Solving the Cholinergic Problem: Cobenfy's Path From Shelf to FDA Approval

Steve Brannan, MD, chief medical officer at Karuna Therapeutics during much of xanomeline-trospium’s development, traced the drug's origins to Eli Lilly in the 1990s, when the compound was shelved because of intolerable cholinergic side effects. The medication, now marketed as Cobenfy, pairs xanomeline, a muscarinic agonist, with trospium, an antagonist that does not cross the blood-brain barrier, preserving central antipsychotic benefits while reducing peripheral adverse events.¹ Early testing showed that simply adding trospium cut adverse events by 50%.

"You keep the central benefits and you ameliorate the peripheral side effects, and that actually turned out to be true," Brannan said. He led the compound's development from phase 1 through phase 3, at which point Bristol Myers Squibb acquired Karuna. Brannan noted that following a single compound from phase 1 through near-approval was unusual across his 25-year pharmaceutical career, since he had typically been involved in only parts of a given project. Phase 2 results showed good tolerability and a large effect size; phase 3 replicated that success without changes to the trial design.¹

Unlike earlier antipsychotics, which generally improved positive symptoms but offered little or no benefit to cognition, Cobenfy showed improvement in both negative and cognitive symptoms.² This distinction became clearer once investigators divided patients by a median split of baseline cognitive testing, roughly 1 standard deviation below the mean. "If you looked at 1 standard deviation and below, it looked like there was actually a quite prominent effect," Brannan said. The finding was replicated in phase 3, and the effect appeared even larger among patients scoring 1.5 standard deviations below the mean at baseline. The broad symptom benefit, Brannan said, likely explained why the drug performed so strongly on the standard schizophrenia symptom-severity scale used across the trials.

Xanomeline-trospium’s side-effect profile also diverged from older antipsychotics: weight gain, extrapyramidal symptoms, and sedation were largely absent, though some gastrointestinal side effects occurred. Brannan called the pairing strategy deceptively simple in hindsight, noting that other companies pursuing muscarinic compounds for schizophrenia had been unable to solve the same tolerability problem before the trospium pairing succeeded.

Dr Brannan is a psychiatrist and former chief medical officer of Karuna Therapeutics.

References

1. Brannan SK, Sawchak S, Miller AC, et al. Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med. 2021;384(8):717-726.

2. Kaul I, Sawchak S, Correll CU, et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet. 2024;403(10422):160-170.