Assorted Interim Comments

1) Scott Gottlieb as FDA Commissioner:
Gottlieb was Deputy Commissioner during the all-too-brief tenure of Mark McClellan, and we have followed his commentaries with interest and generally with agreement over the past decade+. We do believe that he has more appreciation than some for the costs of inaction, the casualties incurred by overcaution and the prioritization of statistical purity. Gottlieb has multiple ties to the pharmaceutical and investment communities, which is a red flag for some observers, but we prefer that the Commissioner know how ‘the sausage is made’, and not enter the regulatory fray with an obstructionist agenda. In terms of balancing attitude and expertise, he is far superior to the other rumored candidate, Jim O’Neill, who even questioned the principle of efficacy testing prior to approval. That would have been a libertarian ideal taken to the absurd extreme. Gottlieb will likely feel some pressure to ‘push back’ against pharma agendas in order to prove his independence, but he is thankfully not an Administration appointee who does not believe in and/or understand his own Agency and role within it (see EPA, HHS, HUD appointees, perhaps State as well). Gottlieb is one of the better picks made by this Administration (not the highest of bars), and we look forward to seeing what pragmatic improvements he can instill at the FDA.

2) Neuren’s trofinetide and Rett Syndrome: Neuren’s Phase IIb showed that trofinetide performed as hoped on three endpoints in this orphan disorder–for which there is no approved therapy, and nothing else that has shown this well in human testing. The investor community appears to have shrugged, for reasons that are unfathomable.

3) Speaking of rare genetic disorders, the AveXis data in Spinal Muscular Atrophy thus far looks highly impressive, and must be worrying Biogen, who already made a serious error in hyper-pricing Spinrazza.

4) Allergan announced Phase II data for Botox in Major Depression, and much of the analyst commentary focused upon it ‘hitting’ statistical significance at the three and nine week timeframes, ‘missing’ it at six weeks. But consider these MADRS changes (compared to placebo) and p values:

Three weeks   -4.2  p=.005

Six weeks -3.9  p=.053

Nine weeks -3.6  p=.049

Setting aside the question of mechanism (one theory being that altering facial musculature impacts a feedback loop mediating subjective mood), and setting aside the question of whether subQ injection of saline is an adequate placebo, or whether Botox functionally unblinds itself due to the specific sensory attributes of botulinum injection: The six week change is barely different from the three and nine week figures, all are relatively mediocre, paling compared to the MADRS change scores reported for vortioxetine, esketamine, and ALKS 5461. The six and nine week p values are almost identical, even though they are on opposite sides of the erstwhile .05 divide. Analysts who treat p values as if they are binary miss the point, the ‘tyranny of .05’, as we have discussed in the past.  In this case, the p values are nearly irrelevant: What is relevant is the mediocrity of the therapeutic impact. Even if this reflects a ‘real’ effect, the world is not waiting for what looks like Viibryd/vilazodone in efficacy, but requires injection. It is not as if Allergan has no good antidepressant options, they have some of the best: Allergan has rapastinel in an extensive Phase III program, and the next-generation version of NRX-1074 is being prepared for testing as an oral rapid-acting antidepressant. Why do they need to squeeze a few more dollars out of the hardest working toxin in the Pharma Biz? The ability to (perhaps) power a study to beat p=.05 does not make it a good idea–ask Lilly. At some point, Allergan will have to accept reality, throw Botox a party, thank it for its services, and buy it a condo in West Palm Beach.

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