Reviva Pharmaceutical Holdings, Inc. (NASDAQ:RVPH) reported preliminary results from its open label extension (OLE) portion of the Phase III RECOVER trial. Brilaroxazine showed a favorable long-term safety profile and improving efficacy over the one-year observation period. The schizophrenia candidate produced discontinuation rates well below other antipsychotics. The update provided both pooled and individual safety and efficacy data. The full data set is expected to be available in the first quarter of 2025.
OLE Background
Following the conclusion of the RECOVER study, patients were given the opportunity to continue on brilaroxazine to gather long term safety and tolerability in an OLE study. A total of 435 patients were actively on treatment in the study across the three doses of 15 mg (139), 30 mg (155) and 50 mg (141). 156 subjects rolled over from the double-blind portion of the Phase III trial and 279 were new participants in the OLE.
The OLE was designed to take place in parallel with RECOVER and evaluate the long-term safety of brilaroxazine. It must evaluate at least 100 subjects and can enroll patients that were part of the RECOVER trial. The study is listed under the identifier NCT05184335 on clinicaltrials.gov in an entry that is shared with the RECOVER trial. It evaluated flexible doses of brilaroxazine of 15, 30 or 50 mg. Data from the trial will be part of the new drug application (NDA) package that Reviva will submit to the FDA along with anticipated RECOVER-2 data.
OLE First Look
Preliminary results include efficacy results for 113 patients who completed a year of treatment. Safety results are for all 435 patients enrolled in the OLE, including those still actively part of the trial. Results showed dose dependent efficacy. Total PANSS scores changed by -15.2 (15 mg), -18.6 (30 mg) and -20.8 (50 mg) from baseline to final observation at one year. See exhibit below for an illustration of the data.
The average PANSS score for all dosages was an 18.6-point decrease from 71.6 at baseline to 53.0 with a p value of less than 0.0001. Positive symptoms for the pooled data declined by 5.2 points (p<0.0001) and negative symptoms fell by 4.5 points (p<0.0001). If measured from the baseline determined at the start of the RECOVER trial, improvement is PANSS score of 30 points or more was achieved in 87% of patients, 40 points or more in 65% of patients and 50 points or more in 34% of patients. Note that the baseline PANSS score at the beginning of RECOVER was 99.
Safety, Tolerability & Adherence
15.2% of participants reported at least one treatment-related adverse event (TRAE), which were classified as mild (12.2%) or moderate (3%). TRAEs were transient and were most frequently weight increase (3.2%) insomnia (1.8%) and somnolence (1.6%). No drug-related serious adverse events (SAEs) were reported and three drug-related SAEs were reported. No observations of movement disorders were recorded, such as tardive dyskinesia or acute dystonia which may occur with many first generation and some second-generation antipsychotics. Discontinuation rates were favorable compared to other approved antipsychotics reaching 35% at the one-year mark. Based on a review of several resources[1],[2],[3],[4], discontinuation for this class ranges anywhere from the mid-40% range to 70%. For Bristol Myers’ recently approved KarXT, discontinuation was 53% after 52 weeks of treatment.
RECOVER-2
Reviva is planning to launch its confirmatory Phase III RECOVER-2 trial in 1Q:25. The trial will have a similar design to the RECOVER trial with a few notable differences. Once it starts, we expect that the second Phase III trial will be able to enroll at a faster pace than the first as much of the ground work has already been completed and the trial managers are experienced. The confirmatory trial will measure endpoints over a 4-week period and will randomize 450 patients 1:1:1 with 30 mg (in place of 15 mg), 50 mg and placebo arms.
On January 9th, 2024 the company entered into a start-up agreement with an additional contract research organization to conduct the RECOVER-2 trial. $1.1 million was paid to the group to start its activities.
An April 15th press release announced that Reviva had come to an agreement with the FDA regarding the content desired in a new drug application (NDA). The agency wants to see two positive Phase III studies showing efficacy at week four that are accompanied by safety data of at least 12 months. It will require a long-term randomized withdrawal study post-approval to support maintenance of effect.
Capital Raise
Reviva had been waiting for the right time to execute its capital raise and this moment arrived following the report of the preliminary OLE data, which provided a boost for shares and further evidence that brilaroxazine is a compelling product. On the morning of December 16th, the company published a press release proposing to offer and sell shares of common stock to fund the RECOVER 2 Phase III clinical trial. Citizens JMP Securities was the bookrunner for the offering.
Later that day, Reviva announced pricing for the deal which raised $18 million gross. 12 million units were sold, with each unit consisting of one share of common equity, 0.5 series A warrant and one series B warrant. The exercise price for the warrants is $1.50 which have a six month life for the series A and a five year life for the series B warrants. Reviva will require up to an estimated $70 million to complete the RECOVER-2 trial and support operations until approval and this transaction will start us along this trajectory. The company is seeking other sources of capital including partnerships that may make up the difference.
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[1] Liberman, J.A., et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. New England Journal of Medicine. September 2005.
[2] Zhang, C., et al. Rates and predictors of one-year antipsychotic treatment discontinuation in first-episode schizophrenia: Results from an open-label, randomized, “real world” clinical trial. Psychiatry Research. March 2019.
[3] Bertolini, F., et al. Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study. Springer. March 2021.
[4] Seung-Ho, J., et al. Factors Affecting Treatment Discontinuation and Treatment Outcome in Patients with Schizophrenia in Korea: 10-Year Follow-Up Study. Psychiatry Investigation. November 2010.
