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

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

The FDA approved Cobenfy based on two Phase 3 clinical trials that showed Cobenfy was effective compared to a placebo in controlling schizophrenia indicators such as hallucinations and depression symptoms (lancet 2023, DOI: 10.1016/S0140-6736(23)02190-6; JAMA Psychiatry 2024, DOI: 10.1001/jamapsychiatry.2024.0785). However, Cobenfy was not directly compared to already available antipsychotics in a published study.

In the 1990s, Eli Lilly and Company attempted to develop xanomeline to treat Alzheimer's disease, but the gastrointestinal side effects were too difficult to control. 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 penetrate the blood-brain barrier, preserving the beneficial effects of xanomeline. However, Cobenfy can still cause side effects, the most common of which are gastrointestinal in nature, such as nausea and vomiting, diarrhea, indigestion and constipation. The FDA says people with known liver impairment or moderate to severe kidney impairment should not take the drug.

Summer Colling, senior analyst at Citeline, says the novel muscarinic mechanism is likely the main factor in the drug's approval. She says that while the safety and effectiveness data are good, “I don't think effectiveness is the deciding factor.”

“There just hasn't been anything new in this field because the heterogeneity of schizophrenia has made identifying improved drug targets really difficult,” she says. This difficulty is due to the lack of animal models as well as the cost of clinical trials, which Colling says have dampened 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 the drug is expected to be available in the U.S. by the end of October, but even with insurance the drug is expected to be expensive. Colling says it is likely that patients will have to try to avoid responding to two generic drugs before Cobenfy is made available to them. However, BMS wants Cobenfy to be “the first brand that people use after generics.”

Additional treatment options for schizophrenia are currently 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 market advantage will set it apart from the crowd, even if twice-daily dosing is inconvenient.