FDA Approves Orchard Therapeutics’ Gene-Edited Cell Therapy Arsa-Cel for Metachromatic Leukodystrophy


Arsa-cel, approved under the name Lenmeldy, is set to be priced at $4.25 million.

This is a developing story and will be updated with new information as it becomes available.

The FDA has approved Orchard Therapeutics’ gene-edited cell therapy atidarsagene autotemcel (arsa-cel, previously referred to as OTL-200 and now marketed in the US under the name Lenmeldy), for the treatment of children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).1 It is the first gene therapy for children with MLD to be approved in the United States.

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks.2 These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research

Peter Marks, MD, PhD

“This is the first FDA-approved treatment option for children who have this rare genetic disease,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in a statement.1 “We remain committed to advancing scientific and regulatory principles that enable the efficient development and review of safe, effective and innovative products that have the potential to change patients’ lives.”

An integrated analysis of results from the aforementioned patients treated in the 2 trials (n = 30) and expanded access frameworks (n = 9), which was presented in August 2023 at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium in Jerusalem, Israel, included measurement of the interval of time from patients’ birth to their first losses of locomotion or sitting without support or their deaths, an end point referred to as severe motor impairment-free survival (sMFS) that the FDA deemed clinically meaningful in discussions with Orchard.2 Compared to disease natural history data from 49 untreated patients, patients treated with arsa-cel achieved clinically meaningful improvements in sMFS in in the study’s subgroups for PS LI (P < .001), PS EJ (P = .042), and ES EJ MLD (P < .001).

According to safety results from the same patient groups presented at the 2024 WORLDSymposium, held February 4-9, in San Diego, California, arsa-cel was generally well-tolerated, with no deaths or serious adverse events (AEs) related to the gene therapy having occurred.3 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. 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.

According to the FDA press release announcing the approval, the decision was based on data from 37 of the aforementioned 39 patients.1 The FDA added that all children in this group with PS LI MLD were alive at 6 years of age; on the other hand, just 58% of children with PS LI MLD in the natural history group were still living at 6 years of age. In addition, at 5 years of age, 71% of children treated with arsa-cel could walk without assistance. Furthermore, 85% of children treated with arsa-cel had normal language and performance IQ scores, a phenomena not reported in untreated patients. The agency also noted that slowing of motor and/or cognitive disease was also observed in patients with PS EJ and ES EJ MLD who were treated with arsa-cel.

In terms of safety, the FDA noted that the most common AEs in patients treated with arsa-cel are fever and low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, fever, gastrointestinal infections, and enlarged liver. The FDA also notes that until engraftment has occurred, patients who have received arsa-cel should be monitored for neutrophil counts and risk of delayed platelet engraftment. Furthermore, although no cases of blood cancers have been observed in patients who received arsa-cel, the FDA lists it as a potential risk and advises lifelong monitoring for such cancers. For this monitoring, the agency calls for complete blood counts with differential each year and integration site analysis as warranted for a minimum of 15 years posttreatment.

Nicole Verdun, MD, the director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research

Nicole Verdun, MD

“MLD is a devastating disease that profoundly affects the quality of life of patients and their families," Nicole Verdun, MD, the director of the Office of Therapeutic Products in CBER, added to the statement.1 "Advancements in treatment options offer hope for improved outcomes and the potential to positively influence the trajectory of disease progression. This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases.”

Orchard Therapeutics originally completed arsa-cel's rolling biologics license application (BLA) submission to the FDA in August 2023.4 The agency accepted the BLA submission with priority review in September 2023.

Arsa-cel was previously approved under the name Libmeldy for MLD indications in the European Union (EU) in 2020 and in the United Kingdom in 2021.6 It has also been approved in several other nonEU European countries: Iceland, Liechtenstein, and Norway.5 It is available under a limited distribution model that includes 5 centers of excellence trained as qualified treatment centers across Europe.6

In the European Union, arsa-cel is approved for an indication covering its use in patients with MLD who have biallelic mutations in the ARSA gene that have caused a decrease in ARSA enzyme activity; patients must be children with the LI or EJ forms without clinical manifestations or patients with the EJ form who have early clinical manifestations and retrain the ability to walk independently and have not yet shown cognitive decline.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces presentation of data comprising the clinical package for the OTL-200 BLA in MLD at the SSIEM Annual Symposium 2023. News release. Orchard Therapeutics. August 31, 2023. Accessed March 18, 2024. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-presentation-data-comprising
3. 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
4. Orchard Therapeutics Completes Submission of Biologics License Application for OTL-200 in MLD to U.S. FDA. News release. Orchard Therapeutics. August 3, 2023. Accessed March 18, 2024. https://finance.yahoo.com/news/orchard-therapeutics-completes-submission-biologics-110000497.html
5. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed March 18, 2024. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
6. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsagene autotemcel (autologous hematopoietic stem cell gene therapy [HSC-GT] for metachromatic leukodystrophy) with up to 11 years follow-up. Presented at: WORLDSymposium 2023, February 22-28; Orlando, Florida. Abstract #125
Related Videos
Frederick “Eric” Arnold, PhD
Jeffrey Chamberlain, PhD, on Exciting New Research at MDA 2024
Alan Beggs, PhD, on Challenges in Therapeutic Development for Rare Diseases
PJ Brooks, PhD
Carlos Moraes, PhD, on Understanding Mitochondrial Mutations for Neurodegenerative Diseases
Frederick “Eric” Arnold, PhD
Jeffrey Chamberlain, PhD
Michael Kelly, PhD
George Tachas, PhD
Jeffrey Chamberlain, PhD
© 2024 MJH Life Sciences

All rights reserved.