Orchard Therapeutics’ Gene Therapy for Rare Neurological Disorder Wins FDA Approval

On March 18, the U.S. Food and Drug Administration (FDA) greenlit Lenmeldy (atidarsagene autotemcel), a one-time gene therapy developed by Orchard Therapeutics for treating children suffering from pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile metachromatic leukodystrophy (MLD). This approval marks a significant milestone as the first FDA-approved treatment for this rare neurological disorder, offering hope to affected individuals and their families.

Related article: Kyowa Kirin to Acquire Orchard Therapeutics, Forging a Path in Genetic Medicine 

Novel Treatment for a Devastating Genetic Disease

MLD is a debilitating condition affecting the brain and nervous system caused by an autosomal recessive deficiency of the enzyme arylsulfatase A (ARSA) due to mutations in the ARSA gene and, in rare cases, the PSAP gene. This genetic defect leads to a failure to break down sulfatides, a family of sulfate-containing glycolipids primarily present in cells in the central and peripheral nervous systems. As excess sulfatides accumulate to a toxic level, these fatty substances will destroy the protective fatty layer (myelin sheath) surrounding the nerves in both the central and peripheral nervous systems, resulting in irreversible nervous system impairment that leads to loss of motor and cognitive functions. 

Globally, the estimated prevalence of MLD ranges from 1 in 40,000 to 1 in 160,000. The disease can be categorized into three types based on the age of onset: late-infantile MLD (usually at 15–24 months), juvenile MLD (3-16 years of age), and adult MLD (after age 16). All of them are currently incurable and often lead to premature death. For example, if untreated, most late-infantile MLD patients die before reaching the age of 5. 

Orchard’s Lenmeldy won European Commission approval in December 2020 and is already marketed in Europe under the name Libmeldy. It is a one-time, individualized single-dose infusion crafted from the patient’s own hematopoietic stem cells (HSCs) that have been genetically modified to carry one or more functional copies of the ARSA gene. These modified stem cells, transplanted back into the patient, can produce the functional ARSA enzyme, potentially halting the progression of MLD. However, it should be noted that the gene therapy must be administered at the pre-symptomatic or early-symptomatic stage, otherwise it will be too late to reverse the course of the disease.

Promising Clinical Trial Results and Safety Considerations

The FDA’s decision was based on comprehensive data from clinical trials assessing the safety and efficacy of Lenmeldy. 37 pediatric MLD patients who received Lenmeldy were compared to untreated children. Results showed significant reductions in severe motor impairment or death compared to untreated children. Notably, all children with pre-symptomatic late infantile MLD treated with Lenmeldy were alive at 6 years of age, compared to only 58% of untreated children. Moreover, treated children demonstrated improved motor and cognitive function, with 85% achieving normal language and performance IQ scores. 

Besides, the therapy exhibited a favorable safety profile, with common side effects including fever and low white blood cell count, among others. Despite potential risks such as blood clot formation and encephalitis that require lifelong follow-up, the absence of blood cancer cases in Lenmeldy-treated patients underscores its safety under careful monitoring.

Orchard Therapeutics Celebrates Lenmeldy’s FDA Approval

Acquired by Japanese global specialty pharmaceutical company Kyowa Kirin in October 2023, Orchard Therapeutics heralds the FDA’s green light for Lenmeldy as a groundbreaking advancement in addressing early-onset MLD. Bobby Gaspar, M.D., Ph.D., co-founder and CEO of the spin-out company from University College London, expressed gratitude towards patients, families, and collaborators for their pivotal role in achieving this milestone. “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 Dr. Gaspar. 

Long Way to Go for Increased Accessibility to the World’s Costliest Therapy

With a U.K. list price of £2.8 million ($3.55 million), Lenmeldy (Libmeldy) stands out as one of the world’s top-priced drugs. On March 20, Orchard Therapeutics announced the U.S. list price for Lenmeldy, an even higher $4.25 million for a single dose, officially replacing Hemgenix, a one-time gene therapy for hemophilia B, as the world’s costliest drug. Therefore, reimbursement is imperative for patient access to the MLD gene therapy with such an exorbitant price.

Besides, patient advocacy groups voice out the need for improved MLD diagnosis. Maria Kefalas, Ph.D., co-founder of the Calliope Joy Foundation, a founding member of Cure MLD and a mother of a child who succumbed to MLD, said, “With the first therapy for this childhood disease now approved, we must act urgently and collaboratively to enable universal newborn screening for MLD in the U.S. so babies with these pathogenic mutations can be diagnosed and referred for appropriate treatment before the onset of symptoms.”

Author

Richard Chau