FDA approves first-ever drug to target rare neurological disorder Alexander disease

Alexander disease is caused by a fault in the gene that makes glial fibrillary acidic protein (GFAP). The fault creates abnormal versions of GFAP, causing the protein to clump into tangles called Rosenthal fibers that stress brain helper cells called astrocytes, which then become damaged along with the brain's myelin. The disease leads to a multitude of problems including loss of mobility, seizures, and issues with speech, and it is often fatal. Current treatments focus on managing symptoms.

FDA approval was partly secured through a clinical trial involving 54 pediatric and adult patients aged up to 53, across 13 sites in eight countries. Motor skills stabilised or improved for younger participants, while older participants' walking speed held steady compared with a decline in those who received no treatment. In treatments lasting more than a year, the drug met all required safety standards.

Side effects were mostly mild or moderate, and serious ones were less common in treated patients than in the control group. The most common side effects were vomiting, back pain, cough, headache, and pain after the spinal injection. The FDA also warns that some patients developed aseptic meningitis, an inflammation of the lining around the brain and spinal cord.

The drug works through antisense oligonucleotides (ASOs), small bits of DNA that suppress GFAP production. It is administered by a healthcare professional via an injection into the spinal canal once every three months. The approval covers patients of all ages, though signs of the disease most commonly appear before age two.

Neuropathologist Albee Messing, from the University of Wisconsin-Madison, who has been investigating the condition for more than 30 years, described the approval as "a wonderful and long-awaited day for the Alexander disease community." Messing, together with colleagues including neurobiologist Michael Brenner from the University of Alabama at Birmingham, originally worked with mice bred to produce too much GFAP. When that led to protein clumps in astrocytes, it put researchers on the path to understanding how Alexander disease develops.

"This provided an obvious and specific strategy for therapy — the GFAP protein," Messing said. Having originally looked at existing FDA-approved drugs to see if any could have an impact, the researchers eventually decided to design their own custom drug to reduce GFAP production levels.

Medical scientist Brett Monia, CEO of Ionis Pharmaceuticals, said the approval "begins a new chapter for people living with Alexander disease and their families, who have long faced this relentlessly progressive and often fatal disease with no treatment options."

The treatment is not a cure, it does not reverse the condition or make it disappear, but it can significantly slow the progression of the disease and improve symptoms by targeting the underlying causes directly.

"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 said.