MYOK - any thoughts on the weak dose response in part B compared to part A? This is a bit fraught, and probably better answered by someone like PGS, but I'll try. So, when you're fiddling with the low end of the dosing range, you can expect increased variability in response, IMO. Patient baseline characteristics weren't given in the PR, but were said to be similar across cohorts.
However, in cohort B, beta blockers were allowed, and in fact, 9 of 10 patients in the cohort were on them. I wondered if they could have confounded the results a bit. But while beta blockers do have some salutary effects on exercise performance, improved pVO2 isn't supposed to be one of them. They do seem to improve exercise time, but not peak capacity. At least that's what the preponderance of studies show. This seems to be reflected in this cohort: half the patients did pretty well on that metric (improvement in pVO2>2.9 ml/kg/min), and apparently half didn't improve much at all. 4/9 on beta blockers showed improvement in pVO2>2.9 ml/kg/min, a similar proportion. So it would seem that allowing them didn't affect efficacy (nor safety or pharmacodynamics, as the company noted), and that was an OK decision.
So I think it's just the low end of the therapeutic window, and small numbers causing the lack of dose response. Would I feel better if they nailed the dosing range before going to P3? That would be ideal, since it would lessen the clinical risk given that the whiffed secondary endpoint we're discussing is to be the primary in the P3. But, of course, that would take considerably more time and money. This is a small cap company going after niche indications, so that strategy isn't realistic.
The company line is that they have enough data for an optimal dose range, and that they'll have a couple of discussions with the FDA on P3 trial design. Several analysts buy it, but they may just be gunning for underwriting biz pursuant to the shelf just filed. I saw a cryptic tweet that Q&A at ACC today was "heated."
Incidentally, the abstract only adds a couple of little data nuggets on cohort A that the aren't contained in the PR. One is just granularity on a couple of population and baseline characteristics, but the other might be be meaningful. The abstract notes that "Resting LVOT gradient was <30 mmHg by week 2 in 9/10 patients." I don't know if that's clinically meaningful, or if it provides any read through to other metrics. Finally, the abstract only talks of cohort A, and notes that "One patient had a serious adverse event (AE) and withdrew from the study. All other AEs were deemed mild to moderate, and most were unrelated to study drug." Except for the SAE, that's the same language as for cohort B.
It is not clear to me if the SAE was deemed related to the study drug. If not, then we need worry even less about the performance of cohort B. If so, problem. The earnings CC shed no light on that - no analyst asked that question, which seems like it would be important (I suppose it's possible all four of them failed to read the abstract) - and the PR doesn't mention it at all. The closest anyone came was this exchange:
"Ian Somaiya (BMO)
Okay. And Mark can you just share with us or characterize the adverse events that we are seeing? I know you've broken them into related-unrelated to mavacamten, but just would appreciate getting an overall sense for the adverse event profile seen in this trial?
Marc Semigran
Sure, there'll be more details by the way at the ACC presentation and in subsequent manuscripts that will be published. But what I can say is that they were things like headache and some mild GI upset, nothing that really approached the level of as serious AE."
MyoKardia 4Q Earnings CC transcript
Since everyone seems to be glossing over it, I assume it was deemed unrelated, but I can't find clear language on that.
Anyhow, I still have no position in real life. I think I have time to resolve the SAE issue, which may require an inquiry to the company's IR dept. I won't take a position before that is cleared up. And I'm very curious about the ACC Q&A.
Cheers, Tuck
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