A second review of two recombinant factor VIII products that treat hemophilia A indicates they are not associated with an increased risk of developing counterproductive antibodies in previously untreated patients (PUPs), the European Medicines Agency (EMA) announced today.

The subjects of the review were Kogenate Bayer and Helixate NexGen, man-made versions of the blood-clotting proteins that are missing or defective in patients with hemophilia A. Both products are made by Bayer Pharma AG.

The EMA's Pharmacovigilance Risk Assessment Committee (PRAC) had first studied the risk for factor VIII inhibition in 2013 after a study published in the New England Journal of Medicine reported that roughly a third of previously untreated children with hemophilia A developed antibodies against the two products. Inhibition development is a known risk for factor VIII products, but the study said the risk was higher for second-generation recombinant products such as Kogenate Bayer and Helixate NexGen compared with third-generation counterparts.

After reviewing this study and other available data, which included that from the European Hemophilia Safety and Surveillance System, PRAC concluded that the evidence did not point to Kogenate Bayer or Helixate NexGen as having an increased risk of developing factor VIII antibodies compared with other products. Both the EMA's Committee on Human Medicinal Products and the European Union's executive branch, the European Commission, agreed.

However, PRAC undertook a second review after two studies published in Blood in 2014 again suggested that PUPs with hemophilia A who take Kogenate Bayer and Helixate NexGen may be at a greater risk for factor VIII inhibition. The committee conducted a meta-analysis of the raw data from the two studies in Blood and the one in the New England Journal of Medicine. The findings suggested there was more antibody development with Kogenate Bayer compared with a third-generation recombinant factor VIII product called Advate (Baxalta US Inc). The company found a similar pattern with other factors, but "the results were even less pronounced due to sample size constraints."

"Although the meta-analysis was well conducted, the PRAC noted several limitations including the possibility of residual confounding," the EMA said in a news release. "Furthermore, the PRAC acknowledged that inhibitor development is multifactorial, where a number of parameters may have an impact on the incidence in PUPs, and that adjusting for all of these factors in the analyses may not be possible.

"The PRAC also noted that there has been no signal for a similar trend of increases in inhibitor incidences with Kogenate Bayer in previously treated patients in other studies, a population where the experience with this product is large."

Overall, PRAC said, the available evidence does not confirm that Kogenate Bayer and Helixate NexGen carry a relatively higher risk for factor VIII inhibition in PUPs compared with other products, which is the same conclusion reached in its 2013 study.

PRAC recommended that manufacturers of recombinant factor VIII products should monitor the scientific literature for new evidence regarding antibody development.

More information on the PRAC study is available on the EMA website.

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