Laxminarayan Bhat

Background: 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 D _2/3/4 and 5‐HT _1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. Methods: An imiquimod‐induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal‐aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1–11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1–12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One‐way ANOVA followed by post hoc Dunnett's t ‐test evaluated significance ( p < 0.05). Results: Imiquimod‐induced animal Baker scores were higher versus Sham non‐induced control's results ( p < 0.001). Brilaroxazine Lipogel had significantly ( p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower ( p = 0.03) versus the induced Psoriasis group (Days 3‐12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki‐67 and TGF‐β levels versus non‐induced Sham controls ( p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki‐67 ( p = 0.001) and TGF‐β ( p = 0.008), and no difference in TNF‐α levels versus Sham non‐induced controls. Conclusion: Brilaroxazine Lipogel displayed significant activity in imiquimod‐induced psoriatic animals, offering a novel therapeutic strategy.

ID 53587 Poster Board 579 Background: Brilaroxazine, a serotonin/dopamine modulator developed for treating schizophrenia, possesses differentiated pharmacological and safety profiles over other antipsychotic treatments. This work describes the pharmacokinetics, metabolism, and excretion (PME) of a single-dose [¹⁴C]-brilaroxazine in mouse, dog, and human studies. Methods: Brilaroxazine PME profile involved three single-dose studies, two animal and one clinical. The animal studies consisted of administering a single oral dose of [¹⁴C]-brilaroxazine 10 mg/kg (400 mCi/kg) and 10 mg/kg (75 mCi/kg) to CD-1 mice and beagle dogs (both male), respectively. Each study collected serial blood and excreta samples up to 144-168 hours post-dose. The clinical study of six healthy male volunteers involved administering a single 15 mg (∼163 mCi) oral dose of [¹⁴C]-brilaroxazine. This study collected serial blood and excreta samples up to 336 hours post-dose. Radioactivity concentrations determination in blood, plasma and excreta samples utilized liquid scintillation counting (LSC) or a combination of combustion with LSC. Plasma concentrations determination of unlabeled brilaroxazine and its metabolite RP5081 used a validated LC-MS/MS method. Calculating plasma pharmacokinetic parameters of total radioactivity, brilaroxazine and metabolite RP5081 employed non-compartmental analysis (WinNonlin). Identifying brilaroxazine-related metabolite structures in biological samples involved mass spectral analysis or via direct comparison with authentic standards. Results: Feces represented the predominant recovery route for administered dose for mice (77.9%), dogs (55.3%), and humans (52.3%). Urine recovery was the secondary route for mice (10.3%), dogs (15.0%), and humans (32.8%). Brilaroxazine accounted for approximately 12%, 7%, and 12% of the total circulating radioactivity, respectively, in mice, dogs and humans. A fragment of brilaroxazine, N-(2,3-chlorophenyl)-glycine (M219), was the major circulating metabolite in all species accounting for approximately 40%, 51% and 72% of the total radioactivity in mice, dogs, and humans, respectively. Human plasma showed no unique human-specific metabolite. All metabolites in human plasma were found in either mice or dogs. The major excreted metabolite identified was mono-hydroxylated brilaroxazine (M465a) in all species. Conclusions: Following a single oral dose of [¹⁴C]-brilaroxazine, the administered dose was predominantly recovered in feces of all species. The major circulating metabolite was the same in all species, and there was no human-specific metabolite in plasma. Oxidation, N- or O-dealkylation with subsequent sulfation and/or conjugation with glucuronic acid were the metabolic pathways of brilaroxazine.

