RECOVER Topline Announcement
Following enrollment completion of the RECOVER trial on August 17th and evaluation of the last patient on September 25th, Reviva Pharmaceutical Holdings, Inc. (NASDAQ:RVPH) announced topline results. RECOVER was a global Phase III, randomized, double-blind, placebo-controlled, multicenter study designed to assess the safety and efficacy of brilaroxazine in patients with acute schizophrenia compared to placebo. It enrolled 412 subjects. Brilaroxazine was administered at fixed doses of 15 mg or 50 mg once daily for 28 days. The primary endpoint was a decrease in the Positive and Negative Syndrome Scale (PANSS) 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.
The trial met its primary endpoint, generating a 10.1-point reduction in PANSS score relative to placebo at four weeks for the 50 mg dose. The brilaroxazine arm generated a 23.9 point reduction whereas the placebo arm produced a 13.8 point reduction. Brilaroxazine also 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. The 15 mg dose of brilaroxazine was numerically superior to placebo on the primary endpoint and most secondary endpoints, and reached statistical significance on two key secondary endpoints.
RECOVER will evolve into an open label extension (OLE) trial continuing with 100 of the subjects who have completed the four-week regimen. It will have a one-year duration. The outpatient OLE will evaluate the long-term safety and tolerability of brilaroxazine with a once daily 15, 30 and 50 mg flexible dose. The extension is expected to be complete by 4Q:24
Reviva held a webcast to review the data release which featured the CEO, Dr. Laxminarayan Bhat, and Reviva’s consultant, Dr. Larry Ereshefsky. The slide deck review walked through the topline data, patient characteristics and analysis of each endpoint with score trend by week. It further summarized the safety and side effect profile of the candidate. The final data point for each of the endpoints is included in the following exhibit.
Brilaroxazine was engineered based on the latest understanding in receptor efficacy and side effect relationships guided by the shortcomings and data generated by preceding therapies. Brilaroxazine possesses a high binding affinity for the D2/3/4 and 5-HT1A/2A/2B/7 receptors, moderate affinity for 5-HT6 and nicotinic acetylcholine (α4β2) receptors and the serotonin transporter, a partial agonist of D2/3/4 and 5-HT1A/2A receptors and antagonist of 5-HT2B/6/7 receptors. The agent has either very weak activity or no activity for off target 5-HT2C, adrenergic α1,2 or muscarinic receptors. See our initiation for additional discussion of the drug design. This configuration sought to reduce the side effect profile of brilaroxazine compared with other antipsychotics. In the RECOVER Phase III study, the goal of the design was achieved as brilaroxazine was generally well tolerated with treatment emergent adverse events (TEAEs) as listed below.
The most common TEAEs above 5% were headache (<6%) and somnolence (<7.5%).
The trial further observed that there was no incidence of suicidal ideation and no significant change in bodyweight, blood glucose levels, lipid levels or endocrine hormones as compared to placebo. In particular, weight gain was measured at a 2.1% increase in the 15 mg arm, 5.9% in the 50 mg arm and 2.9% in placebo. While the 50 mg arm showed an increase in excess of placebo, Dr. Ereshefsky noted that enrolled subjects received meals as part of the treatment regime. This is in contrast to many acutely ill schizophrenia patients who do not receive proper nutrition outside of a clinical trial.
Discontinuation of antipsychotic medication is one of the major problems with treating schizophrenia. This can lead to relapse and can lead to treatment resistance. Many patients stop taking their antipsychotics due to side effects such as sedation, weight gain, movement disorders, or lack of insight into their illness. Estimates range from 50-75% of patients discontinuing within 1-2 years. This hurdle accentuates the need for improved compliance and better adherence to medicine administration. Reviva produced an attractive discontinuation rate for the Phase II and Phase III studies, which was better than placebo in both. As shown below, discontinuation for the RECOVER trial was 22% for placebo, 19% for the 15 mg brilaroxazine dose and 16% for the 50 mg brilaroxazine dose. Discontinuation due to side effects was 4% in the placebo group, 1% for the 15 mg brilaroxazine group and 0% for the 50 mg brilaroxazine group.
In summary, the RECOVER clinical trial met its objectives:
➢ Achieved primary endpoint of clinically meaningful and statistically significant reduction in PANSS score;
➢ Demonstrated improvement in all major symptom domains;
➢ Drug was well-tolerated with side effects comparable to placebo;
➢ Discontinuation rate low and below that of placebo.
Reviva is planning to launch its confirmatory Phase III RECOVER-2 trial in 1Q:24. The trial will have a similar design to the RECOVER trial with a few notable differences. 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 6-week (in contrast to 4-week) period and RECOVER-2 will randomize 450 patients 1:1:1 with 30 mg (in place of 15 mg), 50 mg and placebo arms. Completion is expected in early 2025. This sets Reviva up to compile and submit its new drug application (NDA) in 2H:25.
Based upon the clinically meaningful and statistically significant efficacy and superior safety data produced in RECOVER that confirm the findings in the Phase II study of brilaroxazine, we increase the probability of regulatory and commercial success to 60%. This raises our valuation to $18 per share. Other material points where we will re-evaluate our probabilty of success will follow the the report of the RECOVER-2 trial and upon filing of the new drug application (NDA).
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1. Reviva RECOVER Topline Results Data Presentation, October 30, 2023.
2. Cohen's d is a statistic used to measure the standardized difference between two group means. The statistic quantifies the difference between two group means relative to the standard deviation. This allows results to be compared across studies using different measures. It is calculated as the difference between the two group means, divided by the pooled standard deviation. d = (Mean 1- Mean 2)/Pooled SD The pooled standard deviation is calculated using a weighted average of the variances of the two groups. Cohen provided guidelines for interpreting the size of d: Small effect: d = 0.2; Medium effect: d = 0.5; Large effect: d = 0.8
3. Compiled from data provided in company materials by Zacks analyst
4. Reviva RECOVER Topline Results Data Presentation, October 30, 2023.