Orchard Therapeutics Announces Encouraging Update from Proof-of-Concept Study of OTL-203 for the Treatment of Mucopolysaccharidosis Type I (MPS-I)
Six of Eight Patients Treated to Date with Follow-up Out to 12 Months in First Patient to Receive Treatment
Evidence of Engraftment and Peripheral Blood Alpha-L-iduronidase (IDUA) Enzyme Overexpression Across Cohort
MPS-I is a progressive and often life-threatening inherited lysosomal storage disorder affecting children, with the most severe form known as Hurler syndrome. Patients with MPS-I often suffer from a constellation of devastating symptoms, including neurocognitive impairment, skeletal deformity, loss of vision and hearing, and cardiovascular and pulmonary complications.
Interim Study Results
As of the date of last follow-up, six patients with the severe Hurler subtype of MPS-I have been treated with the cryopreserved formulation of OTL-203 gene therapy. All treated patients were followed for a minimum of two months, with the longest follow-up extending out to 12 months. At the time of treatment, patients ranged in age from 14 months to 35 months. Five out of six patients had previously been treated with enzyme replacement therapy (ERT) and discontinued ERT treatment three weeks prior to enrollment, consistent with trial protocol.
The primary endpoints of the trial are safety, hematological engraftment by day 45 following treatment and preliminary efficacy as measured by IDUA enzyme activity (up to supraphysiologic levels) at one-year post-treatment. Treatment with OTL-203 demonstrated:
- Gene therapy and the selected conditioning regime were well-tolerated.
- Rapid hematologic reconstitution, with neutrophil and platelet engraftment within three weeks following treatment.
- Engraftment in the bone marrow and periphery by assessment of the vector copy number.
- Supranormal IDUA enzyme expression in peripheral blood, with the first patient treated achieving levels 10 times above the normal range and stable over time up to 12 months post gene therapy.
Key secondary and exploratory endpoints include normalization of urinary glycosaminoglycans (GAGs), growth velocity and effects on motor and cognitive function at one- and two-years post-treatment.
- For the first two treated patients, with 12 months and six months of follow-up, respectively:
○ Rapid metabolic correction of GAG levels in the urine and cerebrospinal fluid was observed, reflecting restoration of IDUA enzyme expression in the periphery and in the central nervous system.
- For the patient with 12 months of follow-up:
○ Preliminary clinical evaluation showed signs of resumed growth, improved motor skills and a stable cognitive score.
“The data emerging from the MPS-I program adds to the growing body of evidence that our approach – the expression of the targeted gene delivered via gene-modified blood stem cells – has the potential to permanently correct multiple neurometabolic disorders,” said
The proof-of-concept study is ongoing and expected to enroll eight patients by the first half of 2020, with primary endpoint results reported after one year of follow-up.
About MPS-I and OTL-203
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 (also known as GAGs or mucopolysaccharides). 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. MPS-I occurs at an overall estimated frequency of one in every 100,000 live births.1 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.Id 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 ex vivo, autologous, hematopoietic stem cell-based 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
Orchard’s portfolio of ex vivo, autologous, hematopoietic stem cell (HSC) based gene therapies includes Strimvelis®, a gammaretroviral vector-based gene therapy and the first such treatment approved by the
Orchard currently has offices in the
This press release contains certain forward-looking statements which are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements may be identified by words such as “anticipates,” “believes,” “expects,” “intends,” “projects,” and “future” or similar expressions that are intended to identify forward-looking statements. Forward-looking statements include express or implied statements relating to, among other things, planned marketing and licensing application submissions and next steps for Orchard’s programs, the therapeutic potential of Orchard’s product candidates, including OTL-203 for the treatment of MPS-I, and Orchard’s expectations regarding the timing of announcement of clinical data or enrollment in clinical trials for its product candidates, including OTL-203, the likelihood that such data will be positive and support further clinical development and regulatory approval of its product candidates, and the likelihood of approval of such product candidates by the applicable regulatory authorities. These statements are neither promises nor guarantees, but are subject to a variety of risks and uncertainties, many of which are beyond Orchard’s control, which could cause actual results to differ materially from those contemplated in these forward-looking statements. In particular, the risks and uncertainties include, without limitation: the risk that any one or more of Orchard’s product candidates, including OTL-203, will not be successfully developed or commercialized, the risk of cessation or delay of any of Orchard’s ongoing or planned clinical trials, the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical studies or clinical trials will not be replicated or will not continue in ongoing or future studies or trials involving Orchard’s product candidates, the delay of any of Orchard’s regulatory submissions, the failure to obtain marketing approval from the applicable regulatory authorities for any of Orchard’s product candidates, the receipt of restricted marketing approvals, and the risk of delays in Orchard’s ability to commercialize its product candidates, if approved. Given these uncertainties, the reader is advised not to place any undue reliance on such forward-looking statements.
Other risks and uncertainties faced by Orchard include those identified under the heading “Risk Factors” in Orchard’s annual report on Form 20-F for the year ended
1 Beck et al. The Natural History of MPS I: Global Perspectives from the MPS I Registry. Genetics in Medicine 2014, 16(10), 759
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Source: Orchard Therapeutics