Patients who have a particular genetic disease whose symptoms include progressively worsening muscle control were able to walk faster following treatment with an experimental Ionis Pharmaceuticals genetic medicine, meeting the main goal of a pivotal study. Based on these results, the drugmaker said it plans a regulatory submission for what could become the first FDA-approved therapy for this ultra-rare condition.
The Ionis drug, zilganersen, was developed to treat Alexander disease, an inherited disorder that leads to neurological deterioration and symptoms that include the loss of functional mobility, inability to control muscles, and difficulty breathing and swallowing. As these symptoms worsen, they eventually become fatal. Current treatment of this ultra-rare disease, which occurs in an estimated one in every 1 million births, is supportive care to manage symptoms.
Alexander disease affects astrocytes, a type of cell prevalent in the central nervous system and key to its function. The disease stems from a genetic mutation that leads to abnormal buildup of glial fibrillary acidic protein (GFAP) in astrocytes. Zilganersen is an antisense oligonucleotide (ASO) designed to stop production of excess GFAP caused by mutations in the GFAP gene.
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Ionis evaluated zilganersen in a multiple-ascending dose, placebo-controlled Phase 1-3 study that enrolled Alexander disease patients between the ages of 18 months and 53 years-old. Participants, mostly children, were randomly assigned to receive a low or high dose of the study drug or a placebo administered as an intrathecal injection every 12 weeks. The 50 mg high-dose group was considered the pivotal dose cohort.
The main study goal is measuring, from baseline to 60 weeks, the change in gait speed according to a 10-meter walk test. Ionis said Monday that the high dose of zilganersen showed a 33% increase on the gait-speed goal, which was both statistically significant and clinically meaningful. Secondary goals include measuring patient- and physician-reported scores according to various scales to assess symptoms and disease severity. On these goals, Ionis said only that results showed “consistent favorable trends.”
Ionis said the study drug showed favorable safety and tolerability, adding that most adverse events were mild or moderate. The incidence of serious adverse events was numerically lower in the zilganersen arm compared to the control arm. Detailed data will be presented at an upcoming medical conference. Ionis plans to submit a new drug application to the FDA for zilganersen in the first quarter of 2026.
Ionis specializes in ASOs, a type of genetic medicine that employs small pieces of RNA to bind to messenger RNA in order to reduce expression of a disease-causing protein. The company’s ASO research has led to the FDA-approved neuroscience medicines Spinraza for spinal muscular atrophy and Qualsody for a rare, genetic form of amyotrophic lateral sclerosis. Both were developed and commercialized in partnership with Biogen.
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Ionis still has partnerships, but its strategy now includes developing and commercializing drugs on its own. FDA approval of Tryngolza last year made that familial chylomicronemia syndrome drug Ionis’s first wholly owned commercial asset. The FDA nod last month for hereditary angioedema drug Dawnzera gave Ionis its second one.
In a Monday note sent to investors, William Blair analyst Myles Minter said details on zilganersen’s results according to secondary goals will have readthrough to the drug’s pricing, if this ASO is approved. The firm models $295 million in peak sales for the drug; about $120 million in the U.S.
“Alexander disease is an ultra-orphan condition with an estimated population of less than 500 patients globally,” Minter said. “However, there are currently no approved therapies for Alexander disease, and given the unmet need here we see today’s Phase 3 results as another win for Ionis within its wholly owned neurology franchise, which continues to generate positive clinical results.”
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