Sage Still Sees Approval Path After Depression Drug Fails In Phase III Trial
Executive Summary
Sage Therapeutics points to patient compliance and selection as factors in its failed trial of SAGE-217. The company sees positive implications in the data as it waits for other SAGE-217 studies.
Sage Therapeutics Inc. executives are positioning the failed MOUNTAIN trial of its antidepressant SAGE-217 as more of a molehill and suggesting that the data could still be supportive of a new drug submission to the US Food & Drug Administration.
The firm announced SAGE-217 had missed the primary endpoint in the Phase III trial in acute treatment of major depressive disorder. However, the company’s review of the data indicates that there was a problem with compliance, as many patients had no detectable level of drug in their blood, and that there was a high number of patients with less severe depression. Reanalysis of patients with more severe MDD showed significant effect for SAGE-217.
Sage chief medical officer Stephen Kanes told a 5 December investor call that the company is currently thinking “about how we can use the data at hand, including the results from this study which we referred to as supportive, to put together a filing,” noting that Sage is in “ongoing talks with the FDA.”
Sage is banking on the appeal of a new treatment paradigm unlike that of other oral antidepressants, which require daily maintenance doses to control the condition. SAGE-217, a next-generation positive allosteric modulator optimized for selectivity to synaptic and extrasynaptic GABA-A receptors, is taken for only two weeks and then stopped. The drug is seen as an oral successor to Sage’s postpartum depression drug Zulresso. (Also see "Sage's Zulresso Launch Is Off, But Not Running " - Scrip, 6 Aug, 2019.)
Reanalysis Shows Success
In the MOUNTAIN trial, 581 randomized patients received nightly doses of 20mg, 30mg, or a placebo for two weeks. The 30mg dose was associated with a mean reduction of 12.6 in the Hamilton Rating Scale for Depression (HAM-D) total score after two weeks, compared to 11.2 for placebo (p=0.115). The 20mg dose of SAGE-217 did not show a difference from placebo.
CEO Jeff Jonas told the call that there were two factors potentially affecting trial results. For one thing Sage’s post hoc analysis of the patient blood-level measurements found that 9% of the 30mg group had no measurable drug concentration.
“This is a long half-life drug and the assay is sensitive down literally to the nanogram level. So they had undetectable drug,” he said. Patients were assessed at day 8 and day 15, and “given the pharmacokinetics of the drug and the sensitivity of the assay and the time point that we sampled, they weren't taking drug. There's just no other explanation for it. So that's it. So they just didn't take drug.”
After excluding these patients from the analysis, the company found there was a statistically significant improvement at all timepoints through and including Day 15 (-13.0 for 30mg vs. -11.2 for placebo at Day 15, p<0.048).
Jonas also said that the MOUNTAIN study enrolled more patients with a milder severity of symptoms (less than 24 on the HAM-D scale) than had been enrolled in previous studies of SAGE-217. “Patients with milder symptoms are more heterogeneous, have a more variable response, and of course, statistically, there is numerically less room for improvement,” he said.
When including only patients with a HAM-D of at least 24 (n=124 for SAGE-217 30mg), a post-hoc analysis demonstrated statistical significance at all timepoints through and including Day 15 (-13.7 for 30mg vs. -11.4 for placebo at Day 15, p<0.032). Analyses utilizing a HAM-D cutoff of 25 or 26 were also statistically significant, the company reported.
The company noted that there was rapid onset, with effect showing at Day 3, and that improvements in depressive symptoms were sustained in all treatment groups through Day 42 of the double-blind portion of the study. Long-term follow-up data will be collected at six months.
Secondary endpoints included the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A) total score, among others, but Sage is not releasing secondary endpoint results at this time.
Filing Planned, But Unclear
Sage management attempted to assure investors and analysts that the totality of the data will support FDA approval of SAGE-217, declining to provide clarity about its regulatory plans or address whether it would conduct another study. The drug has already succeeded in one Phase III trial in MDD, and two more – SHORELINE (retreatment) and RAINFOREST (comorbid MDD and insomnia) – will report out in 2020. In addition, the drug has succeeded in a Phase III trial in postpartum depression. (Also see "Sage Impresses With Second Postpartum Depression Therapy" - Scrip, 8 Jan, 2019.) Execs also noted that SAGE-217 has breakthrough designation, so the firm is in close consultation with the FDA.
“We view this study as … strongly supportive of a generalized MDD filing,” Jonas told the call. “Even if you just look at the data we presented, if you look at forest plots, it's all in the right direction in terms of drug activity. So I think at this point, our plans are going to remain the same. We have other studies that will really completely inform how this drug ought to be used. We're encouraged by the maintenance data we've seen here. So I think our intent right now is, based on the data from this study, is that the pathway to MDD and PPD combined remains open for us.”
Jonas did say that MOUNTAIN’s results suggest that Sage rethink study methodology.
“Ultimately, what we'll do is we'll look at the procedures, not the data but the procedures that are going on in the ongoing studies and see if there's anything we need to amend,” he said.
Analysts Hope For Another Trial
Jeffries analyst Andrew Tsai commented that the company’s next steps were “murky” and suggested that Sage’s options might become clearer as it releases SAGE-217 trial results from the other major depression studies. “Our base case assumption is for Sage to ‘wait’ until 2-3 of the MDD expansion studies readout, since company believes at least one of those could serve as a ‘backup’ pivotal,” he said in a 5 December note.
Meanwhile, analyst Tim Lugo of William Blair found some encouragement in the post-hoc data. “We do not view it as a complete failure for the program given the continued rapid effect of SAGE-217.”
Lugo also noted Sage’s “strong pipeline” of neurological and psychiatric drugs, said, “We still see potential for SAGE-217 in several depressive disorders. There is a precedent for approval with [Johnson & Johnson’s] Spravato, which was approved based on a positive Phase II study and a positive Phase III relapse prevention study after failing a prior Phase III study.”
The company’s stock fell 50.7% on the news, closing at $60.18.