FDA Recommends Second Phase 3 Trial for Reviva's Brilaroxazine in Schizophrenia Treatment
Key Insights
The FDA has recommended that Reviva Pharmaceuticals conduct a second Phase 3 trial for brilaroxazine in schizophrenia (search) patients to generate additional efficacy data and expand the safety dataset before NDA submission.
Reviva plans to initiate the RECOVER-2 registrational trial in the first half of 2026, subject to sufficient financing, following the design of the completed RECOVER Phase 3 trial.
Brilaroxazine has demonstrated broad-spectrum efficacy across major symptom domains of schizophrenia (search), including negative symptoms, in 790 subjects from Phase 2 and Phase 3 trials.
The U.S. Food and Drug Administration has recommended that Reviva Pharmaceuticals conduct a second Phase 3 clinical trial for brilaroxazine in patients with schizophrenia (search) before submitting a New Drug Application, the company announced following a pre-NDA meeting with the regulatory agency.
In written feedback, the FDA recommended the additional Phase 3 trial to generate more efficacy data and expand the safety dataset for brilaroxazine, a novel serotonin-dopamine (search) and neuroinflammatory signaling modulator. Subject to sufficient financing, Reviva plans to initiate the RECOVER-2 Phase 3 trial in the first half of 2026, which will follow a similar design to the completed RECOVER Phase 3 trial.
Regulatory Guidance and Trial Design
The FDA provided comprehensive guidance to Reviva beyond the recommendation for a second trial, including methods of data analysis, data presentation approaches, and data requirements for studies of animal pharmacokinetics, human abuse potential, and renal and hepatic impairment.
"We appreciate the clear and constructive feedback from the FDA," said Laxminarayan Bhat, Ph.D., Founder, President, and CEO of Reviva. "Across our robust clinical data package, brilaroxazine continues to show potential to address unmet needs in schizophrenia (search), with data reflecting broad-spectrum efficacy, a well-characterized and generally favorable safety profile, and favorable treatment adherence observed to date, with convenient once-daily oral administration."
Clinical Development Progress
The FDA's recommendation follows review of Reviva's existing nonclinical and clinical data package, which includes two completed randomized, double-blind, placebo-controlled, multicenter clinical trials—one Phase 2 trial and one Phase 3 trial that included a 1-year open label extension—along with clinical pharmacology studies designed to support a potential NDA filing.
Across the clinical development program, brilaroxazine has demonstrated broad spectrum efficacy in major symptom domains of schizophrenia (search), including negative symptoms, in the 790 subjects that participated in the Phase 2 and Phase 3 clinical trials. The drug has shown a generally well-tolerated safety profile in over 900 subjects treated to date.
Mechanism of Action and Clinical Significance
Brilaroxazine differentiates itself from current standard of care agents through its unique mechanism of action. While existing treatments primarily address dopamine D2 (search) and 5-HT2A (search) receptors, brilaroxazine functions as a partial agonist for both receptors and has potent activity—approximately 3 to 4 times more potent—for the 5-HT2B (search) receptor that is highly expressed in neural networks.
According to Bhat, clinical literature implicates 5-HT2B (search) as an upstream target that mediates neuroinflammation in the brain and is involved in the chronicity of schizophrenia (search), including negative symptoms, depressive symptoms, and cognition.
Expert Commentary on Clinical Results
The June 2025 results from the Phase 3 RECOVER open label extension study assessed long-term safety, tolerability, and efficacy of once daily brilaroxazine over a 1-year period. In that study, 446 patients were randomized to receive either 15 mg, 30 mg, or 50 mg brilaroxazine. Investigators reported "robust broad-spectrum efficacy that was sustained over 1-year and was generally well tolerated with a discontinuation rate of 35% in this long-term study."
Stephen R. Marder, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, noted that "dissatisfaction with current standards of care is largely driven by persistent negative symptoms and poor functional outcomes. The robust improvement in negative symptoms and sustained broad-spectrum efficacy support the potential of brilaroxazine to address these unmet needs."
Larry Ereshefsky, PharmD, BCPP, FCCP, retired professor of psychiatry, pharmacology and psychiatry at the University of Texas, highlighted the drug's anti-inflammatory properties, stating: "Brilaroxazine improved multiple biomarkers including reduced levels of inflammatory cytokines that could contribute to enhanced efficacy and mitigate side effects. The impact of reduced inflammation on symptoms may result in improved patient adherence and clinical outcomes. The low discontinuation rates observed in the double-blind and OLE trials are consistent with this beneficial treatment profile."
Path Forward
Reviva remains committed to advancing the development of brilaroxazine for schizophrenia (search) treatment. "We are committed to working closely with the FDA to generate the additional efficacy and safety data necessary to support a potential NDA and to potentially bring brilaroxazine to patients with schizophrenia as quickly as possible," Bhat stated.
The company's current data package highlights brilaroxazine's long-term safety profile, broad-spectrum clinical activity, and favorable adherence observed over up to one year with once-daily administration. The RECOVER-2 trial represents a critical step toward potential regulatory approval for this novel therapeutic approach to schizophrenia (search) treatment.