Rare Brain Disorder Gets Its First FDA Drug Approval

The FDA approved zilganersen (Zanvastro) to treat Alexander disease in pediatric and adult patients, the agency announced Thursday.

The antisense oligonucleotide, the first approved treatment for Alexander disease, directly targets glial fibrillary acidic protein (GFAP) buildup, which drives the disease.

“For patients with Alexander disease and their families, there have been no approved treatment options — only supportive care while the disease progresses,” Emily Freilich, MD, of the FDA’s Center for Drug Evaluation and Research, said in a news release. “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.”

Alexander disease is a progressive neurologic disorder affecting less than one in 1 million people worldwide. It is caused by a mutation in the GFAP gene that leads to overproduction and toxic accumulation of GFAP in astrocytes, which can damage neurons and myelin, leading to a loss of muscle control and difficulty speaking, swallowing, or breathing. The disease can be fatal.

Zilganersen reduces abnormal GFAP production before it accumulates and causes further damage. The drug’s efficacy and safety were evaluated in a randomized controlled trial that enrolled 49 pediatric and adult patients with Alexander disease ages 2 years and older, and in an open-label substudy of four patients under age 2.

“Because Alexander disease is so rare and can affect patients across a wide range of ages, the FDA evaluated the available evidence in support of an indication covering patients from infancy through adulthood,” the agency said.

For patients ages 5 and older with initial mobility challenges, zilganersen improved walking speed at 61 weeks compared with untreated patients. In children ages 2 to 4, researchers evaluated gross motor skills including standing, walking, running, and jumping; children treated with zilganersen improved while those in the control group declined.

The rarity of Alexander disease precluded a control group for patients under age 2 and direct clinical trial data were limited, the FDA noted.

“Pharmacokinetic modeling confirmed that drug levels in this age group are expected to be similar to those seen in older children at the same dose,” the agency stated. “This observation was also supported by safety data from four patients under 2 years of age treated in the study, as well as the safety data observed in the older pediatric patients. This approach supported extending the indication to the youngest patients while maintaining the evidentiary standards required to support approval.”

Zilganersen 50 mg is administered quarterly as an intrathecal injection. Its most common side effects were vomiting, back pain, cough, headache, and post-lumbar puncture syndrome. Aseptic meningitis was reported in patients treated with zilganersen, and patients and caregivers should inform their healthcare professional if symptoms consistent with meningitis develop.

Patients and clinicians should carefully review the full prescribing information when making treatment decisions, the FDA said. Zilganersen will be available in the U.S. in the coming weeks, according to maker Ionis Pharmaceuticals.