Sages and Mariners

The report from SAGE Therapeutics about their pilot data in Post-Partum Depression (PPD) raised plenty of eyebrows, (and their market cap, briefly, by about $420 million). A planned fifteen patient study was cut short after the first four patients showed a complete reversal of their depression, their Hamilton scores nearing zero  60 hours later. SAGE said that they would run a controlled trial to confirm the signal, and this apparent radical improvement in PPD symptoms is well-deserving of a placebo-controlled study.  At the same time, there was some appropriate skepticism about the predictive value of results from four depressed patients receiving an IV infusion of an experimental drug, a set-up for a placebo effect if ever there was one.

There was an eerie correspondence between these SAGE-547 results and the Severe Status Epilepticus ‘compassionate use’ results that launched SAGE towards credibility and Phase II validation. Four patients were treated, all improved, no patients received placebo. Of course, placebo response is less of a concern in patients who are in Status Epilepticus, but it most certainly is in depression, and it could, in theory, explain these pilot results. But there is biology that suggests that SAGE-547 could be useful in this subtype of depression: SAGE-547 is, after all, a form of allopregnanolone, and women with PPD have been reported to have lower levels of endogenous allopregnanolone than their nondepressed PP peers, and it has been suggested that allopregnanolone may be protective against depression (Hellgren & Akerud, Neuropsychobiology, 2014). The results obtained by ketamine, JNJ‘s esketamine, and Naurex‘s GlyX-13 in major depression (not associated with the post-partum period) also have shown that rapid antidepressant impact is achievable.

Unless it turns out that these four women all belonged to the same New Mother’s coffee klatch, and were comparing notes, our guess is that there is a genuine signal showing itself in this pilot study. Its magnitude probably will not turn out to be as remarkable in its impact on the Hamilton as these results indicated, but one does not have to completely reverse depressive symptoms to achieve something of clinical value.

SAGE states they will develop a different, orally bioavailable molecule for PPD, once the signal has been confirmed. The utility of oral administration is obvious, but SAGE also has a pricing problem: They need to maintain SAGE-547 as a premium-priced compound for last-resort, hospital- based interventions in SSRE, a price-level that would not be sustainable for the much larger PPD population. Thus they need an alternative compound, and will go into their massive chemical portfolio to identify one.

This brings us to Marinus Pharmaceuticals. While Marinus has labored in the shadow of SAGE, their reformulated oral version of ganaxolone is itself a form of allopregnanolone, or in other words, similar to the oral compound  SAGE must now bring forward from preclinical development (SAGE would probably argue that their chemical scaffolds have pharmacokinetic advantages, but that is a secondary issue). With clinical trials already ongoing in epilepsy and Fragile X, it would seem an obvious next step for Marinus to run a pilot study in PPD. The results are unlikely to be as dramatic, the bioavailability of ganaxolone given orally is not going to match that of SAGE-547 given IV, but unless SAGE’s results do reflect purely a placebo effect heightened by the IV administration route, or ganaxolone cannot achieve sufficient bioavailability, a signal might be obtainable.

An oral drug that proves useful in Post-Partum Depression could be an option for prophylaxis in the substantial proportion of women who stop their antidepressants during pregnancy, for fear of harmful prenatal effects. It might also be possible to assay serum allopregnanolone levels to identify women at risk, and thus in need. At present, they are defenseless as they go through the extremes of hormonal disruption; stabilizing/protecting them during the storm would be highly useful, and given that the process  simply upregulates levels of an endogenous neurosteroid, it is likely to be safe.

The bottom line is that this likely to be (again) good news for SAGE Therapeutics. It could potentially be as good or better news for Marinus Pharmaceuticals. Assembling better quality, controlled studies to confirm or disconfirm the signal should be a priority for both companies.

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