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20-01-2025 | Parkinson Disease | Editor's Choice | News

TAK-071 fails to improve gait variability in patients with PD and cognitive impairment

Author: Dr. Jonathan Smith

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medwireNews: TAK-071, a muscarinic acetylcholine M1 receptor–positive allosteric modulator, does not improve gait variability in patients with Parkinson’s disease (PD) and cognitive impairment, but may have cognitive benefits, suggests a phase 2 trial.

Specifically, stride time variability (STV), the study’s primary endpoint, which was measured during a 2-minute walk test at a natural pace on a 10 m walkway did not differ significantly after patients had taken 6 weeks of TAK-071 versus 6 weeks of placebo in the crossover, randomized study.

On the other hand, in secondary analyses, the researchers found that TAK-071 significantly improved scores on a cognitive composite measure consisting of seven performance-based tests covering three cognitive domains – attention, executive function, and memory – that are commonly affected early in PD mild cognitive impairment (PD-MCI) and PD dementia (PDD).

“Cognitive impairment is debilitating and widespread among individuals with PD and represents a major unmet need,” write Arthur Simen (Takeda Development Center Americas, Cambridge, Massachusetts, USA) and colleagues in JAMA Neurology.

The study enrolled 54 participants (83% men, 87% White) aged between 40 and 85 years (mean age 70 years) taking regular medication for PD as diagnosed according to the Movement Disorders Society clinical diagnostic criteria. Eligible participants also had at least one fall in the prior 12 months, were able to walk for 2 minutes unaided, and had cognitive impairment as indicated by a score between 11 and 26 points on the Montreal Cognitive Assessment (MoCA), which ranges from 0 to 30 points, with lower scores indicating greater impairment.

The median MoCA score was 24 points, indicating mild to moderate cognitive impairment, and the mean PD duration was 8.2 years. Most (90.7%) of the patients had PD-MCI, while 3.7% were classified as having PDD, and for the remaining 5.6% the type of cognitive impairment was unclear.

The patients were randomly assigned to receive oral TAK-071 once daily for 6 weeks, followed by a washout period of at least 3 weeks, and then placebo for a further 6 weeks (n=28) or vice versa (n=26). The TAK-071 dose was stratified by age, with participants aged 40–65 years receiving 7.5 mg and those aged 66–85 years receiving 5.0 mg.

Both treatment groups had a geometric mean STV of 0.05 when measured without a cognitive load, a serial three subtraction test. With the cognitive load, the TAK-071 group scored a geometric mean STV of 0.07 compared with 0.06 in the placebo group. This equated to nonsignificant mean ratios of TAK-071 to placebo of 1.02 and 1.15, respectively.

One reason that TAK-071 had no significant benefit on gait may have been the low baseline fall rate of a median of 0.5 per month, ranging from 0.1 to 15, compared with previous studies, the investigators write. They suggest that an effect on STV “may have been apparent if only participants with a history of high rates of falls were included or if a minimum STV threshold was applied as an inclusion criterion.”

Nevertheless, the least squares mean change in composite cognitive scores from baseline differed by a significant 0.22 points in favor of TAK-071 treatment compared with placebo (0.18 vs –0.04 points). This was driven by greater improvement with TAK-071 in both the attention and executive function domains, with least squares mean differences of 0.22 and 0.35 points, respectively, whereas changes in memory were not significantly different.

Simen et al observed that TAK-071 was well tolerated, with treatment-emergent adverse events (TEAEs) occurring in 36% of participants when taking TAK-071 compared with 37% when taking placebo. Serious TEAEs involving COVID-19 occurred in two patients while taking TAK-071 and in one patient during placebo treatment, none of which were linked to the study drug. The most common TEAEs with TAK-071 were dizziness (8%) and fatigue (4%), and 8% percent of patients discontinued TAK-071 due to TEAEs.

Simen and colleagues point to the mostly male and White population, and the exclusion of those with certain comorbidities – dyskinesias, depression and other psychiatric disorders, and excessive daytime sleepiness – and those concomitantly taking acetylcholinesterase inhibitors, medications with substantial anticholinergic properties, and moderate or strong CYP3A4 inhibitors or inducers, as a limitation for generalization of the study results.

“Larger and longer studies in more diverse populations are needed to better understand the safety and efficacy of TAK-071 in broader populations,” they conclude.

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group

JAMA Neurol 2025; doi:10.1001/jamaneurol.2024.4519

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