Open-Label Extension Study to Assess the Long-Term Safety and Tolerability of KarXT in Subjects With Psychosis Associated With Alzheimer's Disease (ADEPT-3)
The ADEPT-3 study (NCT05980949) is an open-label extension trial evaluating the long-term safety and tolerability of KarXT (xanomeline/trospium) in patients with psychosis associated with Alzheimer's disease. KarXT represents a novel approach to treating AD psychosis by targeting muscarinic receptors rather than dopamine receptors, potentially avoiding the side effects associated with conventional antipsychotics[@novel2024].
Alzheimer's disease affects millions of individuals worldwide, and psychosis affects up to 50% of AD patients during the disease course, representing one of the most significant unmet medical needs in modern healthcare. The progressive nature of the disease, coupled with the lack of safe and effective treatments for behavioral symptoms, underscores the critical importance of clinical trials like this one in advancing our therapeutic options[@alzheimers2023].
| Parameter | Value |
|---|---|
| NCT Number | NCT05980949 |
| Phase | PHASE3 |
| Status | RECRUITING |
| Sponsor | Karuna Therapeutics |
| Enrollment | 800 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Start Date | 2023-07-11 00:00:00 |
| Completion Date | 2027-09-07 00:00:00 |
| Last Updated | 2026-03-05 00:00:00 |
Alzheimer's disease (AD) is the most common cause of dementia, accounting for approximately 60-80% of all dementia cases. The disease is characterized by progressive cognitive decline, memory loss, and functional impairment. Pathologically, AD is associated with the accumulation of amyloid-beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein in the brain[@alzheimers2023].
Psychosis affects 25-50% of AD patients and is associated with:
Current treatment options are limited and problematic:
KarXT is a fixed-dose combination of:
Rationale:
Advantages over conventional antipsychotics:
Phase 2 EMERALD Trial (Schizophrenia)[@emeraldtrial]:
ADEPT-1 and ADEPT-2 (Phase 2 in AD Psychosis):
ADEPT-3 (This Trial):
This is a Phase 3, open-label extension clinical trial designed to assess the long-term safety and tolerability of KarXT in subjects with psychosis associated with Alzheimer's disease. Open-label extension studies allow participants to continue receiving the investigational treatment after completing the controlled phase, providing crucial long-term safety data[@clinical2023].
Key features of ADEPT-3 include:
Participants eligible for ADEPT-3 include:
| Parameter | Details |
|---|---|
| Drug | KarXT (xanomeline/trospium) |
| Dose | Up to 100/60 mg BID |
| Route | Oral |
| Duration | 52 weeks |
| Frequency | Twice daily with food |
Safety assessments include:
Efficacy maintenance:
Cognitive effects:
Functional measures:
This clinical trial represents a critical step in developing safe and effective treatments for psychosis in Alzheimer's disease[@future2024]:
Address unmet need: Up to 50% of AD patients develop psychosis; current treatments are inadequate and dangerous
Novel mechanism: KarXT targets cholinergic pathways rather than dopamine, potentially avoiding significant side effects
Long-term safety data: Essential for regulatory approval and clinical adoption
Improve quality of life: Reducing psychosis can decrease caregiver burden and delay institutionalization
Potential cognitive benefits: Unlike antipsychotics, KarXT may actually improve cognition through M1 agonism
| Treatment | Mechanism | Key Limitation |
|---|---|---|
| Risperidone | D2 antagonist | Increased mortality, EPS |
| Olanzapine | D2 antagonist | Metabolic syndrome, sedation |
| Quetiapine | D2 antagonist | Limited efficacy |
| Pimavanserin | 5-HT2A inverse agonist | Not approved for AD |
| KarXT | M1/M4 agonist | Long-term data pending |
The cholinergic system plays a crucial role in memory and attention through two primary receptor subtypes: muscarinic (M1-M5) and nicotinic receptors. In Alzheimer's disease, the basal forebrain cholinergic neurons that project to the cortex and hippocampus are among the first to degenerate, leading to impaired acetylcholine transmission that contributes to both cognitive decline and behavioral symptoms[@novel2024].
M1 Receptors:
M4 Receptors:
Traditional antipsychotics work primarily by blocking dopamine D2 receptors. While effective for hallucinations and delusions, this mechanism fails to address the cholinergic deficit in AD and often worsens cognition. The table below illustrates the fundamental difference:
| Property | Traditional Antipsychotics | KarXT (M1/M4 Agonist) |
|---|---|---|
| Primary target | D2 receptor | M1/M4 receptors |
| Cognitive effect | Often worsens | May improve |
| EPS risk | High | Low |
| Metabolic risk | High | Low |
| Dopamine modulation | Indirect reduction | Normalization |
The design of KarXT reflects sophisticated understanding of muscarinic pharmacology:
Xanomeline (M1/M4 Agonist) → Central nervous system
↓
[M1: Hippocampal memory enhancement]
[M4: Psychosis reduction via dopamine modulation]
↓
Trospium (Peripheral Antagonist) → Blocks peripheral side effects
↓
[No: Dry mouth, GI distress, bradycardia]
This combination allows xanomeline to exert beneficial central effects while preventing bothersome peripheral cholinergic side effects that would otherwise limit tolerability.
The NPI-Psychosis subscale specifically assesses:
Each item is scored for:
A reduction of ≥4 points is considered clinically meaningful.
The CGI-C provides global assessment of functional change:
In AD psychosis trials, CGI-C scores of 1-2 are considered positive responses.
Relapse is defined as:
Common adverse events observed in KarXT clinical trials include:
| Adverse Event | Frequency | Management |
|---|---|---|
| Dry mouth | 25-30% | Sugar-free lozenges, hydration |
| Constipation | 15-20% | Laxatives, dietary fiber |
| Nausea | 10-15% | Take with food, antiemetics |
| Urinary retention | 5-10% | Monitoring, catheterization if severe |
| Hypertension | 5-8% | Antihypertensive adjustment |
KarXT may interact with:
Renal Impairment:
Hepatic Impairment:
KarXT has received:
| Drug | Indication | Mechanism | FDA Status |
|---|---|---|---|
| Risperidone | PD/AD psychosis | D2 antagonist | Approved (with black box) |
| Olanzapine | AD psychosis | D2 antagonist | Approved (with black box) |
| Quetiapine | AD psychosis | D2 antagonist | Off-label |
| Pimavanserin | PD psychosis | 5-HT2A inverse agonist | Approved for PD only |
| KarXT | AD psychosis | M1/M4 agonist | Pending |
If approved, KarXT will require:
Future trials may explore:
Potential predictive biomarkers include:
The ADEPT-3 trial is conducted at multiple academic medical centers specializing in Alzheimer's disease and geriatric psychiatry. Sites are selected based on:
| Year | Milestone |
|---|---|
| 2019 | EMERALD Phase 2 (schizophrenia) positive results |
| 2021 | ADEPT-1 Phase 2 initiated |
| 2022 | ADEPT-2 Phase 2 results |
| 2023 | Phase 3 program initiated |
| 2024 | ADEPT-3 extension study initiated |
| 2025 | Expected NDA submission |