KarXT: Illuminating Pathways in Schizophrenia Treatment

• KarXT, likely to receive the nod from the US FDA by late 2024, will significantly impact the market with the potential to reduce the positive, negative, and cognitive symptoms of schizophrenia.
• The long-term data is encouraging, signaling that KarXT is not associated with “burdensome side effects” the major impediments of the current regime.

Schizophrenia, a relapsing life-long illness, like most neuropsychiatric disorders, presents a debilitating human, medical, and socioeconomic burden due to persistent misconceptions and stigma that hinder access to care, timely diagnosis, and consistent treatment. It impairs the perception of reality with variable presentations ranging from hallucinations, delusions, and disorganized thinking to individuals experiencing impaired cognitive abilities and negative symptoms like social withdrawal and anhedonia, among others.

The current treatment regime advocates the use of medication, psychological counseling, social support,  and cognitive behavioral therapies in combination and primarily focuses on managing symptoms and preventing relapses. Antipsychotics, both first- and second-generation, are the gold standard for “positive symptoms” and are recommended as first-line therapies for schizophrenia. Disease heterogeneity, coupled with its multifaceted etiologies, presents significant challenges to the present treatment regime. Most approved treatments, with varied routes of administration, have D2 dopamine receptor-blocking activity, and the efficacy and tolerability limitations of these are well known. Choices are limited for negative symptoms and associated cognitive impairment, with no widely accepted standard treatment. High relapse rates, poor compliance, and high treatment discontinuations, only exacerbate the difficulties.

A high unmet medical need exists for novel, more efficacious, safe, better-tolerated treatments for schizophrenia and its various symptoms. Drug development programs specifically targeting cognitive impairment associated with schizophrenia have suffered from inconsistent findings, and to date, no drug candidates have proven efficacious. Various therapies are being developed by companies like Boehringer Ingelheim, Sumitomo Pharma, Reviva Pharmaceuticals, Minerva Neurosciences/Mitsubishi Tanabe Pharma, Karuna Therapeutics/Bristol Myers Squibb to address the shortcomings of the current regime. 

Bristol Myers Squibb is developing a novel, first-in-class KarXT, a xanomeline–trospium combination, for the treatment of schizophrenia in adults and to improve positive, negative, and cognitive symptoms. It is an oral modulator of muscarinic receptors that acts as a dual M1/M4 muscarinic acetylcholine receptor agonist, designed to preserve the beneficial central nervous system effects of xanomeline while reducing adverse events due to peripheral muscarinic receptor activation, with trospium. Muscarinic receptors are only found in the brain but exist in other places in the body, raising the potential for side effects. Still, Karuna’s approach confines the drug’s impact on the brain, as it does not cross the blood–brain barrier.  

In December 2023, BMS acquired Karuna Therapeutics and its star asset, KarXT, for USD 14 billion. The drug is being reviewed by the US FDA, with a PDUFA date of September 2024, and if approved, the drug will provide BMS a first-mover advantage in this new regime of novel drugs for schizophrenia, that address the unmet of the current regime. 

In the recently concluded Annual Congress of the Schizophrenia International Research Society (2024), in Florence, Italy, Bristol Myers Squibb presented new interim long-term efficacy data from the EMERGENT-4 trial evaluating KarXT in schizophrenia. It also presented results from EMERGENT-5. The EMERGENT-4 and EMERGENT-5 trials are Phase III, outpatient, 52-week, open-label trials evaluating the safety, tolerability, and efficacy of KarXT in adults with schizophrenia. The interim pooled data analysis included 718 patients who received at least one dose of KarXT, with 134 patients having completed one year of treatment. EMERGENT-4 enrolled adults with schizophrenia who previously completed the treatment period of one of Phase III, 5-week, efficacy, and safety studies; EMERGENT -2 or EMERGENT-3. 

Individuals who were part of this interim efficacy analysis, regardless of previous treatment, were started on KarXT dosing (xanomeline/trospium) at 50 mg/20 mg twice daily and increased to a maximum of 125 mg/30 mg. Efficacy analyses were conducted in the modified intent-to-treat population. 

In the interim analysis, KarXT was associated with significant improvement in symptoms of schizophrenia across all efficacy measures like Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and Clinical Global Impression-Severity (CGI-S) scores, at 52 weeks.

• More than 75% of participants achieved >30% improvement in symptoms, with an average reduction of 33.3 points from baseline (98.4), as measured by the PANSS total score.
• There was a mean change of 1.7-point in the CGI-S score from baseline (5.2), representing an average shift from ‘markedly ill’ at baseline to ‘moderately’ or ‘mildly’ ill at one year.
• Participants who had received KarXT in the previous study had a lower mean PANSS total score at baseline compared to those who had received a placebo (placebo 86.5 vs. KarXT 76.1), reflecting greater improvement during 5 weeks of active treatment. 
• The most common treatment-related adverse events in participants receiving KarXT were nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea, occurring in ≥5%. The majority were mild or moderate in severity with low rates of severe AEs and were consistent with prior trials of KarXT in schizophrenia.
• The overall discontinuation rate in the trial was 53%, and the primary reasons for discontinuation included withdrawn consent, treatment-related adverse events, failure in follow-up, and failure to adhere to protocol requirements. 
• KarXT also demonstrated a long-term favorable metabolic profile, as participants experienced improvements or stability in all metabolic parameters over 52 weeks of treatment, including weight, cholesterol, and HbA1. The data showed overall weight reduction in 65% of patients.

After initiating treatment with KarXT, participants who received a placebo in the previous studies also exhibited rapid improvement in symptoms as early as the first assessment point in EMERGENT-4 (Week 2). After 4 weeks of KarXT treatment in EMERGENT-4, there were no meaningful differences in PANSS total score between participants who had previously received KarXT versus those who had received a placebo. For all participants, improvements from baseline continued through 52 weeks of treatment for PANSS total score, PANSS positive subscale, PANSS negative subscale, PANSS Marder negative factor, and CGI-S scores. These interim data from EMERGENT-4 continue to validate the potential of KarXT, and the consistency of efficacy results across all EMERGENT clinical trial programs is encouraging and suggests KarXT could provide a differentiated treatment approach for people living with schizophrenia.

With its unique mechanism of action and promising clinical results, KarXT offers new hope for individuals grappling with the complexities of schizophrenia. As we continue to unlock the mysteries of the human brain, KarXT shines brightly as a beacon of progress in the quest for improved treatments and better outcomes in mental health care. It might provide a new awakening to schizophrenia patients in September when the US FDA decides on the drug.

Though KarXT has a niche, there are some close competitors in the pipeline also, like AbbVie’s (Cerevel Therapeutics) Emraclidine and Neurocrine’s NBI-1117568, which are both in Phase II, behind KarXT in the race for US FDA approval. Emraclidine, which also targets the muscarinic receptor, is promising as it is differentiated from KarXT by its dosing frequency (once daily versus twice daily), its lack of titration needs, and, potentially, its stronger gastrointestinal side-effect profile.