This is a big day for clinical trial data, and unfortunately it didn’t get off to a very good start. Everyone is waiting for more data on Biogen’s Alzheimers program later today, but another anticipated trial has already read out.
Sage Therapeutics made quite a few headlines in 2017 and 2018 when their trials of brexanalone (allopregnanolone) showed efficacy against post-partum depression (PPD), an indication that the drug was approved for this year under the name of Zulresso. This neurosteroid is an allosteric ligand of the GABA-A receptor, and this was believed to be its mode of action. But keep in mind, that’s a bit of a hand-wave: no one actually understands what exactly an allosteric GABA modulator is doing to improve depression symptoms, not in any detail. The fact that we don’t understand the molecular workings of depression in general is the place to start. You can go ask people and hear things about serotonin, about GABA, about dopamine and so on, but to be honest, there are surely connections with all of those but when you try to connect the dots you end up with stuff that’s about a half step away from folklore. We don’t know. Any people who speak confidently about the biochemistry of depression are either fooling themselves or trying to fool you, possibly both simultaneously.
Zulresso has to be given i.v., in a long slow infusion under medical supervision, so Sage has been working on an orally available compound with what should be a similar mechanism, SAGE-217 (zuranolone). That one has been in trials against major depressive disorder (MDD), and that readout has been awaited with a mixture of hope and fear by investors, because getting something to work in that field is very, very hard – but getting a new drug with a new mechanism of action would for the same reasons be very good news indeed. The Phase 2 data looked promising, albeit in a small trial. Sage-217 has naturally also been in trials for PPD, and these have shown positive results so far, and it’s also being looked at in bipolar disorder. It perhaps needs to be pointed out that we don’t understand the detailed biochemical differences between post-partum depression, bipolar depression, and major depressive disorder, either. There’s no basis for a theory-based decision here; clinical data rule, as they always do.
Well, it looks like the “very, very hard” side won out this time, sadly. The drug missed its primary endpoint in the MOUNTAIN trial, showing no benefit versus placebo in a depression rating scale at day 15. The company is trying to put a good face on the numbers, pointing out that statistical significance was reached at the earlier time points, but I honestly don’t think that’s worth much: those effects, if they are real, most certainly seem to wear off. Looking quickly at the data, the placebo group did pretty much the same thing in both Phase 2 and Phase 3, while the drug’s efficacy took a powerful drop in the latter, which is exactly what you don’t want to see. Update: an an interesting side issue is that it appears that nearly 10% of the patients in the trial appear not to have been actually complying with the drug dosing, according to the blood work. Trials in depression are not always easy to interpret, because there often is a noticeable placebo effect, but this looks like just another case of “smaller trial good, larger trial bad”. That positive Sage-217 Phase 2 trail had 45 patients in the treatment group, for example. This nasty transitions happen in CNS, in oncology, in cardiovascular, it happens all over the place and it usually means that a drug just doesn’t work. Remember, the eventual market is going to be a larger and more heterogeneous population than even the largest Phase III trial, so if a therapy can’t make the move to a somewhat larger group in the clinic, well. . .
This is not good news for anyone hoping for something new in this therapeutic area, of course, and it’s not good news for the company’s investors, either. Sage stock had been up to pretty high levels on the hopes for further efficacy in MDD, but as I write this it’s down about $94/share (63%) in the premarket, which means that several billion dollars of market cap have evaporated. The arguments will surely be starting up about whether this selloff is overdone or not, but that comes down (from what I can see) to arguments that rest on our ignorance of the molecular basis of depression, which is not a firm foundation on which to build your financial future. So this is going to be one for the brave and for those with money that they can afford to lose. A lot of it is certainly being lost this morning.