FDA Approves First Disease-Modifying Treatment for AxD

The FDA recently approved zilganersen (ZANVASTRO; Ionis Pharmaceuticals) to treat pediatric and adult patients with Alexander disease (AxD), a rare neurological disorder.^1,2

AxD is an ultra-rare, genetic astrocytopathy characterized by progressive neurological decline. It is caused by pathogenic variants in the glial fibrillary acidic protein (GFAP) gene that lead to overproduction and toxic accumulation of the GFAP protein in the brain’s supportive cells.^1,2 The RNA-targeted drug works by reducing production of this abnormal protein before it can accumulate and cause further damage. Zilganersen is the first and only disease-modifying treatment for AxD, which affects approximately 1 in 1 to 3 million people worldwide.^1,3 The approval reflects an otherwise sparse treatment landscape for AxD; zilganersen received Orphan Drug, Fast Track, Breakthrough Therapy, and Rare Pediatric Disease designations, and the FDA also granted Priority Review and awarded Ionis a Rare Pediatric Disease Priority Review Voucher.^1,3

“Today’s approval of ZANVASTRO begins a new chapter for people living with Alexander disease and their families, who have long faced this relentlessly progressive and often fatal disease with no treatment options,” said Brett P. Monia, PhD, CEO of Ionis, in a press release.¹

Seizures, loss of developmental milestones, difficulty walking, muscle weakness, and increased pressure in the brain are among the disease’s common and potentially life-threatening symptoms.³ ZANVASTRO is administered by a trained health care professional as a 50 mg intrathecal injection once every 12 weeks, meaning patients receive 4 doses per year.¹

Trial Design and Efficacy Findings Supported Approval

The approval was based on results from the pivotal phase 1-3 study (NCT04849741) assessing zilganersen’s safety and efficacy in 54 participants with AxD aged 2 to 53 years.^1,2 During the double-blind treatment period, 49 participants (median age, 11 years [range, 2-53]; 65.3% female) were randomized 2:1 to zilganersen (24 to the 50 mg pivotal dose, 8 to 25 mg) or control (n = 17).²

The study met its primary end point in participants 5 years and older, demonstrating statistically significant and clinically meaningful stabilization of gait speed on the 10-Meter Walk Test at week 61 compared with control (least squares mean difference, 33.3%; P = .041).^1,2 In children aged 2 to 4 years, for whom gait speed is not a reliable outcome measure, zilganersen was associated with improvement in gross motor function on the Gross Motor Function Measure-88.^1,2

Key secondary end points—patients’ self-identified Most Bothersome Symptom, Patient Global Impression of Severity, Patient Global Impression of Change, and Clinician Global Impression of Change—all trended toward improvement with zilganersen vs control, with Patient Global Impression of Change reaching statistical significance (OR, 5.22; P = .010).² In an exploratory analysis, zilganersen also lowered plasma GFAP by 33.6% compared with control (nominal P = .003), consistent with its mechanism of action.²

“For the first time, we can move beyond managing individual manifestations of the disease to addressing its underlying biology, with the potential to meaningfully improve outcomes for this community,” Amy Waldman, MD, MSCE, pediatric neurologist and lead investigator for the ZANVASTRO study at Children’s Hospital of Philadelphia, said in a statement.¹

Zilganersen Demonstrated a Favorable Safety Profile

Zilganersen was also well tolerated: most treatment-emergent adverse events (TEAEs) were mild or moderate, with the most common (vomiting, back pain, cough, headache, and post-lumbar puncture syndrome) occurring in at least 25% of patients. Serious TEAEs occurred less frequently with zilganersen than with control (37.5% vs 47.1%).^1,2 Aseptic meningitis has also been reported in patients treated with ZANVASTRO.¹

References

1. ZANVASTRO (zilganersen) approved by the FDA as the first and only disease modifying treatment for Alexander disease (AxD) in pediatric and adult patients. IONIS. September 3, 2026. Accessed September 8, 2026. https://ir.ionis.com/news-releases/news-release-details/zanvastrotm-zilganersen-approved-fda-first-and-only-disease

2. Waldman A, Lynch D, Tonduti D, et al. Efficacy and safety of Zilganersen, an investigational RNA-targeted antisense therapy, in people living with Alexander disease: results from a pivotal study (PL5.003). Neurology. 2026;106. doi:10.1212/WNL.0000000000213207

3. FDA Newsroom. FDA Approves First Drug to Treat Alexander Disease. FDA. September 3, 2026. Accessed September 8, 2026. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-alexander-disease