Background

KarXT is xanomeline with trospium. Xanomeline is an M1/M4-preferring muscarinic acetylcholine receptor activator that acts throughout the body. Trospium chloride is an FDA-approved muscarinic receptor inhibitor that does not enter the central nervous system. Trospium serves to block xanomeline’s peripheral actions and reduce side effects.

The rationale for muscarinic receptor agonists to treat Alzheimer’s disease is broadly supported. The decline of cholinergic function in Alzheimer's disease contributes to cognitive symptoms. Widely used acetylcholinesterase inhibitors modestly improve function by boosting synaptic acetylcholine levels. An alternative strategy is to directly activate receptors with agonists like xanomeline.

In addition to cognitive benefits, M1 receptor activators may also modify disease progression. M1 agonists attenuate Aβ and tau pathology in animal models, and shift APP processing toward a non-amyloidogenic path (e.g., see Fisher et al., 2016; Caccamo et al., 2009). Development of these agents has been hampered by side effects related to activation of receptors outside the nervous system.

Xanomeline was originally developed by Lilly in the 1990s, to treat cognitive decline in people with AD. A full agonist, it attaches to the receptor at the acetylcholine binding site. In a Phase 3 trial, 150 mg/day modestly improved ADAS-Cog scores. Unexpectedly, the drug significantly reduced behavioral symptoms and psychosis, including hallucinations and delusions. However, development was halted because of dose-limiting gastrointestinal side effects of nausea, diarrhea, vomiting, and hypersalivation, all attributed to activation of peripheral muscarinic receptors (Bodick et al., 1997).

Trospium acts on all muscarinic receptor subtypes. It is prescribed for overactive bladder, and works by relaxing bladder muscles. Its side effects include dry mouth and constipation.

A similar strategy of combining a central activator and peripheral inhibitor to attenuate side effects is being pursued with the β-adrenergic receptor agonist clenbuterol, which is being trialed in combination with the peripherally restricted antagonist nadolol. For a review of therapeutic muscarinic receptor activation, see Paul et al., 2024.

Findings

In a Phase 1 study in healthy adults,  trospium chloride co-administration reduced xanomeline’s peripheral cholinergic side effects of nausea, vomiting, diarrhea, and excessive sweating and saliva production (Breier et al., 2023).

Karuna developed KarXT as a primary or adjunctive therapy for psychosis and cognitive deficits in people with schizophrenia. In a Phase 2 trial, the drug significantly reduced symptoms, without severe side effects. Few people discontinued treatment due to side effects (Brannon et al., 2021; Correll et al., 2022). In two Phase 3 trials, five weeks of KarXT outperformed placebo at reducing symptom severity on the Positive and Negative Syndrome Scale in hospitalized patients. The scale includes positive symptoms like psychosis or delusions, negative symptoms such as apathy or withdrawal, and cognition. Most patients achieved the maximum dose of 125 mg xanomeline and 30 mg trospium, with a similar incidence of serious adverse events in treated and placebo groups. The most common side effects were mainly mild to moderate, and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea. About one-quarter to one-third of patients discontinued treatment in both groups (Kaul et al., 2024; Kaul et al., 2024; Kaul et al., 2024). In these  trials, 60 to 80 percent of participants were black; 20 to 40 percent were white. Post hoc analyses of trial data on individual symptoms suggested that KarXT reduced both positive and negative symptoms, and improved cognition in some patients (Horan et al., 2024; Sauder et al., 2022; Weiden et al., 2022).

Karuna currently has six Phase 3 trials ongoing. In August 2022, the company announced the first Phase 3 results. Five weeks of KarXT was better than placebo at reducing positive schizophrenia symptoms, including psychosis or delusions, negative symptoms like apathy or withdrawal, and cognition, in 252 hospitalized, symptomatic patients (press release). Eighty-one percent of patients achieved the maximum dose of 125 mg xanomeline and 30 mg trospium, with a similar incidence of serious adverse events in treated and placebo groups. The most common side effects were mainly mild to moderate, and included constipation, dyspepsia, nausea, vomiting, headache, increases in blood pressure, dizziness, acid reflux, abdominal discomfort, and diarrhea. About one-quarter of patients discontinued treatment in both groups. In this and in the Phase 2 trial, 75 percent of participants were black; about 20 percent were white. 

In preparation for trials in Alzheimer’s disease, the company performed a Phase 1 dose-ranging study in healthy older people. Flexible dosing over two to three weeks showed that a lower dose ratio of trospium to xanomeline was better tolerated in elderly participants, as compared to the dose used in younger patients with schizophrenia. In this trial, most adverse events were mild. The combination did increase heart rate but not blood pressure or fainting. Most people titrated up to 150-200 mg xanomeline daily, spread over three doses (SEC filing).

In May 2022, Karuna announced a clinical program in Alzheimer's disease. Called ADEPT, the program comprised two Phase 3 registration trials and a long-term safety study. ADEPT-1 began in August 2022 to enroll 380 AD patients with a history of moderate to severe hallucinations or delusions, living at home or in an assisted living facility. In a withdrawal design, all patients would receive treatment for 12 weeks, then be randomized to drug or placebo for an additional 26 weeks. Doses start at 60 mg xanomeline/6 mg trospium daily and can go up to 200/20 mg, given in three divided doses. The primary outcome is time to relapse of psychosis symptoms after randomization; the secondary outcome is time to withdrawal from the trial for any reason. The trial is running in the U.S. and Europe, and is expected to finish in October 2026.

ADEPT-2 began in December 2023 to compare the acute efficacy of 12 weeks of drug to placebo on symptoms of hallucinations and delusions in 400 Alzheimer’s patients. Secondary outcomes include agitation and a clinical global impression of symptom severity.  Dosing will be titrated to a maximum of 200 mg xanomeline/20 mg trospium daily. At more than 150 sites worldwide, this trial is planned to end in July 2025. A one-year, open-label safety extension for both ADEPT-1 and -2 began in 2023, to end in 2026.

In March 2024, Bristol Myers Squibb acquired Karuna (press release). On September 27, the FDA approved KarXT for the treatment of schizophrenia. It will be sold under the name CobenfyTM. A Phase 3 dose increase/food effect trial in 100 people with schizophrenia started recruiting the following month.

In September 2024, an additional  Phase 3 trial began in Alzheimer’s. ADEPT-4 plans to enroll 406 AD patients with moderate to severe psychosis for a 12-week course of KAR-XT, against a primary outcome of change from baseline in the occurrence of hallucinations and delusions. Multiple secondary outcomes span other measures of neuropsychiatric  symptoms, safety, and side effects. Completion is slated for late 2026.

For details on Kar-XT trials, see clinicaltrials.gov.