Cobenfy (KarXT) for Schizophrenia: Xanomeline & Trospium Combo
The first new medication class for schizophrenia in over 35 years...
A new medication called “Cobenfy” (KarXT) was approved by the FDA for the treatment of schizophrenia in 2024 – the first new treatment class for schizophrenia in ~35 years.
Bristol Mysers Squibb owns the drug that was purchased from Karuna for $14 billion and plans to sell the drug for $1,850 per month (mostly will be paid by U.S. gov via rebate discounts).
Brief History of Cobenfy (Xanomeline/Trospium combo)…
Cobenfy, the combination of xanomeline and trospium chloride, originated from research aimed at treating Alzheimer's disease.
In the 1990s, pharmaceutical companies Eli Lilly and Novo Nordisk synthesized xanomeline to delay cognitive decline in Alzheimer’s patients.
During Phase II clinical trials, xanomeline not only demonstrated improvements in cognition but also unexpectedly reduced psychotic symptoms, indicating its potential as an antipsychotic agent.
However, the development of xanomeline as a standalone treatment was hindered by its cholinergic-mediated side effects, including nausea, vomiting, and dizziness, which limited its progression into further trials.
In 2012, Karuna Therapeutics licensed xanomeline and developed KarXT by adding trospium chloride, a muscarinic antagonist that mitigates peripheral side effects without crossing the blood-brain barrier.
This strategic combination aimed to preserve the central therapeutic effects of xanomeline while minimizing its adverse peripheral effects.
By 2021, KarXT successfully met its primary endpoint in Phase II trials.
The subsequent Phase III trial (EMERGENT-3) in March 2023 showed significant efficacy, leading to an FDA submission.
In September 2024, the FDA approved Cobenfy for treating schizophrenia, marking it as the first antipsychotic that targets muscarinic receptors instead of traditional dopamine receptors.
This approval signifies a significant advancement in the pharmacological management of schizophrenia, offering a novel mechanism of action compared to existing treatments.
How Cobenfy (Xanomeline/Trospium combo) works (mechanism of action)…
Cobenfy operates through a dual mechanism of action by targeting muscarinic receptors in the brain, specifically the M1 and M4 subtypes:
1. Xanomeline
Muscarinic Receptor Agonism: Xanomeline selectively stimulates M1 and M4 muscarinic receptors.
Central Effects:
M4 Receptors: Located in the midbrain, M4 receptors influence motor control, decision-making, motivation, and reward perception.
M1 Receptors: Found in the cerebral cortex, M1 receptors are crucial for higher-level cognitive functions such as memory, reasoning, and emotional regulation.
Neurotransmitter Modulation: By activating M1 and M4 receptors, xanomeline indirectly rebalances dopaminergic and glutamatergic circuits, which are implicated in the symptoms of schizophrenia and other neuropsychiatric disorders. This rebalancing helps alleviate both positive symptoms (e.g., hallucinations, delusions) and negative symptoms (e.g., cognitive deficits, social withdrawal).
2. Trospium Chloride
Peripheral Muscarinic Antagonism: Trospium acts as a muscarinic antagonist in the peripheral nervous system.
Mitigation of Side Effects: It counteracts the peripheral muscarinic receptor activation caused by xanomeline, thereby reducing side effects such as dry mouth, gastrointestinal disturbances, and urinary retention.
Blood-Brain Barrier: Trospium does not readily cross the blood-brain barrier, ensuring that it does not interfere with the central therapeutic effects of xanomeline.
By combining these two agents, Cobenfy effectively targets the central nervous system to manage schizophrenia symptoms while minimizing unwanted peripheral effects.
This enhances patient tolerability and adherence to treatment, addressing a significant limitation of xanomeline when used alone.
How effective is Cobenfy (Xanomeline/Trospium combo) for schizophrenia? (vs. other medications?)
Cobenfy has demonstrated significant efficacy in treating schizophrenia, particularly in improving both positive and negative symptoms.
A. Clinical Trial Results
In the Phase III EMERGENT-2 and EMERGENT-3 trials, Cobenfy met its primary endpoints by demonstrating statistically significant reductions in schizophrenia symptoms compared to placebo.
