On two rainy days in May 2018, more than 200 researchers, clinicians, pharmaceutical industry representatives, government officials, and patient advocates from nine countries gathered at the National Institutes of Health’s Bethesda, Maryland, campus for a National Heart, Lung, and Blood Institute (NHLBI) State of the Science (SOS) Workshop.
Their goal was to create a national blueprint for research on the most significant and costly complication affecting those with hemophilia: factor VIII (FVIII) immunogenicity, which occurs when a person develops antibodies against factor concentrates, rendering the therapy ineffective. These antibodies, known as inhibitors, affect about 30% of those with hemophilia A, primarily in infancy and childhood.
A Much-Needed Meeting
“It’s not surprising that the patient’s immune system mounts an immune response to the factor,” says Steven W. Pipe, MD, who directs the Pediatric Hemophilia and Coagulation Disorders Program at the University of Michigan. “This is the most prevalent adverse consequence of treatment with factor products.”
And yet, despite its prevalence, there had been little advancement in the field in nearly 50 years. “The idea of the SOS was to see if we could bring research groups from a wide variety of fields to look at this problem in new ways to advance the science in this area,” Pipe says. “What infrastructure do we need in order to learn more from patients? What data systems do we need? How do we design trials?”
“Before the State of the Science meeting, there really hadn’t been a national focus to come up with a way forward,” says the American Thrombosis and Hemostasis Network chief science officer and Oregon Health & Science University pediatric hematologist Michael Recht, MD, PhD. “There were a lot of supersmart people thinking about inhibitors. But there wasn’t a unified approach to how to address the issues with inhibitors.”
The SOS, he says, provided a road map for the research needed to understand why people developed inhibitors; to devise strategies to avoid inhibitor development; and, if they still developed inhibitors, to prevent the long-term complications that may occur.
“The SOS set a series of research priorities that we needed in order to better understand the risk for inhibitor development,” says W. Keith Hoots, MD, who directs the Division of Blood Diseases and Resources at the NHLBI. That included studies to characterize the immune responses for babies and children with severe hemophilia before, during and after early exposures to factor replacement.
Such research is difficult and costly, he says, and yet that was exactly what SOS participants advocated for, including identifying contributing factors to inhibitors from parental immunity and events during pregnancy and delivery.
The workgroups also recommended significant changes in the design of clinical trials; a blueprint for creating a biorepository and conducting clinical trials, including involving patients in determining outcomes; and priorities for basic and translational research into FVIII immunogenicity.
Fast Forward to Today
Three years later, says Pipe, “we’ve made progress on all fronts.” That includes clinical trials and the start of a biorepository.
“Many of the changes are evolving,” says Margaret Ragni, MD, of the University of Pittsburgh, who helped organize and lead the 2018 summit. However, she adds, “this is not an overnight phenomenon.”
Ragni co-chaired the working group on clinical trials charged with identifying ways to overcome some of the challenges inherent in conducting research into a rare disease. Such trials require multicenter cooperation, she says, but were too often siloed in separate institutions. “It’s a shame because this is a rare disease and it can take years to get answers,” she says. “We need to have a way to make this happen more quickly and get the trials running more efficiently.”
Her group’s recommendations now form the foundation of the INHIBITOR clinical trials platform, including the creation of a Hemophilia Clinical Trials Group (HCTG) collaborative.
The platform is composed of two multicenter studies: the Inhibitor Prevention Trial and the Inhibitor Eradication Trial. The multicenter studies launched in 2020, and both are still recruiting. They will be conducted in the same hemophilia treatment centers (HTCs) with the same physicians, coordinators and protocols, which should greatly improve efficiency and lead to faster results, Ragni says.
The studies use an adaptive design in which results accumulated during the trial can be used to make changes in the trial design while it is ongoing. For instance, if one arm fails it is stopped and a new arm, with different drugs, is added. Plus, as new treatments for the disease emerge, they can be incorporated into the ongoing trials.
In the INHIBIT Trials, which are linked Inhibitor Prevention and Inhibitor Eradication trials, the platform design allows for efficiency, so sites use the same blood draw frequency, data forms and labs for both trials, Ragni says. Further, data from historic controls are incorporated into the trial, thus reducing the sample size needed. “This is ideal for a rare disease,” Ragni says.
