OPC-34712 · program
Brexpiprazole for Post-traumatic stress disorder
Brexpiprazole administered in combination with the SSRI sertraline for the treatment of post-traumatic stress disorder (PTSD) in adults, developed by Otsuka and Lundbeck. A supplemental New Drug Application (sNDA) was accepted by the FDA on 25 Jun 2024 (PDUFA target 8 Feb 2025), supported by three randomized trials: Phase 2 Trial 061 (positive), Phase 3 Trial 071 / NCT04124614 (flexible dose, met its primary CAPS-5 endpoint), and Phase 3 Trial 072 / NCT04174170 (fixed dose, did not meet its primary endpoint). On 18 Jul 2025 an FDA Psychopharmacologic Drugs Advisory Committee voted 1-10 that efficacy of concurrently-initiated brexpiprazole + sertraline was not established. The FDA issued a Complete Response Letter, announced 20 Sep 2025, stating the application did not provide substantial evidence of effectiveness and that additional adequate, well-controlled trials would be needed. Status marked discontinued to reflect that the approval path is, as of the CRL, not advancing; phase 'filed' captures the regulatory-submission state.
Development timeline
- FDA accepted the sNDA for brexpiprazole in combination with sertraline for adult PTSD; PDUFA target action date 8 Feb 2025.↗
- Both Phase 3 PTSD trials of brexpiprazole + sertraline completed in August 2023 (Trial 071 / NCT04124614 completed 8 Aug 2023; Trial 072 / NCT04174170 completed 15 Aug 2023). Trial 071 met its primary CAPS-5 endpoint; Trial 072 did not.
Readouts
- 2025-09-20ReportedRegulatorymissed
FDA issues Complete Response Letter for brexpiprazole + sertraline sNDA in PTSD ↗
Clinical trials in Post-traumatic stress disorder
NCT04174170331-201-00072Phase 3Completedn=591
A Phase 3, Multicenter, Randomized, Double-blind Trial of Fixed-Dose Brexpiprazole as Combination Therapy With Sertraline in the Treatment of Adults With Post-traumatic Stress Disorder
missedprimaryChange from baseline in CAPS-5 total score at week 10 (fixed-dose brexpiprazole + sertraline vs sertraline + placebo)
Phase 3 fixed-dose Trial 072 did NOT meet its primary endpoint. Per the companies, reductions in PTSD symptoms with brexpiprazole + sertraline were directionally consistent with Trials 061 and 071, but the primary CAPS-5 endpoint was not statistically met. This negative result, alongside the positive flexible-dose Trial 071, contributed to the FDA's finding of insufficient substantial evidence.
NCT04124614331-201-00071Phase 3Completedn=450
A Phase 3, Multicenter, Randomized, Double-blind Trial of Brexpiprazole as Combination Therapy With Sertraline in the Treatment of Adults With Post-traumatic Stress Disorder
metprimaryChange from baseline in CAPS-5 total score at week 10 (brexpiprazole + sertraline vs sertraline + placebo) — LSM difference -5.59 (95% CI -8.79 to -2.38); CAPS-5 change -19.2 (brexpiprazole+sertraline) vs -13.6 (sertraline+placebo) (<0.001)
Phase 3 flexible-dose Trial 071 (416 randomized; 205 brexpiprazole+sertraline, 196 sertraline+placebo) met its primary endpoint: brexpiprazole + sertraline produced a statistically significant greater reduction in CAPS-5 total score vs sertraline + placebo from week 1 to week 10. Published in JAMA Psychiatry 18 Dec 2024 (doi:10.1001/jamapsychiatry.2024.3996).
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Brexpiprazole oral tablet (Rexulti) Oral tablets in 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, and 4 mg strengths, administered once daily with or without food. In PTSD studied as combination therapy with sertraline. | Oral | Once daily | t½ 91 h · Tmax 4 h · F 95% |
Mechanism of action
Brexpiprazole is a serotonin-dopamine activity modulator. It is a partial agonist at dopamine D2 and serotonin 5-HT1A receptors and an antagonist at serotonin 5-HT2A receptors, with additional antagonism at adrenergic alpha1B and alpha2C receptors. Relative to aripiprazole it has lower intrinsic activity at D2 and higher 5-HT1A/5-HT2A affinity. In the PTSD program it was given in combination with the SSRI sertraline (a serotonin reuptake inhibitor); the rationale was that brexpiprazole's receptor modulation augments sertraline's serotonergic action to improve PTSD symptom control. Affinity values are from the primary in vitro characterization (Maeda et al. 2014).
| Target | Action | Affinity |
|---|---|---|
| D2primaryDRD2 | Partial agonist | Ki 0.3 nMⓘ |
| 5-HT1AHTR1A | Partial agonist | Ki 0.12 nMⓘ |
| 5-HT2AHTR2A | Antagonist | Ki 0.47 nMⓘ |
← Full OPC-34712 compound page (identity, identifiers, all indications)
Sources
- Brexpiprazole as Combination Therapy With Sertraline in Treatment of Adults With PTSD (Trial 071) — ClinicalTrials.gov
- Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator (Maeda et al., J Pharmacol Exp Ther 2014) — Journal of Pharmacology and Experimental Therapeutics
- Fixed-Dose Brexpiprazole as Combination Therapy With Sertraline in Treatment of Adults With PTSD (Trial 072) — ClinicalTrials.gov
- JAMA Psychiatry Publishes Results of Otsuka and Lundbeck's Phase 3 Trial of Brexpiprazole in Combination with Sertraline in Treatment of PTSD in Adults — Otsuka Pharmaceutical
- Otsuka and Lundbeck Announce FDA Acceptance of sNDA Filing for Brexpiprazole in Combination with Sertraline for the Treatment of Adults with PTSD — H. Lundbeck A/S
- Otsuka and Lundbeck Receive Complete Response Letter from U.S. FDA for sNDA of REXULTI (brexpiprazole) in Combination with Sertraline for the Treatment of Adults with PTSD — Otsuka Pharmaceutical
- REXULTI (brexpiprazole) tablets, for oral use — US Prescribing Information — Otsuka Pharmaceutical / FDA