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FDA grants approval of OTL-200 as the first gene therapy for children with metachromatic leukodystrophy

On March 18th 2024, the US Food and Drug Administration granted the approval of OTL-200 (atidarsagene autotemcel), an autologous hematopoietic stem cell gene therapy, for the treatment of children diagnosed with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD). This milestone approval makes OTL-200 the first treatment available in the US for early-onset MLD…

Metachromatic leukodystrophy

MLD is a rare and life-threatening disease that affects around one in every 100,000 live births.1 The disease presents in three forms: late-infantile (6 months to 4 years of age), juvenile (early juvenile: 4 to 6 years, late juvenile: 6 to 16 years), and adult (beyond 16 years), with late-infantile being the most common and most severe.2 Patients experience severe neurological issues such as motor regression, behavioral changes, cognitive decline, and seizures. Patients gradually lose essential functions like movement, speech, swallowing, eating, and vision, ultimately causing death. Impairments in motor function are frequent initial symptoms of late-infantile MLD, while cognitive and behavioral symptoms predominate first in juvenile and adult forms, followed by a deterioration in motor skills.2,

MLD is inherited through an autosomal recessive pattern and is caused by mutations in the arylsulfatase-A (ARSA) gene, leading to deficient ARSA activity and a consequential accumulation of sulfatides in various organs such as the brain, nervous systems, liver, kidneys, and spleen.2 In some rare cases, mutations in the prosaposin (PSAP) gene also causes MLD. Most notably, sulfatide accumulation triggers neuroinflammation, progressive demyelination, and neurodegeneration in the central and peripheral nervous systems.3

There is a significant need for effective therapies for MLD, especially for the more rapidly progressive late-infantile and early juvenile cases, where current management mainly involves palliative care.4 Allogeneic hematopoietic stem-cell transplantation has shown limited effectiveness in stopping the progression of peripheral demyelination, particularly in early-onset MLD.4 Other experimental treatments such as enzyme replacement therapy and CNS-administered adeno-associated virus gene therapy have shown minimal to no efficacy based on initial clinical data.

OTL-200

The newly FDA approved therapy, OTL-200, consists of a single-dose infusion of genetically modified, autologous hematopoietic stem cells (CD34+ cells).1 The cells undergo ex vivo viral transduction to introduce functional copies of the ARSA gene using a lentiviral vector containing ARSA cDNA. Once the stem cells have been collected and modified, they are transplanted back into the patient and subsequently engraft within the bone marrow. These stem cells serve to supply the body with myeloid cells that produce the ARSA enzyme which helps break down the dangerous sulfatide build-up, potentially halting disease progression.

“The FDA approval of Lenmeldy opens up tremendous new possibilities for children in the U.S. with early-onset MLD who previously had no treatment options beyond supportive and end-of-life care” -Bobby Gaspar, MD, PhD, co-founder and chief executive officer of Orchard Therapeutics.5

FDA approval 

The approval of OTL-200 by the FDA was based on data from 39 pediatric patients diagnosed with late-infantile or juvenile MLD.6 These patients were part of two single-arm, open-label clinical studies or under treatment within European expanded access frameworks. Each patient received a one-time administration of OTL-200 and underwent monitoring at Ospedale San Raffaele in Milan, Italy. With over 12 years of follow-up (median 6.76 years) in the earliest treated patients, OTL-200 significantly extended overall survival and maintained motor function and cognitive skills in most patients beyond the ages where untreated patients typically show severe impairments.6

Severe motor impairment-free survival (sMFS) was assessed as the key composite outcome, defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death.6 Treatment with OTL-200 resulted in statistically significant and clinically meaningful improvement in sMFS in the pre-symptomatic late infantile (p<0.001), pre-symptomatic early juvenile (p=0.042) and early-symptomatic early juvenile (p<0.001) MLD subgroups, compared to disease natural history.6 Most patients gained cognitive skills as expected for their age.

In terms of safety, treatment with OTL-200 was well tolerated and while there were 3 patient deaths in the study, none were attributed to OTL-200. Common non-laboratory adverse reactions included febrile neutropenia (85%), stomatitis (77%), respiratory tract infections (54%), rash (33%), device-related infections (31%), and others.5 Notably, there were no cases of malignancy or insertional oncogenesis, indicating a favorable safety profile.6

Continued research and development

OTL-200 was approved by the European Commission for the treatment of MLD in December 2020, based on data from 20 children with MLD showing a statistically significant reduction in motor decline, compared to historical controls.7

Looking ahead for OTL-200, it is becoming accessible to eligible patients through a network of Qualified Treatment Centers in key regions across the US, beginning with five treatment centers with expertise in transplant and treating neurometabolic diseases such as MLD.1 Furthermore, drawing upon insights from these studies, a collaborative multi-stakeholder group is in the final stages of proposing MLD to be added to the US Recommended Uniform Screening Panel (RUSP). This panel serves to guide states on which medical conditions should be incorporated into their screening protocols. This nomination has the potential to open avenues for enhanced early detection and intervention for MLD on a broader scale.

Written by Saskia Pearl

Reviewed by Juliet Lawrence

References:

  1. Orchard Therapeutics. Orchard Therapeutics Outlines U.S. Launch Plans for LenmeldyTM (atidarsagene autotemcel), the Only Approved Therapy for Children with Early-onset Metachromatic Leukodystrophy [Press Release]. 20 Mar 2024. Accessed 20 Mar 2024.
  2. Lamichhane A, Rocha Cabrero F. Metachromatic Leukodystrophy. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; Jul 2023.
  3. Gieselmann V, Krägeloh-Mann I. Metachromatic leukodystrophy–an update. Neuropediatrics. Feb 2010;41(1):1–6.
  4. Fumagalli F, Calbi V, Natali Sora MG. 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. Jan 2022; 399(10322):372-383.
  5. Orchard Therapeutics. Orchard Therapeutics Receives FDA Approval of LenmeldyTM (atidarsagene autotemcel), the Only Therapy for Eligible Children with Early-onset Metachromatic Leukodystrophy in the U.S. [Press Release]. 18 Mar 2024. Accessed 20 Mar 2024.
  6. Orchard Therapeutics. Orchard Therapeutics Announces Presentation of Data Comprising the Clinical Package for the OTL-200 BLA in MLD at the SSIEM Annual Symposium 2023 [Press Release]. 31 Aug 2023. Accessed 20 Mar 2024.
  7. European Medicines Agency. Libmeldy. Updated Apr 2023. Accessed 20 Mar 2024.