Orchard Therapeutics plc announced the publication in The Lancetof long-term clinical outcomes evaluating the safety and efficacy of Libmeldy for the treatment of early-onset metachromatic leukodystrophy. Libmeldy is the only approved one-time gene therapy intended to correct the underlying cause of MLD for eligible patients in the European Union, UK, Iceland, Liechtenstein and Norway. Also known as OTL-200, it is an investigational therapy in the U.S. Twenty-nine pediatric patients with early-onset MLD, enrolled in either a prospective non-randomized clinical study or treated under expanded access frameworks, were administered Libmeldy and compared with an untreated natural history cohort of 31 patients adjusted for age and disease subtype.

Most patients treated with Libmeldy developed motor skills within the predicted range of healthy children or maintained the ability to walk. Treatment with Libmeldy was well-tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus over the follow up period. There were no treatment-related mortality or serious adverse events.

Most adverse events were related to conditioning or background disease. Four patients developed transient anti-ARSA antibodies, which did not impact clinical outcomes. An integrated analysis was performed on data from 29 pediatric patients with a molecular and biochemical diagnosis of MLD and with either pre-symptomatic late-infantile or pre- or early-symptomatic early juvenile disease and treated with Libmeldy in a prospective non-randomized clinical study or under expanded access frameworks.

These included 16 pre-symptomatic late-infantile patients and 13 early juvenile patients, eight of whom were early-symptomatic at the time of treatment. Patients were treated and monitored at Ospedale San Raffaele, Milan, Italy. Treated patients were compared with a historical cohort of 31 age- and disease subtype-matched MLD patients from a non-interventional natural history study.

At the time of analyses in 2018, results from all treated patients showed: Total gross motor function measure scores were significantly improved in Libmeldy-treated patients compared to the natural history cohort at two years post-treatment (co-primary endpoint) for both late-infantile (66 percentage points [95% Confidence Interval and early juvenile patients. The difference was even larger at three years and remained statistically significant for both late-infantile and early juvenile patients. Most treated patients displayed normal cognitive development, as well as prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up.

Treatment benefits were particularly apparent in patients treated before symptom onset. All treated patients had reconstituted ARSA activity in peripheral blood mononuclear cells within or above normal range from three months post-treatment and onward with levels significantly increased above baseline at two years post-treatment. Twenty-six of 29 patients were alive with median follow-up of 3.2 years in all participants.

Of the three deaths which occurred during the follow-up period, two were due to rapid disease progression in early symptomatic early juvenile patients and were considered unrelated to treatment. The third death was due to ischemic stroke following an infectious event 13.6 months post-treatment in a pre-symptomatic early juvenile patient, which was also determined by study investigators as unlikely related to treatment. Treatment with Libmeldy was well-tolerated, with no treatment-related serious adverse events.

Most adverse events were associated with busulfan conditioning or background disease. The most frequently reported grade =3 AEs were febrile neutropenia, gait disturbance, and stomatitis. Five treatment-related events of anti-ARSA antibodies were reported in four (14%) of patients, which resolved spontaneously or after B-cell depleting therapy, with no obvious impact on clinical outcome or safety profile.

Antibody titers in all cases were generally low and no negative effects were observed in the engraftment of gene-corrected cells or in post-treatment ARSA activity.