NEW ORLEANS — A majority of patients with major depressive disorder (MDD) who responded to investigational zuranolone needed an additional course of therapy over the following year, according to findings from the ongoing, open-label SHORELINE study.
In the single-arm phase III trial, 67.4% of patients who received an initial 2-week course of zuranolone at the 30-mg dose level initially achieved a response on the 17-item Hamilton Rating Scale for Depression (HAMD-17), reported Andrew Cutler, MD, of SUNY Upstate Medical University in Syracuse, New York, at Psych Congress.
And over the 1-year study, 58.5% of these 489 responders (individuals with a 50% or greater reduction from baseline in total HAMD-17 score) received at least one additional 2-week course of the neuroactive steroid and GABAA receptor positive allosteric modulator; 96 patients received four or more total courses at this dose level, and 43 of these initial responders went on to receive a maximum of five courses.
In a smaller cohort that received a 50-mg dose, 75% of patients responded after 2 weeks of therapy. Of these, only 25% needed a subsequent course of therapy. Median time to the first repeat treatment was 135 days for the 30-mg group and 249 days for the 50-mg cohort.
A HAMD-17 total score of 20 or greater was needed for eligibility, and post hoc study-exit data showed scores of 8.6 for patients who completed a year in the study and 11.2 for patients who withdrew early.
Safety and tolerability of the oral therapy was consistent with other clinical studies, Cutler said, with 2.8% and 6.5% of patients in the 30-mg and 50-mg groups, respectively, discontinuing for toxicity; and 6.1% and 18.6% undergoing dose reductions due to adverse events.
“Most patients exiting the study did so with minimal or mild depressive symptoms,” Cutler said. “These data support the long-term safety and efficacy of episodic treatment with zuranolone in adult patients with MDD.”
Findings from SHORELINE were presented in a series of poster presentations at this year’s annual congress. The open-label, single-arm trial — one of five MDD studies in the LANDSCAPE development program for zuranolone — was designed to evaluate the safety, tolerability, and need for retreatment in patients with MDD, among other outcomes.
At last year’s Psych Congress, findings from the phase III placebo-controlled WATERFALL study (another trial in the development program) demonstrated significantly greater improvement in depressive symptoms on HAMD-17 after 2 weeks of once-daily treatment with zuranolone, with responses sustained through week 6.
For eligibility, the 924 patients enrolled in SHORELINE also had to have a Montgomery-Åsberg Depression Rating Scale score of ≥28. Patients were eligible for repeat treatment at day 70, with a minimum of 8 weeks between courses (need for retreatment was assessed every 2 weeks). Responses to subsequent treatments in the 30-mg cohort ranged from 63.6% to 71.8% and remissions (score below 7 on HAMD-17) were recorded in 31.1% to 54.6% after subsequent treatment courses. A subgroup analysis also supported the treatment effect for patients with elevated anxiety at baseline.
Participants had a mean age of 45, over two-thirds were women, and 80.7% were white. All participants began the trial on a 30-mg dose of zuranolone (n=725) but the study protocol was eventually amended to include a 50-mg dose cohort (n=199).
While 68.2% of the patients in the study experienced treatment-emergent adverse events (AEs), the vast majority (89.7%) were considered mild or moderate in severity. The most common AEs associated with zuranolone included headache, somnolence, dizziness, and sedation. Serious AEs occurred in 3.1% of the study population; one death, due to herpes simplex encephalitis and intracranial hemorrhage, occurred 150 days after the last zuranolone dose and was deemed unrelated to treatment.
Zuranolone developers Sage Therapeutics and Biogen announced earlier this year that they submitted a rolling new drug application to the FDA for an approval in MDD. The drug is also being studied in postpartum depression.
SHORELINE was supported by Sage Therapeutics/Biogen. Some co-authors are company employees.
Cutler disclosed relationships with, and/or support from, Sage Therapeutics, AbbVie, Acadia, AiCure, Alfasigma, Alkermes, Allergan, Cognitive Research, Intra-Cellular Therapies, Janssen, Jazz Pharmaceuticals, MedAvante-ProPhase, Neurocrine, Noven, Otsuka, Sunovion, Supernus, Takeda, Terran Biosciences, Teva, Axsome, Biohaven, Lilly, Lundbeck, Novartis, and the Neuroscience Education Institute.