Clinical Summary
Clinical Summary: 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
Patients with treatment-resistant depression need options that work within hours, not weeks, but currently available rapid-acting NMDA-modulating treatments carry dissociative and psychotomimetic risks. This study tests whether onfasprodil, an NR2B-selective NMDA negative allosteric modulator, can deliver rapid antidepressant effects with a more manageable tolerability profile.
Design
a phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study
N
72 patients were randomized
Population
adults (aged 18–65 years) with MDD and prior failure of ≥2 standard antidepressants (where 2 of the failed treatments were different antidepressants, at least 1 of which was being taken in the current depressive episode) of adequate dose and ≥8 weeks duration in a major depressive episode (per DSM-5 criteria) and a Montgomery-Asberg Depression Rating Scale (MADRS) score ≥24
Duration
The total study duration was 14 weeks and comprised a screening period (maximum 4 weeks), a 36-day treatment period, and a 5-week follow-up period
Key Findings
- At 24 hours after start of infusion, onfasprodil beat placebo on the primary end point: the adjusted arithmetic mean difference was −8.25 (P = .0013) for pooled onfasprodil 0.16 mg/kg and −5.71 (P = .0196) for pooled onfasprodil 0.32 mg/kg.
- Ketamine also separated from placebo at 24 hours, with an adjusted mean difference of −5.67 (P = .0461), while the pooled onfasprodil 0.16 mg/kg effect was numerically larger than the pooled onfasprodil 0.32 mg/kg effect.
- At 48 hours after start of first infusion, mean decreases in MADRS total score were −14.94 for pooled onfasprodil 0.16 mg/kg, −15.25 for pooled onfasprodil 0.32 mg/kg, and −18.89 for ketamine, and the difference between the onfasprodil groups and ketamine was not statistically significant.
- At Week 6, 2 regimens remained significantly better than placebo on MMRM analysis: onfasprodil 0.16 mg/kg biweekly showed an adjusted arithmetic mean difference of −6.46 (−11.78 to −1.15; P = .0598), and onfasprodil 0.32 mg/kg weekly showed −5.42 (−10.83 to −0.02; P=.0993).
- Dissociation was reported in 5 (23.8%) patients in the pooled onfasprodil 0.16 mg/kg group and 5 (26.3%) in the pooled onfasprodil 0.32 mg/kg group versus 5 (50.0%) in the ketamine group; the ketamine group had a mean change from baseline in CADSS total score of 10.30 at 1 hour after the start of infusion.
Clinical Bottom Line
Onfasprodil produced antidepressant effects within 24 hours in treatment-resistant depression, with benefit sustained to 48 hours and, for selected regimens, through Week 6. In this small proof-of-concept trial, the 0.16 mg/kg dose—especially biweekly—showed the strongest overall efficacy signal with dissociative adverse effects occurring less often than with ketamine.
Practice Implications
- For patients with TRD who need rapid symptom reduction, an NR2B-selective approach showed placebo-adjusted MADRS improvement by 24 hours, so early follow-up after the first infusion is clinically meaningful.
- Do not assume higher dose is better: the pooled onfasprodil 0.16 mg/kg group showed a larger 24-hour placebo-adjusted effect (−8.25) than the pooled 0.32 mg/kg group (−5.71), and the 0.16 mg/kg biweekly regimen had the greatest overall MADRS benefit versus placebo at Week 6.
- Monitor for infusion-proximal neurobehavioral adverse effects such as dizziness, amnesia, somnolence, and dissociation; onfasprodil-related dissociation began 0 to 0.7 hours after the start of infusion and resolved within 1.6 to 7.0 hours after onset.
- Discuss tolerability in context: at least 1 AE was reported in 61.9% (13/21) of pooled onfasprodil 0.16 mg/kg and 68.4% (13/19) of pooled onfasprodil 0.32 mg/kg groups versus 35.0% (7/20) with placebo, but most AEs were mild in intensity and all TEAEs of interest resolved within a few hours after onset.
