Rare Daily Staff

Orchard Therapeutics reported results from a 20-patient trial evaluating the efficacy and safety of OTL-200, its gene therapy for the treatment of metachromatic leukodystrophy, a rare and life-threatening inherited metabolic disease.

Metachromatic leukodystrophy (MLD) is caused by a mutation in the arylsulfatase A (ARSA) gene that results in the accumulation of sulfatides in the central and peripheral nervous systems and other areas of the body, including the liver, the gall bladder, kidneys, and/or spleen. Over time, the nervous system is damaged and patients with MLD will experience neurological problems, such as motor, behavioral and cognitive regression, severe spasticity and seizures, making it more and more difficult to move, talk, swallow, eat and see. Currently, there are no effective treatments for MLD.

OTL-200 is an ex vivo, autologous, hematopoietic stem cell-based gene therapy developed for the treatment of MLD that Orchard acquired from GSK in April 2018. OTL-200 originated from a collaboration between GSK and the San Raffaele Hospital and the Telethon Foundation, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan.

As of March 2018, twenty early-onset MLD patients (9 late infantile and 11 early juvenile) from the registrational study completed at least three years of follow-up (ranging from 3.0 to 7.5 years in 18 out of 20 patients) to assess the efficacy and safety of OTL-200 following gene therapy. The data, which included updated results on the two-year primary endpoints, in addition to new follow-up data at three years, were featured in an oral presentation at the 45th Annual Meeting of the European Society for Blood and Marrow Transplantation.

A reconstitution of ARSA activity in the hematopoietic system was observed in all treated patients, with values within or above the normal reference range by three months post-treatment and remaining stable throughout the duration of the follow-up period.

A clinically meaningful treatment difference in gross motor function, well above the pre-specified threshold established in the trial, was observed between OTL-200 treated patients and untreated, age-matched participants in the natural history study.

Stable engraftment of gene-corrected cells was observed in treated patients from one-month post-treatment.

At an age when patients in the untreated natural history cohort showed severe cognitive impairment, cognitive performance scores were maintained within normal range for most treated patients, independent of their symptomatic status at the time of treatment.

Changes observed on brain MRIs of patients treated with OTL-200 suggest that OTL-200 may prevent, stabilize, or markedly delay the progressive atrophy and damage to the protective covering of the myelin sheath that surrounds nerve fibers typically observed with MLD. A greater effect was observed in early-onset MLD patients treated prior to the presentation of overt symptoms.

Treatment with OTL-200 was well-tolerated and had a positive benefit-risk profile, with no adverse events or deaths related to treatment and no signs of genotoxicity. To date, no cases of malignancy or adverse events indicative of oncogenic transformation have been reported.

As previously reported, two patients who were symptomatic at the time of treatment died due to rapid disease progression unrelated to treatment with gene therapy. A long-term follow-up phase is ongoing until all patients complete at least 8 years of follow-up post-treatment.

The company said it intends to complete the necessary development work and prepare a marketing application for submission in Europe in 2020.  Work is also underway to prepare an application for marketing approval in the United States.

“Providing effective therapies for metabolic diseases that affect the central nervous system has been an ongoing challenge in the field of gene therapy and beyond. We are thrilled that these data further confirm the potential of Orchard’s HSC approach to treat MLD and other neurometabolic diseases,” said Andrea Spezzi, chief medical officer of Orchard. “Moving forward, our focus is to bring the OTL-200 program to regulatory filings as quickly as possible, while broadly leveraging this technology across our neurometabolic franchise, with a second CNS program, OTL-201 in MPS-IIIA, preparing to enter the clinic.”

Photo: Andrea Spezzi, chief medical officer of Orchard

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