On September 26, 2024, Bristol-Myers Squibb (BMS) announced that the U.S. Food and Drug Administration has approved Cobenfi (xanomeline and trospium chloride) for the treatment of adults with schizophrenia. Cobenfy has a different mechanism of action (MoA) than traditional antipsychotics and represents a new drug class for schizophrenia. However, the schizophrenia market is highly competitive and crowded, as the most widely used drugs to treat schizophrenia are cheap, genericized atypical antipsychotics. This could make it difficult for Cobenfy to penetrate the market.
For more than 60 years, the dopaminergic hypothesis of schizophrenia has led to a schizophrenia treatment paradigm in which atypical antipsychotics target abnormally elevated dopamine concentrations via 5-HT2A and dopamine D2 receptors. It has formed the basis. Because atypical antipsychotics have the same MoA and therefore a similar efficacy profile and are differentiated only by slight differences in safety profile, patients who do not respond well to atypical antipsychotics may be diagnosed with schizophrenia. options for managing symptoms of the disease are limited. In contrast, Cobenfy unlocks the first new drug class for schizophrenia with the first new MoA approved in decades. Cobenfy is a co-formulation of xanomeline, a muscarinic acetylcholine M1 and M4 receptor agonist, and trospium chloride, a peripheral muscarinic acetylcholine antagonist, and does not directly modulate dopaminergic or serotonergic transmission. Cobenfy has been generally well tolerated in clinical trials and, unlike atypical antipsychotics, Cobenfy has been associated with increased mortality in older patients with dementia-related psychosis and suicidal thoughts and behavior when combined with antidepressants. There is no boxed warning that it will increase.
However, with numerous atypical antipsychotics and their generics dominating the schizophrenia market and firmly entrenched in treatment algorithms, Cobenfi could quickly change prescriber habits and reduce the use of atypical antipsychotics. It is unlikely to be replaced as a first-line treatment option. Instead, Cobenfy may be an option for patients who have a partial response to atypical antipsychotics or who cannot tolerate the side effects associated with atypical antipsychotics, such as weight gain, sedation, and movement disorders. There is. However, Cobenfy is contraindicated in patients with urinary retention, liver damage, gastric obstruction, untreated narrow-angle glaucoma, and in patients with a history of hypersensitivity to Cobenfy and its components. It is unclear whether there are any limitations on payer reimbursement for Cobenfy. BMS offered Cobenfy an annual cost of treatment (ACOT) of $22,500. This is significantly more expensive than generic oral aripiprazole, which has an average ACOT of $540. Presumably, payers will require that at least one cheaper atypical antipsychotic drug fail before Cobenfi is reimbursed. Additionally, Cobenfi requires twice-daily oral dosing, which is more frequent than atypical antipsychotics such as aripiprazole or paliperidone, which can impair treatment adherence. Key opinion leaders (KOLs) previously interviewed by leading data analytics firm GlobalData said Cobenfy demonstrated significant reductions in positive and negative syndrome scale scores compared to placebo in EMERGENT’s pivotal clinical trial. , pointed out that there is no data on Cobenfy’s effectiveness against infectious diseases. Active comparators such as atypical antipsychotics. A head-to-head study comparing the efficacy, safety, and treatment adherence of Cobenfy and atypical antipsychotics will help differentiate Cobenfy, change prescriber habits, and improve Cobenfy’s efficacy compared to established atypical antipsychotics. It could help reassure health economists about cost-effectiveness.
Cobenfi is also being developed as an adjunctive therapy for patients who do not respond adequately to atypical antipsychotic therapy alone. The ongoing Phase III ARISE trial is a 6-week, randomized, double-blind, placebo-controlled, multicenter study in patients with schizophrenia who have inadequately responded to current atypical antipsychotic therapy. This is an outpatient study. Currently, there are no approved combination treatments for schizophrenia, although doctors may prescribe a second antipsychotic or antidepressant off-label to enhance the effects of the antipsychotic. Additionally, KOLs reported only modest improvements in efficacy and increased side effect burden with this type of polypharmacy. If the ongoing ARISE trial yields positive results, Cobenfi could become the first approved adjuvant therapy for the treatment of schizophrenia.
Other drug developers are also considering harnessing the muscarinic pathway to treat schizophrenia. According to GlobalData’s drug database, there are seven pipeline products in clinical development (Phase I-III) for schizophrenia that molecularly target muscarinic acetylcholine receptors. Most notably, AbbVie’s emlacridine is a positive modulator of the muscarinic acetylcholine M4 receptor in Phase II development (NCT05227690, NCT05227703, NCT05443724), and Neurocrine Biosciences is a positive modulator of the muscarinic acetylcholine M4 receptor agonist NBI- 1117568 (NCT) 05545111). To date, both pipeline products have been developed as monotherapy and have not been investigated in combination with antipsychotic treatment. Therefore, BMS’s Cobenfy is likely to be ahead of the market and capture a larger patient share if Cobenfy is approved for use as an adjunctive treatment.
“BMS’s Cobenfy wins on schizophrenia, but challenges lie ahead” was originally written and published. clinical trial arenaa brand owned by GlobalData.
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