The FDA has granted accelerated approval to the gene therapy marnetegragene autotemcel (Kresladi, Rocket Pharmaceuticals) for the treatment of pediatric patients with severe leukocyte adhesion deficiency type 1 (LAD-1).

The approval is specifically for children with LAD-1 caused by biallelic variants in the ITGB2 gene who lack a matched sibling donor for hematopoietic stem cell transplant (HSCT). It marks the first gene therapy for the ultrarare disease.

LAD-1 is an inherited immune disorder that occurs in about 1 in 1 million people worldwide. Mutations in the ITGB2 gene leave white blood cells without functional CD18, a protein necessary for the cells to adhere to blood vessel walls and migrate into infected tissue.

Children born with severe LAD-1 develop recurrent, life-threatening bacterial and fungal infections that respond poorly to antimicrobials and require frequent hospitalizations. Without a curative allogeneic HSCT, up to 75% of children with severe disease die before age 2.

Marnetegragene autotemcel (marne-cel) is an alternative to allogeneic HSCT and the first gene therapy approved for LAD-1. 

It’s a one-time treatment consisting of patient-derived hematopoietic stem cells that have been genetically modified to introduce functional copies of the ITGB2 gene. After 4 days of myeloablative busulfan conditioning, patients receive a marne-cel infusion 1-2 days later; the cells migrate to the bone marrow, proliferate, differentiate, and produce white blood cells expressing CD18. 

Accelerated approval was based on a phase 1/2 study in nine children demonstrating that marne-cel increased neutrophil CD18 and CD11a cell-surface expression through month 24 post-infusion. Sustained increases in the two biomarkers serve as a surrogate endpoint that is “reasonably likely” to predict clinical benefit, the FDA said.

Confirmation of clinical benefit will be based on longer-term follow-up data from the ongoing clinical study, as well as through a postmarketing registry, Rocket said in a press release.

In the study, the most common treatment side effects included anemia, low platelet and white blood cell counts, mouth sores, upper respiratory and other viral infections, fever, febrile neutropenia, nausea, vomiting, skin infection, rash, vascular device-related infection, and increased liver enzymes. 

Because the therapy uses a lentiviral vector (LVV), LVV-mediated insertional oncogenesis may occur. Hematologic malignancy is a lifelong risk following treatment, the company said.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com