Fixed doses of N8‐GP prophylaxis maintain moderate‐to‐mild factor VIII levels in the majority of patients with severe hemophilia A

Abstract

Background N8‐GP is an extended half‐life recombinant factor VIII developed for prophylaxis and treatment of bleeds in patients with hemophilia A. Objective To assess pharmacokinetic (PK) characteristics of N8‐GP in previously treated patients with severe hemophilia A, model the time spent at hemophilia thresholds of ≥1 and ≤5 IU/dL (moderate) or >5 IU/dL (mild) FVIII levels during N8‐GP prophylaxis, and investigate the relationship between N8‐GP half‐life and von Willebrand factor (vWF). Methods PK assessments were obtained from patients with severe hemophilia A (FVIII < 1 IU/dL) participating in 4 clinical trials: pathfinder 1 (20‐60 years); pathfinder 2 (12‐17 and ≥18 years); pathfinder 5 (0‐11 years), and pathfinder 7 (25‐71 years). All PK profiles were assessed after washout and considered single‐dose PK profiles. Pre‐ and postdose FVIII activity at steady state was measured at all visits. Results From 69 patients, 108 PK profiles of N8‐GP 50 IU/kg were assessed. Adults/adolescents received 50 IU/kg every 4 days, achieving mean trough levels of 3.0 IU/dL (95% confidence interval, 2.6‐3.5, adults) and 2.7 IU/dL (1.8‐4.0, adolescents). Children received 60 IU/kg twice weekly, leading to mean trough levels of 1.2 IU/dL (0.8‐1.6, 0‐ to 5‐year‐olds) and 2.0 IU/dL (1.5‐2.7, 6‐ to 11‐year‐olds). PK modeling predicted children dosed every 3 days and adults/adolescents dosed every 3 to 4 days would maintain FVIII levels >5 and >1 IU/dL for >80% and 100% of the time, respectively. N8‐GP half‐life correlated linearly with von Willebrand factor levels in adults/adolescents, less in children. Conclusions Prophylaxis with fixed intervals (Q4D/twice weekly) and fixed weight‐based dosing (50/60 IU/kg) ensured >1 IU/dL FVIII trough levels in both adults and children.

The impact of factor infusion frequency on health-related quality of life in people with haemophilia

“…It is this substantial increase in the number of infusions annually that underlies the impact on HRQoL. This dilemma could be resolved with EHL factors, which have the potential to increase trough levels with no increase or even a reduction in weekly infusions [22] .…”

<p>Clinical Evidence and Safety Profile of Emicizumab for the Management of Children with Hemophilia A</p>

“…27 In children, previous studies have shown that FVIII half-life were shorter than those reported in adults receiving the same FVIII product. [28][29][30] However, with the exception of bridging FIXa and FX, emicizumab and FVIII have little in common, and emicizumab pharmacokinetic properties are less likely to be correlated with binding-capacity to VWF or ABO groups, as described recently for FVIII. 31 As a result, same QW, Q2W, and Q4W emicizumab dosing regimens as those used for adults were studied in children with HA.…”

Pharmacokinetic‐tailored approach to hemophilia prophylaxis: Medical decision making and outcomes

“…Although gaining momentum in the United States, the use of popPK has been applied more systematically in other regions such as Canada and the United Kingdom . Provider uncertainty about how to incorporate this type of data into their established prescribing practices and the limited data demonstrating an impact on hemophilia health outcomes and economics in a routine care setting are barriers to the use of PK profiles in clinical practice .…”