Introduction

For the first time in seven decades, a novel medication has emerged for schizophrenia treatment. The FDA has approved Karuna/Bristol Myers Squibb's KarXT (Cobenfy™) for the treatment of schizophrenia in adults. Cobenfy™ is an oral dual M1/M4 muscarinic acetylcholine receptor (mAChR) agonist, administered twice daily.

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Cobenfy™ is gaining attention for its unique approach and promising safety profile. But what makes this drug so special, and why are experts calling it a game-changer? This guide will give you everything you need to know.

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TL;DR:
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- Cobenfy​​™ (KarXT) introduces a new mechanism of action for schizophrenia treatment after 70 years

- It's a dual M1/M4 muscarinic acetylcholine receptor agonist, not directly blocking dopamine receptors

- The drug shows efficacy in reducing both positive and negative symptoms of schizophrenia

- Cobenfy™ has a favorable safety profile with no black box warning and no observed movement disorders

- Phase 3 trial showed no significant effects on weight, lipids, glucose, insulin levels, or alertness

- Potential benefits for cognitive symptoms are being investigated

- Common side effects are all related to the anticholinergic properties of the drug

- The drug is taken twice daily and priced at $22,500 per year. For reference, Caplyta, another branded antipsychotic costs about $25,000 per year.

- BMS acquired KarXT from Karuna Therapeutics for $14 billion. Karuna had acquired the asset from Lilly. 

The Science Behind Cobenfy™

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A Novel Mechanism of Action

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Unlike traditional antipsychotics that directly block dopamine receptors, Cobenfy™ employs a unique mechanism of action involving muscarinic receptors. This novel approach indirectly modulates dopamine levels, offering a new way to manage schizophrenia symptoms.

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The idea that a drug like Cobenfy™ could have cognitive dates back to the use of betel nut. Betel nut contains the cholinergic agonist arecoline and has been used by many cultures to enhance cognition. Clinical trial’s of xanomeline for alzheimer’s dementia produced a significant treatment effect on cognition but the cholinergic side-effects were too severe. 

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Key Features of Cobenfy's™ Mechanism of Action:

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- No direct blocking of dopamine receptors

- Indirect reduction of dopamine in striatal areas to reduce psychotic symptoms

- M4 receptors are not located on cholinergic neurons in the nigrostriatal motor pathway, explaining the absence of motor side effects

- Unlike all other antipsychotics in use, Cobenfy™ does not carry a black box warning, reflecting its favorable safety profile

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Cobenfy's™ mechanism of action involves several complex processes:

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1. Dual M1/M4 Muscarinic Agonism (Xanomeline):
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   - M4 Agonism Effects:

     - Decreases acetylcholine release in the ventral tegmental area (VTA)

     - Reduces dopamine release in areas related to psychosis

     - Spares motor systems controlled by M2 autoreceptors
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   - M1 Agonism Effects:

     - Inhibits GABA-ergic interneurons in the prefrontal cortex (PFC)

     - Decreases glutamate release and subsequent VTA firing

     - May potentially improve cognitive symptoms

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2. Peripheral Muscarinic Antagonism (Trospium):

   - Blocks peripheral M1 receptors to mitigate adverse effects, particularly in the gastrointestinal tract

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Clinical Evidence and Approval and EMERGENT Trials

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Cobenfy's™ approval is based on two key phase III trials:

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1. EMERGENT-2 (N=252):

   - Randomized, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient trial

   - Showed reduction in both positive and negative symptoms

   - Mean change from baseline to week 5 in PANSS total score: -21.2 points (Cobenfy™) vs -11.6 points (placebo)

   - p<0.0001, Cohen's d effect size=0.61

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2. EMERGENT-3 (N=256):

   - Met primary endpoint for reduction in total PANSS score

   - Did not meet secondary endpoint for reduction of negative symptoms

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It's important to note that while EMERGENT-2 showed a reduction in negative symptoms, EMERGENT-3 did not meet this secondary endpoint. This highlights the need for additional data on Cobenfy's™ effect on negative symptoms.

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Additional ongoing trials:

- EMERGENT-4: 52-week, outpatient, open-label extension trial evaluating long-term safety and tolerability in phase III trial participants

- EMERGENT-5: 52-week, outpatient, open-label trial evaluating safety and tolerability in outpatients on other first-line antipsychotics.  

