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FDA Approves First Schizophrenia Treatment in Over 3 Decades
The US Food and Drug Administration (FDA) has approved Cobenfy (xanomeline and trospium chloride) capsules for oral use for the treatment of schizophrenia in adults. The drug, formerly known as KarXT, is the first new pharmacological treatment approved for schizophrenia in over 30 years.
"The FDA approval of xanomeline and trospium capsules is a once-in-a-lifetime moment as rare as seeing Halley's Comet," Craig Chepke, MD, DFAPA, scientific director for the Psych Congress portfolio of CME conferences said in an exclusive conversation with Psych Congress Network.
The first antipsychotic medication for schizophrenia treatment, chlorpromazine, was introduced in 1952. While new treatments emerged in the decades that followed, they all use the same mechanism of action, which involves blocking a dopamine receptor in the brain.
Cobenfy, though, is the first in a new class of medicine and introduces a new approach to managing symptoms by targeting M1 and M4 receptors in the brain without blocking D2 receptors. The new drug is available in 50-mg/20-mg, 100-mg/20-mg, and 125-mg/30-mg capsules.
"For over 70 years, we've been trying to treat schizophrenia by blocking any and every post-synaptic dopamine D2 receptor, even though the evidence points to the real problem being the excessive pre-synaptic release of dopamine from just a small subset of dopamine neurons,” Dr Chepke said. "That's like trying to bail water out of a sinking ship instead of fixing the leak.”
Thursday's approval was supported by data from the EMERGENT clinical program, which comprised 3 placebo-controlled efficacy and safety trials and 2 open-label trials assessing the treatment's long-term safety and tolerability for up to 1 year.
Xanomeline-trospium chloride met the primary endpoint in Phase 3 EMERGENT-2 and EMERGENT-3 trials, demonstrating statistically significant reductions of schizophrenia symptoms compared to placebo. This was measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week 5. At week 5, patients receiving Cobenfy displayed a 9.6-point reduction in PANSS total score compared to placebo (-21.2 xanomeline-trospium chloride vs. -11.6 placebo, p<0.0001) in the EMERGENT-2 trial and an 8.4-point reduction (-20.6 xanomeline-trospium chloride vs. -12.2 placebo; p<0.0001) in the EMERGENT-3 trial. In EMERGENT-2, xanomeline-trospium chloride also showed a significant improvement in illness from the beginning to week 5, as measured by the Clinical Global Impression-Severity (CGI-S) score, a secondary endpoint in the trial.
Related>> Third Xanomeline-Trospium Trial Shows Improvement in Schizophrenia Symptoms
Dr Chepke hopes this treatment will reduce side effects and improve negative symptoms. "Xanomeline-trospium capsules may avoid [previous treatment approaches’] potential unwanted collateral damage (including movement disorders, such as tardive dyskinesia, and weight or metabolic disturbances) by stimulating muscarinic M4 and M1 receptors, which we believe causes a selective reduction in dopamine release from only the overactive dopamine neurons in the associative and sensorimotor striatum," he said. "The clinical trials also contained a possible signal that Cobenfy's M1 agonism could have a benefit for the cognitive dysfunction and negative symptoms of schizophrenia. However, more research is needed to confirm definitively."
The most common side effects of xanomeline and trospium chloride capsules are nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness, and gastroesophageal reflux disease.
The landmark approval is expected to create a shift in the field, one that Dr Chepke looks forward to implementing in his own clinical practice. "This is such a radical departure from every other treatment for schizophrenia that the FDA did not categorize it as an antipsychotic. Instead, it's recognized as the first in the 'muscarinic agonist' class, with the indication 'for the treatment of schizophrenia.'"
"I applaud the FDA for recognizing how distinct this medication is from all previously approved antipsychotics and using neuroscience-based, non-stigmatizing language to classify it. I'm incredibly excited to see how Cobenfy will perform in the real world, and I have a number of candidates from my practice in mind to start once it becomes available."
The xanomeline and trospium chloride capsules are contraindicated in patients with urinary retention, moderate or severe hepatic impairment, gastric retention, a history or hypersensitivity to xanomeline and trospium chloride capsules or trospium chloride, and untreated narrow-angle glaucoma.
The approval of xanomeline and trospium chloride capsules was granted to Bristol-Myers Squibb Company.
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