The FDA approved Zanvastro (zilganersen) on Sept. 3 as the first treatment for Alexander disease, a rare and progressive brain disorder. The drug targets the protein behind the disease and is the first therapy for it that does more than manage symptoms, according to the FDA’s announcement.
What Alexander Disease Does
Alexander disease results from mutations in the gene that makes glial fibrillary acidic protein, known as GFAP. The FDA says the disorder affects fewer than 1 in 1 million people and causes seizures, loss of developmental milestones, difficulty walking, muscle weakness and increased pressure in the brain. Ionis Pharmaceuticals, the drug’s developer, puts the figure at about 1 in 1 million to 3 million people worldwide and says the disease is typically fatal within 14 to 25 years of symptom onset, according to the company’s announcement.
The National Institute of Neurological Disorders and Stroke says on its leukodystrophy page that the disease destroys white matter and builds up clumps of abnormal protein called Rosenthal fibers in brain support cells. It says there is no known cure and that symptoms may be treated. Before the approval, supportive care was all that existed. Emily Freilich, director of the Division of Neurology I in the FDA’s Center for Drug Evaluation and Research, said in the FDA announcement, “Today’s approval is a landmark moment for this community.”
How the Drug Works
Zanvastro is an antisense oligonucleotide, a short strand of genetic material designed to lower production of one protein. In this case the target is GFAP. Because the disease comes from too much damaging GFAP accumulating in astrocytes, the aim is to reduce its production before it builds up.
A trained health care professional gives the drug as an injection into the spinal canal. Ionis says the approved dose is 50 milligrams every three months. By calculation from that schedule, a patient receives four injections and 200 milligrams a year. The FDA granted the drug orphan drug, fast track, breakthrough therapy and rare pediatric disease designations. Ionis received a rare pediatric disease priority review voucher with the approval.
What the Trial Showed
The evidence comes from one trial, registered as NCT04849741. The two official accounts differ on its size. The FDA says the main study enrolled 49 patients ages 2 and older and was joined by an open-label substudy of four patients younger than 2. Ionis says the study enrolled 54 participants ages 1.5 to 53 at 13 sites in eight countries. The company says most were children.
Ionis says participants were randomized 2-to-1 to the drug or a control for a 60-week doubleblind period. A calculation from the 54-person figure gives about 36 patients on the drug and 18 on control across both dose cohorts, though the company does not state the split. The 50milligram cohort was the pivotal group.
For patients ages 5 and older, the primary measure was gait speed on the 10-Meter Walk Test. Ionis reports that at week 61 the drug-treated group showed statistically significant stabilization compared with control, with a least-squares mean difference of 33.3% and a pvalue of 0.041. The FDA says patients on Zanvastro had significantly better walking speed than untreated patients at that point. A p-value of 0.041 sits just under the conventional 0.05 cutoff.
For children ages 2 to 4, walking speed is not a reliable measure, so the FDA says the trial used a broader motor skills assessment covering standing, walking, running and jumping. Treated children improved while the control group declined, the agency says. For children younger than 2, the FDA says direct trial data were limited and it relied on pharmacokinetic modeling suggesting drug levels similar to older children at the same dose.
Side Effects and Warnings
The most common adverse reactions, in at least 25% of patients and more often than with control, were vomiting, back pain, cough, headache and post-lumbar puncture syndrome. The FDA lists aseptic meningitis as a reported risk and tells patients and caregivers to report symptoms that resemble meningitis.
Ionis says one patient had a serious reaction that recurred during open-label treatment. The patient needed a dose interruption and dexamethasone pretreatment, stayed asymptomatic and continued treatment. The company also says serious adverse events occurred less often with the drug than with control.
Three Decades from a Mouse to a Medicine
The University of Wisconsin-Madison traces the drug’s origin to an accident. In the late 1990s, Albee Messing and collaborator Michael Brenner were overexpressing the GFAP gene in mice when the animals developed Rosenthal fibers, the classic feature of the disease. The university’s release says later genetic analysis confirmed GFAP mutations as the cause, which also moved diagnosis from invasive brain biopsy to a blood test.
Messing, now professor emeritus of comparative biosciences and a former director of the Waisman Center, said the approval is “a wonderful and long-awaited day for the Alexander disease community.” He and Tracy Hagemann, an associate research professor at the Waisman Center, then built better rodent models and worked with Ionis on lowering GFAP. The Ionis trial began in the summer of 2021. By calculation, that is about five years from the trial’s start to approval, and about 28 years after the late-1990s mouse finding.
Who Can Get It and When
Ionis says Zanvastro will be available in the United States in the coming weeks. The company has not disclosed a price. Its patient support program, Ionis Every Step, offers education, insurance assistance and information on affordability programs.
Outside the United States, rights belong to Recordati, an Italian pharmaceutical company that holds a licensing agreement with Ionis. Ionis expects to file for approval in Europe and Japan in 2027. Amy Waldman, a pediatric neurologist at Children’s Hospital of Philadelphia and the study’s lead investigator, said in the Ionis announcement, “For the first time, we can move beyond managing individual manifestations of the disease.”
