FDA Approves Bristol Myers' First New Schizophrenia Drug in Decades

Schizophrenia is currently treated with older medications that often have limited efficacy and troublesome side effects, causing many patients to discontinue their use. However, the FDA has recently approved a new drug from Bristol Myers Squibb (BMS) called Cobenfy, marking a significant advancement in the treatment of schizophrenia and introducing the first novel medication for this disorder in decades.

For patients, the approval of Cobenfy signifies a new treatment option with better tolerability. For BMS, the regulatory approval represents a payoff from its substantial investment in acquiring the drug's developer. BMS anticipates that Cobenfy will be available starting in October.

The existing schizophrenia medications are antipsychotics that primarily target and block dopamine receptors in the brain. The first generation of these drugs, dating back to the 1950s, has side effects such as movement disorders. The second-generation antipsychotics that emerged in the 1980s also block dopamine pathways but come with side effects including sleepiness, low blood pressure, weight gain, and sexual dysfunction. BMS estimates that schizophrenia affects around 2.8 million people in the U.S., with approximately 60% not achieving adequate improvement or experiencing intolerable side effects from current medications.

The new BMS drug, Cobenfy, works by targeting muscarinic cholinergic receptors in the brain. There are five types of these receptors in the brain and some peripheral tissues. Biotech companies have been striving to develop drugs that specifically target and activate the M1 and M4 receptors without affecting the other muscarinic receptors, which can cause side effects.

Cobenfy was developed in the laboratories of Karuna Therapeutics, initially known as KarXT (Karuna xanomeline-trospium chloride). Xanomeline, a small molecule targeting muscarinic receptors in the brain, was initially developed by Eli Lilly. Although mid-stage tests by Lilly showed efficacy in treating schizophrenia and Alzheimer’s disease-associated psychosis, side effects were noted from peripheral tissue receptor targeting.

Karuna licensed the rights to xanomeline in 2012 and innovatively paired it with trospium chloride, a molecule that blocks muscarinic receptors only outside the brain and central nervous system. This combination aimed to selectively target the M1 and M4 receptors in the CNS, believed to contribute to psychosis and cognitive impairment, without affecting peripheral muscarinic receptors. When BMS acquired Karuna for $14 billion last December, the drug was already under FDA review.

The FDA approval of Cobenfy was based on two Phase 3 studies in adults. These placebo-controlled studies used the Positive and Negative Syndrome Scale (PANSS) to measure symptom severity in psychotic disorders like schizophrenia. Both trials demonstrated that after five weeks, patients treated with the twice-daily capsule experienced significant reductions in schizophrenia symptoms compared to placebo, achieving the main study goal.

The most common side effects observed in the studies were gastrointestinal issues, including nausea, upset stomach, constipation, abdominal pain, vomiting, and diarrhea. Unlike older antipsychotics, Cobenfy’s label does not carry a black box warning for adverse effects. However, it does include warnings for urinary retention, increased heart rate, gastric retention, and angioedema. The drug is also not recommended for patients with liver impairment.

Summer Colling, a senior analyst at Citeline, mentioned that Cobenfy's new mechanism of action signifies a new era in psychiatric drug development. However, she noted that the twice-daily administration could be less convenient compared to once-daily or extended dosing schedules. Colling also mentioned that the drug might not be used as a first-line treatment due to cost and insurance policies, likely reserved for patients who do not benefit from or cannot tolerate at least two generic antipsychotics like risperidone and olanzapine.

BMS has set a wholesale price of $1,850 per month for Cobenfy, amounting to over $22,000 annually, which aligns with other brand-name antipsychotics. Competition is expected from other muscarinic receptor-targeting drugs in development, such as emraclidine, which AbbVie acquired through its purchase of Cerevel Therapeutics. Emraclidine is currently in Phase 2 studies, with a regulatory submission expected in the latter half of 2025.

Analysts estimate that Cobenfy could achieve peak sales of $2 billion by 2030 in schizophrenia alone, with potential sales reaching $3 billion to $5 billion if approved for other indications like Alzheimer’s-associated psychosis and adjunctive schizophrenia. The novel drug class’s first-mover advantage and favorable profile are expected to support strong early adoption of Cobenfy.