Zilganersen for the Treatment of Alexander Disease

Amy Waldman, MD, pediatric neurologist and Medical Director of the Leukodystrophy Center at the Children’s Hospital of Philadelphia, discusses the approval of Zanvastro (zilganersen) to treat patients with Alexander disease. Alexander disease is a rare leukodystrophy that impairs neuronal signalling. Most cases of Alexander disease begin before age 2 and are described as the infantile form. Signs and symptoms of the infantile form typically include an enlarged brain and head size, seizures, stiffness in the arms and/or legs, intellectual disability, and developmental delay. Alexander disease is also characterized by abnormal protein deposits known as Rosenthal fibers. These deposits are found in specialized cells called astroglial cells, which support and nourish other cells in the central nervous system. Zilganersen is an antisense oligonucleotide that binds to RNA and is designed to inhibit production of excess glial fibrillary acidic protein (GFAP) that accumulates as a result of pathogenic variants in the *GFAP* gene. It is the first and only disease modifying therapy approved for this indication.  The approval is based on positive results from a global, multicenter, randomized, double-blind, controlled, multiple-ascending dose (MAD) phase 1-3 study (NCT04849741) that enrolled 54 participants with Alexander disease.  The study met its primary endpoint in individuals 5 years of age and older, with zilganersen 50 mg demonstrating statistically significant and clinically meaningful stabilization of gait speed as assessed by the 10-Meter Walk Test (10MWT) compared to control at week 61. The treatment also demonstrated a favorable safety and tolerability profile, with most adverse events being mild or moderate in severity. Alexander disease faces a unique challenge to getting on newborn screening panels. Although the disease does typically present in young children, GFAP accumulation may not be high enough to detect at birth. Dr. Waldman explains that research is still being done to determine when the earliest possible diagnosis can be made. However, she highlights the following red flag symptoms that may point to central nervous system involvement and may warrant genetic testing: in younger children these include gross motor and developmental delays, seizures, and in older children, these include more mild symptoms such as hypernasal speech, speech delay, vomiting, and gait imbalance. For more information on the approval, visit https://ir.ionis.com/news-releases/news-release-details/zanvastrotm-zilganersen-approved-fda-first-and-only-disease To learn more about Alexander disease and other rare neurological conditions, visit https://checkrare.com/diseases/neurology-nervous-system-diseases/ **Rare Discussions is produced by CheckRare**, the leading multimedia platform dedicated to advancing education, awareness, and innovation across the rare disease community. Explore additional physician interviews, podcasts, CME activities, and rare disease resources at **CheckRare.com**. Subscribe to the **CheckRare Podcast Network** for expert conversations, weekly news, accredited education, and the latest advances across the rare disease community. Part of the **CheckRare Podcast Network**: Trusted conversations, news, education, and expert insights across the rare disease community.