Parkinson Disease Cognition Improved in Phase 2 Study of TAK-071

Niraj Shanbhag, MD, PhD

Data from a traditional double-blind, placebo-controlled crossover trial (NCT04334317) showed that treatment with Takeda’s TAK-071, an M1 positive allosteric modulator, was associated with improvements in cognition among patients with Parkinson disease (PD). The agent, which is designed to have low cooperativity to reduce cholinergic side effects, did not have an impact on patients’ gait function.¹

The study, which included 54 patients aged 40-85 years, was presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania. Over a 6-week treatment period, investigators observed enhancements in global cognition score among TAK-071-treated participants relative to placebo (least squares [LS] mean difference in change from baseline, 0.216; 95% CI, 0.051-0.382; P = .012).

Led by Niraj Shanbhag, MD, PhD, a medical director in clinical development at Takeda, the study featured patients who had Hoehn and Yahr score between 2 and 4, at least 1 fall in the prior 12 months, and a Montreal Cognitive Assessment score between 11 and 26. Coming into the study, patients were required to be on stable anti-parkinsonian medications and not on acetylcholinesterase inhibitors. As for the design, patients were randomly assigned 1:1 to either once-daily oral TAK-071 or matched placebo for a 6-week treatment period, followed by a 3-week washout, and then 6 weeks of crossover treatment.

The primary end point, change from baseline in gait variability (stride time variability [STV]), was not significantly different between TAK-071 and placebo groups after 6 weeks of treatment. More specifically, there was no differences between active and placebo arms, either with cognitive load (geometric mean ratio [GMR], 1.154; 95% CI, 0.942-1.412; P = .161) or without cognitive load (GMR, 1.020; 95% CI, 0.882-1.180; P = .781). In terms of safety, 4 participants (7.5%) on active drug had adverse events that led to withdrawal of TAK-071, and 4 had gastrointestinal adverse events, all of which were mild.

Over the years, research has shown that the M1 receptor is a promising target to treat cognitive impairment associated with Alzheimer disease and PD. M1 receptor is predominantly expressed in brain regions involved in cognitive function, such as the frontal cortex, hippocampus, and striatum. Based on the expression pattern of M1 receptor and its role in cognitive function, the selective potentiation of activation of this receptor would be expected to result in an amelioration of cognitive deficits.

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Prior to the phase 2 study, TAK-071 was studied in a first-in-human phase 1 study of healthy volunteers. Published in the British Journal of Clinical Pharmacology, TAK-071 was administered as single and multiple doses in a randomized, double-blind, placebo-controlled, parallel-group design in healthy volunteers along and in combination with donepezil. All told, the therapy was considered safe and well tolerated, with no deaths or serious adverse events occurring.²

In the phase 1 study, TAK-071 demonstrated a long mean half-life of 46.3 (25.2%) to 60.5 (51.5%) hours and excellent brain penetration following oral dosing. A quantitative EEG analysis revealed that TAK-071 40-80 mg increased power in the 7-9 Hz range in the posterior electrode group with eyes open and 120-160 mg doses increased power in the 16-18 Hz range and reduced power in the 2-4 Hz range in central-posterior areas with eyes open and eyes closed. Furthermore, functional connectivity was significantly reduced after TAK-071 at high doses and was enhanced with coadministration of donepezil under the eyes-closed condition.

A 2019 preclinical study first demonstrated the potential impacts of TAK-071 in a cohort of rats. All told, combining subeffective doses of TAK-071, but not T-662, with an acetylcholinesterase inhibitor, significantly ameliorated scopolamine-induced cognitive deficits in the rat population. In addition, activation of M1 receptor was shown to increase neural excitability via membrane depolarization, reduced afterhyperpolarization, and generation of afterdepolarization in prefrontal cortical pyramidal neurons.³

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REFERENCES
1. Shanbhag N, Padmanabhan J, Zhang Z, et al. A Phase 2 Randomized Clinical Trial of TAK-071, an Acetylcholine M1 Receptor Positive Allosteric Modulator, in Parkinson Disease with Cognitive Impairment. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 672
2. Yin W, Mamashi F, Buhl DL, et al. Safety, pharmacokinetics, and quantitative EEG modulation of TAK-071, a novel muscarinic M1 receptor positive allosteric modulator, in healthy subjects. Br J Clin Pharmacol. 2022;88(2):600-612. doi:10.1111/bcp.14975.
3. Sako Y, Kurimoto E, Mandai T, et al. TAK-071, a novel M1 positive allosteric modulator with low cooperativity, improves cognitive function in rodents with few cholinergic side effects. Neuropsychopharmacology. 2019;44(950-960). doi:10.1038/s41386-018-0168-8