Welcome to your weekly digest of approaching regulatory and clinical readouts. With one positive trial for postpartum depression under its belt Sage Therapeutics will be keen to keep up the momentum when phase II results with SAGE-217 in bipolar depression read out in the next few months.
The primary endpoints of the Archway study are safety and tolerability, so the results are unlikely to move the needle on Sage shares, which have already increased by 67% since the start of the year.
But secondary endpoints include improvements in depression as measured by the HAM-D and MADRS scores, so success in this particular population would strengthen the case that SAGE-217, a first-in-class oral GABA modulator, differs from the competition.
Further differentiation could come from successive trials. The next big catalyst is phase III results in major depressive disorder (MDD), now expected in the fourth quarter or early 2020.This is where analysts see the most value for SAGE-217.
Success in MDD, alongside significantly derisking the project, would also go some way to justifying Sage’s $7.7bn market cap. This valuation could be further bolstered by the expected approval on March 19 of the group's most advanced project, the IV GABA modulator Zulresso, on which the oral asset SAGE-217 is based.
For now SAGE-217 remains one the biggest projects in the CNS pipeline, but as anyone following the CNS sector knows midstage trials are one thing; the real test is delivering phase III success.
|Selected key SAGE-217 trials|
|Archway||Bipolar depression||H1 2019||Phase II||NCT03692910|
|Mountain||Major depressive disorder||Q4/2020||Phase III||NCT03672175|
Sage’s direct competitor, Marinus, saw its stock spike on recent news that it was starting a pivotal trial of oral ganaxolone in children with a rare genetic form of epilepsy.
But the bulk of ganaxolone’s sellside consensus forecasts concern sales in postpartum depression. As investors now look to the two trials in this disorder due to read out in the first half, they will be keenly aware of the setbacks Marinus has already suffered.
The Magnolia trial, initially testing ganaxolone by 60-hour IV infusion, was delayed before reading out inconclusively in December, and in January the commercial opportunity was turned on its head by positive data from Sage’s SAGE-217. The trifecta of disappointments was completed last month when Marinus’s chief executive resigned.
Still, the two upcoming readouts, from the Amaryllis trial and part two of Magnolia, are important in determining how Marinus might proceed with pivotal development. The idea – at least until SAGE-217 scored – was that a non-hospital postpartum depression drug was needed to rival Sage’s IV Zulresso.
Amaryllis tests undisclosed oral ganaxolone doses, and while its clinicaltrials.gov entry cites a placebo-controlled design Marinus’s latest investor update said the efficacy endpoint would look at changes in HAM-D17 scores versus baseline. Interim data in December showed a 13.2-point HAM-D17 reduction at 28 days, which the company said supported its IV-to-oral approach.
Magnolia, meanwhile, could provide further evidence, thanks to its second part, which Marinus says tests an IV dose of shorter duration than 60 hours, followed by oral ganaxolone. However, clinicaltrials.gov sheds no light on this design, and calls Magnolia a trial of IV ganaxolone.
Leerink analysts reckon the pivotal path in postpartum depression could involve two similarly sized studies like Sage’s, and/or a partnering deal. However, given that the market now thinks SAGE-217 could become the first oral drug for postpartum depression, Marinus will probably need knockout data to attract a licensee.
Given the lack of clarity from Marinus, and the threat from Sage, perhaps focusing on epilepsy is a better bet.
|Marinus’s trials of ganaxolone in postpartum depression|
|Magnolia part 1||IV (60 hours)||NCT03228394||Reported Dec 2018|
|Magnolia part 2||Undisclosed IV to oral||NCT03228394||Topline, H1 2019|
|Amaryllis||Oral (undisclosed)||NCT03460756||Topline, H1 2019|
|Source: company presentation & clinicaltrials.gov.|