Results from the SKYLARK Study

In 2019, the Food and Drug Administration (Fda) permitted brexanolone, promoted by Sage Therapeutics as Zulresso, as a remedy for postpartum depression (PPD).  As a neurosteroid, brexanolone signifies a novel strategy to the procedure of postpartum temper ailments.  A person of the most remarkable points about brexanolone is the rapidity of the reaction, with the first reports indicating remission of despair inside 24 to 48 several hours.  Simply because antidepressants normally take 2-4 months to kick in, an antidepressant agent with quick onset of motion would be especially appealing to women of all ages with severe PPD.  

One particular of the key disadvanges, however, is that Zulresso must be administered intravenously in excess of 60 hrs, which signifies that individuals must be hospitalized for about 3 days. In addition, Zulresso may have perhaps really serious aspect results, like excessive sedation and unexpected reduction of consciousness so the Food and drug administration involves a REMS (Threat Analysis and Mitigation Tactic) for healthcare amenities trying to find to administer Zulresso.  According to the REMS, patients will have to be under 24-hour supervision with checking by an on-web site clinical qualified.  Offered these constraints, the rollout of Zulresso has been slow.  

But we may possibly quickly have obtain to a different possibility for the treatment method of PPD:  zuranolone.  Like brexanolone, zuranolone is a neurosteroid, an analogue of allopregnanolone which is a favourable allosteric modulator of the GABA-A receptor. What distinguishes zuranolone from brexanolone is that it has much improved oral bioavailability and so does not have to be administered intravenously. It can be taken as an oral medication, similar to common antidepressants.  

Benefits from the SKYLARK Analyze

Today Sage Therapeutics, Inc. and Biogen Inc. unveiled knowledge from the Phase 3 SKYLARK Review of zuranolone getting evaluated in ladies with postpartum depression.  The SKYLARK Review was a randomized, double-blind, placebo-controlled study evaluating the efficacy and security of zuranolone 50 mg. Girls with PPD (amongst the ages of 18 and 45) were being qualified for the analyze if they were being less than six months postpartum and had a significant depressive episode beginning throughout the 3rd trimester or before 4 weeks postpartum.  This analyze integrated only gals with extreme PPD, defined as a baseline 17-merchandise Hamilton Ranking Scale for Melancholy (HAMD-17) score of 26 or larger. Members (n=200) were being randomized to get either placebo or zuranolone (50 mg) administered orally every single evening for 2 months.  The research populace included about 22% Black or African American women and 38% Hispanic or Latina women.

A complete of 200 patients were randomized. By day 3, ladies receiving zuranolone experienced a better reduction in HAM-D scores than gals obtaining placebo (indicate reduction, 9.5 vs 6.1 P = .0008).  The variance in imply HAM-D scores steadily elevated up to day 15. At working day 15, the imply reduction in HAM-D scores was 15.6 in gals receiving zuranolone vs. 11.6 in the placebo group (change -4. P = .0007).  

At day 45, gals handled with zuranolone ongoing to clearly show a larger reduction in HAM-D scores than women of all ages acquiring placebo (-17.9 vs -14.4, P = .0067). 

Zuranolone 50 mg was frequently perfectly-tolerated the vast majority of adverse occasions were gentle to reasonable in severity. The most typical adverse activities ended up somnolence, dizziness, sedation, headache, diarrhea, nausea, urinary tract infection and COVID-19.  No proof of withdrawal indications as assessed employing the 20-item Health practitioner Withdrawal Checklist.

There was no sign of an increase in suicidal ideation or suicidal conduct more than baseline, as calculated with the Columbia Suicide Severity Score Scale (C-SSRS).

Looking Ahead

The latest examine suggests that zuranolone has antidepressant effects in ladies with extreme PPD.  Advancements in despair ended up observed at working day 3 and improvements perished above the 45 days of the examine.  

Adverse events ended up moderate to moderate in severity.  Mainly because of worries about  critical adverse activities in gals getting brexanolone (suicidal ideation after the infusion in just one topic and syncope/altered consciousness in a further patient), Zulresso was authorised with a Possibility Analysis and Mitigation Method (REMS).  It would seem not likely that zuranolone will call for a REMS.

Sage Therapeutics and Biogen have initiated a submission of a New Drug Application (NDA) to the U.S. Food stuff and Drug Administration for zuranolone in the treatment method of big depressive diosrder and plan to finish the MDD NDA filing in the next fifty percent of 2022. A separate NDA submitting for zuranolone as a therapy of PPD will be submitted in early 2023.

Ruta Nonacs, MD PhD