NorthWest Biotherapeutics Inc (NWBO)

[Pyrrhonian]

For the Ph II, RECIST criteria is still the primary means by which a response of any kind will be verified. The endpoints are ORR, PFS and OS. ORR is greatly dependent upon RECIST criteria to define PR+CR. SD is not a 'response,' and so 1/100 PR and 99/100 SD = 1% ORR.

A summary of RECIST 1.1:

Baseline documentation of “Target” and “Non-Target” lesions:


• All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline.

• Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically).

• A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor.

• All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up.



Response Criteria:


Evaluation of target lesions:

* Complete Response (CR): Disappearance of all target lesions

* Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD

* Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

* Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started


Evaluation of non-target lesions:

* Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level

* Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits

* Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions (1)

And a chart:

Target lesions +Non-Target lesions+New Lesions=Overall response

CR +CR +No =CR

CR +SD +No =PR

PR +Non-PD +No =PR

SD +Non-PD +No =SD

PD +Any +Yes or No =PD

Any +PD +Yes or No =PD

Any +Any +Yes =PD

It's tougher than you think. If you want to change these rules you can lobby, but they're here to stay for now.

My whole point has always been they need strong ORR (like checkpoint inhibitors (CIs) and CAR-T have shown) to get accelerated approval (AA) without a control group. They may still be able to get AA with a control group that gets no intervention and is enrolled along side active tx group (like they tried to do in the DCVax-L trial initially), though that's hard to keep patients enrolled into. In essence they have to agree to just die and not take any experimental tx out there. So you need a placebo. They could do saline injects.

Why do you need a control group? Because if you can't get some PRs then you have no ORR, and so need to rely on survival as your metric of tx efficacy. But regulators will not accept any survival claim without a control group to compare data against, preferably with a placebo and a blind. It may seem cruel but it is the only way FDA can say with scientific validity that a tx can procure a survival benefit. The few must be sacrificed for the many, it seems.

So SD is great, PFS/OS that looks like it's much better than historical norms is also great--but neither investors or FDA will take it very seriously until it comes from a controlled study.

I was fortunate enough to buy up lots of CLDX just before SNO at $13ish. I felt strongly they would not only show strong survival data from their randomized, placebo controlled rGBM trial, but other clues on their site told me they would be pursuing regulatory approval. Now it's $30. Why? Because of that one thing--a controlled study.

I think investors were coming on en masse here because they were expecting some good ORR from the Direct Ph I. It's clear there is absolutely no ORR. In Ph II there may be some, especially considering they can inject 3/5 target lesions. And especially because patients are being screened better and have more robust immune systems than the Ph I patients. Because it is an immunotherapy, that naturally means they have more armament. And considering the indications (esp st IV sarcoma and pancreatic), even 20% ORR--or hell even 15% (http://news.bms.com/press-release/rd-news/phase-2-objective-response-rate-and-survival-data-opdivo-nivolumab-heavily-pre) would be seen as epic. They might just get it.

But for now, what? Saying 2/3 get progressively more and more necrosis means what? Nothing much yet. It means only there is activity. Encouraging enough to pursue a Ph II. But at the end of these two Ph IIs they will need to conduct another trial to pursue regulatory approval with. No matter though.. If they can show some ORR in the Ph II the investment community will give them the benefit it will work, in line with the degree of ORR seen.

We're back in 'unknown' territory with Direct. It's unclear. As an investor you have to predict how the market will take this. Especially considering the caliber of investor that makes up the brunt of NWBO float (retail). They get impatient, wig out, get scared easily, frustrated easily--they are like little children. And they control your money if you are invested with them. So that's why I grabbed (and will continue to hold) puts. Maybe after the raise I'll convert them back to shares.

The biggest mistake I've made (and keep making, though to a lesser degree) in the market is expecting people will see what I see at least soon after I see it, if not at the same time. No. They don't. It's okay to move out of the way of a falling icicle. It doesn't mean you're no longer 'part of the team.' There is no loyalty in the market. It's the cold hard fact that moves a pps.