Arsa-Cel Continues to Show Durable Benefit in MLD Outcomes Over Natural History


Orchard Therapeutics has also randomized the first patient with Hurler Syndrome in the phase 3, registrational HURCULES trial of OTL-203 gene therapy.

Francesca Fumagalli, MD, PhD

Francesca Fumagalli, MD, PhD

Credit: IRCCS San Raffaele

Atidarsagene autotemcel (arsa-cel; Orchard Therapeutics) has continued to show durable preservation of motor, cognitive, and speech abilities in patients with early-onset metachromatic leukodystrophy (MLD) as compared to natural history data and a favorable risk-benefit profile, with follow-up up to 12 years.1

These long-term data were presented by Francesca Fumagalli, MD, PhD, neurologist, IRCCS San Raffaele Hospital, at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.

Arsa-cel, an ex vivo autologous CD34+ hematopoietic stem cell (HSC)-based gene therapy, is approved under the name Libmeldy in the European Union.

“MLD is an ultra-rare lysosomal disease caused by arylsulfatase A (ARSA) deficiency leading to progressive demyelination, neurodegeneration, loss of cognitive and motor function, and early death, with no approved treatments in the United States (US),” Fumagalli and colleagues wrote in their poster.1

READ MORE: Orchard Therapeutics’ BLA for Metachromatic Leukodystrophy Cell Therapy Arsa-Cel Accepted With Priority Review

The investigators treated 39 patients with presymptomatic (PS) late infantile (LI) and early juvenile (EJ) and early-symptomatic(ES) EJ MLD at San Raffaele-Telethon Institute of Gene Therapy between 2010 and 2020 in 2 clinical trials (NCT01560182, n = 20; NCT03392987, n = 10) and expanded access programs (n = 9). Forty-nine matched patients with MLD treated at the same center were used as natural history comparators.1

The participants that received arsa-cel had a median follow-up of 6.76 years (range, 0.64-12.19); natural history comparators had a median follow-up of 5.13 years (range, 0.38-20.73). Fumagalli and colleagues found that, in the treated participants, ARSA activity was restored in peripheral blood mononuclear cells to normal or supranormal levels by 3 months after infusion and in cerebrospinal fluid to normal levels by 3-6 months post infusion. These levels were sustained throughout follow-up.1

Patients with PS LI MLD experienced clinically meaningful improvements in severe motor impairment free survival (sMFS), overall survival (OS), and cognitive function compared to matched comparators, who experienced rapid losses in these domains and ultimately death. Patients with PS EJ and ES EJ MLD experienced clinically meaningful improvements in sMFS and cognitive function compared to matched comparators, who experienced losses in these domains and, if surviving, are severely debilitated.

In terms of safety, arsa-cel continues to be generally well-tolerated, with no deaths or serious adverse events (AEs) related to the gene therapy. There were 3 deaths during follow-up due to ischemic cerebral infarction in 1 patient with PS EJ MLD and rapid disease progression in 2 patients with ES EJ MLD. One patient experienced prolonged anemia and thrombocytopenia despite engraftment and required infusion of unmanipulated back-up HSCs.Serious AEs related to busulfan conditioning included vomiting, vaso-occlusive disease, anemia, thrombocytopenia, and sepsis (all grade 3, n = 1), as well as delayed platelet engraftment in 4 patients. There were 6 AEs of transient anti-ARSA antibodies related to arsa-cel, 5 of which resolved and 1 of which is ongoing.1

“[Arsa-cel] continues to show a favorable benefit-risk profile, long-term durability of treatment effect, and clinical outcomes consistent with previously published results,” Fumagalli and colleagues concluded.1

Orchard also just announced that it has randomized the first patient with mucopolysaccharidosis type 1, also known as Hurler Syndrome, with OTL-203, another HSC-based gene therapy, in the phase 3 registrational HURCULES trial (NCT06149403) at M Health Fairview Masonic Children’s Hospital. The study plans to enroll 40 patients across clinical sites in the US and Europe.2

“The complications associated with MPS-IH have a detrimental impact on patients’ quality of life, and while transplantation may help improve outcomes, it is associated with significant morbidity and mortality,” study investigator Paul Orchard, MD, professor, Division of Pediatric Blood and Marrow Transplantation and Cellular Therapy Program, University of Minnesota Medical School, said in a statement.2 “New options are needed to better address some of the more severe symptoms of the disease, such as neurocognitive function, growth and other skeletal issues. We look forward to working with the team at Orchard Therapeutics and other clinical sites around the world to facilitate enrollment in this study and characterize the potential clinical impact of OTL-203 on MPS-IH.”

1. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
2. Orchard Therapeutics Announces First Patient Randomized in Registrational Trial of OTL-203 for MPS-I Hurler Syndrome. Orchard Therapeutics. News release. February 5, 2024.
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