Research Publications
Poster: Brilaroxazine Phase 3 RECOVER 52-Week Open-Label Evaluation (OLE) of Efficacy and Safety over 12 Months in Stable Schizophrenia Participants
Laxminarayan Bhat (Presenter), Seema R Bhat, Arulprakash Ramakrishnan, Wasim Khan, and Simeen Khan (Co-authors)
Overall, findings from the brilaroxazine phase 3 OLE part reinforce the initial safety and efficacy results from the double-blind part of the phase 3 trial (RECOVER), emphasizing a dose-dependent effect. Furthermore, they highlight the sustainability of brilaroxazine’s significant, broad-spectrum efficacy on Total PANSS, along with Positive and Negative components, and that patients tolerated this treatment well, as evidenced by low TREAs and high adherence to therapy. Collectively, these findings strengthen the overall efficacy, safety, and treatment adherence profile of brilaroxazine.
Poster: Enrichment Based on Speech Latency Enhances Treatment Effects in a Phase III Study of Brilaroxazine
Alex S. Cohen, Brian Kirkpatrick, Mark Opler, Jan A. Sedway, Kazunori Tatsumi, Seema Bhat, and Laxminarayan Bhat
Speech latency, a measure of verbal response times, is an objective marker of cognitive, social, and motivational factors that can be assayed directly from psychiatric interviews. This study evaluates speech latencies in a clinical trial of schizophrenia. Audio recordings from psychiatric interviews in a Phase 3 trial of brilaroxazine were evaluated (k = 2590 recordings for 408 participants from three countries representing eight languages). Speech latency showed excellent internal consistency, good temporal stability, and minimal convergence with potentially confounds.
Poster: Effectiveness of Brilaroxazine on Functional and Underlying Pathological Inflammation and Fibrosis Parameters in a Bleomycin-induced Idiopathic Pulmonary Fibrosis in Male Sprague Dawley Rats
Laxminarayan Bhat and Seema Bhat
This study aimed to evaluate the efficacy of brilaroxazine, SB-269970, and nintedanib in bleomycin-induced IPF in male Sprague Dawley rats. Specific intents included the validation of 1) brilaroxazine’s previous efficacy data in the bleomycin-induced IPF model, 2) involvement of 5-HT2B/7 in IPF’s pathobiology by comparing 5-HT7antagonist and nintedanib, a tyrosine kinase inhibitor, and 3) IPF efficacy by comparing the positive control nintedanib, an approved treatment for this condition
Poster: Absorption, Metabolism, and Excretion of Brilaroxazine in Rats
Laxminarayan Bhat, Seema Bhat, and Palaniappan Kulanthaivel
This research evaluated brilaroxazine’s mass balance, metabolism, and excretion profile in intact and bile duct-cannulated (BDC) male Sprague Dawley rats after a single 14C-brilaroxazine dose.
Oral brilaroxazine at 20 mg/kg in male SD rats underwent rapid and near complete absorption (at least 85%), extensive metabolism, and elimination as mostly metabolites via hepatobiliary excretion. Recovery of the dose was over 90% for both BDC and intact rats. The plasma PK profile involved a long elimination half-life (5.3 hr) for TRA and brilaroxazine, and a parent-to-total radioactivity based on a AUClast of ~12%. Metabolites, M641a, RP5081, and M219, were the predominant entities circulating in rats.
Poster: Brilaroxazine Displays Limited Interaction with Clinically Relevant Drug Transporters
Laxminarayan Bhat, Seema Bhat, and Palaniappan Kulanthaivel
This in vitro study’s primary focus is to evaluate brilaroxazine’s interaction potential with 11 clinically relevant drug transporters as a substrate and inhibitor. These included efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP); and uptake transporters multi-drug and toxin extrusion 1 (MATE1), MATE2-K, organic anion transporter 1 (OAT1), OAT3, organic cation transporter 1 (OCT1), OCT2, organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3.
