Novel NMDA Receptor Modulator Onfasprodil Shows Rapid Antidepressant Effects with Reduced Side Effects in Phase 2 Trial
Key Insights
Onfasprodil, a selective NR2B (search) NMDA receptor (search) modulator, demonstrated rapid improvement in treatment-resistant depression (search) within 24 hours, with effects sustained through 6 weeks in a phase 2 proof-of-concept trial.
The investigational drug showed significantly fewer dissociative side effects compared to ketamine, with only 23.8-26.3% of onfasprodil patients experiencing dissociation versus 50% of ketamine patients.
The lower dose regimen (0.16 mg/kg biweekly) provided the greatest overall benefit, suggesting potential for less frequent dosing compared to current rapid-acting antidepressants.
A novel investigational antidepressant targeting a specific subtype of NMDA receptors has demonstrated rapid improvement in treatment-resistant depression (search) with significantly fewer dissociative side effects than ketamine in a phase 2 clinical trial.
Onfasprodil (MIJ821), a selective negative allosteric modulator of the NR2B (search) subtype of NMDA receptors, showed statistically significant reductions in depression (search) scores within 24 hours of administration and maintained efficacy through 6 weeks in the randomized, double-blind, placebo-controlled study published in the Journal of Clinical Psychiatry.
Rapid Onset with Sustained Benefits
The multicenter trial enrolled 70 adults with treatment-resistant depression (search) who had failed at least two different antidepressant regimens. Participants were randomized to receive onfasprodil at two doses (0.16 mg/kg or 0.32 mg/kg), administered either weekly or biweekly, placebo, or ketamine 0.5 mg/kg as an active comparator.
The primary endpoint measured changes in Montgomery-Asberg Depression (search) Rating Scale (MADRS) scores at 24 hours after the first infusion. Both onfasprodil dose groups achieved statistically significant improvements compared to placebo, with adjusted mean differences of -8.25 points for the 0.16 mg/kg group (P = .0013) and -5.71 points for the 0.32 mg/kg group (P = .0196).
"This proof-of-concept trial demonstrates onfasprodil may be effective for the rapid reduction of depressive symptoms in patients with TRD, with mild dissociative side effects that resolve rapidly," reported lead author Richard Shelton, MD, from the University of Alabama at Birmingham.
The efficacy was maintained at 48 hours, with mean MADRS reductions of -7.06 and -7.37 points for the lower and higher dose groups, respectively. Notably, the 0.16 mg/kg biweekly regimen demonstrated the greatest overall benefit compared to placebo, with effects lasting at least 2 weeks between doses.
Improved Safety Profile
A key advantage of onfasprodil over ketamine was its superior tolerability profile. Dissociative effects, measured using the Clinical-Administered Dissociative States Scale (CADSS), were significantly less pronounced with onfasprodil treatment.
Dissociation was reported in 23.8% of patients receiving onfasprodil 0.16 mg/kg and 26.3% receiving the higher dose, compared to 50% of patients treated with ketamine. The maximum increase in CADSS total score was substantially higher in the ketamine group (10.3 mean maximum change) compared to onfasprodil treatment groups (≤5).
The most common treatment-emergent adverse events with onfasprodil were dizziness, transient amnesia, and somnolence. All treatment-related adverse events resolved within a few hours after onset, with no clinically relevant changes in laboratory values, vital signs, or ECG parameters.
Mechanism and Development Background
Onfasprodil represents the latest development in selective NMDA receptor (search) modulation for depression (search) treatment. The drug follows the discontinued traxoprodil (CP-101,606 (search)), another NR2B (search)-selective modulator that showed promise but was halted due to QTc prolongation concerns.
Unlike ketamine, which blocks NMDA receptors non-selectively, onfasprodil specifically targets the NR2B (search) subunit. This selectivity appears to preserve antidepressant efficacy while reducing the psychotomimetic and dissociative effects associated with broader NMDA receptor (search) antagonism.
The sustained efficacy beyond the drug's 7-hour half-life suggests that onfasprodil, like other NR2B (search)-selective antagonists, may trigger lasting neuroplastic changes. Previous studies have shown that ketamine and similar compounds can affect protein synthesis and synaptogenesis, potentially explaining the prolonged therapeutic effects.
Clinical Implications and Future Development
The study results suggest onfasprodil could offer significant advantages over current rapid-acting antidepressants. The biweekly dosing regimen showing optimal efficacy would be "much more acceptable to patients than weekly or twice per week" dosing required for ketamine treatments, according to Shelton.
"I have treated hundreds of patients with IV ketamine or intranasal esketamine and participated as an investigator in the onfasprodil trial, [and] it seemed to be very well tolerated compared with ketamine products," Shelton noted in discussing the findings.
The magnitude of improvement with onfasprodil was consistent with previous studies of traxoprodil and high-dose esketamine, showing 5-9 point reductions in MADRS scores compared to placebo. This represents substantially larger effect sizes than the 2-4 point improvements typically seen with traditional selective serotonin reuptake inhibitors.
Study Limitations and Next Steps
The proof-of-concept trial had several limitations, including a relatively small sample size of 70 participants and conduct at a limited number of research sites. The dropout rate varied across treatment groups, ranging from 10% in the ketamine group to 33.3% in one of the onfasprodil arms.
Despite these constraints, the study demonstrated sufficient assay sensitivity with ketamine showing statistically significant separation from placebo, validating the trial's internal validity. The researchers noted that larger registration trials would employ more stringent two-sided statistical tests compared to the one-sided analysis used in this early-stage development study.
The findings support continued development of onfasprodil as a potential treatment for treatment-resistant depression (search), with the lower-dose biweekly regimen appearing most promising for future investigation. Additional studies will be needed to confirm these preliminary results and establish the drug's position in the evolving landscape of rapid-acting antidepressants.