Design of a multi-center randomized active controlled phase 3 clinical trial (HURCULES) evaluating the safety and efficacy of OTL-203 in patients with MPS IH versus standard of care with allogeneic hematopoietic stem cell transplantation

Introduction Mucopolysaccharidosis type I Hurler (MPS-IH) is an autosomal recessive lysosomal storage disorder characterized by deficiency of alpha-L-iduronidase (IDUA), which is responsible for the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs throughout the body and brain results in multi-organ dysfunction causing a wide range of musculoskeletal, cardiopulmonary, ophthalmic and auditory abnormalities, progressive neurologic disease, and early death. Objectives Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the current standard of care (SoC) but is associated with significant complications and residual disease burden, with limited effect on skeletal abnormalities. Based on data from an ongoing open-label Phase I/II proof-of-concept trial (NCT03488394), treatment with autologous hematopoietic stem cell-based gene therapy (OTL-203) has the potential to address a range of multisystemic manifestations of MPS-IH. Here, we describe a multi-center, randomized, open-label, Phase 3 clinical trial designed to evaluate the efficacy and safety of OTL-203 in patients with MPS-IH compared to SoC with allo-HSCT. Methods A total of 40 patients with confirmed diagnosis of MPS-IH who meet study eligibility criteria will be randomized 1:1 to receive a one-time infusion of either OTL-203 or allo-HSCT. To ensure efficient engraftment of cells, all patients will undergo a myelo- and lympho-ablative conditioning regimen. There will be up to six trial sites globally. Results The study is powered to demonstrate superiority of OTL-203 over SoC with allo-HSCT. The primary endpoint comprises a composite of clinically meaningful outcomes, including death, need for rescue allo-HSCT, treatment failure, immunological complications, severe cognitive and growth impairment. This will be assessed at the time of the primary analysis at two years post-treatment. Secondary endpoints include biochemical markers, additional clinical outcomes, and assessment of safety and tolerability. Conclusions Patients will be followed-up on the study for 5 years post-treatment and invited to enroll in a long-term follow-up study for a total of 15 years.