The treatment landscape for Mucopolysaccharidosis Type I (MPS I) is poised for significant transformation as four innovative therapies advance through clinical development, challenging the two-decade dominance of Sanofi's Aldurazyme. These emerging treatments specifically target the critical unmet need of central nervous system involvement, which current enzyme replacement therapy cannot address due to its inability to cross the blood-brain barrier.
MPS I is a progressive genetic disorder caused by deficiency of the alpha-L-iduronidase enzyme (IDUA), leading to accumulation of glycosaminoglycans in tissues and organs. The disorder affects approximately 1 in 100,000 live births and manifests as skeletal deformities, cardiopulmonary complications, and in severe cases, neurocognitive decline. Despite Aldurazyme's patent expiration, no biosimilars are currently available, making it the sole FDA-approved enzyme replacement therapy for MPS I.
Gene Therapy Frontrunner Advances to Phase III
Orchard Therapeutics, in collaboration with Kyowa Kirin, is leading the charge with OTL-203, a one-time gene therapy for MPS IH. The treatment uses patients' own hematopoietic stem and progenitor cells collected from mobilized peripheral blood, which are genetically modified ex vivo with a lentiviral vector carrying functional IDUA complementary DNA to restore enzyme production and reduce GAG accumulation.
OTL-203 is currently in Phase III clinical trials across North America and Europe, developed in collaboration with the San Raffaele-Telethon Institute for Gene Therapy. Orchard Therapeutics plans to submit a US application in 2028, with potential approval expected in 2029 under priority review. The therapy has received Fast Track Designation, Orphan Drug Designation, and Rare Pediatric Disease Designation from the FDA, as well as PRIME status from the EMA.
At the 21st Annual WORLDSymposium in February 2025, Orchard Therapeutics presented updated findings from a proof-of-concept study highlighting improvements in neurological, skeletal, and other clinical outcomes. The company announced the first patient's randomization in the registrational trial in February 2024, marking a key milestone in clinical development.
Blood-Brain Barrier Breakthrough Shows Promise
JCR Pharmaceuticals is advancing JR-171 (lepunafusp alfa), an advanced enzyme replacement therapy designed specifically to address central nervous system complications in MPS I. The treatment is a recombinant fusion protein combining an antibody targeting the human transferrin receptor with IDUA, the deficient enzyme in MPS I patients. By leveraging transferrin receptor-mediated transcytosis, JR-171 effectively crosses the blood-brain barrier, addressing a critical gap in CNS treatment.
Developed using JCR Pharmaceuticals' proprietary J-Brain Cargo and J-MIG System platforms, JR-171 has completed a 13-week Phase I/II clinical trial in Japan and the US, with an extension study currently underway. The therapy has received Fast Track Designation and Orphan Drug Designation from both the FDA and EMA.
In September 2024, JCR Pharmaceuticals presented data at the Society for the Study of Inborn Errors of Metabolism Annual Symposium, highlighting improvements in both neurobehavioral and somatic symptoms in MPS I patients treated with JR-171.
Strategic Partnership Strengthens Gene Therapy Development
REGENXBIO is developing RGX-111, an investigational gene therapy that delivers a functional copy of the IDUA gene directly to the central nervous system, enabling brain cells to produce the enzyme. This approach aims to slow or prevent cognitive decline and neurological damage associated with MPS I.
Interim results from an ongoing Phase I/II trial have shown encouraging biological activity and a favorable safety profile. RGX-111 has been granted Orphan Drug Designation, Rare Pediatric Disease Designation, and Fast Track Designation by the US FDA.
In March 2025, REGENXBIO finalized its strategic partnership with Nippon Shinyaku. Under this agreement, the two companies will collaborate on the development and commercialization of RGX-111 for mucopolysaccharidosis type I in both the United States and Asia.
Cell Therapy Platform Reports Encouraging Results
Immusoft is developing ISP-001, an autologous B cell therapy engineered to produce human alpha-L-iduronidase for treating MPS I. The drug is currently being tested in a Phase I clinical trial and received Orphan Drug Designation and Rare Pediatric Disease Designation from the US FDA in 2018.
In January 2025, Immusoft announced encouraging results from the first human trial of ISP-001, which were presented at the WORLDSymposium 2025 in San Diego.
Market Transformation on the Horizon
The future of MPS I treatment extends beyond traditional enzyme replacement therapy, with advancements in gene therapy, substrate reduction therapy, and small molecule treatments offering new hope for better outcomes. While current ERT has been effective in addressing some systemic symptoms, it is limited by its inability to cross the blood-brain barrier and fully address neurological complications.
Gene therapy is emerging as a transformative approach with the potential to provide one-time treatment addressing the underlying genetic defect. AAV and lentiviral vectors are being explored to deliver functional copies of the defective gene, potentially enabling sustained production of the missing enzyme. Early-stage clinical trials have shown encouraging results, with reduced GAG accumulation and improved cognitive function.
Beyond gene therapy, novel approaches such as substrate reduction therapy and chaperone therapy are being developed to improve cellular metabolism and enhance the stability and activity of endogenous enzymes. Intrathecal and intracerebroventricular delivery methods are also being tested to enhance CNS penetration and address neurological symptoms more effectively.
The battle for market leadership in MPS I will hinge on neurological efficacy, patient convenience, and long-term value. Successful market entrants will need to demonstrate tangible CNS benefit alongside systemic efficacy, lower administration frequency, compelling safety profiles, and cost-effectiveness in orphan pricing frameworks. These advances have the potential to significantly improve both quality of life and life expectancy for MPS I patients.
