Risk of developing inhibitors varies depending on therapy type: Study

Lower risk of FVIII inhibitors for plasma-derived vs. lab-made products

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The development of neutralizing antibodies, or inhibitors, against the clotting factor in replacement therapies administered to people with hemophilia may depend on the type of product used, a recent study has found.

In previously untreated people with severe hemophilia A, or those who lack the clotting factor VIII (FVIII), the risk of inhibitors was significantly lower — by about 30% — in patients who were on plasma-derived FVIII products than in those who were on recombinant (lab-made) treatments. The rate of inhibitor development also varied between different types of recombinant FVIII products.

However, this was not observed in previously untreated patients with severe hemophilia B, who are missing the clotting factor IX (FIX). Their rate of inhibitor development was similar across different treatments.

The study, “Inhibitor development according to concentrate in severe hemophilia: reporting on 1392 PUPs from Europe and Canada,” was published in the journal Research and Practice in Thrombosis and Haemostasis.

Hemophilia is caused by defective or missing blood clotting factors, impairing the body’s ability to prevent excessive bleeding. The type of hemophilia a patient has depends on the specific clotting factor they are missing: FVIII in the case of hemophilia A and FIX in the case of hemophilia B.

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Inhibitor development occurs in about 30% of people with severe hemophilia A

Preventive treatment with concentrated forms of FVIII and FIX remains the mainstay option for managing hemophilia. However, about 30% of patients with severe hemophilia A and 10% of those with hemophilia B develop an immune response against such therapies, which is characterized by the formation of inhibitors that may render replacement therapies ineffective.

However, whether the risk of inhibitor development is the same among the different types of current replacement therapies is unknown.

To answer this, a team of scientists analyzed 11-year data from the European Hemophilia Safety Surveillance and eight-year data from the Canadian Hemophilia Surveillance System. Both programs have been monitoring the safety of replacement therapies and the risk of inhibitor development according to the type of therapy used in previously untreated patients with severe hemophilia. The study was co-funded by several of the pharmaceutical companies marketing the different therapies.

The analysis included data from 1,219 patients with severe hemophilia A and 173 with severe hemophilia B. From these, 312 patients with hemophilia A and 14 with hemophilia B developed inhibitors.

Inhibitors developed quickly, within a median of 13 days of exposure in the case of hemophilia A patients, and within 10 days of exposure for those with hemophilia B.

FVIII replacement therapies included 10 different standard half-life recombinant (SHL-rFVIII) concentrates, which were used by 80.1% of hemophilia A patients. Extended half-life recombinant concentrates (EHL-rFVIII) were used by 4.4%, and plasma-derived (pdFVIII) products by 15.4%.

Standard half-life concentrates have a short half-life, meaning it takes a small amount of time for their levels to drop to half after being administered. For that reason, and to maintain clotting factor levels high enough to prevent bleeds, these medications must be administered regularly (generally several times per week). Owing to certain modifications, extended half-life products contain clotting factors that have a longer half-life, and can, therefore, be administered less often.

Overall, inhibitor development was lower in hemophilia A patients treated with plasma-derived products (19.7%) when compared with standard half-life recombinant concentrates (26.9%).

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Study compared incidence of inhibitor development of several products

The researchers then compared the incidence of inhibitor development of several rFVIII products with the incidence seen with Advate, a SHL-rFVIII product used as the study’s reference and is marketed by Takeda Pharmaceuticals. These therapies included Kogenate (octocog alfa), a SHL-rFVIII product marketed by Bayer that has since been discontinued; Xyntha (moroctocog alfa), a SHL-rFVIII concentrate sold by Pfizer; Nuwiq (simoctocog alfa), a SHL-rFVIII product marked by Octapharma; and Eloctate (efmoroctocog alfa), a EHL-rFVIII marketed by Sanofi and Sobi.

Results showed inhibitors developed in 26.1% of the patients treated with Advate. Similar rates were seen in patients treated with Kogenate, Xyntha, and Eloctate. The rate of inhibitor development was higher for Nuwiq, with 43.1% of the treated patients developing inhibitors.

In hemophilia B patients, inhibitor development was similar for plasma-derived products (10.5%), and standard half-life (7.6%), and extended half-life products (6.7%).

“Due to the low patient numbers, it was impossible to reliably compare inhibitor development for individual FIX concentrates,” the researchers wrote.

These “preliminary data suggest variation in inhibitor development among different SHL-rFVIII and EHL-rFVIII concentrates,” the researchers wrote, adding “these findings need confirmation by additional data collection and longer follow-up of cohorts.”