High-Cost Therapy Profile

January 12, 2024

Detailed information about Atidarsagene Autotemcel Intravenous (IV)

High-cost therapy profile

Atidarsagene Autotemcel Intravenous (IV)


Proposed Indications

Metachromatic leukodystrophy (MLD)

FDA approval timeline

March 18, 2024

  • Orphan drug
  • Priority review
  • Rare pediatric disease (RPD)
  • Regenerative Medicine Advanced Therapy (RMAT)

Place in therapy

Atidarsagene autotemcel (arsa-cel) is an ex vivo autologous hematopoietic stem cell-based gene therapy that uses a lentiviral vector (LVV) to encode a corrected arylsulfatase-A (ARSA) gene into a patient’s own stem cells which allows the edited cells to produce a functional version of the ARSA enzyme.

  • If approved, arsa-cel will be the first and only approved therapy for MLD in ambulatory patients with either late infantile (LI) or early juvenile (EJ) forms of the disease.
  • Treatment with arsa-cel resulted in improvements in motor performance, development, demyelination, and brain atrophy; in extended follow-up, most patients continue to have sustained motor function preservation and cognitive development.
  • The one-time infusion of arsa-cel resulted in ARSA levels in the normal or above normal range, increase in survival, and greater severe motor impairment-free survival.
  • Presymptomatic children with early forms of MLD remained either asymptomatic or with mild symptoms after receiving arsa-cel therapy; however, durability of effect and long-term outcomes may be uncertain.
  • The Institute for Clinical and Economic Review (ICER) determined that there is high certainty of a substantial net health benefit (“A”) in use of arsa-cel for MLD in presymptomatic LI and EJ compared to usual supportive care of patients with MLD.
  • Arsa-cel is also being studied in children with late juvenile MLD (> 7 to <17 years of age).

Understanding your data

Arsa-cel is an LVV gene therapy that encodes the ARSA gene into a patient’s own stem cells to produce a functional ARSA enzyme which aids in breaking down toxic fatty substances in the brain and other parts of the body. Arsa-cel has demonstrated significant improvement in cognitive and motor function across a small population of patients with pre-symptomatic LI and EJ and early symptomatic EJ MLD. Clinical trials evaluating arsa-cel in MLD are limited and include the following:

  • NCT01560182: A phase 1/2 clinical trial of hematopoietic stem cell gene therapy for the treatment of MLD.
  • NCT03392987: A single arm, open label, clinical study of cryopreserved autologous CD34+ cells transduced with LVV containing human ARSA cDNA (arsa-cel), for the treatment of early onset MLD.
  • NCT04283227: An open label, non-randomized trial to evaluate the safety and efficacy of a single infusion of arsa-cel in patients with late juvenile (LJ), MLD.

Identification of patients would reflect the clinical trials criteria listed in the studies above, as well as diagnosis codes identified from claims data requiring among others:

Common Measurable Inclusion Criteria:

  • Age: ≤ 17 years old
  • ICD-10 for metachromatic leukodystrophy

Common Measurable Exclusion Criteria:

ICD-10 for: HIV, myelodysplastic syndrome, or acute myeloid leukemia


Metachromatic Leukodystrophy ICD-10: E75. 25
HIV ICD-10: B20, Z21
Myelodysplastic Syndrome ICD-10: D460, D461, D4620, D4621, D4622, D464, D469, D46A, D46B, D46C, D46Z
Acute Myeloid Leukemia ICD-10: C9200, C9201, C9202, C9240, C9241, C9242, C9250, C9251, C9252, C9260, C9261, C9262, C92A0, C92A1, C92A2, C9300, C9301, C9302, C9400, C9401, C9402, C9420, C9421, C9422

