Orchard Therapeutics has announced the publication of long-term safety and efficacy outcomes for Lenmeldy (atidarsagene autotemcel) in the April 24 issue of the New England Journal of Medicine. The study details clinical outcomes in children with early-onset metachromatic leukodystrophy (MLD), a rare and fatal neurometabolic disease.
The publication, titled "Long-term effects of atidarsagene autotemcel for metachromatic leukodystrophy," presents data from pediatric patients with early-onset MLD who received the one-time hematopoietic stem cell (HSC) gene therapy treatment. With more than 12 years of follow-up in the earliest treated patients (median 6.76 years) and over 250 patient-years of cumulative experience, the results demonstrate significant clinical benefits.
Breakthrough Treatment for a Devastating Disease
MLD is an ultra-rare, rapidly progressive neurometabolic disease affecting approximately one in 100,000 live births. Caused by mutations in the gene encoding arylsulfatase A (ARSA), the disease leads to accumulation of sulfatides in the brain and other organs, resulting in severe neurological damage and developmental regression.
In its most severe form, children with late infantile MLD develop normally but begin to rapidly lose motor and cognitive abilities in late infancy. Without treatment, these children typically deteriorate to a vegetative state and most die within five years of symptom onset.
"Lenmeldy represents a significant step forward in the treatment of MLD, a cruel and ultimately fatal disease for which there were previously no approved treatment options beyond supportive and end-of-life care," said Bobby Gaspar, M.D., Ph.D., chief executive officer of Orchard Therapeutics. "These compelling results continue to demonstrate the ability of Lenmeldy to preserve motor and cognitive function in eligible children with MLD, particularly when treatment is administered prior to the onset of symptoms."
Clinical Outcomes and Efficacy Data
The primary endpoint of the studies was severe motor impairment-free survival (sMFS), defined as the interval from birth to the first occurrence of loss of locomotion and loss of sitting without support, or death.
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 impairments. The therapy also preserved motor function and cognitive skills in some early juvenile MLD patients, outcomes not expected in untreated individuals.
The treatment was well-tolerated, with no treatment-related serious adverse events reported. Most adverse events were associated with busulfan conditioning or background disease. Common adverse reactions included febrile neutropenia (85%), stomatitis (77%), and respiratory tract infections (54%).
Expanding Research in Gene Therapy
Orchard Therapeutics also announced six presentations at the upcoming American Society of Gene and Cell Therapy (ASGCT) 28th Annual Meeting taking place May 13-17 in New Orleans. These presentations will showcase clinical, biochemical, and functional outcomes from the company's commercial and clinical-stage neurometabolic portfolio.
The presentations will cover not only MLD but also other conditions including the Hurler subtype of mucopolysaccharidosis type I (MPS-IH) and mucopolysaccharidosis type IIIA (MPS-IIIA), also known as Sanfilippo syndrome type A.
Dr. Gaspar emphasized the importance of early intervention: "These long-term results, coupled with the homogenous, predictable and precipitous decline and eventual death observed in the natural history cohort, underscores the urgent need to enable timely and accurate diagnosis and intervention through the proliferation of universal newborn screening for MLD."
About Lenmeldy
Lenmeldy (atidarsagene autotemcel) is the only approved therapy in the U.S. for the treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ), or early-symptomatic early juvenile (ESEJ) metachromatic leukodystrophy.
The therapy works by genetically modifying a patient's own blood stem cells outside the body and then reinserting them, with the goal of correcting the underlying cause of disease with a single treatment. In Europe, the treatment is known as Libmeldy and has been approved by both the European Commission and UK Medicines and Healthcare products Regulatory Agency.
The program was originated by and developed in partnership with the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) in Milan, Italy.
Future Directions
Leslie Meltzer, Ph.D., chief medical officer of Orchard Therapeutics, will give an invited talk at the ASGCT meeting titled "Developing and delivering hematopoietic stem cell gene therapies to patients with rare neurometabolic diseases," exploring key insights into the development and delivery of one-time treatments for rare neurometabolic diseases and beyond.
The company is also advancing research into automated manufacturing processes for HSC gene therapy production and developing approaches for other lysosomal storage disorders, including Pompe disease.
Orchard Therapeutics, now a Kyowa Kirin company, continues to focus on discovering, developing, and commercializing new treatments that leverage the curative potential of hematopoietic stem cell gene therapy for genetic and other severe diseases where current treatment options are limited or non-existent.
