5HT-6 and Power

Axovant suffered (as of this morning) a 25% hit to its valuation in the wake of Pfizer having revealed that it terminated the Phase II trial for its 5HT-6 antagonist as an adjunct in Alzheimer’s due to a futility analysis–it was obvious that it had no chance of reaching whatever pre-specified benchmark for minimal viability they had defined. The knee-jerk reaction in the Market was to see this as being the harbinger of reduced expectations for RVT-101. But this seems off-the-mark. As NeuroPerspective and Neurogram+ have discussed at length in the past, the extensive history for RVT-101 when it was being developed by GSK suggests a consistent albeit mediocre signal in boosting cognition in AD–the efficacy data from GSK’s last Phase IIb trial showed a minuscule impact on rating scales used over a 48 week period (e.g. ADAS-cog decline altered by less than two points).
Lundbeck/Otsuka’s three current Phase III trials for idalopirdine are enrolling 720, 840, 930 patients each. Axovant is now enrolling a Phase III trial that aims for a total of 1150 patients. In other words, these two programs seek to achieve statistical significance through jamming large numbers of patients through, regardless of whether this represents a truly meaningful effect in terms of clinical function. The fact that the Alzheimer’s landscape has continued to be bleak leaves open the possibility–arguably the probability–that mediocrity will sell, for lack of anything else that can be offered as a new hope for patients and families.
The Pfizer trial was planned to enroll 186 patients–the question is begged as to why they bothered in the first place. They had the choice of either quadrupling the planned enrollment, in which case they would have been better off constructing it as a pivotal trial, or else pulling the plug on a futile enterprise. From a strategic point of view, Pfizer may have decided that arriving third, after Axovant and perhaps Lundbeck/Otsuka, was not an avenue to sufficient commercial success by their standard.
Had the Pfizer program been terminated due to an adverse event/safety issue, that would have been news. The bottom line is that this does not tell us anything about Axovant’s program that we did not already know. If anything, it reduces by one the number of companies seeking to scrape the bottom of the efficacy barrel.

Other Notes
In the January/February issue of NeuroPerspective, we had noted that the absence of news for two programs was a potential indicator of failure-yet-to-be revealed. As it turns out, while Methylation Science’s Phase II trial of Strada did not hit its endpoint, a post hoc analysis did show what they believe is a signal worth pursuing, details yet to be disclosed.  And the timeline for Neuren’s trial of NNZ-2566 in TBI extended beyond what we had expected, and simply has not been wrapped up yet–data is expected in early April.

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