In a recent Phase 2 clinical trial, researchers evaluated the efficacy of TAK-071, a novel muscarinic acetylcholine M1 positive allosteric modulator, in addressing both motor and cognitive symptoms in Parkinson's disease (PD) patients. The study, published in JAMA Neurology, revealed mixed results with notable implications for future therapeutic developments.
Primary Endpoint Results and Motor Function
The randomized, double-blind, placebo-controlled crossover trial failed to meet its primary endpoint of improving gait variability. Researchers measured stride time variability (STV) during a 2-minute walk test, both with and without cognitive load, finding no significant difference between TAK-071 and placebo after 6 weeks of treatment.
Cognitive Performance Improvements
Despite missing the primary endpoint, the trial demonstrated encouraging results in cognitive function. Among the 36 participants with available composite scores, TAK-071 showed superiority over placebo in improving cognitive performance, with a mean difference of 0.29 between treatment groups. This finding is particularly significant given that up to 80% of PD patients eventually develop Parkinson's disease dementia (PDD).
Trial Design and Patient Population
The study, conducted from October 2020 to February 2023, enrolled 54 participants across 19 U.S. sites. The cohort consisted predominantly of men (83%) with a mean age of 69.7 years. Key inclusion criteria comprised:
- Confirmed PD diagnosis
- Ability to walk unassisted for 2 minutes
- At least one fall in the previous 12 months
- Montreal Cognitive Assessment scores between 11 and 26
- Stable medication regimens
Safety and Tolerability Profile
The safety profile of TAK-071 appeared comparable to placebo:
- 19 of 53 participants receiving TAK-071 reported treatment-emergent adverse events
- 18 of 49 participants in the placebo group experienced adverse events
- Four participants discontinued treatment due to adverse events in the TAK-071 group
Future Therapeutic Potential
Dr. Niraj M. Shanbhag, Executive Director at Takeda Pharmaceuticals, and colleagues suggest that TAK-071's mechanism of action could have broader applications. They note potential benefits for patients with mild cognitive impairment and early PDD, as well as other conditions characterized by cholinergic deficits, such as Alzheimer's disease and schizophrenia.
The findings underscore the complex nature of treating neurodegenerative disorders and highlight the potential value of targeting specific molecular pathways in addressing cognitive symptoms, even when motor function improvements remain elusive.
