Dec 3, 2014

The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) has assessed three recent publications (1-3) in peer-reviewed scientific journals suggesting elevated alloantibody inhibitor rates for one specific product (Kogenate FS / Helixate NexGen) in previously untreated patients (PUPS) with hemophilia A (factor VIII deficiency) when compared to other recombinant factor VIII (FVIII) products. Each of these publications relies on the similarity of its individual observations and statistical analyses to strengthen their conviction that PUPs should not receive this product as their initial treatment until further research and analysis are conducted. The authors of these publications have all recognized the innate limitations of their own data to reach their conclusion.

The development of inhibitors is a known risk for all FVIII products. MASAC is concerned whenever new data associated with a specific product raise safety issues. Based on the totality of available and emerging scientific data, MASAC has determined that a precautionary Medical Advisory is warranted as the potential risk of harm outweighs the uncertainty around the conclusions of these publications.

MASAC believes that it is important for clinicians to fully discuss the risks of inhibitor development and the implications of these studies with their patients’ families when making the initial product selection decision for a PUP. Patients who have been treated with Kogenate FS / Helixate NexGen for a significant time period without forming an inhibitor can probably safely be continued on the product. No increased inhibitor risk has been found for previously treated patients (PTPs) with the use of this product.

In reaching its conclusion, MASAC also makes the following observations:

  • MASAC has considered that Kogenate FS / Helixate NexGen has been marketed for more than a decade with a good safety record.
  • In the UK study (3) the increased risk of inhibitors for Kogenate was found in the first eight years of the study, but not thereafter. An increased risk of inhibitors was also associated with the use of B-domain deleted products.
  • Recently presented European Haemophilia Safety Surveillance (EUHASS) data (6) indicate that there is not a signal for increased immunogenicity for Kogenate FS / Helixate NexGen.
  • The EPIC study (4, 5) indicated that Advate, when used in PUPs, was associated with an incidence of alloantibody inhibitors approaching rates similar to the three studies involving Kogenate FS / Helixate NexGen. EPIC, although a small study, had a very rigorous selection of patients based on their inhibitor risk. Small studies such as EPIC may generate results that are not totally reflective of the real world and can be misinterpreted as real findings. A full analysis of the EPIC study has not been published.
  • Collectively, the above referenced observations on the UK (3), EUHASS (6) and EPIC (4,5) data indicate that there may be a study design or analytical problem with the three Kogenate FS / Helixate NexGen publications, which led to their common conclusion. The differences in study conclusions may represent differences in study design and not innate differences among the treatment products.

MASAC urges healthcare providers to become knowledgeable about how the conclusions of the studies involving Kogenate FS / Helixate NexGen were reached, how the limitations of their study designs might have influenced their biostatistical conclusions and how these findings should be employed to influence therapeutic decision making.

The US Food and Drug Administration (FDA) has indicated that it will review the biostatistical approaches employed by the authors of these studies. However, no time line has been provided for this analysis. MASAC will work with the FDA to facilitate this independent analysis of the databases employed by these published studies.

The World Federation of Hemophilia (WFH) and the European Medicine Agency (EMA) have also issued statements on this topic, which are referenced below. (7-8)

Scientific knowledge about risk factors for developing an inhibitor and the immunogenicity of individual treatment products will continue to evolve. As additional analyses and data emerge, MASAC will review and update this advisory.


  1. Gouw SC et al. Factor VIII products and inhibitor development in severe hemophilia A. New Engl J Med 2013; 368(3): 231-9.
  2. Calvez T et al. Recombinant Factor VIII products and inhibitor development in previously untreated boys with severe hemophilia A. Blood 2014; DOI 10.1182/blood-2014-07-586347.
  3. Collins PW et al. Factor VIII brand and the incidence of factor VIII inhibitors in previously untreated UK children with severe haemophilia A, 2000-2011. Blood 2014; doi:10.1182/blood-2014-07-580498.
  4. Auerswald G et al. The EPIC Study: a clinical trial to assess whether early low dose prophylaxis in the absence of immunologic danger signals reduces inhibitor incidence in previously untreated patients (PUPS) with hemophilia A. ASH Abstract #576, Dec 9, 2013.
  5. Early Prophylaxis Immunologic Challenge (EPIC) study.
  6. Fischer K et al. Inhibitor development according to concentrate in severe hemophilia A: 4-year results from the EUHASS registry. Presented at World Federation of Hemophilia 2014 Congress; May 10-15, 2014; Melbourne, Australia.
  7. World Federation of Hemophilia. Third publication suggests recombinant FVIII product associated with higher risk of inhibitor development in newly diagnosed, previously untreated patients with severe hemophilia A. Statement issued Nov. 17, 2014.
  8. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Meeeting 3-6 November 2014. PRAC recommends further assessment of risk of developing inhibitors with Kogenate Bayer/Helixate NexGen.


PHYSICIANS: Please distribute this information to all providers in your area who treat patients with hemophilia.

CHAPTERS: Please distribute this information to your membership.

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This material is provided for your general information only. NHF does not give medical advice or engage in the practice of medicine. NHF under no circumstances recommends treatment for specific individuals and in all cases recommends that you consult your physician or local hemophilia treatment center before pursuing any course of treatment.