FDA Approves First-In-Class Muscarinic Agonist for the Treatment of Schizophrenia in Adults

Bristol Myers Squibb recently announced the US  FDA has approved COBENFY (xanomeline and trospium chloride), an oral medication for the treatment of schizophrenia in adults. COBENFY represents the first new class of medicine in several decades and introduces a fundamentally new approach to treating schizophrenia by selectively targeting M₁ and M₄ receptors in the brain without blocking D₂ receptors.

“Today’s landmark approval of our first-in-class treatment for schizophrenia marks an important milestone for the community, where after more than 30 years, there is now an entirely new pharmacological approach for schizophrenia — one that has the potential to change the treatment paradigm,” said Chris Boerner, PhD, Board Chair and Chief Executive Officer at Bristol Myers Squibb. “As we reenter the field of neuropsychiatry, we are dedicated to changing the conversation around serious mental illness, beginning with today’s approval in schizophrenia.”

Schizophrenia is a persistent and often disabling mental illness affecting how a person thinks, feels, and behaves. It is estimated to impact approximately 2.8 million people in the US. Symptoms typically first appear in early adulthood and present differently in each person, making symptoms difficult to diagnose and manage. While the current standard of care can be effective in managing symptoms of schizophrenia, up to 60% of people experience inadequate improvement in symptoms or intolerable side effects during therapy.

“For people living with schizophrenia, it’s often difficult to find a treatment that works for them. Having a variety of treatment options gives patients and healthcare providers the tools to help manage this serious condition,” said Gordon Lavigne, Chief Executive Officer of the Schizophrenia & Psychosis Action Alliance. “People living with schizophrenia want and deserve more. Today’s approval provides a new option as people with schizophrenia move forward with proper support to rebuild their lives.”

The FDA approval of COBENFY is supported by data from the EMERGENT clinical program, which includes three placebo-controlled efficacy and safety trials and two open-label trials evaluating the long-term safety and tolerability of COBENFY for up to one year. In the Phase 3 EMERGENT-2 and EMERGENT-3 trials, COBENFY met its primary endpoint, demonstrating statistically significant reductions of schizophrenia symptoms compared to placebo, as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week five. COBENFY demonstrated a 9.6-point reduction (-21.2 COBENFY vs. -11.6 placebo, p<0.0001) and an 8.4-point reduction (-20.6 COBENFY vs. -12.2 placebo; p<0.0001) in PANSS total score compared to placebo at week five in EMERGENT-2 and EMERGENT-3, respectively. In EMERGENT-2, COBENFY demonstrated a statistically significant improvement in illness from baseline to week five, as measured by the Clinical Global Impression-Severity (CGI-S) score, a secondary endpoint in the trial.

The safety and tolerability profile of COBENFY has been established across acute and long-term trials. In the Phase 3 EMERGENT-2 and EMERGENT-3 trials, the most common adverse reactions (≥5% and at least twice placebo) were nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness and gastroesophageal reflux disease. COBENFY does not have atypical antipsychotic class warnings and precautions and does not have a boxed warning.

“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 Rishi Kakar, MD, Chief Scientific Officer and Medical Director at Segal Trials and investigator in the EMERGENT program. “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 company today also announced the launch of COBENFY Cares, a program designed to support patients who have been prescribed COBENFY. Patients will be able to enroll in the COBENFY Cares program in late October corresponding with product availability. The COBENFY Cares phone number is 1-877-COBENFY.

COBENFY (xanomeline and trospium chloride), formerly KarXT, is an oral medication for the treatment of schizophrenia in adults. COBENFY combines xanomeline, a dual M₁– and M₄-preferring muscarinic receptor agonist, with trospium chloride, a muscarinic receptor antagonist that does not appreciably cross the blood-brain barrier, primarily acting in peripheral tissues. While the exact mechanism of action of COBENFY is unknown, its efficacy is thought to be due to the agonist activity of xanomeline at M₁ and M₄ muscarinic acetylcholine receptors in the central nervous system.

The EMERGENT clinical program evaluating COBENFY for the treatment of schizophrenia in adults includes three placebo-controlled efficacy and safety studies, including the Phase 3 EMERGENT-2 and EMERGENT-3 trials, and two open-label studies evaluating the long-term safety and tolerability of COBENFY for up to one year.

The Phase 3 EMERGENT-2 and EMERGENT-3 trials were five-week, inpatient trials that evaluated the efficacy, safety and tolerability of COBENFY compared to placebo in adults with schizophrenia. In both trials, COBENFY met its primary endpoint, demonstrating statistically significant reductions of schizophrenia symptoms compared to placebo as measured by the Positive and Negative Syndrome Scale (PANSS) total score change from baseline to week five.

COBENFY demonstrated a 9.6-point reduction (-21.2 COBENFY vs. -11.6 placebo, p<0.0001) and an 8.4-point reduction (-20.6 COBENFY vs. -12.2 placebo; p<0.0001) in PANSS total score compared to placebo at week five in EMERGENT-2 and EMERGENT-3, respectively. In EMERGENT-2, COBENFY demonstrated a statistically significant 0.6 change (-1.2 COBENFY vs. -0.7 placebo; p<0.0001) in the Clinical Global Impression-Severity (CGI-S) score compared to placebo at week five, a secondary endpoint in the trial.

The most common adverse reactions (≥5% and at least twice placebo) of COBENFY compared to placebo were nausea (19% vs. 4%), dyspepsia (18% vs 5%), constipation (17% vs 7%), vomiting (15% vs 1%), hypertension (11% vs 2%), abdominal pain (8% vs 4%), diarrhea (6% vs 2%), tachycardia (5% vs 2%), dizziness (5% vs 2%) and gastroesophageal reflux disease (5% vs. <1%).