KarXT · program

Xanomeline/trospium chloride (Cobenfy) for Alzheimer's disease psychosis

Phase 3RecruitingBristol-Myers Squibb Company (BMY)

Indications for KarXT: Schizophrenia · Approved Alzheimer's disease psychosis · Phase 3

Xanomeline/trospium chloride (Cobenfy/KarXT) for psychosis associated with Alzheimer's disease (ADP) — the ADEPT Phase 3 program, the franchise's largest post-approval bet. There is no FDA-approved treatment for ADP, and off-label D2 antipsychotics carry a boxed warning for increased mortality in elderly dementia patients. Five trials: ADEPT-1 (NCT05511363, randomized-withdrawal relapse prevention, primary endpoint time to relapse over 38 weeks, started 2022-08-23), ADEPT-2 (NCT06126224, acute efficacy, primary endpoint change in NPI-C Hallucinations+Delusions score, started 2023-08-28), ADEPT-3 (NCT05980949, open-label long-term safety extension), ADEPT-4 (NCT06585787, second acute efficacy study, started 2024-09-26), and ADEPT-5 (NCT06947941, KarXT + KarX-EC, started 2026-03-25). The program has slipped twice. On 2025-12-03 BMS disclosed 'irregularities due to clinical trial execution at a small number of study sites' in ADEPT-2: it excluded those sites' data from the primary analysis, brought in an independent assessor, and — on the Data Monitoring Committee's recommendation, remaining blinded — continued the study with additional enrollment, guiding ADEPT-1/-2/-4 readouts to end-2026. On the Q2 2026 earnings (2026-07-30) BMS pushed again, citing enrollment pace in ADEPT-2/-4 and slower-than-projected relapse accrual in ADEPT-1: topline readouts are now anticipated to begin in early 2027 and be spread across the year, with a potential ADEPT-1 interim analysis later in 2026. No efficacy data from any ADEPT trial has been reported; all five trials are recruiting as of 2026-08-12.

Data current as of

Development timeline

Phase 3Nov 2021 – Jun 2027
  1. UpcomingTopline from ADEPT-4, the second acute-efficacy Phase 3 of Cobenfy in Alzheimer's disease psychosis (NPI-C H+D primary endpoint): among readouts beginning early 2027 and spread across the year.↗
  2. UpcomingTopline from ADEPT-1, the Phase 3 relapse-prevention (randomized-withdrawal) study of Cobenfy in Alzheimer's disease psychosis: among readouts beginning early 2027 and spread across the year, with a potential interim analysis later in 2026.↗
  3. UpcomingTopline results from ADEPT-2, the first acute-efficacy Phase 3 of Cobenfy in Alzheimer's disease psychosis (primary endpoint: change in NPI-C Hallucinations and Delusions score), now expected among readouts beginning early 2027.↗
  4. ADEPT-2 continuation announcement: BMS identified 'irregularities due to clinical trial execution at a small number of study sites', excluded those sites' patient data from the primary analysis, had an independent party assess the collected data, and per the Data Monitoring Committee's recommendation continued the trial with additional enrollment (BMS remaining blinded). ADEPT-1/-2/-4 readouts guided to end-2026 at that time; on 2026-07-30 (Q2 2026 earnings) guidance moved again to topline readouts beginning early 2027, spread across the year. Phase and status unchanged — recorded because the enrollment extension and readout slips are material program events with no fitting event_type code.↗
  5. AcquisitionBristol Myers Squibb completes its $14.0 billion acquisition of Karuna Therapeutics↗
  6. ADEPT-1 (NCT05511363, CN012-0026) started per ClinicalTrials.gov: the ADP program opened directly in Phase 3 with a randomized-withdrawal relapse-prevention design (open-label KarXT, then randomization to continue or withdraw; primary endpoint time from randomization to relapse over 38 weeks). Started under Karuna Therapeutics, pre-acquisition.
  7. Licensing dealKaruna licenses KarXT Greater China rights to Zai Lab ($35M upfront)↗

Readouts

  • 2027DelayedTopline dataNCT06585787

    Topline from ADEPT-4, the second acute-efficacy Phase 3 of Cobenfy in Alzheimer's disease psychosis (NPI-C H+D primary endpoint): among readouts beginning early 2027 and spread across the year. ↗

  • 2027 (potential interim analysis late 2026)DelayedTopline dataNCT05511363

    Topline from ADEPT-1, the Phase 3 relapse-prevention (randomized-withdrawal) study of Cobenfy in Alzheimer's disease psychosis: among readouts beginning early 2027 and spread across the year, with a potential interim analysis later in 2026. ↗

  • early 2027DelayedTopline dataNCT06126224

    Topline results from ADEPT-2, the first acute-efficacy Phase 3 of Cobenfy in Alzheimer's disease psychosis (primary endpoint: change in NPI-C Hallucinations and Delusions score), now expected among readouts beginning early 2027. ↗

Clinical trials in Alzheimer's disease psychosis

NCT06947941CN012-0034Phase 3Recruitingn=325

ADEPT-5: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of KarXT + KarX-EC for Psychosis Associated With Alzheimer's Disease

Started Mar 2026· Primary completion Feb 2028· 📍 22 sites across 5 countries (United Kingdom, United States, Canada, Japan)

NCT06585787CN012-0056Phase 3Recruitingn=406

ADEPT-4: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Safety and Efficacy of KarXT for Psychosis Associated With Alzheimer's Disease

