KarXT · program

Xanomeline/trospium chloride (Cobenfy) for Schizophrenia

ApprovedApprovedBristol-Myers Squibb Company (BMY)

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

Xanomeline/trospium chloride (KarXT) for schizophrenia — the lead and approved indication. FDA-approved as COBENFY on 2024-09-26 (NDA 216158) for schizophrenia in adults: the first antipsychotic acting through muscarinic receptors rather than dopamine D2 blockade, and the first new mechanism of action for schizophrenia in decades. Approval rested on the EMERGENT program: EMERGENT-1 (Phase 2, PANSS -11.6 vs placebo), EMERGENT-2 and EMERGENT-3 (Phase 3, PANSS -9.6 and -8.4 at week 5, both p<0.0001) plus the EMERGENT-4/-5 long-term safety studies. Approved in China 2025-12-23 via licensee Zai Lab; a UK MHRA application via the International Recognition Procedure is planned with a 2026 launch. Within-schizophrenia lifecycle: the ADJUNCTIVE thrust (Cobenfy added to atypical antipsychotics in inadequately controlled patients) MISSED its primary endpoint in the Phase 3 ARISE trial on 2025-04-22 (PANSS -2.0 vs placebo, p=0.11; BMS said preliminary analyses suggested benefit in patients on non-risperidone backgrounds and that it would discuss the data with the FDA — no adjunctive filing has followed). Ongoing: EMERGENT TEEN (adolescents 13-17, Phase 3), a relapse-prevention randomized-withdrawal Phase 3, Japan and China registration studies, a Phase 1 long-acting injectable, and Phase 4 urological-safety and lactation studies. Cobenfy revenue was $63M in Q2 2026 (+81% y/y).

Data current as of

Development timeline

ApprovedSept 2024 – Dec 2025
  1. NMPA approval (China)China's NMPA approves COBENFY for schizophrenia in adults (via Zai Lab)↗
  2. missedARISE (Phase 3, adjunctive to atypical antipsychotics) MISSED its primary endpoint: Cobenfy added to an atypical antipsychotic reduced PANSS total score by 2.0 points vs placebo+antipsychotic at week 6, not statistically significant (p=0.11).↗
  3. FDA approved COBENFY (xanomeline and trospium chloride) capsules, NDA 216158, for the treatment of schizophrenia in adults, on the PDUFA date. First-in-class muscarinic antipsychotic; openFDA records the original approval as a TYPE 1 (new molecular entity) submission by Bristol-Myers Squibb.↗
  4. FDA approvalFDA approves COBENFY (xanomeline and trospium chloride) for schizophrenia in adults↗
Filed (NDA)Sept 2023 – Mar 2024
  1. AcquisitionBristol Myers Squibb completes its $14.0 billion acquisition of Karuna Therapeutics↗
  2. PDUFA date setFDA accepts the KarXT NDA and sets a PDUFA date of September 26, 2024↗
  3. Karuna submitted the NDA for KarXT for schizophrenia in adults in September 2023 (exact day not disclosed in the acceptance release; dated month-end as an upper bound). FDA accepted the NDA on 2023-11-29 and set a PDUFA action date of 2024-09-26. Supported by EMERGENT-1/-2/-3 (efficacy) and EMERGENT-4/-5 (long-term safety).↗
  4. NDA/BLA filedKaruna submits the KarXT NDA for schizophrenia to the FDA↗
Phase 3Dec 2020 – Mar 2023
  1. metEMERGENT-3 (Phase 3) topline positive: KarXT met the primary endpoint with an 8.4-point reduction in PANSS total score vs placebo at week 5, the third consecutive positive registrational trial.↗
  2. metEMERGENT-2 (Phase 3) topline positive: KarXT met the primary endpoint with a statistically significant 9.6-point reduction in PANSS total score vs placebo at week 5 (p<0.0001), and met key secondary endpoints on PANSS positive, negative and Marder negative-factor subscales.↗
  3. Licensing dealKaruna licenses KarXT Greater China rights to Zai Lab ($35M upfront)↗
  4. metEMERGENT-1 (Phase 2) published in NEJM: xanomeline-trospium reduced PANSS total score by 11.6 points more than placebo at week 5 (p<0.001) in 182 hospitalized adults with acute schizophrenia, without D2-antagonist-typical adverse events.↗
  5. EMERGENT-2 (NCT04659161, KAR-007) started: first Phase 3, 252 acutely psychotic hospitalized adults, PANSS total at week 5. Topline positive 2022-08-08 (-9.6 points vs placebo, p<0.0001); published in The Lancet 2024-01-13. EMERGENT-3 (NCT04738123) followed in April 2021 and read out positive 2023-03-20 (-8.4 points).
Phase 2Sept 2018
  1. EMERGENT-1 (NCT03697252, KAR-004) started: Phase 2, randomized, double-blind, placebo-controlled, 182 hospitalized adults with acute schizophrenia; primary endpoint change in PANSS total at week 5. Positive: -11.6 points vs placebo (published NEJM 2021-02-25). Xanomeline itself had earlier Lilly-era clinical history in the 1990s; this history starts with the KarXT combination.

