Fidanacogene elaparvovec

Fidanacogene elaparvovec is a gene therapy designed to introduce in the transduced cells a functional copy of the factor IX gene encoding a high-activity FIX variant (FIX-R338L, hFIX Padua).

The AAVRh74var capsid is able to transduce hepatocytes, the natural site of factor IX synthesis. Single intravenous infusion of fidanacogene elaparvovec results in cell transduction and increase in circulating factor IX activity in patients with hemophilia B.

Biodistribution (Within the Body) and Vector Shedding (Excretion/Secretion)

Fidanacogene elaparvovec vector DNA levels were measured and quantified in blood and various shedding matrices using a quantitative polymerase chain reaction (qPCR) assay. This assay is sensitive and specific to fidanacogene elaparvovec vector DNA, but could also detect DNA fragments. Saliva, semen, and urine samples from a subset of patients in the clinical study 1 were further characterized by measuring encapsidated vector DNA by a modified assay.

Nonclinical Biodistribution

Biodistribution of fidanacogene elaparvovec was evaluated approximately 92 days after intravenous administration in healthy male non-human primates (NHPs) at dose levels up to 5 × 10¹² vg/kg. Vector DNA was detected in all tissues assessed, including the testes. The highest levels of vector DNA were detected in the liver, spleen, and inguinal lymph nodes.

Clinical Data

Vector shedding after infusion with fidanacogene elaparvovec was assessed in 60 patients at multiple time points in clinical studies (clinical study 1 and clinical study 2). In clinical study 1 a subset of patients (n=17) provided optional samples at early timepoints (2, 24 and 72 hours post-infusion) to better define parameters such as maximum vector DNA level (C_max) and time to maximum vector DNA level (T_max). The maximum vector DNA concentrations were found in plasma followed by saliva, peripheral blood mononuclear cells (PBMC), semen and urine. The mean T_max was 1.2 days for plasma and saliva and 1.6 days for urine. The mean T_max was 3.8 days and 7.4 days for semen and PBMC, respectively. For pooled analysis of clinical data (N=60 patients), full clearance of vector DNA was defined as having 3 consecutive negative results (i.e., below quantification limit). Vector DNA fully cleared from plasma, saliva, and semen within a mean of 1 to 4 months after infusion and PBMC was the slowest fluid to full clearance within a mean of 12 months. In semen, the maximum observed time for vector DNA full clearance was 154 days. In urine, the peak vector DNA concentration was very low relative to plasma and declined to full clearance within a mean of 4 weeks after infusion.