Beating placebo with a neuroscience asset in phase III is no small achievement, yet Sage Therapeutics managed to deliver this twice today, with two positive trials for brexanolone in postpartum depression.
Looking beyond the top-line numbers reveals a notable decline in efficacy from phase II and questions about durability of effect in certain patients. But jubilant investors judged these issues unlikely to harm the product’s chances of regulatory approvals, and sent shares in the company soaring 53% in early trading.
The advance takes Sage's market cap to close to $3.6bn, a huge valuation for a CNS-focused company that has yet to launch a product. Coming up behind brexanolone, which is delivered intravenously, is a pill called SAGE-217; both are described as neuroactive steroid GABA modulators, the latter being a first-in-class, novel molecule.
Phase II results for SAGE-217 in major depressive disorder are due before the end of the year and while investors seem similarly assured of the project’s success, another strong data set is crucial, if only to provide Sage with a chance at a longer revenue stream. Brexanolone is a reformulation of allopregnanolone and will only get around five years of exclusivity should it reach the market.
Off to market
The data released today make those regulatory approvals look likely. Formerly known as SAGE-457, brexanolone was studied in two trials in patients with moderate or severe postpartum, or postnatal, depression. Both trials met their primary endpoint, yielding a significant mean reduction from baseline in the Hamilton Rating Scale for Depression (HAM-D) total score compared to placebo.
No safety concerns were raised and with breakthrough therapy designation in the US and its equivalent, Prime, in Europe, brexanolone’s chances of gaining approval next year look high.
Red flags in the data set will probably only become relevant when brexanolone reaches the market and has to compete with other options. True, there is nothing specifically approved to treat the condition, though various anti-depressants are prescribed. But that could change in the near future – Marinus Pharmaceuticals is due to start reporting data from its phase II postpartum depression programme early next year, with a similar agent called ganaxolone. Shares in the company opened 17% higher today on hopes for comparable success.
Results from Marinus will be held up against the data below, which shows that Sage delivered a stronger placebo-adjusted reading in patients with more severe depression. These patients also demonstrated a sustained, significant effect through a 30-day follow up period; a statistically significant difference in effect size was not seen over 30 days in moderate patients.
In the trial patients were infused with brexanolone continually for 60 hours, evaluated for the primary endpoint, then assessed again on days 7, 14 and 30.
|Placebo-adjusted HAM-D score change - brexanolone's clinical performance|
|Phase III||Phase II|
|Study 202B; severe (n=122)||Study 202C; moderate (n=104)||Study 202A; severe (n=21)|
|High dose: 3.7||High dose: 2.2||Active arm: 12|
|Low dose: 5.9||Not tested||-|
Sage executives put the loss of significance over time in moderate patients down to variability in the placebo arm, maintaining that in the active drug arm the effect seen at 60 hours was sustained out to day 30.
Variability was all due to the placebo arm, executives maintained, saying that they expected to see more variability at this stage than in phase III.
While the drop in effect size from phase II might not be enough to derail the brexanolone project, it should remind investors what to expect with SAGE-217. Take the placebo-adjusted effect size soon to be reported in phase II, cut it in half, then trim it a little bit more. If it still looks big enough to be clinically relevant, then perhaps the company is worth $3.6bn.