Presentation of data comprising the clinical package for the OTL 200 BLA in metachromatic leukodystrophy at the SSIEM Annual Symposium 2023

The data were presented at the ongoing Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium in Jerusalem.

“MLD is a devastating and ultimately fatal disease for which there are no alternative treatment options beyond supportive care,” said Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics. “These data, which now encompass more than a cumulative 250 years of patient experience, continue to show sustained preservation of cognitive function and motor development in most patients compared to disease natural history consistent with previously published results. Moreover, results from the updated integrated analysis presented at SSIEM are key components of the clinical package in the OTL 200 BLA we recently submitted to the FDA.”

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 (sMFS), 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 greater than 5) or death. Importantly, use of sMFS was discussed with the 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: Efficacy: i. 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. a. 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. b. 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. ii. 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. iii. all treated patients had reconstituted arsa activity in peripheral blood mononuclear cells (pbmcs) 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.