Peer-Reviewed EMERGENT-2 Trial Data Supports Xanomeline-Trospium for Schizophrenia

Karuna Therapeutics announced on December 14, 2023, that The Lancet published the peer-reviewed data from the phase 3 EMERGENT-2 trial. The findings demonstrated how xanomeline-trospium (KarXT) significantly reduces positive and negative symptoms of adults with schizophrenia.¹

Just last month, Karuna Therapeutics announced the US Food and Drug Administration (FDA) had accepted the New Drug Application for xanomeline-trospium, an oral muscarinic receptor agonist.² The FDA will decide to approve the drug or not by September 26, 2024. The New Drug Application included 5 trials—3 trials comparing xanomeline-trospium with a placebo to test efficacy and safety and 2 trials to evaluate the drug’s long-term safety.³

“The data is really encouraging,” Rishi Kakar, MD, lead investigator of the EMERGENT trials, said in an interview with HCPLive. “It’s very encouraging to see that across three different studies, KarXT did show that difference across the timeframe where the study was conducted.”

Inder Kaul, MD, senior vice president of clinical development at Karuna, served as the lead author of The Lancet paper. Kaul and colleagues wrote how the phase 3 EMERGENT-2 trial aimed at evaluating xanomeline-trospium versus placebo, with the primary endpoint being change from baseline to week 5 in the Positive and Negative Syndrome Scale score. The positive symptoms of schizophrenia include delusions and hallucinations, and the negative symptoms include constricted affect and asociality.

“On the primary endpoint, KarXT treatment showed a significant 9.6-point difference in mean change from baseline to week 5 in [Positive and Negative Syndrome Scale] total score compared with placebo (p<0.0001) with an effect size of 0.61,” the investigators wrote. “Combining this result with the effect size observed in the EMERGENT-1 trial (0.75) suggests the potential for KarXT to be an efficacious treatment with a unique pharmacology for people with schizophrenia.”

For this randomized, double-blind, placebo-controlled, flexible-dose, 5-week trial, participants were selected from December 16, 2020 – April 13, 2022.

Participants were included in the study if they had a Positive and Negative Syndrome Scale score of ≥80, and a Clinical Global Impression-Severity score of ≥4. They had to be aged 18 – 65 years old, had a schizophrenia diagnosis, and had a worsening of psychosis needing hospital admission. The team recruited 252 participants from 22 inpatient sites and were randomized to receive xanomeline-trospium (n = 126) or placebo (n = 126) twice a day.

Participants taking xanomeline-trospium began with 50 mg of xanomeline and 20 mg of trospium twice a day for the first 2 days. After that, they took 100 mg of xanomeline and 20 mg trospium twice a day for days 3 – 7. On day 8, the xanomeline-trospium dose had an optional increase to 125 mg of xanomeline and 30 mg of trospium twice a day. If they couldn’t handle the increase, participants were free to return to 100 mg of xanomeline and 20 mg of trospium.

Baseline Positive and Negative Syndrome Scale total scores were 98.3 for participants in the xanomeline-trospium group and 97.9 for participants in the placebo group. For there to be clinically meaningful change, the score needs ≥20% reduction.

The trial achieved its primary endpoint with a mean change from baseline to week 5 in the Positive and Negative Syndrome Scale total scores of -21.2 points, SE 1.7 for xanomeline-trospium and -11.6 points, SE 1.7) (-9.6; 95% CI, - 13.9 to -5.2; P <.0001; Cohen’s d effect size = 0.61). The baseline change shows xanomeline-trospium helped symptoms of schizophrenia more than placebo.

The xanomeline-trospium group had a statistically significant 9.6-point greater reduction (95% CI, - 13.9 to - 5.2) at week 5 than the placebo group. In the positive subscale score, the xanomeline-trospium group had a 2.9-point reduction (95% CI, - 4.3 to – 1.5). Meanwhile, in the negative subscale score, the xanomeline-trospium group had a 1.8-point reduction (95% CI, -3.1 to – 0.5). Then, in the negative factor score, the xanomeline-trospium group had a 2.2-point reduction (95% CI, - 3.6 to -0.8).

Overall, 55% (n = 51) of participants in the xanomeline-trospium group had a ≥ 30% improvement from baseline to week 5 compared to 28% of the placebo group (n = 28).

Moreover, xanomeline-trospium demonstrated a roughly 50% lower incidence of adverse events than just xanomeline alone, with most events being gastrointestinal. Rates of serious or severe adverse events were low. For 4 serious adverse events, they were determined to be non-drug related. Discontinuation due to adverse events were similar between the xanomeline-trospium group (7%) versus the placebo group (6%).

“KarXT was not associated with common problematic adverse events of currently available antipsychotic medications, such as extrapyramidal motor symptoms or akathisia, weight gain, metabolic changes, prolactin elevation, or somnolence,” the investigators wrote.

The investigators also noticed similar extrapyramidal motor symptoms or akathisia and mean blood pressures. The team also observed participants on xanomeline-trospium were associated with an increased supine heart rate compared to placebo.

“Consistent with the EMERGENT-1 trial, EMERGENT-2 demonstrated statistically significant improvement in negative symptoms with KarXT compared with placebo based on changes from baseline to week 5,” the investigators wrote. “Together, these results support further testing of KarXT as a treatment for primary negative symptoms in an appropriately designed study in people with persistent negative symptoms, as the Marder negative factor might be less susceptible to influence by improvement in positive symptoms than the [Positive and Negative Syndrome Scale] negative subscale.”

References

1. ^{Kaul, I. Sawchak, S, Correll, C. Efficacy And Safety Of The Muscarinic Receptor Agonist KarXT (Xanomeline–Trospium) In Schizophrenia (EMERGENT-2) In The USA: Results From A Randomised, Double-Blind, Placebo-controlled, Flexible-Dose Phase 3 Trial. Lancet. 2023. https://doi.org/10.1016/S0140-6736(23)02190-6}
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 December 15, 2023.}
3. ^{Derman, C. Rishi Kakar, MD: EMERGENT Trials, FDA Accepts Xanomeline-Trospium Application. HCPLive. December 1, 2023. https://www.hcplive.com/view/rishi-kakar-md-emergent-trials-fda-accepts-xanomeline-trospium-application. Accessed December 15, 2023.}