Brilaroxazine is a third-generation antipsychotic drug and dopamine-serotonin system modulator due to its unique actions on dopamine and serotoninneurotransmitter systems compared to other antipsychotics.[9][10][11] 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.[9][12][13]
In October 2023, Reviva Pharmaceuticals released topline results from their pivotal RECOVER phase III clinical trial (NCT05184335). The RECOVER study was a 4-week, randomized, double-blind, placebo-controlled, multicenter trial where 411 patients received brilaroxazine 15 mg, 50 mg, or placebo once daily. The trial cohort consisted of 60% USA, 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.
RECOVER Phase III Trial Brilaroxazine 50 mg vs Placebo at Week 4
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.
There was no >=7% mean change in bodyweight, blood glucose, lipids, prolactin, or thyroid hormones compared to placebo. The percentage of patients who gained weight during the trial was 2.1% for brilaroxazine 15 mg, 5.9% for 50 mg, and 2.9% for placebo. This is a significant improvement over the currently prescribed third-generation antipsychotics aripiprazole (Abilify), brexpiprazole (Rexulti), and cariprazine (Vraylar). In comparable short-term (4-6 week) acute schizophrenia clinical trials, the percentage of patients taking a third-generation antipsychotic that had clinically relevant weight gain (>= 7% gain) was 9.2% for aripiprazole vs 4.3% for placebo, 10.4% for brexpiprazole vs 4.1% for placebo, and 9.2% for cariprazine vs 4.7% for placebo. Cariprazine had a 3% weight gain over placebo on its highest dose which was equivalent to the weight gain for brilaroxazine.[16][17]
Akathisia and extrapyramidal symptom (EPS) rates were very low and were 0% for brilaroxazine 15mg, 0.7% for 50 mg, and 0% for placebo. The percentage of patients with elevated LDL cholesterol compared to baseline was 0% for brilaroxazine 15 and 50 mg vs 2.9% for placebo, and the percentage of patients with low HDL cholesterol compared to baseline was 0.7% for brilaroxazine 15 mg, 1.4% for 50 mg, and 1.4% for placebo.
Reviva also has an ongoing 52-week, single-arm, phase III open-label extension (OLE) study of stable schizophrenia patients to further evaluate the long-term safety and tolerability of brilaroxazine as part of the RECOVER program (NCT05184335). In this study, rollover patients from the RECOVER 4-week double-blind trial as well as de novo stable schizophrenia patients receive brilaroxazine in a 15-30-50 mg flexible dosing schedule. Completion is expected in Q4 2024. In Q1 2024 Reviva plans to initiate RECOVER-2 in Q2 2024. RECOVER-2 is a confirmatory 4-week, randomized, double-blind, placebo-controlled, multicenter phase III clinical trial of 450 acute schizophrenia patients, where patients will receive brilaroxazine 30 mg, 50 mg, or placebo once daily. Completion is expected in Q2 2025 and brilaroxazine FDA new drug application (NDA) submission is expected in Q3 2025. If successful, commercial availability is anticipated by 2026.
Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay, together with mood stabilizers, in the treatment of bipolar disorder. Moreover, they are also used as adjuncts in the treatment of treatment-resistant major depressive disorder.
Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given orally, by intramuscular injection, or intravenously.
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder, as well as aggressive and self-injurious behaviors associated with autism spectrum disorder. It is taken either by mouth or by injection. The injectable versions are long-acting and last for 2–4 weeks.
Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used in the treatment of schizophrenia, bipolar disorder, bipolar depression, and major depressive disorder. Despite being widely prescribed as a sleep aid due to its tranquillizing effects, the benefits of such use may not outweigh the risk of undesirable side effects. It is taken orally.
Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.
Olanzapine, sold under the brand name Zyprexa among others, is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. It is also sometimes used off-label for treatment of chemotherapy-induced nausea and vomiting and as an appetite stimulant. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.
Aripiprazole, sold under the brand names Abilify and Aristada, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as an add-on treatment for major depressive disorder and tic disorders. Aripiprazole is taken by mouth or via injection into a muscle. A Cochrane review found low-quality evidence of effectiveness in treating schizophrenia.
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabenazine to treat chorea associated with Huntington's disease. Although other drugs had been used "off label," tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s.
Pipamperone, sold under the brand name Dipiperon, is a typical antipsychotic of the butyrophenone family used in the treatment of schizophrenia and as a sleep aid for depression. It is or has been marketed under brand names including Dipiperon, Dipiperal, Piperonil, Piperonyl, and Propitan. Pipamperone was discovered at Janssen Pharmaceutica in 1961, and entered clinical trials in the United States in 1963.
Iloperidone, sold under the brand name Fanapt among others, is an atypical antipsychotic for the treatment of schizophrenia and bipolar I disorder.
Perospirone (Lullan) is an atypical antipsychotic of the azapirone family. It was introduced in Japan by Dainippon Sumitomo Pharma in 2001 for the treatment of schizophrenia and acute cases of bipolar mania.
Lurasidone, sold under the brand name Latuda among others, is an atypical antipsychotic medication used to treat schizophrenia and bipolar depression. It is taken by mouth.
Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. It is taken by mouth.
Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.
Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia and bipolar disorder. It is also prescribed as an add-on treatment for bipolar depression and major depressive disorder. Cariprazine acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. It is a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. It is taken by mouth. The most prevalent side effects include nausea, mild sedation, fatigue, and dizziness. At higher dosages, there is an increased risk for restlessness, insomnia, and tremors.
Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.
Lumateperone, sold under the brand name Caplyta, is an atypical antipsychotic medication of the butyrophenone class. It is approved for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy. It is developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb. Lumateperone was approved for medical use in the United States in December 2019 with an initial indication for schizophrenia, and became available in February 2020. It has since demonstrated efficacy in bipolar depression and received FDA approval in December 2021 for depressive episodes associated with both bipolar I and II disorders. Part of the drug shows structural similarity to Pirlindole.
Aripiprazole lauroxil, sold under the brand name Aristada, is a long-acting injectable atypical antipsychotic that was developed by Alkermes. It is an N-acyloxymethyl prodrug of aripiprazole that is administered via intramuscular injection once every four to eight weeks for the treatment of schizophrenia. Aripiprazole lauroxil was approved by the U.S. Food and Drug Administration (FDA) on 5 October 2015.
Ulotaront is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube.
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