The FDA (arsa-cel; Lenmeldy), the first gene therapy to treat children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD), the agency announced on Monday.
"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, said in a statement.
MLD is caused by a mutation in the ARSA gene that results in sulfatides accumulating in the central nervous system and peripheral nervous system, leading to progressive dysmyelination, neuroinflammation, and neurodegeneration. This causes loss of motor and cognitive functions and, ultimately, death. There is no cure for the disease.
MLD has three variants, depending on age at first symptom onset: late infantile (younger than 30 months); juvenile, which is subdivided into early juvenile (30 months to 6 years) and late juvenile (7 to 16 years); and adult (17 and older). Earlier age or the presence of motor symptoms at onset are associated with a more severe, rapid disease course.
Arsa-cel is a one-time single-dose infusion made from a patient's hematopoietic stem cells that have been modified to include functional copies of the ARSA gene.
The safety and effectiveness of arsa-cel were based on data from 37 children who received treatment in two single-arm, open-label clinical trials and in an expanded access program in Milan. Children who received arsa-cel were compared with natural history data.
Arsa-cel significantly reduced the risk of severe motor impairment or death compared with no treatment. All children with pre-symptomatic late infantile MLD who received treatment were alive at 6 years, compared with 58% of children in the natural history group.
At 5 years of age, 71% of treated children could walk without assistance, and 85% had normal language and performance IQ scores, which had not been reported in untreated children, the FDA said. Children with pre-symptomatic early juvenile and early symptomatic early juvenile MLD also showed slowing of motor or cognitive decline.
One-time treatment with arsa-cel showed the potential to restore enzymatic function to with up to 12 years of follow-up (median 6.76 years), drug maker Orchard Therapeutics said in a press release.
The most common adverse events were fever, low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, gastrointestinal infections, and enlarged liver. After treatment, patients should be monitored for neutrophil counts and risk of delayed platelet engraftment until engraftment has been achieved, the FDA added.
Arsa-cel treatment may be associated with blood clots or encephalitis, the agency cautioned. There is a potential risk of blood cancer associated with treatment, although no cases have been seen.
"Patients receiving this product should have lifelong monitoring for hematologic malignancies, including a complete blood count (with differential) annually and integration site analysis, as warranted, for at least 15 years after treatment," the FDA said.