Cobenfy: A New Mechanism of Action for the Treatment of Schizophrenia

Author: Caryssa Drinkuth
Editor: Keita Yokoyama

Today, we will be covering Bristol-Myers Squibb’s Cobenfy (xanomeline and trospium chloride). On September 26, 2024, the Food and Drug Administration (FDA) approved Cobenfy for the treatment of schizophrenia in adults, designating Cobenfy as the first antipsychotic drug to utilize a novel mechanism of action for the treatment of schizophrenia in over 50 years.1,2 In this post, we will provide an overview of schizophrenia and the available options for its treatment, discuss the mechanism of action and clinical trials for Cobenfy, and conclude with the clinical impact of Cobenfy’s approval.

Overview of Schizophrenia

Schizophrenia spectrum disorder is a complex, chronic mental health disorder that affects 24 million people worldwide  and approximately 2.5 million adults in the United States between the ages of 18 to 65.3,4 Individuals with schizophrenia disorder typically report an onset of symptoms between the ages of 20 to 30 years old, and they often exhibit an array of psychotic symptoms including delusions, paranoia, visual or auditory hallucinations, disorganized behavior, and cognitive impairment.5 Symptoms of schizophrenia disorder are often classified as “positive”  in that the patient presents aberrant excess or distortion in normal cognitive function (e.g. hallucinations) or “negative” in that patients exhibit the absence or lack of normal cognitive function (e.g. social withdrawal, blunted affect, apathy).6 In particular, negative symptoms are associated with both greater risk of morbidity and worse treatment outcomes due to their impairment of social functioning and difficulty to assess in clinical settings.5,6 The complex combination of positive and negative symptoms, as well as the early onset of the disease, makes schizophrenia particularly damaging to the lives of patients affected by this disorder. 

While the pathophysiology of schizophrenia disorder is still unclear, abnormal activity at the dopamine D2 receptor is the most widely studied candidate. Specifically, alterations in neurotransmission in the ventral tegmental area (VTA), a key brain region involved in dopamine release, are thought to contribute to much of the dysregulation of dopamine signaling seen in schizophrenia.5, 13 Neurons originating in the VTA project to, and release dopamine in, the prefrontal cortex (PFC) to form the mesocortical pathway. The mesocortical pathway is involved in the regulation of emotional and cognitive processes.22 Reduced dopamine release through the mesocortical pathway is thought to produce negative symptoms and cognitive deficits by dysregulating emotional and cognitive processes.5 The VTA also sends inputs to brain regions involved in reward, fear, and anxiety, such as the nucleus accumbens (NAc) and amygdala, forming the mesolimbic pathway. Increased dopamine release through the mesolimbic pathway is thought to contribute to positive symptoms of schizophrenia by dysregulating reward and emotional processes.5

Figure 1: Overview of Schizophrenia. Schizophrenia affects over 2.5 million people in the U.S. and over 24 million people globally.3,4 It is a lifelong mental health disorder related to abnormal dopamine signaling in the brain that results in the occurrence of positive and negative symptoms. (Figure made by Caryssa Drinkuth using BioRender.)

Available Treatments

Prior to the approval of Cobenfy in September 2024, all FDA-approved antipsychotic treatments for schizophrenia were aimed at blocking activity at the dopamine D2  receptor.7 Pharmacological treatments are considered the first-line treatment for schizophrenia and can be classified as either first- or second-generation antipsychotics. Non-pharmacological treatments such as psychotherapy also play an important role in the treatment of schizophrenia disorder.

