Open-Label, Phase 2 Trial of the Oral Neuroactive Steroid GABAA Receptor Positive Allosteric Modulator Zuranolone in Bipolar Disorder I and II

Background: Bipolar disorder (BPD) is a chronic, episodic illness affecting nearly 50 million globally, with disability mostly due to depressive episodes (MDEs). Zuranolone is an investigational oral neuroactive steroid GABAA receptor positive allosteric modulator. This open-label Phase 2 trial (NCT03692910) evaluated the safety and tolerability of zuranolone in patients with bipolar depression.

Methods: Patients were adults (18-65 years old), diagnosed with BPD I or II, a history of mania or hypomania, a current MDE, and a 17-item Hamilton Rating Scale for Depression total score (HAMD-17) ‚â•22. Open-label zuranolone 30mg capsule was self-administered daily for two weeks, with follow-up through Day 42. The primary endpoint was safety and tolerability evaluated by adverse event (AE) reporting and the Young Mania Rating Scale. Secondary endpoints included change from baseline (CFB) in HAMD-17 and the Montgomery-Äsberg Depression Rating Scale (MADRS), and HAMD-17 response (reduction ‚â•50%).

Results: Of 35 patients who received study drug, 71% completed treatment, and 46% reported TEAEs. The most common AEs (‚â•5%) were somnolence, headache, diarrhea, sedation, and hypomania. No serious AEs, drug discontinuations, or mania were observed. Both MADRS and HAMD-17 CFB showed similar results at Day 15 (MADRS: -15.5; HAMD-17: -11.4) and at Day 42 (MADRS: -16.4; HAMD-17: -11.5). HAMD-17 response was 45% at Day 15 and 50% at Day 42.

Conclusions: In this open-label study, zuranolone was generally well tolerated, and improved depressive symptoms. This study supports the evaluation of zuranolone in placebo-controlled trials in patients with BPD.