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B3 - Lysosomal Storage Diseases

1: Atidarsagene Autotemcel (Hematopoietic Stem Cell GeneTherapy) Preserves Cognitive and Motor Development in Metachromatic Leukodystrophy with up to 12 Years Follow-Up

Type: General Session

Presentation Details
Session Title: Presidential Symposium

Introduction: Metachromatic leukodystrophy (MLD) is a rare neurometabolic disorder caused by deficiency of arylsulfatase A (ARSA), leading to accumulation of sulfatides in the central and peripheral nervous systems, and subsequently progressive demyelination, neurodegeneration, loss of all motor and cognitive skills and early death.
We present long-term results from an integrated analysis of 39 patients with early-onset MLD (19 late infantile, 20 early juvenile) treated with autologous ex vivo hematopoietic stem cell gene therapy (atidarsagene autotemcel, “arsa-cel”) across two prospective clinical trials (n=30) and expanded access frameworks (n=9). Arsa-cel consists of autologous CD34+ cells transduced ex vivo with a lentiviral vector encoding for the human ARSA gene. After busulfan conditioning, arsa-cel was administered intravenously. Clinical outcomes were compared with natural history (NHx) data from 49 untreated early-onset MLD patients.
The median length of follow-up was 6.76 years (range 0.64-12.19). All patients demonstrated stable multilineage engraftment of gene-corrected cells and restoration of ARSA activity in peripheral blood mononuclear cells to normal or supranormal levels by 3 months post-treatment and restoration in cerebrospinal fluid to normal levels by 3-6 months post-treatment, which were sustained throughout follow-up. The risk of experiencing severe motor impairment or death was significantly reduced in the pre-symptomatic late-infantile (PSLI, p<0.001), pre-symptomatic early-juvenile (PSEJ, p=0.042), and early-symptomatic early-juvenile (ESEJ, able to walk independently and without cognitive impairment prior to treatment, p<0.001) treated subgroups versus MLD subtype-matched NHx patients. Arsa-cel treatment resulted in substantial improvements in motor and cognitive outcomes as compared with NHx, particularly among patients treated before symptom onset. Over 95% (25/26) of treated PSLI and PSEJ patients retained the ability to walk at last follow-up, and most treated patients showed clinically meaningful preservation of cognitive abilities and speech. In contrast, most NHx patients experienced rapid motor and cognitive decline and loss of speech, progressing to a severely debilitated state or death. Three treated patients died, all considered unrelated to arsa-cel. There were no serious adverse events related to arsa-cel, no malignancies, and no evidence of abnormal clonal expansion or replication-competent lentivirus. The most common adverse events (AEs) were consistent with the known safety profile of busulfan or symptoms of MLD. The only arsa-cel-related AEs were 6 events of transient and low titer anti-ARSA antibodies with no impact on pharmacodynamic or clinical outcomes.
Conclusions: With up to 12 years follow-up in the earliest treated patient and a cumulative 251 patient-years of follow-up, arsa-cel shows a favorable benefit-risk profile with clinically meaningful, sustained efficacy, preventing severe motor and cognitive impairment, preserving speech, and slowing disease progression in early-onset MLD patients.

Valeria Calbi1, Francesca Fumagalli1, Fabiola De Mattia1, Alberto Zambon1, Vera Gallo1, Salvatore Recupero1, Elena Sophia Fratini2, Alessia Ippolito1, Francesca Ciotti1, Maddalena Fraschini1, Marina Sarzana1, Stefano Scarparo1, Eugenio Montini1, Sara Locatelli1, Marcella Facchini1, Alessandra Clerici1, Francesco Morena3, Sabata Martino3, Muska Yarzi4, Sean L. Moro5, Andrew Shenker6, Jean Brooks4, Alan Richardson4, Laura Campbell4, Alessandro Aiuti2

1San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Milan, Italy,2San Raffaele Telethon Institute for Gene Therapy (SR-Tiget); Vita Salute San Raffaele University, Milan, Italy,3University of Perugia, Perugia, Italy,4Orchard Therapeutics, London, United Kingdom,5Orchard Therapeutics, Boston, MA,6Clinical Consultant, Pennington, NJ"

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