M1 Modulatory TAK-091 Improves Cognition in Parkinson Disease, Study Shows

Niraj Shanbhag, MD, PhD

Findings from a recently published phase 2, randomized, placebo-controlled crossover trial (NCT04334317) showed that treatment with investigational TAK-091 (Takeda), a muscarinic acetylcholine M1 positive allosteric modulator, resulted in improved cognition among patients with Parkinson disease (PD). While the agent did not meet its primary end point of improving gait, the results do warrant further examination in more diverse populations.¹

Published in JAMA Neurology, the results of the study were originally first reported at the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS). Overall, the trial featured 54 patients with PD who had at least 1 fall in the prior 12 months, with a Montreal Cognitive Assessment score of 11 to 26, and had been receiving stable antiparkinsonian medications and no acetylcholinesterase inhibitors.

Led by Niraj Shanbhag, MD, PhD, a medical director in clinical development at Takeda, patients were randomly assigned 1:1 to either once-daily TAK-071 or placebo for 6 weeks, followed by washout and 6 weeks of crossover treatment. After 6 weeks of treatment, TAK-071 did not meet its primary end point in change in gait variability (stride time variability [STV]) on a 2-minute walk test in comparison with placebo. Overall, the results were similar with cognitive load (geometric mean ratio, 1.15; 95% CI, 0.94-1.41; P = .16) or without cognitive load (geometric mean ratio, 1.02; 95% CI, 0.88-1.18; P = .78).

Cognition, a secondary end point, was shown to be approved with TAK-071 treatment relative to placebo at week 6. Investigators recorded a least square mean difference of 0.22 (95% CI, 0.05-0.38; P = .01) in cognitive composite score favoring the investigational therapy. Based on data from 36 participants who had available cognitive composite scores from both periods, the mean difference was 0.29 (SD, 0.53) and the standardized effect size was 0.54.

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"Currently, only AChEIs are approved to treat mild to moderate Parkinson disease dementia (PDD), and several studies have not shown benefit in patients with PD-MCI, for which there are no approved pharmacological therapies," Shanbhag et al wrote. "In our study, TAK-071 demonstrated efficacy in a population in which more than 90% of participants had PD-MCI. Given its mechanism of action and the growing understanding of the continuum of cognitive impairment in PD, TAK-071 could have beneficial effects in patients with PD-MCI and early PDD, as well as in other conditions in which cholinergic loss likely contributes to cognitive deficits, such as Alzheimer disease and schizophrenia."

In terms of safety, Treatment-emergent adverse events (TEAEs) occurred in 37% of participants on placebo (18 of 49) and 36% on TAK-071 (19 of 53). Three serious TEAEs, all protocol-defined as COVID-19-related, were reported—two during TAK-071 treatment and one during placebo—and were deemed unrelated to the study drug, resolving by the study's end. No deaths occurred. TEAEs led to treatment interruption in one participant from each group, while four participants (8%) on TAK-071 discontinued treatment due to TEAEs, including palpitations, asthenia, dizziness, gait disturbance, muscle spasms, insomnia, night sweats, fall, on-and-off phenomenon, tremor, and anxiety. No additional tremor-related TEAEs were reported.

On exploratory end points, investigators observed no statistically significant differences for the memory domain or for individual tests within the memory domain. After 6 weeks, treatment with the investigational agent was not associated with a different fall or near-fall rate compared with placebo as measured by the falls diary.

"TAK-071 was estimated to improve attentional control of gait primarily via augmenting acetylcholine neurotransmission in the neocortex, where M1 receptors are widely distributed," the study authors wrote. "Cholinergic signaling in other regions, such as the brainstem pedunculopontine nucleus–thalamus complex, has also been associated with various aspects of gait and balance in PD. It is possible that targeting acetylcholine receptor subtypes that are more predominant in these regions—such as nicotinic α4β2 receptors57—may prove beneficial for falls in PD."

They added, "falls are multifactorial, and it is possible that only a portion of the variance in fall risk in PD is due to cholinergic dysfunction, and our study was not large enough to detect this. An ongoing large multicenter trial of rivastigmine in participants with PD and risk of falls may provide valuable information regarding these issues."

REFERENCE
1. Shanbhag NM, Padmanabhan JL, Zhang Z, et al. An Acetylcholine M1 Receptor–Positive Allosteric Modulator (TAK-071) in Parkinson Disease With Cognitive Impairment. JAMA Neurol. 2025;82(2):152-159. doi:10.1001/jamaneurol.2024.4519