NEW YORK — Brexanolone (Sage Therapeutics), an intravenous (IV) formulation of allopregnanolone, decreases symptoms of moderate and severe postpartum depression (PPD), results from two phase 3 trials show.
In the first trial, which included about 100 women with moderate PPD, those who received IV brexanolone 90 µg/kg/hr as a 60-hour inpatient infusion showed a significantly greater reduction from baseline total score on the Hamilton Rating Scale for Depression (HAM-D) to hour 60 compared with those who received matching placebo (reductions of 14.2 points vs 12 points).
Even more exciting, note the investigators, was the significant decrease in baseline HAM-D total score seen as early as hour 48 in the active-treatment group, which was maintained through day 7.
The second trial included women with severe PPD who were randomly assigned to receive brexanole at 90 or 60 µg/kg/hr or placebo. Both the higher- and lower-dose groups had significantly greater reductions in mean HAM-D total scores from baseline to hour 60 than the placebo group (reductions of 18 and 20 points vs 14 points).
In addition, those treated with any dose of brexanolone in either trial showed significantly greater improvement at hour 60 in scores on the Clinical Global Impression–Improvement (CGI) scale than those treated with placebo.
The most common adverse events (AEs) in the trials were headache, dizziness, and somnolence.
Both studies were presented in posters here at the American Psychiatric Association (APA) 2018 annual meeting.
C. Neill Epperson, MD, professor of psychiatry and obstetrics/gynecology at the University of Pennsylvania Perelman School of Medicine, Philadelphia, who was one of the site principal investigators, told Medscape Medical News the results are especially important because there are currently no therapies indicated specifically for the treatment of PPD.
“We saw a rapid effect that was durable up to 30 days, which I think is just a game changer for women in the postpartum period. Having something that would work more quickly in this population would be a godsend,” said Epperson.
“Double Problem”
Immediate former president of the APA Anita Everett, MD, told Medscape Medical News that PPD is a “double problem” that hurts both the mother and the child.
Dr Anita Everett
“Postpartum depression is much more common than we thought several years ago, and we’re also learning more about the disruption in mother-child bonding. So any kind of intervention that works quicker, because of the developing infant, is really important,” commented Everett, who was not involved with this research.
The investigators note that overall, 11.5% of new mothers experience PPD in United States each year. Estimates among individual states vary from 8% to 20%. Current treatment includes psychotherapy “and judicious use of antidepressants,” they write.
“Traditional medications take quite a while, at around 6 weeks or even longer, to adjust the dose or to understand the tolerance of side effects,” said Everett. “So something that had a little bit greater likelihood of it working to begin with, and quickly, is something that would be of great interest to the field.”
Brexanolone (known previously as SAGE-547 injection) is an allosteric modulator of gamma-aminobutyric acid A (GABAA) receptors.
The drug has been granted breakthrough therapy designation by the US Food and Drug Administration (FDA) and priority medicines designation by the European Medicines Agency. The manufacturer announced last month that it has submitted a new drug application to the FDA for the treatment of PPD.
As reported by Medscape Medical News, findings from a phase 2 trial of the study drug were presented at last year’s American Society of Clinical Psychopharmacology annual meeting. Results showed that, among 21 patients with severe PPD, those treated with brexanolone had a signficantly greater reduction in HAM-D score vs those treated with placebo. Improvement in depressive symptoms was shown as early as 24 hours post treatment.
Hummingbird Studies
The two new phase 3 trials were created as part of Sage’s Hummingbird Program to evaluate efficacy, safety, tolerability, and pharmacokinetics of the injectable drug for treating moderate and severe PPD.
All participants were aged 18 to 45 years and had given birth no more than 6 months prior to screening. “Subjects were diagnosed with PPD based on a major depressive episode no earlier than the third trimester and no later than the first 4 weeks following delivery,” write the researchers.
For the study on moderate PPD, investigators enrolled women with a baseline HAM-D total score of between 20 and 25. Patients were randomly assigned to receive a 60-hour inpatient infusion of brexanolone 90 µg/kg/hr (n = 54; baseline HAM-D score, 22.6) or matching placebo (n = 54; baseline HAM-D score, 22.7).
The primary endpoint of significant change from baseline HAM-D score to hour 60 was met by the group that received brexanolone vs the group that received placebo (mean -14.2 points vs -12.0 points; P < .05).
The mean reduction in baseline score was also significant at hour 48 in comparison with placebo (P < .05), as well as at hour 72 (P < .01) and on day 7 (P < .05).
Regarding secondary endpoints at hour 60, a greater percentage of patients in the brexanolone group than in the placebo group achieved a “HAM-D response” (defined as a reduction in score of at least 50%), HAM-D remission (a total score of 7 or less), and a “very much improved” or “much improved” response on the CGI-I (for all three comparisons, P < .05).
Among 51 members of the brexanole group and 53 members of the placebo group assessed for safety and tolerability, AEs of any kind were reported by 49.0% and 45.3%, respectively. Most of these AEs were mild and occurred during the first 24 hours of infusion.
There were three serious AEs in the active-treatment group (one patient each with fatigue, presyncope, and altered state of consciousness with syncope) and one in the placebo group (headache). Two patients discontinued drug use because of an AE — the patient with altered state of consciousness and syncope, and a patient with presyncope with vertigo.
