Despite some encouraging top-line data from Sage Therapeutics Inc.’s phase III Mountain study of SAGE-217 on depressive symptoms in adults with major depressive disorder (MDD), the company, the market and analysts were taken aback at the trial’s failure to hit its primary endpoint. 

J.P. Morgan analysts were “surprised by the highly disappointing” results, which also “came as a complete surprise” to Jefferies analysts. SVB Leerink analysts noted it was “a major surprise to investors.” Guggenheim Securities added the results were “disappointing (and highly unexpected).” 

That they were. The stock (NASDAQ:SAGE) closed down 59.7% at $60.18 on Thursday for a loss of $89.03.

In the study, 581 patients were randomized to receive SAGE-217 20 mg or 30 mg, or placebo, once-nightly for two weeks. The endpoint was a statistically significant reduction from baseline in the 17-item Hamilton Rating Scale for Depression (HAM-D) total score at day 15. The top-line results showed SAGE-217 30 mg, given once daily as an oral treatment, was associated with a mean reduction of 12.6 in HAM-D total score compared to 11.2 for placebo (p=0.115). Patients in the SAGE-217 30-mg group achieved statistically significant reductions in the HAM-D total score at days three, eight and 12 (p<0.018 for each timepoint).  

There was an upside. 

Jeffrey M. Jonas, CEO, president and director, Sage

“Looking at the data from the primary analysis, SAGE-217 demonstrated statistical significance on the HAM-D at days three, eight and 12,” said Jeffrey M. Jonas, Sage’s CEO, president and director, on Thursday morning’s conference call for investors. “Also, part of the Mountain study design was to obtain real-world naturalistic follow-up data on people treated with SAGE-217. As you will see from the preliminary data we've obtained, long-term follow-up suggests maintenance of effect on depressive symptoms.” 

The one consistent finding, Jonas said, was that SAGE-217 worked rapidly, noting its effects on days three, eight and 12. One of the problems, he added, was that about 9% of the patients who were administered SAGE-217 had no measurable drug levels, meaning ”they most likely did not take the drug. When we move the data from these patients who apparently did not take drug, the 30-milligram dose hit statistical significance at all treatment timepoints through and including day 15.”  

Also, the study enrolled more patients with an overall distribution of milder severity of symptoms than the previous trials. A post-hoc analysis revealed that when including only patients with a HAM-D score of at least 24, which was “closer to the populations we've studied previously,” Jonas said, “statistical significance was achieved at all treatment time points [day] six through and including day 15.”   

The results reinforce that SAGE-217 is an active drug with safety data that are consistent with Sage’s two earlier trials in major depressive disorder and postpartum depression, said Steve Kanes, the company’s chief medical officer. 

SAGE-217 is an oral neuroactive steroid GABAA receptor positive allosteric modulator. The GABA system is the brain and the central nervous system’s major inhibitory signaling pathway. 

Jefferies analysts wrote Thursday that “we wouldn't be surprised if Sage eventually decided to run another randomized phase III MDD study (we think it could be prudent as well), possibly with a narrower trial design such as utilizing an in-patient/out-patient criteria (ensures patient compliance) and/or enrolling more severe MDD patients. However, we'd argue utilizing such an inclusion criteria would hurt SAGE-217's appeal and commercial adoption.” 

Sage has SAGE-217 in two other clinical trials, both phase IIIs – Shoreline and Rainforest – with top-line data due next year. Shoreline is an open-label, long-term pivotal trial evaluating the safety of as-needed repeat treatment with SAGE-217. Patients receive an initial two-week course of therapy and as-needed retreatment, then are assessed for potential relapse of depressive symptoms for up to one year. Rainforest is a placebo-controlled pivotal trial evaluating SAGE-217 in patients with co-morbid major depressive disorder and insomnia.  

Despite Thursday’s brutal day on the market, Cambridge, Mass.-based Sage had enjoyed a strong performance this year, with its shares (NASDAQ:SAGE) up 71% when the FDA approved Sage’s 60-hour intravenous Zulresso (brexanolone) to treat postpartum depression. Zulresso consists of allopregnanolone, a potent, positive, allosteric modulator of synaptic and extrasynaptic GABA type A receptors. 

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