The Scottish Medicines Consortium (SMC) has accepted atidarsagene autotemcel (Libmeldy, Orchard Therapeutics Limited) for routine use within NHS Scotland to treat metachromatic leukodystrophy (MLD) in children with biallelic ARSA mutations, after reassessment under the ultra-orphan pathway.

The gene therapy had previously been available while further evidence on its effectiveness was collected. It is indicated for presymptomatic children with late-infantile or early juvenile MLD, and for those with early-juvenile disease who still retain independent walking ability before cognitive decline begins.

A Rare Childhood Disease 

MLD is an autosomal recessive lysosomal storage disorder caused by ARSA gene mutations, resulting in severe deficiency of the arylsulfatase A enzyme. This deficiency leads to sulfatide accumulation in central oligodendrocyte myelin and peripheral Schwann cells, causing progressive microglial damage, neurodegeneration, and demyelination.

The disease is classified according to age at onset as late infantile (before 30 months), early juvenile (30 months to 7 years), late juvenile (7-17 years), or adult (17 years or older). Late-infantile MLD typically follows an aggressive course, with retrospective data showing median survival of 2.7 years for late-infantile disease and 9 years for juvenile disease.

Until now, treatment has largely focused on supportive care.

SMC Chair Dr Rob Peel described MLD as a “devastating hereditary disorder” and said patient group representatives had shared “powerful testimony” about the extent of disability it causes and its life-changing impact on patients and families. After reassessment, he said, the committee was satisfied that atidarsagene autotemcel had the potential to improve patients’ lives and had now accepted it for routine use.

A Single Infusion Targets Early Disease 

Atidarsagene autotemcel is an ex vivo gene therapy that uses the patient's own CD34-positive haematopoietic stem and progenitor cells. Cells are collected from blood or bone marrow, modified to carry a functional copy of the ARSA gene, and reinfused following myeloablative conditioning. The modified cells then produce ARSA enzyme, which breaks down the sulfatide that would otherwise accumulate and damage myelin in the central and peripheral nervous systems.

Treatment is given once, as a single intravenous infusion. The minimum recommended dose is 3 × 10⁶ CD34-positive cells/kg, though studies have used doses up to 30 × 10⁶ cells/kg.

Evidence Shows Lasting Protection 

Clinical evidence came from Study OTL-200-10, an ongoing observational study including patients from phase 1/2 studies and three early access programmes, with outcomes compared with a natural history cohort.

Among 39 treated and 49 untreated patients followed for a median of 6.76 years, treatment was associated with a significantly lower risk for severe motor impairment or death in patients with presymptomatic late-infantile MLD (P <.001), presymptomatic early juvenile MLD (P = .04), and early symptomatic early-juvenile MLD (P < .001).

At 6 years, 100% of patients with presymptomatic late-infantile MLD who received treatment were estimated to have survived without severe motor impairment, compared with 0% of untreated patients. At 10 years, the corresponding proportions for early-juvenile MLD were 87.5% among patients treated presymptomatically and 80.0% among those treated after symptom onset, compared with 11.2% in untreated patients.

The therapy also improved gross motor function and supported attainment of developmental milestones, including independent standing and walking. ARSA activity remained within or above the reference range during follow-up in most treated patients, while those treated before symptom onset maintained motor and cognitive function within normal ranges.

Safety and Monitoring 

The safety profile was consistent with haematopoietic stem cell transplantation preceded by myeloablative conditioning. In total, 98% of patients experienced an adverse event during follow-up. The most frequent adverse events, each occurring in more than 25% of patients, were febrile neutropenia, stomatitis, upper respiratory tract infection, raised blood immunoglobulin E, gait disturbance, and gastroenteritis. Febrile neutropenia was the most common grade 3 or higher event. Anti-ARSA antibodies were detected transiently in 6 of 39 patients (15%). Three deaths occurred during follow-up, all judged unrelated to the gene therapy, and no evidence of insertional oncogenesis was identified. No treatment-related serious adverse events were reported.

Clinicians should monitor patients for infection and infusion-related or hypersensitivity reactions, as well as thyroid function, cytopenia and anti-ARSA antibody status. SMC clinical experts highlighted the importance of early diagnosis, as treatment is expected to provide the greatest benefit before substantial neurologic deterioration.

Implementation Barriers 

SMC's decision applies only within the approved NHS Scotland Patient Access Scheme arrangements underpinning its cost-effectiveness case.

Implementation requires specialist facilities for stem-cell collection and transplantation-related care, including myeloablative conditioning and hospitalisation.

Identifying presymptomatic children may also be challenging, particularly when there is no previously diagnosed affected sibling. Clinical experts suggested that newborn screening programmes may be needed to facilitate earlier identification. The therapy’s very high upfront cost also presents substantial service and financial challenges if the predicted long-term benefits are not realised.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.