on the SAP regarding subgroups. While your conjecture may be reasonable, what comments the FDA did or did not include in the SAP is merely speculation. What’s certain is that UCLA and NWBO knew about mesenchymal responsiveness since, at a minimum, 2013. If they could prospectively add subgroups thereafter, they almost certainly would have. Hopefully they did add them at some point.

Your comment about what NWBO “extensively” deals with in its SAP is likewise conjecture. NWBO’s letter certainly sends the message that regulators could and should analyze more than p-value to determine efficacy, but this does not provide outside knowledge as to actual FDA SAP comments or SAP content.

Your attempt to tether NWBO’s recent letter and the publicly unknown contents of the SAP as somehow known seems an unbalanced argument.

What we do know is that NWBO is technically blinded, and therefore any guideline drafting that might prevent unreasonable draconian responses to whatever results the DCVAx-l trial presents - clear or unclear — are wisely ameliorated in advance. (Although, I do wonder out loud whether NWBO submitted their letter in time. That letter could have been written and submitted much earlier.)

[longfellow95]

Umibe. Just by way of chewing the cud while I'm domestically confined, I thought I'd make a comment or two.

NWBO has a legitimate concern on P-value particularly as it pertains to separation between the cross-over/placebo and Tx arms OS.

Yes, it has a legitimate concern on P value. It doesn't know if it will be able to demonstrate stat sig on OS (or unadjudicated PFS).

Nobody knows the degree of effectiveness of post-progression DCVax-L, particularly when the vaccine was produced from the nd tumor.
None, a bit, quite a bit, a lot?
Well OK, we still have 30 patients who didn't cross over. Well probably less. Some of these went off trial, some died, some opted for palliative care, some had chemo or rad re-challenge, a few misguided individuals opted for Optune.
There is simply no clean comparison.

This is particularly noteworthy and when coupled with the extremely flexible FDA guidelines might permit approval for recurrent GBM as well which is a large market in and of itself.

'Extremely flexible guidelines'?
The FDA have always exercised their flexibility to do whatever they wish. New guidelines are unlikely to make any difference at all in the case of NWBO, imo.
They have have made many, many BP approvals based on the flimsiest of evidence.

If you think that this trial could lead to a specific approval for rGBM, I would just say (imo) 'no chance'.
But yes, if approval for ndGBM is forthcoming, then off label use for recurrent operable GBM is not unreasonable, with eventual label extension.

It should be noted that the FDA did NOT require NWBO to have a cross-over arm.

Well, yes they perhaps did. I haven't saved the precise LL quote on this, but it suggested that the FDA effectively did require it.
You seem to be suggesting that it was NWBO who proposed the crossover to aid recruitment, and the FDA simply concurred.
Absolutely no evidence that it was this way round at all.

On subgroups. Yes, meth / unmeth was identified at the outset.
Even back then, it was being recognised as perhaps the most significant prognostic / predictive biomarker in GBM. And yes, meth status was established by a central lab for 293 out of 331 (88.5%).
This is a viable subgroup comparison, though it would have been better in statistical terms if an even greater percentage had their meth status established.
Very different from a post-unblind trawl, which might, for example, come up with a spurious stat sig finding that those subjects born on a Thursday did even better on DCVax-L.

There is a somewhat comparable biomarker for ICI's, namely PD-L1 expression. Merck have used every trick in the book to get additional approvals for pembro based on various PD-L1 cut-offs (1, 5, 50%) and even adjusting thresholds mid-trial as it suits them. The FDA has allowed them to do this.
And the FDA has gone even further and extended the first line NSCLC approval to all above 1%, despite no evidence that this is beneficial to patients. (NSCLC is the largest ICI indication and use of an ICI accelerates disease and death in 10-25% of NSCLC patients.)

But in the case of our trial, meth status is a legitimate pre-identified subgrouping for which there was proper stratification by site and country, and is a universally accepted significant GBM biomarker.
As for the molecular subtypes; imo, these are a complete non-starter for trial subgrouping purposes.
Because I don't believe that trial subjects have even been tested for molecular subtype, let alone stratified by subtype.
And because of intra-tumoral heterogeneity, and tumor heterogeneity over time, you cannot conclusively label any particular patient with any particular molecular subgroup.
(Even though many have attempted to do just that.)

There have been extensive discussions with the FDA on all this. The FDA did provide comments with respect to NWBO's SAP.

This is surely no more than conjecture on your part.
I'd like to think that there has been lots of facilitative interaction between NWBO and the FDA, but I don't know that there has been. I imagine by this juncture that the FDA has responded with comments to an SAP submission, but I don't know that either..

NWBO deals with these foregoing issues rather extensively in its SAP upon which the FDA has provided its comments.

How do you know?
I would certainly expect that NWBO has included a proposal to perform a statistical analysis by meth status, as well as by entire ITT. But I don't know it.
And a subsequent BLA might also make reference to meth status.

I can't think of any other subgroupings that would come into a statistical analysis (other than the usual obvious stratifications of age, extent of resection, gender, country).

The FDA guidelines and, indeed, relatively recent approvals demonstrate a paradigm shift in the way that regulatory agencies view novel therapies and should go about evaluating and approving them. NWBO's trial will be a treasure trove of data and the most extensive of any GBM trial.

Well, we're really into opinion here. I view the new proposed guidelines as little more than sophisticated window-dressing, rather than a 'paradigm shift'.
They didn't need these guidelines previously, when they made dozens of dubious approvals in oncology. The only difference is now they will be able to say that they formally consulted all the stakeholders who asked for more 'flexibility', which will give a veneer of legitimacy to ever more dubious BP approvals in the future.

As to the data from the trial being a 'treasure-trove', I would just say it's all we've got, and I hope it is good enough to both warrant and elicit approval (at least for meth)..

JMO!



P.S. As to what sort of interesting 'burger' we might get at ASM, I had previously committed to a prediction. Then Coronavirus came along...
Which kind of means 'all bets are off'.
Anything that had not been signed, sealed, and delivered by that point, is likely now in abbeyance unfortunately, imo.
But it would have been a prediction based largely on European players and finance from Asia.
Topline is now looking a fairly remote possibility, imo.
So the burger is looking likely to be a calorie-controlled, vegetarian option (though if a quarterpounder comes along, all well and good).