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Brilaroxazine
Brilaroxazine (developmental code name RP5063), also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of schizoaffective disorder, bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADHD), irritability in autism, tics, psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis (topical gel). The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
Brilaroxazine is a third-generation antipsychotic drug and dopamine-serotonin system modulator due to its unique actions on dopamine and serotonin neurotransmitter systems compared to other antipsychotics. Clinical data from phase I, phase II (NCT01490086), and phase III (NCT05184335) trials suggest that brilaroxazine may have favorable efficacy and a significantly improved side effect profile compared to existing second and third-generation antipsychotics.
Brilaroxazine acts as a potent partial agonist of D2, D3, D4 and 5-HT1A receptors, and as an antagonist of 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors. Brilaroxazine exhibits high affinity for D2S, D2L, D3, D4.4, 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT7 receptors, and moderate affinity for D1, D5, 5-HT2C, 5-HT3, 5-HT6, H1 and α4β2 nicotinic receptors, the serotonin transporter, and the α1B adrenergic receptor. It lacks significant affinity for 5-HT1B, α2 adrenergic, and muscarinic acetylcholine receptors, as well as for the norepinephrine and dopamine transporters.
Brilaroxazine is identical to aripiprazole in chemical structure except for the replacement of a methylene group in aripiprazole's quinolinone ring system with an oxygen atom, resulting instead in a benzoxazinone ring system. This structural change is within the molecule's secondary pharmacophore, which plays a major role in modulating its binding and intrinsic efficacy at dopamine and serotonin receptors. The drug is also related structurally to brexpiprazole and cariprazine.
In October 2023, Reviva Pharmaceuticals released topline results from their pivotal RECOVER phase III clinical trial (NCT05184335).[citation needed] The RECOVER study was a 4-week, randomized, double-blind, placebo-controlled, multicenter trial where 411 patients with schizophrenia received brilaroxazine 15 mg, 50 mg, or placebo once daily. The trial cohort consisted of 60% American, 34% Indian, and 6% Bulgarian patients with balanced randomization and diverse demographic representation across all three trial arms. The primary endpoint was PANSS Total Score change from baseline vs placebo at week 4. Secondary endpoints were PANSS Positive Symptoms, PANSS Negative Symptoms, PANSS Negative Marder Factor, PANSS Social Cognition, PANSS Excitement/Agitation, CGI-S, and Personal and Social Performance (PSP) score changes from baseline vs placebo at week 4.
Brilaroxazine 50 mg successfully met all primary and secondary endpoints with statistically significant and clinically meaningful improvements over placebo across all major symptom domains. The primary endpoint PANSS Total Score change from baseline was -23.9 for brilaroxazine 50 mg vs -13.8 for placebo at week 4, resulting in a 10.1 point reduction over placebo (p < 0.001). Within the first week of dosing, brilaroxazine 50 mg already achieved separation from placebo in the primary endpoint and several secondary endpoints.
The lower brilaroxazine 15 mg dose met two secondary endpoints at week 4, PANSS Social Cognition and Personal and Social Performance (PSP), and showed a clear improvement trend and increasing separation from placebo in the primary endpoint PANSS Total Score and PANSS Positive Symptoms score starting at week 3.
Brilaroxazine was very well tolerated and safe, with overall treatment emergent adverse event (TEAE) rates of 34.5% for brilaroxazine 15 mg, 35.5% for 50 mg, and 30% for placebo. Discontinuation rates for brilaroxazine were lower than for placebo and were 19% for brilaroxazine 15 mg, 16% for 50 mg, and 22% for placebo. Discontinuation rates due to drug side effects were also lower for brilaroxazine than for placebo and were 1% for brilaroxazine 15 mg, 0% for 50 mg, and 4% for placebo. Common TEAEs (>5%) were headache (<6%) and somnolence (<=7.5%) but these were mild-to-moderate in severity and generally transient in nature. There were no incidences of suicidal ideation.
