FDA Approves First Novel Drug for Schizophrenia in Decades

The FDA on Thursday approved xanomeline and trospium chloride (Cobenfy) for schizophrenia in adults, the first new class of drug for the condition in more than 30 years.

In contrast to antipsychotics that work on dopaminergic and serotonergic receptors in the brain, the oral agent targets the M1 and M4 muscarinic receptors instead. The novel approach may help patients that don’t respond to or tolerate dopamine-blocking agents.

“This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed,” said Tiffany Farchione, MD, of the FDA’s Center for Drug Evaluation and Research, in a statement.

“Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life,” she added.

The drug has no boxed warning and does not carry the class warnings associated with atypical antipsychotics.

Formerly known as KarXT, the hotly anticipated drug proved its safety and efficacy in the phase III EMERGENT-2 and EMERGENT-3 studies.

Both 5-week trials met their primary endpoint, demonstrating significantly greater reductions in the Positive and Negative Syndrome Scale (PANSS) total score compared with placebo (P<0.0001 for both):

• EMERGENT-2: -21.2 vs -11.6, respectively
• EMERGENT-3: 20.6 vs -12.2

And some key secondary endpoints were met in EMERGENT-2 as well.

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” said investigator Rishi Kakar, MD, of Segal Trials, in a statement from drugmaker Bristol Myers Squibb. “The approval of Cobenfy is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, Cobenfy offers a new option to manage this challenging condition.”

The most common side effects of xanomeline-trospium chloride (in ≥5% of patients and at least twice placebo) included nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastrointestinal reflux disease. The increase in heart rate occurred at the beginning of the trial, but dropped back down by week 5.

The combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist, was not associated with side effects typically common of other schizophrenia agents, such as weight gain, somnolence, and extrapyramidal symptoms like tardive dyskinesia.

Labeling for the drug lists contraindications for patients with urinary retention, moderate or severe hepatic impairment (Child-Pugh Class B or C), gastric retention, a history of hypersensitivity to the ingredients, or untreated narrow-angle glaucoma. It also warns about angioedema of the face and lips, central nervous system effects, increased heart rate, and use in patients with biliary disease.

Because it’s substantially excreted by the kidneys, xanomeline-trospium is not recommended in patients with moderate to severe renal impairment (eGFR <60 mL/min/1.73 m²).

The drug should be stopped in patients with symptoms of liver disease like yellowing of the skin or the white part of the eyes, dark urine, and unexplained itching.

Xanomeline-trospium is available in 50 mg/20 mg, 100 mg/20 mg, and 125 mg/30 mg capsules.

Bristol Myers Squibb said the drug is expected to launch in late October.