RP5063: Retroactive Comparison Against 32 Antipsychotics
An estimated 0.25% to 1% of the global population suffers from schizophrenia. To address this estimated 20 million individuals with the chronic disorder there are numerous antipsychotics approved for use. However, a high discontinuation rate due to suboptimal efficacy and serious side effects reveals an unmet need. Commonly prescribed antipsychotics leave many patients suffering from neuroleptic, endocrine and metabolic reactions that frequently lead to discontinuation. These therapies do not provide efficacy uniformly across the spectrum of symptoms. Many of these agents are prescribed at a lower than medically needed level in order to limit the severity of side effects but fail to provide a therapeutic effect at that dose leading patients to discontinue therapy.
Exhibit I – RP5063 Receptor Binding Affinities (1)
RP5063, with its better balance of receptor activity, may allow for therapeutic doses to be used in difficult to treat patients while limiting the impact of the common neurological, metabolic and endocrine side effects associated with commonly prescribed agents. The agent offers a faster onset of action compared with alternatives, a feature that is expected to limit discontinuation by patients using alternatives that suffer weeks of side effects without therapeutic benefit.
Reviva (NASDAQ:RVPH) will soon launch registrational studies addressing acute and maintenance treatment for schizophrenia that will be completed over the next few years. Although pivotal data has not been generated for RP5063, we analyze the candidate’s Phase II data against a comprehensive systematic review and network meta-analysis published in The Lancet, comparing 32 existing antipsychotics to reveal trends in line with RP5063’s efficacy and low intensity side effects.
RP5063 pivotal studies are expected to be complete by 2024, after which a new drug application (NDA) will be filed in the United States and other geographies. Assuming customary review periods, approval is anticipated in 2025 followed by near immediate commercialization in the United States and following a short delay in other regions. Pricing is forecast to be in line with other newly launched branded antipsychotics and penetration is modeled to be in the low single digit range of the addressable market. If the drug profile is better than expected, we anticipate higher penetration levels to occur.
Lancet Systematic Review and Network Meta-Analysis
Huhn et al. published in The Lancet, is the largest known, most comprehensive systematic review and network meta-analysis comparing the efficacy and side effects of 32 oral antipsychotics in acute treatment of adults with multi-episode schizophrenia (2). The publication was a comprehensive comparison of antipsychotic drugs, including first and second generation. The meta-analysis evaluated each of the antipsychotics on measures of efficacy and side-effects. The study employed a meta-analysis that combined the results from 402 studies, including 53,463 participants and built on the group’s past efforts. The 32 drugs were compared, in terms of efficacy, by reduction in overall, positive, and negative symptoms. Dropout, depression, quality of life and functioning were also assessed. Side effects compared included use of antiparkinsonian drugs, extrapyramidal side effects, akathisia, weight gain, prolactin levels, sedation, QTc prolongation and anticholinergic side effects.
Comparison parameters included in the review were standardized to accommodate studies of varying measures. The studies’ results were standardized via Standardized Mean Difference (SMD), Risk Ratio (RR) and Mean Difference (MD) where appropriate. To facilitate our comparison, data from the Phase II study of RP5063 (brilaroxazine) (NCT01490086) was standardized in a similar manner, using SMD, RR and MD, to the extent the collected data was analogous (3) and the data compared against those published in the meta-analysis.
REFRESH: Phase II Evaluation of RP5063 in Schizophrenia
Phase II (REFRESH) was a randomized, double blind, placebo controlled, multi-center trial intended to assess safety and efficacy of RP-5063 in acute exacerbation of schizophrenia or schizoaffective disorder (4). 22 clinical sites located in the Philippines, India, Malaysia, Moldova and the United States participated in the trial. The primary endpoint for the study was reduction in total PANSS at end of treatment from baseline vs placebo. Secondary endpoints included change from baseline to day 4, 8 15, 22 and 28 on PANSS total, positive and negative subscales, 20% improvement in PANSS total and one-point improvement on the clinical global impressions scale severity (CGI-S) (5). 234 subjects were enrolled. Patients were randomized into five arms including 15 mg (n=60), 30 mg (n=60) and 50 mg (n=60) doses as well as placebo (n=40) and aripiprazole 15 mg (n=20). Approximately one week of screening was followed by 28 days of dosing and follow up afterward of one and two weeks for men and women, respectively. Pharmacokinetic analysis was also performed. 186 of 234 enrolled subjects completed the study.
