Efficacy and Safety of Zilganersen, an Investigational RNA-targeted Antisense Therapy, in People Living with Alexander Disease: Results from a Pivotal Study
Amy Waldman1, David Lynch2, Davide Tonduti3, Marjo Van Der Knaap4, Geneviève Bernard5, Florian Eichler6, Jacinda Sampson7, Ayelet Zerem8, Jeremy Chataway2, Chloe Cunningham9, Enrico Bertini10, Yael Hacohen11, Takashi Saito12, Stephanie Keller13, Ylenia Vaia3, Nee Na Kim14, Amanda Nagy6, Keith Van Haren7, Elske Van den Berg4, Chen Chen15, Norma Ruiz15, Abigail Collins15, Anne Smith15
1Division of Neurology, Children’s Hospital of Philadelphia, and Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, 2Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; National Institute for Health Research, University College London Hospitals, Biomedical Research Centre; Inherited White Matter Disorders Highly Specialised Service, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, 3Unit of Pediatric Neurology, COALA (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, University of Milan, 4Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, 5Department of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, 6Department of Neurology, Massachusetts General Hospital, Harvard Medical School, and the Center for Genomic Medicine, Massachusetts General Hospital, 7Department of Neurology and Neurological Sciences, Stanford Neuroscience Health Center, 8Dana-Dwek Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv University, 9Murdoch Children’s Research Institute, 10Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children’s Hospital, IRCCS, 11Department of Pediatric Neurology, Great Ormond Street Hospital for Children, 12Department of Child Neurology National Center of Neurology and Psychiatry, 13Department of Pediatrics, Division of Pediatric Neurology, Emory University School of Medicine, 14Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London; Department of Neurology, Great Ormond Street Hospital for Children, 15Ionis
Objective:
To report efficacy and safety of zilganersen in people with Alexander disease (AxD).
Background:
AxD, a rare, genetic astrocytopathy arising from pathogenic variants in the glial fibrillary acidic protein (GFAP) gene, is characterized by progressive neurologic deterioration. Zilganersen, an investigational antisense therapy targeting GFAP RNA, is being evaluated as the first potential disease-modifying treatment for AxD.
Design/Methods:
In this pivotal phase 1–3, global, randomized, controlled study (NCT04849741), participants (2–65 years of age) with AxD were randomized 2:1 to intrathecal zilganersen (25 or 50 mg) or control every 12 weeks for 60 weeks, after which all participants received open-label zilganersen. The primary endpoint was the percent change from baseline (CFB) at Week (W)61 in gait speed assessed by the 10-meter walk test. Key secondary endpoints included CFB in participants’ self-identified Most Bothersome Symptom (MBS), Patient Global Impression (of severity and change; PGIS and PGIC), and Clinician Global Impression of Change (CGIC) scores at W61. Safety and tolerability were assessed.
Results:
During the double-blind treatment period, 49 participants (median age, 11 years [range, 2–53 years]; 65.3% female) were randomized (zilganersen 50 mg, 24; zilganersen 25 mg, 8; control, 17). The primary endpoint was met (least squares mean difference, 33.3%; P=0.041) and key secondary endpoints trended towards improvement with zilganersen (50 mg) vs control (MBS, odds ratio [OR]=2.79, P=0.142; PGIS, OR=1.66, P=0.463; PGIC, OR=5.22, P=0.010; CGIC, OR=2.32, P=0.160; nominal P-values). Plasma GFAP was lowered by 33.6% (zilganersen 50 mg vs control; P=0.003). Most treatment-emergent adverse events (TEAEs) were mild or moderate; incidence of serious TEAEs was 37.5% for pooled zilganersen vs 47.1% for control.
Conclusions:
Zilganersen shows potential as a disease-modifying therapy for AxD, with statistically significant and clinically meaningful stabilization of motor function, a consistent trend towards benefit across key secondary endpoints, a favorable safety profile, and target engagement vs control.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.