In May 2018, more than 200 people representing scientific researchers, hemophilia patients, advocates, clinicians and the pharmaceutical industry gathered in Bethesda, Maryland, for the two-day National Heart, Lung, and Blood Institute (NHLBI) State of the Science (SOS) Workshop “Factor VIII Inhibitors: Generating a National Blueprint for Future Research.”
Attendees went to the National Institutes of Health campus to develop ways to better track and research the formation, prevention and treatment of factor VIII (FVIII) inhibitors, antibodies that destroy infused clotting factor. While groundbreaking progress has been made in hemophilia treatment, inhibitors remain the most burdensome, and most expensive, hemophilia complication.
Inhibitors at a glance
Studies show that people with hemophilia and inhibitors are twice as likely to be hospitalized for bleeding episodes, experience more joint bleeds and joint disease, report a reduced quality of life and have a greater risk of death than those without inhibitors. In addition, the overall cost of care for a person with an inhibitor is four to five times greater than it is for someone with hemophilia without an inhibitor, exceeding $1 million a year in some cases.
Anyone, regardless of age or diagnosis, can develop inhibitors, but they are most common in people with severe hemophilia A, affecting 20% to 30% of people within this group. Other risk factors include a family history of inhibitors, ethnicity (blacks and Hispanics are at higher risk) and the type of hemophilia gene mutation. Despite these known factors, accurately predicting who will develop inhibitors is difficult, as is their prevention and treatment.
Against this backdrop, the SOS Workshop’s goal was to “solicit input from all constituencies within the US hemophilia community, as well as international collaborators, into the development of a coordinated and collaborative national blueprint for future basic, translational, and clinical research focused on factor VIII (FVIII) immunogenicity and FVIII inhibitor prevention and eradication,” stated an executive summary of the workshop’s proceedings published in the journal Haemophilia.
The 2018 SOS Workshop evolved from a multi‐stakeholder summit on inhibitor monitoring held in January 2017 by the Centers for Disease Control and Prevention’s (CDC) Division of Blood Disorders. That summit identified the need for a national coordinated scientific agenda on inhibitors.
Following the January summit, the National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council’s (MASAC) Inhibitor Prevention and Eradication Working Group, in collaboration with the NHLBI, developed the concept of the SOS Workshop. The MASAC group established four working groups to identify priorities and make recommendations. The makeup of these working groups was intentionally diverse, encompassing researchers and people with hemophilia, along with representatives from patient advocacy groups, hemophilia treatment centers and the pharmaceutical industry. The working groups’ findings were presented for discussion at the SOS Workshop and also published in four separate articles in the journal Haemophilia.
Working Group 1
Aim: Establish scientific priorities and innovative implementation strategies to conduct inhibitor prevention and eradication trials.
At the workshop and in Working Group 1’s Haemophilia article, “The national blueprint for future factor VIII inhibitor clinical trials,” it proposed two clinical trial concepts, one for inhibitor prevention and one for inhibitor eradication.
The prevention trial concept would consider whether weekly treatment with emicizumab (Hemlibra) combined with FVIII concentrate is “superior to weekly FVIII alone in reducing the rate of inhibitor formation” in people with severe hemophilia A. The eradication trial would test “the capacity of gene therapy to induce FVIII tolerance or to break FVIII tolerance following gene transfer” in adults with severe hemophilia A and inhibitors in whom immune tolerance induction has not been successful.
The working group’s article also outlined a plan for a Hemophilia Clinical Trials Group Infrastructure, which would include federal partners, foundations, industry, insurers, consumers and professional societies. This group would vet and prioritize trial concepts with the goal of developing “scientifically valid and time‐sensitive clinical trials.”
Working Group 2
Aim: Assess the current state and recommend the best future state for 21st century data and biospecimens collection across the life span in support of the US clinical research enterprise.
In its Haemophilia paper, “The national blueprint for 21st century data and specimen collection and observational cohort studies,” Working Group 2 identifies “data management, standardization and harmonization challenges” that prevent “the exchange of data across systems.” It also highlights that “a national systematic biospecimen collection does not currently exist.”
To achieve progress in research and care, the working group recommends that the data collection system “receive standardized and harmonized data from multiple patient‐ and clinician‐generated sources” and calls for the creation of a centralized biorepository with “the capability to perform real‐time processing of samples.” These actions are key to maximizing the scientific data obtainable from the limited pool of people with inhibitors.
