Orchard Therapeutics announced long-term results from an updated integrated analysis of 39 patients with metachromatic leukodystrophy treated with investigational OTL-200 in the clinical development program. The data were presented at the ongoing Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium in Jerusalem. Thirty-nine pediatric patients with early-onset MLD, enrolled in two prospective non-randomized clinical studies (n=30) or treated under expanded access frameworks (n=9), were administered OTL-200 and compared with natural history data from 49 untreated patients.

All treated patients were administered OTL-200 and subsequently monitored at Ospedale San Raffaele in Milan, Italy. The composite endpoint used in the updated integrated analysis is severe motor impairment-free survival, defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support (Gross Motor Function Classification-MLD [GMFC-MLD] Level = 5) or death. Importantly, use of sMFS was discussed with the U.S. Food and Drug Administration (FDA) who agreed it is clinically meaningful.

At the time of the updated integrated analysis (median follow-up 6.76 years, range 0.64-12.19 years), results from treated patients showed: Treatment with OTL-200 resulted in statistically significant and clinically meaningful improvement in sMFS in the pre-symptomatic late infantile (p<0.001), pre-symptomatic early juvenile (p=0.042) and early-symptomatic early juvenile (p<0.001) MLD subgroups compared to disease natural history. Seventeen of 18 pre-symptomatic late infantile patients maintained the ability to walk at last assessment (GMFC-MLD Level 2 or better; range of age at last assessment: 3.2 to 13.4 years), in contrast to untreated late infantile natural history patients, all of whom lost all locomotion (GMFC-MLD Level 5 or worse) by a median age of 2.6 years. All seven surviving pre-symptomatic early juvenile patients maintained the ability to walk without support with quality and performance normal for age at last assessment (GMFC-MLD Level 0; range of age at last assessment: 2.1 to 11.9 years), and seven of nine surviving early-symptomatic early juvenile patients maintained the ability to sit without support and/or crawl/roll at last assessment (GMFC-MLD Level 4 or better; range of age at last assessment: 5.1 to 19.1 years), in contrast with untreated early juvenile natural history patients, all of whom lost all locomotion (GMFC-MLD Level 5 or worse) by a median age of 6.4 years.

Seventeen of 18 pre-symptomatic late infantile, all seven surviving pre-symptomatic early juvenile, and six of nine surviving early-symptomatic early juvenile patients have continued to acquire cognitive skills as expected for age, shown by the upward trajectory of performance and verbal age-equivalents over chronological ages. All treated patients had reconstituted ARSA activity in peripheral blood mononuclear cells with geometric mean values within or above normal range by three months post-treatment and in cerebrospinal fluid by three to six months post-treatment, which has been sustained throughout follow-up. Safety With more than a cumulative 250 patient-years of follow-up, treatment with OTL-200 was generally well-tolerated, with no treatment-related serious adverse events or deaths.

Most adverse events were associated with busulfan conditioning or background disease. There were three patient deaths observed in the study, none of which were considered related to treatment with OTL-200. Six treatment-related adverse events of anti-ARSA antibodies reported, which resolved either spontaneously or after B-cell depleting therapy with no impact on clinical outcome.

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. Delayed platelet engraftment occurred in four patients all of which resolved within the first four months after conditioning with no bleeding events reported. One patient with a complex medical history and comorbidities experienced prolonged anemia and thrombocytopenia requiring infusion of unmanipulated back-up cells and remains in good clinical condition.

There have been no cases of malignancy or insertional oncogenesis and no evidence of clonal dominance or expansion reported to date, consistent with other Orchard lentiviral HSC gene therapy studies. As previously announced, the company has completed the rolling submission of its Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for OTL-200, in children with early-onset MLD. OTL-200 previously received both Rare Pediatric Disease (RPD) and Regenerative Medicine Advanced Therapy (RMAT) designations from the FDA.

Orchard Therapeutics has requested priority review, which if granted, would put OTL-200 on track for a potential U.S. approval in the first half of 2024. MLD is a rare and life-threatening inherited disease of the body?s metabolic system estimated to occur in approximately one in every 100,000 live births based on existing literature. 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% and 44% at 10 years for juvenile patients.

Libmeldy, also known as OTL-200, has been approved by the European Commission for the treatment of metachromatic leukodystrophy (MLD) in 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 of Libmeldy, the safety profiles of these interventions were consistent with their known safety and tolerability.