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Emraclidine for Treatment of Schizophrenia

A phase 1b trial supports further investigation of a novel, brain-penetrant, highly selective M4 receptor-positive allosteric modulator, emraclidine, as a once-daily treatment for schizophrenia without titration and with a potentially favorable adverse-effect profile.

In the U.S., a 2-part, randomized, phase 1b trial recruited eligible participants who were 18–50 years old (part A) or 18–55 years old (part B) with a primary diagnosis of schizophrenia. Part A evaluated the safety and tolerability of ascending oral doses of emraclidine 5–40 mg or placebo in 5 cohorts of participants with stable schizophrenia at a single site. In part B, participants at 5 U.S. sites were randomized to emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A).

Based on a primary endpoint of safety and tolerability, the investigators found: “Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n = 27), emraclidine 20 mg twice daily (n = 27), or placebo (n = 27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6.”

Source: Lancet