Orchard Therapeutics, a Kyowa Kirin company, announced the completion of patient enrollment in its pivotal HURCULES trial evaluating OTL-203, an investigational hematopoietic stem cell gene therapy for mucopolysaccharidosis type I Hurler syndrome (MPS-IH). The milestone was achieved nearly one year ahead of the original schedule, with primary analysis results anticipated two years post-treatment.
The HURCULES trial (NCT06149403) represents a critical step forward for patients with MPS-IH, a devastating rare disease that affects approximately 60% of children born with MPS-I. The condition occurs in an estimated 1 in 100,000 live births globally, with untreated patients rarely surviving past age 10.
Addressing Critical Unmet Medical Need
"The completion of study enrollment nearly a year ahead of schedule underscores the urgent medical need that still exists in MPS-IH, and the hopefulness of physicians and patients to contribute to the development of new treatment options," said Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics.
MPS-IH is caused by a deficiency of the alpha-L-iduronidase (IDUA) lysosomal enzyme, which is required to break down glycosaminoglycans (GAGs). The accumulation of GAGs across multiple organ systems results in severe neurocognitive impairment, skeletal deformities, cardiovascular and pulmonary complications, impaired motor function, hearing loss, and corneal clouding.
Current treatment options include allogeneic hematopoietic stem cell transplant (allo-HSCT) and enzyme replacement therapy (ERT), both of which have significant limitations including inadequate impact on severe disease manifestations and substantial morbidity and mortality risks.
Promising Early Clinical Evidence
Previous proof-of-concept data from eight patients treated at Ospedale San Raffaele in Milan, Italy between July 2018 and December 2019 demonstrated encouraging results. According to Maria Ester Bernardo, M.D., Ph.D., clinical coordinator at the San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) and HURCULES study investigator, the earlier study showed "robust metabolic correction, continued cognitive, motor, and physical development, as well as early improvements in skeletal, ocular and auditory health."
Dr. Bernardo emphasized that "one-time treatment with OTL-203 has the potential to positively impact a broad range of clinical manifestations not fully addressed by the current standard of care."
Trial Design and Regulatory Status
The HURCULES study is a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL-203 compared to standard allogeneic HSCT. Patients with confirmed MPS-IH diagnosis were enrolled across four clinical sites in the U.S. and Europe and randomized 1:1 to receive either OTL-203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL-203 over allogeneic HSCT.
OTL-203 uses a modified virus to insert a functional copy of the human IDUA gene into a patient's cells. The therapy has received Fast Track and Rare Pediatric Disease designations from the U.S. FDA, as well as priority medicines (PRIME) status from the European Medicines Agency.
Future Outlook
The completion of enrollment coincides with increased adoption of newborn screening for MPS-I in Europe and the U.S. "We are working toward a future where affected children may be able to avoid some of the most devastating consequences of this life-limiting disease," Dr. Bernardo noted.
The program was originated by and initially developed in partnership with SR-TIGET in Milan, Italy. As part of Kyowa Kirin's global business, Orchard continues to advance a pipeline of hematopoietic stem cell gene therapies designed to address serious diseases where current treatment options are limited or nonexistent.
