Written By: Gayatri Bhor BPharm
Reviewed By: Pharmacally Editorial Team
Ionis Pharmaceuticals announced positive topline results from its pivotal Phase 1–3 trial of Zilganersen at late September 2025, through a company release. The results mark a historic moment in neurology, as Zilganersen is the first investigational therapy to demonstrate disease-modifying benefit in Alexander Disease (AxD) a rare, progressive, and often fatal disorder with no approved treatments. Ionis planned NDA submission in first quarter of 2026, reflecting the company’s intention to move rapidly toward regulatory review.
About Zilganersen
Zilganersen is an antisense oligonucleotide (ASO) therapy, a class of precision medicines designed to target the root cause of genetic diseases. It binds to the messenger RNA (mRNA) of the glial fibrillary acidic protein (GFAP) gene, preventing excessive GFAP protein production. This directly reduces the toxic buildup of GFAP in the brain’s white matter, which is central to AxD pathology. If approved, Zilganersen would become the first-ever disease-modifying therapy for Alexander Disease, establishing a new benchmark for treatment similar to how ASO therapies transformed outcomes in spinal muscular atrophy (SMA) and SOD1-ALS.
About Alexander Disease
Alexander Disease is an ultra-rare neurodegenerative disorder that affects about 1 in 1-3 million people worldwide. It is caused by mutations in the GFAP gene, which lead to abnormal protein accumulation in astrocytes, a type of brain cell. These cells play a critical role in maintaining brain function and supporting the myelin sheath, and when they become dysfunctional, patients experience severe neurological decline. The disease manifests with a wide range of symptoms, including loss of mobility, speech and swallowing difficulties, seizures, cognitive impairment, and in many cases respiratory complications. Prognosis is poor, with most patients dying within 14 to 25 years after symptom onset, and earlier-onset forms progressing more aggressively. Currently, there are no approved disease-modifying therapies, which make the success of Zilganersen particularly significant for patients and their families.
Clinical Evidence: The Zilganersen Trial
Study Design
The pivotal trial (NCT04849741) was a global, multicenter, randomized, double-blind, placebo-controlled study that enrolled 54 participants between the ages of 1.5 and 53 years across eight countries. Most of the participants were children, reflecting the disease’s early onset and severity in pediatric populations. Participants were randomized in a 2:1 ratio to receive Zilganersen or placebo for 60 weeks. Two dose levels, 25 mg and 50 mg, were investigated, with the 50 mg cohort designated as the pivotal dose. Treatment was given once every 12 weeks, and the primary endpoint was the percent change in gait speed, assessed using the 10-Meter Walk Test (10MWT). Secondary endpoints included changes from baseline in patient- and clinician-reported measures such as the Most Bothersome Symptom (MBS) Score, Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Clinician Global Impression of Change (CGIC) assessed at the end of the double-blind treatment period.
Results
At week 61, patients treated with Zilganersen 50 mg demonstrated a statistically significant and clinically meaningful 33.3% improvement in gait speed compared to placebo (p=0.0412). Beyond the primary outcome, the drug showed consistent benefits across key secondary endpoints, including improvements in the Most Bothersome Symptom (MBS) Score, Patient Global Impression of Severity (PGIS), Patient Global Impression of Change (PGIC), and Clinician Global Impression of Change (CGIC). These results collectively suggest slowed disease progression, stabilization, or even improvement in functional and quality-of-life measures. Following the double-blind period, participants entered an open-label extension phase for continued long-term evaluation of safety and efficacy.
Safety Profile
Zilganersen demonstrated a favorable safety and tolerability profile:
- Most adverse events were mild or moderate.
- Serious adverse events were less frequent in the treatment group compared to placebo.
- No unexpected safety signals were reported, supporting its long-term development.
Implications
The success of Zilganersen carries important implications for both patients and the broader rare disease field. Most importantly, it represents the first disease-modifying option for Alexander Disease, offering long-awaited hope to families who have had no therapeutic alternatives beyond supportive care. Looking ahead, Ionis has confirmed plans to submit a New Drug Application (NDA) in the first quarter of 2026, with the goal of working closely with the FDA to bring zilganersen to patients as quickly as possible. While details around pricing, insurance coverage, and patient support programs (PSPs) have not yet been announced, the company’s statements suggest a commitment to ensuring broad access, particularly given the urgency and lack of alternatives in Alexander Disease.
Key Opinions
Experts at Ionis emphasized both the clinical importance of the findings and the broader impact of antisense technology in neurology.
Holly Kordasiewicz, Ph.D., Senior Vice President of Neurology at Ionis, highlighted the potential of zilganersen to reshape care for Alexander Disease, noting that the therapy directly targets the root genetic cause of the condition. She stressed that these results demonstrate not only the scientific promise of antisense approaches but also the possibility of transforming the future treatment landscape for a disorder that has never had a disease-modifying option. She also expressed gratitude to the patients, families, and researchers whose participation made the trial possible.
Brett P. Monia, Ph.D., Chief Executive Officer of Ionis, framed the results as part of the company’s growing legacy in rare neurology. He drew parallels to the success of previous Ionis programs in spinal muscular atrophy and SOD1-amyotrophic lateral sclerosis, noting that zilganersen could establish a new treatment standard in yet another devastating disease. He further emphasized the company’s commitment to advancing this wholly owned therapy through close collaboration with the FDA, with the goal of making it available to individuals and families who urgently need it.
References
Ionis announces positive topline results from pivotal study of Zilganersen in Alexander disease, Ionis, 22 Sept 2025, https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-pivotal-study
A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD), ClinicalTrials.gov ID NCT04849741, https://www.clinicaltrials.gov/study/NCT04849741
Ionis Plans Application Submission for Zilganersen as Potential First Treatment for Alexander Disease Following Positive Data, https://www.neurologylive.com/view/ionis-plans-application-submission-zilganersen-potential-first-treatment-alexander-disease-following-positive-data