Orchard Therapeutics’ Arsa-cel Restores ARSA Enzyme Activity in Patients With Late Juvenile MLD

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The gene-edited cell therapy also showed a safety profile consistent with that previously seen in patients with early-onset MLD.

Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy

Vera Gallo, MD
Credit: San Raffaele Telethon Institute for Gene Therapy

Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel, also referred to as OTL-200 and approved as Libmeldy in the European Union, UK, Iceland, Liechtenstein, and Norway), a gene-edited cell therapy intended to treat metachromatic leukodystrophy (MLD), has enabled restoration of arylsulfatase A (ARSA) enzyme activity among patients with the late juvenile (LJ) form of MLD. The results, which come from participants in a phase 3 clinical trial (NCT04283227), were presented in a poster at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.

Among the 5 patients with LJ MLD who were included in the ad hoc interim analysis, all who had available data showed normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. Furthermore, in the peripheral blood mononuclear cells (PBMCs) and in CD15+ cells ARSA activity reached supranormal levels. In 3 patients for whom central nervous system pharmacodynamic efficacy measures were available, ARSA activity in the cerebrospinal fluid (CSF) increased to normal levels.

First author Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy, and colleagues noted that at 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

READ MORE: Orchard Therapeutics’ Arsa-cel Restores ARSA Enzyme Activity in Peripheral Blood of Patients With MLD in US Compassionate Use Study

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. Gallo and colleagues noted that 1 patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus

Key Takeaways

  • Among the 5 patients with LJ MLD who were included in the ad hoc interim analysis, all who had available data showed normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings.
  • In the peripheral blood mononuclear cells PBMCs and in CD15+ cells ARSA activity reached supranormal levels. In 3 patients for whom central nervous system pharmacodynamic efficacy measures were available, ARSA activity in the cerebrospinal fluid increased to normal levels.
  • In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel.

As of the December 2023 data cutoff, the 5 patients’ follow-up ranged from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had disease that was presymptomatic (PS) and 2 had disease that was early symptomatic (ES). The group included a 2.7 year old girl (PS), a 9.9 year old boy (ES), a 15.2 year old boy (PS), a 6.6 year old girl (PS), and 10.9 year old boy (ES).

“Results from 5 patients (as of December 2023) show an emerging safety profile for arsa-cel in LJ-MLD patients that is comparable to date with the safety profile observed in early-onset (late infantile and early juvenile), with similar timing of hematological recovery, and with similar type, nature, and frequency of AEs,” Gallo and colleagues concluded. “Initial results show pharmacodynamics efficacy with stable levels of gene-corrected cells as well as reconstitution of ARSA activity to normal or supranormal levels both in peripheral blood and CSF in LJ MLD patients, comparable to those observed in other patients with early-onset MLD treated in the clinical development program.”

REFERENCES
1. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsagene autotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96
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