The working group also identified other areas for advancement, including utilizing and supporting HTCs in data and specimen collection; engaging people with hemophilia in all stages of studies and providing study participants timely feedback; training care providers and researchers in human subject research protection; and training researchers, clinicians and study participants in data sharing issues.
Working Group 3
Aim: Develop the scientific priorities for acquiring an actionable understanding of FVIII immunogenicity and the immunology of the host response and FVIII tolerance to inform predictive models for inhibitor development and novel therapeutic targets.
Given its charge to prioritize basic and translational research into the immune response to FVIII to better predict inhibitor development and new ways to treat inhibitors, Working Group 3 outlined three goals. The group weighted the goals “based on required effort and potential impact and identified approaches, methods/technologies and models to complete the studies.”
The three objectives were summarized in the group’s Haemophilia journal article, “The national blueprint for future basic and translational research to understand factor VIII immunogenicity.” The first priority is studying “activation signals and immune regulation that shape the response to FVIII.” Second is the “utility of non-animal approaches (in silico, genetic, -omics, in vitro) to help predict inhibitor formation.” Third is “how does the site of FVIII expression, its structure and von Willebrand factor determine immunogenicity and tolerance?”
Working Group 3 also outlined strategies for biospecimen collection and suggested that “advancing basic science and clinical immunology in the field of FVIII inhibitor formation would greatly benefit from recruitment of scientists from various disciplines.”
Working Group 4
Aim: To consider the design of longitudinal studies beginning in the antenatal/neonatal period and the use of new technologies to better understand hemophilia inhibitors.
Although it is possible for inhibitors to develop at any age, generally they occur in young children soon after starting FVIII infusion. As Working Group 4 notes in its Haemophilia journal article, “The national blueprint for pregnancy/birth longitudinal cohorts to study factor VIII immunogenicity,” the fact that inhibitors typically develop early in life “supports the hypothesis that the ability of the immune system to respond to exogenous FVIII is established during the antenatal/neonatal period.” Thus, studying children in utero and as newborns “would offer the first insights into the factors that influence inhibitor development prior to the first exposure” to FVIII.
Accomplishing the above requires enrolling pregnant carriers of hemophilia, and their children, into the long-term group study. Working Group 4 suggests this could be accomplished through outreach by HTCs, CDC, and through public awareness campaigns by bleeding disorders organizations like NHF and the Foundation for Women & Girls with Blood Disorders. The working group notes that “patients and families with hemophilia have been very receptive to research.”
Of course gathering data and specimens from this new cohort is the first step. The working group also addressed how “technical advances in -omics and computational biology could bring new insights in this area and enable work in small samples.” And the working group highlighted how “cross‐disciplinary expertise will be necessary for breakthrough discoveries in hemophilia,” suggesting cross-disciplinary training for experts in fields like hemostasis, immunology, genomics, epidemiology, bioethics, biostatistics and data science.
“The impact of the SOS can already be seen in the designs of research studies launching or being developed through the American Thrombosis and Hemostasis Network,” Steven Pipe, MD, MASAC chair and medical director of the Pediatric Hemophilia and Coagulation Disorders Program and medical director of the Special Coagulation Laboratory at the University of Michigan, says. “This research is establishing cohort studies in previously untreated patients and cohorts designed to describe the impact of new therapies such as emicizumab and gene therapy.” Also, Pipe says, “New grants through the NHLBI will be focused on implementing the principles for research identified at the SOS. I would also anticipate that international research groups will look to implement these core research principles to advance insights on inhibitor prevention and eradication.”
Accomplishing the goals of the SOS Workshop will require improvements in research infrastructure, enhanced funding and a commitment to expanded training within the broader research community. “The infrastructure needs and implementation of prospective cohorts will need time to be addressed properly,” Pipe says. These are all key elements if the National Blueprint for Future Research on inhibitors is to succeed.
In an executive summary, the Workshop Executive Steering Committee acknowledged another essential element to success—the hemophilia community itself. “The engagement of the entire hemophilia community is crucial to the success of the future national research enterprise,” the authors wrote. “People with hemophilia and their families are at the core of data and sample collection within this national blueprint for inhibitor research over the life span. Ideally, the perspective of people with hemophilia would be sought and considered within all of the scientific objectives within this national blueprint.”