Research Publications
Engineered neuroreceptor-specificity set to deliver next-generation schizophrenia therapeutics.
June 2021
Laxminarayan Bhat
Reviva Pharmaceuticals, a clinical-stage biopharmaceutical company based in Cupertino, California, USA, is applying a chemical genomics–powered technology platform supported by novel and proprietary chemistries to develop next-generation therapeutics for conditions of the central nervous system (CNS), and the respiratory and metabolic systems.
Brilaroxazine (RP5063) Clinical Experience in Schizophrenia: A New Option to Address Unmet Needs.
October 22, 2018
Laxminarayan Bhat, Marc Cantillon, and Robert Ings
Schizophrenia is a condition comprising of both treatment and comorbidity factors that both complicate its management and present multiple unmet needs. Brilaroxazine (RP5063), a dopamine (D)/serotonin (5-HT) modulator, possesses a broad in vitro pharmacology profile against D2/3/4 and 5-HT1A/2A/2B/6/7 receptors, nicotinic acetylcholine (α4β2) receptors, and the serotonin transporter. In Phase 1 and 2 clinical experience in healthy volunteers, patients with schizophrenia and schizoaffective disorder, brilaroxazine was well tolerated, with the repeated 100 mg oral dose as the maximum tolerated dose.
A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder.
April 4, 2018
Marc Cantillon, Robert Ings, Arul Prakash, Laxminarayan Bhat
RP5063 is a novel multimodal dopamine (D)–serotonin (5-HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A, antagonist activity for 5-HT2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships.
Initial clinical experience of RP5063 following single doses in normal healthy volunteers and multiple doses in patients with stable schizophrenia.
July 2018
Marc Cantillon, Robert Ings, Laxminarayan Bhat
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.
Pharmacokinetics of RP5063 Following Single Doses to Normal Healthy Volunteers and Multiple Doses Over 10 Days to Stable Schizophrenic Patients
July 2018
Marc Cantillon, Robert Ings, Laxminarayan Bhat
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.
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 the monocrotaline-induced pulmonary arterial hypertension rat model.
May 15, 2018
Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G. Reddy, Seema R. Bhat, Charles-E. Laurent, Annie Bouchard, Marzena Biernat, Dany Salvailc
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.
Dopamine Serotonin Stabilizer RP5063: A Randomized, Double-blind, Placebo-controlled Multicenter Trial of Safety and Efficacy in Exacerbation of Schizophrenia or Schizoaffective Disorder.
November 2017
Marc Cantillon, Arul Prakash, Ajay Alexander, Robert Ings, Dennis Sweitzer, Laxminarayan Bhat
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.
RP5063, an atypical antipsychotic drug with a novel mechanism of action, improves cognition and psychosis in mouse models of schizophrenia.
August 2017
Lakshmi Rajagopal, Sunoh Kwon, Mei Huang, Eric Michael, Laxminarayan Bhat, Marc Cantillon, Herbert Y. Meltzer
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 α4β2 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.
A closer look at the preclinical experience of RP5063 in pulmonary arterial hypertension (PAH).
Laxminarayan Bhat and Dany Salvail
Pulmonary arterial hypertension (PAH) is a chronic, debilitating condition with a 5- to 7-year survival rate of approximately 50% following diagnosis. It is defined by pulmonary vasculature constriction and remodeling, and its pathobiology involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT in the pulmonary arteries. RP5063 is a novel, multimodal dopamine (D)–serotonin (5-HT) stabilizer with partial agonist activity for D and 5-HT, antagonist activity for 5-HT, and moderate affinity for the serotonin transporter (SERT).
RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-induced pulmonary arterial hypertension in rats.
September 5, 2017
Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G Reddy, Seema R Bhat, Charles E. Laurent, Annie Bouchard, Marzena Biernat, and Dany Salvail
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.
RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats.
September 5, 2017
Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G Reddy, Seema R Bhat, Charles E. Laurent, Annie Bouchard, Marzena Biernat, and Dany Salvail
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.