Data Compilation and Presentation
Data from the REFRESH study was compared to the data presented in the meta-analysis. The meta-analysis compared 32 antipsychotics by their reduction in overall, positive, and negative symptoms, dropout, depression, quality of life and functioning. Side effects compared included use of antiparkinsonian drugs, extrapyramidal side effects, akathisia, weight gain, prolactin levels, sedation, QTc prolongation and anticholinergic side effects. Of these parameters, overall, positive and negative change in symptoms, dropout, akathisia, weight gain, change in prolactin levels and sedation were comparable based on data available from the REFRESH study publication. As positive and negative symptom reduction were endogenous to overall symptom reduction, reduction in overall symptoms was solely used as a measure of efficacy. Side-effects ultimately compared included akathisia, weight gain, change in prolactin levels and sedation. All-cause discontinuation is compared on its own to evaluate treatment adherence across the antipsychotics. As Reviva will proceed with the 15 mg dose of RP5063 in pivotal trials, our analysis is centered on data specific to the 15mg dose. Furthermore, though the Lancet review featured 32 antipsychotics, we also focus our attention on the major antipsychotics: olanzapine, risperidone, quetiapine, aripiprazole, cariprazine and brexpiprazole.
REFRESH study data was then standardized to be comparable with the meta-analysis data. Symptom reduction measures were standardized using Standardized Mean Difference (SMD), where the mean difference between symptom reduction in the 15 mg and placebo arms was determined, and the standard deviation (SD), derived from standard error (SE) of the placebo arm was used to standardize the therapeutic reduction. This number was then directly compared to the results presented in the Lancet meta-analysis review which were also presented in SMD. This was performed for change in total PANSS, which correlated with the meta-analysis’ change in overall symptoms parameter.
Other parameters, such as all-cause discontinuation, were presented as Risk Ratio (RR) in the meta-analysis, and REFRESH data was treated accordingly, taking the percentage discontinued in the 15 mg arm, and dividing by the same in the placebo arm. Akathisia and sedation parameters were processed in the same manner. We note that no placebo arm patients experienced akathisia in the REFRESH trial, rendering an error in the RR calculation. We used a surrogate datapoint for akathisia placebo prevalence of 3.7% (6). No patients experienced sedation in treated and placebo arms and the RR was taken to be one.
Finally, in cases where Mean Difference (MD) was compared, such as change in weight, the mean weight gain for the placebo arm was subtracted from the treatment arm. Change in prolactin, another factor compared using MD, was in mIU/L, or milli-international units per liter, in the REFRESH trial, and was converted at a rate of 21.2 μg per mIU to ng/mL, as presented in the meta-analysis.
Data was compiled from REFRESH and the meta-analysis, and percentile rankings were determined for each antipsychotic, for each parameter. Missing data was ignored. Again, efficacy axis comprised only the overall reduction in symptoms parameter to rank the antipsychotics, where no average was taken. Side-effect parameters were averaged with equal weighting. An equal weighting was determined to be best practice, in this application, as assigning weights to the side effects implied that one side effect was less desirable than another, which could rely, both in terms of sensitivity and severity, on the individual patient. The ranking and averaging also reconciled differences between the standardization measures and minimized distortion from missing data. The overall reduction in symptoms and average of side effect ranking were used to produce a two-dimensional projection of efficacy versus side effects. A higher efficacy ranking and lower side effect ranking are most desirable.
Exhibit II – RP5063 vs Major Antipsychotics, Efficacy and Side Effects (7)
Based on the analysis, it appears that 15 mg brilaroxazine is differentiated among the major antipsychotics. Brilaroxazine efficacy is only above average compared with other treatments; however, the drug offers a class-leading lack of side-effects. Side effects are a material deterrent to treatment adherence and patients are forced to weigh the benefits against the side effects. Also noteworthy is that RP5063 is superior to aripiprazole in both efficacy and side effects. RP5063 is a chemical evolution of aripiprazole, sharing the same underlying structure but making one key change, namely replacement of a carbon atom with an oxygen atom in the quinoline ring, resulting in a benzoxazinone ring. RP5063 is also structurally similar to cariprazine and brexpiprazole. The attributes of above average efficacy combined with class-leading lack of side effects holds up when the analysis is extended to all 32 available antipsychotics included in the meta-analysis.
