KarXT is an investigational medication developed for the treatment of schizophrenia in adults. Its developer, Karuna Therapeutics, submitted it to the U.S. Food and Drug Administration (FDA) for approval. Bristol Myers Squibb (BMS) later acquired Karuna Therapeutics in March 2024.
The Science Behind KarXT
KarXT, now marketed as Cobenfy, represents a unique pharmacological approach by targeting muscarinic acetylcholine receptors in the brain, unlike most current antipsychotics that primarily work on dopamine pathways. This mechanism is the first new pharmacological approach for schizophrenia in over 50 years. The drug is a combination of two components: xanomeline and trospium. Xanomeline acts as an agonist, activating M1 and M4 muscarinic receptors within the central nervous system. It crosses the blood-brain barrier to stimulate these receptors, which is thought to improve both positive and negative symptoms. The second component, trospium, reduces xanomeline’s peripheral side effects. Trospium does not cross the blood-brain barrier, acting peripherally to mitigate common cholinergic adverse events.
Clinical Trial Performance
The efficacy and safety data for KarXT submitted to the FDA came primarily from the EMERGENT Phase 3 program, which included acute 5-week trials (EMERGENT-1, -2, and -3) and long-term 52-week open-label extension trials (EMERGENT-4 and -5). The primary goal of these acute trials was to measure the drug’s effectiveness using the Positive and Negative Syndrome Scale (PANSS), a standard tool for assessing schizophrenia symptoms. KarXT demonstrated significant reductions in PANSS total scores compared to a placebo. For instance, the EMERGENT-2 trial showed a 9.6-point reduction in PANSS total score with KarXT compared to placebo at week 5.
The long-term EMERGENT-4 study further supported these findings, with continued symptom improvement over 52 weeks. More than 75% of participants achieved a greater than 30% improvement in symptoms from baseline, as measured by the PANSS total score, after one year of treatment.
KarXT was well tolerated across the EMERGENT trials. Common side effects were typically mild to moderate and included cholinergic effects such as constipation, nausea, vomiting, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea.
A notable aspect of KarXT’s safety profile is the absence of certain side effects that are often associated with existing antipsychotics. The trials showed no significant changes related to weight gain, prolactin elevation, or clinically meaningful changes in movement disorder scale scores, such as extrapyramidal symptoms. In fact, 65% of patients in the long-term trials experienced weight reductions, with an average decrease of 2.6 kg over one year, and obese patients showing a mean reduction of 4.1 kg.
FDA Review and Decision Status
The FDA accepted this application in November 2023 and assigned a Prescription Drug User Fee Act (PDUFA) target action date of September 26, 2024. On this target date, the FDA approved KarXT, now known as Cobenfy, for the treatment of schizophrenia in adults. A Complete Response Letter (CRL) is an official communication from the FDA indicating that the agency cannot approve an application in its current form and requires additional information or data before approval can be granted. While a CRL can delay a drug’s availability, it is not an outright rejection. In the case of KarXT for schizophrenia, the FDA did not issue a CRL; instead, it granted approval, allowing the medication to move forward as a new treatment option.
Implications of a New Schizophrenia Treatment
The approval of KarXT, marketed as Cobenfy, introduces a new mechanism of action for schizophrenia treatment. For decades, most antipsychotic medications have primarily targeted dopamine receptors. KarXT’s unique approach, by activating muscarinic acetylcholine receptors, offers a novel pathway for managing symptoms. This development is particularly impactful for individuals with schizophrenia who may not respond adequately to existing therapies or who experience debilitating side effects from current medications, such as significant weight gain or movement disorders. The availability of a treatment with a different mechanism and a favorable metabolic and movement-related side effect profile could improve adherence and overall outcomes for patients. This approval provides a new option in the evolving landscape of psychiatric care.