Overviewing Pivotal Data Supporting Zilganersen as First Treatment for Alexander Disease: Amy Waldman, MD

“To see a meaningful change in gait speed in a progressive disease like Alexander disease is incredibly encouraging. It suggests we may finally be able to alter the course of this condition.”

Alexander disease is a rare, progressive leukodystrophy caused by pathogenic variants in the glial fibrillary acidic protein (GFAP) gene, leading to astrocyte dysfunction and widespread neurologic impairment. Patients may present across a broad age range with symptoms including gait disturbance, bulbar dysfunction, seizures, and cognitive decline. Despite its severity, there are currently no approved disease-modifying therapies. zilganersen is an RNA-targeted antisense oligonucleotide designed to reduce GFAP expression and address the underlying disease biology, representing a potential first-in-class therapeutic approach.

At the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18-22 in Chicago, Illinois, investigators presented results from a global, randomized, controlled phase 1–3 study (NCT04849741) evaluating zilganersen in patients aged 2 to 65 years. Participants 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.

The trial met its primary endpoint, demonstrating a significant improvement in gait speed at week 61 (least squares mean difference, 33.3%; P = .041). Secondary endpoints showed directional improvement across patient- and clinician-reported outcomes, including Patient Global Impression of Change (PGIC), while plasma GFAP levels were reduced by 33.6% (P = .003), supporting target engagement. Safety findings indicated that most adverse events were mild to moderate, with a lower incidence of serious events in the treatment group compared with control.

Following the presentation, Amy Waldman, MD, associate professor of neurology at the Perelman School of Medicine at the University of Pennsylvania, spoke with NeurologyLive® about the implications of these findings. In the discussion, she reviews the efficacy and safety data, highlights key clinical and biomarker signals, and reflects on the potential impact of zilganersen as a first disease-modifying therapy for patients living with Alexander disease.

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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