AAN 2026 | Findings from a Phase III trial evaluating zilganersen in Alexander disease

The pathophysiology of Alexander Disease has been very well described, including the genetic variant in GFAP, which is the name of the gene that produces glial fibrillary acidic protein, which is a protein that accumulates in astrocytes. With that accumulation of protein in astrocytes, there is a further buildup of fibers called Rosenthal fibers throughout the brain, but it’s not exactly known how those fibers disrupt brain function and cause patient symptoms. There are actually no approved treatments for this disease, so we really are only left with the option of treating symptoms. For example, using anti-seizure medicines in the subset of patients that have seizures, or using medications to help with tone or spasticity, or those to help with some of the GI side effects in this disease. Zilganersen is an antisense oligonucleotide, or ASO, that binds to the GFAP RNA, and by doing so, causes the body to make less GFA protein. So ultimately, the goal is to reduce the amount of protein being made to slow or halt disease progression. In this study, 49 patients were randomized in total, beginning at the start of the study with eight participants in the initial Phase I cohort of 25 milligrams compared to the control. And ultimately, 24 participants were randomized in the Phase III or the 50 milligram cohort. And across both cohorts, there were 17 control participants. And over the course of the study, there was a stabilization of gait speed in those patients who received zilganersen at week 61, whereas there was a steady decline in motor skills in the patients receiving control. There were also a number of other outcome measures that favored zilganersen treatment that really covered the gastrointestinal, other motor symptoms, cognitive and autonomic symptoms in this disease. The safety profile is generally tolerable and acceptable. There were some mild to moderate adverse events and serious adverse events occurring in the zilganersen group actually occurred at a frequency that was decreased compared to the pooled control and generally consisted of seizures, vomiting, and scoliosis, some of which was deemed to be related to the underlying condition rather than the treatment itself. This has been a major milestone for this disease community and a major advancement in having a potential first disease-modifying therapy. And in the future, it’ll be exciting for us to learn more about the different presentations, how zilganersen can halt or stop disease progression, and ultimately how we improve how patients are feeling who are suffering from this disorder. I would just like to thank the entire disease community, the patients that were participating in this trial, but also all of those participants who visited me at CHOP, helped me to understand this disease in incredible detail, and it would not have been possible without the tremendous efforts of the entire Alexander Disease community.

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