The US Food and Drug Administration has approved the first therapy for metachromatic leukodystrophy (MLD), a rare fatal genetic disorder. The lysosomal storage disease affects about 40 children each year in the USA. It is caused by a mutation in the gene encoding the arylsulfatase enzyme that leads to progressive demyelination and progressive loss of motor and cognitive functions. There were previously no treatments. The new gene therapy, Orchard Therapeutics’ Lenmeldy (atidarsagene autotemcel), has a price tag of $4.25 million, making it the world’s most expensive drug. It inserts functional copies of the arylsulfatase A (ARSA) gene into the patient’s own hematopoietic stem ex vivo with a lentiviral vector. The repaired stem cells are re-infused, correcting the enzyme deficiency and preventing the harmful buildup of sulfatide fats that cause nerve cell demyelination.

The approval is based on results from 37 pediatric patients showing that Lenmeldy improved motor impairment and survival compared with the natural history of MLD. All presymptomatic patients treated with Lenmeldy who had the late infantile form of MLD were alive at age 6 years, compared with just over half of the natural history group. Treated patients could walk and had normal language and cognitive skills. In patients with pre- or early symptomatic juvenile forms of MLD, the gene therapy also slowed motor and cognitive decline.