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

Phase 1

Active, not recruiting

• Conditions: Multiple System Atrophy
• Interventions: Drug: ION464; Drug: Placebo

• Registration Number: 2024-512528-13-00
• Lead Sponsor: Ionis Pharmaceuticals Inc.

Brief Summary

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

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.

Study Timeline

• Study First Posted: 2024-08-14
• Last Update Posted: 2025-06-18

Recruitment & Eligibility

• Status: Ongoing, recruitment ended
• Sex: All
• Target Recruitment: 32

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)

Key

Exclusion Criteria

• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2: ION464	ION464	ION464 will be administered at the same doses as Part 1 by IT injection, at regular intervals, for 72 weeks.
Part 2: Placebo	Placebo	ION464-matching placebo will be administered by IT injection, at regular intervals, for 72 weeks.
Part 1: ION464	ION464	ION464 will be administered at multiple-ascending doses by IT injection at regular intervals over 12 weeks.
Part 1: Placebo	Placebo	ION464-matching placebo will be administered by IT injection at regular intervals over 12 weeks.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration of ION464	Baseline up to approximately 36 weeks
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
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

Trial Locations

Locations (11)

Medizinische Universitaet Innsbruck; 🇦🇹 Innsbruck, Austria

Hospital De Loures EPE; 🇵🇹 Loures, Portugal

Hospices Civils De Lyon; 🇫🇷 Bron, France

Assistance Publique Hopitaux De Paris; 🇫🇷 Paris, France

Centre Hospitalier Universitaire De Toulouse; 🇫🇷 Toulouse, France

Universitaetsmedizin Goettingen; 🇩🇪 Goettingen, Germany

Medizinische Hochschule Hannover; 🇩🇪 Hanover, Germany

Universitaetsklinikum Ulm AöR; 🇩🇪 Ulm, Germany

Universitaetsklinikum Duesseldorf AöR; 🇩🇪 Duesseldorf, Germany

Philipps-Universitaet Marburg; 🇩🇪 Marburg, Germany

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Medizinische Universitaet Innsbruck

🇦🇹Innsbruck, Austria

Florian Krismer

Site contact

+4351250480932

mui-oversight@i-med.ac.at