FDA approves Cobenfy, a first-in-class schizophrenia drug

The US Food and Drug Administration has approved Cobenfy, also known as KarXT, a new schizophrenia treatment. The drug was developed by Karuna Therapeutics, which was bought by Bristol Myers Squibb (BMS) last year for $14 billion.

This is the first new class of treatment for the psychiatric disorder since clozapine, the first atypical antipsychotic, was approved in 1989. Cobenfy is a combination of xanomeline and trospium. Xanomeline is a muscarinic agonist that engages regulatory pathways in the brain to lower dopamine levels, which is thought to alleviate schizophrenia symptoms.

The FDA approved Cobenfy based on the strength of two Phase 3 clinical trials that showed Cobenfy was effective in controlling schizophrenia indicators including hallucinations and depression-like symptoms compared with a placebo (Lancet 2023, DOI: 10.1016/S0140-6736(23)02190-6; JAMA Psychiatry 2024, DOI: 10.1001/jamapsychiatry.2024.0785). But Cobenfy has not been directly compared with already-available antipsychotics in a published trial.

In the 1990s, Eli Lilly and Company tried to develop xanomeline as a treatment for Alzheimer’s disease, but the gastrointestinal side effects were too difficult to manage. Andrew Miller, then an executive at PureTech Health, licensed xanomeline in 2012 and founded Karuna to develop the treatment. Karuna solved the side effect problem by adding trospium, a muscarinic antagonist, to block xanomeline from the muscarinic receptors outside the brain. Trospium does not cross the blood-brain barrier, preserving xanomeline’s beneficial activity. But Cobenfy can still cause side effects, the most common of which are gastrointestinal in nature like nausea and vomiting, diarrhea, indigestion, and constipation. The FDA says people with known liver impairment or moderate to severe kidney impairment should not use the drug.

Summer Colling, a senior analyst at Citeline, says the novel muscarinic mechanism is likely the main factor for the drug’s approval. She says that while the safety and efficacy data is good, “I don’t think efficacy is what is differentiating it here.”

“There’s just been nothing new in this field because the heterogeneity of schizophrenia has made identification of improved drug targets really difficult,” she says. This difficulty stems from a lack of animal models, as well as the costliness of clinical trials, which Colling says has cooled enthusiasm for developing new drugs. With this approval, “it’s really exciting that there’s a new drug with a new mechanism of action.”

In a statement, BMS said that it expects the drug to be available in the US in late October, but the drug is likely to be costly even with insurance. Colling says it is likely that patients will have to try and fail to respond to two generics before Cobenfy will be made available to them, But BMS will want Cobenfy to be “the first brand that people use after generics.”

Other schizophrenia treatments are being developed. Cerevel Therapeutics and AbbVie have emraclidine, Neurocrine Biosciences has NBI-1117568, and Anavex Life Sciences has ANAVEX 3-71. Colling predicts that Cobenfy’s first-to-market advantage will set it apart from the pack, even though its twice-a-day dosing is inconvenient.