Specifically, there was a 9.6-point reduction (−21.2 Cobenfy vs. −11.6 placebo, p<0.0001) in the Positive and Negative Syndrome Scale (PANSS) total score in EMERGENT-2, and an 8.4-point reduction (−20.6 Cobenfy vs. −12.2 placebo; p<0.0001) in EMERGENT-3 at week five.
In EMERGENT-2, Cobenfy also showed a statistically significant improvement in illness severity, as measured by the Clinical Global Impression-Severity (CGI-S) score (−1.2 Cobenfy vs. −0.7 placebo; p<0.0001).
B. Comparison vs. Other Antipsychotics
Efficacy: Cobenfy’s efficacy is comparable to or exceeds that of established antipsychotics like risperidone and olanzapine.
Cognitive Improvements: Unlike many traditional antipsychotics, Cobenfy has shown promise in enhancing cognitive functions, which are often impaired in schizophrenia patients.
Side Effect Profile: Cobenfy is associated with a lower incidence of extrapyramidal symptoms (EPS) and metabolic side effects compared to conventional atypical antipsychotics. This includes reduced risks of weight gain, diabetes, and dyslipidemia.
Novel Mechanism: By targeting muscarinic receptors instead of dopamine receptors, Cobenfy provides an alternative for patients who are resistant to or intolerant of dopamine-centric treatments.
Overall, Cobenfy represents a promising addition to the antipsychotic arsenal, offering effective symptom control with a favorable side effect profile, especially beneficial for patients who have not responded well to traditional dopamine-blocking medications.
What are the most common side effects of Cobenfy (Xanomeline/Trospium combo)?
While Cobenfy is designed to minimize peripheral side effects through the inclusion of trospium chloride, some adverse effects may still occur. The most frequently reported side effects include:
Gastrointestinal Symptoms:
Nausea and Vomiting: Nausea (19%) and vomiting (15%) are common, especially during the initial stages of treatment.
Constipation and Diarrhea: Constipation (17%) and diarrhea (6%) may occur due to affected gastrointestinal motility.
Dyspepsia and Gastroesophageal Reflux Disease (GERD): Dyspepsia (18%) and GERD (5%) have been reported.
Central Nervous System Effects:
Headache: A common side effect reported by patients.
Dizziness: Dizziness (5%) may occur, particularly when initiating therapy.
Tachycardia: An increased heart rate (5%) has been observed in some individuals.
Cardiovascular Effects:
Hypertension: Elevated blood pressure (11%) may occur in certain patients.
Other Side Effects:
Abdominal Pain: Reported in 8% of patients.
Urinary Retention: Although trospium mitigates this effect, it can still occur in rare cases.
Angioedema: Rare instances of swelling of the face and lips have been reported.
These side effects are generally mild to moderate in severity and tend to decrease with continued use of the medication.
The combination of xanomeline and trospium effectively reduces the incidence and severity of peripheral side effects compared to xanomeline monotherapy, enhancing overall patient tolerability.
Are there any potentially significant advantages of Cobenfy (Xanomeline/Trospium) vs. prior medications?
Yes, Cobenfy may offer several significant advantages over existing antipsychotic medications.
1. Mechanism of Action:
Muscarinic Receptor Targeting: Unlike traditional antipsychotics that target dopamine receptors, Cobenfy targets muscarinic receptors (M1 and M4), providing a novel therapeutic pathway for schizophrenia treatment.
Alternative for Resistant Cases: This offers an option for patients who are resistant to or intolerant of dopamine-blocking antipsychotics.
2. Enhanced Efficacy:
Broad Symptom Improvement: Cobenfy effectively reduces both positive and negative symptoms of schizophrenia, including cognitive deficits, which are often inadequately addressed by other antipsychotics.
3. Improved Cognitive Function:
M1 Receptor Activation: By stimulating M1 receptors, Cobenfy may enhance cognitive functions such as memory and reasoning, offering benefits beyond symptom control.
4. Lower Risk of Dopamine-related Side Effects
Reduced Extrapyramidal Symptoms (EPS): Cobenfy is associated with a lower incidence of EPS, such as tremors and rigidity, compared to traditional antipsychotics.
