Orchard Therapeutics Reports New Interim Data from Proof-of-Concept Study of Gene Therapy for MPS-I

Orchard Therapeutics said new interim data from an ongoing proof-of-concept clinical trial evaluating the safety and efficacy of OTL-203, its gene therapy in development for the treatment of mucopolysaccharidosis type I, met its first primary outcome measure with all eight patients achieving hematologic engraftment, and improved motor skills, stable cognitive scores, and normal growth seen in the first two patients.

Photo: Bobby Gaspar, CEO of Orchard

The data was presented at the American Society of Gene & Cell Therapy 23rd Annual Meeting.

Mucopolysaccharidosis type I (MPS-I) is a rare inherited neurometabolic disease caused by a deficiency of the IDUA (alpha-L-iduronidase) lysosomal enzyme required to break down glycosaminoglycans (GAGs). The accumulation of GAGs across multiple organ systems results in the symptoms of MPS-I including neurocognitive impairment, skeletal deformity, loss of vision and hearing, hydrocephalus, and cardiovascular and pulmonary complications. There are three subtypes of MPS-I; approximately 60 percent of MPS-I patients have the severe Hurler subtype and, when untreated, these patients rarely live past the age of 10.

Treatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have significant limitations. OTL-203 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MPS-I.

OTL-203 is an ex vivo autologous hematopoietic stem cell gene therapy. Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the gene therapy program for the treatment of MPS-I developed by the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

As of April 2020, all eight patients in the study with the severe Hurler subtype of MPS-I, which is being conducted at the San Raffaele Telethon Institute for Gene Therapy in Milan, have been treated with OTL-203. Patients have been followed for a minimum of three months, with the longest follow-up extending out to 18 months.

The primary outcome measures of the trial include overall survival, safety, hematological engraftment by day 45 following treatment and biological efficacy as measured by alpha-IDUA lysosomal enzyme activity in the blood at one-year post-treatment. Treatment with OTL-203 and the selected conditioning regime were well-tolerated across all eight patients and demonstrated rapid hematologic reconstitution, with neutrophil and platelet engraftment within 21 days following treatment, and biological efficacy demonstrated by supranormal IDUA enzyme expression in peripheral blood, with the first two patients treated achieving stable supranormal levels up to 12 months post gene therapy.

Key secondary and exploratory outcome measures include normalization of urinary GAGs, growth velocity and effects on motor and cognitive function at one- and two-years post-treatment. All eight patients showed high levels of metabolic correction with reduction in GAG levels in urine and cerebral spinal fluid (CSF). For the first two treated patients with 18 and 12 months of follow-up, the data showed rapid metabolic correction of GAG levels in the urine and CSF, improved motor function and acquisition of cognitive and language skills, continued growth progressing above the 50th percentile of normal, improved range of motion (an indicator of joint stiffness), and improvement of brain and spine MRI scores.

“We are extremely encouraged by data emerging from the MPS-I program, where we are seeing correction of biochemical parameters as well as early clinical evidence of the potentially transformative effects of OTL-203,” said Bobby Gaspar, CEO of Orchard. “These data further support the hypothesis that our hematopoietic stem cell gene therapy approach could have potential future applications to treat a range of genetic neurometabolic disorders.”

The proof-of-concept study is ongoing and Orchard plans to report additional interim results in the second half of 2020. The company also expects to release full proof-of-concept results and initiate the registrational study for OTL-203 in 2021.

Orchard was granted an exclusive worldwide license to intellectual property rights to research, develop, manufacture and commercialize the gene therapy program for the treatment of MPS-I developed by the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy.

Author: Rare Daily Staff