In 2015, we first reported on SAGE-547 (SAGE Therapeutics), a new medication for the treatment of postpartum depression (PPD).  SAGE-547, now called brexanolone, is a neurosteroid, an analogue of allopregnanolone and an allosteric modulator of GABAA receptors.  Since that time, Sage Therapeutics has conducted three randomized controlled trials, enrolling a total of 247 women diagnosed with moderate to severe postpartum depression.  Last year, the US Food and Drug Administration (FDA) advisory panel voted unanimously in favor of approval for brexanolone intravenous infusion for the treatment of PPD.  

One of the obvious downsides of brexanolone is that it must be given intravenously and thus may require inpatient hospitalization in order to administer.  Although this might seem like an obstacle, I suspect that many women with severe PPD would easily sign on for this type of treatment if they had a significant chance of improving within a few days.  We could also argue that being in the hospital, even for a few days, might be beneficial, in that it could provide some respite from the demands of caring for a newborn. However, this will significantly increase the cost of treatment.

The Robin Study of SAGE-217

Sage Therapeutics has also been developing an oral analogue of allopregnanolone – SAGE-217.  Last week the company released the results of a Phase 3 clinical trial in postpartum depression.  In this randomized controlled trial, the Robien Study,  151 women diagnosed with severe PPD (HAMD-17 ?26) were treated with 30 mg of SAGE-217 or placebo.

After two weeks of outpatient treatment, women receiving SAGE-217 had a statistically significant greater improvement in the Hamilton Rating Scale for Depression (HAMD-17) scores than women taking placebo, 17.8 points with active treatment versus 13.6 for placebo.  The effect was maintained through the four-week follow-up (-19.2 vs. -15.1; p=0.0027).

After two weeks of treatment, remission (as measured using HAM-17 scores) was achieved in 45% of women treated with SAGE-217 compared to 23% of women receiving placebo.  At the four-week follow-up timepoint, 53% of patients receiving SAGE-217 achieved remission compared to 30% of women receiving placebo.

The press release notes that women receiving SAGE-217 showed statistically significant improvements on the Hamilton Anxiety Rating Scale (HAM-A) compared to placebo but did not provide specific data on this aspect of the study.

What’s Next?

This is all very exciting.  Here is an antidepressant which appears to have efficacy for the treatment of postpartum depression and which also seems to work very quickly.  Given traditional antidepressants which typically take 4 to 6 weeks to have a significant effect, having a treatment which may result in remission of depression within two weeks seems something like a miracle.  

But other questions need to be answered.  How long do the effects of these allopregnanolone analogues last?  We know that women remain well two weeks after stopping treatment, but how long will the effect last?   Patients taking conventional antidepressants experience high rates of relapse if they discontinue an antidepressant prematurely (before six to nine months after remission).  Will agents like SAGE-217 yield more sustained remissions?

Thinking even farther down the road, could we use these agents to prevent postpartum depression in women who are at risk – for example, women with histories of PPD after a previous pregnancy?  (However, we will need to have more data on how these medications pass into the breast milk and how they affect nursing infants before we pursue this option.)

Stay tuned.

Ruta Nonacs, MD PhD

Sage Therapeutics Announces SAGE-217 Meets Primary and Secondary Endpoints in Phase 3 Clinical Trial in Postpartum Depression




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