Relationship between Dose, Factor IX Activity Levels and Bleeding Probability for rIX‐FP Prophylaxis in Hemophilia B: A Repeated Time‐to‐Event Analysis

In hemophilia B, pharmacokinetic (PK)-guided dosing of extended half-life factor IX (EHL-FIX) concentrates can secure targeted FIX exposure. Target FIX activity levels in plasma should be individually set primarily taking bleeding tendency into account, alongside the presence of target joints, physical activity, and preferred dosing schedules. In other words, both PK and pharmacodynamics (PD) are relevant when individualizing therapy. Our objective was to examine the relationship between dose, FIX activity levels, and bleeding specifically for EHL-FIX concentrate recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP). Data from hemophilia B patients with endogenous FIX activity level ≤ 2 IU/dL from five clinical trials were combined. Bleeding probability was described with a parametric repeated time-to-event (RTTE) model. Data included 2,493 FIX activity levels and 514 bleeds from 114 unique patients with a median age of 26 years (range: 1-61) followed for a median of 416 days (range: 6-1,233). Joints were the most frequent bleeding site (46%), and more than half of the bleeds were trauma-related (52%). Overall, 60% and 40% were categorized as damage-causing or nuisance bleeds, respectively. A baseline hazard of 7.3 bleeds per year was calculated when FIX activity levels were set at zero. The probability of all bleeding decreased by 50% when the FIX activity level was 12 IU/dL. Variability in bleeding hazard between individuals with similar FIX activity levels was substantial (182%). Simulations showed that targeting trough FIX activity levels to 20 IU/dL resulted in a median annual bleeding rate (ABR) of zero (range: 0-3).