Dexmedetomidine sublingual film (BXCL501)

Mechanism of action

Dexmedetomidine is a potent, highly selective alpha-2 adrenergic receptor agonist (the pharmacologically active S-enantiomer of medetomidine), with reported alpha-2:alpha-1 selectivity on the order of ~1600:1. Agonism at the presynaptic alpha-2A adrenoceptor (ADRA2A) in the locus coeruleus reduces noradrenergic outflow, producing sedation/anxiolysis without significant respiratory depression. In agitation, sublingual dexmedetomidine is hypothesized to calm hyperadrenergic arousal that drives acute agitation episodes. Alpha-2B and alpha-2C subtypes are additional adrenoceptor targets.

Formulations

Dexmedetomidine sublingual film (BXCL501) for Agitation in Alzheimer's disease

Phase 3ActiveAgitation in Alzheimer's disease indication →

Phase 3 TRANQUILITY program evaluating PRN sublingual dexmedetomidine (BXCL501) for the acute treatment of agitation associated with Alzheimer's dementia. TRANQUILITY I (NCT04251910, Phase 1b/2) supported the FDA Breakthrough Therapy designation for dementia-related agitation. The pivotal TRANQUILITY II study (NCT05271552, Phase 3, n=151) MET its primary endpoint, with the 60 mcg dose producing a statistically significant 7.5-point reduction from baseline in PEC total score at 2 hours vs 5.4 with placebo (p=0.0112). Two confirmatory PRN studies, TRANQUILITY III (NCT05665088) and BXCL501-203 (NCT05276830), were terminated for business reasons (not safety/efficacy). On 10 Apr 2024 BioXcel announced a single confirmatory TRANQUILITY In-Care pivotal Phase 3 (~150 patients in care settings, 60 mcg, 12-week PRN, PEC at 2h primary). As of the 15 May 2026 Q1-2026 business update the In-Care trial had not yet started; the molecule remains separately FDA-approved (Igalmi) for bipolar/schizophrenia agitation but is NOT approved for the Alzheimer's-agitation indication. Note: BioXcel disclosed substantial-doubt going-concern as of Q1 2026.

Dexmedetomidine sublingual film (BXCL501) for Schizophrenia

Filed (NDA)ActiveSchizophrenia indication →

Supplemental NDA (sNDA) FILED to expand the IGALMI (BXCL501, sublingual dexmedetomidine) label to AT-HOME / outpatient use for the acute treatment of agitation associated with bipolar I/II disorder or schizophrenia. IGALMI is already FDA-approved (Apr 2022) for this agitation indication but only in a healthcare-supervised setting; the SERENITY At-Home program seeks the first approved at-home (patient/caregiver-administered) agitation therapy. The pivotal study is SERENITY III / 'SERENITY At-Home' (NCT05658510, Phase 3, 2-part, 452 enrolled). Part 1 (single-day in-clinic, 60 mcg, PEC change at 2h) MISSED its primary efficacy endpoint at 2h (p=0.077; 4h p=0.049; PEC-responder secondary p=0.019) when reported 25 May 2023. Part 2 (12-week at-home, 120 mcg PRN) was a SAFETY trial whose primary tolerability endpoint was MET (27 Aug 2025), with positive but non-powered exploratory efficacy (mCGI-S reduction at 2h across 2,433 episodes, p<0.05). Following a positive pre-sNDA meeting (18 Aug 2025), BioXcel submitted the sNDA on 14 Jan 2026; the FDA accepted it with a PDUFA target action date of 14 Nov 2026 (announced 01 Apr 2026). BXCL501 holds Fast Track designation for this indication. Reviewer caveat: BioXcel disclosed substantial-doubt going-concern as of Q1 2026.

Dexmedetomidine sublingual film (BXCL501) for Acute Stress Disorder

Phase 2RecruitingAcute Stress Disorder indication →

Phase 2a investigator-/government-sponsored program evaluating sublingual dexmedetomidine (BXCL501) for the early treatment of acute stress reactions / acute stress disorder (ASD) and prevention of progression to chronic posttraumatic neuropsychiatric symptoms. The single trial, RISE (NCT06943404, 'BXCL501 After Stress to Increase Recovery Success'), is sponsored by the University of North Carolina, Chapel Hill (Institute for Trauma Recovery; PI Samuel McLean, MD, MPH), with BioXcel Therapeutics supplying the drug, and is funded by a $2.8M U.S. Department of Defense / Department of War grant (HT9425-24-1-1108) to UNC running Sept 15 2024 - Sept 14 2026. The randomized, double-blind, placebo-controlled study (n=100, estimated) enrolls adults presenting to the emergency department with acute stress reactions after a motor vehicle collision; BXCL501 is dosed sublingually (120 mcg in the ED, a second dose at/before bedtime, then daily bedtime doses for 14 days). Primary endpoint: change in Acute Stress Disorder Scale (ASDS) at Week 1 and Week 3. The trial started 23 Feb 2026 and first-patient enrollment was announced 8 Apr 2026; estimated primary completion 29 Sep 2026. No regulatory designations are held for the ASD indication (Breakthrough/Fast Track designations apply to the agitation indications, not ASD).

Dexmedetomidine sublingual film (BXCL501) for Opioid use disorder

Phase 1/2ActiveOpioid use disorder indication →

Investigator-sponsored Phase 1/2 program evaluating PRN/twice-daily sublingual dexmedetomidine (BXCL501) for the treatment of acute opioid withdrawal during a 7-day inpatient methadone taper. The defining study, NCT05712707 (registered lead sponsor New York State Psychiatric Institute; Columbia University-led, NIDA-funded; BioXcel a drug-supplying collaborator), is a 4-arm trial (BXCL501 180 ug BID, BXCL501 240 ug BID, placebo, lofexidine 0.54 mg QID positive control). On 5 Mar 2026 BioXcel announced positive topline results: the 240 ug BID dose reduced opioid-withdrawal symptoms vs placebo (>30% reduction in SOWS-Gossop, peak days 3-4) and numerically exceeded the lofexidine control with a better tolerability profile (orthostatic hypotension 18% for 180 ug vs 50% for lofexidine, p<0.05; no sedation/somnolence in BXCL501 arms vs 5% for lofexidine). No p-value was disclosed for the placebo efficacy comparison. The data were framed as non-pivotal and supportive of potential future development requiring larger confirmatory trials; no regulatory path or timing has been committed. BXCL501 is NOT approved for opioid withdrawal or opioid use disorder (the molecule is separately approved as Igalmi for acute agitation in bipolar I/II disorder and schizophrenia).

Clinical trials