First drug to treat Alexander disease just approved by the FDA after three decades of research at UW–Madison

By Charlene N. Rivera-Bonet

The U.S. Food and Drug Administration (FDA) recently approved the first drug to treat  Alexander disease, a rare, progressive, and often fatal neurological disorder that can affect motor, cognitive, autonomic, and gastrointestinal functions. The drug, Zanvastro, is the first and only disease modifying treatment for Alexander disease. Until now, treatment of the disease has been limited to symptom management.

The drug, which directly targets the protein that drives the disease, was developed from research done at the Waisman Center, University of Wisconsin-Madison, in the laboratory of Albee Messing, VMD, PhD, professor emeritus of comparative biosciences and former director of the Waisman Center. Individuals with Alexander disease treated with Zanvastro showed improved gross motor function during clinical trials of the drug.

“This is a wonderful and long-awaited day for the Alexander disease community,” Messing says.

Alexander disease is an ultra-rare disease that affects fewer than 1 in a million people worldwide. Individuals with the disease present a wide range of serious and potentially life-threatening symptoms including seizures, loss of developmental milestones, difficulty walking, eating, speaking, and increased pressure in the brain. Initial signs of Alexander disease can appear from infancy through adulthood and may vary depending on age of onset.

The approval of this drug is the culmination of more than 30 years of work by Messing, who first discovered the genetic root cause of the disease in the late 1990s along with his collaborator Michael Brenner, PhD, professor emeritus of neurobiology in the University of Alabama at Birmingham.

Together, Messing and Brenner designed a mouse model to overexpress the gene for glial fibrillary acidic protein (GFAP). To their surprise, the mice died soon after birth. When they examined the brains of these mice, they found clumps of proteins strewn throughout, localized in a special cell type in the brain called astrocytes. “We had, really without intending to, created a mouse that produced these classic lesions of Alexander disease,” Messing says.

These clumps of GFAP in astrocytes are known as Rosenthal fibers, and are a classic marker of Alexander disease. Further genetic analysis of individuals with the disease confirmed GFAP genetic mutations as the root cause. “This provided an obvious and specific strategy for therapy – the GFAP protein,” Messing explains. This discovery also allowed neurologists to diagnose the disease through a blood test to identify the mutation.

With this confirmation, Messing, in collaboration with Tracy Hagemann, PhD, associate research professor at Waisman, developed accurate rodent models of Alexander disease that allowed them to search for effective therapies, focusing on a drug that could reduce the levels of GFAP.

Working with Ionis Pharmaceuticals, they developed antisense oligonucleotides (ASOs), small pieces of DNA that can be used to stop the production of a targeted protein, to halt the production of GFAP. Positive results in rodents using this ASO led to a clinical trial for the first-ever treatment of Alexander disease, which began in the summer of 2021.

The clinical trial, run by Ionis Pharmaceuticals, measured the efficacy and safety of the new drug in 13 sites around the world. The treatment is now approved by the FDA for children and adults with Alexander disease.

Zanvastro works by reducing the production of GFAP protein before it can accumulate and cause further damage. It is administered as an injection into the spinal canal every three months by a trained healthcare professional.

In the clinical trial, individuals aged 5 years and older who had measurable difficulties with walking at baseline and were treated with Zanvastro showed significantly better walking speed at 61 weeks compared to those who received placebo. For children aged 2 to 4 years, a broader assessment of motor skills — including standing, walking, running, and jumping —showed improvement in children treated with the drug while those in the control group declined.

Because Alexander disease is so rare and can affect patients across a wide range of ages, the FDA evaluated the available evidence and approved its use in patients from infancy through adulthood.

Zanvastro will be available in the U.S. in the coming weeks. Use in all other countries will occur through a licensing agreement Ionis established with Recordati, a large pharmaceutical company based in Italy.

This historic breakthrough is the capstone of Messing’s work at the Waisman Center and a translational research success story.

“The whole program of research would not have been possible without the support and participation from the patient and family community, to whom we will always be grateful,” Messing says.