Clinical deep dive

Disease state overview

Leukocyte adhesion deficiency (LAD) is a rare genetic disorder of the immune system (B cell and T cell immunodeficiency). LAD-I is caused by mutations in the ITGB2 gene that encodes for the beta chain-2 protein, also known as CD18. The CD18 protein plays a key role in fighting infections by facilitating leukocyte migration to infection sites where they kill invading microbes. Pediatric patients with LAD-I are predisposed to recurrent and fatal bacterial and fungal infections and present with infections immediately after birth. LAD-I is an immune disorder that is invariably fatal in childhood without an allogeneic hematopoietic stem cell transplant (HSCT). If patients with LAD-1 survive past infancy, they suffer recurrent severe infections, such as gingival ulcers, necrotic skin ulcers, pneumonia, and septicemia; survival beyond childhood is uncommon. The hallmark sign of LAD-I is delayed umbilical cord stump detachment and lack of pus formation at the infection site.

Epidemiology

The exact prevalence of LAD is unknown, possibly due to difficulty in diagnosing LAD. Prevalence has been estimated based on less than 350 cases being reported in literature. LAD-I is estimated to impact 1 in 1,000,000 persons annually.

Treatment

Currently, the only treatment option for patients with severe LAD-1 is allogeneic HSCT; however, finding a matched donor may not occur in a timely manner, and without HSCT, death usually occurs by 2 years of age. Other treatments for severe LAD-1 focus on controlling and preventing the infections with the use of antimicrobial agents, as well as white blood cell (WBC) transfusions for life-threatening infections.

Drug and clinical trial overview

In a global phase 1/2 study, the efficacy and safety of marnetegragene autotemcel were evaluated in patients (n=9) with severe LAD-1, ages 3 months and older who did not have availability of a medically eligible human leukocyte antigen (HLA)-identical sibling donor transplant. The primary end points (phase 2) were the proportion of patients alive at least one year after treatment with marnetegragene autotemcel without allogeneic HSCT and the proportion of patients alive at age 2 years without allogeneic HSCT, if they were < 1 year old at the beginning of the study. Interim analysis reported that all primary and secondary end points (e.g., post infusion CD18 expression, genetic correction, incidence of infection) were met. At data cut-off, marnetegragene autotemcel demonstrated 100% overall survival at 12 months after infusion for all patients with 12 to 24 months of available follow-up. Those patients also demonstrated significant reductions in all-cause hospitalizations and severe infections. When compared to pre-treatment history, data showed restoration of wound repair capabilities and large decreases in the incidence of significant infections and skin lesions. Marnetegragene autotemcel was well tolerated, with no severe treatment related adverse events.

Treatment with marnetegragene autotemcel involves a lengthy process including pre-collection preparation; CD34+ hematopoietic stem and progenitor cell (HSPC) mobilization, and apheresis. This is followed by ex vivo transduction of autologous hematopoietic cells with the lentiviral vector encoding the ITGB2 gene. Patients also receive myeloablative conditioning followed by a one-time IV infusion of edited HSPCs.