First patient randomized in registrational trial of OTL-203 for MPS-I Hurler syndrome. Orchard Therapeutics.
Orchard Therapeutics, recently acquired by Kyowa Kirin with the goal of accelerating the delivery of new gene therapies to patients around the globe, announced the first patient has been randomized at the M Health Fairview Masonic Children’s Hospital in a registrational trial evaluating the efficacy and safety of OTL 203, an investigational hematopoietic stem cell (HSC) gene therapy, in patients with the Hurler subtype of mucopolysaccharidosis type I (MPS-IH).
The trial, referred to as HURCULES , compares treatment with OTL-203 to standard of care with allogeneic hematopoietic stem cell transplant (HSCT), and is expected to enroll 40 MPS-IH patients at sites across the U.S. and Europe.
“This is a substantial milestone in the development of OTL 203 as we work toward bringing an important new treatment option to children with MPS-IH and their families,” said Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics. “Previously reported results from an earlier proof-of-concept study in patients showed robust metabolic correction, continued cognitive, motor, and physical development, as well as early improvements in skeletal, ocular and auditory health demonstrating 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.”
“The complications associated with MPS-IH have a detrimental impact on patients’ quality of life, and while transplantation may help improve outcomes, it is associated with significant morbidity and mortality,” said Paul Orchard, M.D., a study investigator and professor in the Division of Pediatric Blood and Marrow Transplantation and Cellular Therapy Program at the University of Minnesota Medical School. “New options are needed to better address some of the more severe symptoms of the disease, such as neurocognitive function, growth and other skeletal issues. We look forward to working with the team at Orchard Therapeutics and other clinical sites around the world to facilitate enrollment in this study and characterize the potential clinical impact of OTL-203 on MPS-IH.”
Currently, the University of Minnesota is actively recruiting patients with additional trial sites expected to begin recruitment in the coming months.
Summary of Previous OTL 203 Clinical Results : Interim results from the earlier PoC study published in The New England Journal of Medicine showed all patients had supraphysiological IDUA enzyme activity with an associated sustained decrease in GAG levels and stable cognitive performance post-treatment. In addition, all participants had progressed along expected growth percentiles of healthy children and exhibited longitudinal growth that was considered within the normal range adjusted for age and gender. In subsequent follow-up, study investigators have observed progressive acquisition of fine and gross motor skills, as well as evidence of continued growth within normal range and improvements in skeletal health with a median follow-up of 3.78 years (range: 3.14 to 4.58 years) as of May 2023.
In addition, Dr. Maria Ester Bernardo, clinical coordinator, pediatric clinical research unit at SR-TIGET and the principal investigator of the PoC study, detailed the first findings on other treatment outcomes, including ocular (eye) symptoms and auditory (hearing) function at the European Society of Cell and Gene Therapy (ESGCT) 30th Annual Congress. The presentation outlined favorable results for disease manifestations not fully addressed by the current standard of care and further highlights the potential of genetically repaired HSCs to migrate into and correct abnormalities in multiple tissues and organs.
Throughout the PoC study , treatment with OTL 203 has been generally well-tolerated with a safety profile consistent with the selected conditioning regimen. The viral vector integration profile was comparable with other Orchard Therapeutics lentiviral-based HSC gene therapy studies, and all participants had a stable and highly polyclonal repertoire. As part of the study, ERT was discontinued at least three weeks prior to any patient receiving gene therapy, and none of those patients needed to re-start ERT post-treatment. Patients who entered the study with anti-IDUA antibodies present because of prior ERT treatment were no longer antibody positive within two months of treatment with OTL 203.
About the HURCULES Study : HURCULES—a study name that combines the target indication HURler syndrome and HerCULES, the classical mythological character—is a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of OTL 203 in patients with MPS-IH compared to standard of care with allogeneic HSCT. A total of 40 patients with a confirmed diagnosis of MPS-IH who meet the study inclusion criteria are being randomized 1:1 to receive either OTL 203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL 203 over allogeneic HSCT. The primary endpoint, which will be measured at two years post-treatment, comprises a composite of clinically meaningful outcomes, including death, the need for rescue transplant, treatment failure, immunological complications, as well as severe cognitive and/or growth impairment.
Secondary endpoints include biochemical markers, additional clinical assessments, as well as safety and tolerability. The company expects to activate six sites in the United States and Europe.
See- Gentner B, Tucci F, Galimberti S et al. "Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome". N Engl J Med. 2021, 385:1929 doi: 10.1056/NEJMoa210659
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