Allosteric modulator nonsuperior to placebo in Parkinson’s disease

Key takeaways:

• Change from baseline in gait variability did not differ between groups, regardless of cognitive load.
• Treatment with TAK-071 improved cognitive composite scores vs. those given placebo.

Treatment with an oral allosteric modulator was nonsuperior to placebo at 6 weeks in adults with Parkinson’s disease whose symptoms included fall risk and cognitive issues, data from JAMA Neurology show.

“Up to 80% of patients with PD eventually develop Parkinson disease dementia (PDD),” Niraj M. Shanbhag, MD, PhD, executive director of exploratory medicine and pharmacology, and neuroscience at Takeda Pharmaceuticals, and colleagues wrote.

“Notably, cognitive impairment in [mild cognitive impairment] and PDD at all stages increases disability, diminishes function, and reduces quality of life.”

As falls and cognitive issues are prevalent in PD, both of which require careful monitoring and treatment, Shanbhag and colleagues sought to examine the safety and efficacy of TAK-071 — muscarinic acetylcholineM1 positive allosteric modulator — in a small cohort of patients with PD as well as increased fall risk and cognitive impairment.

Their phase 2, randomized, double-blind, placebo-controlled crossover clinical trial was conducted from October 2020 to February 2023 at 19 sites across the United States. The study included 54 patients with a diagnosis of PD (mean age, 69.7 years; 83% men), ability to walk unaided for 2 minutes, a record of at least one fall in the prior 12 months, a Montreal Cognitive Assessment score of 11 to 26, as well as stable regimens of appropriate medications.

Participants were given once-daily oral TAK-071 or placebo over a pair of 6-week double-blind treatment periods, separated by at least one 3-week washout period. At-home assessments were made during the third week of each 6-week treatment period, after which a follow-up safety assessment call was made roughly 14 days after final dosing.

The study’s primary endpoint was change from baseline in gait during a 2-minute walk test (stride time variability [STV]) with or without cognitive load. For this task, all enrollees wore six motion sensors at various locations on the body and the extremities for the duration. A secondary endpoint of change from baseline in a cognitive composite score from a neurocognitive battery was also considered, comprised of seven performance-based tests across three cognitive domains, all but one of which were administered via a computerized platform.

The final analysis set included 46 individuals who completed all study visits.

After 6 weeks of treatment, results showed that the change from baseline in STV did not differ between participants receiving TAK-071 or placebo, either with or without cognitive load. However, Shanbhag and colleagues noted that treatment with TAK-071 improved cognitive composite scores compared with those given placebo. According to data from 36 participants for whom composite scores were available, the mean difference was 0.29 between groups.

Treatment-emergent adverse events were recorded in 18 of 49 participants who received placebo and 19 of 53 administered TAK-071. Four participants given the study drug suffered withdrawal-necessary adverse events.

“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 [mild cognitive impairment] and early PDD as well as in other conditions in which cholinergic loss likely contributes to cognitive deficits, such as Alzheimer disease and schizophrenia,” Shanbhag and colleagues wrote.