Objective: To provide an update on the baseline demographics and safety from the HORIZON Clinical Trial of ION464

Background: Multiple System Atrophy (MSA) is a fatal α-synucleinopathy with no disease modifying treatments to date. Affected individuals present with parkinsonism, cerebellar ataxia, autonomic failure, and pyramidal signs in various combinations; average survival is limited to approximately 10 years. It is hypothesized that the glial cell inclusions  containing α-syn aggregates underly disease pathogenesis and progression. ION464 is an antisense oligonucleotide (ASO) that specifically targets SNCA RNA for degradation and is being developed as a potential disease-modifying treatment for MSA. Reducing levels of SNCA mRNA and subsequently decreasing synthesis of α-synuclein protein may decrease the rate of aggregation and spread of α-synuclein pathology. The ongoing clinical trial (HORIZON) is a Phase 1/2a study being conducted in Europe.

Method: HORIZON is a first-in-human, randomized, double-blind, placebo-controlled, multiple-ascending-dose (MAD) study (Part 1) to evaluate the safety, tolerability, PK, and PD of ION464 in approximately forty adult patients with MSA, followed by an open-label long-term extension (LTE) (Part 2). Key inclusion criteria include diagnosis of Probable or Possible MSA, either parkinsonian-type (MSA-P) or cerebellar-type (MSA-C); ability to walk unassisted for at least 10 meters; and screening SPECT with DaTscan™ (ioflupane I123 injection) results demonstrating loss (whether symmetric or asymmetric) of dopamine nerve terminals in the striatum consistent with neurodegenerative parkinsonism, as assessed with qualitative, visual read. The primary outcome is safety/tolerability, and secondary outcomes include the evaluation of ION464 PK and the PD effect of ION464 on CSF levels of total α-synuclein.

Results: Baseline characteristics of the first 22 participants include average age of 59 years, with 36% female, 91% white, 45% MSA-P and 73% Probable MSA. ION464 has been well tolerated with no SAEs or deaths related to the study drug. The most common TEAEs thus far include: falls (25), urinary tract infection (12), headache (6), contusion (5), neck pain (3).

Conclusion: ION464 is an SNCA RNA targeting ASO being developed as a potential disease-modifying treatment for MSA. To date, ION464 has been safe and well tolerated in MSA-affected individuals enrolled in the HORIZON Study.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/snca-antisense-oligonucleotide-for-multiple-system-atrophy-horizon-trial-update/