BMRN – Comments on AdComm relevant to Drisapersen (I’ll comment later on portions that appear relevant to Sarepta).
First, the no surprise items:
a) The rate of thrombocytopenia (the most significant adverse event category) – well known as the primary concern for Dris (if you were paying attention – although most SRPT bulls focused almost exclusively on proteinurea).
b) The severity of the thrombo – again well known since patients were hospitalized. But the exact details are, of course, new.
c) The late onset of thrombo – again not news. The severe thrombo events all occurred in the extension study.
d) The rate and severity of proteinurea – not generally news (but see one comment below).
e) The rate and severity of injection site reactions – not generally news since the AE levels were known. (That said, the images of the severe cases are fairly unpleasant even if they aren’t technically news).
f) The FDA commentary was pretty much as expected – e.g. the slam on anything without strong clinical efficacy data is completely in line with their prior guidance (although the Sarepta bulls bizarrely overlook it).
The new bad items (to me at least):
a) The sudden onset of the severe thrombo – which means it will be difficult to prevent. This is bad (as I’ve noted for some time – a key piece of the review will be how the SAE can be handled)
b) The case of glomerulonephritis
c) The duration of the skin reactions (literally years in some cases)
d) The fact that the long duration single arm patients that have done so well were healthier than normal. (Note that this very likely to be an issue for Sarepta as well – as I’ve noted before their lung data indicates they were substantially healthier at baseline than typical.)
e) The blood vessel inflammation in monkeys (although I haven’t yet gotten to any section discussing it in humans).
f) The FDA asked for CINRG natural history data that was not delivered with the NDA (and the FDA couldn’t get it either).
g) The FDA has been pushing for RCTs that are 2 to 3 years long. (My comment is that this is probably the right duration – 1 year is too short given the disease course.)
The new good items (again, new to me at least):
a) The Cumulative Distribution Curves for the 6MWD RCTs look fairly repeatable, which lends credibility.
b) The totality of the CK data is fairly strong – although, as the FDA notes, the CK can be fooled. But as some know it is the first thing I look for because it is a much more standardized (and thus reliable) assay than the various dystrophin markers. E.g. It is, in fact, often the first indicator that a patient has DMD.
And the ‘who knows’ items:
1) The one off events – i.e. the MI, the GI blockage and the thrombosis – are all known to be in areas more common in DMD. Thus it wouldn’t be possible to determine the drug dangers (if any) in this area without a much bigger RCT.
2) The dystrophin assay data.
Note that the reveals are generally of the magnitude that I expected - so I am a little surprised at the twitter reaction by the biotech cognoscenti. The only item where I am somewhat disappointed in Biomarin for not being more forthright is the sudden onset nature of the severe thrombo - the rest is just par for the course unless we start expecting every company to publish a 200 page self flagellation piece. (And note that even the Clinical Trials site doesn't allow for that level of self disclosure).
