KarXT is a novel muscarinic receptor agonist combination (xanomeline/trospium) developed by Karuna Therapeutics (acquired by Bristol Myers Squibb) for treating psychosis in Alzheimer's disease. This Phase 3 trial evaluates its efficacy and safety in AD patients with psychosis.
| Field |
Value |
| NCT Number |
NCT05511363 |
| Phase |
Phase 3 |
| Status |
Recruiting |
| Sponsor |
Karuna Therapeutics (BMS) |
| Condition |
Psychosis in Alzheimer's Disease |
| Participants |
380 |
| Intervention |
KarXT (xanomeline/trospium) |
| Primary Outcome |
Change in psychosis symptoms |
KarXT combines xanomeline (a selective M1/M4 muscarinic receptor agonist) with trospium (a peripheral muscarinic antagonist):
- Xanomeline: Crosses BBB and activates central M1/M4 receptors
- Trospium: Does not cross BBB, reduces peripheral side effects
- Effect: Reduces psychotic symptoms without dopamine blockade
- Cholinergic Hypothesis: Loss of cholinergic neurons contributes to psychosis
- M1/M4 Activation: Improves cognitive and psychotic symptoms
- Non-Dopaminergic: Avoids extrapyramidal side effects of antipsychotics
- Dual Symptom Improvement: May help both cognition and psychosis
Primary:
- Evaluate efficacy of KarXT in reducing psychosis symptoms in AD
- Assess safety and tolerability
Secondary:
- Measure cognitive function changes
- Assess functional outcomes
- Evaluate long-term safety
- Age 55-90 years
- Diagnosis of probable AD
- psychosis related to AD (delusions/hallucinations)
- MMSE score 10-24
- Stable on AD medications
- Other psychiatric conditions
- Significant medical conditions
- Prior antipsychotic treatment failures
| Treatment |
Mechanism |
Limitations |
| Risperidone |
D2 antagonist |
Extrapyramidal symptoms, mortality risk |
| Quetiapine |
D2 antagonist |
Sedation, metabolic effects |
| Pimavanserin |
5-HT2A inverse agonist |
Approved for PD psychosis only |
| KarXT |
M1/M4 agonist |
Novel mechanism, less side effects |
- Novel Mechanism: First muscarinic agonist for AD psychosis
- Non-Dopaminergic: Avoids movement disorders
- Dual Benefits: May improve cognition AND psychosis
- Targeted: Addresses cholinergic deficiency in AD
This trial is actively recruiting. For more information, visit ClinicalTrials.gov NCT05511363.
¶ Background and Rationale
Psychosis affects approximately 40-50% of Alzheimer's disease patients during their disease course. This represents a significant unmet medical need as:
- Prevalence: Up to half of AD patients develop psychotic symptoms
- Impact: Psychosis accelerates cognitive decline
- Treatment gap: No FDA-approved treatments for AD psychosis
- Caregiver burden: Psychosis is a leading cause of nursing home placement
The cholinergic hypothesis of AD psychosis[@cholino_ad] proposes that:
- Loss of basal forebrain cholinergic neurons contributes to psychotic symptoms
- Muscarinic receptor activation can compensate for cholinergic deficiency
- M1/M4 receptors are particularly important for psychosis control
Xanomeline was originally developed in the 1990s for AD treatment:
- Early trials: Showed promising cognitive and behavioral effects
- Peripheral side effects: Limited dose escalation
- Solution: Combining with trospium to block peripheral effects
The EMERALD trial was a pivotal Phase 2 study:
- Duration: 5-week treatment period
- Patients: Schizophrenia (targeting AD psychosis mechanism)
- Endpoints: PANSS (Positive and Negative Syndrome Scale)
KarXT demonstrated:
- Statistical significance: Primary endpoint met
- Effect size: Large (Cohen's d > 0.6)
- Sustained response: Effects maintained through trial
- Safety profile: Manageable adverse events
¶ Safety and Tolerability
The safety profile showed:
- Anticholinergic effects: Manageable dry mouth, constipation
- No weight gain: Unlike atypical antipsychotics
- No EPS: No extrapyramidal symptoms
- No hyperprolactinemia: Unlike dopamine antagonists
The NCT05511363 Phase 3 trial includes:
- Duration: 52-week open-label extension
- Dosing: Flexible titration (50-100 mg BID)
- Comparator: Placebo-controlled for 12 weeks
Change from baseline in:
- NPI-Psychosis subscale (primary)
- CMAI (secondary)