Readouts

  • 2025-04-22ReportedTopline datamissedNCT05145413

    ARISE (Phase 3, adjunctive to atypical antipsychotics) MISSED its primary endpoint: Cobenfy added to an atypical antipsychotic reduced PANSS total score by 2.0 points vs placebo+antipsychotic at week 6, not statistically significant (p=0.11). ↗

  • 2023-03-20ReportedTopline datametNCT04738123

    EMERGENT-3 (Phase 3) topline positive: KarXT met the primary endpoint with an 8.4-point reduction in PANSS total score vs placebo at week 5, the third consecutive positive registrational trial. ↗

  • 2022-08-08ReportedTopline datametNCT04659161

    EMERGENT-2 (Phase 3) topline positive: KarXT met the primary endpoint with a statistically significant 9.6-point reduction in PANSS total score vs placebo at week 5 (p<0.0001), and met key secondary endpoints on PANSS positive, negative and Marder negative-factor subscales. ↗

  • 2021-02-25ReportedFull resultsmetNCT03697252

    EMERGENT-1 (Phase 2) published in NEJM: xanomeline-trospium reduced PANSS total score by 11.6 points more than placebo at week 5 (p<0.001) in 182 hospitalized adults with acute schizophrenia, without D2-antagonist-typical adverse events. ↗

Clinical trials in Schizophrenia

NCT07686263CN012-0006Phase 3Activen=472

A Phase 3 Double-blind, Placebo-controlled Randomized Withdrawal Maintenance (Relapse Prevention) Trial of KarXT in Participants With Schizophrenia

Started Sept 2026· Primary completion Mar 2029

NCT07288567CN012-0020Phase 3Recruitingn=166

EMERGENT TEEN: A Phase 3, Randomized, Double-blind, Placebo-controlled Study of KarXT for Schizophrenia in Adolescents (13 to 17 Years of Age)

Started Jan 2026· Primary completion Dec 2029· 📍 41 sites across 5 countries (United States, Romania, Japan, Argentina)

NCT07061288CN012-0016Phase 1Recruitingn=116

An Open-label, Phase 1, Dose-Finding Study of a Long-Acting Injectable KarXT Formulation in Participants With Schizophrenia

Started Sept 2025· Primary completion Jun 2027· 📍 8 sites across 1 country (United States)

NCT06882785CN012-0019Phase 3Recruitingn=250

A Phase 3, Randomized, Two-part Study (5-week Double-blind, Placebo-controlled + 52-week Open-label Extension) of KarXT in Acutely Psychotic Japanese Adults With Schizophrenia

Started Jun 2025· Primary completion Sept 2028· 📍 56 sites across 1 country (Japan)

NCT06572449CN012-0048Phase 3Completedn=173

A Phase 3 Study to Assess Safety and Effectiveness of a Slower Titration and Food Effect of KarXT in Adults With Schizophrenia

Started Oct 2024· Primary completion Mar 2025· 📍 6 sites across 1 country (United States)

NCT05919823CN012-0063Phase 3Completedn=202

A Phase 3 Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Chinese Adults With DSM-5 Schizophrenia (double-blind part + 12-week open-label extension)

Started May 2023· Primary completion Sept 2024· 📍 28 sites across 1 country (China)

NCT05643170KAR-014Phase 3Discontinuedn=4

A Multi-center, Open-label Study to Assess the Effectiveness, Long-term Safety, Tolerability, and Durability of Effect of KarXT in Patients With DSM-5 Diagnosis of Schizophrenia

Started Nov 2022· Primary completion Mar 2023· 📍 5 sites across 1 country (United States)

NCT05304767CN012-0009Phase 3Completedn=290

An Open-label Extension Study to Assess the Long-term Safety and Tolerability of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia

Started Mar 2022· Primary completion Mar 2026· 📍 175 sites across 9 countries (United States, Bulgaria, India, Serbia)

NCT05145413CN012-0008Phase 3Completedn=396

ARISE: A Phase 3 Study to Evaluate the Safety and Efficacy of Adjunctive KarXT in Subjects With Inadequately Controlled Symptoms of Schizophrenia

Started Nov 2021· Primary completion Mar 2025· 📍 166 sites across 8 countries (United States, Bulgaria, India, Serbia)

NCT04820309CN012-0007Phase 3Completedn=566

EMERGENT-5: An Open-label Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in De Novo Subjects With DSM-5 Schizophrenia

Started Jun 2021· Primary completion May 2024· 📍 117 sites across 2 countries (United States, Puerto Rico)

NCT04738123KAR-009Phase 3Completedn=256

EMERGENT-3: A Phase 3 Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adults With DSM-5 Schizophrenia

Started Apr 2021· Primary completion Nov 2022· 📍 32 sites across 2 countries (United States, Ukraine)

NCT04659174KAR-008Phase 3Completedn=152

EMERGENT-4: An Open-label Extension Study to Assess the Long-term Safety, Tolerability, and Efficacy of KarXT in Subjects With DSM-5 Schizophrenia

