Bristol Myers Squibb is testing the first muscarinic agonist for manic episodes in bipolar I disorder, a completely different approach than existing medications.
A drug that works through an entirely new mechanism is now in Phase 3 clinical trials for the treatment of manic episodes in bipolar I disorder. Bristol Myers Squibb has launched multiple large-scale trials of KarXT, also known as Cobenfy (xanomeline and trospium chloride), with results expected later in 2026.
What makes KarXT different from every bipolar medication currently on the market is how it works. Existing antipsychotics used to treat mania, including olanzapine, quetiapine, and aripiprazole, all work primarily by blocking dopamine receptors. KarXT instead activates muscarinic receptors, a completely separate signaling system in the brain. It is the first drug to use this mechanism for bipolar mania.
The drug was already approved by the FDA for schizophrenia under the brand name Cobenfy. Now Bristol Myers Squibb is testing whether it can also address acute mania.
Three Trials Running Simultaneously
Bristol Myers Squibb has registered three Phase 3 trials under the BALSAM program, all focused on bipolar I mania:
BALSAM-1 evaluates the efficacy and safety of KarXT compared to placebo during a three-week inpatient treatment period. It is estimated to be completed by November 2026.
BALSAM-2 is a second efficacy trial with a similar design, also expected to be completed by November 2026.
BALSAM-3 is an open-label extension study designed to evaluate the long-term safety of KarXT for mania and mania with mixed features. This study runs through June 2028.
Why a New Mechanism Matters
Dopamine-blocking antipsychotics are effective for many patients, but they come with well-documented side effects, including weight gain, metabolic syndrome, movement disorders, and sedation. These side effects are a leading reason patients stop taking their medications, which can trigger relapse.
A muscarinic agonist could potentially treat mania while avoiding some of these dopamine-related side effects. That possibility is what makes the BALSAM trials closely watched in the bipolar research community.
KarXT combines xanomeline, which activates muscarinic receptors in the brain, with trospium, which blocks muscarinic receptors outside the brain to limit gastrointestinal side effects. The combination was designed to preserve the psychiatric benefit while reducing peripheral side effects.
The trials are currently recruiting participants. Results from BALSAM-1 and BALSAM-2 are expected in late 2026 or early 2027.
Sources:
ClinicalTrials.gov: BALSAM-1
ClinicalTrials.gov: BALSAM-2
ClinicalTrials.gov: BALSAM-3
Bristol Myers Squibb
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