re: Northwest Biotherapeutics (NWBO) - DCVAX-L Trial

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As I think you imply GBM is a nasty disease but affects a small number of people in the big picture.

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Im not sure anyone would reasonably disagree with this. it affects less than 1 per 10,000 people.

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The big picture for this study showing positive effects IMO would be more about the potential of the technical approach for not just GBM but for other cancers

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the primary picture for the study is time of disease free progression of GBM with their treatment. drugs are not approved in clinical trials for big picture reasons, that just isnt how it works. they are specific use cases for approval. you suggesting this makes me a little curious about your background/knowledge .

also im not sure how a vaccine targeting cancer cells only found in the brain with a specific function would have implications for big picture 'other cancers'. the pathology is rather unique to other cancers. most brain cancer is from metastasis, not primary tumors. the only other implications it may have are for more rare primary brain tumors which already have much more favorable prognosis.

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im not sure how a vaccine targeting cancer cells only found in the brain with a specific function would have implications for big picture 'other cancers

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I can't tell how familiar you are with chemotherapy protocols. From your response it sounds like you believe this is no different than the traditional types of cancer treatments people have used for decades.

Oh come on.

You seem to have entered into the discussion ignorant of the specifics and then attempted to plant false flags about what is being discussed.

Every post in this thread seems to reflect a good understanding of the risky nature of the investment. You have made it more difficult than necessary to have a civil and interesting discussion about the investment. And if you indeed have some expertise or interest in advances in immunotherapy as oncology you could have meaningfully engaged in that discussion as well.

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statement you did quote says this therapy only targets specific brain cells with specific functions.
if you would have quoted the next sentence you would have seen I acknowledged GBM is a rather unique pathology vs other cancers.

I dont see how you conclude I believe its the same as traditional measures when I explicity describe it as unique pathology and targeting specific cells. that is obviously not traditional treatments.

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Because you didn't express understanding of the study design and therefore probably had other major gaps in understanding.

I don't think we can have a reasonable discussion. The longer than expected statement was consistent with the the expectations of the people who designed the study.

Let's save the back and forth about what those expectations are and should be. I don't feel like arguing about whether or not you actually know anything about study inclusion bias. We've already been through that and both of us have made separate comments indirectly or directly to that effect.

I hope this discussion reads better for others than it reads in my eyes.

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dont even know how to respond anymore, when you are assuming I am saying the opposite of what I am clearly saying.

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On this statement we absolutely agree.

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internal med doc

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Knew it. Someone sort of expert but not really

Real experts don't behave in any way like you have. And FWIW I likely have 20 years of postdoctoral experience more than you and have worked on a variety of research projects in different roles.

But none of this nonsense is germane to the facts on the ground. We have a binary event on Tuesday. It took much longer than expected to complete.

You said you would not recommend investing. You know only a little about this project and probably nothing before you jumped into the middle of a discussion trying to show off

Yikes this conversation escalated quickly.

Nothing wrong with disagreeing and raising concerns. I will however say that we have highlighted that this is an extremely high risk, binary event. I think that means the risk of failure is noted by everyone.

Anyway, to get back on actual discussion, you comment on the inclusion criteria being limiting for approval but I’m not sure I agree there. The inclusion criteria eliminates some of the patients with a bad prognosis, yes, but it also eliminates a fair portion of patients with better prognoses as well. Patients will small tumors or low grade gliomas were eliminated, so that’s a significant portion with a longer expected OS.

Also, you seem to say the inclusion criteria will put approval at risk. I would agree that it may not make the results stat sig, as a (for example) 20% increase in OS over SOC May be reflected in the control as well. But in terms of approval, the control undergoes the same inclusion criteria as the treatment arm. So if endpoints are met and data are good, I think you have a perfectly fine population to get your approval.

Even aside from all of this, the 2018 review of patient demographics in the blended blinded data peak show a high level of consistency with populations of prior and current GBM trials. For all this, I don’t think this inclusion criteria is nearly as risky to the stat sig outcome as you are alluding. But I do certainly see your concern.

WRT the size of the study, I agree it’s smaller than you’d like. However, with 90% of the population eventually receiving DCVax because of crossover you’ve got something close to 290? treatments. Then, by using an ECA, you’ve effectively increased the trial size to almost 500 patients (which is still small, but better). Also, they are now able to analyze results for both new GBM and rGBM. There is currently no standard of care for rGBM so given the excellent safety profile of DCVax it has a strong change of approval for rGBM if it shows any impact.