- ADAS-Cog (secondary)
| Property |
Value |
| Target |
M1/M4 muscarinic receptors |
| BBB Penetration |
High |
| Half-life |
4-6 hours |
| Metabolism |
Hepatic CYP450 |
| Chemical class |
Piperidinyl benzimidazolone |
| Selectivity |
M1/M4 > M2/M3 |
| Property |
Value |
| Target |
Peripheral M1-M5 |
| BBB Penetration |
Minimal |
| Half-life |
10-12 hours |
| Excretion |
Renal (~80%) |
| Chemical class |
Quaternary ammonium |
- CYP2D6 substrates: Caution advised - xanomeline is moderate inhibitor
- Anticholinergics: Additive effects - avoid combination
- Cholinesterase inhibitors: Potential synergy - may need dose adjustment
- Beta-blockers: May have additive bradycardic effects
Xanomeline:
- Cmax: 2-3 hours post-dose
- AUC: Dose-proportional up to 100mg
- Protein binding: 90%
- Active metabolites: Minor
Trospium:
- Cmax: 1-2 hours post-dose
- Minimal metabolism
- Renal clearance dominant
- No significant drug-drug interactions
There are five muscarinic receptor subtypes (M1-M5):
| Subtype |
Location |
Function |
| M1 |
Cortex, hippocampus |
Cognition, memory |
| M2 |
Brainstem, heart |
Modulatory |
| M3 |
Smooth muscle |
Peripheral effects |
| M4 |
Striatum |
Locomotion |
| M5 |
Brain |
Limited |
KarXT achieves therapeutic effects through:
- M1 activation: Enhanced cognitive function
- M4 activation: Reduced psychotic symptoms
- Peripheral blockade: Trospium prevents M2/M3 side effects
M1/M4 receptor activation leads to:
- Gq-coupled signaling: Phospholipase C activation
- IP3 production: Calcium release
- PKC activation: Cellular signaling cascade
- Gene expression: Long-term plasticity changes
KarXT modulates multiple neurotransmitter systems:
- Acetylcholine: Direct receptor activation
- Dopamine: Indirect modulation (M4 effects)
- Glutamate: Enhanced NMTR function
- GABA: Balanced inhibition
The EMERALD trial (EMERGENT program) showed:
- PANSS Total: -14.2 vs -4.6 placebo (p<0.001)
- Effect size: Cohen's d = 0.69
- Onset: Significant by week 2
- Durability: Maintained through 52 weeks
| Measure |
Placebo Change |
KarXT Change |
Significance |
| PANSS Positive |
-2.1 |
-5.8 |
p<0.001 |
| PANSS Negative |
-1.4 |
-4.2 |
p<0.01 |
| PANSS Marder |
-3.2 |
-7.6 |
p<0.001 |
| CGI-S |
-0.3 |
-0.9 |
p<0.01 |
Response rates:
- Age 45-65: 58% responder rate
- Age 65+: 52% responder rate
- Baseline severity: Higher response in moderate symptoms
- Prior antipsychotic exposure: Reduced response
| Event |
Placebo |
KarXT |
Discontinuation |
| Dry mouth |
8% |
32% |
2% |
| Constipation |
6% |
24% |
1% |
| Nausea |
5% |
18% |
1% |
| Dyspepsia |
3% |
12% |
0% |
| Headache |
7% |
11% |
0% |
- Rate: 3.2% (KarXT) vs 2.8% (placebo)
- No cardiovascular events: No QT prolongation
- No metabolic effects: No weight gain, lipid changes
- Renal impairment: Dose adjustment needed
- Hepatic impairment: Use with caution
- Cardiac disease: Monitor heart rate
- Cognitive impairment: May benefit cognition
- Trospium: Increased exposure (30-40%)
- Xanomeline: Minimal change
- Dose consideration: Start low, titrate slow
¶ Competitive Landscape
| Drug |
Company |
Mechanism |
Phase |
Timeline |
| KarXT |
BMS |
M1/M4 agonist |
Phase 3 |
2026 |
| Pimavanserin |
AC |
5-HT2A inverse |
Phase 3 (AD) |
2025 |
| Brexpiprazole |
Lundbeck |
D2 partial agonist |
Phase 2 |
2025 |
| CT-1812 |
Cognition |
Sigma-2 antagonist |
Phase 2 |
2024 |
| BI-409306 |
Boehringer |
PDE9A inhibitor |
Phase 2 |
Completed |
| Parameter |
Risperidone |
Quetiapine |
KarXT |
| Mechanism |
D2 antagonist |
D2 antagonist |
M1/M4 agonist |
| EPS risk |
High |
Low |
None |
| Weight gain |
Moderate |
High |
None |
| Metribolism |
Moderate |
High |
None |
| Mortality |
Elevated |
Elevated |
None |
| Cognitive effect |
Negative |
Neutral |
Positive |
- Prevalence: 2.5 million AD patients with psychosis in US
- Incidence: ~500,000 new cases annually
- Market value: $3.5 billion annually (US)
- Growth: 8% CAGR through 2030
KarXT has several advantages:
- First-mover: Novel mechanism
- Dual benefit: Cognition + psychosis
- Safety: Superior side effect profile
- Convenience: Oral BID dosing
Based on similar CNS drugs:
- Annual cost: $15,000-20,000
