Zilganersen Gains FDA Fast Track for Alexander Disease, a Rare Leukodystrophy

Eugene Schneider, MD

Recently, the FDA granted fast track designation to Ionis’ antisense oligonucleotide zilganersen as a potential treatment of Alexander disease (AxD), an ultra-rare, progressive and ultimately fatal type of leukodystrophy. Otherwise known as ION373, the investigational agent is currently being studied in a phase 1-3 trial (NCT04849741), with topline data anticipated in the second half of 2025.¹

AxD, a disease estimated to occur in 1 in 1 million people in the US, has no FDA-approved treatments to date. The disease, generally characterized by cognitive dysfunction and progressive neurologic deterioration, is a result of genetic variants in the glial fibrillary acidic protein (GFAP) gene that disrupts the structure and function of astrocytes in the brain. Zilganersen is designed to stop the excess GFAP that accumulates because of disease-causing variants in the GFAP gene, with the goal of slowing or stabilizing disease progression in people living with AxD.

"With no approved treatments available for people living with AxD, receiving this Fast Track designation for zilganersen reflects the seriousness of this ultra-rare disease and the significant unmet need for treatment in this patient population,” Eugene Schneider, MD, executive vice president and chief clinical development officer at Ionis, said in a statement.¹ "Zilganersen was designed to address the underlying cause of disease and help improve the functioning of people living with AxD. We look forward to a data readout next year and working closely with the FDA to potentially bring forward the first approved AxD treatment."

READ MORE: European Commission Grants NLX-112 Orphan Medicinal Product Designation for Spinocerebellar Ataxia

The phase 1-3 study is a global, randomized, double-blind, multiple-ascending dose (MAD) trial that spans across 13 sites in 8 countries. In the study, patients with AxD aged 2 to 65 are randomly assigned 2:1 to either zilganersen or control for a 60-week double-blind treatment period. At 60 weeks, all participants will receive the study drug for a 180-week open-label treatment period, followed by a 28-week post-treatment follow-up period. The study also includes an open-label sub-study in eligible participants under the age of 2 years with AxD, which will continue to enroll into 2025.

Investigators of the study will use percent change in 10-meter walk test, an assessment of gait speed, as the primary end point. Other secondary measures include change in patients’ self-identified Most Bothersome Symptom score, Patient Global Impression of Severity score, Patient Global Impression of Change Score, and Clinician Global Impression of Change score at the end of the double-blind treatment period. The study also includes other end points that test changes in motor function, quality of life, autonomic symptoms, and GFAP levels.

Months ago, in July, Ionis announced it had completed enrollment of the pivotal trial.² According to clinicaltrials.gov, the study has an anticipated enrollment of 73 patients who had clinical phenotype and brain imaging consistent with a diagnosis of AxD. These patients also have documented genetic mutation in the GFAP gene. The study excludes those with clinically significant abnormalities, previous treatment with an oligonucleotide, a history of gene therapy or cell transplantation, or presence of ventriculoperitoneal shunt for a cerebrospinal fluid or implanted central nervous system catheter.

There has been little movement in terms of drug development for AxD; however, researchers have started to look at gene therapies for the disease. Earlier this year, Umass Chan Medical School and Astellas Pharma entered a sponsored research agreement to continue development of an adeno-associated virus vector mediated gene therapy for AxD. The research efforts, are led by Guangping Gao, PhD, and Jun Xie, PhD, who developed an AAV vector that can express a small RNA silencer that suppresses the mutant proteins that cause AxD in mice.³

REFERENCES
1. Zilganersen granted U.S. FDA Fast Track designation for people living with Alexander disease. News release. Ionis Pharmaceuticals. October 1, 2024. Accessed October 7, 2024. https://www.prnewswire.com/news-releases/zilganersen-granted-us-fda-fast-track-designation-for-people-living-with-alexander-disease-302263365.html
2. Ionis completes enrollment in pivotal trial evaluating zilganersen in people living with Alexander disease. July 18, 2024. Accessed October 7, 2024. https://ir.ionis.com/news-releases/news-release-details/ionis-completes-enrollment-pivotal-trial-evaluating-zilganersen
3. UMass Chan Medical School joins sponsored research agreement with Astellas Pharma. News release. June 20, 2024. Accessed October 7, 2024. https://www.umassmed.edu/news/news-archives/2024/06/umass-chan-medical-school-joins-sponsored-research-agreement-with-astellas-pharma/