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

NCT ID: NCT04849741

Last Updated: 2025-11-28

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 54 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-01
• Study Completion Date: 2029-09-30

Brief Summary

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.

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.

Conditions

Alexander Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

zilganersen

Intervention Type: DRUG

zilganersen will be administered by ITB injection.

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

zilganersen-matching placebo will be administered by ITB injection.

Interventions

zilganersen

zilganersen will be administered by ITB injection.

Intervention Type: DRUG

Placebo

zilganersen-matching placebo will be administered by ITB injection.

Intervention Type: DRUG

Other Intervention Names

ION373

Eligibility Criteria

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)

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Lucile Packard Children's Hospital Stanford

Palo Alto, California, United States

Children's Hospital of Atlanta

Atlanta, Georgia, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Murdoch Children's Research Institute

Parkville, Victoria, Australia

McGill University Health Centre

Montreal, Quebec, Canada

Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center

Tel Aviv, , Israel

Ospedale dei Bambini Vittore Buzzi

Milan, , Italy

Ospedale Pediatrico Bambino Gesù

Roma, , Italy

National Center of Neurology and Psychiatry

Tokyo, Kodaira-shi, Japan

Amsterdam Universitair Medische Centra - Academisch Medisch Centrum

Amsterdam, North Holland, Netherlands

University College London Hospitals NHS Foundation Trust

London, , United Kingdom

Great Ormond Street Hospital for Children NHS Foundation Trust

London, , United Kingdom

Countries

United States; Australia; Canada; Israel; Italy; Japan; Netherlands; United Kingdom

Other Identifiers

2024-510603-11-00

Identifier Type: CTIS

Identifier Source: secondary_id

ION373-CS1

Identifier Type: -

Identifier Source: org_study_id