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

April 24, 2026 updated by: Ionis Pharmaceuticals, Inc.

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

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

40

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Austria
      • Innsbruck, Austria, 6020
        • Recruiting
        • Medizinische Universität Innsbruck
  • France
      • Lyon, France, 69500
        • Recruiting
        • CHU de Lyon - Hospices Civils de Lyon-H6pital Pierre Wertheimer, Neurologique HCL
      • Paris, France, 75013
        • Recruiting
        • Groupe Hospitalier Pitie-Salpetriere
      • Toulouse, France, 31059
        • Recruiting
        • Hopital Purpan
  • Germany
      • Düsseldorf, Germany, 40225
        • Recruiting
        • Universitaetsklinikum Duesseldorf AoeR
      • Göttingen, Germany, 37075
        • Recruiting
        • University Medical Center Göttingen, Clinic for Neurology
      • Hanover, Germany, 30625
        • Completed
        • Medizinische Hochschule Hannover (MHH)
      • Marburg, Germany, 35043
        • Recruiting
        • University Hospital Marburg
      • München, Germany, 81377
        • Recruiting
        • Klinikum der Universtiatet Muenchen -Campus Grosshadern
    • Baden-Wurttemberg
      • Ulm, Baden-Wurttemberg, Germany, 89081
        • Recruiting
        • Universitaetsklinikum Ulm
  • Portugal
      • Loures, Portugal, 2674-514
        • Recruiting
        • Hospital Beatriz Ângelo
  • United Kingdom
      • Salford, United Kingdom, M6 8HD
        • Recruiting
        • Salford Royal Hospital
      • Southampton, United Kingdom, SO16 6YD
        • Recruiting
        • Southampton General Hospital
    • England
      • London, England, United Kingdom, WC1N 3BG
        • Recruiting
        • Institute of Neurology & The National Hospital for Neurology and Neurosurgery
      • Oxford, England, United Kingdom, OX3 9DU
        • Recruiting
        • The John Radcliffe Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

40 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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)

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Triple

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ionis Pharmaceuticals, Inc.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 21, 2022

Primary Completion (Estimated)

September 1, 2027

Study Completion (Estimated)

September 1, 2027

Study Registration Dates

First Submitted

November 14, 2019

First Submitted That Met QC Criteria

November 14, 2019

First Posted (Actual)

November 18, 2019

Study Record Updates

Last Update Posted (Actual)

April 27, 2026

Last Update Submitted That Met QC Criteria

April 24, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ION464-CS1
  • 2019-001105-24 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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