Objective: Development of a Phase 1, First-in-Human (FIH) clinical trial evaluating ALN-SNCA, a novel, intrathecally (IT) delivered small interfering RNA (siRNA) targeting SNCA mRNA to reduce alpha-synuclein protein (⍺Syn, encoded by SNCA), for the treatment of patients with Parkinson’s disease (NCT07216066).

Background: Parkinson’s disease is a common neurodegenerative disorder with an estimated global burden of 10 million cases and no available disease-modifying treatments. It is characterized by neurodegeneration caused by pathological ⍺Syn aggregation. Therapeutic strategies aimed at reducing ⍺Syn are hypothesized to slow disease progression. ALN-SNCA is a novel, IT-administered, investigational siRNA that targets SNCA mRNA to reduce ⍺Syn production. Preclinical studies in a synucleinopathy mouse model showed that ⍺Syn-targeting siRNAs reduced ⍺Syn and pathological aggregates in brain and prevented dopaminergic neurodegeneration and motor decline. In non-human primates, IT administration of single doses of ALN-SNCA resulted in dose-dependent reductions of ⍺Syn up to ~70–90% in various central nervous system tissues. Reductions were sustained over the duration of the studies. In GLP toxicology studies, the No Observed Adverse Effect Level was identified at maximum doses tested. Supported by these data, ALN-SNCA has entered clinical development as a potentially disease-modifying therapy for Parkinson’s disease.

Method: This FIH, Phase 1, double-blind, randomized, placebo-controlled trial is designed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of single IT doses of ALN-SNCA. Pharmacodynamic effects will be evaluated by measuring cerebrospinal fluid (CSF) levels of ⍺Syn over an extended period of time, to account for the expected duration of activity.

Results: Study participants include patients with early-stage Parkinson’s disease. The primary objective of the study is to establish whether ALN-SNCA is sufficiently safe and well-tolerated to continue testing in future studies. The secondary objective is to determine the extent and duration over which ALN-SNCA reduces ⍺Syn in the CSF.

Conclusion: The learnings from this FIH study will inform further clinical development of ALN-SNCA as a potentially disease-modifying treatment for Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/first-in-human-single-ascending-dose-trial-of-aln-snca-an-intrathecally-administered-sirna-for-reducing-%ce%b1-synuclein-in-patients-with-early-stage-parkinsons-disease/