First-Generation Antipsychotics (FGAs): The earliest of the FGAs is chlorpromazine, which was approved for the treatment of schizophrenia in 1953.7 Chlorpromazine is thought to exert its antipsychotic effects via postsynaptic blockade of the dopamine D2 receptor in the mesolimbic pathway.8 While blocking dopamine activity in the mesolimbic pathway reduced positive symptoms of schizophrenia, chlorpromazine and other FGAs also block D2 receptors within the nigrostriatal pathway. This led to broader ‘extrapyramidal’ side effects, such as dystonia, restlessness and pacing, and Parkinson’s disease-like symptoms like tremor, rigidity, and bradykinesia.8 Additionally, blockade of D2 receptors within the mesocortical pathway may worsen the negative and cognitive symptoms of schizophrenia,7 leading to treatment-resistant schizophrenia. Only 10% to 30% of patients experience symptomatic improvement after multiple trials of FGAs, while nearly 30% to 60% of these patients experience harmful side effects in response to FGA treatment.5 

Second-Generation Antipsychotics (SGAs): To overcome FGAs’ burdensome extrapyramidal side effects and poor ability to ameliorate negative symptoms, SGAs such as clozapine were developed. Clozapine was first synthesized in Europe in 1956,9 though it would not be FDA-approved for treatment-resistant schizophrenia in the United States until 1989.10 Like chlorpromazine, clozapine acts as an antagonist at the D2 receptor. However, clozapine preferentially antagonizes the dopamine D4 receptor while also acting as a partial agonist at the serotonin 5-HT1A receptor.9 As a result, clozapine mitigates many of the extrapyramidal side effects of FGAs while also aiding negative symptoms of schizophrenia. Specifically, treatment with clozapine has been demonstrated to reduce suicidal behavior and improve cognitive function in patients with treatment-resistant schizophrenia.9 Thanks to these features, clozapine is now the most effective pharmacotherapy for patients with treatment-resistant schizophrenia. Schizophrenic episodes were reduced by 30%, a massive improvement from the 4% efficacy rate seen for chlorpromazine.5

Unfortunately, clozapine also has a problematic safety profile. Patients taking high doses of clozapine may have increased risk of developing agranulocytosis, a complication causing low neutrophil count in the blood that may increase risk of fatal infection.11 High doses of clozapine may also induce life-threatening toxicity manifesting in coma, seizures, hypotension, and tachycardia.8, 11,19 Despite being one of the only FDA-approved treatments for treatment-resistant schizophrenia, clozapine is only prescribed to approximately 4% of patients with schizophrenia in the United States.20 This underutilization reflects major barriers that restrict the effective use of clozapine, including patients’ fear of serious side effects, lack of training amongst healthcare providers, and the burdensome requirement for continuous blood monitoring throughout clozapine treatment.21

Non-Pharmacological Therapies: Cognitive behavioral therapy (CBT) is frequently used in conjunction with FGAs or SGAs to treat symptoms of schizophrenia. CBT for patients with schizophrenia disorder aims to promote effective coping strategies, address and ameliorate comorbid disorders, such as substance use, anxiety, and depression, and improve adherence to FGA or SGA treatment.12 CBT has demonstrated efficacy for reducing positive symptoms of schizophrenia, though negative symptoms remain difficult to address through CBT alone.12

In addition to CBT, addressing social determinants of health (SDoH) may improve the health outcomes of people with schizophrenia. SDoH, such as housing instability, discrimination, and poverty, are associated with greater incidence of schizophrenia disorder and worse health outcomes26 by impacting social connections, access to health care, and increasing risk of comorbid mental disorders. While improving SDoH by improving access to resources and fostering social support may improve the outcomes of people with schizophrenia, the effectiveness of interventions related to SDoH remains poorly studied.26 While individual-level interventions may improve health outcomes, properly addressing SDoH associated with schizophrenia will likely require dismantling large systemic inequities that exist regarding access to mental health care. Due to the challenging and extensive nature of addressing SDoH related to schizophrenia disorder, pharmacological approaches are often favored as primary therapies for the treatment of schizophrenia, with non-pharmacological approaches being considered as adjunctive therapies.

