Drug Development

The FDA just signed off on a Formula 1 pivotal track for Sage’s postpartum depression drug

Jeff Jonas, Sage

Jeff Jonas, Sage

Sage Therapeutics says the FDA has signed off on an astonishingly short clinical development pathway for postpartum depression which may allow for an approval after a pair of tiny Phase II studies which are already underway.

These two mid-stage studies — 202B and 202C — will read out in the second half of next year. And Cambridge, MA-based Sage says that the minutes of its FDA meeting make clear that the biotech only needs to make a few small adjustments, including an increase in sample size, to make these studies registrational.

If successful, Sage would be on track to seek out an approval in 2018. And its shares jumped 8% on the news.

According to clinicaltrials.gov, the two Phase II studies combined were set to enroll fewer than 100 patients — the kind of trial size you might expect to see for a very rare disease. The biotech is looking to build on some excitement triggered by their first tiny study.

In an email to Endpoints News, CEO Jeff Jonas says that transitioning to a pivotal effort will require about 200 patients in both studies. And the biotech is also opening up sites in the EU. But Jonas cautions against reading too much into possible implications for other biotechs.

Jonas writes:

We designed the earlier programs in the hopes of achieving this expedited review.  We felt that many factors justified an efficient development strategy.  In brief, recall that SAGE-547 is based on a naturally occurring compound, has had a reassuring safety profile with a couple hundred patients exposed to the drug across multiple settings, has a short half-life, and is administered only over 60 hours in a medical setting for PPD.  So we view this (as) a decision specifically based on the data package available regarding SAGE-547.

The green light, though, comes at a time that the FDA is attracting increasing comment for its willingness to fundamentally rewrite the rules on drug development in favor of the developers. As a “breakthrough” therapy, SAGE-547 is expected to get quick handling at the FDA. But regulators have maintained a high bar on studies related to depression, where the placebo effect has frequently scuttled clinical trial efforts.

By its own count, Sage is shooting at a disease population of 500,00 to 750,000 women in the US alone who suffer from PPD each year.

Paul Matteis at Leerink looked at the implications for Sage:

We assumed a (very) late 2019 launch previously – with just $3MM in 2019E PPD sales – thus, the updated guidance, including a 2018E NDA, may move sales a full year ahead. SAGE noted that “other minor modifications” have been asked by the FDA, but most importantly, the clinical endpoints of the study – which are standard in depression – remain the same. SAGE also believes it does not need to initiate any other studies beyond those that are currently underway; additional safety data can be obtained through open-label trials. Recall that the PPD program as it was previously outlined totaled two studies (total N = ~100) across severe and moderate PPD. For registration, we had been cautious that a larger safety database – and possibly other studies – might be required given the lack of regulatory precedent in PPD. And while SAGE did not disclosed the finalized (larger N), the ability to still generate top-line data in 2H17 represents a positive on timing, and the totality of the announcement is positive on conveying a clear development path forward.

Sage, though, has attracted plenty of short interest along the way as it hustled from tiny proof-of-concept studies to registrational studies for SAGE-547.

Sahm Adrangi’s Kerrisdale Capital has singled out Sage Therapeutics $SAGE as a big biotech short seller play, laying out a detailed argument aimed at stoking doubt in the biotech’s rare disease drug while trying to slash the company’s stock price. The Wall Street hedge fund issued a 28-page report last spring asserting that SAGE-547 — also designed to treat rare cases of protracted seizures called super-refractory status epileptics — is essentially doomed, likely poised to fail the ongoing Phase III study or come up far short on a market that’s much smaller than the developer has asserted.

In its last PPD study, Sage said that the drug–aimed at GABAA receptors in the brain–hit the primary endpoint in the Phase II, which involved only 21 patients; and only a few patients actually got the drug. Investigators tracked a 60% remission rate at 60 hours with a 30-day follow-up.

Remission, Sage reported, as determined by a HAM-D ≤7, measured at 60 hours, was seen in 7 of 10 of the SAGE-547 group compared with 1 of 11 in the placebo group (p=0.008). Similarly, at 30 days, 7 of 10 of the SAGE-547 group and 2 of 11 in the placebo group were in remission (p=0.03).

“We are encouraged by the FDA’s feedback and appreciate their guidance regarding our SAGE-547 development program in postpartum depression,” said Sage CEO Jeff Jonas. “Based on our meeting, we have clear and efficient direction for the expedited development path forward for SAGE-547 to potentially support a New Drug Application (NDA) in 2018.”

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RAPS Regulatory Convergence 2017