Calling Sage Therapeutics Inc.'s drug candidate for postpartum depression (PPD) "completely unlike anything we see in psychiatry currently," principal investigator Samantha Meltzer-Brody told BioWorld Today that the resoundingly successful phase II trial with SAGE-547 showed safety and efficacy that researchers need to investigate further but offers great hope for patients. "Obviously, this study has to lead to the next study," she said. "All of these are stepwise increments."

Meanwhile, shares of Cambridge, Mass.-based Sage (NASDAQ:SAGE) closed at $46.21, up $12.56, or 37.3 percent, Tuesday after the top-line results were disclosed from an experiment in 11 patients. "It was always meant to be this size," said Meltzer-Brody, director of the perinatal psychiatry program at the University of North Carolina (UNC)-Chapel Hill Center for Women's Mood Disorders. UNC, she said, "did the open-label trial last year with four subjects, and the response was so robust that, rather than continue a larger open-label trial, a decision was made to move to the double-blind study" that yielded Tuesday's data.

SAGE-547 achieved the primary endpoint of a significant reduction in the Hamilton Depression Rating (HAM-D) score compared to placebo at 60 hours (p=0.008). The drug, an allosteric modulator of both synaptic and extra-synaptic type-A gamma-aminobutyric acid, or GABAA, receptors, achieved a greater than 20-point mean reduction in the depression scores of the SAGE-547 group at the primary endpoint of 60 hours through trial completion, with a greater than 12-point difference from placebo. The statistically significant difference in treatment effect began at 24 hours (p=0.006), with an effect that was maintained at similar magnitude through to the 30-day follow-up (p=0.01), the company said. Remission from depression, as determined by a HAM-D ≤7, measured at 60 hours, was seen in seven of 10 of the SAGE-547 group compared with one of 11 in the placebo group (p=0.008).

At 30 days, seven of 10 of the SAGE-547 group and two of 11 in the placebo group were in remission (p=0.03).

SAGE-547 was found to be generally well-tolerated with no serious adverse events reported during the treatment and follow-up periods. A greater number of adverse events were reported in the placebo arm than in the treatment arm of the trial.

There are no approved therapies specifically for PPD and therapeutic options in severe PPD are limited, Sage noted.

Meltzer-Brody said antidepressants and psychotherapy "can be effective in many women. It's just that the response rate is not as high as we would ideally like to see," and time is needed to find the right combination of drugs – as well as four to six weeks for the drugs to take effect. UNC has "the first and still one of the only in-patient perinatal psychiatry units in the country," she said, so the facility was "very well poised" to get the right patients for the Sage trials.

OVERCOMES PLACEBO RESPONSE

PPD's underlying causes are unknown, Meltzer-Brody said, and selecting subjects for such experiments represents a challenge in itself. "If you just screen a population of women postpartum and see if they're depressed, you have to factor in how many of those people have had chronic depression for 20 years," she said. "We know from the epidemiology that the first month [marks] the greatest prevalence of depression that you will see any time in a woman's life. We know that there are extremely high levels of the gonadal hormones, estrogen and progesterone, during pregnancy, and in all women, these plummet at the time of childbirth."

Susceptibility to the fall of the hormones likely has a genetic component, she said. One in eight women suffers PPD, though not all as severely as others. Along with symptoms of major depressive disorder (of which PPD is a subset), including low energy and suicidal thoughts, "you can also see a lot of anxiety, worry and ruminating," she said. "One thing that makes [PPD] particularly difficult is that this occurs at a very inopportune time."

SAGE-547 performed well despite a strong placebo response in the trial, Cowen and Co. analyst Ritu Baral pointed out. "Based on conversations with key opinion leaders [KOLs] and reviews of the literature, we estimate the placebo response (10 patients) to be on the higher end of normal (KOLs expected a placebo response in 6-7 patients, with literature showing up to a about a 13-point benefit on HAM-D in published studies)," she wrote in a research report. The drug prevailed despite the placebo response, "further underscoring its potential clinical utility," she said.

Even more enthusiastic was J.P. Morgan analyst Cory Kasimov, who said he was "very impressed" by the results. "Overall, we view the data as a best-case scenario for a small phase II trial, given the dramatic treatment effect and clean safety profile," he wrote in a report, observing that "it appears [the drug] had a more tolerable profile than placebo with fewer adverse events reported in the treatment group. While we're looking forward to seeing more nuanced data in future presentations and publications, the data were everything we were hoping to see and we aren't surprised to see the Street's welcome reaction. Going forward, we anticipate these results will give investors a boost of confidence in SAGE-547, as well as management's ability to design and execute a controlled clinical trial."

The news is good for Ligand Pharmaceuticals Inc., too. "SAGE-547 is one of 'The Big 6' products for Ligand as a future potential royalty revenue driver and today's news in PPD could represent a big boost to this revenue in the future," Roth Capital Partners analyst Joseph Pantginis wrote in a report.