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FDA Approval and Indications for Cobenfy™

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- Approved for twice-daily oral administration in adult schizophrenia patients

- Available in multiple dosage strengths: 50-mg/20-mg, 100-mg/20-mg, and 125-mg/30-mg capsules

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Benefits and Side Effects of Cobenfy™

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Potential Benefits:

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1. Efficacy in treating positive symptoms

2. Possible improvement in negative symptoms (more data needed due to mixed results in trials)

3. Potential cognitive benefits due to increased dopamine signaling in the prefrontal cortex. M1 agonism leads to an increase of dopaminergic signaling specifically in the prefrontal cortex, which may improve cognitive function. However, this potential benefit is still under investigation.

4. No observed extrapyramidal symptoms or movement disorders

5. No black box warning, indicating a favorable safety profile

6. No concerns about weight gain or metabolic syndrome

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Side Effects:
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Most common side effects are gastrointestinal, including:

- Nausea

- Indigestion

- Constipation

- Vomiting

- Abdominal pain

- Diarrhea

- Gastroesophageal reflux disease

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Other side effects:

- Tachycardia

- Dizziness

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Anticholinergic Side Effects:

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Clinicians should be aware of potential anticholinergic side effects, remembered by the mnemonic:
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- Red as a beet: Flushing

- Dry as a bone: Dry skin and mucus membranes

- Blind as a bat: Mydriasis (dilated pupils)

- Mad as a hatter: Delirium

- Hot as a hare: Fever

- Full as a flask: Urinary retention

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These side effects could be significant if Cobenfy™ is combined with other anticholinergic drugs like diphenhydramine, hydroxyzine or antipsychotics with strong anticholinergic properties such as olanzapine

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Practical Considerations for Cobenfy™

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Dosing and Adherence for Cobenfy™

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- Twice-daily dosing may present adherence challenges

- In general for medications, studies suggest there is a 10% decrease in adherence when going from once to twice per day of a drug (79% -> 69%)

- In schizophrenia patients, studies suggest a higher 12% drop in adherence from once daily as well as a lower level of adherence overall (66% -> 54%)

- Potential for future development of long-acting formulations, including injectables

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Cost and Access of Cobenfy™

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- List price: $22,500 per year but manufacturer rebates will drive the actual price down

- Expected 80% coverage under Medicare and Medicaid

- All state Medicaid plans will cover the drug, but coverage build-up may take up to six months

-Commercial plans are likely to impose a prior authorization process

-While FDA approved, the drug is expected to become commercially available in late October/early November 2024. 

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Patient Selection

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Potential candidates:

- Adult patients with schizophrenia who haven't benefited from or tolerated dopamine-blocking antipsychotics

- Patients without moderate-severe liver disease or pre-existing urinary retention

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Combination Therapy

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- Studies underway for co-administration with other antipsychotics 

- Caution advised when combining with anticholinergic medications

- Consider antipsychotics with low anticholinergic activity (e.g., risperidone) for combination therapy

- Potential for lower doses of atypical antipsychotics when combined with Cobenfy™

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The Future of Schizophrenia Treatment

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Emerging Competition

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Other muscarinic receptor-targeting drugs are in development. Emraclidine, an M4 positive allosteric modulator acquired by AbbVie from Cerevel Therapeutics, is currently the most advanced competitor. This once-daily drug is completing two Phase 2 studies designed to support a regulatory submission. The development of once-daily formulations could address some of the adherence concerns associated with Cobenfy's™ twice-daily dosing.

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Potential Expansions

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- Possible future indications for bipolar disorder and other mood disorders

- Ongoing research into cognitive benefits

- Clinicians may choose to explore off-label use in adolescents and for other disorders 

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Cost-Effectiveness Considerations

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The Institute for Clinical and Economic Review (ICER) has conducted an assessment of Cobenfy.™ Their preliminary findings suggest that the value of Cobenfy™ may not outweigh that of generic aripiprazole (Abilify). This assessment may impact insurance coverage and prescribing patterns, particularly given Cobenfy's™ annual cost of $22,500.

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Conclusion

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Cobenfy™ introduces a new approach to schizophrenia treatment, offering a different mechanism of action with promising efficacy and safety data. While questions remain about long-term effects, optimal use in clinical practice, and cost-effectiveness, its approval marks a significant development in addressing the complex challenges of schizophrenia. 

As research continues and real-world data accumulates, Cobenfy's™ role in the treatment of schizophrenia will become clearer. It's important to note that the primary trials were only 5 weeks long, which is relatively short for assessing long-term efficacy and safety. Future studies and clinical experience will provide more insights into Cobenfy's™ place in the treatment landscape of schizophrenia.