KarXT Effective in Improving Schizophrenia Symptoms at 52 Weeks

Bristol Myers Squibb announced on Friday, April 6, 2024, that KarXT (xanomeline-trospium) demonstrated meaningful reductions in the symptoms of schizophrenia at 52 weeks.¹

The results came from the phase 3 EMERGENT-4 open-label extension trial evaluating the long-term efficacy, safety, and tolerability of xanomeline-trospium in adults with schizophrenia. Investigators presented the positive long-term efficacy data in the poster, “Maintenance of Efficacy of KarXT (Xanomeline and Trospium) in Schizophrenia” (Poster F264), at the Annual Congress of the Schizophrenia International Research Society (SIRS) taking place April 3 – 7, 2024, in Florence, Italy.

“The consistency of efficacy results across all EMERGENT clinical trial programs is encouraging and suggest KarXT could provide a differentiated treatment approach for people living with schizophrenia,” said investigator Elan Cohen, PhD, from the CenExel Hassman Research Institute.

EMERGENT-4 is a phase 3, 52-week, outpatient, open-label extension study assessing the long-term efficacy, safety, and tolerability of xanomeline-trospium in adults. Xanomeline-trospium is an investigational muscarinic antipsychotic in the development for the treatment of schizophrenia and acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system. Karuna Therapeutics announced on November 29, 2023, the US Food and Drug Administration (FDA) accepted the New Drug Application (NDA) for xanomeline-trospium for the treatment of adults with schizophrenia.^2,3

“This particular compound of KarXT is unique and is potentially really differentiated from the others,” investigator Rishi Kakar, MD, from Segal Trials, told HCPLive.⁴

People with schizophrenia may struggle to maintain jobs, live independently, and manage relationships.1 Although current treatments can be effective in improving select symptoms, approximately 30% of people do not respond to therapy, and about 50% only experience partial improvement in schizophrenia symptoms or face unpleasant adverse events. Unlike current schizophrenia treatments, xanomeline-trospium does not directly block dopamine receptors, offering a new approach to treating the psychiatric disorder.

Participants in EMERGENT-4 previously partook in either EMERGENT-2 or EMERGENT-3, 2 phase 3, 5-week, double-blind, and placebo-controlled trials. At the data cutoff date of April 17, 2023, 110 participants were a part of EMERGENT-4, with 29 patients completing 52 weeks of treatment.

At the end of EMERGENT-4, ≥ 75% of participants achieved ≥ 30% improvement in symptoms, with an average reduction of 33.3 points from baseline (98.4) in the Positive and Negative Syndrome Scale (PANSS) total score. Participants had a mean 1.7-point change in Clinical Global Impression-Severity (CGI-S) score from baseline (5.2), demonstrating an average shift from “markedly ill” at baseline to “moderately” or “mildly” ill at 1 year.

Regardless of whether participants were previously randomized with xanomeline-trospium or placebo during EMERGENT-2 and EMERGENT-3, in EMERGENT-4 they continued to have improvements in schizophrenia symptoms throughout the 52 weeks. Participants on placebo in the acute trials had a significantly greater mean PANSS total score compared to participants who had taken xanomeline-trospium (placebo 86.5 vs KarXT 76.1).

Additionally, participants dosed with xanomeline-trospium who were previously on placebo had significant improvements in symptoms within 2 weeks of xanomeline-trospium treatment. After 4 weeks, the team saw PANSS total scores were comparable for participants who received xanomeline-trospium or placebo in the acute trials.

Furthermore, xanomeline-trospium positively impacted weight and long-term metabolic profile as many patients experienced stability or improvements in metabolic parameters throughout the 52 weeks of the treatment. Xanomeline-trospium was considered well-tolerated, with a similar adverse event profile consistent with prior trials of xanomeline-trospium in schizophrenia. Moreover, over 52 weeks xanomeline-trospium was not linked to significant changes concerning prolactin or clinically meaningful changes in movement disorder scale scores.

“We are pleased to see a continued and consistent meaningful reduction in symptoms of schizophrenia across 52 weeks in an outpatient setting, beyond what was seen in the short-term, in-patient five-week trials (EMERGENT-2 and EMERGENT-3),” said Roland Chen, MD, senior vice president and head, Immunology, Cardiovascular and Neuroscience development, Bristol Myers Squibb, in a press release. “We look forward to continued conversations with the FDA and to sharing additional data from the EMERGENT program later this year.”

^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. Bristol Myers Squibb. April 6, 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. Accessed April 8, 2024.}
2. ^{Derman, C. FDA Accepts Xanomeline-Trospium Drug Application for Schizophrenia Treatment. HCPLive. November 29, 2023. https://www.hcplive.com/view/fda-xanomeline-trospium-drug-application-schizophrenia-treatment. Accessed April 8, 2024.}
3. ^{Derman, C. Andrew Miller, PhD: Inventor of KarXT Discusses Pivotal EMERGENT-2 Data. HCPLive. December 22, 2023. https://www.hcplive.com/view/andrew-miller-phd-inventor-of-karxt-discusses-pivotal-emergent-2-data. Accessed April 8, 2024.}
4. ^{Rishi Kakar, MD: EMERGENT Trials, FDA Accepts Xanomeline-Trospium Application. HCPLive. December 1, 2024. https://www.hcplive.com/view/rishi-kakar-md-emergent-trials-fda-accepts-xanomeline-trospium-application. Accessed April 8, 2024.}