Hunter Syndrome (Mucopolysaccharidosis Type II, MPS II) is a rare, progressive genetic disorder caused by a deficiency in the enzyme iduronate-2-sulfatase (I2S). This deficiency leads to the accumulation of glycosaminoglycans (GAGs) in various tissues, resulting in severe physical and cognitive impairments.
Traditionally, treatment options have been limited, but recent advancements in drug development and gene therapy are transforming the landscape of care for individuals with Hunter Syndrome.
The Current Treatment Landscape
Currently, the primary treatment for Hunter Syndrome is enzyme replacement therapy (ERT), with Elaprase (idursulfase) being the most widely used. Elaprase is a recombinant form of the I2S enzyme administered via intravenous infusion.
While ERT can help manage some symptoms, it requires lifelong administration and does not effectively address neurological manifestations of the disease. The high cost of Elaprase poses significant financial challenges for healthcare systems and families.
Emerging Therapies and Gene Therapy Innovations
The field of Hunter Syndrome treatment is witnessing a surge in innovative therapies, particularly in gene therapy, offering the potential for more effective and durable solutions.
1. RGX-121 (clemidsogene lanparvovec) by RegenXBio/Nippon Shinyaku
- RGX-121 is the first gene therapy based on an adeno-associated virus (AAV9) for Hunter Syndrome.
- It is designed to deliver (Intracisternal) a functional copy of the IDS gene directly to the central nervous system (CNS).
- It has the potential for one-time treatment for Hunter syndrome to address neurocognitive development, with the potential to meaningfully change the course of the disease.
- FDA BLA submitted in Q1 2025 and potential accelerated approval in H2 2025.
2. Tividenofusp alfa (DNL310) - Denali Therapeutics
- DNL310 is a recombinant IDS enzyme and is engineered to cross the blood-brain barrier and replace the IDS enzyme, and treat neuropathic and systemic forms of the Hunter Syndrome.
- It is the only candidate therapy to normalize key biomarkers, CSF HS, urine HS, and NfL, in LSDs.
- The company is in alignment with the US FDA on the accelerated approval path and expects to complete the BLA rolling submission first half of May 2025 and is preparing for U.S. launch (late 2025/early 2026).
- The company is also conducting a Phase II/III COMPASS study to support global approval
3. Verenafusp alfa (GNR-055) by Generium/Actigen
- GNR-055 is a recombinant modified ID2S capable of penetrating to the blood-brain barrier and thus expected to prevent neurodegenerative consequences and cognitive deficit and to attain a significant improvement in the life quality and expectancy of patients with Hunter Syndrome.
- Generium’s Phase II/III trials of GNR-055 established proof-of-concept with a favorable side effects profile.
4. JR-141 (Pabinafusp alfa, IZCARGO®) – by JCR Pharmaceuticals
- It is a recombinant fusion protein of an antibody against the human transferrin receptor and iduronate-2-sulfatase (IDS) enzyme
- Approved in Japan under the brand name of IZCARGO®.
- JCR is currently conducting a global Phase III clinical trial of JR-141 in the U.S., Brazil, and Europe.
Competitive Landscape and Market Implications
The race to develop effective therapies for Hunter Syndrome has intensified, with several companies advancing promising candidates through clinical trials. RegenXBio's RGX-121 is poised to be the first gene therapy approved for Hunter Syndrome, potentially revolutionizing treatment paradigms. However, other candidates like DNL310 and JR-141 are also showing encouraging results, contributing to a competitive and rapidly evolving market.
Conclusion:
The introduction of gene therapies could significantly reduce the long-term treatment burden and costs associated with Hunter Syndrome. However, challenges remain, including the need for long-term safety data, accessibility of advanced therapies in low-resource settings, and the high cost of gene therapies.
