Novel Drug Impresses in Postpartum Depression Phase 3 Trial

Liam Davenport

September 20, 2019

COPENHAGEN, Denmark — Results of a phase 3 trial show the novel drug SAGE-217 (Zuranolone, Sage Therapeutics) for postpartum depression (PPD) was associated with significantly greater reductions in depressive symptoms over placebo that were maintained after just 2 weeks of treatment.

The drug was also associated with increased depression-remission rates vs placebo, as well as a significant reduction in anxiety scores.

The results were presented here at the 32nd European College of Neuropsychopharmacology (ECNP) Congress.

Lead author Eduard Vieta, MD, PhD, chair of the Department of Psychiatry and Psychology at the University of Barcelona Hospital Clinic, Spain, told meeting attendees that the drug was "highly effective, with an effect size that was larger than what we usually see with antidepressants."

SAGE-217 is a neurosteroid with oral bioavailability. It acts as a positive allosteric modulator of synaptic and, unlike benzodiazepines, extrasynaptic gamma-aminobutyric acid (GABA) A receptors.

Possible Mechanisms

Vieta noted that there are a number of potential genetic, epigenetic, and environmental factors driving the pathophysiology of major depressive episodes.

In PPD, mechanisms may include endocrine, neuroactive steroid, neural network, stress, inflammatory, and epigenetic factors, with one hypothesis being that reduced GABA function leads to dysregulated neural networks and, ultimately, a postpartum depressive episode, he said.

As reported by Medscape Medical News, another of Sage's neuroactive steroids, brexanolone intravenous infusion (Zulresso, Sage Therapeutics), was approved in March by the US Food and Drug Administration (FDA) as the first-ever drug indicated for the treatment of PPD. 

SAGE-217, which can be given orally, is currently in clinical development for PPD and major depressive disorder. Positive results with this agent in major depression were published online September 5 in the New England Journal of Medicine, and were reported by Medscape Medical News at that time.

The phase 3 trial that Vieta reported on included more than 150 women aged 18 to 45 years who were no more than 6 months postpartum, had been diagnosed with PPD, and had a score of at least 26 on the Hamilton Depression Rating Scale (HAM-D).

The women were randomly assigned in a double-blind 1:1 fashion to SAGE-217 30 mg or placebo once daily for 14 days, followed by naturalistic follow-up out to 45 days.

Primary Outcome Met

Results showed that by day 3, the SAGE-217 group had achieved a significantly greater reduction in HAM-D scores over baseline than the placebo group (mean reduction, 12.5 vs 9.8, respectively; P = .025).

The difference in mean scores steadily increased up to day 15, the primary endpoint, when the mean reduction in HAM-D scores over baseline was 17.8 vs 13.6, respectively (P = .003).

By day 45, women treated with SAGE-217 had experienced an average reduction in HAM-D scores over baseline of 19.2 vs 15.1 for those treated with placebo (P = .003).

The active treatment group also experienced significantly greater reductions over baseline in Montgomery–Åsberg Depression Rating Scale (MADRS) scores vs placebo (day 15 average reductions, 22.1 vs 17.6, respectively; P = .018).

By day 45, the mean reductions in MADRS scores had increased to 24.8 for the SAGE-217 group and 19.0 for those given placebo (P = .002).

In addition, at days 8, 15, and 45, significantly more women given the active drug had a HAM-D response, defined as a 50% or greater reduction in total score (P < .05).

Moreover, significantly more achieved HAM-D remission, defined as a total score of 7 or greater, at days 3, 15, and 45 (P < .05).

Interestingly, treatment with SAGE-217 was also associated with a significant reduction in Hamilton Anxiety Rating Scale scores over baseline compared with placebo, at a mean reduction of 16.6 vs 12.7 (P = .006).

"Excellent Tolerability"

Vieta said that the proportion of patients with treatment-emergent adverse events (AEs) was similar in the SAGE-217 and placebo groups (60.3% vs 52.1%, respectively).

The most common AEs for the active treatment were somnolence (15.4%), headache (9%), dizziness (7.7%), upper respiratory tract infection (7.7%), and diarrhea (6.4%).

There was no indication of an increase in suicidal ideation or suicidal behavior over baseline, as measured with the Columbia Suicide Severity Rating Scale (C-SSRS).

With no worrisome safety signals, the drug has gone forward for further development, Vieta reported.

He noted that one of its advantages is its early onset of action, which is similar to that seen with glutamatergic agents, although it has the "opposite mechanism of enhancing GABA rather than opposing glutamine."

In addition, SAGE-217 has "excellent tolerability" and its oral formulation "is an advantage over other drugs that are available or close to being available, which have to be given as an infusion or intravenously," Vieta said. "Last but not least...the patients were treated only for 2 weeks."

With the benefits continuing to be seen out to 45 days, this means that there were "permanent improvements after 2 weeks of treatment. So I think this changes the paradigm of the treatment of postpartum depression," Vieta concluded.

Help for the Next Generation?

On the same day these trial results were presented, Lisa Hammond, MPH, codirector of the perinatal mental health advocacy group More Than A Tick Box and a perinatal and pregnancy mental health ambassador for the UK National Health Service, addressed a conference session dedicated to PPD.

She described her own experience with PPD, characterized by obsessive fears, debilitating tiredness, and feelings of dread.

"I would continuously check the windows, check the doors, over and over again because I was convinced that somebody was going to steal my baby," Hammond said. "No matter what anyone said, that was absolutely going to happen.

"With dread comes guilt, because you feel really guilty about dreading the days with your baby, dreading the nights with your baby, dreading trying to feed your baby; and then it's a cycle of guilt because you feel regret that you're dreading it."

Gisèle Apter, MD, PhD, professor of child and adolescent psychiatry, University Rouen, France, introduced Hammond during the session on PPD and underlined that it is an extremely serious and under-recognized illness.

In fact, it is "the most common condition and complication that one can find in perinatal health, not just mental health," she said. "This is the most important, most unrecognized, underdiagnosed condition, and we really need to talk about it."

Apter said that PPD has consequences for both mother (it's France's leading cause of death during the postpartum period) and child (effects on mental health are seen out to adolescence).

"So we're working for mothers and we're working for the next generation when we're talking about diagnosing and treating PPD," she said.

The phase 3 study was sponsored by Sage Therapeutics. Vieta has received grants from Ab-Biotics, Almirall, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, the European 7th Framework Program, Ferrer, Forest, GlaxoSmithKline, Janssen-Cilag, Novartis, Otsuka, Pfizer, Richter, sanofi-aventis, Seny Foundation, Servier, the Spanish Ministry of Health, Telefonica, the Spanish Ministry of Science and Education, and the Stanley Medical Research Institute; served on advisory boards for Allergan, Angelini, AstraZeneca, Bristol-Meyers Squibb, Sumitomo Dainippon Pharma, Eli Lilly, Esteve, Ferrer, GlaxoSmithKline, Janssen, Lundbeck, MSD, Novartis, Otsuka, Pfizer, Richert, Roche, Sage Therapeutics, sanofi-aventis, Servier, Shire, Sunovion, Takeda, Teva, and UBC; and consulted for Abbott, Angelini, AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, Forest Research Institute, GlaxoSmithKline, Janssen, Jazz, Lundbeck, MSD, Novartis, Otsuka, Pierre Fabre, Pfizer, sanofi-aventis, Servier, Shire, Solvay, and Sunovion.

32nd European College of Neuropsychopharmacology (ECNP) Congress: Presented September 8, 2019.

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