Orchard Therapeutics announced a range of interim clinical outcomes, in addition to the previously reported neurological and skeletal results, from the company?s ongoing proof-of-concept (PoC) study of OTL-203, a hematopoietic stem cell (HSC) gene therapy in development for the treatment of the Hurler subtype of mucopolysaccharidosis type I (MPS-IH). The data were presented at the European Society of Gene and Cell Therapy (ESGCT) 30th Annual Congress taking place October 24-27, 2023, in Brussels. MPS-I is a rare, inherited neurometabolic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) lysosomal enzyme resulting in the accumulation of glycosaminoglycans (GAGs) in multiple organs, including the eyes, ears, heart, as well as the musculoskeletal and central nervous systems. It is estimated to occur globally in approximately 1 in 100,000 live births. Approximately 60 percent of children born with MPS-I have the most severe subtype, MPS-IH, also called Hurler syndrome, and rarely live past the age of 10 when untreated. Current treatment options for MPS-IH include allogeneic hematopoietic stem cell transplant (HSCT) and chronic enzyme replacement therapy (ERT), neither of which effectively address the broad range of clinical manifestations of the disease. In the single-center PoC study, eight patients diagnosed with MPS-IH were treated at Ospedale San Raffaele in Milan, Italy with investigational OTL-203 between July 2018 and December 2019. Interim results published in The New England Journal of Medicine showed all patients had 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. Additional Ocular and Auditory Clinical Data Presented at ESGCT 2023 At ESGCT, Dr. Maria Ester Bernardo, clinical coordinator, pediatric clinical research unit at San Raffaele Telethon-Institute for Gene Therapy (SR-TIGET) and the principal investigator of the PoC study, detailed the first findings on other treatment outcomes, including ocular (eye), and auditory (hearing) function. Results showed: Treatment with OTL-203 resulted in improvement (62.5% of patients; n=5/8) or stabilization (37.5% of patients; n=3/8) of corneal clouding at the time of last follow-up (ranging from 3.14-4.58 years) compared to baseline measured prior to administration with OTL-203.
Importantly, following treatment with OTL-203, no patients reported photophobia (light sensitivity), or any other ophthalmological symptoms typically associated with MPS-IH. At last follow-up, 50.0% of patients (n=4/8) showed normal hearing function, and none developed severe hearing loss. In addition, no treated patients have required a hearing aid or any intervention for hearing loss following administration with OTL-203 as of last follow-up.
Follow-up to fully assess and characterize the potential impact of HSC gene therapy on ocular and auditory manifestations of MPS-IH is ongoing. Summary of Previously Reported Safety Results Treatment with OTL-203 has been generally well-tolerated with a safety profile consistent with the selected conditioning regimen. Anti-alpha-L-iduronidase (IDUA) antibodies present prior to gene therapy as a result of ERT were not seen in any patient within two months following treatment. In addition, ERT was discontinued at least three weeks prior to any patient receiving gene therapy treatment, and no patients have re-started ERT post-treatment. The lentiviral vector integration profile was consistent with other lentiviral-based HSC gene therapy studies, and all participants had a stable and highly polyclonal repertoire. Global Registrational Trial Expected to Commence by Year-end Following the promising results observed in the proof-of-concept study, Orchard Therapeutics is initiating 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 will be randomized 1:1 to receive either OTL-203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL-203 over 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 treatment, treatment failure, immunological complications, as well as severe cognitive and growth impairment. Secondary endpoints include biochemical markers, additional clinical assessments, as well as safety and tolerability. The company expects to activate up to six sites in the United States and Europe, the first of which is planned to open enrollment later this year.