Frequently Asked Questions

Onfasprodil (MIJ821) is a selective NMDA receptor NR2B negative allosteric modulator being studied as a rapid-acting treatment for treatment-resistant depression (TRD). The rationale is that NMDA-modulating treatments can reduce depressive symptoms quickly, but currently used agents such as ketamine and esketamine can cause dissociative and psychotomimetic effects; in this study, onfasprodil was evaluated to see whether it could provide rapid antidepressant benefit with acceptable tolerability.

Onfasprodil improved depressive symptoms within 24 hours after the first infusion. Compared with placebo, the adjusted arithmetic mean difference in MADRS total score at 24 hours was -8.25 for pooled onfasprodil 0.16 mg/kg (P = .0013) and -5.71 for pooled onfasprodil 0.32 mg/kg (P = .0196), meeting the study's primary outcome.

Yes. The study found that the antidepressant effect was maintained at 48 hours after the first infusion for both pooled onfasprodil dose groups. At 48 hours, mean decreases in MADRS total score were -14.94 for pooled onfasprodil 0.16 mg/kg and -15.25 for pooled onfasprodil 0.32 mg/kg, versus -18.89 for ketamine; the differences between onfasprodil and ketamine were not statistically significant.

At Week 6, 2 specific onfasprodil regimens remained significantly better than placebo on MMRM analysis: 0.16 mg/kg biweekly showed an adjusted arithmetic mean difference of -6.46 (80% CI, -11.78 to -1.15; P = .0598), and 0.32 mg/kg weekly showed -5.42 (80% CI, -10.83 to -0.02; P = .0993).

The 0.16 mg/kg biweekly regimen showed the strongest overall sustained efficacy signal versus placebo in this proof-of-concept trial. At Week 6, that group had an adjusted arithmetic mean difference in MADRS total score of -6.46 (80% CI, -11.78 to -1.15; P = .0598), and the authors stated that this regimen demonstrated the greatest overall MADRS benefit compared with placebo.

The pooled 0.16 mg/kg dose group also showed the larger placebo-adjusted 24-hour effect (-8.25) compared with the pooled 0.32 mg/kg dose group (-5.71), so the higher dose did not produce a stronger early efficacy signal in this study.

In this small subgroup comparison, onfasprodil showed similar apparent antidepressant efficacy to ketamine, although the study was not formally powered for those comparisons. At 24 hours, ketamine was also superior to placebo, with an adjusted mean difference in MADRS total score of -5.67 (P = .0461), and at 48 hours the differences between onfasprodil groups and ketamine were not statistically significant.

The safety profile differed: dissociation was reported in 5 patients (23.8%) in pooled onfasprodil 0.16 mg/kg and 5 patients (26.3%) in pooled onfasprodil 0.32 mg/kg, compared with 5 patients (50.0%) in the ketamine group. The mean maximum CADSS change from baseline was also higher with ketamine (10.30 at 1 hour) than with onfasprodil treatment groups (≤5).

The most common treatment-emergent adverse events reported in the onfasprodil groups were dizziness, amnesia, somnolence, and feeling abnormal. Across pooled groups, at least 1 adverse event was reported in 61.9% (13/21) of patients receiving onfasprodil 0.16 mg/kg and 68.4% (13/19) receiving onfasprodil 0.32 mg/kg, compared with 35.0% (7/20) in the placebo group.

Most adverse events were mild in intensity. The article also states that there were no clinically relevant changes in laboratory tests, vital signs, or ECGs.

Yes, onfasprodil was associated with dissociative-type and other neurobehavioral adverse effects, but in this study they were generally mild and resolved within hours. Dissociation was reported in 5 patients (23.8%) in pooled onfasprodil 0.16 mg/kg and 5 patients (26.3%) in pooled onfasprodil 0.32 mg/kg; onset ranged from 0 to 0.7 hours after infusion start, and resolution ranged from 1.6 to 7.0 hours after onset.

Short periods of amnesia were reported in 10 onfasprodil-treated patients, with onset from 0 to 0.7 hours after infusion start and resolution from 0.7 to 9.2 hours after onset. The maximum time to onset of significant adverse events with onfasprodil was 4.4 hours, and the maximum time to resolution after onset was 9.2 hours.

The study enrolled adults aged 18 to 65 years with major depressive disorder who had failed at least 2 standard antidepressant treatments at adequate dose, with treatment failure during a major depressive episode lasting at least 8 weeks. Participants also had to have a baseline MADRS score of 24 or higher.

Overall, 72 patients were randomized, 2 discontinued before receiving treatment, and 70 received study drug. The mean age of treated patients was 47.7 years, and 53 of 70 participants (75.7%) completed the study.

This was a phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter proof-of-concept study with 70 treated patients. Patients received intravenous infusions over 40 minutes and were assigned to onfasprodil 0.16 mg/kg or 0.32 mg/kg given weekly or biweekly, placebo, or ketamine 0.5 mg/kg weekly; the ketamine arm was included in Spain but not in the United States.

The primary end point was change in MADRS total score at 24 hours after a single dose. The study used 1-sided testing for its primary proof-of-concept comparisons and was not formally powered for all between-group comparisons, especially comparisons with ketamine, so the results should be interpreted as preliminary dose-finding and signal-detection data rather than definitive comparative efficacy evidence.

The main limitations were the small sample size, the limited number of research sites, and dropout during acute treatment. The dropout rate ranged from 10% in the ketamine group to 33.3% in the onfasprodil 0.32 mg/kg weekly group.

Interpretation of the ketamine comparison is also limited because ketamine was given only once weekly rather than the more standard twice-weekly initial dosing, and it was administered with a fixed-dose cap rather than customary weight-based dosing in some higher-weight patients. The authors therefore describe the findings as preliminary and state that larger studies are needed to confirm them.