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Orchard Therapeutics Announces Additional Interim Results From Proof-Of-Concept Study Of OTL-203 For MPS-I

Data on all eight patients demonstrate sustained engraftment and supranormal IDUA enzyme expression Translation of metabolic correction to clinical outcomes in first two patients continues to support potential of

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Data on all eight patients demonstrate sustained engraftment and supranormal IDUA enzyme expression

Translation of metabolic correction to clinical outcomes in first two patients continues to support potential of hematopoietic stem cell gene therapy in a second neurometabolic disorder

Data support planned initiation of registrational trial in 2021

BOSTON and LONDON, Sept. 01, 2020 (GLOBE NEWSWIRE) -- Orchard Therapeutics (NASDAQ:ORTX), a global gene therapy leader, today announced additional interim data from an ongoing proof-of-concept clinical trial evaluating the safety and efficacy of OTL-203, an investigational ex vivo autologous hematopoietic stem cell (HSC) gene therapy in development for the treatment of mucopolysaccharidosis type I (MPS-I) at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy. The readout from the primary endpoint at one year of follow-up is expected in 2021. Today's results are being shared virtually in an invited oral presentation at the 46th Annual Meeting of the European Society for Blood and Bone Marrow Transplantation (EBMT).

“We continue to see encouraging data from the ongoing clinical trial in MPS-I, including promising preliminary clinical effects on motor development, acquisition of cognitive skilIs and growth in the first two patients that were treated now 1.5 and 2 years ago, respectively. Additionally, new preliminary analyses of radiological outcome measures suggest that treatment with OTL-203 leads to stabilization or improvement in disease-related neurological abnormalities, as measured by brain and spine MRI, which we look to confirm with longer follow-up,” said Maria Ester Bernardo, M.D., Ph.D., principal investigator at SR-Tiget. "These data, taken together with those from clinical studies of HSC gene therapy for other metabolic disorders and leukodystrophies, support the potential for this therapeutic approach to correct a wide spectrum of multisystemic manifestations of the disease, bringing clinically meaningful benefits for patients.”

Interim Study Results

Eight patients with the severe Hurler subtype of MPS-I had been treated with OTL-203 in the ongoing proof-of-concept study, which completed enrollment in December 2019. As of July 2020, all patients had been followed for a minimum of six months, with the longest follow-up extending out to 24 months. Treatment with OTL-203 was generally well-tolerated with a safety profile consistent with the selected conditioning regimen. Consistent with previous analyses, treatment across all eight patients continued to demonstrate:

  • Rapid hematologic reconstitution, with neutrophil and platelet engraftment within 21 days following treatment.
  • Biological efficacy established by sustained supranormal alpha-L-iduronidase (IDUA) enzyme expression in peripheral blood for all patients within 3 months post-gene therapy and up to 18 months in the first treated patient.
  • Metabolic correction as measured by reduction in glycosaminoglycan (GAG) levels in urine achieved in all patients by 6 months post-gene therapy, with sustained correction out to 18 months in the first treated patient.



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  • Further results for the first two treated patients demonstrated:
    • Rapid metabolic correction of GAG levels in the cerebral spinal fluid (CSF), reflecting restoration of IDUA enzyme expression in the central nervous system. 
    • Improved motor function and acquisition of cognitive and language skills. 
    • Stabilization or improvement in white matter abnormalities, cervical canal stenosis, kyphosis and vertebra deformity, as measured by brain and spine MRI scores. 
    • Continued growth progression above the 50th percentile of normal. 
    • Improved range of motion (an indicator of joint stiffness).

“We continue to see positive trends in all biomarker and clinical measures as we follow patients in the OTL-203 proof of concept study for longer periods of time,” said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard. “With a growing amount of data to support advancing this program, we have recently convened a panel of disease experts to develop a design for a registrational trial that we intend to take to the regulators in advance of initiating the study in 2021 and ultimately progressing towards commercialization.”

About OTL-203 and MPS-I

Mucopolysaccharidosis type I (MPS-I) is a rare, inherited neurometabolic disease caused by a deficiency of the alpha-L-iduronidase (IDUA) lysosomal enzyme, which is required to break down sugar molecules called glycosaminoglycans (also known as GAGs). The accumulation of GAGs across multiple organ systems results in symptoms including neurocognitive impairment, skeletal deformity, loss of vision and hearing, and cardiovascular and pulmonary complications. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births. There are three subtypes of MPS-I; approximately 60 percent of children born with MPS-I have the most severe subtype, called Hurler syndrome, and rarely live past the age of 10 when untreated. 

Treatment options for MPS-I include hematopoietic stem cell transplant and chronic enzyme replacement therapy, both of which have significant limitations. Though early intervention with enzyme replacement therapy has been shown to delay or prevent some clinical features of the condition, it has only limited efficacy on neurological symptoms. OTL-203 is an investigational ex vivo autologous hematopoietic stem cell gene therapy being studied for the treatment of MPS-I. 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.