ID 53571 Poster Board 376 Background: The metabolism of standard antipsychotics (e.g., aripiprazole, lurasidone, risperidone, quetiapine, cariprazine, brexpiprazole, and clozapine) involves CYP3A4. Most treatments realize significant plasma drug concentration changes when co-administered with CYP3A4 inhibitors or inducers. Such interactions are of clinical concern as schizophrenia patients take concomitant medications interacting with CYP3A4, leading to dose adjustment to ensure treatment efficacy, safety, and tolerability. Brilaroxazine, a serotonin/dopamine modulator, is a novel compound in phase 3 development for schizophrenia. It possesses differentiated pharmacological and safety profiles over other treatments in this class. Preclinical in vitro work identified CYP3A as the primary enzyme involved in the metabolism of brilaroxazine. This clinical study evaluated itraconazole’s (a strong CYP3A inhibitor) and phenytoin’s (a strong CYP3A inducer) effects on brilaroxazine’s pharmacokinetic (PK) profile. Methods: This study involved a single-center, open-label, fixed-sequence, two-part, drug-drug interaction design in healthy adult male and female subjects. Part A evaluated the effects of itraconazole (200 mg QD) dosed to a steady state on the single-dose PK of brilaroxazine and metabolite RP5081 in 13 subjects. Part B assessed the effect of phenytoin (100 mg TID) dosed to a steady state on the single-dose PK of brilaroxazine and metabolite RP5081 in 16 subjects. Determination of brilaroxazine and metabolite RP5081 C_max, AUC_0-t and AUC_0-∞ used noncompartmental methods and statistical inference involving log-transformation and a linear mixed-effects model with treatment as a fixed effect and subject as a random effect. The analysis involved calculating the geometric least squares mean for each treatment, the ratio of the geometric least squares means, and their 90% confidence intervals (CIs). Results: Single brilaroxazine dose co-administered with itraconazole resulted in a slight increase of 8, 15 and 13% in C_max, AUC_0-t, and AUC_0-∞, respectively (90% CI within 80-125%). No difference in the brilaroxazine mean elimination half-life existed between when brilaroxazine administered alone and concomitantly with itraconazole. Alternatively, a single brilaroxazine dose with co-administered phenytoin decreased brilaroxazine C_max, AUC_0-t, and AUC_0-∞ by 33, 57, and 54%, respectively. Conclusions: Itraconazole (a strong CYP3A inhibitor) exerted no effect on brilaroxazine’s PK. Accordingly, brilaroxazine may be co-administered with itraconazole and other strong CYP3A inhibitors. In contrast, phenytoin (a strong CYP3A inducer) decreased brilaroxazine exposure by approximately 50%. Thus, brilaroxazine dose modification may be needed when co-administering with strong CYP3A inducers. This profile presents a useful addition to the clinical management of schizophrenia to minimize the clinical risks associated with drug-drug interactions seen with other antipsychotics, particularly with CYP3A inhibitors.

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. Investigators observed no cardiometabolic, cardiovascular, prolactin, or neurologic complications. Adherence in Phase 2 was good with discontinuation rates generally less than placebo. In a Phase 2 evaluation of patients with acute exacerbations in schizophrenia and schizoaffective disorders, brilaroxazine met its primary endpoint of significance versus placebo for Total Positive and Negative Symptom Scale (PANSS) Score at Day 28 as compared to baseline. In Phase 1 multi-dose pharmacodynamic evaluation, brilaroxazine displayed clinical activity in patients with stable disease and a PANSS greater than 50, as early as Day 10 of treatment. Pharmacokinetic analyses demonstrated brilaroxazine to have a substantial and relatively rapid oral absorption, linear (dose proportional) increases in maximum concentration (Cmax) and area under the curve (AUC), lack of excessive accumulation, and a relatively long terminal half-life of about 60 hours. Early clinical findings with brilaroxazine in schizophrenia and schizoaffective disorders indicate that this compound appears to be effective, well tolerated, and possess a straightforward once-daily dosing pharmacokinetic profile.

RP5063 is a multimodal dopamine (D)‐serotonin (5‐HT) stabilizer with a high affinity for D_2/3/4 and 5‐HT_1A/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. Orthostatic hypotension (n = 6), nausea (n = 5), and dizziness (n = 4) were the most common. One serious adverse event (SAE), seen in a patient who should not have been in the study due to a history of seizures, involved brief seizure‐like symptoms. In the multiple‐dose study, 75 TEAEs were reported. Akathisia (n = 20) and somnolence (n = 14) were the most frequent. No clinically significant changes were seen in glucose or prolactin levels, lipid profiles, weight, or electrocardiographic recordings. In both studies, all TEAEs resolved and none led to withdrawal from the study or death. A pharmacodynamic evaluation reflected significant improvements with RP5063 (P < 0.05) over placebo in an analysis of patients with a baseline Positive and Negative Syndrome Scale (PANSS) score ≥50 for positive subscale scores. Improvements of the Trail Making A and Trail Making B test results were observed for patients treated in the 50 mg dose group for days 5, 10, and 16. These findings indicate that RP5063 is well‐tolerated up to 100 mg and displays promising preliminary clinical behavioral and cognition activity signals in patients with stable disease over a 10‐day period.

RP5063 is a novel multimodal dopamine (D)–serotonin (5-HT) stabilizer possessing partial agonist activity for D_2/3/4 and 5-HT_1A/2A, antagonist activity for 5-HT_2B/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.

RP5063, a multimodal dopamine (D)–serotonin (5‐HT) stabilizer, possesses high affinity for D_2/3/4 and 5‐HT_{1A/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. RP5063 displayed a dose‐dependent C_max at 4 to 6 h, linear dose proportionality for both C_max and AUC, and a half‐life between 40 and 71 h. In the single‐dose study, food slightly increased the extent of drug absorption. In the multiple‐dose study, steady‐state was approached after 120 h of daily dosing. Pooled data in the single‐dose study indicate that the pharmacokinetic profile appears to be comparable between Japanese and Caucasians. RP5063 appears to have a straightforward pharmacokinetic profile that supports for phase II and III evaluation as a once‐daily oral administered agent.