Английская Википедия:Brilaroxazine

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Brilaroxazine (developmental code name RP5063), also known as oxaripiprazole,[1][2] is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders.[3][4][5][6] 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 bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADD/ADHD), 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).[3][7] The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.

Brilaroxazine is a further evolution of third-generation antipsychotics and described as a dopamine-serotonin system stabilizer or modulator due to its unique actions on dopamine and serotonin neurotransmitter systems compared to other antipsychotics.[8][9][10] 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 third-generation drugs.[8][11][12]

Pharmacology

Pharmacodynamics

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.[8][10] Brilaroxazine exhibits high affinity for D2S, D2L, D3, D4.4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT7 and H1 receptors, and moderate affinity for D1, D5, 5-HT2C, 5-HT3, 5-HT6 and [[Alpha-4 beta-2 nicotinic receptor|αШаблон:SubβШаблон:Sub nicotinic]] receptors, the serotonin transporter, and the α1B adrenergic receptor.[8][10] It lacks significant affinity for 5-HT1B, α2 adrenergic, and muscarinic acetylcholine receptors, as well as for the norepinephrine and dopamine transporters.[10]

Binding profile [8][9]
Site Ki (nM) Action
D1 100 Шаблон:Abbr
D2L 0.45 Partial agonist
D2S 0.28 Partial agonist
D3 3.7 Partial agonist
D4 6.0 Partial agonist
D5 200 Шаблон:Abbr
5-HT1A 1.5 Partial agonist
5-HT2A 2.5 Weak partial agonist/
Antagonist
5-HT2B 0.19 Antagonist
5-HT2C 39 Antagonist
5-HT3 78 Шаблон:Abbr
5-HT6 51 Antagonist
5-HT7 2.7 Antagonist
H1 Шаблон:Abbr Шаблон:Abbr
[[Alpha-4 beta-2 nicotinic receptor|αШаблон:SubβШаблон:Sub nicotinic]] 36.3 Шаблон:Abbr
Шаблон:Abbrlink 107 Шаблон:Abbr
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Chemistry

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.[13][14] The drug is also related structurally to brexpiprazole and cariprazine.

Recent Developments

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
Endpoint Point Reduction / Improvement Cohen's d Effect Size P Value
PANSS Total Score 10.1 0.6 <0.001
PANSS Positive Symptoms 2.8 0.5 <0.001
PANSS Negative Symptoms 2.0 0.4 0.003
PANSS Negative Marder Factor 2.1 0.4 0.002
PANSS Social Cognition 1.6 0.5 <0.001
PANSS Excitement/Agitation 2.1 0.5 <0.001
Personal and Social Performance (PSP) 6.3 0.5 <0.001
CGI-S >= 1 0.5 <0.001

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 significant 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.[15][16] The meta-analysis studies used pooled data from each drug's entire schizophrenia dose range, therefore the results for the highest 50 mg dose of brilaroxazine would likely show even more significant improvement in weight change against comparable highest dosages of third-generation antipsychotics if the breakdown were available.

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, a confirmatory 6-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 early 2025 and brilaroxazine FDA new drug application (NDA) submission is expected afterwards. If successful, commercial availability is anticipated by late 2025 or early 2026.

See also

References

Шаблон:Reflist

External links

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  1. ↑ Ошибка цитирования Неверный тег <ref>; для сносок pmid29767995 не указан текст
  2. ↑ Ошибка цитирования Неверный тег <ref>; для сносок Jordan2018 не указан текст
  3. ↑ 3,0 3,1 Ошибка цитирования Неверный тег <ref>; для сносок RevivaCorpPres не указан текст
  4. ↑ Шаблон:Cite report
  5. ↑ Шаблон:Cite journal
  6. ↑ Шаблон:Cite journal
  7. ↑ Шаблон:Cite web
  8. ↑ 8,0 8,1 8,2 8,3 8,4 Шаблон:Cite journal
  9. ↑ 9,0 9,1 Шаблон:Cite journal
  10. ↑ 10,0 10,1 10,2 10,3 Шаблон:Cite web
  11. ↑ Шаблон:Cite journal
  12. ↑ Шаблон:Cite web
  13. ↑ Шаблон:Cite journal
  14. ↑ Шаблон:Cite journal
  15. ↑ Шаблон:Cite journal
  16. ↑ Шаблон:Cite journal
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