Bleeding Risk Reduction in Relation to Predicted Factor IX Levels in Hemophilia B Patients Receiving Idelvion (rIX-FP)

Factor IX (FIX) replacement is an effective therapy for hemophilia B patients. The current clinical rationale for maintaining higher trough levels of FIX is to transition patients from a severe hemophilia phenotype (eg. FIX <1% of normal) to a moderate (FIX of 1-5%) or mild disease state (FIX >5%), thereby reducing the total number of bleeding events. Although there is a tentative linkage between trough FIX levels and bleeding tendency which guides hemophilia B management, a thorough quantitative analysis was undertaken for rIX-FP (Idelvion) to robustly define the FIX exposure versus clinical outcome relationship.

Pooled adult hemophilia B data from the rIX-FP Phase III development program was utilized for the analysis. A Cox proportional hazards model was employed to relate time-to-bleed event data and various individual measures of exposure (FIX activity) and dosing regimen, while testing the influence of covariates (e.g. baseline FIX). FIX activity levels were simulated using a validated rIX-FP population pharmacokinetic (PK) model. The analysis included all recorded bleeding episodes in subjects receiving either prophylaxis and/or on-demand regimens. Dose amounts and intervals included 50 IU/kg (every 1 week) and 75 IU/kg (every 2 weeks, or every 10 days). A total of 478 bleeding episodes (267 spontaneous bleeds, 190 traumatic bleeds, 21 other bleeds) from 57 adult patients were included in the primary analysis. The highest proportion of bleeds occurred during the on-demand portion of the clinical studies.

Patients maintaining cumulative FIX activity trough levels above 5% and 10% were predicted to have significant reductions in bleeding risk of 83% and 81%, respectively, per 1 year above these levels, compared to patients not maintaining these FIX activity trough levels. Cumulatively, maintaining FIX levels above 2% was not statistically significant for risk reduction. Furthermore, a time-direct evaluation relating daily FIX trough activity to daily bleeding risk found that >2%, >5% and >10% FIX activity thresholds were significant predictors of bleeding events with 69% (95% CI, 53 to 80) 77% (95% CI, 67 to 84) and 78% (95% CI, 69 to 85) risk reductions, respectively. Although >2% was significant, the wider confidence intervals suggest a more reliable risk reduction at the >5% and >10% levels.

This in-depth exposure-response analysis of rIX-FP determined a strong relationship between FIX activity levels and hemophilia B bleeding risk reduction. Trough FIX activity above 5% (either cumulatively or on any given day) was identified as a statistically significant and overall sufficient pharmacological threshold for reduction of bleeding risk in adult hemophilia B patients receiving rIX-FP. Trough FIX activity > 10% was also a predictor of significant risk reduction, and the magnitude of risk reduction was similar to that of achieving levels > 5%. These results are aligned with existing World Hemophilia Foundation (WFH) hemophilia severity definitions where patients with a range of observed FIX activity 5-40% are categorized as a single mild hemophilia phenotype. Post-approval clinical exposure versus response relationships may also be affected by an individual's level of physical activity which was not assessed in the current analysis. Overall, this analysis demonstrates the quantitative clinical rationale for optimization of adult rIX-FP dose regimens through targeting and maintaining FIX activity trough levels above 5% to 10%.