Experimental Drug Shows Promise for Rare Genetic Disorder 

A new experimental therapy has shown encouraging results in treating a rare and progressive lysosomal storage disorder, according to findings from a multi-year clinical trial published in the New England Journal of Medicine. 

Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare genetic disorder primarily affecting boys, caused by a deficiency in the enzyme needed to break down sugar molecules. This harmful buildup in cells and tissues impacts multiple body systems, causing frequent infections, organ enlargement and developmental disabilities. Management involves supportive care and enzyme replacement therapy, as there is currently no cure, said Barbara Burton, ’73 MD, ’75 ’77 GME, professor emeritus of Pediatrics in the Division of Genetics, Birth Defects and Metabolism, who was a co-author of the study. 

“In addition to all of these physical issues, two-thirds of MPS II patients have progressive involvement of the brain, such that they develop normally for a period of two to three years, but then their development slows down, and subsequently they begin to regress and lose developmental milestones and go through a process of progressive neurodegeneration,” Burton said.  

In the study, 47 male participants under the age of 18 diagnosed with MPS II were given weekly intravenous doses of tividenofusp alfa, a drug engineered to cross the blood-brain barrier to target both neurological and systemic symptoms of the disease.  

After a 24-week primary treatment period, followed by nearly three years of long-term follow-up, investigators found that the study participants had lower levels of heparan sulfate, the main harmful substrate that accumulates in MPS II. Cerebrospinal fluid concentrations reduced by 91 percent and urinary levels by 88 percent from baseline, according to the study. 

“We also noted that there was improvement in hearing; hearing loss is a common finding in the disease. All patients had an improvement in hearing,” Burton said. “Some patients also had the acquisition of new skills – this is significant because typically by the age of five to six years, patients with MPS II are no longer acquiring any new skills.” 

Despite the encouraging results, some side effects were reported in the study. All participants experienced at least one treatment-emergent adverse event, most commonly infusion-related reactions such as fever, hives or vomiting. Three serious treatment-related events were reported, but all patients continued therapy. 

The study authors noted that while adverse events were frequent, the biochemical and functional improvements suggest tividenofusp alfa could represent a major advance for patients with MPS II, who currently have limited treatment options.  

Further trials are underway to confirm the findings, Burton said. 

“We need to see the response of patients at varying ages, because it’s likely that this is going to be most efficacious in the youngest patients, because there comes a point when you may not be able to reverse damage that’s already been done,” Burton said. “We’re hopeful that the FDA will approve the therapy under the accelerated approval pathway, but we will need a confirmatory study that is standard-of-care controlled.” 

The study was funded by Denali Therapeutics.