Orchard Therapeutics announces early results from PoC study of OTL-201

Orchard Therapeutics announced early clinical findings, including the first neurocognitive results, from its ongoing proof-of-concept study of OTL-201, an investigational hematopoietic stem cell gene therapy being developed for the treatment of mucopolysaccharidosis type IIIA, also known as Sanfilippo syndrome type A. The data are being featured as part of an oral presentation at the ongoing 64th American Society of Hematology Annual Meeting & Exposition in New Orleans.The oral presentation at ASH 2022 will showcase the first neurocognitive data for all five patients enrolled in the trial and extend upon previously presented biochemical results. Trial patients were 6 to 24 months of age at the time of administration of OTL-201, and the preliminary results are based on a median follow-up of 1.5 years. Specifically, the biochemical results show the following in all patients: Engraftment is sustained to date, with supraphysiological levels of N-sulphoglucosamine sulphohydrolase enzyme measurable in leukocytes 38- to 91-fold above median normal range at one-month post-treatment. Supraphysiological SGSH levels were also rapidly detected in CD15+ cells, CD3+ cells, and plasma and have been maintained through the last follow-up visit for each patient. SGSH levels in cerebrospinal fluid were within or above normal range by 6-months post-treatment and at the most recent follow-up. Abnormal heparan sulfate levels at baseline were rapidly reduced post-treatment in urine, plasma, as well as CSF, and has continued to be maintained at these levels in all evaluated patients. Early neurocognitive outcomes also indicate that: Since receiving the investigational gene therapy, four out of five patients showed gain of cognitive skills in line with development in healthy children compared to natural history of MPS-IIIA. A marked improvement compared with natural history of the disease was observed in one patient at 18 months of follow up. Three additional patients are currently within the normal development quotient range at 9 to 18 months post-treatment but require longer follow-up to assess outcomes. Gain of cognitive skills is assessed in this study through evidence of speech acquisition, continence and complex play requiring concentration. Treatment with OTL-201 was generally well-tolerated in the initial study population. Of the six serious adverse events reported to date, four were thought to be due to conditioning or leukapheresis and one was related to background disease. One patient had delayed platelet engraftment until day 52 post-treatment likely due to Cytomegalovirus infection around the time of infusion. The lentiviral vector integration profile was consistent with other lentiviral-based HSC gene therapy studies and there has been no indication of insertional oncogenesis and no evidence of clonal dominance due to integration into oncogenes in samples analyzed to date. Five patients aged 6 to 24 months, with a rapidly progressive MPS-IIIA phenotype confirmed by an independent metabolic disease expert, were administered investigational OTL-201 as part of this ongoing PoC trial, sponsored by The University of Manchester, conducted at Royal Manchester Children’s Hospital, and funded by Orchard Therapeutics. Primary study objectives include safety, tolerability and peripheral expression of SGSH in total leukocytes at 12 months. Secondary study objectives include overall survival and neurocognition as measured by the Bayley Scales of Infant and Toddler Development or the Kaufman Assessment Battery for Children. The OTL-201 program and this investigator-led clinical trial follow over a decade of development and pre-clinical work by Brian Bigger, Ph.D., professor of cell and gene therapy at UoM. Patients enrolled in the ongoing PoC trial will be followed for a minimum of three years during which time the study investigators will continue to report additional biochemical and clinical outcomes. The OTL-201 program in MPS-IIIA presents multiple development and commercial synergies with Orchard’s other neurometabolic programs, and the condition represents a significant medical need given there are no approved therapies and treatment with allogeneic HSC transplant has not been shown to be effective for MPS-IIIA patients.