The results found that brilaroxazine displays limited interaction with clinically relevant drug transporters. Further work in the clinic will help to confirm these in vitro findings.
Poster: Brilaroxazine Phase 3 RECOVER Trial in Acute Schizophrenia Supports Efficacy, Safety, and Effects on Neuroinflammation
Laxminarayan Bhat (Presenter), Seema R Bhat, Arulprakash Ramakrishnan, Wasim Khan, Amardeep Neburi, and Simeen Khan (Co-authors)
Schizophrenia, affecting ~1.1% of the world’s population1, presents as positive, negative, and mood symptoms, cognitive impairment, and immune system abnormalities (neuroinflammation).2-5 Up to 30% of patients fail current therapies,6-10 which only manage major symptom domains.11,12 The suboptimal, broad-spectrum efficacy, intolerable AEs, and drug-induced comorbidities,13,14 define unmet needs.
Brilaroxazine is a novel multimodal neuromodulator of serotonin and dopamine receptors and a mitigator of multiple inflammatory cytokines.15-18 Phase 1 and 2 trials, including the Phase 2 REFRESH study, established its unique efficacy, safety, and pharmacokinetic profile.15-18
Poster: Brilaroxazine Efficacy and Safety in the Phase 3 Recover Trial In Acute Schizophrenia
Laxminarayan Bhat (Presenter), Seema R Bhat, Arulprakash Ramakrishnan, Wasim Khan, Amardeep Neburi, and Simeen Khan (Co-authors)
Schizophrenia, affecting ~1.1% of the world’s population1, presents as positive, negative, and mood symptoms, cognitive impairment, and immune system abnormalities (including neuroinflammation).2-5 Up to 30% of patients fail current therapies,6-10 which only manage major symptom domains.11,12
Brilaroxazine demonstrated strong efficacy and was well tolerated. The 50 mg dose provided a significant decrease in primary (Total PANSS) and secondary endpoints vs. placebo; the 15 mg dose showed strong directional improvements. Side effects (metabolic, neuroleptic) were similar to placebo with favorable lipid profile and endocrine effects; the discontinuation rate was 6% lower in 50 mg vs. Placebo.
Paper: Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model
Laxminarayan Bhat, Seema R. Bhat, Arulprakash Ramakrishnan, Muthukumar Amirthalingam
Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology.
Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.
Paper: Evaluation of Brilaroxazine (RP5063) in a Bleomycin-Induced Rodent Model of Idiopathic Pulmonary Fibrosis
Laxminarayan Bhat, Seema R Bhat, Marie-Claude Nault, Marzena Biernat, Sebastien M. Labbe
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and debilitating lung disease1. This condition presents with a global prevalence of ~3 million, a median survival time of two to five years, and 50,000 deaths annually in the U.S.1–6.
The objective of this parallel-design study was to evaluate the effectiveness of brilaroxazine started on Day 1 and Day 10 following BLM-induction on the functional, histologic, and pathophysiological parameters in the BLM-induced model29,30.
Poster: Evaluation of Brilaroxazine (RP5063) in a Bleomycin-Induced Rodent Model of Idiopathic Pulmonary Fibrosis
Laxminarayan Bhat, Seema R Bhat, Marie-Claude Nault, Marzena Biernat, Sebastien M. Labbe
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and debilitating lung disease with a global prevalence of ~3 million, 2-5 years in median survival time, and 50,000 annual U.S. deaths1–6. It involves chronic inflammation and progressive alveolar fibrosis, leading to destroyed architecture, reduced capacity, impaired oxygenation, and declined function2,7,8 This study evaluated whether brilaroxazine (15 mg twice-daily), started on Day 1 or Day 10, displays efficacy in a bleomycin (BLM)-induced rat model of IPF.
