Cobenfy could break dopamine dominance in schizophrenia treatment: GlobalData

The FDA has recently approved Karuna/Bristol Myers Squibb’s KarXT (Cobenfy), an oral medication for the treatment of schizophrenia in adults. Diverging from the traditional dopamine-based therapies, Cobenfy is said to address the critical gaps in the current treatments by targeting muscarinic acetylcholine receptors. Its success can pave the way for broader adoption of non-dopaminergic approaches in the psychiatric market, reshaping the treatment landscape, says GlobalData.

Cobenfy is a twice-daily oral medication that combines xanomeline, a muscarinic receptor agonist, and trospium chloride, a muscarinic receptor antagonist. This innovative mechanism of action (MoA) targets M1 and M4 muscarinic receptors, increasing striatal acetylcholine levels to reduce psychosis and improve cognition while minimising the side effects commonly associated with dopamine-based therapies. Trospium chloride antagonizes M2 and M3 receptors, mitigating peripheral side effects.

Eleni Tokali, Pharma Analyst at GlobalData, comments: “Cobenfy’s approval marks a critical shift in schizophrenia treatment. By moving beyond dopamine modulation, this therapy addresses critical gaps in the current treatment paradigm, offering a safer and potentially more effective option for patients.”

According to GlobalData’s Drugs Database, the schizophrenia market remains dominated by dopamine-targeted mechanisms, such as D2 receptor antagonists. Muscarinic pathways, as introduced by Cobenfy, rank 42nd among the schizophrenia treatment MoAs, underscoring the innovative leap represented by this approval. Unlike dopamine-based therapies, Cobenfy’s mechanism avoids the FDA’s boxed warning tied to motor side effects and increased mortality in elderly dementia patients, enhancing its appeal for certain populations.

Cobenfy’s market entrance contrasts sharply with AbbVie’s emraclidine, another muscarinic-targeting candidate acquired from Cerevel Therapeutics. Despite the initial promise, emraclidine failed to meet its primary endpoint in two Phase II trials, leaving its future in the schizophrenia market uncertain.

Tokali concludes, “While muscarinic modulation offers significant potential, emraclidine’s setbacks illustrate the challenges of pioneering new mechanisms in psychiatry. Cobenfy’s success, however, sets the stage for muscarinic therapies to complement the established dopamine and serotonin approaches, reshaping the market landscape.

“Cobenfy’s approval could inspire further innovation in non-dopaminergic therapies, providing safer and more effective treatment options. As the market evolves, Cobenfy’s progress and the future of muscarinic modulation will be closely watched by the industry.”