EFFICACY AND SAFETY OF XANOMELINE AND TROSPIUM CHLORIDE FOR MANIA IN BIPOLAR DISORDER: DESIGN OF THE BALSAM-1 AND BALSAM-2 TRIALS

Introduction

Conventional antipsychotic medications are an effective treatment for acute mania related to bipolar-I disorder (BP-I); however, they can be associated with treatmentlimiting side effects, including extrapyramidal symptoms, neuroleptic malignant syndrome, hyperprolactinemia, orthostasis, oversedation, seizures, QTc prolongation, and tardive dyskinesia, which may be permanent. Newer second-generation antipsychotics, particularly serotonin-dopamine antagonists, are also effective in reducing mania and mixed features; however, they are associated with significant metabolic events, including weight gain, hyperglycemia, dyslipidemia, and metabolic syndrome. A novel formulation of a dual M1/M4 preferring muscarinic receptor agonist xanomeline in combination with the peripherally restricted pan muscarinic receptor antagonist trospium chloride (KarXT) is approved for the treatment of schizophrenia in adults by the US FDA. KarXT has shown antipsychotic effects and a favorable safety profile in patients with schizophrenia with a lower incidence of weight gain, extrapyramidal symptoms, metabolic syndrome, prolactin elevation, or tardive dyskinesia associated with most other antipsychotic drugs; therefore, KarXT may offer an effective and tolerable treatment option for individuals with acute mania or mania with mixed features related to BP-I.

Methods

Two identical randomized, double-blind, placebo-controlled, phase 3 trials (NCT06951698 and NCT06951711) are assessing the efficacy and safety of KarXT monotherapy with flexible dosing in adults diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) with BP-I with acute mania or mania with mixed features. The trials include a maximum 14-day screening period, a 3week inpatient treatment period, and a safety follow-up visit 2 weeks following end of treatment. Participants who complete the treatment period will have the option to enter a long-term, openlabel extension study where all participants receive KarXT. Adults aged 18-65 years are eligible for the study if they have a BP-I diagnosis based on DSM-5-TR criteria, are experiencing an acute episode or relapse of mania or mania with mixed features (≤3 weeks), require hospitalization for the acute exacerbation or relapse of mania, and have a Young Mania Rating Scale (YMRS) score ≥20 and a Clinical Global Impressions–Bipolar (CGI-BP) score ≥4 (moderate) at screening and baseline. The primary endpoint is the change from baseline in YMRS score at week 3, and the key secondary endpoint is the change from baseline in CGI-BP score at week 3. The difference between KarXT and placebo will be estimated using a mixed model for repeated measures. Safety and tolerability will be monitored, including the risk of drug-induced movement disorders and suicide.

Results

Each trial will screen approximately 457 individuals across 60 sites globally and randomize approximately 274 participants 1:1 to receive either KarXT or placebo twice daily.

Conclusions

The objective of these trials is to assess efficacy and safety of KarXT in participants experiencing mania or mania with mixed features associated with BP-I, with the intent of providing an effective and tolerable novel treatment option for these individuals.