BXCL501 (Sublingual Dexmedetomidine) for Treatment of Agitation Associated With Bipolar Disorder or Schizophrenia in the Home Setting: a Phase 3 Study Leslie Citrome1 , Lavanya Rajachandran 2 , Robert Risinger 3 , Michael De Vivo 2 , Heather Robison 2 , Dusan Kostic 2 , Matt Mandel 2 , Rashmi Deshpande 2 , Frank Yocca 4 1New York Medical College, 2BioXcel Therapeutics, Inc., 3BioXcel Therapeutics, Inc. (former), 4Bioxcel Therapeutics, BioXcel Corporation 1BioXcel Therapeutics, New Haven, CT, USA; 2BioXcel Therapeutics Clinical Consultant Conclusions Introduction • Patients with schizophrenia or bipolar disorder frequently experience episodes of agitation. • In the home setting, where most episodes of agitation occur, there are no FDA-approved therapies for this indication. • BXCL501 is a sublingual film formulation of dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, which has been approved for treatment of agitation under the supervision of a healthcare provider. A Phase 3 safety trial of BXCL501 was initiated with the goal of expanding the indication into the unsupervised (home) setting. • 246 patients randomized • 31 patients had no recorded episodes over 12 weeks • 7 patients did not take study treatment for their episodes • 2437 agitation episodes were treated in 208 patients • 81% of treated patients completed the study • At home, adverse events frequencies with a single dose were similar to those observed under medical supervision in previously completed Phase 3 studies (Table 1) • Over repeated administration, the incidence of adverse events did not increase (Tables 1 and 2) • No patient in the active arm discontinued due to TEAE • Although not powered for efficacy, the reduction in mCGI-S score was greater in the active group compared with placebo (P<0.05) • There was a mean reduction in mCGI-S score of 1.2 following the first 12 doses and a mean reduction of 1.4 following 13 or more doses of BXCL50, indicating no attenuation of benefit with repeat dosing. • Complete resolution of agitation was significantly higher with BXCL501 compared to placebo across agitation episode severity (P<.0001, Figure 1) Methods • A randomized, double-blind, placebo-controlled, Phase 3, 12-week trial (SERENITY At-home, NCT05658510) in the home setting • The primary outcome measure of the trial was the incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs), defined as adverse events occurring within 24 hours of dosing. • An exploratory objective was to evaluate whether repeated dosing would continue to provide treatment benefit. The exploratory outcome measures included a modified clinical global impression – severity (mCGI-S), scored by patients and by caregivers/informants, if present, on a scale of 0 (no agitation) to 3 (severe agitation) • Patients could also use meditation, alcohol, cannabis, OTC medications etc. to reflect real-world coping strategies Table 1: Most common TEAEs in SERENITY At-Home and comparison with studies done under medical supervision • In this pivotal safety study, sublingual dexmedetomidine 120 mcg was safe and well tolerated over a 12-week treatment period when administered on an as-needed basis​ • Over repeat dosing, no increase in TEAEs was observed • The reduction in symptoms remained consistent throughout the duration of the trial • Significantly more patients experienced full resolution of agitation symptoms with BXCL501 than with placebo 10% Results Male and female patients ages 18– 75 years with bipolar I or II disorder, schizophrenia, schizoaffective, or schizophreniform disorder On a stable psychotropic regimen for ≥30 days prior to screening History of ≥3 agitation episodes in past 3 months Unstable or serious medical illness (e.g., CHF, recent MI, hepatic disease) Diagnosis of antisocial, borderline, or narcissistic personality disorder that predated schizophrenia or bipolar disorder Moderate to severe substance use disorder in past 6 months Agitation due primarily to acute intoxication or substance use INCLUDED PATIENTS EXCLUDED PATIENTS Primary Outcome: Safety and Tolerability Treatment-Emergent Adverse Event SERENITY I & II1 1 SERENITY AT-HOME Adverse Event by Dose (Episode) 1 SINGLE DOSE FIRST DOSE ALL DOSES IGALMI 120 MCG (N=255) n (%) PLACEBO (N=252) n (%) BXCL501 120 MCG (N=102) 1 n (%) 2 PLACEBO (N=106) 1 n (%) 2 BXCL501 120 MCG (N=1160) 1 n (%) 2 PLACEBO (N=1277) 1 n (%) 2 Somnolence 3 56 (22%) 16 (6%) 23 (22.5%) 18 (17.0%) 161(13.9%) 103 (8.1%) Oral Paresthesia/Hypoesthesia 14 (6%) 2 (1%) 2 (2%) 1 (0.9%) 6 (0.5%) 1 (0.1%) Dizziness 10 (4%) 2 (1%) 5 (4.9%) 1 (0.9%) 19 (1.6%) 2 (0.2%) Dry Mouth 19 (7%) 3 (1%) 7 (6.9%) 1 (0.9%) 56 (4.8%) 24 (1.9%) Nausea 6 (2%) 4 (2%) 1 (1.0%) 0 (0%) 6 (0.5%) 1 (0.1%) Headache 12 (5%) 12 (5%) 0 (0%) 2 (1.9%) 4 (0.3%) 4 (0.3%) 1SERENITY I and II evaluated a single agitation episode in each patient. SERENITY AT-Home evaluated a total of 2437 episodes in 208 patients. Adverse events are presented on an episode basis. N denotes number of episodes. Only AEs observed in Serenity At-Home Pivotal Phase 3 trial are listed. 2Percent of TEAE events per dosing episode 3 Includes fatigue Treatment-Emergent Adverse Event After Doses 1-3 After doses 4 to 12 After doses 13 and beyond BXCL501 (N=266) 1 n (%) 2 PLACEBO (N=274) 1 n (%) 2 BXCL501 (N=398) 1 n (%) 2 PLACEBO (N=485) 1 n (%) 2 BXCL501 (N=496) 1 n (%) 2 PLACEBO (N=518) 1 n (%) 2 Somnolence 3 58 (22.0%) 43 (16.0%) 61 (15.3%) 52 (10.8%) 42 (8.5%) 8 (1.5%) Oral Paresthesia/Hypoesthesia 4 (1.5%) 1 (0.4%) 2 (0.5%) 0 (0%) 0 (0%) 0 (0%) Dizziness 10 (3.8%) 1 (0.4%) 7 (1.8%) 1 (0.2%) 2 (0.4%) 0 (0%) Dry mouth 14 (5.3%) 2 (0.7%) 29 (7.3%) 2 (0.4%) 13 (2.6%) 20 (3.9%) Nausea 1 (0.4%) 1 (0.4%) 3 (0.8%) 0 (0%) 2 (0.4%) 0 (0%) Headache 3 (1.1%) 2 (0.7%) 0 (0%) 2 (0.4%) 1 (0.2%) 0 (0%) 1Number of Dosed Episodes 2Percentage of Dosed Episodes 3 Includes Fatigue Table 2: TEAEs per dosed episode by dose numbers Exploratory Outcome: Efficacy Figure 1: Percent of fully resolved episodes by baseline severity and overall