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

The Food and Drug Administration recently approved the first drug to treat Alexander disease, a rare, progressive and often fatal neurological disorder that can affect motor, cognitive and autonomic functions like heart rate and breathing. 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 in collaboration with Ionis Pharmaceuticals from research done at the University of Wisconsin–Madison’s School of Veterinary Medicine and Waisman Center in the laboratory of Albee Messing, professor emeritus of comparative biosciences and former Waisman Center director.

Individuals with Alexander disease treated with Zanvastro showed stabilization of motor function during clinical trials of the drug. In some cases, patients’ motor function improved.

“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 one in a million people worldwide. Individuals living with Alexander disease may experience progressive and potentially life-threatening symptoms, including seizures, loss of developmental skills, mobility challenges, difficulties with eating and 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, professor emeritus of neurobiology at the University of Alabama at Birmingham.

In the early years of their research, Messing and Brenner designed a mouse to overexpress the gene that makes glial fibrillary acidic protein (GFAP). To their surprise, the mice developed clumps of proteins strewn throughout their brains, localized in a special cell type 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 feature 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. The discovery also transformed the approach for diagnosis from invasive brain biopsies to simple blood tests to identify the genetic mutations.

With this confirmation, Messing, in collaboration with Tracy Hagemann, associate research professor at Waisman, developed improved 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 suppress the production of a targeted protein, in this case GFAP. Positive results in rodents using this ASO led to a clinical trial in humans, which began in the summer of 2021.

Zanvastro works by reducing the production of the 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.

Results from the clinical trial showed that patients taking Zanvastro for a little over a year had significantly better walking speeds than patients who received no treatment.

The clinical trial, run by Ionis Pharmaceuticals, measured the efficacy and safety of the new drug in 54 patients at 13 sites around the world. The treatment has now been approved by the FDA for the entire age range, infancy through adulthood, in people with Alexander disease.

Zanvastro will be available in the United States 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 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.