Mechanism of Action

Taken twice daily, Cobenfy is an oral prescription medication composed of xanomeline and trospium chloride.13 Unlike FGAs and SGAs, xanomeline does not directly target dopamine receptors. Instead, it acts as a preferential agonist at M1 and M4 muscarinic acetylcholine receptors.13 Xanomeline’s activity at the M1 and M4 receptors has been demonstrated to relieve psychosis and improve cognition in individuals with schizophrenia.13 Muscarinic acetylcholine receptors are a family of metabotropic G-protein coupled receptors (GPCRs) that may produce either inhibitory or excitatory neuronal responses to the binding of an agonist. Specifically, the M1 receptor produces excitatory responses by coupling with the Gq subtype G protein, while the M4 receptor produces inhibitory responses by coupling with the Gi/o subtype G protein.13 Additionally, the M4 receptor is located presynaptically and may act as an autoreceptor to inhibit release of acetylcholine, a key neurotransmitter that modulates communication between neurons.23

Preclinical studies suggest that xanomeline’s agonism with M1 and M4 receptors impart downstream effects on dopamine release, leading to its antipsychotic effects. One possible way that this could happen is for postsynaptic M1 receptors to excite GABAergic interneurons that synapse onto pyramidal neurons, resulting in increased GABA inhibition of excitatory signals that would otherwise travel from the glutamatergic pyramidal neurons onto dopamine neurons of the ventral tegmental area (VTA). This is critical since the VTA is a key region involved in dopamine transmission and the dysregulation of dopamine signaling in schizophrenia.5, 13 Another mechanism may involve xanomeline activating presynaptic M4 receptors within the VTA. This would blunt the stimulatory effects of acetylcholine on dopamine neurons to reduce downstream dopamine transmission.14 

Muscarinic receptor agonism is not without side effects. In addition to the M1 and M4 receptors, which are predominantly localized to the brain, xanomeline may also act as an agonist at M2 and M3 muscarinic receptors, which are found throughout the gastrointestinal tract, bladder, and lungs.13, 14  Use of xanomeline alone may produce peripheral side effects, including nausea and vomiting.14 To combat this, Cobenfy also contains trospium chloride, a pan-muscarinic antagonist with high affinity for the M2 and M3 muscarinic receptors.27 Trospium chloride does not readily cross the blood-brain barrier,27 allowing it to preferentially bind to M2 and M3 muscarinic receptors to block peripheral side effects and improve tolerability.13

Figure 2: Mechanism of Action of Cobenfy (xanomeline-trospium). Xanomeline acts as an agonist at the M1 and M4 muscarinic receptors and is thought to exert antipsychotic effects via reduction of downstream dopamine transmission in brain regions such as the VTA.13 (Figure made by Caryssa Drinkuth using BioRender.)

Clinical Trials

The safety and efficacy of Cobenfy was tested in three separate inpatient, five-week, double-blind, placebo-controlled, randomized control trials. These studies (EMERGENT-1, EMERGENT-2, and EMERGENT-3) enrolled a total of 608 participants aged 18-65 with a confirmed diagnosis of schizophrenia as based on Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria.13 Cobenfy’s efficacy was determined by changes between baseline and week 5 scores on a Positive and Negative Symptom Scale (PANSS), a test that numerically ranks severity of positive and negative schizophrenia symptoms on a scale of 30-120, with higher scores reflecting greater severity.13 Participants with a PANSS score of 80 or higher at baseline were determined to be eligible for the clinical trial. All participants discontinued their existing antipsychotic treatments for at least 2 weeks prior to the start of the trial and were given either placebo or flexible dosing of twice-daily Cobenfy over the 5 week trial. Participants were also monitored for adverse symptoms, including weight gain, gastrointestinal distress, and drowsiness.13 