Avoidance of Tardive Dyskinesia: The risk of developing tardive dyskinesia, a serious movement disorder, is minimized.
5. Favorable Metabolic Profile
Reduced Metabolic Side Effects: Cobenfy carries a lower risk of weight gain, diabetes, and dyslipidemia compared to atypical antipsychotics like olanzapine and clozapine.
6. Improved Patient Adherence
Enhanced Tolerability: By minimizing common side effects, Cobenfy improves patient comfort and adherence to treatment regimens.
7. Support Programs
COBENFY Cares™: Bristol Myers Squibb has launched the COBENFY Cares™ program to support patients prescribed Cobenfy, enhancing patient access and adherence.
Are there any potentially significant drawbacks of Cobenfy (Xanomeline/Trospium) vs. other medications?
Despite its advantages, Cobenfy has several drawbacks compared to existing antipsychotic treatments:
1. Limited Long-Term Data:
New Medication: As Cobenfy was only approved in September 2024, long-term efficacy and safety data are still being accumulated. This may make some clinicians hesitant to prescribe it as a first-line treatment until more data becomes available.
2. Cholinergic Side Effects:
Persistent Gastrointestinal Symptoms: Some patients may still experience nausea, vomiting, and constipation despite the inclusion of trospium chloride, potentially affecting quality of life and adherence.
Urinary Retention and Angioedema: Although rare, these side effects can be serious and may limit the use of Cobenfy in certain patients.
3. Cost and Accessibility:
High Cost: With a wholesale cost of approximately $1,850 per month, Cobenfy is significantly more expensive than many traditional antipsychotics. This high cost could be a barrier for patients without adequate insurance coverage or those in lower-income settings.
Availability: Being a newer medication, Cobenfy may be less accessible in some healthcare settings compared to established generic antipsychotics.
4. Potential for Drug Interactions:
Metabolic Pathways: The combination of xanomeline and trospium may interact with other medications metabolized by the same hepatic pathways, necessitating careful management in patients on multiple medications.
5. Specific Indication:
Limited Approved Uses: Currently, Cobenfy is primarily approved for the treatment of schizophrenia. Its efficacy and safety in other psychiatric or neurological disorders remain to be fully explored, unlike some antipsychotics that have broader indications.
6. Complex Pharmacodynamics:
Dual-Action Mechanism: The need to balance the muscarinic agonism of xanomeline with the antagonism of trospium chloride requires precise dosing strategies. This complexity may complicate treatment protocols compared to single-agent therapies.
7. Insurance Coverage and Reimbursement:
Potential Coverage Issues: Given its high cost, insurance companies may impose restrictions or require prior authorization, potentially delaying access for patients.
8. Contraindications and Precautions:
Urinary Retention: Cobenfy is contraindicated in patients with urinary retention and certain hepatic and biliary impairments.
Risk of Angioedema: Serious allergic reactions like angioedema necessitate caution and immediate discontinuation if they occur.
Narrow-angle Glaucoma: Risk of acute angle closure attacks requires careful patient selection and monitoring.
The problem with medication to treat schizophrenia…
Schizophrenia is primarily of genetic origin.
So any medication attempting to treat the condition fails to address the “root” underlying cause.
And no, there’s usually not a single “gene” that causes the condition – but combinations of genetic variants massively increase risk.
Many have argued that “environment” contributes to schizophrenia, but these people are mostly misguided fools.
Environment might make a difference in a tiny percentage of cases, but mostly it’s genetic.
There are likely some people misdiagnosed with schizophrenia who somehow “recover” after doing some lifestyle change etc. – but these individuals never had the condition in the first place (some studies show that 1/3 psychiatric patients are misdiagnosed).
Overall, medication is still the best thing we’ve got to treat this condition - but it’s far from optimal.
What needs to be done to cure schizophrenia?
Gene therapy trials. The benefits of accelerating trials will outweigh the cumulative harm/suffering by a longshot.