Started Sept 2024· Primary completion Nov 2026· 📍 289 sites across 25 countries (United States, Japan, China, South Korea)

NCT06126224CN012-0027Phase 3Recruitingn=500

ADEPT-2: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Safety and Efficacy of KarXT for Psychosis Associated With Alzheimer's Disease

Started Aug 2023· Primary completion Dec 2026· 📍 154 sites across 14 countries (United States, China, United Kingdom, Poland)

NCT05980949CN012-0028Phase 3Recruitingn=1000

ADEPT-3: Open-Label Extension Study of the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease

Started Jul 2023· Primary completion Sept 2027· 📍 428 sites across 31 countries (United States, China, Japan, Italy)

NCT05511363CN012-0026Phase 3Recruitingn=410

ADEPT-1: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Relapse Prevention Study of KarXT for Psychosis Associated With Alzheimer's Disease

Started Aug 2022· Primary completion Oct 2026· 📍 116 sites across 11 countries (United States, Serbia, Italy, Spain)

Formulations

FormulationRouteRegimenPharmacokinetics
COBENFY oral capsule (xanomeline/trospium chloride 50/20, 100/20, 125/30 mg BID)
Capsules of xanomeline (as tartrate) / trospium chloride: 50 mg/20 mg, 100 mg/20 mg, 125 mg/30 mg. Start 50/20 twice daily for at least 2 days, increase to 100/20 twice daily for at least 5 days, then optionally to 125/30 twice daily based on response and tolerability. Must be taken at least 1 hour before or 2 hours after a meal; capsules must not be opened.
OralTwice dailyt½ 5 h · Tmax 2 h

Mechanism of action (compound-wide)

Dual-component muscarinic strategy with no direct dopamine D2 blockade. Xanomeline is a muscarinic acetylcholine receptor agonist; per the FDA label its antipsychotic efficacy 'could be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system', with the mechanism otherwise not fully established. M4 activation on striatal cholinergic interneurons and M1 activation in cortical/hippocampal circuits are the hypothesized routes to indirect modulation of dopaminergic and glutamatergic signaling. Because muscarinic agonism in the periphery produces nausea, vomiting, diarrhea, sweating and salivation — the tolerability failure mode of xanomeline monotherapy in Eli Lilly's 1990s programs — the combination adds trospium chloride, a quaternary-ammonium pan-muscarinic antagonist that does not meaningfully cross the blood-brain barrier and therefore antagonizes muscarinic receptors primarily in peripheral tissues, offsetting the agonist's peripheral cholinergic effects without blunting central exposure. This architecture (central muscarinic agonist + peripherally restricted antagonist) defined the class that MapLight's ML-007C-MA now follows. In the pivotal EMERGENT trials the combination reduced PANSS total score by 9.6 points (EMERGENT-2) and 8.4 points (EMERGENT-3) versus placebo at week 5 without the weight gain, extrapyramidal symptoms or prolactin elevation characteristic of D2 antagonists.

TargetActionAffinity
M4primaryCHRM4Agonist—ⓘ
M1CHRM1Agonist—ⓘ

← Full KarXT compound page (identity, identifiers, all indications)

Sources

  1. Bristol Myers Squibb Announces Continuation of ADEPT-2 Phase 3 Study in Psychosis Associated with Alzheimer's Disease (2025-12-03; site-conduct irregularities, data exclusion, additional enrollment, readouts guided to end-2026) — Bristol Myers Squibb
  2. Bristol Myers Squibb Completes Acquisition of Karuna Therapeutics, Strengthening Neuroscience Portfolio (2024-03-18; $330/share, $14.0B) — Bristol Myers Squibb
  3. Bristol Myers Squibb Reports Second Quarter Financial Results for 2026 (2026-07-30; Cobenfy revenue $63M, +81%) — Bristol Myers Squibb
  4. COBENFY (xanomeline and trospium chloride) capsules — FDA prescribing information (SPL, E.R. Squibb & Sons; mechanism 12.1, PK 12.3, dosage 2.2) — DailyMed (U.S. National Library of Medicine)
  5. NCT05511363 (CN012-0026) — ADEPT-1, Phase 3 randomized-withdrawal relapse-prevention study of KarXT in ADP (primary endpoint: time to relapse over 38 weeks) — ClinicalTrials.gov (U.S. National Library of Medicine)
  6. NCT05980949 (CN012-0028) — ADEPT-3, open-label long-term safety and tolerability extension of KarXT in ADP — ClinicalTrials.gov (U.S. National Library of Medicine)
  7. NCT06126224 (CN012-0027) — ADEPT-2, Phase 3 acute-efficacy study of KarXT in ADP (primary endpoint: change in NPI-C Hallucinations and Delusions score) — ClinicalTrials.gov (U.S. National Library of Medicine)
  8. NCT06585787 (CN012-0056) — ADEPT-4, Phase 3 acute-efficacy study of KarXT in ADP (registered under condition 'Alzheimer Disease'; ADP asserted by the official title) — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT06947941 (CN012-0034) — ADEPT-5, Phase 3 study of KarXT + KarX-EC in ADP (started 2026-03-25) — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. Zai Lab and Karuna Therapeutics Announce Strategic Collaboration for Development, Manufacturing, and Commercialization of KarXT in Greater China (2021-11-09; $35M upfront) — Zai Lab / Karuna Therapeutics (via GlobeNewswire)