Replies to post #187446 on Biotech Values

[iwfal]

BMRN - I agree with much of Ohad Hammers post and agree that Biomarin is taking a risk. Which they acknowledge themselves. And I agree with him that:

There is no doubt that new DMD treatments are urgently needed but one has to wonder whether this can be an excuse for approving drugs based on unmet need while ignoring basic tenets of evidence-based medicine.

I certainly agree it is setting a bad science precedent - and risks patients going forward (see my later comment on ph 3 failure)

But I'd suggest he is overstating the poorness of the data - and the non-approvability (BMRNs decision is a commercial one and clearly politics matter). As for other commentary I have I would suggest the most important thing with which I disagree is the first of the below:

The phase III failure and the lack of any positive subset analysis are an order of magnitude more reliable than any positive indication from smaller studies (either placebo controlled or single arm).

Certainly the failed ph 3 is an issue. But there was actually an almost positive subset analysis - the patients enrolled at the same trial centers used in the phase 2s. In any case a failed phase 3 is not a proof of inefficacy, unless it was strongly the other way (I'm ignoring post hoc issues). So the p value in the ph2s are hard to explain away unless you think there was cheating/bias.

I'd suggest the big loss in the failed ph3 is that you get less of what you ordinarily get in this situation - a better understanding of the subgroups that work, how well it works, and the true clinical robustness of the treatment. And without that data care providers and patients will make less optimal decisions about treatment.

Altogether the failed ph3 matters a lot. I'd just suggest not a complete deal killer?

For example, the “time since diagnosis” graph gives a sense of a 3-4 fold difference while in fact the actual difference was only 29%.

I'd suggest this ignores the fact that there is now enough natural history data to make it clear that DMD behaves very non linearly wrt degradation.

PTC Therapeutics (PTCT), which is developing ataluren for another subset of DMD patients, also used subset analysis from its randomized phase II and reached the opposite conclusion. PTC decided to recruit older patients with more advanced stage DMD for their ongoing phase III study based on the idea that it will be hard to show a clinical benefit in patients with early-stage disease because they experience very limited deterioration initially (up to 48 weeks).

I've made oblique reference to this before. PTC's ph2 told them the opposite from the message that RNA got from their failed ph 3. PTC's ph3 is to a large extent the very kids that SRPT and BMRN claim are patients in whom efficacy cannot realistically be measured. I agree that that provides some doubt over the BMRN and SRPT thesis. But Ataluren is a very very different MOA - e.g. Etep and Dris both seem to have the issue that they can't easily enter muscle cells unless they are DMD damaged which could create weird pk issues. That said, PTC may potentially unblinding their trial before Dris or Etep are approved and if PTCs ph3 is positive it might add more doubt to Dris thesis.