Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy
Authors: Francesca Fumagalli, Valeria Calbi, Vera Gallo, Alberto Andrea Zambon, Salvatore Recupero, Francesca Ciotti, Marina Sarzana, Maddalena Fraschini, Stefano Scarparo, Fabiola De Mattia, Simona Miglietta, Clelia Pierini, Matias Soncini, Francesco Morena, Eugenio Montini, Federica Barzaghi, Giulia Consiglieri, Francesca Ferrua, Maddalena Migliavacca, Francesca Tucci, Elena Sophia Fratini, Alessia Ippolito, Paolo Silvani, Maria Rosa Calvi, Alessandra Clerici, Ambra Corti, Marcella Facchini, Sara Locatelli, Mara Sangalli, Stefano Zancan, Federica Miotto, Maria Grazia Natali Sora, Cristina Baldoli, Sabata Martino, Angélica Córdoba-Claros, Sean L. Moro, Nicholas D. Gollop, Jeff Abate, Muska N. Yarzi, Philippa Nutkins, Andrew Shenker, Mattia Calissano, Jean Brooks, Alan Richardson, Laura Campbell, Massimo Filippi, Luigi Naldini, Maria Pia Cicalese, Fabio Ciceri, Maria Ester Bernardo, Alessandro Aiuti
Journal: New England Journal of Medicine (2025)

Metachromatic leukodystrophy (MLD) is an ultrarare, severe lysosomal storage disorder caused by a deficiency of arylsulfatase A (ARSA). We treated patients who had MLD with atidarsagene autotemcel (arsa-cel), a hematopoietic stem-cell-based gene therapy, in two prospective open-label clinical studies and expanded-access programs. We compared their outcomes with those of untreated patients (natural history cohort). The primary end point was survival free from severe motor impairment (the time from birth to the first occurrence of loss of locomotion and of sitting without support or death from any cause). A total of 39 treated patients and 49 untreated patients were included. The median follow-up was 6.76 years (range, 0.64 to 12.19). Arsa-cel resulted in a significantly lower risk of severe motor impairment or death than no treatment among patients with presymptomatic late-infantile MLD (P<0.001), those with presymptomatic early-juvenile MLD (P = 0.04), and those with early-symptomatic early-juvenile MLD (P<0.001). The estimated percentage of patients surviving without severe motor impairment at 6 years of age was 0% (95% confidence interval [CI], not evaluable) among untreated patients with late-infantile MLD and 100% (95% CI, 100 to 100) among treated patients with presymptomatic late-infantile MLD. The estimated percentage of patients surviving without severe motor impairment at 10 years of age was 11.2% (95% CI, 0.9 to 36.4) among untreated patients with early-juvenile MLD and 87.5% (95% CI, 38.7 to 98.1) and 80.0% (95% CI, 40.9 to 94.6) among treated patients with presymptomatic and early-symptomatic early-juvenile MLD, respectively. No evidence of insertional oncogenesis was found. The most common grade 3 or higher adverse event was febrile neutropenia. Anti-ARSA antibodies were detected transiently in 6 of 39 patients (15%). Three deaths occurred, all of which were considered by the investigators to be unrelated to arsa-cel. Among patients with presymptomatic late-infantile or early-juvenile MLD and those with early-symptomatic early-juvenile MLD, the risk of severe motor impairment or death was significantly lower among those who received treatment with arsa-cel than in a natural history cohort that did not receive treatment. (Funded by Orchard Therapeutics and others; ClinicalTrials.gov numbers, NCT01560182 and NCT03392987.).