Modeling The Impact of Potential Differences In Real-Wolrd Adherence With Extended-Half-Life Vs. Conventional Factor Viii And Ix on Bleeding

To model the impact of potential differences in adherence to routine prophylaxis with extended-half-life vs. conventional factor VIII and IX on bleeding efficacy for patients with severe haemophilia. Systematic literature reviews identified studies of routine prophylaxis in patients with severe haemophilia with conventional recombinant factor VIII (rFVIII) and IX (rFIX) for comparison with published studies of two extended-half-life agents (rFVIII and rFIX Fc fusion protein, rFVIIIFc and rFIXFc). We developed a model that extrapolates the ABR for a given adherence level as the weighted average of two ABRs from clinical trials: those associated with prophylaxis (interpreted in the model as ABR associated with 100% adherence) and episodic treatment (interpreted as the ABR associated with 0% adherence). We used the model to extrapolate ABRs for conventional products assuming real-world adherence of 76% of clinical trial levels, and ABRs for rFVIIIFc and rFIXFc at simulated adherence levels ≥76%. Extrapolated ABRs were compared using simple differences. We also mapped simulated adherence improvements into changes in Validated Haemophilia Regimen Treatment Adherence Scale for Prophylaxis (VERITAS-Pro) scores, allowing us to illustrate specific aspects of adherence improvements with extended-half-life products potentially associated with significant reductions in ABRs. Extrapolated ABRs for rFVIII and rFIX at 76% adherence were 12.7 and 7.4, respectively. The extrapolated rFVIIIFc ABR was significantly lower vs. conventional rFVIII for adherence levels >82% (ΔABR >3.0, P<0.05). The extrapolated rFIXFc ABR was significantly lower vs. conventional rFIX for adherence levels >85% (ΔABR >2.0, P<0.05). Depending upon initial adherence levels, our estimates suggest these adherence improvements are comparable to improvements in VERITAS-Pro total scale of 5-22 points. Simulations using a model to understand the relationship between adherence and ABR suggest improved adherence to prophylaxis associated with rFVIIIFc and rFIXFc may lead to significant reductions in bleeding rates.