Rare Daily Staff

Orchard Therapeutics announced an integrated data analysis and an update from a proof-of-concept study from its experimental gene therapies for rare diseases: OTL-200, which is in development for the treatment of metachromatic leukodystrophy; and OTL-203, which is in development for the treatment of mucopolysaccharidosis type 1.

The data were highlighted in oral presentations at the Society for the Study of Inborn Errors of Metabolism symposium in Rotterdam, the Netherlands. The gene therapies were developed at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy, where the trials are being conducted. SR-Tiget is collaborative effort between GlaxoSmithKline and the Hospital San Raffaele and Fondazione Telethon, initiated in 2010.

Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the body’s metabolic system caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, the gallbladder, kidneys, and/or spleen. Over time, damage to the nervous system leads to difficulty moving, talking, swallowing, eating, and seeing. Currently, there are no effective treatments for MLD. In its late infantile form, mortality at five years from onset is estimated at 50 percent, and 44 percent at 10 years for juvenile patients.

“This analysis confirms and expands upon previously reported results for the primary efficacy endpoint, with significantly superior gross motor function measure scores compared with untreated patients, along with positive effects on cognitive function,” said Valeria Calbi, a hematologist at San Raffaele Scientific Institute and SR-Tiget, regarding the presentation of additional integrated data from a total of 29 patients treated with OTL-200. “These data demonstrate that the majority of patients treated with gene therapy at pre-symptomatic and early symptomatic stages of their disease experienced clinical benefit, while all patients in the natural history cohort showed the expected rapid decline in motor and cognitive function.”

Orchard’s OTL-200 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy being studied for the treatment of MLD that Orchard acquired from GSK in April 2018. Data from 29 early-onset MLD patients (16 late infantile and 13 early juvenile) treated with gene therapy were analyzed to assess the efficacy and safety of OTL-200. Results from patients treated with OTL-200 were compared with those from an age-matched natural history cohort of 31 untreated MLD patients.

The treatment difference in gross motor function was more than six times greater than the pre-specified endpoint of 10 percent. As of the date of last follow-up, 26 patients are alive and have completed up to 7.5 years of follow-up (median 3.2 years) post-gene therapy. In addition, treatment with OTL-200 was well tolerated and had a positive benefit-risk profile, with no treatment-related adverse events or deaths and no signs of genotoxicity. The three patient deaths were deemed unrelated to treatment with OTL-200.

“The results of the integrated data analysis further underscore our commitment to bring one-time, potentially curative treatment options to patients living with MLD and other devastating rare genetic diseases that lack meaningful treatment options,” said Mark Rothera, president and CEO of Orchard.

Rothera said Orchard anticipates submissions for regulatory approval in Europe in the first half of 2020 and the United States approximately one year later.  

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.

The ongoing proof-of-concept clinical trial evaluating the safety and efficacy of OTL-203, an ex vivo, autologous hematopoietic stem cell-based gene therapy being studied for the treatment of MPS-1, involves six patients with severe Hurler subtype of MPS-1 who have been treated with a 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.

The primary endpoints of the trial are safety, hematological engraftment by day 45 following treatment and preliminary efficacy at one-year post-treatment. Early data show that treatment with OTL-203 was well tolerated, and there was evidence of engraftment of gene-corrected hematopoietic stem cells after a single administration, as well as greater than expected expression of the missing enzyme and signs of metabolic disease correction.

“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 Andrea Spezzi, chief medical officer of Orchard. “We believe our gene therapies could fundamentally change the lives of patients born with MPS-I and other devastating and rapidly progressive diseases affecting the central nervous system and remain committed to advancing our programs in this area as quickly as possible.”

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.

Photo: Mark Rothera, president and CEO of Orchard

X