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