MPS-IH HSC Gene Therapy Gets IND Clearance


Promising results were previously reported from a proof-of-concept study involving 8 patients.

Orchard Therapeutics’ OTL-203, an investigational hematopoietic stem cell (HSC) gene therapy intended to treat the Hurler subtype of mucopolysaccharidosis type I (MPS-IH), has received clearance of its investigational new drug (IND) application from the FDA.1

OTL-203, which is being developed in a collaboration with the San Raffaele Telethon Institute for Gene Therapy, consists of patients’ own CD34+ HSCs which have been modified ex vivo with a lentiviral vector that encodes IDUA, the disease-targeted gene.1,2 It was previously evaluated in a non-randomized, single-center, proof-of-concept study for 8 patients with MPS-IH, who were dosed between July 2018 and December 2019. According to a November 2021 press release summarizing the results of the study, which were originally published in the New England Journal of Medicine, all of the patients achieved supraphysiologic blood IDUA activity, with a median of 107.95 μmol/L/h (range: 30-138.6) at 12 months, which is above the 97.5 percentile (24.8 μmol/L/h) of age-matched healthy children. IDUA activity above the upper limit of normal was maintained in all patients at last follow-up (range: 12-24 months). Furthermore, all participants showed a decrease in urinary levels of glycosaminoglycans (GAG) to normal or near-normal levels by 3 to 6 months post-treatment, which remained stable through final available follow-up. At the last follow-up, levels of IDUA in the cerebrospinal fluid (CSF) ranged from 0.12 to 4.78 μmol/L/h (median, 0.5), up from being undetectable at baseline, and corresponded with a rapid decrease in GAG in the CSF. In addition, at the last follow-up, all participants demonstrated stable cognitive development, progressive acquisition of motor skills over time, progression along expected growth percentiles of healthy children, and longitudinal growth considered within the range of normal. Improvements were also observed in range of motion evaluations.

In terms of safety, OTL-203 was generally well-tolerated with an overall survival rate of 100% at last available follow-up, and there were no cases of graft-versus-host disease. There were 19 serious adverse events (SAEs) reported, which included 7 related to known complications of MPS-IH. These 7 SAEs were present at baseline and have since resolved. The lentiviral vector integration profile was noted to be consistent with other lentiviral-based HSC gene therapy studies. All 7 patients on enzyme replacement therapy (ERT) stopped ERT 3 weeks or more prior to administration of OTL-203, and none of these patients restarted ERT at a later point. No evidence of insertional oncogenesis or clonal dominance due to integration into oncogenes was observed in the treated patients.

“Based on data from the proof-of-concept trial, treatment with a single administration of OTL-203 has the potential to address a range of multisystemic manifestations of MPS-IH,” Leslie Meltzer, PhD, chief medical officer, Orchard Therapeutics, said in a statement regarding the IND clearance.1 “Our recent interactions with the FDA have been productive and we look forward to advancing this registrational study designed to generate the data necessary to enable global regulatory submissions and potentially provide an urgently needed new treatment option for the MPS-IH community.”

Orchard Therapeutics intends to initiate a new clinical trial in the second half of this year. The global, 1:1 randomized, active controlled study will seek to recruit 40 patients with MPS-IH and will evaluate OTL-203 against allogeneic hematopoietic stem cell transplant (HSCT), a current standard of care. The trial’s primary end point will be a composite measure accounting for death, the need for rescue treatment, treatment failure, immunological complications, and severe cognitive and growth impairment. Secondary end points will include measures related to biochemical markers and safety and tolerability, along with other clinical measures. The company expects that up to 6 sites in the United States and Europe could be opened. OTL-203 has previously been granted rare pediatric disease designation by the FDA and priority medicines designation from the European Medicines Agency.

“The complications associated with MPS-IH involve multiple organ systems and have a lasting impact on patients’ quality of life despite treatment with allogeneic HSCT,” Paul Orchard, MD, 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, added to the statement.1 “Existing therapeutic options are associated with significant morbidity and mortality. There is experience acquired over decades that treatment with allogeneic HSCT does not adequately impact manifestations of the disorder such as growth and other skeletal issues. Furthermore, patients can still experience an irreversible decline in neurocognitive function. We look forward to facilitating this study to characterize the potential clinical impact of OTL-203 for MPS-IH patients.”

1. Orchard Therapeutics announces U.S. FDA clearance of IND application for OTL-203 in MPS-IH. News release. Orchard Therapeutics. January 5, 2023. 
2. Orchard Therapeutics announces New England Journal of Medicine publication of interim proof-of-concept study results of OTL-203 for Hurler syndrome. News release. Orchard Therapeutics. November 18, 2021. 
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