An Unholy Trinity of Bad News
In descending order of Disappointment to Disgust:
1)SAGE Therapeutics and Brexanolone in SRSE:
When asked this year what nearterm clinical trial results inspired the most confidence for us, we often mentioned the SAGE Therapeutics trial of SAGE-547/brexanolone in Super-Refractory-Status-Epilepticus. After all, in a pilot study of four patients who had not responded to multiple attempts to wean them from anesthetics, brexanolone had allowed three of them to be weaned without relapsing into continual seizure activity. Seizures are, compared to most neurological signs and virtually all psychiatric signs, objectively verifiable, and there was a seemingly sufficient biological ‘explanation’ for brexanolone’s efficacy in SRSE. Because of this, we sipped the Kool-Aid around the concept that this tiny pilot study was more predictive than most.
So much for confidence. Brexanolone underperformed, placebo overperformed, the two treatment conditions were identical in their impact upon anesthetic weaning. Admittedly, SRSE is a heterogeneous disorder with multiple causes and comorbid conditions, and the standards of care for different clinical settings can differ. But still, in a population that heretofore had been considered pretty intractable, being tried on their third epilepto-suppressive option after failing the first two, we never expected that the third option would produce a 42% remission rate on its own, without brexanolone. We do not see any changes in enrollment criteria between Phase II and III that would appear problematic, there is the variability incurred by the reliance upon multiple clinical trial sites, and perhaps data-mining could eventually provide a better explanatory hypothesis. But SAGE is abandoning the SRSE indication, it is Post-Partum Depression coming up next, with a back story of very impressive pilot data that is less reassuring than it was in SRSE. The rationale for PPD remains pretty solid and warrants some optimism, whereas the hopes for brexanolone’s efficacy in Major Depression are on much softer biological ground; the endpoints for both are ‘squishy’.
2) Axovant and Intepirdine:
On the other hand, we were never enamored of the RVT-101/intepirdine thesis in Alzheimer’s. As we said in NeuroPerspective’s Alzheimer’s review last month:
“…the premise is that an earlier, mediocre differentiation from the control group can be buttressed and enhanced via a higher-powered trial. Our view is that the higher-powered trial may provide intepirdine’s results with statistical significance, though the idalopirdine outcome is a cautionary note that trial size does not guarantee a better statistical profile. But even if it does accomplish this for intepirdine, GSK’s data points to a clinically mediocre, arguably meaningless effect.”
As it turns out, the close-up focus provided by powering up the trial by enrolling over 1300 patients did not reveal subtle benefits, but instead highlighted the flaws; brexanolone failed where it counted. Which saves the field from having to contend with, as it almost did with solanezumab, the cynical calculations weighing statistical significance versus clinical meaninglessness. That is an ethico-statistical conundrum that will likely come up again, with aducanumab, if not before.
3)Allergan Cooks Up An Imaginary Casino
NIR has republished several of Brent Saunders’ eloquent comments regarding the relevance of social responsibility to the longterm viability of the pharmaceutical industry, the implicit ‘social contract’ he admirably invoked in limiting annual price increases for marketed products. And Allergan has executed some of the most promising partnerships/acquisitions in the CNS sector: e.g. Naurex, Heptares, and Lysosomal
Therapeutics. But they just squandered much if not all of their accumulated good will with one of the most bone-headed, tone-deaf tactical decisions we have ever seen: Transferring their Restasis IP to an American Indian tribe in the hope of protecting their IP from a patent challenge. It is the kind of brazenly cynical maneuver that draws Congressional attention and public derision. For NIR, watching a Company that seemed to be feeling its way towards an intelligent balancing of business and ethical obligations pursue this kind of brazen end-around is like seeing surveillance video of Santa Claus brewing meth in an RV out in the New Mexico desert–we had believed that they were better than that.