Several companies—including JCR Pharmaceuticals, Denali Therapeutics and Regenxbio— have products in the pipeline that could improve treatment options for this rare disease.
Hunter syndrome is a rare, X‐linked disease caused by a deficiency of the lysosomal enzyme iduronate‐2‐sulfatase that limits heparan sulfate breakdown in children. Also known as mucopolysaccharidosis type II, this disease affects less than 2,000 patients worldwide. Hunter syndrome complications include skeletal abnormalities, facial changes, developmental delays, liver and spleen enlargement and respiratory and ear infections.
While patients can survive into adulthood with milder forms of this disease, more severe forms can reduce life expectancy to ten to twenty years of age.
Although weekly intravenous infusions of enzyme replacement therapy (Elaprase), produced by Shire Pharmaceuticals, have been approved for use since 2006, idursulfase replacement does not address cognitive impairment since the enzyme does not cross from the bloodstream into the brain.
Hematopoietic stem cell transplantation is another currently approved option, but the procedure is invasive and requires a bone marrow donor. It also involves the use of chemotherapy to suppress the immune system to prevent organ rejection.
To help this patient population, several clinical-stage companies are working on products to treat Hunter syndrome from novel angles.
The frontrunner among these contenders, JCR Pharmaceuticals, is working on JR-141 (also known as pabinafusp alfa or TAK-141), an intravenous infusion consisting of iduronate-2-sulfatase fused with an anti–human transferrin receptor antibody administered weekly.
JR-141 is currently approved and marketed by JCR and Sumitomo as Izcargo in Japan for Hunter syndrome, and JCR is running the STARLIGHT Phase III trial in the U.S. for the drug. In previous Phase I/II trials, JR-141 crossed from the bloodstream into the brain and showed promising signs of limiting neurodegeneration.
Meanwhile, Denali Therapeutics is advancing DNL310 (tividenofusp alfa), a weekly intravenous treatment that uses Enzyme Transport Vehicle technology to bring iduronate‐2‐sulfatase from the bloodstream into the brain.
While DNL310 is now in Phase I/II and Phase II/III trials for Hunter syndrome, Denali is also recruiting for a separate Phase II/III Hunter syndrome trial called COMPASS examining how neuronopathic nuances between different Hunter syndrome populations affect treatment with DNL310. Denali announced in January that it intends to submit a Biologics License Application submission early in 2025.
Finally, Regenxbio is working on RGX-121, an AAV9 vector to deliver the human iduronate-2-sulfatase gene into the central nervous system using intracisternal or intracerebroventricular delivery.
Unlike the other investigational treatments, RGX-121 is designed to treat Hunter syndrome through a one-time administration. Regenxbio announced in February 2024 that in the CAMPSIITE Phase I/II/III trial, RGX-121 led to an 86% reduction in cerebrospinal fluid D2S6, a biomarker highly correlated with Hunter syndrome severity. As of June 2024, Regenxbio was undergoing a Biologics License Application submission process for the candidate.
While Esteve and Immusoft are also working on Hunter syndrome investigational products, both companies are in the preclinical stages. Esteve’s EGT-301 uses AAV-9 gene therapy technology, and Immusoft’s ISP-002 uses engineered B cells to express iduronate 2-sulfatase.
If all goes well with the BLA processes for Denali and Regenxbio, their Hunter syndrome approvals could arrive from the FDA within two to three years. Given JCR’s head start with Izcargo’s approval in Japan in 2021, it could also potentially obtain approval from the FDA within two to three years at the earliest depending on the outcome of its Phase III trials.
Keep an eye on the Hunter syndrome space as competition heats up among the three front-runners.
