Schizophrenia is currently treated with older medications with limited efficacy and troublesome side effects that lead many patients to stop taking them. The FDA has approved a novel Bristol Myers Squibb drug that takes a different approach to schizophrenia, introducing the first novel medication for the disorder in decades.
For patients, approval of the drug, Cobenfy, offers a new treatment option with better tolerability. For BMS, the late Thursday regulatory decision marks a payoff for its multi-billion dollar acquisition of the drug’s developer as the pharmaceutical giant looks for new medicines with blockbuster potential to offset the loss of patent protection facing key products. BMS expects Cobenfy will become available in October.
The schizophrenia drugs currently available are antipsychotics that target and block dopamine receptors in the brain. The first generation of these drugs date to the 1950s and their side effects include movement disorders. Second-generation antipsychotics that emerged in the 1980s also block dopamine pathways, but their side effects include sleepiness, low blood pressure, weight gain, and sexual dysfunction. BMS estimates that schizophrenia affects 2.8 million people in the U.S. The company calculates that about 60% of these patients either do not adequately improve or they experience intolerable side effects from currently available medications.
The BMS drug treats schizophrenia by blocking muscarinic cholinergic receptors. There are five types of muscarinic receptors found in the brain and some peripheral tissues. Biotech companies have been trying to develop drugs that specifically target and activate the M1 and M4 receptors without stimulating the other muscarinic receptors and causing side effects.
Cobenfy was developed in the labs of Karuna Therapeutics, where the drug was known in development as KarXT, shorthand for Karuna xanomeline-trospium chloride. Xanomeline, a small molecule that targets muscarinic receptors in the brain, was initially developed by Eli Lilly. While Lilly’s mid-stage tests showed efficacy in treating schizophrenia and Alzheimer’s disease-associated psychosis, results also showed side effects from the molecule’s targeting of receptors in peripheral tissue.
Karuna licensed xanomeline’s rights in 2012. The biotech’s innovation was pairing xanomeline with trospium chloride, a molecule that blocks muscarinic receptors — but only outside the brain and the central nervous system. This drug combination was designed to selectively target the M1 and M4 receptors in the CNS whose disrupted signaling is believed to contribute to psychosis and cognitive impairment. At the same time, this drug left alone the peripheral muscarinic receptors. When BMS reached a $14 billion deal to acquire Karuna last December, the schizophrenia drug was already under FDA review.
FDA approval of Cobenfy was based on the results of two Phase 3 tests of the drug in adults. The identically designed placebo-controlled studies assessed patients using the Positive and Negative Syndrome Scale (PANSS), a rating scale that measures symptom severity in psychotic disorders such as schizophrenia. Both trials showed that after five weeks, patients treated with the twice-daily capsule experienced statistically significant reductions in schizophrenia symptoms compared to placebo, achieving the main study goal.
The most common side effects reported in the studies were gastrointestinal and included nausea, upset stomach, constipation, abdominal pain, vomiting, and diarrhea. Unlike the first- and second-generation antipsychotics, Cobenfy’s label does not carry a black box warning for adverse effects. The BMS drug’s label does include warnings for urinary retention, increased heart rate, gastric retention, and angioedema. The label also recommends against use of the drug in patients with liver impairment.
Summer Colling, a senior analyst at Citeline, said the BMS drug’s new mechanism of action marks a new era in psychiatric drug development. But she added that one drawback is the drug’s twice-daily administration, which is less convenient than available antipsychotics with once-daily dosing or even longer dosing schedules.
“KarXT has a strong efficacy profile, but it is difficult to compare PANSS reduction scores to marketed atypical antipsychotics without head-to-head trials,” Colling wrote in an email. “Having said that, statistically significant effects were observed as early as week two after KarXT treatment, which could be an important differentiating factor for the drug since current therapies take much longer, often three to four weeks, to show clinical improvement.”
Colling said it’s unlikely the BMS drug will be used as a first-line schizophrenia treatment due to cost and insurance policies. She expects it will be prescribed for patients who do not benefit from or cannot tolerate at least two generic antipsychotics, such as risperidone and olanzapine.
BMS set a $1,850 per month wholesale price for Cobenfy, or more than $22,000 per year, which is in line with other brand name antipsychotics. Competition is coming from other muscarinic receptor-targeting drugs in development. The most advanced is emraclidine, which AbbVie added to its pipeline through the $8.7 billion Cerevel Therapeutics acquisition that closed in August. The once-daily drug is currently completing two Phase 2 studies designed to support a regulatory submission. In note sent to investors on Friday, Leerink Partners analyst David Risinger said AbbVie expects to seek approval for emraclidine in the second half of 2025, potentially setting the stage for a regulatory decision in the first half of the following year. He added that available data suggests AbbVie’s schizophrenia drug likely offers lower efficacy but better safety than Cobenfy, but the BMS drug will have about an 18-month head start.
William Blair estimates Cobenfy could achieve peak sales of $2 billion in 2030 in schizophrenia alone. But in a Friday research note, analysts Matt Phipps and Myles Minter noted that pivotal tests are underway testing the drug in Alzheimer’s-associated psychosis and adjunctive schizophrenia. If Cobenfy wins approval in these indications, the drug’s sales yearly sales could reach between $3 billion and $5 billion.
“We believe the first-mover advantage in this novel drug class for schizophrenia, meaningful enthusiasm around the availability of a new modality in schizophrenia, and favorable product profile for Cobenfy should support strong early adoption,” the William Blair analysts wrote.
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