The FDA's approval of KarXT (Cobenfy) on September 26, 2024, signals a paradigm shift in schizophrenia treatment, introducing the first new mechanism of action in nearly seven decades. Developed by Karuna Therapeutics, KarXT combines xanomeline and trospium to target muscarinic cholinergic receptors, offering a novel, nondopaminergic approach to managing schizophrenia symptoms. This approval follows fifteen years of research, driven by the vision of developing a medication with a fundamentally different pharmacology than existing antipsychotics.
The Science Behind KarXT
KarXT's development stems from the observation that xanomeline, a muscarinic receptor agonist, showed promise in treating cognitive and psychotic symptoms in Alzheimer's patients. However, its use was limited by peripheral nervous system side effects. The innovative approach involved combining xanomeline with trospium, an anticholinergic agent that does not cross the blood-brain barrier, to mitigate these peripheral side effects while preserving the central nervous system benefits. Xanomeline has a strong affinity to all 5 mAChRs but significantly agonizes only 2: the M1 and the M4. Its action at these 2 mAChRs in the brain is hypothesized to decrease presynaptic dopamine release in the circuits relevant to schizophrenia while not affecting the circuits involved in motor function or hormones. Trospium, which poorly crosses the blood-brain barrier, has minimal effects on the central nervous system but mitigates the procholinergic adverse effects of xanomeline in the peripheral nervous system through its anticholinergic activity.
Clinical Trial Efficacy
The efficacy of KarXT was demonstrated in several clinical trials. The phase 2 EMERGENT-1 trial showed a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score, with a least square mean (LSM) improvement of 11.6 points greater than placebo (effect size of 0.81) in patients experiencing a significant relapse of schizophrenia symptoms. This was further supported by two identically designed phase 3 trials, EMERGENT-2 and EMERGENT-3, which showed similar improvements in PANSS scores compared to placebo (LSM improvements of 9.6 and 8.4 points, with effect sizes of 0.61 and 0.60, respectively). Long-term safety, tolerability, and efficacy were assessed in the EMERGENT-4 and EMERGENT-5 open-label phase 3 studies, reinforcing the findings of the earlier trials.
A Non-Antipsychotic Approach
Notably, Cobenfy's FDA product insert does not classify it as an antipsychotic, distinguishing it from other schizophrenia medications that primarily target the dopamine-2 receptor (D2R). While D2R antagonists can effectively manage positive symptoms like hallucinations and delusions, they often exacerbate cognitive and negative symptoms and are associated with various adverse effects, including muscle dystonia, akathisia, weight gain, and tardive dyskinesia. Cobenfy has not demonstrated these adverse events.
Adverse Events and Contraindications
Common adverse events associated with Cobenfy result from its procholinergic and anticholinergic activity, reflecting the balance between xanomeline and trospium. Cobenfy is contraindicated in patients with moderate to severe hepatic impairment and those with urinary retention. Caution is advised in patients with moderate to severe renal impairment and when co-administering with other anticholinergic medications. It is crucial to instruct the patient to take Cobenfy on an empty stomach, either 1 hour before or 2 hours after a meal.
Future Directions
Cobenfy represents the first of a new class of medications targeting the muscarinic cholinergic system for schizophrenia treatment. Several other drug candidates with similar mechanisms, such as emraclidine and NBI-1117568, are currently in phase 2 clinical trials. These developments promise to further diversify the treatment landscape for schizophrenia and deepen our understanding of the role of muscarinic receptor subtypes in managing this complex disorder.