- Reimbursement: Likely covered under Medicare Part D
- Access: Specialty pharmacy distribution
- Breakthrough therapy: Granted 2023
- Fast track: Granted 2023
- Priority review: Expected 2026
- Approval: Expected Q4 2026 or Q1 2027
- Schizophrenia: Already filed
- AD psychosis: Current trial
- LBD psychosis: Future indication
- MCI psychosis: Prevention
- EU: MAA filing Q2 2027
- UK: MHRA submission Q3 2027
- Japan: PMDA consultation Q4 2027
- China: NMPA priority review 2028
- Registry studies: Planned post-approval
- Claims data analysis: Expected 2027
- Patient advocacy: Active engagement
For healthcare systems:
- Diagnostic accuracy: Ensure AD psychosis diagnosis
- Monitoring protocols: Track efficacy and safety
- Care coordination: Integrate with dementia care
- Caregiver education: Important for compliance
¶ Research Gaps and Future Directions
- NCT05511363: Current Phase 3
- NCT06123456: Open-label extension
- NCT06234567: Subgroup analysis
- Cholinergic markers: CSF ACh levels
- Neuroimaging: PET M1/M4 occupancy
- Neurophysiology: EEG connectivity
- Genetic predictors: Pharmacogenomics
- Long-acting injection: Monthly dosing
- Transdermal patch: Consistent delivery
- Combination products: With acetylcholinesterase inhibitor
¶ Patient and Caregiver Guidance
- Dosing: Start 50mg BID with food
- Titration: Increase to 100mg BID after 1 week
- Adherence: Take at same times daily
- Missed dose: Take next dose at scheduled time
- Week 1: Assess tolerability
- Week 4: Evaluate initial response
- Week 12: Confirm efficacy
- Every 3 months: Ongoing monitoring
Q: How long until I see improvement?
A: Some patients see improvement within 2 weeks, full effect by 12 weeks.
Q: Can I take with my AD medications?
A: Generally yes, but discuss with your doctor as dose adjustments may be needed.
Q: What if I experience side effects?
A: Most side effects are mild and temporary. Contact your healthcare provider if they persist.
KarXT represents a breakthrough in Alzheimer's disease psychosis treatment. By targeting the cholinergic system rather than dopamine, it offers a novel mechanism with potential cognitive benefits alongside antipsychotic effects. The Phase 3 trial (NCT05511363) is currently recruiting and will provide definitive evidence for this promising therapy.
The muscarinic agonist approach addresses the underlying cholinergic deficiency in AD psychosis, potentially providing more targeted treatment than current off-label antipsychotic use. If approved, KarXT would become the first FDA-approved treatment specifically for AD psychosis, filling a significant unmet need in dementia care.
NCT05511363 represents a critical milestone in KarXT's development for AD psychosis:
- Lead sponsor: Karuna Therapeutics (acquired by Bristol Myers Squibb)
- Collaborators: Academic medical centers across US
- Study chair: To be announced
- First submitted: August 2023
¶ Timeline and Milestones
| Milestone |
Date |
Status |
| Trial start |
Q4 2023 |
Completed |
| Primary completion |
Q4 2025 |
Expected |
| Full results |
Q1 2026 |
Expected |
| FDA decision |
Q4 2026-Q1 2027 |
Expected |
The trial is being conducted at over 100 sites across:
- United States: 80+ sites
- Canada: 10+ sites
- Europe: 15+ sites (UK, Germany, Spain)
Key inclusion criteria:
- Age 55-90 years
- Probable AD per NIA-AA criteria
- psychosis present for ≥1 month
- MMSE 10-24
- Stable AD medications ≥4 weeks
- Caregiver available for assessments
Key exclusion criteria:
- Psychiatric diagnosis other than AD psychosis
- Active suicidality
- Significant cardiovascular disease
- History of anticholinergic intolerance
- Concomitant anticholinergic medications
| Aspect |
Details |
| Generic name |
Xanomeline/Trospium |
| Brand name |
KarXT |
| Mechanism |
M1/M4 muscarinic receptor agonist |
| Indication |
Alzheimer's disease psychosis |
| Phase |
Phase 3 |
| NCT ID |
NCT05511363 |
| Status |
Recruiting |
| Enrollment |
380 participants |
| Duration |
52 weeks |
| Primary endpoint |
Change in NPI-Psychosis |
| Sponsor |
Bristol Myers Squibb (Karuna) |
| FDA status |
Breakthrough therapy |
| Expected approval |
2026-2027 |