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Brilaroxazine
Brilaroxazine (developmental code name RP5063), also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of schizoaffective disorder, bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADHD), irritability in autism, tics, psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis (topical gel). The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
Brilaroxazine is a third-generation antipsychotic drug and dopamine-serotonin system modulator due to its unique actions on dopamine and serotonin neurotransmitter systems compared to other antipsychotics. Clinical data from phase I, phase II (NCT01490086), and phase III (NCT05184335) trials suggest that brilaroxazine may have favorable efficacy and a significantly improved side effect profile compared to existing second and third-generation antipsychotics.
Brilaroxazine acts as a potent partial agonist of D2, D3, D4 and 5-HT1A receptors, and as an antagonist of 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6 and 5-HT7 receptors. Brilaroxazine exhibits high affinity for D2S, D2L, D3, D4.4, 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT7 receptors, and moderate affinity for D1, D5, 5-HT2C, 5-HT3, 5-HT6, H1 and α4β2 nicotinic receptors, the serotonin transporter, and the α1B adrenergic receptor. It lacks significant affinity for 5-HT1B, α2 adrenergic, and muscarinic acetylcholine receptors, as well as for the norepinephrine and dopamine transporters.
Brilaroxazine is identical to aripiprazole in chemical structure except for the replacement of a methylene group in aripiprazole's quinolinone ring system with an oxygen atom, resulting instead in a benzoxazinone ring system. This structural change is within the molecule's secondary pharmacophore, which plays a major role in modulating its binding and intrinsic efficacy at dopamine and serotonin receptors. The drug is also related structurally to brexpiprazole and cariprazine.
In October 2023, Reviva Pharmaceuticals released topline results from their pivotal RECOVER phase III clinical trial (NCT05184335).[citation needed] The RECOVER study was a 4-week, randomized, double-blind, placebo-controlled, multicenter trial where 411 patients with schizophrenia received brilaroxazine 15 mg, 50 mg, or placebo once daily. The trial cohort consisted of 60% American, 34% Indian, and 6% Bulgarian patients with balanced randomization and diverse demographic representation across all three trial arms. The primary endpoint was PANSS Total Score change from baseline vs placebo at week 4. Secondary endpoints were PANSS Positive Symptoms, PANSS Negative Symptoms, PANSS Negative Marder Factor, PANSS Social Cognition, PANSS Excitement/Agitation, CGI-S, and Personal and Social Performance (PSP) score changes from baseline vs placebo at week 4.
Brilaroxazine 50 mg successfully met all primary and secondary endpoints with statistically significant and clinically meaningful improvements over placebo across all major symptom domains. The primary endpoint PANSS Total Score change from baseline was -23.9 for brilaroxazine 50 mg vs -13.8 for placebo at week 4, resulting in a 10.1 point reduction over placebo (p < 0.001). Within the first week of dosing, brilaroxazine 50 mg already achieved separation from placebo in the primary endpoint and several secondary endpoints.
The lower brilaroxazine 15 mg dose met two secondary endpoints at week 4, PANSS Social Cognition and Personal and Social Performance (PSP), and showed a clear improvement trend and increasing separation from placebo in the primary endpoint PANSS Total Score and PANSS Positive Symptoms score starting at week 3.
Brilaroxazine was very well tolerated and safe, with overall treatment emergent adverse event (TEAE) rates of 34.5% for brilaroxazine 15 mg, 35.5% for 50 mg, and 30% for placebo. Discontinuation rates for brilaroxazine were lower than for placebo and were 19% for brilaroxazine 15 mg, 16% for 50 mg, and 22% for placebo. Discontinuation rates due to drug side effects were also lower for brilaroxazine than for placebo and were 1% for brilaroxazine 15 mg, 0% for 50 mg, and 4% for placebo. Common TEAEs (>5%) were headache (<6%) and somnolence (<=7.5%) but these were mild-to-moderate in severity and generally transient in nature. There were no incidences of suicidal ideation.
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