First gene therapy for children with rare disease gets US sign-off

Gene therapy

Lenmeldy (atidarsagene autotemcel) has become the first Food and Drug Administration (FDA)-approved gene therapy for the treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile metachromatic leukodystrophy (MLD).

Metachromatic leukodystrophy 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 build-up of sulfatides (fatty substances) in the cells.

This build-up causes damage to the central and peripheral nervous system, manifesting with loss of motor and cognitive function and early death. It is estimated that MLD affects one in every 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 who have this rare genetic disease,” said Peter Marks, 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.”

A one-time treatment

Lenmeldy is a one-time, individualised single-dose infusion made from the patient’s own haematopoietic (blood) 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 (attach and multiply) within the bone marrow. The modified stem cells supply the body with myeloid (immune) 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.

“MLD is a devastating disease that profoundly affects the quality of life of patients and their families. Advancements in treatment options offer hope for improved outcomes and the potential to positively influence the trajectory of disease progression,” said Nicole Verdun, Director of the Office of Therapeutic Products in CBER. “This approval represents important progress in the advancement and availability of effective treatments, including gene therapies, for rare diseases.”

Positive clinical trial results

The safety and effectiveness of Lenmeldy was assessed based on data from 37 children who received Lenmeldy in two single-arm, open-label clinical trials and in an expanded access programme. In children with MLD, treatment with Lenmeldy significantly reduced the risk of severe motor impairment or death compared with untreated children.

All children with pre-symptomatic late infantile MLD who were treated with Lenmeldy were alive at six years of age, compared to only 58% of children in the natural history group. At five years of age, 71% of treated children were able to walk without assistance.

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

After infusion with Lenmeldy, the FDA has cautioned that patients should be monitored for neutrophil counts and risk of delayed platelet engraftment until engraftment has been achieved. Patients receiving this product should have lifelong monitoring for haematologic malignancies. and integration site analysis, as warranted, for at least 15 years after treatment.

“The FDA approval of Lenmeldy opens up tremendous new possibilities for children in the US with early-onset MLD who previously had no treatment options beyond supportive and end-of-life care,” said Bobby Gaspar, Co-Founder and Chief Executive Officer of Orchard Therapeutics. “MLD is a rapidly progressing, life-limiting and ultimately fatal rare disease that has a devastating impact on afflicted children and their families. This achievement is the culmination of decades of research and development in partnership with our academic and clinical collaborators at the San Raffaele-Telethon Institute for Gene Therapy.”

Diana Spencer, Senior Digital Content Editor, DDW

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