Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of ION464 Administered to Adults With Multiple System Atrophy (HORIZON)

Study Overview
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Brief Summary
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The primary objectives are to evaluate the safety and tolerability of multiple doses of ION464 administered via intrathecal (IT) injection (Part 1) and to evaluate the long-term safety and tolerability of ION464 (Part 2) in participants with multiple system atrophy (MSA). The secondary objectives are to evaluate the pharmacodynamic (PD) effect of ION464 on the level of a potential biomarker of target engagement (Parts 1 and 2) and to evaluate the pharmacokinetic (PK) profile of ION464 in serum (Part 1).

Detailed Description
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This is a first-in-human, randomized, blinded, placebo-controlled, multiple-ascending-dose (MAD) study (Part 1) to evaluate the safety, tolerability, PK, and PD of ION464 in adult participants diagnosed with MSA with a long-term extension (LTE) (Part 2). The study will include up to approximately 40 participants. Part 1 of the study consists of a Screening Period of up to 6 weeks, a Treatment Period of 12 weeks, and a Follow-up Period of 24 weeks. The study duration for each participant in Part 2 will be approximately 96 weeks, which consists of a 72-week Treatment Period and a 24-week Follow-up Period.

Official Title
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A Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of ION464 Administered Intrathecally to Adults With Multiple System Atrophy

Conditions
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Multiple System Atrophy

Intervention / Treatment
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* Drug: ION464
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Screening single-photon emission computed tomography (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. Diagnosed with probable or possible MSA, either parkinsonian-type (MSA-P) or cerebellar-type (MSA-C). Must be able to walk unassisted for at least 10 meters (approximately 30 feet) Presence of cognitive dysfunction (defined as Montreal Cognitive Assessment (MoCA) score <25) Family history of ataxia or parkinsonism and known genetic cause of ataxia or parkinsonism. NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: ION464<br>ION464 will be administered at multiple-ascending doses by IT injection at regular intervals over 12 weeks. | Drug: ION464<br>* ION464 will be administered by IT injection.<br>|
| Placebo Comparator: Part 1: Placebo<br>ION464-matching placebo will be administered by IT injection at regular intervals over 12 weeks. | Drug: Placebo<br>* ION464-matching placebo will be administered by IT injection.<br>|
| Experimental: Part 2: ION464<br>ION464 will be administered at the same doses as Part 1 by IT injection, at regular intervals, for 72 weeks. | Drug: ION464<br>* ION464 will be administered by IT injection.<br>|
| Placebo Comparator: Part 2: Placebo<br>ION464-matching placebo will be administered by IT injection, at regular intervals, for 72 weeks. | Drug: Placebo<br>* ION464-matching placebo will be administered by IT injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) |  | Baseline up to approximately 36 weeks | 
| Number of Participants with Serious Adverse Events (SAEs) |  | Baseline up to approximately 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Cerebrospinal Fluid (CSF) Levels of Total alpha-synuclein (α-syn) |  | Baseline up to approximately 36 weeks | 
| Serum Concentration of ION464 |  | Baseline up to approximately 36 weeks | 
| Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration of ION464 |  | Baseline up to approximately 36 weeks | 
| Maximum Observed Concentration (Cmax) of ION464 |  | Baseline up to approximately 36 weeks | 
| Time to Reach Maximum Observed Concentration (Tmax) of ION464 |  | Baseline up to approximately 36 weeks |