Exhibit III – RP5063 vs 32 Antipsychotics (8)
Brilaroxazine differentiates itself from the cluster of the 32 antipsychotics in terms of its relatively low level of side effects while maintaining efficacy.
If approved, patients may finally have a therapeutic option that involves less of a trade-off between efficacy and side effects. Again, adherence to treatment may be improved if the side effects are minimized. Below is an analysis of compiled discontinuation ranking. A lower risk ratio (RR) is better.
Exhibit IV – All-cause Discontinuation, RP5063 vs Major Antipsychotics (9)
RP5063 is ranked highest among major antipsychotics for lowest risk of discontinuation and also has the most favorable side effect ranking, consistent with the trends observed comparing against all 32 antipsychotics, reiterating the role of side effects as a cause of discontinuation.
Exhibit V – All-cause Discontinuation, RP5063 vs Best of 32 Antipsychotics (10, 11)
We conducted a comparison analysis using data provided in the Huhn et al. meta-analysis and standardized the data presented in Reviva’s Phase II trial of brilaroxazine (RP5063) in acute exacerbation of schizophrenia or schizoaffective disorder (12). The standardized data was compared directly, where possible, to the data in the meta-analysis. Rankings were established for overall reduction in symptoms, our measure of efficacy. Side-effects that were comparable from the Reviva study were standardized, ranked, and averaged to project the side effect data in one dimension. Together, the data could be displayed in two dimensions, evaluating Reviva’s candidate against major antipsychotics in terms of efficacy and side effects. Analysis was also conducted for all-cause discontinuation, a major hindrance in schizophrenia treatment. Patients often must weigh and evaluate the tradeoff of efficacy and side effects. Based on our analysis, brilaroxazine appears to offer above average efficacy with class-leading lack of side effects, in line with the pharmaco-engineering that led to RP5063 as a candidate. If approved, brilaroxazine should offer patients an option with less of a compromise. Reviva will soon launch registrational studies addressing acute and maintenance treatment for schizophrenia that will be completed over the next few years. RP5063 pivotal studies are expected to be complete by 2024, after which a new drug application (NDA) will be filed in the United States and other geographies. Assuming customary review periods, approval is anticipated in 2025 followed by near immediate commercialization in the United States and following a short delay in other areas. Pricing is forecast to be in line with other newly launched branded antipsychotics and penetration is modeled to be in the low single digit range of the addressable market. If the drug profile is better than expected, we anticipate higher penetration levels to occur.
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1. Rajagopal L, Kwon S, Huang M, Michael E, Bhat L, Cantillon M, Meltzer H. RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia. 2017. Behavioral Brain Research
2. Huhn, M., Nikolakopoulou, A., Schneider-Thoma, J., Krause, M., Samara, M., Peter, N., … & Leucht, S. (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. The Lancet, 394(10202), 939-951.
3. Cantillon, M., Prakash, A., Alexander, A., Ings, R., Sweitzer, D., & Bhat, L. (2017). Dopamine serotonin stabilizer RP5063: a randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder. Schizophrenia research, 189, 126-133.
4. Schizoaffective disorder is a combination of schizophrenia symptoms and mood disorder symptoms
5. The CGI-S is a measure of clinician’s view of patient’s global functioning
6. Chow, C. L., Kadouh, N. K., Bostwick, J. R., & VandenBerg, A. M. (2020). Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 40(6), 565-574.
7. Compiled, Zacks Analyst Research
8. Compiled, Zacks Analyst Research
9. Compiled, Zacks Analyst Research
10. Compiled, Zacks Analyst Research
11. Legend for antipsychotics abbreviations can be found in the Huhn et al. meta-analysis.
12. Schizoaffective disorder is a combination of schizophrenia symptoms and mood disorder symptoms