The U.S. Food and Drug Administration has given its approval for Lenmeldy (atidarsagene autotemcel), marking the first-ever FDA-sanctioned gene therapy designated for treating children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD).
MLD is a rare and incapacitating genetic disorder impacting the brain and nervous system, resulting from a deficiency in arylsulfatase A (ARSA) enzyme, leading to an accumulation of sulfatides in cells. This buildup causes severe damage to both the central and peripheral nervous systems, leading to motor and cognitive function loss and early mortality. Roughly one in every 40,000 individuals in the United States is estimated to be affected by MLD, with no existing cure. Standard treatment usually revolves around providing supportive care and managing symptoms.
Lenmeldy is a personalized, one-time infusion composed of the patient's own hematopoietic (blood) stem cells (HSCs), which have been genetically altered to contain functional copies of the ARSA gene. Stem cells are harvested from the patient and genetically modified by introducing a functional ARSA gene copy. These modified stem cells are then transplanted back into the patient's body, where they attach and proliferate within the bone marrow. The modified stem cells generate myeloid (immune) cells that produce the ARSA enzyme, aiding in breaking down the harmful sulfatide accumulation and potentially halting MLD progression. Prior to treatment, patients must undergo high-dose chemotherapy to clear out bone marrow cells, allowing for the infusion of modified cells in Lenmeldy.
The safety and efficacy of Lenmeldy were evaluated based on data from 37 children who received the treatment in two single-arm, open-label clinical trials and through an expanded access program. Treated children were compared to untreated children (control group) from a natural history perspective. The primary efficacy endpoint was severe motor impairment-free survival, defined as the time from birth to the first occurrence of mobility loss, loss of independent sitting, or death. In children with MLD, Lenmeldy treatment substantially decreased the risk of severe motor impairment or death compared to untreated children. All pre-symptomatic late infantile MLD children treated with Lenmeldy survived until the age of 6, contrasting with only 58% of the natural history group. At 5 years of age, 71% of treated children could walk independently. Additionally, 85% of treated children exhibited normal language and performance IQ scores, a phenomenon not observed in untreated children. Furthermore, children with pre-symptomatic early juvenile and early symptomatic early juvenile MLD showed a slowdown in disease progression, both motor and cognitive.
The most prevalent side effects of Lenmeldy include fever, low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, gastrointestinal infections, and liver enlargement.
Post-Lenmeldy infusion, patients should undergo monitoring for neutrophil counts and potential delayed platelet engraftment until engraftment is achieved. Lenmeldy treatment may lead to blood clot formation or encephalitis (brain tissue swelling). While there's a possible risk of blood cancer associated with this therapy, no instances have been observed in Lenmeldy-treated patients. Individuals receiving this treatment should undergo lifelong monitoring for hematologic malignancies, including annual complete blood count (with differential) assessments and integration site analysis for at least 15 years post-treatment.
The Lenmeldy application received Priority Review, Orphan Drug, Rare Pediatric Disease, and Regenerative Medicine Advanced Therapy (RMAT) designations.