Objective: To study the safety and efficacy of TAK-071, an M₁ positive allosteric modulator, in adults with Parkinson disease (PD) with increased risk for falls and cognitive impairment.

Background: Increased fall risk and cognitive impairment are prevalent, frequently comorbid, and burdensome in PD, and in need of efficacious, safe, well-tolerated treatment. Deficits in acetylcholine neurotransmission are implicated in both falls and cognitive impairment in PD.

Method: This was a phase 2 randomized, double-blind, placebo-controlled, crossover trial (NCT04334317). Eligible participants (aged 40-85 years) had a diagnosis of PD, Hoehn and Yahr score ≥ 2 and < 4, at least 1 fall in the prior 12 months, and a Montreal Cognitive Assessment score between 11 and 26. All participants were required to be on stable anti-parkinsonian medications and not on acetylcholinesterase inhibitors. Participants were randomized 1:1 to six weeks of once-daily oral TAK-071 (dose adjusted for age), or matched placebo, followed by a washout period of at least 3 weeks, then six weeks of crossover treatment. The primary endpoint was change from baseline in gait variability (stride time variability, STV) during a 2-minute walk with or without cognitive load. The secondary efficacy endpoint was change from baseline in a global cognition score comprising tests of attention, executive function, and memory.

Results: Among 54 participants randomized, 83.3% were male; the mean (SD) age was 69.7 (6.9) years. After 6 weeks of treatment, STV did not differ between active and placebo arms, either with cognitive load (geometric mean ratio (GMR) = 1.154, 95% CI = 0.942 – 1.412, p = 0.161) or without cognitive load (GMR = 1.020, 95% CI = 0.882 – 1.180, p = 0.781). TAK-071 resulted in improvement in the global cognition score compared with placebo; the least-squares mean difference in the change from baseline was 0.216, 95% CI = 0.051 – 0.382, p = 0.012. Four participants (7.5%) on TAK-071 had adverse events resulting in withdrawal of study drug, and 4 had gastrointestinal adverse events, all of which were mild.

Conclusion: In adults with PD with increased risk for falls and cognitive impairment, TAK-071 was generally safe and well-tolerated, did not improve gait parameters, but improved cognition compared with placebo.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-phase-2-randomized-clinical-trial-of-tak-071-an-acetylcholine-m1-receptor-positive-allosteric-modulator-in-parkinson-disease-with-cognitive-impairment/