Kresladi Approved by FDA: First Gene Therapy for Severe LAD-I

　　Indication and Target Population

　　Kresladi is indicated for pediatric patients with severe leukocyte adhesion deficiency type I(LAD-I)​caused by biallelic ITGB2 variants,who lack an available HLA-matched sibling donor​for allogeneic hematopoietic stem cell transplantation.

　　FDA Leadership Perspective:Breakthrough Therapy and Regulatory Flexibility

　　Dr.Vinay Prasad,FDA Chief Medical Officer and Director of the Center for Biologics Evaluation and Research,stated:"Today’s accelerated approval provides a breakthrough treatment​for pediatric patients with severe LAD-I—the first gene therapy approved by the FDA for this disease.The FDA applied regulatory flexibility​throughout the review,considering small patient cohorts and all available evidence to advance life-changing therapies while upholding rigorous scientific standards."

　　Challenges of Severe LAD-I

　　Severe LAD-I is a rare genetic immunodeficiency caused by ITGB2 mutations that impair leukocyte infection-fighting ability.Patients experience recurrent,life-threatening bacterial/fungal infections in the first decade of life,with high morbidity and mortality.Allogeneic hematopoietic stem cell transplantation carries significant risks,especially without an HLA-matched sibling donor.

　　Mechanism of Action:Autologous Stem Cell Gene Modification

　　Kresladi consists of patient-derived autologous hematopoietic stem cells​genetically modified to introduce a functional copy of the ITGB2 gene.After preconditioning,a single intravenous infusion restores surface expression of CD18 and CD11a​on leukocytes(including neutrophils),addressing the root cause of severe LAD-I.

　　Clinical Trial Evidence and Accelerated Approval Basis

　　Efficacy was established in an open-label,single-arm,multicenter study​using increased neutrophil CD18/CD11a surface expression​(a disease-specific biomarker reflecting improved immune activity)as a surrogate endpoint.This effect was observed at 12 months post-infusion and sustained through 24 months,reasonably predicting clinical benefit and supporting accelerated approval.Post-marketing studies will confirm clinical benefit in severe LAD-I patients.

　　Safety Profile and Common Adverse Reactions

　　Most common adverse reactions in clinical studies include:

　　Hematologic:Anemia,decreased platelet and white blood cell counts

　　Infectious:Oral ulcers,upper respiratory tract infections,viral infections,skin infections,vascular access device-related infections

　　Systemic:Fever,febrile neutropenia,nausea,vomiting

　　Others:Rash,elevated liver enzymes

　　Regulatory Designations and Follow-Up Requirements

　　The application received four designations:Orphan Drug,Rare Pediatric Disease,Regenerative Medicine Advanced Therapy,and Fast Track.The FDA will monitor post-marketing data to ensure long-term benefit.