On 26 September 2024, Bristol Myers Squibb (BMS) announced that the US Food and Drug Administration approved Cobenfy (xanomeline and trospium chloride) for the treatment of adults with schizophrenia. Cobenfy has a mechanism of action (MoA) distinct from traditional antipsychotics and represents a new drug class for schizophrenia. However, as the drugs most widely used to treat schizophrenia are inexpensive, genericised atypical antipsychotics, the schizophrenia market is competitive and crowded. This could make it difficult for Cobenfy to penetrate the market.

For over 60 years, the dopaminergic hypothesis of schizophrenia has formed the basis of the schizophrenia treatment paradigm, whereby atypical antipsychotics target the abnormally elevated concentration of dopamine through the 5-HT2A receptors and dopamine D2 receptors. As the atypical antipsychotics have the same MoA, and therefore a similar efficacy profile, differentiated only by slight nuances in their safety profiles, patients who do not respond well to atypical antipsychotics have limited options to manage their schizophrenia symptoms. In contrast, Cobenfy unlocks the first new drug class for schizophrenia with a novel MoA to be approved in decades. Cobenfy is a coformulation of a muscarinic acetylcholine M1 and M4 receptor agonist, xanomeline, and peripheral muscarinic acetylcholine antagonist, trospium chloride, and does not directly modulate dopaminergic or serotonergic transmission. Cobenfy has been generally well tolerated in clinical trials and unlike the atypical antipsychotics, Cobenfy does not have a boxed warning of increased mortality in older patients with dementia-related psychosis or suicidal thoughts and behaviours with concomitant antidepressant drug usage.

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However, as numerous atypical antipsychotics and their generics dominate the schizophrenia market and are very well-entrenched in the treatment algorithm, it is unlikely that Cobenfy will immediately change prescriber habits and replace atypical antipsychotics as a first-line treatment option. Instead, Cobenfy could be an option for patients who have a partial response to atypical antipsychotics or those who cannot tolerate the side effects of weight gain, sedation, and movement disorders associated with atypical antipsychotics. But Cobenfy is contraindicated in patients with urinary retention, hepatic impairment, gastric retention, untreated narrow-angle glaucoma, and patients with a history of hypersensitivity to Cobenfy and its components. It is unclear whether there will be a restriction in reimbursement by payers for Cobenfy. BMS has proposed an annual cost of therapy (ACOT) of $22,500 for Cobenfy. This is a significant premium compared to generic oral aripiprazole, which has an average ACOT of $540. It is likely that payers will require failure on at least one cheaper atypical antipsychotic before Cobenfy is reimbursed. Furthermore, Cobenfy requires twice-daily oral administration, a more frequent dosing regimen than atypical antipsychotics such as aripiprazole or paliperidone, which could impair adherence to treatment. Key opinion leaders (KOLs) previously interviewed by leading data and analytics company GlobalData noted that while Cobenfy has demonstrated a large reduction in Positive and Negative Syndrome Scale scores against placebo in the EMERGENT pivotal trials, there is no data on the efficacy of Cobenfy against an active comparator like an atypical antipsychotic. A head-to-head study comparing the efficacy, safety, and treatment adherence of Cobenfy and an atypical antipsychotic could help differentiate Cobenfy, change prescriber habits, and reassure health economists about Cobenfy’s cost-effectiveness compared with established atypical antipsychotics.

Cobenfy is also being developed as an adjunctive therapy in patients who have an inadequate response to atypical antipsychotic monotherapy. The ongoing Phase III ARISE trial is a six-week, randomised, double-blind, placebo-controlled, multicentre, outpatient study in patients with schizophrenia with an inadequate response to their current atypical antipsychotic treatment. At present, although physicians will occasionally prescribe a second antipsychotic or antidepressant off-label to augment the effects of an antipsychotic, there are no approved combination therapeutic regimens for schizophrenia. Furthermore, KOLs reported only modest improvements in efficacy and increased side-effect burden with this type of polypharmacy. If positive results are found in the ongoing ARISE trial, Cobenfy could be the first approved adjunctive therapy for the treatment of schizophrenia.

Other drug developers are also looking to exploit the muscarinic pathway for the treatment of schizophrenia. According to GlobalData’s drug database, there are seven pipeline products in clinical development (Phase I-III) for schizophrenia that have muscarinic acetylcholine receptors as a molecular target. Most notably, AbbVie’s emraclidine is a positive modulator at muscarinic acetylcholine M4 receptors in Phase II development (NCT05227690, NCT05227703, and NCT05443724) and Neurocrine Bioscience has reported positive Phase II results for its muscarinic acetylcholine M4 receptor agonist NBI-1117568 (NCT05545111). Thus far, both pipeline products are being developed as monotherapies and concurrent use with antipsychotic treatments have not been investigated.  As such, BMS’ Cobenfy is likely to have the first-to-market advantage and will command greater patient share if Cobenfy receives approval to be used as an adjunctive treatment.

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