Prophylaxis EHL products FVIII bring improvements in clinical and pharmacokinetic results

Introduction

The standard of care for patients with severe hemophilia A or those with bleeding symptoms is prophylaxis with coagulation factor VIII (FVIII) concentrate. Prophylaxis reduces the risk of bleeding and consequently joint damage, which typically accompanies moderate to severe forms of this disease. Long-term prophylaxis has been traditionally based on body weight, but in the last two decades, pharmacokinetically (PK) driven management has been adopted. Prophylaxis dosing should thus also reflect the individual PK properties of the specific concentrate for each patient.

A few years ago, new technologically modified forms of FVIII with prolonged biological half-lives were introduced. Most often, these modifications involve pegylation (PEG) or fusion with the Fc fragment of immunoglobulin. These so-called EHL (extended half-life) products are designed to reduce the frequency of drug administration, lessen the burden associated with frequent intravenous infusions, enhance compliance, and potentially allow higher plasma levels of FVIII to be achieved, especially the so-called trough levels—the minimum values measured before administering the next planned dose.

Study Methodology

The work of the Spanish authors presents a comparison of PK-guided prophylactic treatment, both with the original standard half-life (SHL) products and the same patients after being switched to EHL products. These data are from routine clinical practice collected in an open observational cross-sectional multicenter prospective study, which ran for a total of 2 years. In the first year, the original SHL product treatment was assessed, and in the second year, the results of therapy after switching to EHL were evaluated, focusing on FVIII consumption, annual bleeding rate (ABR), and annual joint bleeding rate (AJBR). The web-based WAPPS-Hemo platform, an academic project calculating the PK properties of FVIII regardless of the specific concentrate used, was employed to calculate PK parameters for individual patients.

Results

A total of 75 patients with a median age of 26 years were included. After switching to EHL, a one-third reduction in the weekly frequency of infusions and a 20.4% decrease in the weekly dose was observed. This led to a savings of 39.1 infusions per patient per year.

When administering EHL, significant improvements were observed in all monitored PK parameters—the ratio of biological half-lives was on average 1.5, and the ratio of areas under the curve (AUC) was 1.9. A significant reduction was also observed in the median ABR (2.0 vs. 0.0), AJBR (1.0 vs. 0.0), and the occurrence of so-called target joints (i.e., joints with ≥ 3 bleeds in the last 6 months). The number of patients with zero bleeding incidents increased (27.4% on SHL vs. 54.8% on EHL), as did the number of patients with zero joint bleeding incidents (42.5% vs. 72.6%). The same improvement was observed for both the patient group under 12 years old and the older age group.

The authors did not demonstrate differences in PK parameters between the various EHL products, but lower AJBR was associated with pegylated products.

Conclusion

The authors of this study from real-world clinical practice demonstrated that switching patients with severe hemophilia in a prophylactic treatment setting to EHL FVIII products led to significant improvements in PK parameters as well as clinical parameters (reduction in the bleeding rate and the burden associated with intravenous administration). Lower FVIII consumption was also observed.

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Source: Megías-Vericat J. E., Bonanad Boix S., Berrueco Moreno R. et al. Pharmacokinetic and clinical improvements after PK-guided switch from standard half-life to extended half-life factor VIII products. Thromb Res 2022 Aug; 216: 35−42, doi: 10.1016/j.thromres.2022.06.001.