Efficacy and Safety of Two Pharmacokinetically-Driven Prophylactic Regimens in People with Hemophilia A

Introduction

Available evidence suggests that a target trough level of factor VIII 1% may not be sufficient to prevent bleeding episodes in all individuals with hemophilia A. It is hypothesized that achieving a minimum FVIII level of ≥ 10% reduces the annual risk of joint bleeding to zero, and it is generally known that the bleeding rate in patients on prophylactic regimens decreases with higher achieved levels of FVIII. The aim of this phase III clinical study was to elucidate the efficacy and safety of rurioktokog alfa pegol prophylaxis based on pharmacokinetics with target trough levels of 1–3% and 8–12%.

Methods and Study Course

The prospective, randomized, open-label, multicenter phase III PROPEL clinical study included patients aged 12–65 years with severe hemophilia A (factor VIII level < 1%) with an annual bleeding rate (ABR) ≥ 2 in the 12 months prior to study entry.

Patients were randomized in a 1:1 ratio to a reference group with a target trough level of 1–3% and a group with a higher target trough level of 8–12%. The total treatment duration was 12 months, with the first 6 months allocated as a therapy adjustment period. The primary aim of the study was to assess the development or absence of bleeding episodes in the second 6 months of the study. Secondary aims included evaluating the proportion of patients who achieved zero spontaneous bleeding and zero spontaneous joint bleeding in the second 6 months of the study.

Study Population

A total of 115 patients were randomized for therapy (57 in the reference group, 58 in the higher trough level group). All patients were male, with a median age of 29 years (12–61 years). Compared with the reference group, the higher trough group had a higher proportion of patients with ≥ 4 spontaneous bleeding episodes into ≥ 4 joints and a higher proportion of patients with hemophilic arthropathy. No significant differences in reported physical activity were observed between groups.

Results

In the FAS (full analysis set), 42% of patients in the reference group had zero bleeding occurrences (95% confidence interval [CI] 29–55%) compared with 62% in the higher trough group (95% CI 49–75%). In the per protocol analysis, 40% of patients in the reference group had zero bleeding occurrences (95% CI 27–55%) compared with 67% in the higher trough group (95% CI 52–81%; n = 95; p = 0.015). Similar results were observed in parameters of spontaneous bleeding and spontaneous joint bleeding, with an apparent higher efficacy of the therapeutic regimen with higher trough levels.

Adverse events occurred in 60.9% of patients (70/115), with severe adverse events in 6% (7/115). Only 1 case was assessed as therapy-related − a transient occurrence of a coagulation FVIII inhibitor in the higher trough level group.

No cases of death, severe thrombotic events, or therapy discontinuation due to adverse events were recorded during the study. Pharmacokinetically driven prophylaxis was considered effective and feasible in both groups. No new safety risks were observed in the higher trough level group.

Conclusion

This clinical study concluded that higher target trough levels of FVIII ranging from 8–12% can increase the proportion of individuals with hemophilia A with zero bleeding episodes, highlighting the significance of an individualized approach to therapy based on pharmacokinetics.

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Source: Klamroth R., Windyga J., Radulescu V. et al. Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study. Blood 2021; 137 (13): 1818–1827, doi: 10.1182/blood.2020005673.