Objective: To evaluate the efficacy and safety of KW-6356 in Parkinson’s disease (PD) patients with levodopa therapy, irrespective of the presence of wearing-off (WO).

Background: KW-6356 is a novel selective adenosine A_2A receptor antagonist/inverse agonist under development for the treatment of PD. This is the first study evaluating the efficacy and safety of KW-6356 in PD patients on levodopa therapy. The efficacy and safety of KW-6356 as a monotherapy has been demonstrated in a Phase 2a study [1] (NCT02939391). PD patients are suffering from not only motor symptoms but also a wide range of non-motor symptoms (NMS) including sleep problems, which can negatively impact their quality of life [2, 3]. Preclinical studies suggested that adenosine A_2A receptors of the nucleus accumbens regulate the sleep-wake cycle via the region [4, 5].

Method: The Phase 2b study was a multicenter, randomized, placebo-controlled, double-blind study in levodopa treated Japanese PD patients (NCT03703570). Patients were randomized to placebo, KW-6356 3 mg or 6 mg and were treated for 24 weeks. The primary efficacy endpoint was the change from baseline (CFB) in the Movement Disorder Society-sponsored revision of Unified PD Rating Scale (MDS-UPDRS) Part III total score and the key secondary efficacy endpoint was the CFB in the Mean OFF time/day in patients with WO. Additional efficacy assessments on NMS including sleep were evaluated.

Results: 503 patients were randomized to 3 groups (placebo=168: KW-6356 3 mg=168: 6 mg=167). In the primary efficacy endpoint, KW-6356 significantly decreased the MDS-UPDRS Part III total score (p=.006 for 3 mg, p=.049 for 6 mg vs placebo, respectively). KW-6356 also decreased the Mean OFF time/day in the key secondary efficacy endpoint. KW-6356 was well tolerated. As the result of post-hoc analysis, KW-6356 6 mg significantly improved the PD Sleep Scale-2 total score for subjects with sleep problems at baseline (p=.013 vs placebo) in addition to overall population (p=.018 vs placebo).

Conclusion: This study demonstrates that KW-6356 has a favorable efficacy and acceptable safety profile as an adjunct to levodopa in PD patients and justifies further development as a new antiparkinsonian treatment. Post-hoc analyses suggest KW-6356 6 mg could provide potential benefits for PD patients with sleep problems.

References: 1 T. Maeda, M. Yamamoto, T. Kimura, N. Hattori, A novel adenosine A2A receptor antagonist KW-6356 in early Parkinson’s disease: A randomized controlled trial for efficacy and safety. World Congress on Parkinson’s Disease and Related Disorders, (2018).
2 Duncan GW, Khoo TK, Yarnall AJ, et al. Health-related quality of life in early Parkinson’s disease: The impact of nonmotor symptoms: Quality of Life in Early Parkinson’s disease. Mov Disord 29(2014) 195-202.
3 Barone P, Antonini A, Colosimo C, Marconi R, Morgante L, Avarello TP, et al. The Priamo study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Disord 24(2009) 1641-49.
4 M. Lazarus, H.Y. Shen, Y. Cherasse, W.M. Qu, Z.L. Huang, C.E. Bass, R. Winsky-Sommerer, K. Semba, B.B. Fredholm, D. Boison, O. Hayaishi, Y. Urade, J.F. Chen, Arousal effect of caffeine depends on adenosine A2A receptors in the shell of the nucleus accumbens, The Journal of neuroscience : the official journal of the Society for Neuroscience 31(27) (2011) 10067-75.
5 M. Lazarus, Z.L. Huang, J. Lu, Y. Urade, J.F. Chen, How do the basal ganglia regulate sleep-wake behavior?, Trends in neurosciences 35(12) (2012) 723-32.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/effect-of-kw-6356-a-novel-adenosine-a2a-receptor-antagonist-inverse-agonist-on-motor-and-non-motor-symptoms-in-parkinsons-disease-patients-as-an-adjunct-to-levodopa-therapy-results-of-phas/