FDA Approves First Gene Therapy for Metachromatic Leukodystrophy

The U.S. Food and Drug Administration recently approved Lenmeldy™ (atidarsagene autotemcel), the first gene therapy for the treatment of children with presymptomatic late infantile, presymptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD). 

What happens in metachromatic leukodystrophy?

MLD is a debilitating, rare genetic disease affecting the brain and nervous system. It is caused by a deficiency of an enzyme called arylsulfatase A (ARSA), leading to a buildup of sulfatides in the cells. This buildup causes damage to the central and peripheral nervous system, manifesting as loss of motor and cognitive function and early death. It is estimated that MLD affects 1 in 40,000 individuals in the United States. 

There is no cure for MLD, and treatment typically focuses on supportive care and symptom management.

“This is the first FDA-approved treatment option for children with this rare genetic disease,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER). “We remain committed to advancing scientific and regulatory principles that enable the efficient development and review of safe, effective, and innovative products that have the potential to change patients’ lives.”

Lenmeldy™ is a one-time, individualized single-dose infusion made from the patient’s hematopoietic stem cells (HSCs), which have been genetically modified to include functional copies of the ARSA gene. The stem cells are collected from the patient and modified by adding a functional copy of the ARSA gene. The modified stem cells are transplanted back into the patient where they engraft within the bone marrow. 

The modified stem cells supply the body with myeloid cells that produce the ARSA enzyme, which helps break down the harmful build-up of sulfatides and may stop the progression of MLD. Prior to treatment, patients must undergo high-dose chemotherapy, a process that removes cells from the bone marrow so they can be replaced with the modified cells in Lenmeldy™. 

Safety, effectiveness, and side effects

The safety and effectiveness of Lenmeldy™ were assessed based on data from 37 children who received the therapy in two single-arm, open-label clinical trials and an expanded access program. Children who received treatment with Lenmeldy™ were compared to untreated children (natural history). The primary efficacy endpoint was severe motor impairment-free survival, defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support or death. 

In children with MLD, treatment with Lenmeldy™ significantly reduced the risk of severe motor impairment or death compared with untreated children. All children with presymptomatic late infantile MLD who were treated with Lenmeldy™ were alive at six years of age, compared to only 58 percent of children in the natural history group. At five years of age, 71 percent of treated children were able to walk without assistance. 

Some 85 percent of the children treated had normal language and performance IQ scores, which has not been reported in untreated children. In addition, children with presymptomatic early juvenile and early symptomatic early juvenile MLD showed slowing of motor and/or cognitive disease.

The most common side effects of Lenmeldy™ are fever and low white blood cell count, mouth sores, respiratory infections, rash, medical line infections, viral infections, fever, gastrointestinal infections, and hepatomegaly. 

After infusion with Lenmeldy™, patients should be monitored for neutrophil counts and risk of delayed platelet engraftment until engraftment has been achieved. Treatment with Lenmeldy™ may be associated with the formation of blood clots or encephalitis. 

There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in patients treated with Lenmeldy™. 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.

- This press release was originally published on the U.S. Food and Drug Administration website