The U.S. Food and Drug Administration recently 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 leukocyte adhesion deficiency I (LAD-I) due to biallelic variants in ITGB2 without an available human leukocyte antigen (HLA)-matched sibling donor for allogeneic hematopoietic stem cell transplant.

“Today’s accelerated approval provides a breakthrough treatment for pediatric patients with severe Leukocyte Adhesion Deficiency Type I—the first FDA-approved gene therapy to treat this disease,” said Vinay Prasad, M.D., M.P.H., Chief Medical and Scientific Officer and Director of the FDA’s Center for Biologics Evaluation and Research. “The FDA continues to exercise significant regulatory flexibilities as applicable, during both Chemistry, Manufacturing and Control (CMC) and Clinical review of licensing applications. For rare diseases, the FDA considers small patient populations in clinical trials and all available sources of evidence to advance life-changing treatments while still meeting its rigorous scientific standards.”

Severe LAD-I is a rare, inherited immune deficiency caused by mutations in the ITGB2 gene, which prevent white blood cells from effectively fighting infections. Patients with severe LAD-I experience recurrent, life-threatening bacterial and fungal infections with substantial morbidity and mortality in the first decade of life. Allogeneic hematopoietic stem cell transplant is considered in some patients but is associated with significant morbidity and mortality, especially in patients without an HLA-matched sibling donor.

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.

The safety and effectiveness of Kresladi were established in one 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 reflect 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 M.D., M.S., Acting Deputy Director of the CBER 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.”

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

The FDA granted accelerated approval of Kresladi, as well as a Rare Pediatric Disease Priority Review Voucher, to Rocket Pharmaceuticals, Inc. As a condition of accelerated approval, Rocket Pharmaceuticals, Inc., is required to conduct post-approval studies to verify and describe the clinical benefit of Kresladi. Continued approval may be contingent upon verification of clinical benefit in confirmatory trials.

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