2. Academic Validation
  3. 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

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

  • J Clin Psychiatry. 2025 Aug 6;86(3):23m15246. doi: 10.4088/JCP.23m15246.
Richard C Shelton 1,  Robert E Litman 2,  Howard Hassman 3,  David P Walling 4,  Salvador Ros Montalbán 5,  Joan Salvà-Coll 6,  John Zajecka 7,  Oleksandr Sverdlov 8,  Baltazar Gomez-Mancilla 9 10 11,  Mark P Healy 9 12,  Y Gopi Shanker 9 13,  Maria Berkheimer 9,  Thomas Faller 10,  Florian von Raison 14,  Carmen Serban 10,  Jang-Ho Cha 9,  S Nassir Ghaemi 9 15 16
Affiliations

Affiliations

  • 1 Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
  • 2 Georgetown University Medical School, Washington, DC.
  • 3 Hassman Research Institute, Marlton, New Jersey.
  • 4 Collaborative Neuroscience Network Garden Grove, Garden Grove, California.
  • 5 Instituto Internacional de Neurociencias Aplicadas Barcelona, Barcelona, Spain.
  • 6 Hospital Universitari Son Espases, Servicio de Psiquiatría, UIB, IdISBa, Palma de Mallorca, Spain.
  • 7 Psychiatric Medicine Associates, LLC, Skokie, Illinois.
  • 8 Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
  • 9 Novartis Biomedical Research, Cambridge, Massachusetts.
  • 10 Novartis Pharma AG, Basel, Switzerland.
  • 11 McGill University, Montreal, Québec, Canada.
  • 12 Corresponding Author: Mark P. Healy, PhD, Global Discovery Chemistry, Novartis Biomedical Research, 22 Windsor St, Cambridge, MA 02478 ([email protected]).
  • 13 Beam Therapeutics, Cambridge, Massachusetts.
  • 14 Novartis Pharma S.A.S., Rueil Malmaison, France.
  • 15 Tufts University School of Medicine, Boston, Massachusetts.
  • 16 Harvard Medical School, Boston, Massachusetts.
PMID: 40767837 DOI: 10.4088/JCP.23m15246
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.

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