Rapid Onset and Sustained Efficacy of Onfasprodil (MIJ821), a Novel NR2B Negative Allosteric Modulator, in Patients With Treatment-Resistant Depression: A Phase 2, Randomized, Placebo-Controlled, Proof-of-Concept Study

Abstract

Background: Onfasprodil (MIJ821) is a highly potent and novel selective NR2B subunit negative allosteric modulator. This phase 2, randomized, placebo-controlled, proof-of-concept study evaluated efficacy and safety of onfasprodil in patients with treatment-resistant major depression (TRD).

Methods: Adults with TRD who did not respond to ≥2 antidepressants were randomized (3:3:3:3:6:4) to receive a 40-minute intravenous infusion of onfasprodil 0.16 mg/kg weekly (n = 11), onfasprodil 0.16 mg/kg biweekly (n = 10), onfasprodil 0.32 mg/kg weekly (n = 10), onfasprodil 0.32 mg/kg biweekly (n = 9), placebo weekly (n=20), or ketamine 0.5 mg/kg weekly (n= 10) for 6 weeks. Primary end point was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score at 24 hours. Secondary end points were change in MADRS score at 48 hours and at final follow-up at 6 weeks. Safety and tolerability were assessed during the study.

Results: Of 70 randomized patients, 53 (75.7%) completed the study. At 24 hours, adjusted mean differences versus placebo for pooled onfasprodil 0.16 mg/kg, 0.32 mg/kg, and ketamine groups were -8.25 (P = .001), -5.71 (P = .019), and -5.67 (P = .046), and at 48 hours, -7.06 (P = .013), -7.37 (P = .013), and -11.02 (P = .019), respectively. At Week 6, adjusted arithmetic mean MADRS difference between ketamine and placebo was -5.24 (80% CI, -10.42 to -0.06; P= .0974). At Week 6, the difference versus placebo on MADRS was -5.78 (P= .0427) for pooled 0.16 mg/kg and -4.24 (P= .1133) for pooled 0.32 mg/kg groups. The commonest treatment-emergent adverse events in the onfasprodil groups were dizziness (14.3%), transient amnesia (14.3%), and somnolence (11.4%). It had overall a good safety profile and was well tolerated.

Conclusion: Onfasprodil appeared to be effective and well-tolerated across all dosing regimens in patients with TRD and demonstrated rapid onset of action (24 hours) with evidence of antidepressant effects to be maintained at Week 6, particularly for the lower-dose group.

Trial Registration: ClinicalTrials.gov identifier: NCT03756129.