FDA Approves First Gene Therapy for Children with MLD

Rare Daily Staff

The U.S. Food and Drug Administration approved Orchard Therapeutics’ Lenmeldy, the first FDA-approved gene therapy for the rare and fatal condition metachromatic leukodystrophy.

Lenmeldy will carry a wholesale price of $4.25 million, making it the most expensive drug in the world. It is approved for the treatment of children with pre-symptomatic late infantile, pre-symptomatic early juvenile or early symptomatic early juvenile metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is caused by a mutation in the gene responsible for encoding the enzyme arylsulfatase A(ARSA) leading to neurological damage and developmental regression due to the accumulation of fats called sulfatides in the brain and other areas of the body which, when not broken down, damage the central nervous system over time. In its most severe form, babies develop normally but in late infancy start to rapidly lose the ability to walk, talk and interact with the world around them. These children eventually deteriorate into a vegetative state, which may require 24-hour intensive care, and the majority pass away within five years of disease onset, creating an enormous emotional and financial burden on the family. There is no cure for MLD, and treatment typically focuses on supportive care and symptom management.

“The FDA approval of Lenmeldy opens up tremendous new possibilities for children in the U.S. with early-onset MLD who previously had no treatment options beyond supportive and end-of-life care,” said Bobby Gaspar, co-founder and CEO of Orchard Therapeutics, which was recently acquired by Kyowa Kirin. “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.”

In Europe, Lenmeldy is known as Libmeldy, where it has been approved by the European Commission, UK Medicines and Healthcare products Regulatory Agency, and Swiss Agency for Therapeutic Products.

Lenmeldy seeks to correct the underlying genetic cause of MLD by inserting one or more functional copies of the human ARSA gene ex vivo into the genome of a patient’s own hematopoietic stem cells using a lentiviral vector. The genetically repaired cells are infused back into the patient, where, once engrafted, they differentiate into multiple cell types, some of which migrate across the blood-brain barrier into the central nervous system and express the functional enzyme. This approach has the potential to restore enzymatic function to stop or slow disease progression with a single treatment. 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.

The application received Priority Review, Orphan Drug, Rare Pediatric Disease and Regenerative Medicine Advanced Therapy (RMAT) designations.

Lenmeldy was granted Priority Review in September 2023. It was previously given both Rare Pediatric Disease and Regenerative Medicine Advanced Therapy designations from FDA. In connection with the approval, Orchard Therapeutics received a Priority Review Voucher, which will be transferred to GSK in accordance with the terms of the original licensing agreement.

The FDA approval of Lenmeldy is based on data from 37 pediatric patients with early-onset MLD, enrolled in two single-arm, open-label clinical studies or treated under European expanded access frameworks, who received a one-time administration of the gene therapy and compared with natural history data. All treated patients were administered Lenmeldy and subsequently monitored at Ospedale San Raffaele in Milan, Italy.

With more than 12 years of follow-up in the earliest treated patients (median 6.76 years), treatment with Lenmeldy significantly extended overall survival and resulted in the preservation of motor function and cognitive skills in most late infantile MLD patients past ages at which untreated patients showed severe cognitive and motor impairments. Lenmeldy also resulted in the preservation of motor function and cognitive skills in some early juvenile MLD patients which is not expected when compared to untreated patients.

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 enlarged liver.

Photo: Bobby Gaspar, co-founder and CEO of Orchard Therapeutics