Turoctocog Alfa Pegol with Extended Half-Life in the Treatment of Severe Hemophilia A
GlycoPEGylated recombinant factor VIII (rFVIII) with an extended half-life, turoctocog alfa pegol, has demonstrated prophylactic efficacy in patients with severe hemophilia A aged over 12. This product is administered only once every 4 days. In addition to a comparable reduction in the annual bleed rate to standard FVIII prophylaxis products, it has also shown sufficient efficacy in bleeding treatment and a minimal risk of inhibitory antibody formation.
Factor VIII in the Treatment of Hemophilia A
Substitution therapy with rFVIII concentrates is the standard of care for patients with severe hemophilia A. In children and many adults, its prophylactic administration is preferred over on-demand (bleed-responsive) treatment due to lower bleeding incidence and prevention of chronic arthropathy development. Standard products are usually administered prophylactically via intravenous injection at least three times a week.
GlycoPEGylated rFVIII with Extended Half-Life
Turoctocog alfa pegol (N8-GP) has an extended biological half-life (18.4 hours) and showed longer plasma activity in initial studies compared to the product previously used by the patient. In 2017, the results of an international open-label phase III study were published, which included the incidence of FVIII inhibitors (≥ 0.6 Bethesda units) and the annual bleeding rate in patients with prophylactic N8-GP treatment as coprimary endpoints.
International Phase III Study
The study took place at 77 centers in 22 countries from January 2012 to September 2013. It included men with previously treated severe hemophilia A (FVIII activity < 1%) aged 12–66 years. Of them, 175 (including 25 adolescents aged 12–17) received regular N8-GP (50 IU/kg every 4 days) in a prophylactic regimen, while another 12 adult men were treated on-demand. Bleeds were treated with N8-GP at doses of 20–75 IU/kg.
Results: Prophylactic Efficacy and Incidence of Inhibitors
The total exposure to N8-GP in the study was 159 patient-years. In the prophylaxis arm, the median annual bleeding rate (ABR) was 1.33 (interquartile range [IQR] 0–4.61), matching the results observed with standard half-life rFVIII. The mean ABR was 3.7 (95% confidence interval [CI] 2.94–4.66), confirming the prophylactic efficacy of N8-GP. 40% of patients on prophylactic treatment experienced no bleeds during the study. In the on-demand treatment arm, ABR was 30.87 compared to 36.0 with previous treatment. Bleeds were resolved with one N8-GP injection in 77.5% of prophylactic patients and 88.5% of on-demand patients, and with a maximum of two injections in 93.6% and 97.0% of patients, respectively.
Inhibitory antibodies against FVIII were detected in only one patient, after 93 N8-GP administrations. This patient had been using rFVIII three times a week for 58 months before enrolling in the study.
N8-GP demonstrated a favorable safety profile and was well-tolerated. The frequency and type of adverse events corresponded to expected data for this population.
This study also confirmed the extended biological half-life of N8-GP compared to standard rFVIII products.
Conclusion
N8-GP reduces the burden of prophylactic treatment in patients with severe hemophilia A aged over 12, as it maintains a low bleeding incidence even with less frequent dosing compared to standard products.
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Source: Giangrande P., Andreeva T., Chowdary P. et al.; Pathfinder™2 Investigators. Clinical evaluation of glycoPEGylated recombinant FVIII: efficacy and safety in severe haemophilia A. Thromb Haemost 2017; 117 (2): 252–261, doi: 10.1160/TH16-06-0444.
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