Zilganersen demonstrates stabilization of gait speed for Alexander disease

Zilganersen demonstrates stabilization of gait speed for Alexander disease | Image Credit: © DragonImages - © DragonImages - stock.adobe.com.

Zilganersen met the primary endpoint of gait stabilization in a pivotal Phase 1-3 study (NCT04849741) of patients with Alexander disease (AxD), according to topline results released by Ionis Pharmaceuticals. The trial showed that zilganersen 50 mg achieved a statistically significant 33.3% mean difference in gait speed on the 10-Meter Walk Test (10MWT) compared with control at week 61 (P = 0.0412). The company reported favorable safety and tolerability, with most adverse events mild or moderate in severity.^1,2

“These unprecedented results highlight the potential of zilganersen to create new possibilities for people living with Alexander disease,” said Holly Kordasiewicz, PhD, senior vice president of neurology, Ionis. “These data demonstrate the promise of zilganersen to potentially transform the future treatment landscape for this condition and reinforce the power of our technology to address neurological diseases by directly targeting the underlying cause.”¹

Zilganersen study outcomes

In addition to the primary endpoint, zilganersen showed consistent benefit across key secondary measures, including patients’ self-identified Most Bothersome Symptom Score, Patient Global Impression of Severity, Patient Global Impression of Change, and Clinician Global Impression of Change. Ionis said the data indicate slowed disease progression, stabilization, or improvement in these patient- and clinician-reported outcomes.

The safety profile was favorable, and the incidence of serious adverse events was numerically lower in the zilganersen group compared with control.

“Today’s news is a monumental step forward in advancing a potential treatment for Alexander disease,” said Brett P. Monia, PhD, chief executive officer, Ionis. “These data show the power of Ionis’ innovation to once again potentially establish a treatment standard for a devastating condition where none currently exists.”

Study design

The pivotal trial was a global, multicenter, randomized, double-blind, controlled, multiple-ascending dose study that enrolled 54 participants between ages 1.5 and 53 years across 13 sites in eight countries. Most participants were children, reflecting the early onset of AxD. Patients were randomized 2:1 to zilganersen or control for 60 weeks, with dosing every 12 weeks.

The pivotal analysis focused on the 50 mg dose cohort. After the double-blind period, all eligible participants entered an open-label phase, followed by a 120-week long-term extension. The study’s primary endpoint was percent change from baseline in gait speed by 10MWT. Key secondary endpoints were based on patient- and clinician-reported symptom assessments.

Ionis plans to submit a new drug application for zilganersen to FDA in Q1 2026. The company is also evaluating the possibility of initiating an expanded access program in the United States before commercial approval. Detailed results are expected to be presented at an upcoming medical conference.

Zilganersen, also known as ION373, is an investigational antisense oligonucleotide targeting glial fibrillary acidic protein (GFAP) overproduction, the genetic cause of AxD. FDA has granted the therapy Orphan Drug and Rare Pediatric designations, and the European Medicines Agency has granted Orphan Drug designation.

References:

1. Ionis announces positive topline results from pivotal study of zilganersen in Alexander disease. Ionis Pharmaceuticals. Press release. September 22, 2025. Accessed September 22, 2025. https://www.businesswire.com/news/home/20250922674696/en/Ionis-announces-positive-topline-results-from-pivotal-study-of-zilganersen-in-Alexander-disease
2. A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD). ClinicalTrials.gov. Updated August 26, 2025. Accessed September 22, 2025. https://clinicaltrials.gov/study/NCT04849741