Clinical deep dive

Disease State Overview

Metachromatic leukodystrophy (MLD) is a rare, autosomal recessive, genetic, eventually fatal lysosomal storage disorder. MLD is caused by mutations in the arylsulfatase-A (ARSA) gene affecting the production of the ARSA enzyme. This results in the body producing insufficient amounts of ARSA enzyme leading to accumulation of fatty substances (sulfatides) which are toxic to the brain and white matter or myelin of the nervous system causing progressive loss of motor and cognitive function. There are 3 general categories of MLD based on the age of onset: late infantile (LI) is the most common form (50% to 60%), juvenile (20% to 30%), and adult (10%). Although commonly misdiagnosed, it is usually identified around ages 3 to 4 years old. Patients usually succumb to the disease by 5 years of age for infantile form, within 10 to 20 years following symptom onset in juvenile form, and 6 to 14 years in adult onset. Those symptoms can include difficulty talking and swallowing, difficulty walking, seizures, behavior and personality changes. Early-onset forms of MLD are rapidly progressive and fatal.


The exact prevalence of MLD is unknown but is estimated to range from 1 in 40,000 to 1 in 160,000 (about 3,600 babies born annually); the incidence is estimated at 1 case in 40,000 births in the US. The prevalence rate is higher in the Navajo (about 1 in 2,500) and is more common among certain Middle Eastern populations compared to general population.


MLD has no cure and currently there are no FDA approved treatments for the disorder. In treating patients with MLD, a stem cell transplantation can be considered in pre- or minimally symptomatic children to delay the progression of disease in some cases. Otherwise, treatment is supportive and focuses on symptomatic relief.

Drug and clinical trial overview

In two phase 1/2 open-label, single-arm studies and one expanded access framework, efficacy and safety of atidarsagene autotemcel (arsa-cel) were evaluated in an integrated analysis of 39 patients compared to the natural course of disease in 49 untreated patients; median follow-up in integrated analysis was 6.76 years (range, 0.64 to 12.91). The composite endpoint from an integrated analysis was severe motor impairment-free survival (sMFS); the time measured from a patient’s birth to their first loss of locomotion (ability to move) or sitting without support or their death. Patients treated with arsa-cel had statistically significant and clinically meaningful improvement in sMFS compared to natural course of disease in pre-symptomatic LI (p<0.001) and EJ MLD (p=0.042), as well as early symptomatic EJ (p<0.001) MLD subgroups. Most treated pre-symptomatic LI patients maintained the ability to walk compared to untreated LI group who lost all ability to move by a median age of 2.6 years. Also, most surviving pre-symptomatic EJ maintained the ability to walk, and early symptomatic EJ group maintained the ability to sit unassisted and/or crawl/roll compared to untreated EJ group who all lost the ability to move by a median age of 6.4 years. Treated patients continued to have preserved motor and cognitive function through 12 years of follow-up. Arsa-cel was well-tolerated with no serious treatment-related adverse events and no reports of malignancy or insertional oncogenesis. Patients experienced febrile neutropenia, primarily due to busulfan conditioning; 3 deaths occurred but were unrelated to treatment. Anti-ARSA antibodies developed in 6 patients that subsequently resolved with no observed impact on clinical outcomes.

Arsa-cel is given as a one-time IV infusion. Stem and progenitor cells are retrieved through mobilization and apheresis, functional ARSA genes are inserted into CD34+ cells outside the body using LVV, then treated cells are reinfused; also requires myeloablation of the bone marrow and conditioning with busulfan prior to reinfusion of cells.

Pipeline (late-stage development)








(outside of US)


Adeno-associated virus vector; brain gene therapy

Early onset MLD

Phase 1/2


(formerly  SHP611 and HTG-1111)



Recombinant human ARSA (rhARSA) enzyme replacement therapy

LI-MLD with previous HSCT

(did not meet primary/secondary endpoints)