What would I do? Exact steps:
Whole genome analyses of patients with schizophrenia
Document all symptoms, age of onset, etc. – analyze data with AI to determine which genes account for the majority of schizophrenia symptoms
Consider sorting genotypes based on schizophrenia subtype/symptoms (e.g. positive symptoms, negative symptoms, cognitive symptoms, etc.)
Identify edits likely to provide maximum benefit in majority of patients
Recruit patients with specific genotypes for trial of gene therapy
Ideally make the gene therapy reversible in case problematic
Start testing ASAP: These patients already have horrible quality of life… Many would be willing to engage in gene therapy (as they basically have nothing to lose).
What are some potential gene targets for the treatment of schizophrenia?
a. DISC1 (Disrupted in Schizophrenia 1)
Role: DISC1 is involved in neurodevelopment, neuronal migration, and synaptic function. Mutations or disruptions in DISC1 have been associated with increased risk for schizophrenia and other psychiatric disorders.
Therapeutic Potential: Restoring normal DISC1 function could ameliorate neurodevelopmental abnormalities and synaptic deficits associated with schizophrenia.
b. COMT (Catechol-O-Methyltransferase)
Role: COMT is critical in the metabolism of dopamine, especially in the prefrontal cortex. The Val158Met polymorphism in COMT affects enzyme activity and has been linked to cognitive function and schizophrenia risk.
Therapeutic Potential: Modulating COMT activity could help regulate dopamine levels, potentially improving cognitive symptoms and reducing psychosis.
c. NRG1 (Neuregulin 1)
Role: NRG1 is involved in neural development, synaptic plasticity, and myelination. Variants in NRG1 have been associated with schizophrenia susceptibility.
Therapeutic Potential: Enhancing NRG1 signaling might support synaptic function and neural connectivity, addressing some of the underlying neural deficits in schizophrenia.
d. DTNBP1 (Dystrobrevin Binding Protein 1)
Role: DTNBP1 is implicated in synaptic vesicle trafficking and neurotransmitter release. Altered expression of DTNBP1 has been observed in individuals with schizophrenia.
Therapeutic Potential: Correcting DTNBP1 dysfunction could improve synaptic transmission and neuronal communication.
e. CACNA1C (Calcium Voltage-Gated Channel Subunit Alpha1 C)
Role: CACNA1C encodes a subunit of L-type voltage-dependent calcium channels, which are essential for neuronal excitability and synaptic plasticity. Variants are associated with schizophrenia and bipolar disorder.
Therapeutic Potential: Modulating calcium channel function could enhance neuronal signaling and plasticity, potentially alleviating both positive and negative symptoms.
f. ZNF804A (Zinc Finger Protein 804A)
Role: ZNF804A is involved in neurodevelopment and synaptic formation. Certain polymorphisms in ZNF804A are linked to altered brain connectivity and increased schizophrenia risk.
Therapeutic Potential: Enhancing ZNF804A function may improve neural network connectivity and cognitive function.
g. Other Relevant Genes Identified by GWAS
Examples: TCF4, MHC locus genes, and others identified in recent Genome-Wide Association Studies (GWAS) contribute to schizophrenia risk through various biological pathways.
Therapeutic Potential: Targeting these genes may offer multifaceted benefits by influencing immune function, synaptic plasticity, and other relevant processes.
What are the final takeaways re: Cobenfy (KarXT)?
Basically new mechanism of action to treat schizophrenia without altering dopamine which could offer significant benefits (cognitive function, less weight gain, fewer metabolic & extrapyramidal effects, etc.).
The medication is not a panacea, but probably better for those who can tolerate it due to the side effect profile. We still don’t know about the long-term effects, but at least good to have more options for people with this condition.
It’s expensive but many patients can get the drug through the Cobenfy Cares program… so should be accessible for most who need it.
In order for Cobenfy to perform well for BMY it’ll need to offer significant improvements in efficacy and/or tolerability relative to existing options AND sell – I think it has potential.
I don’t think Bristol Myers Squibb (BMY) significantly increases in valuation, but some think it’s a reasonable investment due to slight undervaluation relative to comparable industry peers – I wouldn’t be in a rush to invest.
Perhaps I’ll write an article about other drugs in development for schizophrenia.