FDA Approves Ionis' Zanvastro, First Treatment for Alexander Disease

The Food and Drug Administration on September 3 approved Zanvastro (zilganersen) injection from Ionis Pharmaceuticals for pediatric and adult patients with Alexander disease, the agency announced. The FDA said Zanvastro is the first approved treatment for the disease and the first therapy to directly target the protein buildup that drives it.

Alexander disease is a rare, progressive neurological disorder caused by mutations in the gene for glial fibrillary acidic protein (GFAP). The abnormal protein accumulates in the brain's supportive cells and damages the nervous system over time, and the disease can cause seizures, loss of developmental milestones, difficulty walking and muscle weakness, according to the FDA. The agency said it affects fewer than one in a million people.

Zanvastro is an antisense oligonucleotide designed to reduce production of the abnormal GFAP protein before it builds up. A trained healthcare professional injects it into the spinal canal every three months.

The clinical evidence

The FDA said it evaluated Zanvastro in a multicenter, randomized, controlled study (NCT04849741) of 49 children and adults aged 2 and older with Alexander disease, plus an open-label substudy of four patients younger than 2.

Patients aged 5 and older who had measurable difficulty walking at the start of the study and received Zanvastro had significantly better walking speed at 61 weeks than those who received no treatment, the agency said. In children aged 2 to 4, for whom walking speed is not a reliable measure, the study used a broader assessment of motor skills such as standing, walking, running and jumping; children treated with Zanvastro improved on that measure while those in the control group declined.

For patients under 2, the FDA said trial data were limited, and it relied on pharmacokinetic modeling showing that drug levels at the same dose should be similar to those in older children, along with safety data from the four youngest patients. That approach supported extending the indication to the youngest patients, the agency said.

"Today's approval is a landmark moment for this community, offering the first therapy that addresses the underlying cause of this rare and serious disease," said Emily Freilich, director of the Division of Neurology I in the FDA's Center for Drug Evaluation and Research.

Safety, designations and market

The most common side effects are vomiting, back pain, cough, headache and post-lumbar puncture syndrome. Aseptic meningitis has been reported in patients treated with Zanvastro, according to the FDA.

The drug received Orphan Drug, Fast Track and Breakthrough Therapy designations, as well as a Rare Pediatric Disease designation and priority review voucher. Ionis did not immediately respond to a request for comment on pricing, and William Blair analysts projected in April that the drug could reach peak annual sales of $295 million, an analyst estimate, as reported by Reuters, via Medical Dialogues.