Background:
Factor VIII (FVIII) pharmacokinetic (PK) parameters and other patient characteristics may play a role in effectiveness of FVIII prophylaxis. Objective: A post-hoc analysis was conducted to assess the association between PK parameters and BAY 81-8973 (Kovaltry® ) prophylaxis regimen in patients with severe hemophilia A.
Methods:
LEOPOLD I was a randomized, open-label, phase 2/3 trial to investigate use of BAY 81-8973 routine prophylaxis for treatment of bleeds in adolescents and adults with severe hemophilia A. In the efficacy part of the trial (part B), patients received BAY 81-8973 at a dose of 20‒50 IU/kg 2x/week (n=18) or 3x/week (n=44) for 12 months. Prophylaxis regimens were determined by study investigators, independent of BAY 81-8973 PK data. A subset of 20 patients (2x/week, n=7; 3x/week, n=13) had data from an earlier PK study (part A), in which patients received a single 50-IU/kg injection of BAY 81-8973 and had blood samples collected over 48 hours to assess PK parameters, including area under the curve (AUC), half-life (t½), and clearance (CL). Estimates of PK parameters were also derived using a population PK model based on data from all patients. This analysis compared model-based PK parameters, baseline characteristics, total annual dosing, and bleed outcomes between 2x/week and 3x/week prophylaxis groups. A similar analysis was done among the subset of patients in part A who had PK data. Differences between 2x/week and 3x/week dosing were assessed using Wilcoxon rank sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables.
Results:
In the full trial population, model-based AUC [mean (SD): 1957.1 (648.3) vs 2139.1 (875.7), 2x/week and 3x/week, respectively], t½ [15.0 (3.7) vs 15.9 (6.6)], and CL [0.028 (0.009) vs 0.027 (0.011)] were comparable between groups. The proportion of patients with ≥3 bleeds at 12 months was 33% for 2x/week and 48% for 3x/week. The 3x/week group had more bleeds in the past 12 months, higher baseline Gilbert bleeding scores, were more likely to have target joints at baseline, and received higher doses of BAY 81-8973 during the 12- month treatment period. In the part A subset analysis, observed and model-based AUC, t½, and CL were similar in both groups. The proportion of patients with ≥3 bleeds at 12 months was 0% for 2x/week and 46.2% for 3x/week (P=0.052).
Conclusions:
The similarity of PK parameters in patients successfully treated with 2x/week and 3x/week regimens suggests that clinical factors other than t½, AUC, and CL are important in predicting success of prophylaxis with BAY 81-8973. Physician decisions, taking into consideration clinical factors to identify appropriate patients for specific prophylaxis regimens, appear to be an important factor for 2x/week or 3x/week dosing with BAY 81-8973. These factors should be considered when individualizing BAY 81-8973 prophylaxis frequency.