FDA Recommends Additional Phase 3 Trial for Brilaroxazine for Schizophrenia

The US Food and Drug Administration recommended a second phase 3 trial for brilaroxazine for patients with schizophrenia to “generate additional efficacy data and expand the safety dataset,” Reviva Pharmaceuticals reported.¹ Reviva is developing the novel serotonin-dopamine and neuroinflammatory signaling modulator to treat schizophrenia.

Pending financing, Reviva plans to initiate the RECOVER-2 trial in the first half of 2026; the phase 3 trial will be similar to the RECOVER phase 3 trial, although the FDA shared guidance with the company on “methods of data analysis, methods of data presentation, and data requirements for studies of animal pharmacokinetics, human abuse potential, and renal and hepatic impairment.”¹

In June 2025, the company released results from the phase 3 RECOVER open label extension of brilaroxazine (RP5063; NCT05184335) for patients with schizophrenia, which assessed long-term safety, tolerability, and efficacy of once daily brilaroxazine over a 1-year period. In that study, patients (N=446) were randomized to receive either 15 mg (N=140), 30 mg (N=158), or 50 mg (N-148) 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.”²

In an exclusive interview with Psychiatric Times, Laxminarayan Bhat, PhD, founder, president and chief executive officer of Reviva Pharmaceuticals Holdings Inc, explained the significance of the research. “All the standard of care agents currently available, by and large, address dopamine D2 and the 5SD2A target. Our drug also targets these 2 receptors with the differential activity partial agonist for both receptors.” Brilaroxazine goes further than that, he said, adding it “has potent activity almost 3 to 4 times more potent for a receptor called 5-HT2B that is highly expressed in the neural network,” and “There is a lot of clinical literature available to implicate that 5-HT2B is an upstream target to mediate neuroinflammation in the brain.” He further noted that 5-HT2B is implicated in the chronicity of schizophrenia, including the negative symptoms, depressive symptoms, and cognition.³

Leaders in psychiatry had previously praised the potential of brilaroxazine. Stephen R Marder, MD, professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, applauded the work, noting, “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.”²

Similarly, Larry Ereshefsky, PharmD, BCPP, FCCP, retired professor of psychiatry, pharmacology and psychiatry at the University of Texas, hailed the promise of the drug based on the RECOVER results, saying, “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.”²

The company remains committed to advancing care for patients with schizophrenia, according to the press statement. “We appreciate the clear and constructive feedback from the FDA,” Bhat said. “Across our robust clinical data package, brilaroxazine continues to show potential to address unmet needs in schizophrenia, 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.”1

“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. Subject to sufficient financing, we plan to initiate RECOVER-2 in the first half of 2026.”¹

References

1. Reviva Announces Regulatory Update Regarding the Development of Brilaroxazine for the Treatment of Schizophrenia. Press statement. December 23, 2025. Reviva Pharmaceuticals. Accessed December 23, 2025. https://www.globenewswire.com/news-release/2025/12/23/3209836/0/en/Reviva-Announces-Regulatory-Update-Regarding-the-Development-of-Brilaroxazine-for-the-Treatment-of-Schizophrenia.html

2. Reviva Announces Positive Full Dataset for 1-Year Phase 3 RECOVER Open Label Extension Study Evaluating Brilaroxazine in Schizophrenia. Press statement. June 2, 2025. Accessed December 23, 2025. https://www.globenewswire.com/news-release/2025/06/02/3091710/0/en/Reviva-Announces-Positive-Full-Dataset-for-1-Year-Phase-3-RECOVER-Open-Label-Extension-Study-Evaluating-Brilaroxazine-in-Schizophrenia.html

3. 2. Bhat L, Duerr HA. Open Label Phase 3 Study of Brilaroxazine for Schizophrenia Shows Efficacy, Tolerability. Psychiatric Times. June 2, 2025.Accessed December 23, 2025. https://www.psychiatrictimes.com/view/open-label-phase-3-study-of-brilaroxazine-for-schizophrenia-shows-efficacy-tolerability