FDA approves first novel drug for schizophrenia in decades

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

Unlike antipsychotics, which act on dopaminergic and serotonergic receptors in the brain, the oral agent instead targets muscarinic receptors M1 and M4. The novel approach could help patients who do not respond to or cannot tolerate dopamine blockers.

“This drug represents the first new approach to treating schizophrenia in decades. “This approval provides a new alternative to the antipsychotics previously prescribed to people with schizophrenia,” said Dr. Tiffany Farchione from the FDA's Center for Drug Evaluation and Research made a statement.

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

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

The highly anticipated drug, formerly known as KarXT, demonstrated its safety and efficacy in the Phase III EMERGENT-2 and EMERGENT-3 trials.

Both 5-week studies met their primary endpoint and demonstrated significantly greater reductions in Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (P

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

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

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all disorder, and people often find themselves in a cycle of discontinuing and switching treatments,” Segal Trials researcher Rishi Kakar, MD, said in a statement from drugmaker Bristol Myers Squibb. “The approval of Cobenfy is a transformative moment in the treatment of schizophrenia, as historically medications approved to treat schizophrenia rely on the same primary signaling pathways in the brain. By leveraging a novel signaling pathway, Cobenfy offers a new option for treating this difficult disease.”

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

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

The drug's labeling lists contraindications for patients with urinary retention, moderate or severe hepatic impairment (Child-Pugh class B or C), gastric retention, known hypersensitivity to the ingredients, or untreated angle-closure glaucoma. It also warns against angioedema of the face and lips, central nervous system effects, increased heart rate and use in patients with biliary diseases.

Because it is largely eliminated by the kidneys, xanomeline trospium is not recommended in patients with moderate to severe renal impairment (eGFR 2).

In patients with symptoms of liver disease such as yellowing of the skin or the whites of the eyes, dark urine, and unexplained itching, the medication should be discontinued.

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 hit the market in late October.