Laxminarayan Bhat

Dopamine serotonin stabilizer RP5063: A randomized, double-blind, placebo-controlled multicenter trial of safety and efficacy in exacerbation of schizophrenia or schizoaffective disorder

The study objectives were to evaluate the efficacy, safety, tolerability, and pharmacokinetics of RP5063 versus placebo. The study was conducted in adults with acute exacerbation of schizophrenia or schizoaffective disorder. This 28-day, multicenter, placebo-controlled, double-blind study randomized 234 subjects to RP5063 15, 30, or 50mg; aripiprazole; or placebo (3:3:3:1:2) once daily. The aripiprazole arm was included solely to show assay sensitivity and was not powered to show efficacy. The primary endpoint was change from baseline to Day 28/EOT (End-of-Treatment) in Positive and Negative Syndrome Scale (PANSS) total score; secondary endpoints included PANSS subscales, improvement ≥1 point on the Clinical Global Impressions-Severity (CGI-S), depression and cognition scales. The primary analysis of PANSS Total showed improvement by a mean (SE) of -20.23 (2.65), -15.42 (2.04), and -19.21 (2.39) in the RP5063 15, 30, and 50mg arms, versus -11.41 (3.45) in the placebo arm. The difference between treatment and placebo reached statistical significance for the 15mg (p=0.021) and 50mg (p=0.016) arms. Improvement with RP5063 was also seen for multiple secondary efficacy outcomes. Discontinuation for any reason was much lower for RP5063 (14%, 25%, 12%) versus placebo (26%) and aripiprazole (35%). The most common treatment-emergent adverse events (TEAE) in the RP5063 groups were insomnia and agitation. There were no significant changes in body weight, electrocardiogram, or incidence of orthostatic hypotension; there was a decrease in blood glucose, lipid profiles, and prolactin levels. In conclusion, the novel dopamine serotonin stabilizer, RP5063 is an efficacious and well-tolerated treatment for acute exacerbation of schizophrenia or schizoaffective disorder.

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia

&NA; Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5‐HT)1A, and 5‐HT2A receptors (Rs), full agonism at &agr;4&bgr;2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5‐HT2B, 5‐HT6, and 5‐HT7Rs. Most atypical APDs are 5‐HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)‐as well as amphetamine‐induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP‐induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co‐administration of a sub‐effective dose (SED) of RP5063 with SEDs of a 5‐HT7R antagonist, a 5‐HT1BR antagonist, a 5‐HT2AR inverse agonist, or an &agr;4&bgr;2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre‐treatment with a 5‐HT1AR, a D4R, antagonist, but not an &agr;4&bgr;2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co‐administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP‐treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia. HighlightsRP5063, an atypical antipsychotic drug (APD), blocked acute phencyclidine (PCP)‐ as well as amphetamine‐induced hyperactivity.Acute treatment with RP5063 reversed the subchronic (scPCP)‐induced novel object recognition (NOR) deficit in mice.Co‐administration of PCP and RP5063 for seven days, bid, delayed the onset of the deficit in NOR deficit for one week.ScRP5063 administered beginning one week after scPCP withdrawal reversed the NOR deficit for one week.RP5063 significantly increased cortical dopamine efflux in mice.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats

ABSTRACT Pulmonary arterial hypertension (PAH), a condition characterized by pulmonary vasculature constriction and remodeling, involves dysregulation of the serotonin (5‐HT) receptors 5‐HT2A and 5‐HT2B. A rat model of monocrotaline (MCT)‐induced PAH was used to examine the potential beneficial effects of RP5063, a 5‐HT receptor modulator. After a single 60 mg/kg dose of MCT, rats were gavaged twice‐daily (b.i.d.) with vehicle, RP5063 (1, 3, or 10 mg/kg), or sildenafil (50 mg/kg) for 28 days. RP5063 at a dose as low as 1 mg/kg, b.i.d. reduced pulmonary resistance and increased systemic blood oxygen saturation. The highest dose of RP5063 (10 mg/kg, b.i.d.) reduced diastolic, systolic, and mean pulmonary pressure, right systolic ventricular pressure, ventilatory pressure, and Fultons index (ratio of right to left ventricular weight). Doses as low as 3 mg/kg RP5063, b.i.d. also increased weight gain and body temperature, suggesting an improvement in overall health of MCT‐treated animals. Similar reductions in pulmonary, right ventricular, and ventilatory pressure, pulmonary resistance, and Fultons index as well as increased systemic blood oxygen saturation were observed in animals treated with the reference agent sildenafil at a higher dose (50 mg/kg, b.i.d.). Histological examination revealed that RP5063 produced dose‐dependent reductions in pulmonary blood vessel wall thickness and proportion of muscular vessels, similar to sildenafil. RP5063 completely blocked MCT‐induced increases in the plasma cytokines TNF&agr;, IL‐1&bgr;, and IL‐6 at all doses. In summary, RP5063 improved pulmonary vascular pathology and hemodynamics, right ventricular pressure and hypertrophy, systemic oxygen saturation, and overall health of rats treated with MCT.

RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia–induced pulmonary arterial hypertension in rats

ABSTRACT RP5063, a multimodal dopamine (DA) and serotonin (5‐HT) modulator with high affinity for DA2/3/4 and 5‐HT2A/2B/7 receptors and moderate affinity for SERT, is a novel therapeutic of special interest in the treatment of pulmonary arterial hypertension (PAH). Evidence indicates that therapeutics targeting the 5‐HT2A/2B receptors can influence the pathogenesis of PAH. However, the therapeutic effect of RP5063 in humans has yet to be investigated. A Sugen 5416‐hypoxia (SuHx)–induced PAH model was used to evaluate twice‐daily (b.i.d.) RP5063 at 10 mg/kg (RP‐10) and 20 mg/kg (RP‐20), as compared with positive (sildenafil 50 mg/kg b.i.d.; Sil‐50) and negative controls (SuHx+vehicle; SuHx+veh), in 24 adult male Wistar‐Kyoto rats. RP5063 showed significantly lower systolic pulmonary arterial (both doses) and systolic right ventricular (RP‐10) pressures, and improvement in oxygen saturation (RP‐20). It significantly reduced small‐vessel wall thickness (RP‐20), lowered the percentage of muscular vessels (both doses). Both doses limited arterial obliteration due to endothelial cell proliferation, prevented plexiform lesion formation, and stemmed the release of leukotriene B4. Sildenafil showed statistically greater effects on vessel structure than that seen in both RP5063 groups and improved oxygen saturation. Additionally, Sildenafil did not demonstrate any significant effect on arterial obliteration, plexiform lesion development, or pulmonary arterial or right ventricular pressure. As PAH gains in severity, the impact of RP5063 inhibition of 5HT2B increases, preventing arterial constriction and improving pulmonary hemodynamics. Due to its functional, structural, and chemokine effects, RP5063 represents a promising candidate for investigation in late‐phase PAH.

Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model

Abstract Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5‐HT) receptors, 5‐HT2A/2B/7. In a rat model of monocrotaline (MCT)‐induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5‐HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice‐daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single‐agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO2, and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO2 measurements, as compared with MCT+Veh (P < 0.05), and diastolic pulmonary artery pressure (P < 0.05), as compared with single‐agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single‐agent RP in PAH. RP, as mono and adjunctive therapy compared with induced‐control, mitigated the functional and structural effects of MCT‐induced PAH.

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

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.

Pharmacokinetics of RP5063 Following Single Doses to Normal Healthy Volunteers and Multiple Doses Over 10 Days to Stable Schizophrenic Patients

RP5063, a multimodal dopamine (D)–serotonin (5‐HT) stabilizer, possesses high affinity for D2/3/4 and 5‐HT1A/2A/2B/2C/6/7 receptors and moderate affinity for the serotonin transporter. Two phase I studies characterized the pharmacokinetics of a single dose (10 and 15 mg fasting, 15 mg fed/fasting) in healthy volunteers and multiple doses (10, 20, 50, and 100 mg fed) over 10 days in patients with stable schizophrenia. RP5063 displayed a dose‐dependent Cmax at 4 to 6 h, linear dose proportionality for both Cmax and AUC, and a half‐life between 40 and 71 h. In the single‐dose study, food slightly increased the extent of drug absorption. In the multiple‐dose study, steady‐state was approached after 120 h of daily dosing. Pooled data in the single‐dose study indicate that the pharmacokinetic profile appears to be comparable between Japanese and Caucasians. RP5063 appears to have a straightforward pharmacokinetic profile that supports for phase II and III evaluation as a once‐daily oral administered agent.