There are several other interesting things at play here. Regarding the GBM reclassification, the new definition eliminates the IDH mutant type tumors from GBM classification. This is a form with a significantly better prognosis and thus will drop the OS of GBM. Now, methylation status of the tumor is basically the number 1 classification that defines the prognosis. The blinded results show that both MGMT positive (methylated) AND MGMT negative patients in the trial responded, with OS moving ~9-12 months right in both populations. This means that, for the DCVax trial, mOS of the control is actually going to be lower than expected and mOS of the treatment arm will look even more improved, assuming there isn’t a surprise in the control arm which is certainly possible, I won’t deny that. The interesting thing here is that temo + chemorad works very well in methylated cases (mOS bumps to 30 months) but not so well in unmethylated.

Finally, you have to look at the long fat tail of this trial for even more validation. The KM curve of the top 100 patients shows an expected survival of over 40 months. 30% of the patients living longer than 40 months is awesome. That’s one of the reasons that they didn’t unblind in 2018, is because so many patients were late entries and so many hadn’t evented yet that they wanted to build the tail as much as possible.

I know it’s high risk, but this is a very attractive gamble for me when you consider all of these things, plus consider you KNOW the date of the binary event, you know you’re getting a multiple of 2x on your investment in the event of a good readout. If you’re willing to take a risk, this is about as good as it gets in the small cap biotech pre revenue sector. Yeh, good results may be no better than a coin flip and probably closer to 25%, but when the upside is a 10 bagger minimum even with the downside being a total loss that’s still great odds I’d take every time.

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I think of it like pot odds in hold em.

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Precisely how I’m looking at it. Fully aware i may lose this hand but, if I play em the same every time, I’m a winner in the end with these odds.

And yeh, I’ve got a swing play I bought down at $1.20 just before this run started that I’m probably going to exit. Profits on that alone will cover about a third of my cost basis.

I’ll be honest, I’m excited but also terrified about tomorrow. If it’s no news and another rug pull I’m gonna be a sad panda.

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Also, you seem to say the inclusion criteria will put approval at risk. I would agree that it may not make the results stat sig, as a (for example) 20% increase in OS over SOC May be reflected in the control as well. But in terms of approval, the control undergoes the same inclusion criteria as the treatment arm. So if endpoints are met and data are good, I think you have a perfectly fine population to get your approval.
Even aside from all of this, the 2018 review of patient demographics in the blended blinded data peak show a high level of consistency with populations of prior and current GBM trials. For all this, I don’t think this inclusion criteria is nearly as risky to the stat sig outcome as you are alluding. But I do certainly see your concern.

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I wasnt saying that it biases the data so negatively that the study will fail, I even acknowledged it was a necessity for the study. This may not even threaten phase 3 but be an amplified effect in post approval monitoring. drugs can/do perform differently post approval than during clinical trials. a drug that passes p3 but gets pulled post approval isnt great news for an investment.

my point about inclusion criteria (aside from potential bias implications) was more about how it may influence use of the therapy in the market for treating GBM as a whole. theres several metrics of health involved which potentially might limit the DCVAX market in the real world.

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Now, methylation status of the tumor is basically the number 1 classification that defines the prognosis.

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from your link there was a section that mentioned this as well. they also reported a subpopulation of 30% or so who had longer survival than expected which was not explainable by prognostic factors. this could be good or bad depending on the statistics or unintentionally by random chance from their sampling.

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know it’s high risk, but this is a very attractive gamble for me when you consider all of these things, plus consider you KNOW the date of the binary event, you know you’re getting a multiple of 2x on your investment in the event of a good readout. If you’re willing to take a risk, this is about as good as it gets in the small cap biotech pre revenue sector. Yeh, good results may be no better than a coin flip and probably closer to 25%, but when the upside is a 10 bagger minimum even with the downside being a total loss that’s still great odds I’d take every time.

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i suppose this depends on your timeframe for investment. if youre swing trading a known event on a specified date, that's much different assessment than long haul holding. swing trading it is more appealing than long hauling it when they have had delays in trials. but i generally have a different connotation for 'investing' vs 'trading'.\ which may have hurt some feelings.

anyway dilly dilly