FDA Approves Gene Therapy for Rare Immune Disorder

The U.S. Food and Drug Administration (FDA) has approved Kresladi (marnetegragene autotemcel), the first gene therapy for the treatment of severe leukocyte adhesion deficiency type I (LAD-I). Kresladi is indicated for the treatment of pediatric patients with severe LAD-I due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic hematopoietic stem cell transplant.

Kresladi consists of the patient’s own hematopoietic (blood) stem cells (HSCs), which are genetically modified to introduce functional copies of the ITGB2 gene. Following conditioning, a single dose of Kresladi is infused intravenously to address the underlying cause of severe LAD-I by restoring CD18 and CD11a cell surface expression in white blood cells, including neutrophils.

Approval was based on an open-label, single-arm, multicenter study based on increases in neutrophil CD18 and CD11a cell surface expression (disease-specific biomarkers indicative of improved immune activity) at month 12 with sustained effect through month 24 post-infusion. Increases in neutrophil CD18 and CD11a cell surface expression reflected improved function of a protein complex of the two biomarkers on the surface of neutrophils, which is used as a surrogate endpoint that is reasonably likely to predict clinical benefit in LAD-I for accelerated approval. The clinical benefit of Kresladi will be confirmed in patients with severe LAD-I through post-marketing requirements. The most common side effects identified in the clinical study included anemia, low platelet and white blood cell counts, mouth sores, upper respiratory infections, viral infections, fever, febrile neutropenia, nausea, vomiting, skin infection, rash, vascular device-related infection and increased liver enzymes.

“Kresladi offers a potentially transformative treatment option that targets the root cause (pathophysiology) of this serious condition. Our office and FDA remain committed to advancing innovative gene therapies for rare pediatric diseases and making them available to patients as quickly as possible via accelerated approval pathway supported by use of novel surrogate endpoints,” said Megha Kaushal MD, MS, acting deputy director of FDA’s Center for Biologics Evaluation and Research Office of Therapeutic Products and pediatric hematologist. “For children with severe LAD-I and their families, this treatment allows them to participate in day-to-day activities and hopefully experience a better quality of life.”