Multicenter Pharmacokinetic Evaluation of rFVIII-Fc (Elocta) in a Real Life and Comparison with Non-Extended Half-Life FVIII Concentrates

Background: The use of extending half-life (EHL) FVIII or FIX products is today a current strategy in Hemophilia A (HA) patients for improving prophylaxis and reducing the number of IV injections. Fc fusion technology is based on the use of the neonatal Fc receptor and endogenous Fc recycling pathway, thereby prolonging the half-life (T_1/2) of rFVIII-Fc. A single dose phase 1/2 pharmacokinetic (PK) study performed in 16 severe HA patients demonstrated a prolonged T _½ of rFVIII-Fc equal to 18.8 hours (mean) compared to 12.2 hours with one conventional rFVIII (Malhangu et al. Blood 2014).

The aim of the present study was to analyze PK data collected with Elocta^® in "real life" i.e. in a large cohort of patients treated in 13 different French hemophilia care centers, and results were compared to those obtained with conventional FVIII, when available. Importantly, this study was performed without any involvement of Sobi, the pharmaceutical company that provides Elocta^® in France.

Patients and methods: 113 severe Hemophilia A (HA) patients with the following characteristics were included: mean age 30 years (range 3 - 70); weight 65 Kg (17-125); total FVIII-Fc dose injected 2650 IU (500-5750); FVIII-Fc IU/Kg: 41 (25 - 59); VWF Ag 98% (41-279). The FVIII recovery (R) was calculated as follows: (body weight (Kg) x observed increased in FVIII (%))/administered dose (IU/Kg). The T_1/2 was calculated with the following formula: Ln2/((Ln FVIII% T1 - Ln FVIII%T2)/T2 - T1)), with T1 ≥ 4 hours and T2 ≥ 24 hours.

Results were compared to those performed with conventional FVIII (non EHL-FVIII) in 48 patients (Advate^® n = 14, Refacto^® n = 2, Helixate^®/Kogenate^®/Kovaltry^® n = 29, Factane^® n = 3)

Results: rFVIII-Fc activity measured by one stage clotting assay (OSA) was 20% lower than those obtained with chromogenic assay (CSA) in samples with FVIII levels higher than 20%, but this difference was lower than 10% when FVIII levels < 20%. Therefore, rFVIII-Fc recovery (R) always appeared lower when measured with OSA (Mean 2.38, range 1.33 - 5.7) than with CSA (mean 2.82, ranges 1.35 - 5.5) (p < 0.0001). No correlation was found between this recovery and age, weight, injected doses or VWF Ag levels. Mean T_1/2 measured with rFVIII-Fc equaled 15 hours whatever the measurement method used (OSA or CSA), and was strongly correlated with vWFAg levels (R² = 0.57). Using OSA, significantly lower recovery (1.86 vs. 2.49, p = 0.0002) and T_1/2 values (11.75 vs. 15.13 hours, p = 0.0004) were measured in children (< 10 years, n = 19) compared to adults. Similar differences were evidenced with data obtained by CSA (recovery : 2.26 vs. 2.93, p = 0.0009 and T_1/2 : 11.4 vs. 15.6 h, p = 0.004, n = 14 children < 10 years).

PK parameters of FVIII-Fc were compared to those obtained with non EHL-FVIII (rFVIII or pdFVIII) in 47 patients (mean T_1/2 equal to 10.0 hours; range 5.3 - 21.2), and half-lives of these two categories of products were well correlated (r² = 0.57). However, the apparent benefit provided by FVIII-Fc was variable from one patient to another, with a mean T_1/2 rFVIII-Fc / T_1/2 FVIII ratio ranging from 0.6 to 2.4 (mean 1.4). Interestingly, the increase in T_1/2 with FVIII-Fc was lower than 20% only in patients previously treated with BHK-derived rFVIII i.e. Helixate^®/Kogenate^®/ Kowaltry^® (n=10). Whatever the FVIII injected (FVIII-Fc or other non EHL-FVIII), the T_1/2 measured was also strongly correlated to vWF levels, which were significantly lower in patients for whom the mean T_1/2 rFVIII Fc / T_1/2 FVIII ratio was > 1.3 (mean 79% vs 116% in the others, p=0.017).

Conclusion: This study is the first to report PK data obtained with rFVIII-Fc (Elocta^®) in a large group of HA patients. Our results confirm the benefit of rFVIII-Fc in most HA patients, adults or children, but also emphasize the impact of vWF on half-life of rFVIII-Fc or conventional non EHL-FVIII. Indeed, the benefit of rFVIII-Fc clearly appears higher in patients with lower vWF levels, with a more significant prolongation of T_1/2.