Ionis Plans Application Submission for Zilganersen as Potential First Treatment for Alexander Disease Following Positive Data

Ionis announced new positive data from its phase 1-3 trial (NCT04849741), with results demonstrating disease-modifying therapeutic effects of investigational zilganersen in patients with Alexander disease (AxD), a rare and often fatal neurological disease. Based on the findings, the company is planning to submit a new drug application (NDA) in Q1 2026, paving the path for zilganersen to potentially be the first approved treatment for this patient population.¹

The double-blind, controlled trial comprised 54 patients between the ages of 1.5 and 53 years who were randomly assigned 2:1 to either zilganersen 25 mg, 50 mg, or placebo, for a 60-week double-blind treatment period. At the conclusion of this period, results showed a 33.3% mean difference in change of 10-Meter Walk Test (10MWT) for those on the higher dose of zilganersen, the pivotal dose cohort, relative to placebo controls (P = .0412). According to the company, this marked the first time that a medication showed positive disease-modifying effects in AxD.

Other key secondary end points, such as change in patients’ self-identified Most Bothersome Symptom (MBS) score, Patient Global Impression of Severity (PGIS) score, Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) score all trended in favor of zilganersen. These findings, which indicate evidence of slowed disease progression, stabilization, or improvement, will be further detailed at an upcoming medical conference.

"These unprecedented results highlight the potential of zilganersen to create new possibilities for people living with Alexander disease, a devastating, progressive and often fatal condition that most commonly begins in early childhood and can take away fundamental functions like walking, speaking and swallowing," Holly Kordasiewicz, PhD, senior vice president of neurology at Ionis, said in statement.¹ "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."

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Zilganersen, an antisense oligonucleotide, is designed to stop production of excess glial fibrillary acidic protein (GFAP) that accumulates because of disease-causing variants in the GFAP gene. By lowering GFAP levels, the therapy aims to restore astrocyte homeostasis, improve myelin support, and slow or halt the neurodegenerative process. Currently, there are no FDA-approved disease-modifying treatments for AxD, and management has been supportive only.

The phase 1-3 study continues on with a 120-week, open-label, long-term extension treatment period, during which participants in the 25 mg dose cohort move to the 50 mg dose cohort. Following this, the trial concludes with a 28-week post-treatment follow-up period. Of note, Ionis is planning on initiating an expanded access program in the U.S. to allow for greater exposure to zilganersen to wider AxD community.

"These data show the power of Ionis' innovation to once again potentially establish a treatment standard for a devastating condition where none currently exists. Building on our legacy of delivering transformational treatments for spinal muscular atrophy and SOD1-amyotrophic lateral sclerosis, this outcome further underscores the strength of our proven platform to address severe neurological diseases,” Brett P. Monia, PhD, chief executive officer at Ionis, said in a statement.¹

He added, “We look forward to working closely with the FDA to bring this wholly owned potential treatment forward for individuals and families in urgent need.”

REFERENCE
1. Ionis announces positive topline results from pivotal study of zilganersen in Alexander disease. News release. Ionis. 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. Zilganersen granted U.S. FDA Fast Track designation for people living with Alexander disease. News release. Ionis Pharmaceuticals. October 1, 2024. Accessed September 22, 2025. https://www.prnewswire.com/news-releases/zilganersen-granted-us-fda-fast-track-designation-for-people-living-with-alexander-disease-302263365.html