Poster: Single-Dose Brilaroxazine Pharmacokinetics, Metabolism, and Excretion Profile in Animals and Humans
May 2023
Laxminarayan Bhat, Seema R Bhat, and Palaniappan Kulanthaivel
Brilaroxazine is a serotonin-dopamine modulator displaying a high affinity for D2/3/4 and 5-HT2A/2B/7 receptors and a moderate affinity for the serotonin transporter (SERT)1-3. This agent brings an established efficacy, safety, and pharmacokinetic profile based on its phase 1 and 2 clinical experience1-8. It possesses differentiated pharmacological and safety profiles over other antipsychotics1-8. Currently, brilaroxazine is proceeding through phase 3 development for schizophrenia9. This research describes the PME profiles associated with a single oral dose of [14C]-brilaroxazine in separate studies involving mice, canines, and humans.
Poster: CYP3A Inhibition and Induction Exert Limited Effects on Brilaroxazine Pharmacokinetics
May 2023
Laxminarayan Bhat, Seema R Bhat, Arulprakash Ramakrishnan, and Palaniappan Kulanthaivel
Preclinical in vitro work identified CYP3A4 as the primary enzyme involved in brilaroxazine’s metabolism17. Due to the potential for drug-drug interaction via this pathway, the need exists to evaluate the extent of potential drug-drug interaction between brilaroxazine with a strong CYP3A4 inhibitor (itraconazole) and inducer (phenytoin) to provide clinicians with dosing guidance when using this new treatment in practice6. The objective involved comparing brilaroxazine’s pharmacokinetic (PK) parameters (Cmax, AUC0-∞, and AUC0-t) after a single 15 mg oral dose tablet on 1) Day 1 alone, 2) Day 17 with steady-state itraconazole (a strong CYP3A4 inhibitor), and 3) Day 27 steady-state phenytoin (a strong CYP3A4 inducer)6.
Poster: Brilaroxazine Topical Liposomal-gel Formulation Displays Efficacy in the Imiquimod-induced Psoriatic Mouse Model
May 2023
Laxminarayan Bhat, Seema R Bhat, Arulprakash Ramakrishna, Muthukumar Amirthalingam
Psoriasis is a systemic immune-mediated, chronic-residual dermal inflammatory disease with a global prevalence of ~125 million1-4. It presents as recurrent episodes of hyperkeratotic, erythematous plaques and silvery-coated scales on the skin1-2. Mental illness exists as a major comorbidity3–7. This preclinical study assesses the efficacy of topical brilaroxazine in lipogel (Brilaroxazine Formulation) in a 5% imiquimod-induced psoriatic mouse model (BALB/c)20.
Paper: Brilaroxazine (RP5063), a novel serotonin-dopamine stabilizer, displays antipsychotic efficacy in rodents
Laxminarayan Bhat, Kouacou Adiey, Seema R Bhat, and Prabhu Mohapatra
Schizophrenia is a complex, chronic, and debilitating psychiatric syndrome affecting approximately 1% of the world’s population1. This disorder is characterized by a complex mix of positive symptoms, negative symptoms, mood symptoms, cognitive impairment and immune system abnormalities2,3.
Brilaroxazine possesses a broad in vitro pharmacology profile against key dopamine and serotonin receptors involved in schizophrenia and other neuropsychiatric disorder pathology 32,38. Brilaroxazine showed animal proof-of-concept activity by mitigating pharmacologically induced behaviors in rodents reflecting psychotic symptoms in humans.
Poster: Brilaroxazine (RP5063), a novel serotonin-dopamine stabilizer, displays antipsychotic efficacy in rodents
April 2023
Laxminarayan Bhat, Kouacou Adiey, Seema R Bhat, and Prabhu Mohapatra
This research represents the first findings of brilaroxazine’s treatment effect for schizophrenia in animal models of induced behaviors. It provides pre-clinical proof-of-concept support that brilaroxazine mitigates behaviors modeled to reflect those schizophrenia patients’ experience. These studies use the most relevant translational rodent models(14-17). Considering relevant signaling pathways and symptom presentation, they evaluate brilaroxazine’s spectrum of antipsychotic activity.
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.