Category: Parkinsonism, Atypical: MSA
Objective: To evaluate the safety, tolerability, and pharmacokinetics (PK) profile of YA-101 in healthy volunteers with single dose and multiple dose
Background: Multiple System Atrophy (MSA) is a rare, sporadic, adult-onset, fatal, rapid progressive neurodegenerative disorder [1,2]. Unfortunately, MSA is an unmet medical need and urgently waits for treatment development. Until now, the pathogenesis of MSA has not been fully elucidated and the potential mechanism is accumulation of misfolded α-synuclein in oligodendrocytes [3]. Previous studies indicated that α-synuclein aggregates cause NMDA receptor (NMDAR) hypofunction and increased microglial activation [4,5]. Moreover, abnormal deposition of α-synuclein activate NLRP3 inflammasome leading to IL-1β release in MSA [6]. These findings provide a novel strategy to treat MSA. YA-101, known as RS-D7, is a dual Inhibitors of D-amino acid oxidase and NLRP3 inflammasome that leads to enhance of NMDAR function and attenuate brain inflammation as a therapeutic potential for a broad spectrum of central nervous system disorders.
Method: Clinical study with YA-101 treatment consisted of two parts: single dose with three cohorts (900, 3000, and 9600 mg) for 1 day, and multiple doses with two cohorts (1500 and 4500 mg BID) over a 2-weeks period. In all cohorts, 6 participants were recruited in the active arm and 2 participants were in placebo arm. All the healthy volunteers in each cohort will be randomized to participate in either active arm or matching placebo arm. All adverse events (AEs) and PK parameters were systematically investigated and recorded.
Results: After single dose of YA-101, the Cmax and AUC0-last led to dose-dependent increases from 900 to 9600 mg treatment under fed conditions. In the multiple dose study, the Cmax and AUC0-last also exhibited an increased tendency with dosage and treatment duration. In all cohorts, most AEs were mild in severity; none were severe or serious.
Conclusion: The Phase I trial of YA-101 successfully established a favorable safety and PK profile, supporting the potential of YA-101 as a novel therapeutic agent. Notably, the results validate the feasibility of YA-101 with twice-daily dosing regimens, paving the foundation of subsequent YA-101 clinical development for investigating efficacy and safety in MSA.
References: [1] Fanciulli A, Stankovic I, Krismer F, Seppi K, Levin J, Wenning GK (2019) Multiple system atrophy. Int Rev Neurobiol 149: 137-192
[2] Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, Palma JA, Meissner WG, Krismer F, Berg D et al (2022) The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord 37: 1131-1148
[3] Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94: 79-100
[4] Chen Y, Yang W, Li X, Li X, Yang H, Xu Z, Yu S (2015) alpha-Synuclein-induced internalization of NMDA receptors in hippocampal neurons is associated with reduced inward current and Ca(2+) influx upon NMDA stimulation. Neuroscience 300: 297-306
[5] Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T (2004) Microglial activation parallels system degeneration in multiple system atrophy. J Neuropathol Exp Neurol 63: 43-52
[6] Li F, Ayaki T, Maki T, Sawamoto N, Takahashi R (2018) NLRP3 Inflammasome-Related Proteins Are Upregulated in the Putamen of Patients With Multiple System Atrophy. J Neuropathol Exp Neurol 77: 1055-1065
To cite this abstract in AMA style:
YJ. Tseng, BH. Su, O. Lin, DZ. Luo, TF. Lo, YC. Huang, CC. Li. Pharmacokinetics And Safety Of YA-101, A Dual Inhibitors Of D-Amino Acid Oxidase (DAAO) And NLRP3 Inflammasome, In Healthy Subjects: A Double-Blind, Placebo-Controlled, Randomized, Single Dose and Multiple Dose Phase I Study [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/pharmacokinetics-and-safety-of-ya-101-a-dual-inhibitors-of-d-amino-acid-oxidase-daao-and-nlrp3-inflammasome-in-healthy-subjects-a-double-blind-placebo-controlled-randomized-single-dose-and-mul/. Accessed October 5, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/pharmacokinetics-and-safety-of-ya-101-a-dual-inhibitors-of-d-amino-acid-oxidase-daao-and-nlrp3-inflammasome-in-healthy-subjects-a-double-blind-placebo-controlled-randomized-single-dose-and-mul/