Ionis Pharmaceuticals, Inc. has announced positive topline results from the pivotal study of zilganersen in children and adults living with Alexander disease (AxD), a rare, progressive and often fatal neurological condition with no approved disease-modifying treatments.
Zilganersen 50 mg demonstrated statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed as assessed by the 10-metre walk test (10MWT) compared to control at week 61 (mean difference 33.3%, p=0.0412) with favourable safety and tolerability. Zilganersen also demonstrated consistent benefit in key secondary endpoints. These data mark the first time an investigational medicine has shown a positive disease-modifying impact in AxD.
AxD is a rare, progressive and often fatal neurological disease that occurs in approximately 1 in 1 to 3m people worldwide and affects a type of cell in the brain called astrocytes. Astrocytes have multiple roles in the brain to support neurons and oligodendrocytes, including maintenance of the myelin sheath that protects nerve fibres.
AxD is caused by disease-causing variants in the glial fibrillary acidic protein (GFAP) gene and is generally characterized by progressive neurological deterioration resulting in loss of functional mobility, loss of independence and the inability to control muscles for large movements, swallowing and airway protection, though symptoms can vary depending on age of onset. AxD usually leads to death within 14-25 years after symptom onset. There are no approved disease-modifying medicines.
“These unprecedented results highlight the potential of zilganersen to create new possibilities for people living with Alexander disease, a devastating, progressive and often fatal condition that most commonly begins in early childhood and can take away fundamental functions like walking, speaking and swallowing,” said Holly Kordasiewicz, senior vice president of neurology at Ionis.
“These data demonstrate the promise of zilganersen to potentially transform the future treatment landscape for this condition and reinforce the power of our technology to address neurological diseases by directly targeting the underlying cause. We are deeply grateful to the patients, families and researchers whose participation has helped make this progress possible.”
In addition to achieving the primary endpoint, zilganersen demonstrated consistent favourable trends across key secondary endpoints, indicating evidence of slowed disease progression, stabilization or improvement. Key secondary endpoints include change from baseline in patients’ self-identified Most Bothersome Symptom (MBS) Score, Patient Global Impression of Severity (PGIS) Score, Patient Global Impression of Change (PGIC) Score and Clinician Global Impression of Change (CGIC) Score.
“Today’s news is a monumental step forward in advancing a potential treatment for Alexander disease, offering long-awaited hope for people living with this condition, their families and the community,” said Brett P. Monia, chief executive officer of Ionis.
“These data show the power of Ionis’ innovation to once again potentially establish a treatment standard for a devastating condition where none currently exists. Building on our legacy of delivering transformational treatments for spinal muscular atrophy and SOD1-amyotrophic lateral sclerosis, this outcome further underscores the strength of our proven platform to address severe neurological diseases. We look forward to working closely with the FDA to bring this wholly owned potential treatment forward for individuals and families in urgent need.”
Zilganersen demonstrated a favourable safety and tolerability profile, with most adverse events being mild or moderate in severity. Incidence of serious adverse events was numerically lower in the zilganersen arm as compared to the control arm.
Ionis plans to submit a new drug application (NDA) to the U.S. Food and Drug Administration in Q1 2026 and is evaluating the potential to initiate an Expanded Access Program (EAP) in the U.S. Detailed data will be presented at an upcoming medical conference.
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