Initial Clinical Experience of RP5063 Following Single Doses in Normal Healthy Volunteers and Multiple Doses in Patients with Stable Schizophrenia

Abstract

RP5063 is a multimodal dopamine (D)‐serotonin (5‐HT) stabilizer with a high affinity for D2/3/4 and 5‐HT1A/2A/2B/7 receptors and moderate affinity for the serotonin transporter. Single‐dose (10 and 15 mg fasting, 15 mg fed) safety in healthy volunteers and multiple‐dose (10, 20, 50, and 100 mg fed, 10 days) safety and pharmacodynamics in patients with stable schizophrenia were defined in two phase I studies. In the single‐dose study, 32 treatment‐emergent adverse events (TEAEs) were observed. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common. One serious adverse event (SAE), seen in a patient who should not have been in the study due to a history of seizures, involved brief seizure‐like symptoms. In the multiple‐dose study, 75 TEAEs were reported. Akathisia (n = 20) and somnolence (n = 14) were the most frequent. No clinically significant changes were seen in glucose or prolactin levels, lipid profiles, weight, or electrocardiographic recordings. In both studies, all TEAEs resolved and none led to withdrawal from the study or death. A pharmacodynamic evaluation reflected significant improvements with RP5063 (P < 0.05) over placebo in an analysis of patients with a baseline Positive and Negative Syndrome Scale (PANSS) score ≥50 for positive subscale scores. Improvements of the Trail Making A and Trail Making B test results were observed for patients treated in the 50 mg dose group for days 5, 10, and 16. These findings indicate that RP5063 is well‐tolerated up to 100 mg and displays promising preliminary clinical behavioral and cognition activity signals in patients with stable disease over a 10‐day period.

A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder

“…Two-phase 1 studies characterized the safety of a single dose (10- and 15-mg fasting; 15-mg fed/fasting) in healthy volunteers and multiple doses of RP5063 (10, 20, 50, and 100 mg fed) over 10 days in patients with stable schizophrenia [ 19 , 20 ]. In both studies, the compound was generally well tolerated and safe with all TEAEs resolved and none leading to withdrawal or death [ 20 ].…”

“…An initial pharmacodynamic evaluation in the multiple-dose study also showed promising preliminary clinical behavioral and cognition activity signals in patients with stable disease over 10-day period [ 20 ]. Significant improvements were seen with RP5063 ( P < 0.05) over placebo in a secondary analysis of patients with a baseline PANSS score > 50 for Positive Subscale Scores.…”

“…Significant improvements were seen with RP5063 ( P < 0.05) over placebo in a secondary analysis of patients with a baseline PANSS score > 50 for Positive Subscale Scores. Furthermore, improvements of Trails A and Trails B Test results were observed for patients treated in 50-mg dose group for Days 5, 10, and 16 [ 20 ].…”

Experimental Serotonergic Agents for the Treatment of Schizophrenia

“…Therefore, this study reported promising preliminary findings of the efficacy of RP5063 on clinical symptoms and cognition in patients with the stable illness. 57 A phase-II, 57-day, double-blind, multi-centric RCT was conducted in order to assess the safety and efficacy of RP5063 in 234 patients with an acute exacerbation of SCZ disorder (REFRESH study; NCT01490086), randomized to brilaroxazine (15, 30, or 50 mg), aripiprazole (15 mg) or placebo once daily. The primary endpoint was the change from baseline to day 28 of PANSS total score.…”

“…53,54 Brilaroxazine is a candidate for a further phase-III RCT as a result of the evidence of a statistically significant improvement of positive symptoms and some neurocognitive domains in acute SCZ patients. [56][57][58] Four selective 5-HT5AR antagonists (AS2030680, AS2674723, ASP5736 and SB699551) showed some pro-cognitive and antipsychotic-like properties in animal models, suggesting a possible clinical application to treat SCZ. [43][44][45][46] Two 5-HT1AR agonists, 8-OH-DPAT and LASSBio-579, the selective 5-HT1BR agonist RU-24969 as well as the selective 5-HT2A and 5-HT2CRs antagonist ritanserin are research chemicals which were developed some years ago in order to study the role of serotonergic mechanisms in SCZ.…”