The once-daily, 14-day, oral therapy is being investigated for fast-acting clinical response in patients with major depressive disorder or postpartum depression.
New phase 3 open-label data show investigative therapy zuranolone may be eligible, in 2 dose forms, as a fast-acting, as-needed therapy for the treatment for major depressive disorder (MDD).
The findings from the phase 3 SHORELINE study complement a building clinical portfolio for the two-week oral treatment, which Sage Therapeutics aims to result in the indicated treatment of MDD, per the US Food and Drug Administration (FDA).
Zuranolone, previously called SAGE-217, is a once-daily oral neuroactive steroid (NAS) positive allosteric modulator (PAM) of the GABAA receptor—a factor associated with the major inhibitor signaling pathway of the brain and central nervous system (CNS).
In June 2018, it was given an expedited development plan following a Breakthrough Therapy designation and a meeting between Sage and FDA officials. The development plan included the placebo-controlled phase 3 SHORELINE trial in patients with MDD, as well an ongoing placebo phase 3 trial in patients with postpartum depression as a pivotal study.
“We believe a medicine with rapid onset and robust response could be truly paradigm shifting,” Sage leadership said in a statement at the time. “SAGE-217, if successfully developed and approved, may rewrite the textbook on how the tens of millions of people suffering from MDD are treated, ultimately turning depression into a disorder, not an identity.”
The phase 3, open-label, one-year longitudinal SHORELINE study is observing the safety, tolerability, and need for repeat dosing of zuranolone among adult patients with MDD.
Investigators are assessing a pair of cohorts: one with zuranolone 30 mg as a starting dose, another with 50 mg zuranolone. Both cohorts were administered therapy once nightly for 14 consecutive days.
Repeated dosing needs were assessed every 14 days thereafter, based on patient-reported results of the Patient Health Questionnaire-9 (PHQ-9) and Hamilton Depression Rating Scale-17 (HAMD-17) scores. Repeated doses were warranted on scores of ≥10 and ≥20 from the assessments, respectively.
A minimum of 56 days were permitted between the 14-day regimens of zuranolone, to allow for a maximum of 5 treatments during the 12-month study.
Sage investigators reported that zuranolone was generally well-tolerated among patients with MDD treated with either 30 mg or 50 mg doses. Adverse events were observed as consistent with previous clinical trials involving the therapy.
For 30 mg dose assessment, 725 patients with MDD were observed. Mean HAM-D score at baseline was 25.3±4.1. Investigators observed that 173 (23.9%) did not achieve clinical response after their first course and exited the study. The remaining patients were continued into the naturalistic follow-up period.
At day 15, mean patient HAM-D change from baseline was -15.2±7.1. Another 505 (73.5%) patients achieved response, and 276 (40.2%) achieved remission.
Beyond the treatment course, 489 patients who responded to 30 mg zuranolone continued into secondary treatment courses. Among them, 210 (42.9%) had only used the single course; 125 (25.6%) used 2 courses; 58 (11.9%) used 3 courses; 53 (10.8%) used 4 courses; 43 (8.8%) used 5 courses.
Secondary endpoints, including response and remission per HAMD-17 and the rate of patient repeated doses, showed patients with a clinical response of ≥50% reduction in baseline HAMD-17 score after 14-day 30 mg zuranolone required just a mean 2.2 treatments over 12 months.
Data from the 50 mg dose cohort is planned for reporting in the later half of 2021, according to Sage. Additional SHORELINE data will also be presented at upcoming medical conferences and in peer-reviewed journals.
In a statement accompanying the new data release, Barry Greene, chief executive officer at Sage, expressed anticipation toward sharing phase 3 pivotal data for zuranolone in MDD later this year.
The naturalistic makeup of the trial, as well as the indicated benefit across 2 dosing regimens, has left optimism for the company in treating what’s become a more burdensome condition.
“Sage embarked on the LANDSCAPE clinical program to evaluate the safety and efficacy of zuranolone with the ambition of reimagining the treatment for depression with the goal of a rapid-acting, durable, treat-as-needed option in a disease where innovation is lacking and the incidence rate has unfortunately increased exponentially in the last 20 years,” Greene said. “We look forward to the results of the WATERFALL and CORAL Phase 3 pivotal data readouts in MDD this year.”