A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)

A Phase 1-3, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION373 in Patients With Alexander Disease

The purpose of this study is to evaluate the safety and efficacy of zilganersen (ION373) in improving or stabilizing gross motor function across the full range of affected domains in patients with AxD.

Study Overview

• Status: Active, not recruiting
• Conditions: Alexander Disease
• Intervention / Treatment: Drug: zilganersen; Drug: Placebo

Detailed Description

This is a Phase 1-3, multi-center, double-blind, placebo-controlled, multiple-ascending dose (MAD) study in approximately 73 patients with AxD. Participants will be randomized in a 2:1 ratio to receive zilganersen (ION373) or matching placebo for a 60-week double-blind treatment period; then all participants will receive zilganersen for a 60-week open-label treatment period followed by a 120-week open-label, long-term extension period, and a 28-week post-treatment follow-up period. Multiple dose cohorts will be evaluated in the study. Cohorts will be enrolled sequentially. The initial participants in each dose cohort must be at least 8 years of age at the time of screening.

The study will include an optional open-label sub-study in participants <2 years of age at some sites.

Treatment extension period was added to provide continued access to open label zilganersen for patients completing the main study and sub-study until the drug may be commercially available in the patient's country, or until the Sponsor discontinues the zilganersen development program, whichever occurs earlier.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Murdoch Children's Research Institute
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3A 0G4
      • McGill University Health Centre
• Israel
  • Tel Aviv, Israel, 6423906
    • Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center
• Italy
  • Milan, Italy, 20154
    • Ospedale dei Bambini Vittore Buzzi
  • Roma, Italy, 165
    • Ospedale Pediatrico Bambino Gesu
• Japan
  • Kodaira-shi
    • Tokyo, Kodaira-shi, Japan, 187-8551
      • National Center of Neurology and Psychiatry
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1105 AZ
      • Amsterdam Universitair Medische Centra - Academisch Medisch Centrum
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS Foundation Trust
  • London, United Kingdom, WC1N 3BG
    • University College London Hospitals Nhs Foundation Trust
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital Stanford
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Hospital of Atlanta
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Clinical phenotype and brain imaging consistent with a diagnosis of Alexander disease
2. Documented genetic mutation in the GFAP gene
3. Aged ≥ 2 to 65 years old at the time of informed consent
4. Able and willing to meet all study requirements, including travel to Study Center, procedures, measurements and visits
5. Patients < 18 years old at Screening must have a trial partner (parent, caregiver or other)

Key Exclusion Criteria:

1. Clinically significant abnormalities in medical history or physical examination
2. Any clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion
3. Any contraindication or unwillingness to undergo MRI
4. Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational agent, whichever is longer; concurrent participation in any other clinical study (including observational and non-interventional studies)
5. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose received, or within 12 months of Screening if multiple doses received. This exclusion does not apply to vaccines (both messenger ribonucleic acid [mRNA] and viral vector vaccines).
6. History of gene therapy or cell transplantation or any other experimental brain surgery [ROW]
7. Obstructive hydrocephalus
8. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
9. Known brain or spinal disease that would interfere with the lumbar puncture (LP) process, CSF circulation or safety assessment.
10. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
11. Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with the patient participating in or completing the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: zilganersen; Zilganersen will be administered by intrathecal bolus (ITB) injection once every 12 weeks through Week 49. The 60-week double-blind treatment period will be followed by the open-label and long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 229.	Drug: zilganersen; zilganersen will be administered by ITB injection.; Other Names: ION373
Placebo Comparator: Placebo; Matching placebo will be administered by ITB injection once every 12 weeks through Week 49. It will be followed by the open-label and long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 229.	Drug: Placebo; zilganersen-matching placebo will be administered by ITB injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change from Baseline in the 10-Meter Walk Test (10MWT)	10-Meter Walk Test (10MWT) is an assessment of gait speed.	Baseline and Week 61

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Most Bothersome Symptom (MBS)	Baseline and Week 61
Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels	Baseline and Week 61
Change From Baseline in Body Weight Percentile (for participants < 18 years old at screening) or body weight (for participants ≥ 18 years old at screening)	Baseline and Week 61
Change From Baseline in Patient Global Impression of Severity (PGIS) Score	Baseline and Week 61
Change From Baseline in Patient Global Impression of Change (PGIC) Score	Baseline and Week 61
Change From Baseline in Clinical Global Impression of Change (CGIC) Score	Baseline and Week 61
Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score	Baseline and Week 61
Change From Baseline in 9-Hole Peg Test (9HPT) Score	Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score	Baseline to Week 61
Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score	Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score	Baseline to Week 61
Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score	Baseline and Week 61
Change From Baseline in Clinical Global Impression of Severity (CGIS) Score	Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score	Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score	Baseline and Week 61

Other Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in Pediatrics Quality of Life Inventory (PedsQL) Generic Core Scales Score	Baseline and Week 61

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2021
• Primary Completion (Actual): August 22, 2025
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: April 16, 2021
• First Submitted That Met QC Criteria: April 16, 2021
• First Posted (Actual): April 19, 2021

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: AxD
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Demyelinating Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Alexander Disease; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: ION373-CS1; 2024-510603-11-00 (Ctis)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes