New Data Demonstrates KarXT’s Positive Long-Term Metabolic Profile

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According to new data, KarXT (xanomeline-trospium) shows a positive long-term metabolic profile in adults with schizophrenia, with patients experiencing metabolic stability or improvements over a 52-week course of treatment.¹ If approved by the US Food and Drug Administration (FDA), KarXT would be the first new pharmacological treatment for schizophrenia in decades.

Data from the phase 3 EMERGENT program evaluating the long-term safety, tolerability, and metabolic outcomes of KarXT in adults with schizophrenia were presented via poster^2,3 and oral session^4,5 at the Annual Congress of the Schizophrenia International Research Society (SIRS) on April 3-7, 2024, in Florence, Italy.

“Unlike current schizophrenia treatments that are often associated with a variety of adverse events such as weight gain and hyperlipidemia, KarXT offers a new and unique mechanism of action that does not directly block dopamine receptors. Rather by exerting effect on muscarinic receptors, KarXT offers a differentiated approach to treating schizophrenia. This unique mechanism of action is likely responsible for favorable long-term weight and metabolic profile,” Rishi Kakar, MD, told Psychiatric Times. Kakar is chief scientific officer and medical director of Segal Trials, as well as an investigator in the EMERGENT program.

A majority of patients (65%) experienced reductions in weight over the course of the trial, with a mean weight decrease of 2.6kg observed at 1 year. Data show no significant changes related to prolactin or clinically meaningful changes in movement disorder scale scores over 52 weeks.

“Most of the patients suffering with schizophrenia in the community require long term treatment for their symptoms. Therefore, it becomes important for clinicians to evaluate potential efficacy and safety of a treatment option over long term. The data presented at SIRS is an important milestone as it focused on efficacy and safety of KarXT in clinical trials over 52 weeks. In these long-term studies, KarXT was found to exhibit a favorable weight and metabolic profile with associated mean weight reduction of 2.56Kg at 52 weeks without any meaningful change in cholesterol or hbA1c over this time,” Kakar told Psychiatric Times. “Additionally, the symptom improvement in symptoms of schizophrenia continued throughout 52 weeks. This long-term data offers significant support to potential of KarXT as a unique, first in class medication to treat schizophrenia.”

The phase 3 trials EMERGENT-4 and EMERGENT-5 are outpatient, 52-week, open-label trials that evaluated the safety, tolerability, and efficacy of KarXT in adults with schizophrenia. As of August 18, 2023, the interim pooled data analysis included 718 patients who received at least 1 dose of KarXT and 134 patients who completed 1 year of treatment.

According to the pooled analysis, KarXT had a favorable impact on weight and long-term metabolic profile. Most patients experienced stability or improvements on key metabolic parameters over the 52-week course of treatment, with 65% of patients experiencing an overall reduction in weight over the course of the trial, and 18% of patients experiencing potentially clinically significant (≥7% change) decreases in weight, compared with 4% of patients experiencing increases in weight (≥7% change). An average reduction in weight of 2.6kg was observed in patients who completed 52 weeks of treatment with KarXT, with a larger mean reduction in weight of 4.1kg observed in clinically obese patients (BMI > 30 kg/m2). There were no meaningful changes in total cholesterol, triglyceride, and HbA1c levels over 1 year of treatment.

“These long-term safety results and metabolic outcomes from the EMERGENT program are extremely encouraging, allowing us to further understand the tolerability profile of KarXT in people living with schizophrenia,” said Roland Chen, MD, senior vice president and head, Immunology, Cardiovascular and Neuroscience development, Bristol Myers Squibb. “It is promising to see that over one year of treatment, KarXT was not associated with burdensome side effects, specifically weight gain and metabolic dysfunction, as well as extrapyramidal symptoms, which underscores its potential to provide a meaningful and differentiated option for people living with schizophrenia.”¹

Furthermore, KarXT was generally well-tolerated across 52 weeks of treatment with an adverse effect profile consistent with prior trials. The trial discontinuation rate was 53% and primary reasons for discontinuation included withdrawn consent (19%), treatment-related adverse events (15%), participant lost to follow-up (8%), and participant failed to adhere to protocol requirements (7%).

Across all the long-term EMERGENT trials, 62% of participants reported at least 1 treatment-related adverse event, with the most common treatment-related adverse events (≥5%) being nausea, vomiting, constipation, dry mouth, dyspepsia, dizziness, hypertension, and diarrhea. Almost all were mild or moderate in severity and transient in nature.

In additional interim long-term data presented at the congress, KarXT was associated with significant improvements in symptoms of schizophrenia across all efficacy measures at 52 weeks in the EMERGENT-4 trial. Improvements in symptoms of schizophrenia continued throughout the open-label extension regardless of whether participants were previously treated with KarXT or placebo during the acute trials, EMERGENT-2 or EMERGENT-3 (Poster F264).

“Patients’ lives are profoundly impacted by recurring symptoms of schizophrenia. For many patients, current treatment create an ongoing battle between controlling their symptoms and managing the side effects. Current medications, though effective in some, often cause long term side effect burden including weight gain, drowsiness and metabolic effects causing many patients to stop their treatments. KarXT, a unique, first in class medication with its novel mechanism of action combined with favorable long term weight and metabolic profile has a potential to offer a meaningful benefit to our patients without the problematic long term side effects of existing treatments.”

BMS anticipates an FDA decision on the possible approval of KarXT by September 26, 2024.

References

1. Bristol Myers Squibb presents new interim long-term efficacy data from the EMERGENT-4 trial evaluating KarXT in schizophrenia at the 2024 Annual Congress of the Schizophrenia International Research Society. News release. April 6, 2024. Accessed April 7, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-New-Interim-Long-Term-Efficacy-Data-from-the-EMERGENT-4-Trial-Evaluating-KarXT-in-Schizophrenia-at-the-2024-Annual-Congress-of-the-Schizophrenia-International-Research-Society/default.aspx

2. Kaul I, Cohen EA, Miller AC, et al. Maintenance of efficacy of KarXT (xanomeline and trospium) in schizophrenia. Poster presented at: Annual Congress of the Schizophrenia International Research Society; April 3-7, 2024; Florence, Italy.

3. Marcus R, Kakar R, Miller AC, et al. Long-term safety of KarXT (xanomeline and trospium) in schizophrenia. Poster presented at: Annual Congress of the Schizophrenia International Research Society; April 3-7, 2024; Florence, Italy.

4. Horan W, Sauder C, Harvey PD, et al. The impact of KarXT on cognitive impairment in acute schizophrenia: replication in pooled data from phase 3 trials. Paper presented at: Annual Congress of the Schizophrenia International Research Society; April 3-7, 2024; Florence, Italy.

5. Claxton A, Konis G, Kaul I, et al. Long-term metabolic outcomes associated with KarXT (xanomeline and trospium): interim results from pooled, long-term safety studies EMERGENT-4 and EMERGENT-5. Paper presented at: Annual Congress of the Schizophrenia International Research Society; April 3-7, 2024; Florence, Italy.