Ionis Pharmaceuticals today revealed that it has finalized enrollment in its pivotal trial evaluating zilganersen (ION373), an investigational RNA-targeted therapy aimed at treating children and adults with Alexander disease (AxD), a rare, progressive, and ultimately fatal neurological disorder. The trial’s primary endpoint is the percent change from baseline in gait speed, measured by the 10-Meter Walk Test (10MWT), with topline data expected in the second half of 2025.
Alexander disease, which affects approximately one in a million people in the U.S., can manifest at any age. It results from genetic mutations in the glial fibrillary acidic protein (GFAP) gene, disrupting the structure and function of astrocytes in the brain. The disease is characterized by cognitive dysfunction and progressive neurological decline, including loss of independence and impaired muscle control for movements, swallowing, and airway protection. Zilganersen aims to reduce excess GFAP caused by these genetic mutations, potentially slowing or stabilizing the disease’s progression.
“While current treatments for Alexander disease can alleviate some symptoms, they do not address the underlying cause or slow disease progression. Our zilganersen trial is the first to evaluate a treatment specifically designed to target the root cause of Alexander disease,” stated Eugene Schneider, M.D., Executive Vice President and Chief Clinical Development Officer at Ionis. “We extend our gratitude to the patients, families, and investigators in the Alexander disease community, whose support has been crucial to reaching this milestone.”
About the Zilganersen Study
The global, multicenter, randomized, double-blind, controlled, multiple-ascending dose (MAD) study, identified as Phase 1-3 (NCT04849741), has enrolled participants aged 2 to 65 with Alexander disease at 13 sites across eight countries. Participants are randomly assigned in a 2:1 ratio to receive zilganersen or a control for a 60-week double-blind treatment period. Following this, all participants will receive zilganersen during a 180-week open-label treatment phase, with a subsequent 28-week post-treatment follow-up. The study’s primary endpoint is the change in gait speed from baseline measured by the 10-Meter Walk Test (10MWT) at the end of the double-blind phase. Secondary endpoints include changes in patients’ self-reported Most Bothersome Symptom (MBS) Score, Patient Global Impression of Severity (PGIS) Score, Patient Global Impression of Change (PGIC) Score, and Clinician Global Impression of Change (CGIC) Score.
An additional open-label sub-study for eligible participants under two years of age will continue to enroll through 2025.
About Zilganersen (ION373)
Zilganersen is an investigational antisense oligonucleotide designed to treat genetically confirmed Alexander disease (AxD) by inhibiting the excess production of glial fibrillary acidic protein (GFAP) due to disease-causing mutations in the GFAP gene. The U.S. Food and Drug Administration (FDA) granted zilganersen Orphan Drug and Rare Pediatric designations in 2020, while the European Medicines Agency (EMA) granted Orphan Drug designation in 2019.
About Alexander Disease (AxD)
Alexander disease is a rare, progressive, and ultimately fatal neurological condition that affects astrocytes, a type of brain cell. Astrocytes support neurons and oligodendrocytes, including maintaining the myelin sheath that protects nerve fibers. Caused by mutations in the GFAP gene, AxD is marked by cognitive decline and progressive neurological deterioration, often leading to death within 14-25 years of symptom onset. There are currently no approved disease-modifying treatments.
About Ionis Pharmaceuticals, Inc.
For over thirty years, Ionis Pharmaceuticals has been at the forefront of developing medicines that offer improved outcomes for individuals with serious diseases. The company has five marketed drugs and a leading pipeline in neurology, cardiology, and other high-need areas. As a pioneer in RNA-targeted therapies, Ionis continues to innovate in RNA medicine and gene editing, driven by a deep understanding of disease biology and a commitment to delivering transformative advancements for patients.
