Ionis’ Zilganersen Earns FDA Breakthrough Therapy Designation for Ultra Rare Alexander Disease (AxD)

Ionis Pharmaceuticals has received U.S. FDA Breakthrough Therapy designation for its antisense oligonucleotide zilganersen (ION373) for the treatment of Alexander disease (AxD), supported by positive pivotal trial data in both children and adults. Zilganersen is administered intrathecally every 12 weeks to directly target central nervous system pathology. This makes Zilganersen the first and only investigational therapy to reach this stage for AxD, an ultra‑rare, progressive, and often fatal leukodystrophy with no approved disease‑modifying treatments.

Zilganersen: mechanism and designations

Zilganersen (ION373) is an investigational antisense oligonucleotide designed to reduce production of glial fibrillary acidic protein (GFAP), which accumulates due to disease‑causing variants in the GFAP gene and drives Alexander disease pathology. By lowering excess GFAP, Zilganersen aims to slow or stabilize disease progression, offering a potentially disease‑modifying approach rather than symptomatic control.​

The therapy has already received multiple regulatory designations, including FDA Orphan Drug and Rare Pediatric Disease designations, and Orphan Drug designation from the European Medicines Agency (EMA). In 2024, FDA also granted Fast Track designation to Zilganersen for AxD, further supporting close, iterative engagement with regulators.

Clinical Evidence

The Breakthrough Therapy designation is based on topline results from a global pivotal Phase 1–3 trial (NCT04849741) evaluating Zilganersen in children and adults with genetically confirmed Alexander disease. The multicenter, double‑blind, placebo‑controlled study includes a 60‑week randomized treatment period followed by long‑term open‑label extensions to characterize durability of effect and long‑term safety.​

At the 50 mg dose, Zilganersen achieved statistically significant and clinically meaningful stabilization of gait speed on the primary endpoint, the 10‑Meter Walk Test (10MWT), at week 61 versus control, with a mean difference of approximately 33% and a favorable safety profile. Consistent benefits were also reported across key secondary endpoints related to motor function and overall neurologic status, marking the first time an investigational therapy has demonstrated potential disease‑modifying impact in AxD.

Alexander disease

Alexander disease is an ultra‑rare leukodystrophy, estimated to affect roughly 1 in 1–3 million people worldwide, characterized by progressive neurological decline, loss of motor control, and eventual loss of independence. Patients experience worsening gait, spasticity, bulbar dysfunction (including speech and swallowing difficulties), and in severe cases respiratory compromise, leading to substantial morbidity and early mortality.​

The condition is caused by pathogenic variants in the GFAP gene, leading to toxic accumulation of GFAP in astrocytes and widespread white matter damage. With no approved disease‑modifying therapies and current care limited to symptomatic and supportive management, any agent that can stabilize or slow decline represents a major advance for this community.

Next regulatory steps

Ionis plans to submit a New Drug Application (NDA) for Zilganersen to the U.S. FDA in the first quarter of 2026, leveraging Breakthrough Therapy, Orphan, Rare Pediatric, and Fast Track pathways to support an efficient review. The company is also evaluating the initiation of a U.S. Expanded Access Program (EAP) to provide pre-approval access for eligible AxD patients. Ionis has not yet activated an EAP and will share further details as plans are finalized

In parallel, Zilganersen holds EMA Orphan Drug designation, positioning Ionis to pursue future regulatory submissions in the European Union and potentially other regions once U.S. regulatory discussions progress. For clinicians and families, the Breakthrough Therapy designation signals growing regulatory confidence in the clinical data package and bring the field closer to the first targeted therapy for Alexander disease

Breakthrough Therapy designation

FDA Breakthrough Therapy designation is reserved for investigational drugs that treat serious or life‑threatening conditions and show preliminary clinical evidence of substantial improvement over existing therapies on clinically meaningful endpoints. For AxD, where current management is purely supportive, this designation underscores the potential of Zilganersen to change the disease course rather than just alleviate symptoms.​

The designation enables more intensive FDA guidance, eligibility for rolling review, and the possibility of an expedited development and review timeline. For patients and families facing AxD, it can translate into faster regulatory interactions and earlier access pathways if efficacy and safety are confirmed.