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Recombinant Factor VIII product increased inhibitor development risk
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One recombinant Factor VIII product was associated with an increased risk for inhibitor formation compared with similar products for the treatment of severe hemophilia A, according to study results.
Thierry Calvez, MD, MSc, of Sorbonne University and Institut Pierre Louis d'Epidémiologie et de Santé Publique in Paris, and colleagues sought to confirm the results of the Research of Determinants of Inhibitor Development (RODIN) study. Results of this analysis indicated Kogenate FS (Bayer Healthcare), a second-generation full-length recombinant Factor VIII product, increased the risk for inhibitor formation in previously untreated patients with severe hemophilia A.
Calvez and colleagues evaluated data from 303 boys with previously untreated severe hemophilia A who had not participated in the RODIN trial. All patients received one of six recombinant Factor VIII products.
Kogenate FS — the recombinant factor associated with an increased risk for inhibitor development in the RODIN trial —was the most commonly used product for the first infusion in the current analysis (36.6%). The second most commonly utilized product, Advate (Baxter Bioscience), was used for the first infusion in 32% of boys.
Results showed 114 boys (37.6%) developed a clinically significant inhibitor after a median of 13 exposure days (interquartile range [IQR], 8-19). The median age of these boys at the time of inhibitor diagnosis was 15.2 months (IQR, 11.1-22.8).
After 75 exposure days, the cumulative incidence of clinically significant inhibitors was 40.2% (95% CI, 34.8-46.2) and the cumulative incidence of high-titer inhibitors was 23.9% (95% CI, 19.1-29.6).
Multivariate analyses indicated Kogenate FS was associated with an increased risk for inhibitor development compared with Advate for all inhibitors (adjusted HR=1.55; 95% CI, 0.97-2.49) and for high-titer inhibitors (adjusted HR=1.56; 95% CI, 0.82-2.98).
The other two recombinant Factor VIII products evaluated — Recombinate (Baxter Healthcare), administered to 15.8% of boys in the study, and ReFacto (Wyeth), administered to 8.9% of boys in the study — were not associated with increased risk for inhibitor development compared with Advate. The HRs were 0.97 (95% CI, 0.4-2.37) for Recombinate vs. Advate, and 1.2 (95% CI, 0.47-3.08) for ReFacto vs. Advate.
However, multivariate analysis showed Recombinate (HR=1.87; 95% CI, 0.59-5.89) and ReFacto (HR=1.94; 95% CI, 0.54-6.91) were associated with an increased risk for high-titer inhibitors compared with Advate.
Two other products — Kogenate (Bayer) and ReFacto AF (Pfizer) — were administered as first treatment to only 10 boys (3.3%) each, so individual results for those products were not published as part of the study results.
“Our findings and those of the RODIN study highlight the need to strengthen the power and responsiveness of post-marketing monitoring of hemophilia treatments worldwide,” Calvez and colleagues wrote. “This is a major issue, as several new Factor VIII products, including human cell-derived and long-acting recombinant Factor VIII, are reaching an advanced stage of their clinical development and should be marketed shortly in numerous countries. Given the heavy burden of inhibitors for individual patients and the high costs of bypassing agents and immune tolerance induction, this mobilization would not only benefit patients but would also lead to substantial saving for national health care budgets.”
Disclosure: See the study for a list of the researchers’ relevant financial disclosures.
Perspective
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Katherine A. High, MD
The study by Calvez and colleagues reports data from French hemophilia centers regarding the prevalence of inhibitors in previously untreated patients as a function of the type of recombinant Factor VIII product used. The impetus for the study was the publication in 2013 of data from RODIN, a large cohort study conducted in Europe, Canada and Israel that sought to determine risk factors for inhibitor development in severe hemophilia A (Gouw SC. Blood. 2013;121:4046-4055). The first publication from the RODIN study showed an unexpected finding of higher risk of inhibitor development with one specific second-generation full-length Factor VIII product, Kogenate FS (Bayer Healthcare). The European Medicines Agency conducted a review of results and concluded that the data did not support this contention.Calvez and colleagues have taken advantage of a prospective data cohort established in 1994 by the health authorities in France to monitor hemophilia treatment safety, and they have examined incidence of inhibitor development in previously untreated patients based on recombinant Factor VIII product used. The data on 303 boys with severe hemophilia A reveal an overall inhibitor incidence of 37.6% and an adjusted HR of 1.55 (95% CI, 0.97-2.49) with Kogenate FS. These findings are in line with those of the RODIN study.
It should be noted that — as is the case with all biologics — “the process is the product,” so it is certainly scientifically plausible that recombinant protein products with identical amino acid sequences can nonetheless vary in terms of immunogenicity, based on differences in post-translational modifications, minor contaminants, final formulation or other factors. Nonetheless, these results should be interpreted with caution. The 95% CI of the adjusted HR crosses 1, leaving some uncertainty as to the significance of the findings. Combining the results of this study with the RODIN study results leads to an adjusted HR of 1.58, with a 95% CI of 1.17-2.14. A larger study may be required to settle the point with
certainty.
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