Open Label Outpatient Switch Study Demonstrates Symptom Stability During Transition from Oral Atypical Antipsychotics to Cobenfy™ (xanomeline and trospium chloride)
High treatment completion and no discontinuations due to lack of efficacy observed across faster and slower switch strategies
“While transitioning patients is common in schizophrenia, clinicians have historically had limited data to help guide these decisions, especially for differentiated treatments like Cobenfy,” said
This 8-week, open-label trial evaluated two cross-titration strategies in adults with schizophrenia (n=105): tapering the existing atypical antipsychotic down over the faster 2 week (n=52) or slower 4 week (n=53) period while simultaneously up-titrating Cobenfy to the target dose of 125/30 mg BID, over two weeks in both arms. Patients were required to have a PANSS total score at or below 80 at screening and baseline, Clinical Global Impression-Severity (CGI-S) score of ≤4, and to be on a stable dose of an oral atypical antipsychotic for at least 6 weeks.
The primary objective of the trial was to evaluate the rate of all-cause Cobenfy discontinuation over a period of 8 weeks. Key secondary endpoints included Cobenfy discontinuation due to a lack of efficacy, incidence of, and discontinuations due to adverse events (AEs), change from baseline (CFB) to week 8 in the PANSS total score, CGI-S, Personal and Social Performance (PSP), and Medication Satisfaction Questionnaire (MSQ).
In the trial, approximately 86% of patients completed 8 weeks of treatment, with discontinuation rates of 15.1% (n=8) and 13.5% (n=7) in the slower and faster transition groups. No patients discontinued treatment with Cobenfy due to lack of efficacy. Mean changes in PANSS total scores from baseline to week 8 were −4.2 in the slower transition group and −3.1 in the faster transition group. Mean change in CGI-S scores was −0.2 in both the slower and faster transition groups. From baseline to week 8, mean PSP scores improved by 1.1 and 0.7 in the slower and faster transition groups, respectively.
Across both cross-titration groups, treatment with Cobenfy was generally well tolerated, with no new safety or tolerability issues emerging. In the trial, 49% of patients had ≥1 treatment-emergent adverse event (TEAE) and none were serious. TEAE rates were consistent with those reported in the EMERGENT trials. In the slower and faster transition groups, 1 (1.9%) patient and 2 (3.8%) patients, respectively, discontinued treatment early due to TEAEs.
“Cobenfy represents a fundamentally different approach to treating schizophrenia as the first novel mechanism in decades, and physicians are naturally curious as to how they can switch and transition adult patients with schizophrenia to this innovative medication,” said
About Schizophrenia
Schizophrenia is a persistent and often disabling mental illness impacting how a person thinks, feels and behaves. There are three symptom domains of schizophrenia, which include positive symptoms (e.g., hallucinations, delusions, disordered thinking and speech), negative symptoms (e.g., lack of motivation, lack of emotional expression/flat affect, social withdrawal) and cognitive dysfunction (e.g., impaired attention, deficits in memory, concentration and decision-making). The symptoms of schizophrenia can affect all areas of people’s lives, making it difficult to maintain employment, live independently, and manage relationships. Schizophrenia affects nearly 24 million people worldwide, including 2.8 million people in
About Cobenfy™ (xanomeline and trospium chloride)
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 confining its effects on 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.
INDICATION
COBENFY™ (xanomeline and trospium chloride) is indicated for the treatment of schizophrenia in adults.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
COBENFY is contraindicated in patients with:
- urinary retention
-
moderate (Child-
Pugh Class B ) or severe (Child-Pugh Class C ) hepatic impairment - gastric retention
- history of hypersensitivity to COBENFY or trospium chloride. Angioedema has been reported with COBENFY and trospium chloride.
- untreated narrow-angle glaucoma
WARNINGS AND PRECAUTIONS
Risk of Urinary Retention: COBENFY can cause urinary retention. Geriatric patients and patients with clinically significant bladder outlet obstruction and incomplete bladder emptying (e.g., patients with benign prostatic hyperplasia (BPH), diabetic cystopathy) may be at increased risk of urinary retention.
COBENFY is contraindicated in patients with pre-existing urinary retention and is not recommended in patients with moderate or severe renal impairment.