Phase 2

  1. Atidarsagene autotemcel for metachromatic leukodystrophy. Institute for Clinical and Economic Review (ICER). Published July 26, 2023. Available at: https://icer.org/wp-content/uploads/2023/10/ICER_MLD_2023_Policy-Recommendations_10302023.pdf. Accessed October 6, 2023.
  2. Biffi A, Montini E, Lorioli L, et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013;341(6148):1233158. DOI:10.1126/science.1233158.
  3. Blenda AV, Windle ML, Rohena LO, et al. Metachromatic Leukodystrophy. Updated: Jan 22, 2021. Available at: https://emedicine.medscape.com/article/951840-overview#a6. Accessed October 6, 2023.
  4. FDA assigns review date for gene therapy atidarsagene autotemcel. Available at: https://www.formularywatch.com/view/fda-assigns-review-date-for-gene-therapy-atidarsagene-autotemcel. Accessed December 13, 2023.
  5. Fumagalli F, Calbi V, Sora MGN, et al. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022 Jan 22; 399(10322): 372–383. DOI: 10.1016/S0140-6736(21)02017-1: 10.1016/S0140-6736(21)02017-1.
  6. Gomez-Ospina N. Arylsulfatase A Deficiency. GeneReviews. Arylsulfatase A Deficiency – GeneReviews® – NCBI Bookshelf (nih.gov).
  7. Metachromatic Leukodystrophy. National Institute of Health. Available at: https://www.ninds.nih.gov/health-information/disorders/metachromatic-leukodystrophy#:~:text=There%20is%20no%20cure%20for,MLD%20and%20in%20clinical%20trials. Accessed October 6, 2023.
  8. National Institute of Neurological Disorders and Stroke. Metachromatic Leukodystrophy. National Institutes of Health (NIH). Available at: https://www.ninds.nih.gov/health-information/disorders/metachromatic-leukodystrophy#:~:text=The%20prognosis%20for%20MLD%20is,years%20following%20onset%20of%20symptoms. Accessed December 14, 2023
  9. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/study/NCT01560182. Accessed December 18, 2023.
  10. NCT ClinicalTrials.gov. Available at: https://classic.clinicaltrials.gov/ct2/show/NCT03392987. Accessed December 18, 2023.
  11. NCT ClinicalTrials.gov. Available at: https://www.clinicaltrials.gov/study/NCT04283227. Accessed December 18, 2023.
  12. Orchard Therapeutics announces presentation of data comprising the clinical package for the OTL-200 BLA in MLD at the SSIEM annual symposium 2023. Available at: https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-presentation-data-comprising. Accessed December 14, 2023.
  13. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. September 18, 2023. Available at:  https://www.globenewswire.com/news-release/2023/09/18/2744644/0/en/Orchard-Therapeutics-Announces-Acceptance-of-Biologics-License-Application-for-OTL-200-in-MLD-and-Receives-Priority-Review.html. Accessed December 13, 2023.
  14. Park B. Gene Therapy candidate gets priority review for metachromatic leukodystrophy. September 18, 2023. Available at: https://www.empr.com/home/news/drugs-in-the-pipeline/gene-therapy-candidate-gets-priority-review-for-metachromatic-leukodystrophy/. Accessed December 13, 2023.
  15. Rare Disease Organization. Metachromatic leukodystrophy. Updated March 22, 2022. Available at: https://rarediseases.org/rare-diseases/metachromatic-leukodystrophy/. Accessed October 6, 2023.
  16. Stansfield N. Arsa-cel continues to show benefit up to 12 years of follow-up in metachromatic leukodystrophy. September 5, 2023. Available at: https://www.cgtlive.com/view/arsa-cel-libmeldy-continues-show-benefit-12-years-follow-up-metachromatic-leukodystrophy. Accessed December 13, 2023.
  17. Sessa M, Lorioli L, Fumagalli F, et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016;388(10043):476-487. DOI:10.1016/S0140-6736(16)30374-9.
  18. Wang RY, Bodamer OA, Watson MS, et al. Lysosomal storage diseases: Diagnostic confirmation and management of presymptomatic individuals. ACMG Standards and Guidelines. Genet Med. 2011;13:457-84.
  19. What is MLD? Cure MLD.Org. Available at: https://www.curemld.com/what-is-mld. Accessed October 6, 2023.

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