Inhibitors—antibodies to infused factor VIII or factor IX produced by the immune system, making treatment ineffective—are the foremost treatment complication faced by people with hemophilia today, associated with increased morbidity, increased mortality, and a greatly increased financial burden, said Dr. Mike Soucie of the U.S. Centers For Disease Control And Prevention (CDC) in the inhibitors session at the 2015 WFH Global Forum.
For clinicians and researchers, inhibitors are a multi- factorial event. To investigate inhibitors in a rare disease large international collaborations are required in the future. Following U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) inhibitor workshops in 2003 and 2005, the regulatory agencies stated that clinical trials are inadequate to assess risk and recommended long-term surveillance using registries.
Inhibitor surveillance in the U.S.
The U.S. Hemophilia Inhibitor Research Study (HIRS) was initiated in 2006 as a pilot project for prospective national inhibitor surveillance. Key findings of the HIRS study reported in 2012 confirmed that all hemophilia patients are at risk; the largest risk is in severe hemophilia A with an incidence rate of 25-30% during the first 50 exposure days. Inhibitors occur also in patients with mild hemophilia, patients with low-risk mutations, and patients with over 150 exposure days; although the risk for inhibitors after 150 exposure days is very rare. National inhibitor surveillance requires a standardized protocol specifying the patients to be tested, testing intervals, and standardized, centralized testing, Dr. Soucie emphasized.
FDA immunogenicity workshop
Inhibitors present numerous challenges to different stakeholders, noted Dr. Glenn Pierce, medical member of the WFH Board of Directors. For patients, caregivers, and the healthcare system, inhibitors present economic costs as well as human costs in terms of increased morbidity and possibility of life-threatening circumstances leading to mortality. For industry, inhibitor development during the production of new drugs presents added risks to drug development costs. The lack of predictive tools means antibodies are detected only in late phase 3 trials after significant expenses have accrued. For regulatory agencies, novel bioengineered products are becoming the norm, however, the immune consequences of neo-epitopes are difficult to evaluate and need large patient populations
Dr. Pierce presented a summary report on the FDA Public Workshop on New Methods to Predict the Immunogenicity of Therapeutic Coagulation Proteins, held in September 2015. The workshop focused on the genetic determinants of immunogenicity and highlighted the importance of well-characterized clinical samples. It also looked at resources such as hemophilia registries and databases, genotyping initiatives and biological samples and highlighted the importance of integrating data for better patient outcomes.
Novel engineered coagulation proteins emerging from the drug development pipeline present new concerns and greater risks have been identified for subsets of patients, Dr. Pierce said. “Virtually all biotechnology drugs provoke immune response in some patients, though usually just tiny fractions. However, the reactions are becoming of greater concern as the number of protein drugs increases.”
EMA workshop on hemophilia registries
The key challenge with hemophilia registries is that there is no overarching structure for how to manage, design or host data collection, said Dr. Anneliese Hilger of Germany’s Paul-Ehrlich Institute and the EMA. She presented a summary of the EMA workshop on hemophilia registries held in London in July 2015.
The workshop addressed a number of crucial questions, including whether the current number of hemophilia registries improve patient safety and lead to a better research in the field of hemophilia. Workshop participants reached a number of important consensus points on what is needed to improve hemophilia data collection. Ideally, every patient should be in a disease registry, and patients enrolled in clinical trials should remain in registries. Patient identifiers are needed to avoid overlap between registries and reduce double-counting. There is a need for collaboration among all stakeholders, and need for agreement with regulators and other stakeholders on a minimum protocol or dataset. Furthermore, it is important to link with the initiatives of other rare disease registries as there will be common issues. Finally, there is a need to harmonize national registries and promote and support more national registries and quality assurance.