A PHASE 2 clinical trial suggests that TAK-071, a positive allosteric modulator of acetylcholine M1 receptors, improves cognitive performance in individuals with Parkinson disease (PD) and cognitive impairment, though it does not reduce gait variability.
Parkinson disease is characterised by motor symptoms, cognitive decline, and an increased risk of falls, which collectively pose significant challenges for patients and clinicians. The trial, conducted across 19 US sites, evaluated the safety and efficacy of TAK-071 in 54 individuals aged 40 to 85 years with PD, a history of falls, and mild-to-moderate cognitive impairment (Montreal Cognitive Assessment score 11-26). Participants were randomised to receive once-daily TAK-071 or placebo for six weeks, followed by a washout period and crossover treatment. Primary outcomes assessed stride time variability (STV) during walking tasks, with and without cognitive load. Secondary outcomes included a composite cognitive score measuring attention, executive function, and memory.
The study found no significant difference in the primary outcome of STV between participants receiving TAK-071 and those on placebo (geometric mean ratio, with cognitive load: 1.15, 95% CI, 0.94-1.41, P = .16; without cognitive load: 1.02, 95% CI, 0.88-1.18, P = .78). However, the cognitive composite score showed significant improvement with TAK-071 compared to placebo (least squares mean difference, 0.22; 95% CI, 0.05-0.38; P = .01). Adverse events were comparable between groups, with 8% of participants on TAK-071 discontinuing due to side effects, primarily gastrointestinal issues.
These findings indicate that while TAK-071 does not mitigate gait variability, its potential to improve cognitive function is noteworthy. This underscores the need for larger, longer trials in diverse populations to clarify its clinical utility, particularly regarding safety and efficacy in real-world settings. Clinicians should consider the limitations of current data when exploring TAK-071 as an adjunct therapy, especially for patients prioritising cognitive improvement. Future studies could further explore its effects on daily functioning and quality of life.
Katrina Thornber, EMJ
Reference
Shanbhag NM et al. An Acetylcholine m1 receptor–positive allosteric modulator (TAK-071) in parkinson disease with cognitive impairment: a phase 2 randomized clinical trial. JAMA Neurol. 2025;DOI:10.1001/jamaneurol.2024.4519.