Started Feb 2021· Primary completion Oct 2023· 📍 44 sites across 2 countries (United States, Ukraine)

NCT04659161KAR-007Phase 3Completedn=252

EMERGENT-2: A Phase 3 Study to Evaluate the Efficacy and Safety of KarXT in Acutely Psychotic Hospitalized Adults With DSM-5 Schizophrenia

Started Dec 2020· Primary completion May 2022· 📍 22 sites across 1 country (United States)

NCT03697252KAR-004Phase 2Completedn=182

EMERGENT-1: A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults With DSM-5 Schizophrenia

Started Sept 2018· Primary completion Sept 2019· 📍 12 sites across 1 country (United States)

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. Brannan SK, et al. Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia (EMERGENT-1). N Engl J Med. 2021;384(8):717-726 — New England Journal of Medicine / PubMed
  2. Bristol Myers Squibb Announces Topline Results from Phase 3 ARISE Trial of Cobenfy as an Adjunctive Treatment to Atypical Antipsychotics in Adults with Schizophrenia (2025-04-22; primary endpoint not met, PANSS -2.0, p=0.11) — Bristol Myers Squibb
  3. Bristol Myers Squibb Completes Acquisition of Karuna Therapeutics, Strengthening Neuroscience Portfolio (2024-03-18; $330/share, $14.0B) — 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. Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-2 Trial of KarXT in Schizophrenia (2022-08-08; PANSS -9.6 vs placebo, p<0.0001) — Karuna Therapeutics
  6. Karuna Therapeutics Announces Positive Results from Phase 3 EMERGENT-3 Trial of KarXT in Schizophrenia (2023-03-20; PANSS -8.4 vs placebo) — Karuna Therapeutics
  7. Karuna Therapeutics Announces U.S. FDA Accepts New Drug Application for KarXT for the Treatment of Schizophrenia (2023-11-29; PDUFA 2024-09-26; NDA submitted September 2023) — Karuna Therapeutics (via BioSpace)
  8. NCT03697252 (KAR-004) — EMERGENT-1, Phase 2, KarXT in hospitalized adults with schizophrenia — ClinicalTrials.gov (U.S. National Library of Medicine)
  9. NCT04659161 (KAR-007) — EMERGENT-2, Phase 3, KarXT in acutely psychotic hospitalized adults — ClinicalTrials.gov (U.S. National Library of Medicine)
  10. NCT04659174 (KAR-008) — EMERGENT-4, open-label long-term safety extension — ClinicalTrials.gov (U.S. National Library of Medicine)
  11. NCT04738123 (KAR-009) — EMERGENT-3, Phase 3, KarXT in acutely psychotic hospitalized adults — ClinicalTrials.gov (U.S. National Library of Medicine)
  12. NCT04820309 (CN012-0007) — EMERGENT-5, open-label long-term safety in de novo subjects — ClinicalTrials.gov (U.S. National Library of Medicine)
  13. NCT05145413 (CN012-0008) — ARISE, Phase 3 adjunctive KarXT in inadequately controlled schizophrenia — ClinicalTrials.gov (U.S. National Library of Medicine)
  14. NCT05304767 (CN012-0009) — ARISE open-label extension (adjunctive KarXT long-term safety) — ClinicalTrials.gov (U.S. National Library of Medicine)
  15. NCT05643170 (KAR-014) — open-label durability study, TERMINATED after 4 participants ('Company's business decision') — ClinicalTrials.gov (U.S. National Library of Medicine)
  16. NCT05919823 (CN012-0063) — Phase 3 KarXT in acutely psychotic hospitalized Chinese adults (supported the NMPA approval) — ClinicalTrials.gov (U.S. National Library of Medicine)
  17. NCT06572449 (CN012-0048) — Phase 3 slower-titration and food-effect study of KarXT — ClinicalTrials.gov (U.S. National Library of Medicine)
  18. NCT06882785 (CN012-0019) — Phase 3 KarXT in acutely psychotic Japanese adults (5-week DB + 52-week OLE) — ClinicalTrials.gov (U.S. National Library of Medicine)
  19. NCT07061288 (CN012-0016) — Phase 1 dose-finding study of a long-acting injectable KarXT formulation — ClinicalTrials.gov (U.S. National Library of Medicine)
  20. NCT07288567 (CN012-0020) — EMERGENT TEEN, Phase 3 KarXT in adolescents 13-17 with schizophrenia — ClinicalTrials.gov (U.S. National Library of Medicine)
  21. NCT07686263 (CN012-0006) — Phase 3 randomized-withdrawal relapse-prevention trial of KarXT — ClinicalTrials.gov (U.S. National Library of Medicine)
  22. U.S. FDA Approves Bristol Myers Squibb's COBENFY (xanomeline and trospium chloride), a First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults (2024-09-26) — Bristol Myers Squibb
  23. 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)
  24. Zai Lab Announces Approval of COBENFY (xanomeline and trospium chloride) in China, a First-in-Class Therapy for Schizophrenia (NMPA approval 2025-12-23) — Zai Lab Limited