FDA Accepts Phase III RECOVER-2 Study for Brilaroxazine in Schizophrenia


Reviva Pharmaceuticals and the FDA have reached alignment on the 4-week global registrational study.

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Reviva Pharmaceuticals has gained alignment from the FDA on its registrational Phase III program for brilaroxazine in schizophrenia. The FDA has also indicated that two Phase III studies showing efficacy at week 4 that are accompanied by long-term safety data of at least 12 months could be supportive of an New Drug Application (NDA) submission for the acute treatment of schizophrenia. In addition, the FDA indicated that it will require a long-term randomized withdrawal study post-approval to support maintenance of effect.1

The Phase III RECOVER-2 clinical trial is a global, randomized, double-blind, placebo-controlled, multicenter, 4-week study. It will assess the safety and efficacy of brilaroxazine in approximately 450 patients with acute schizophrenia compared to placebo. Brilaroxazine will be administered at fixed doses of 30 mg or 50 mg once daily for 28-days. The primary endpoint is a decrease in Positive and Negative Symptoms Assessment total score compared to placebo from baseline to Day 28. Key secondary endpoints include clinical global impression (CGI) severity, positive and negative symptoms, social functioning, and cognition, and key biomarkers implicated in neuroinflammation. Reviva plans to initiate the first clinical site in the second quarter of 2024.

“We are pleased to receive positive feedback from the FDA and acceptance of a 4-week registrational study for our brilaroxazine program,” Laxminarayan Bhat, PhD, founder, president, and CEO of Reviva said in a press release. “The FDA also clarified that our NDA submission could include two 4-week phase III studies showing efficacy and a 12-month long-term safety study. Importantly, we have already successfully completed and announced the results of our pivotal Phase III RECOVER trial in October 2023, and we are set to initiate our RECOVER-2 trial during this quarter. We expect topline data from our 1-year OLE trial in the fourth quarter of this year. Collectively, we expect to have completed all of the outlined NDA submission requirements by the third quarter of 2025.”

According to an earlier announcement from Reviva in October 2023, the Phase III RECOVER trial (NCT05184335) successfully met its primary endpoint. At the 50 mg dose, brilaroxazine achieved a statistically significant and clinically meaningful 10.1-point reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo (-23.9 brilaroxazine 50 mg vs. -13.8 placebo, p<0.001) at week 4. Additionally, brilaroxazine achieved statistically significant and clinically meaningful reductions in all major symptom domains and secondary endpoints at week 4 with the 50 mg dose vs. placebo.2

“We are excited to report positive topline results for our Phase III RECOVER trial, further confirming the well-tolerated safety profile and improvements in all major symptom domains including PANSS total score, positive and negative symptoms, and CGI severity score as previously observed in our Phase II REFRESH trial,” Bhat said in a earlier press release. “Importantly, we believe the unique multifaceted mechanism of action of brilaroxazine, a serotonin-dopamine signaling modulator, has potential to improve additional key disease drivers like neuroinflammation. The RECOVER pivotal results highlight the potentially differentiated therapeutic profile of once-daily brilaroxazine and underscore the potential to address treatment limitations for the 24 million people living with schizophrenia around the world. We expect to report long-term data from our OLE trial in the fourth quarter of 2024 and initiate a registrational Phase III RECOVER-2 trial in the first quarter of 2024, which if successful will help support our planned NDA submission to the FDA expected in 2025.”

Brilaroxazine was discovered in-house by Reviva. It is a new chemical entity with potent affinity and selectivity against key serotonin and dopamine receptors implicated in schizophrenia and its comorbid symptoms.


1. Reviva Announces FDA Alignment on Brilaroxazine Clinical Trials for NDA in Schizophrenia. News release. April 15, 2024. Accessed April 16, 2024. https://revivapharma.com/reviva-announces-fda-alignment-on-brilaroxazine-clinical-trials-for-nda-in-schizophrenia/

2. Reviva Announces Positive Topline Results from Global Pivotal Phase 3 RECOVER Trial of Brilaroxazine in Schizophrenia. News release. October 30, 2023. Accessed April 16, 2024. https://revivapharma.com/reviva-announces-positive-topline-results-from-global-pivotal-phase-3-recover-trial-of-brilaroxazine-in-schizophrenia/#:~:text=About%20the%20Phase%203%20RECOVER%20Trial&text=The%20primary%20endpoint%20is%20a,symptoms%2C%20social%20functioning%20and%20cognition

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