In patients taking COBENFY, monitor for symptoms of urinary retention, including urinary hesitancy, weak stream, incomplete bladder emptying, and dysuria. Instruct patients to be aware of the risk and promptly report symptoms of urinary retention to their healthcare provider. Urinary retention is a known risk factor for urinary tract infections. In patients with symptoms of urinary retention, consider reducing the dose of COBENFY, discontinuing COBENFY, or referring patients for urologic evaluation as clinically indicated.
Risk of Use in Patients with Hepatic Impairment: Patients with hepatic impairment have higher systemic exposures of xanomeline, a component of COBENFY, compared to patients with normal hepatic function, which may result in increased incidence of COBENFY-related adverse reactions.
COBENFY is contraindicated in patients with moderate or severe hepatic impairment. COBENFY is not recommended in patients with mild hepatic impairment.
Assess liver enzymes prior to initiating COBENFY and as clinically indicated during treatment.
Risk of Use in Patients with Biliary Disease: In clinical studies with COBENFY, transient increases in liver enzymes with rapid decline occurred, consistent with transient biliary obstruction due to biliary contraction and possible gallstone passage.
COBENFY is not recommended for patients with active biliary disease such as symptomatic gallstones. Assess liver enzymes and bilirubin prior to initiating COBENFY and as clinically indicated during treatment. The occurrence of symptoms such as dyspepsia, nausea, vomiting, or upper abdominal pain should prompt assessment for gallbladder disorders, biliary disorders, and pancreatitis, as clinically indicated.
Discontinue COBENFY in the presence of signs or symptoms of substantial liver injury such as jaundice, pruritus, or alanine aminotransferase levels more than five times the upper limit of normal or five times baseline values.
Decreased Gastrointestinal Motility: COBENFY contains trospium chloride. Trospium chloride, like other antimuscarinic agents, may decrease gastrointestinal motility. Administer COBENFY with caution in patients with gastrointestinal obstructive disorders because of the risk of gastric retention. Use COBENFY with caution in patients with conditions such as ulcerative colitis, intestinal atony, and myasthenia gravis.
Risk of Angioedema: Angioedema of the face, lips, tongue, and/or larynx has been reported with COBENFY and trospium chloride, a component of COBENFY. In one case, angioedema occurred after the first dose of trospium chloride. Angioedema associated with upper airway swelling may be life-threatening. If involvement of the tongue, hypopharynx, or larynx occurs, discontinue COBENFY and initiate appropriate therapy and/or measures necessary to ensure a patent airway. COBENFY is contraindicated in patients with a history of hypersensitivity to trospium chloride.
Risk of Use in Patients with Narrow-angle Glaucoma: Pupillary dilation may occur due to the anticholinergic effects of COBENFY. This may trigger an acute angle closure attack in patients with anatomically narrow angles. In patients known to have anatomically narrow angles, COBENFY should only be used if the potential benefits outweigh the risks and with careful monitoring.
Increases in
Anticholinergic Adverse Reactions in Patients with Renal Impairment: Trospium chloride, a component of COBENFY, is substantially excreted by the kidney. COBENFY is not recommended in patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) <60 mL/min). Systemic exposure of trospium chloride is higher in patients with moderate and severe renal impairment. Therefore, anticholinergic adverse reactions (including dry mouth, constipation, dyspepsia, urinary tract infection, and urinary retention) are expected to be greater in patients with moderate and severe renal impairment.
Central Nervous System Effects: Trospium chloride, a component of COBENFY, is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported with trospium chloride, including dizziness, confusion, hallucinations, and somnolence. Monitor patients for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how COBENFY affects them. If a patient experiences anticholinergic CNS effects, consider dose reduction or drug discontinuation.
Most Common Adverse Reactions (≥5% and at least twice placebo): nausea, dyspepsia, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia, dizziness, and gastroesophageal reflux disease.
Use in Specific Populations:
- Moderate or Severe Renal Impairment: Not recommended
- Mild Hepatic Impairment: Not recommended
COBENFY (xanomeline and trospium chloride) is available in 50mg/20mg, 100mg/20mg, and 125mg/30mg capsules.
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Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that future study results may not be consistent with the results to date and that Cobenfy (xanomeline and trospium chloride) may not receive any additional regulatory approvals for the treatment of schizophrenia for adults described in this release, any marketing approvals, if granted, may have significant limitations on their use, and, whether Cobenfy will be commercially successful. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended
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