Ionis finishes enrollment for zilganersen trial in Alexander disease patients

Ionis Pharmaceuticals, Inc. has announced the completion of participant enrollment in the pivotal trial of zilganersen (ION373), an investigational RNA-targeted medicine for treating Alexander disease (AxD), a rare and fatal neurological disorder. The trial aims to assess the effectiveness of zilganersen in both children and adults.

Alexander disease occurs in approximately one in a million people in the U.S. and can manifest at any stage of life. It is caused by genetic mutations in the glial fibrillary acidic protein (GFAP) gene, which disrupts the structure and function of astrocytes in the brain. The disease typically leads to cognitive decline and progressive neurological deterioration, affecting the ability to perform large movements, swallow, and protect the airway. Zilganersen is designed to inhibit the production of excess GFAP, potentially slowing or stabilizing disease progression.

The primary endpoint of the trial is the percent change from baseline in gait speed, measured by the 10-Meter Walk Test (10MWT). The study is expected to produce topline data in the latter half of 2025.

Dr. Eugene Schneider, executive vice president and chief clinical development officer at Ionis, remarked on the milestone, emphasizing the collaborative effort from patients, families, and investigators. He noted that current management strategies for Alexander disease can alleviate some symptoms but do not address the root cause or halt disease progression. This study marks the first trial of a medicine specifically designed to target the underlying genetic cause of Alexander disease.

The zilganersen study is a global, multicenter, randomized, double-blind, controlled, multiple-ascending dose (MAD) study (NCT04849741). Patients aged two to 65 years with Alexander disease were enrolled across 13 sites in eight countries. Participants were randomized in a 2:1 ratio to either receive zilganersen or a control for a 60-week double-blind treatment period. Following this period, all participants will receive zilganersen during a 180-week open-label treatment phase, culminating in a 28-week post-treatment follow-up.

Secondary endpoints of the study include changes from baseline in several patient-reported and clinician-assessed outcomes. These encompass the 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 at the end of the double-blind phase.

An open-label sub-study is ongoing for eligible participants under the age of two years with Alexander disease and will continue enrolling participants until 2025.

Zilganersen is an investigational antisense oligonucleotide medicine developed as a potential treatment for patients with genetically confirmed Alexander disease. It targets the excess production of GFAP resulting from disease-causing mutations in the GFAP gene. The U.S. Food and Drug Administration (FDA) granted zilganersen Orphan Drug designation and Rare Pediatric designation in 2020. Similarly, the European Medicines Agency (EMA) granted it Orphan Drug designation in 2019.

Alexander disease is a progressive, fatal neurological disorder that affects astrocytes, which support various brain functions, including neuron and oligodendrocyte maintenance. The disease is marked by cognitive dysfunction and progressive neurological decline, often leading to death within 14-25 years post-symptom onset. There are currently no approved disease-modifying treatments for Alexander disease.

Ionis Pharmaceuticals has been a pioneer in RNA-targeted medicines for over three decades, focusing on serious diseases. The company boasts a robust pipeline in neurology, cardiology, and other high-need areas, driven by a deep understanding of disease biology and cutting-edge technology. Ionis remains committed to delivering transformative medical advancements for patients in need.