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.

Findings

Karuna is developing 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).

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. The company is planning to apply for FDA approval in mid-2023, based on these results and other, ongoing trials.

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 (company slide show).

In May 2022, Karuna announced a clinical program in Alzheimer's disease, to begin in the latter half of 2022 (see slide show above). Called ADEPT, the program comprises two Phase 3 registration trials and a long-term safety study. ADEPT-1, planned to begin in late 2022, will enroll 400 AD patients with a history of moderate to severe hallucinations or delusions, living at home or in assisted living facility. In a withdrawal design, all patients receive treatment for 12 weeks, then are randomized to drug or placebo for an additional 26 weeks. The primary outcome is time to relapse of psychosis symptoms or withdrawal from the trial. ADEPT-2, planned for 2023, will also enroll 400 participants, and compare acute efficacy of 12 weeks of drug to placebo on psychiatric symptoms. Dosing will be titrated to a maximum of 200 mg xanomeline/20 mg trospium daily. A one-year, open-label safety extension is planned to begin in 2023, and end in 2025 .

To date, no Alzheimer’s disease trials are registered. For details on schizophrenia trials, see clinicaltrials.gov.