FDA Approves Ionis’ Zanvastro for Alexander Disease

Rare Daily Staff

The U.S. Food and Drug Administration has approved Ionis Pharmaceuticals’ Zanvastro as the first treatment for the rare, progressive neurological disorder Alexander disease.

Zanvastro is the first FDA-approved therapy for Alexander disease and the first designed to address its underlying biological cause: the accumulation of an abnormal form of glial fibrillary acidic protein, or GFAP.

Alexander disease is caused by mutations in the gene that encodes GFAP, a protein produced in the brain’s supportive glial cells. The abnormal protein can build up in those cells, progressively damaging the nervous system. The disease affects fewer than 1 in 1 million people and may cause seizures, loss of developmental milestones, impaired walking, muscle weakness and increased pressure in the brain.

Zanvastro is an antisense oligonucleotide designed to reduce production of the abnormal GFAP protein. The medicine is administered intrathecally — by injection into the spinal canal — once every three months by a trained health care professional. Zanvastro received Orphan Drug, Fast Track, Breakthrough Therapy and Rare Pediatric Disease designations, as well as a priority review voucher.

The FDA based its approval on a multicenter, randomized, controlled clinical trial involving 49 patients with Alexander disease ages 2 and older, as well as an open-label substudy involving four patients younger than 2.

Among patients ages 5 and older with measurable walking impairment at baseline, those treated with Zanvastro showed significantly better walking speed at 61 weeks than patients who received no treatment, the FDA said.

For children ages 2 to 4, walking speed was not considered a reliable measure of disease progression. Instead, investigators used a broader motor-skills assessment that evaluated standing, walking, running and jumping. Children treated with Zanvastro improved on that measure, while children in the control group declined, according to the agency.

Direct clinical-trial evidence in children younger than 2 was limited because of the disease’s rarity and the lack of a concurrent control group. The FDA said pharmacokinetic modeling indicated that drug exposure in those patients should be comparable to exposure in older children receiving the same dose. That conclusion was supported by safety results in the four children younger than 2 treated in the study and by safety data from older pediatric patients.

The agency said the findings supported an indication spanning infancy through adulthood.

The most common adverse effects associated with Zanvastro were vomiting, back pain, cough, headache and post-lumbar-puncture syndrome. The FDA said aseptic meningitis has been reported in patients receiving the drug and advised patients and caregivers to alert a health care provider if symptoms consistent with meningitis develop.