Objective: Development of a Phase 1 clinical trial evaluating LY3962681, a novel, intrathecally delivered siRNA directly targeting α-synucleinmRNA (SNCA) to reduce α-synuclein protein (ASYN), for the treatment of patients with Parkinson’s disease.

Background: LY3962681 is a first-in-class, intrathecally administered, investigational small interfering RNA (siRNA) agent that targets SNCA mRNA to reduce ASYN protein production. Strong genetic, epidemiologic, nonclinical, and clinical evidence supports the causative role of ASYN in development of Parkinson’s disease (PD). Preclinical data indicates a dose-dependent and sustained suppression of SNCA mRNA and ASYN protein in the brain, including the substantia nigra and dorsal striatum. ASYN reduction was also observed in the NHP CSF. In a GLP-toxicology study, intrathecal administration was well tolerated with no notable adverse clinical or pathological findings.

Method: Given the potential extended duration of activity of LY3962681, an overlapping study design of single ascending dose cohorts in healthy participants, followed by multiple dosing cohorts in participants with PD will evaluate safety and the effects of LY3962681 on CSF ASYN levels, and inform the dosing intervals.

Results: Study design, including patient population, objectives and endpoints will be presented.

Conclusion: m

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MDS Abstracts - https://www.mdsabstracts.org/abstract/first-in-human-single-and-multiple-ascending-dose-trial-design-of-ly3962681-a-novel-intrathecally-delivered-sirna-targeting-%ce%b1-synuclein-mrna-for-the-treatment-of-patients-with-parkinson/