Advancing Care in Alexander Disease: Insights From Phase 1-3 Trial of Zilganersen

Alexander disease is a rare, progressive leukodystrophy driven by pathogenic variants in the glial fibrillary acidic protein (GFAP) gene, leading to astrocyte dysfunction and widespread neurologic decline. With no approved disease-modifying therapies, care has largely remained supportive, underscoring the need for targeted approaches that can address the underlying biology of the disease.

At the 2026 American Academy of Neurology (AAN) Annual Meeting, investigators presented data from a pivotal phase 1–3 global, randomized, controlled trial (NCT04849741) evaluating zilganersen, an investigational antisense oligonucleotide designed to reduce GFAP expression. The study enrolled 49 patients aged 2 to 65 years who were randomized 2:1 to receive intrathecal zilganersen (25 mg or 50 mg) or control every 12 weeks for 60 weeks, followed by an open-label extension.

All told, Zilganersen met its primary end point, demonstrating a statistically significant improvement in gait speed at week 61 as measured by the 10-meter walk test (least squares mean difference, 33.3%; P = .041). Additional findings included a 33.6% reduction in plasma GFAP levels (P = .003) and directional improvements across patient- and clinician-reported outcomes, alongside a safety profile largely characterized by mild to moderate adverse events.

Amy Waldman, MD, associate professor of neurology at the Perelman School of Medicine at the University of Pennsylvania, spoke with NeurologyLive^® at the meeting to discuss the therapeutic rationale behind zilganersen, key efficacy and safety findings from the trial, and how these results may begin to shape diagnosis, treatment expectations, and future research in Alexander disease.

NeurologyLive: Can you provide an overview of Alexander disease and the rationale behind targeting GFAP with zilganersen, and then walk us through the phase 1–3 study design and key findings?

Amy Waldman, MD: Alexander disease is caused by a pathogenic, or likely pathogenic, variant in the GFAP gene, which stands for glial fibrillary acidic protein. As a result, you have an accumulation of GFAP, a buildup of it in the astrocyte, and it is ultimately considered a leukodystrophy, as much of the pathology is in the white matter, but there is also gray matter involvement as well.

Zilganersen is an antisense oligonucleotide that was designed to bind to the RNA to essentially turn off the production of GFAP. So instead of having these very high amounts of GFAP in the astrocytes, it was designed to lower GFAP, which in animal models was very effective in reducing the GFAP pathology, including something called Rosenthal fibers, throughout the brain.

This was a phase 1 through 3 clinical trial, which is somewhat unique. It included dose escalation cohorts typical of a phase 1 study and then progressed into a pivotal phase 3 portion with multiple ascending doses into the 50 mg target dose. Because this is a rare disease, identifying patients and moving efficiently through regulatory steps was critical. I remember in one of our early meetings, there was a statement made that the purpose of a clinical trial is actually to enroll the fewest number of patients necessary to determine safety and efficacy. That’s especially important in a first-in-human study like this, where we want to limit exposure until we understand the drug’s profile.

The study was double blind and controlled, with patients receiving drug every 12 weeks through the first 60 weeks, and then those in the control arm were able to receive open-label treatment. I’m delighted to share that the trial met its primary end point, which was a measure of gait speed at week 61 using the 10-meter walk test in patients aged 5 years and older. There was a significant improvement in gait speed in patients treated with zilganersen compared with placebo, which is a major advance for this disease community.

How did the safety and tolerability profile of zilganersen appear in this study?

The safety and tolerability profile for a drug that is injected intrathecally every 12 weeks was actually acceptable. There were mostly mild to moderate safety signals. There were a few serious adverse events, but these were predominantly related to the underlying disease itself, such as seizures, which are part of Alexander disease, or scoliosis.

There was one patient who continued to progress during the double-blind portion and sadly passed away during the open-label phase. It’s important to remember that this is a progressive and fatal disease, so interpreting safety always requires that context.

If approved, what would zilganersen mean for the Alexander disease community?

It would be huge. It provides a tremendous amount of hope for this patient community. Of course, it’s imperative that there is an accurate diagnosis. Younger patients are often easier to recognize because of the classic triad of developmental delay, seizures, and macrocephaly, although that can appear later. Teenagers and adults can be more difficult to diagnose, as they may present with intractable vomiting, short stature, gait abnormalities, or autonomic dysfunction, often with less obvious white matter changes.

Earlier treatment did seem to have a better effect in the trial, so identifying patients early is key. At the same time, it’s important to counsel patients and families appropriately. In a progressive disease like this, stabilization is often the goal. It can be difficult to reverse neurologic symptoms, especially if there is already neuronal loss. So helping families understand that repeated intrathecal treatments may result in stabilization rather than improvement is an important part of care.

What are some clinical pearls for improving early diagnosis of Alexander disease?

As clinicians, we rely heavily on MRI and genetic testing, but in adolescent and adult forms—what I refer to as bulbar or bulbospinal forms—there may be fewer classic MRI findings. In those cases, changes are often in the brainstem or cerebellum rather than supratentorial white matter, which may not immediately suggest Alexander disease.

One key point is not to anchor too heavily on MRI findings. The absence of classic imaging does not exclude the diagnosis. In progressive neurologic disease without a clear cause, genetic testing should be pursued. While targeted panels can be helpful, in some cases, moving to whole exome or even whole genome sequencing is warranted, especially now that there may be a treatment available.

What additional research is still needed in Alexander disease moving forward?

This study enrolled patients across a wide age range, from 2 to 65 years, but the disease is highly heterogeneous. We still need to better understand the different subtypes, why some patients develop more frontal symptoms versus brainstem involvement, and how those differences relate to outcomes.

It will take time and continued follow-up, particularly as patients receive treatment through expanded access or potentially commercially if the drug is approved. Ultimately, we need to understand how to optimize outcomes across these subgroups and continue improving quality of life for patients over time.

Transcript edited for clarity. Click here for more AAN 2026 coverage.

REFERENCE
1. Waldman A, Lynch D, Tonduti D, et al. Efficacy and Safety of Zilganersen, an Investigational RNA-targeted Antisense Therapy, in People Living with Alexander Disease: Results from a Pivotal Study. Presented at: 2026 AAN Annual Meeting; April 18-22; Chicago, Illinois. ABSTRACT 000941