Orchard Therapeutics’ Arsa-Cel Continues to Show Safety in Late Juvenile MLD

Orchard Therapeutics’ atidarsagene autotemcel (arsa-cel, marketed in the US under the name Lenmeldy and under the name Libmeldy in the European Union, UK, Iceland, Liechtenstein, and Norway), a gene-edited cell therapy intended to treat metachromatic leukodystrophy (MLD), has continued to show safety in updated data from a phase 3 clinical trial (NCT04283227) in patients with the late juvenile (LJ) form of MLD.^1,2 The new data was presented in an updated poster at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting, held May 7 to 10, 2024, in Baltimore, MD.

The trial includes 6 patients with presymptomatic (PS) or early-symptomatic (ES) LJ MLD, with the definition for ES noted to refer to patients who are able to walk independently and do not show cognitive decline. The patients’ follow-up time ranged from 2.6 months to 24.2 months as of the March 2024 data cutoff. There were no serious adverse events (SAEs) attributed to arsa-cel reported, with no evidence of clonal expansion, replication-competent lentivirus, or malignancy observed. A single AE, a case of erythematous rash during infusion, was the only AE deemed likely to be related to arsa-cel. AEs deemed potentially related to the busulfan conditioning regimen for arsa-cel included febrile neutropenia, cytopenia, and stomatitis; none of these AEs were serious. One patient experienced a SAE of upper respiratory tract infection, but it was not deemed potentially related to arsa-cel or the conditioning regimen. All patients were still alive at the most recent follow-up.

The time to neutrophil engraftment for the patients ranged from 26 to 42 days posttreatment (median, 34) and the time to platelet engraftment ranged from 25 to 50 days posttreatment (median, 28.5). First author Valeria Calbi, MD, staff hematologist, San Raffaele Telethon Institute for Gene Therapy, and colleagues also noted that there was no engraftment failure, but that a single patient, who had previously received an unsuccessful allo-transpant because of autologous reconstitution, experienced a case of prolonged thrombocytopenia necessitating TPO-agonist therapy for 5 months.

In terms of efficacy, it was noted that in 5 patients for whom data was available at 6 months posttreatment, arylsulfatase A (ARSA) enzyme activity in the peripheral blood mononuclear cells (PBMCs) reached supranormal levels. In 4 patients for whom central nervous system pharmacodynamic efficacy measures were available, ARSA activity in the cerebrospinal fluid (CSF) increased to normal levels at this time point. The authors also stated that all of the patients who received arsa-cel while PS and 1 of 2 who received arsa-cel while ES remained neurologically stable; the other patient who received arsa-cel while ES experienced disease progression early after receiving the treatment, from Gross Motor Function Classification in MLD (GMFC-MLD) level 1 to GMFC-MLD level 2, but achieved stabilization by 12 months after treatment.

At the time the 6 patients originally received treatment with arsa-cel, 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), 10.9 year old boy (ES), and 15.5 year old boy (PS). The poster presented at ASGCT constituted an update to data previously presented in a poster at the 2024 WORLDSymposium, held February 4-9, in San Diego, California.

“Preliminary results from 6 patients (as of March 2024) 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,” Calbi and colleagues concluded.¹ “As of December 2023, initial results show pharmacodynamics efficacy with stable engraftment of gene-corrected cells as well as reconstitution of ARSA activity 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.”

Arsa-cel was recently approved by the FDA for the treatment of children with PS late infantile, PS early juvenile, or ES early juvenile metachromatic leukodystrophy (MLD).² It is not currently approved for use in patients with LJ-MLD.

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REFERENCES
1. Calbi V, Gallo V, De Mattia F, et al. Lentiviral Haematopoietic Stem Cell Gene Therapy for Late Juvenile Metachromatic Leukodystrophy. Presented at: ASGCT Annual Meeting 2024, May 7-10; Baltimore, Maryland. Poster #1905
2. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed May 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph