FDA Approves First Gene Therapy for Severe LAD-1

The Food and Drug Administration approved marnetegragene autotemcel (Kresladi, Rocket Pharmaceuticals) for the treatment of pediatric patients with severe leukocyte adhesion deficiency type I (LAD-1), a rare, inherited primary immunodeficiency.

LAD-1 is caused by mutations in the ITGB2 gene that prevent white blood cells from effectively fighting infections. Allogeneic hematopoietic stem cell transplant (HSCT) may be considered in some patients, but it is associated with significant morbidity and mortality in patients without an HLA-matched sibling donor.

Marnetegragene autotemcel is indicated for patients with severe LAD-1 due to biallelic variants in ITGB2 who lack an available HLA-matched sibling donor for allogeneic HSCT. The therapy works by introducing functional copies of the ITGB2 gene to patients’ hematopoietic stem cells, restoring CD18 and CD11a cell surface expression in white blood cells, including neutrophils.

FDA based its approval on findings from an open-label, single-arm study that evaluated increases in neutrophil CD18 and CD11a cell surface expression. According to the agency, these increases reflect improved function of a protein complex composed of the two biomarkers on the surface of neutrophils, which was used as a surrogate endpoint reasonably likely to predict clinical benefit in LAD-1 under the accelerated approval pathway.

As a condition of accelerated approval, Rocket Pharmaceuticals is required to conduct postmarketing studies to verify and describe clinical benefit. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.

The application was granted Orphan Drug, Rare Pediatric Disease, Regenerative Medicine Advanced Therapy and Fast Track designations.