Orchard Therapeutics (Nasdaq: ORTX), a global gene therapy leader, today announced the publication in The Lancet of long-term clinical outcomes evaluating the safety and efficacy of Libmeldy® (atidarsagene autotemcel) for the treatment of early-onset metachromatic leukodystrophy (MLD). 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.
“MLD is a cruel and ultimately fatal disease for which there were previously no approved treatment options beyond supportive care,” said Professor Alessandro Aiuti, deputy director of the San Raffaele Telethon Institute for Gene Therapy in Milan and full professor of pediatrics at the Vita-Salute San Raffaele University of Milan and a senior author of The Lancet manuscript. “Libmeldy represents a significant step forward in the treatment of MLD. These data highlight the potential long-term benefits of HSC gene therapy for these children, especially when intervention prior to symptom onset is possible.”
Twenty-nine pediatric patients with early-onset MLD, enrolled in either a prospective non-randomized clinical study (n=20) or treated under expanded access frameworks (n=9), 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.
“Treatment with Libmeldy resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving motor development and cognitive function in most patients,” said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. “These are compelling results that underscore the potential of our HSC gene therapy approach to end the devastation caused by severe genetic diseases with a single treatment. We are commercializing Libmeldy in Europe and intend to pursue future potential regulatory approvals.”
Summary of Results Published in The Lancet
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 (typically ranging from six to 30 months old at symptom onset) or pre- or early-symptomatic early juvenile (typically between 30 months and less than seven years old at symptom onset) disease and treated with Libmeldy in a prospective non-randomized clinical study or under expanded access frameworks. These included 16 (55%) pre-symptomatic late-infantile patients (one pre-symptomatic at enrollment became symptomatic by the time of treatment) and 13 (45%) 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 (GMFM) 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 (CI) 48.9–82.3], p<0.0001) and early juvenile patients (42 percentage points [95% CI 12.3–71.8], p=0.036). 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 (PBMCs) within or above normal range from three months post-treatment and onward with levels significantly increased above baseline at two years post-treatment (co-primary endpoint).
- Twenty-six of 29 patients (90%) were alive with median follow-up of 3.2 years (range 0.64 to 7.51 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 (8- and 15-months post-treatment, respectively) 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 (n=23, 79%), gait disturbance (n=15, 52%), and stomatitis (n=12, 41%).
- 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.
MLD is a rare and life-threatening inherited disease of the body’s metabolic system occurring in approximately one in every 100,000 live births. MLD is 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, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. 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.i
About Libmeldy / OTL-200
Libmeldy (atidarsagene autotemcel), also known as OTL-200, has been approved by the European Commission for the treatment of MLD in eligible early-onset patients characterized by biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with i) late infantile or early juvenile forms, without clinical manifestations of the disease, or ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline. Libmeldy is the first therapy approved for eligible patients with early-onset MLD.
The most common adverse reaction attributed to treatment with Libmeldy was the occurrence of anti-ARSA antibodies. In addition to the risks associated with the gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions were consistent with their known safety and tolerability.
For more information about Libmeldy, please see the Summary of Product Characteristics (SmPC) available on the EMA website.
Libmeldy is approved in the European Union, UK, Iceland, Liechtenstein and Norway. OTL-200 is an investigational therapy in the U.S.
Libmeldy was developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.