The most commonly reported AEs were headache (17.6% of the active-treatment group vs 11.3% of the placebo group), dizziness (9.8% vs 7.5%), infusion site pain (9.8% vs 3.8%), nausea (9.8% vs 3.8%), somnolence (7.8% vs 3.8), and fatigue (5.9% vs 3.8%).
Severe PPD
For the study of severe PPD, the investigators enrolled 138 patients (average age, 27.5 years) whose baseline HAM-D total score was greater than 25. These participants were randomly assigned in a 1:1:1 ratio to receive a 60-hour inpatient infusion of brexanolone 60 µg/kg/hr (n = 47; baseline HAM-D score, 29.1), a 60-hour infusion of brexanolone 90 µg/kg/hr (n = 45; baseline HAM-D, 28.4), or matching placebo (n = 46; baseline HAM-D, 28.6).
There was a 19.9-point mean reduction in baseline HAM-D total score at hour 60 for the lower-dose group vs a 14.0-point reduction for the placebo group (P < .01). The higher-dose group also had a significantly greater reduction in HAM-D score (-17.7 points; P < .05). These rates for both doses were sustained at day 30.
HAMD-D response and CGI-I response were achieved by more members of the active-treatment groups than the placebo group (for all comparisons, P < .05). HAM-D remission was also achieved by significantly more members of the 60-µg/kg/hr group than the placebo group (P < .05).
Among 38 members of the 60-µg/kg/hr active-treatment group, 41 members of the 90-µg/kg/hr active-treatment group, and 43 members of the placebo group, 50.0%, 53.7%, and 51.2%, respectively, reported experiencing any AE.
There were two severe AEs reported by the lower-dose group: one patient with somnolence and loss of consciousness, and one with suicidal ideation and intentional overdose. The only AE leading to drug discontinuation in this group was infusion site pain. Infusion site extravasation led to discontinuation in one member of the placebo group.
The most commonly reported AEs were headache (by 18.4% and 14.6% of the low- and high-dose groups, respectively, vs 16.3% of the placebo group), dizziness (15.8% and 14.6% vs 2.3%), somnolence (18.4% and 4.9% vs 7.0%), and infusion site pain (2.6% and 9.8% vs 2.3%).
Paradigm Shift?
Academic principal investigator and poster presenter Samantha Meltzer-Brody, MD, Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, told Medscape Medical News that these findings “extend and echo” what was found in earlier phase 2 trials.
Dr Samantha Meltzer-Brody
“We saw a robust effect and a rapid onset of action in women with a range of symptoms. This is very exciting in terms of this being a paradigm shift on how we can consider treating postpartum depression,” she said.
“Instead of saying, ‘We’ll start an antidepressant and hope that in 4 to 6 weeks you’ll have some response,’ we could talk about people no longer suffering 60 hours later. And that’s just mind-blowing in terms of the degree of suffering that women have and our ability to address that quickly,” said Meltzer-Brody.
“We’ll have to see what the FDA says about this, but hopefully, we’ll have this on the market as an option for women in the not-so-distant future,” added Epperson, who is also director of the Penn Center for Women’s Behavioral Wellness.
“As a clinician and as a physician-scientist who has worked with pregnant and postpartum women for more than 20 years, I’m looking forward to hopefully being able to have additional treatment options,” she said.
Asked whether there were any concerns about the drug entering breast milk, Epperson said, “Theoretically, no,” but noted that more research is needed to address that question.
“While women were participating in these studies, they did have to stop breastfeeding, and the company collected some breast milk samples so they could start to analyze breast milk content,” she said.
“Allopregnanolone is sort of a substance that our bodies produce naturally, so you could wonder why we’d be concerned about it in breastfeeding. But we want to make sure there’s absolutely no reason a baby shouldn’t be exposed,” she said.
Women’s Health “Breakthrough”
Asked to comment, Elizabeth M. Fitelson, MD, New York–Presbyterian Hospital and director of the Women’s Program in the Department of Psychiatry at Columbia University, New York City, told Medscape Medical News that although the data are preliminary, “this is such an exciting intervention” for an often overlooked population.
Dr Elizabeth Fitelson
“This really is a breakthrough in terms of women’s mental health, because of the specificity of the mechanism of action and because of how quickly it can help,” said Fitelson.
PPD “can be torturous for women at a time when they really want to be there for their babies,” she added. Starting treatment with a selective serotonin reuptake inhibitor (SSRI) “and then having to wait and wait and wait for it to kick in is very difficult. So if this intervention, even for some proportion of women, could be quick and safe and effective, I think it’s potentially a wonderful thing.”
Asked whether women would be hesitant because of the commitment needed to receive the intervention over several days in an inpatient setting, Fitelson said no, especially in comparison with the weeks often needed before experiencing an effect from an SSRI.
“I think many of my patients would say, ‘Okay, I’ll do 60 hours if that’s really going to get me well more quickly so I can get home to my baby,’ ” she said.
“Nothing works for every single person. But as a psychiatrist who treats perinatal women all the time, if I have this other powerful tool, and I have a patient who is really suffering, it’s incredibly meaningful to say, ‘You know what, let’s consider this. It might be helpful for you.’ “
The studies were funded by Sage Therapeutics. Dr Epperson has reported no relevant financial relationships. Although Dr Melzer-Brody did not personally receive any compensation from Sage, her institution received consultation fees for time spent developing the protocol for the studies and a research grant from Johnson & Johnson that was unrelated to this research. Dr Fitelson has reported no relevant financial relationships.
American Psychiatric Association (APA) 2018. Abstracts P5-168 and P5-169, presented May 7, 2018.
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