Pooled analyses of the three EMERGENT trials demonstrated that participants who received Cobenfy showed significant improvement in both positive and negative symptoms of schizophrenia. Participants in the EMERGENT-2  and EMERGENT-3 trials had statistically significant reductions of 9.6 and 8.4 points on the PANSS, respectively.13 Furthermore, over 75% of participants displayed a 30% or greater improvement in PANSS score.13 Importantly, changes in weight gain, metabolic parameters, or extrapyramidal symptoms did not appear to differ between treatment groups, highlighting the improved safety profile of Cobenfy compared to other antipsychotic medications.13, 15

It should be noted that some adverse effects of Cobenfy were reported. These include gastrointestinal-related events, hypertension, and tachycardia, though the severity of these events were rated as mild to moderate.13, 15 Cobenfy may also pose risks of liver damage and is not recommended for patients with mild hepatic impairment.1, 15 Despite these risks, Cobenfy appears to have relatively high tolerability, safety, and efficacy for the treatment of positive and negative symptoms of schizophrenia compared to other FDA-approved antipsychotic medications. Altogether, the FDA approved Cobenfy for the treatment of schizophrenia based on meaningful reductions in the severity of positive and negative schizophrenia symptoms over a 5 week trial.1 

Clinical Significance

Addressing Unmet Needs: The FDA’s approval of Cobenfy marks a turning point in the treatment and management of schizophrenia disorder. To date, Cobenfy is the only FDA-approved treatment for schizophrenia that does not directly act on dopamine receptors, which offers a distinct advantage that mitigates adverse extrapyramidal side effects and confers increased safety and tolerability.15 Cobenfy’s novel mechanism of action may also prove to be promising for patients with schizophrenia disorder who cannot rely on other antipsychotics due to issues with tolerability or reducing negative symptoms.13 

Prescribing and Costs: How Cobenfy will change the landscape of antipsychotic prescribing practices remains to be seen. There are at least 20 other FDA-approved treatments for schizophrenia disorder,16 many of which have been long-established by clinicians as first-line antipsychotics. Additionally, concerns about cost may serve as a barrier to the prescription of Cobenfy. Bristol Myers’ listed price of a year’s supply of Cobenfy is $22,500, and it remains unclear to what extent this cost will be covered by insurers.17 Cobenfy was granted new chemical entity exclusivity until September of 2029,25 which means that cheaper generic alternatives may potentially become available after this date.

Due to the availability of cheaper alternatives, patients may be required to trial multiple antipsychotics before being approved for treatment with Cobenfy.17 Unfortunately, this means many patients may endure ineffective treatments or intolerable adverse effects before receiving approval for Cobenfy prescription. Currently, Cobenfy is intended for use as a second- or third-line treatment in patients that partially respond to FGAs or SGAs. However, Cobenfy is actively undergoing development as an adjunctive therapy in combination with FGAs/SGAs and may become the first approved adjunctive treatment for schizophrenia if positive results emerge from ongoing clinical trials.24 Questions remain for whether clinicians and payors decide to embrace Cobenfy after these additional studies, as well as whether Cobenfy may replace FGAs/SGAs as first-line treatments.

Future of Muscarinic Agonists: Given the success of Cobenfy, multiple biopharmaceutical companies have begun to work on muscarinic drugs for treatment-resistant schizophrenia that may rival Cobenfy, such as Cerevel Therapeutics’ emraclidine. Bristol Myers Squibb has also begun testing Cobenfy as a treatment for psychosis and cognitive decline in patients with Alzheimer’s disease.18 M1 muscarinic receptor agonists such as Cobenfy are also actively being investigated for managing symptoms of bipolar disorder, Parkinson’s disease, and opioid use disorder.18

Figure 3: Clinical impact of Cobenfy. Cobenfy may address unmet needs for alternative treatments to schizophrenia disorder; however, the cost and resistance to changing prescribing habits may serve as a barrier to treatment with Cobenfy. However, the approval of Cobenfy marks an important step in therapeutic development, as muscarinic agonists are being actively investigated as potential therapies for a number of neurological disorders. (Figure made by Caryssa Drinkuth using BioRender.)

References

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