The prevention trial is studying 66 previously untreated children ages 4 months to 4 years with hemophilia who are randomly given either factor VIII-Fc fusion protein, shown in some studies to prevent or delay inhibitor formation, or the monoclonal antibody emicizumab for 48 weeks. Patients who develop inhibitors during this time can then enroll in the eradication trial, where they will be randomly given either FVIII immune tolerance induction plus emicizumab or immune tolerance induction alone.
Another recommendation from the 2018 summit was for greater engagement of the patient community. That’s now happening through the National Hemophilia Foundation’s (NHF) Community Voices in Research, in which patients and their families provide their input during clinical trial planning, and Ragni says there’s greater incorporation of patient-related outcomes in clinical trials. The INHIBIT trials’ protocols, for instance, planned to hold town meetings and seek feedback from local NHF chapters.
The recommendation for a registry to track patients over time is also now a reality, with the American Thrombosis & Hemostasis Network spearheading the ATHN Transcends study. It is designed to provide a secure method to collect long-term safety and efficacy data on the multitude of new therapies emerging in genetic and acquired blood diseases, including hemophilia, as well as track the natural history of the diseases, including inhibitor formation.
All the clinicians interviewed here noted that in 2018, emicizumab had not yet been approved. “But those of us who were participants in those trials had a good understanding of the life-changing aspects of that medication,” Recht says.
Now, says Pipe, it’s time to learn more about the therapy. For instance, will the very young children, including infants, starting on emicizumab develop inhibitors later because they’re not getting FVIII as often? “I don’t think we were really able to anticipate all the new questions that came up with the use of this drug,” he says, “because there was just so little experience with using it.”
While the 2018 meeting was critical in moving the field forward, much work remains. So in September 2021, NHF held a four-day, virtual State of the Science Research Summit to design and implement a national research blueprint that addresses the priorities voiced by the bleeding disorders community.
“I think we’re capturing a much larger vision,” Pipe said, in an interview prior to the meeting. He hoped the September meeting would establish a new agenda of research priorities.
“There was a lot of momentum coming out of the 2018 meeting,” said Recht, who co-chaired the September summit. “COVID derailed that. What I’m really hoping with the NHF State of the Science summit is that we get that momentum back and are able to keep ourselves accountable for the results that come out of the meeting.”
Ragni predicted that the NHF’s summit would “propel the effort forward and promote the collaboration and networking and partnerships we so greatly need to keep up the momentum.”
On the inhibitor side, Recht said: “My hope is that the working group looking into issues about inhibitors will take what we developed in 2018 and use that to say, ‘OK, this is what we were thinking three years ago, we’re now three years further. Is there anything else we have to change? Or do we just move forward?’”
In an interview prior to the meeting, Hoots said the summit “should further the discussion concerning the pathobiology of inhibitor development while building on the needed resource development required to expand research in all areas of inherited bleeding disorders.” He added that it will also “incorporate discussions on gene therapies and the clinical impact of new protein therapeutics such as emicizumab on inhibitor development and other hemophilic complications.”
“I think the two successive SOS efforts will be complementary and will further the downstream scientific agenda for care and research in the bleeding disorders arena,” he said.
Although similar, there was what Leonard A. Valentino, MD, NHF president and CEO, called a major “twist” between the NIH and NHF State of the Science meetings. “That was to bring in the extensive patient voice to ensure we had as many opportunities as possible to hear what is impactful for people with these disorders and where there are gaps in care,” he said.
Pipe said that even though they did have patient participation in the State of the Science for inhibitors, “now we have to magnify that, so patients are involved from the beginning.”
Thus, patients and advocates served on the organizing and steering committees of NHF’s meeting to help develop priorities for the summit. Several also gave presentations during the meeting.
“We have to make sure we’re addressing the questions that are important to the patient,” Recht said. “As a clinical researcher for the past 25 years, I’ve come up with a lot of ideas that I think have been very important.” But the State of the Science meetings, he said, “were really the first time that the patient voice was coming forward and helping define the important questions for them.”
NHF’S First SOS Summit
NHF’s inaugural State of the Science Research Summit in September 2021 was organized by Donna M. DiMichele, MD, the former deputy director of the Division of Blood Diseases and Resources at NHLBI, who also spearheaded the 2018 meeting.
DiMichele used the same blueprint for the 2021 meeting, says NHF President and CEO Leonard A. Valentino, MD, which included working groups meeting for months prior to the summit to develop recommendations.
Topics included research priorities for hemophilia A and B and other ultra-rare inherited bleeding disorders, which group leaders highlighted during the meeting. The participants also presented recommendations for research priorities for diversity, equity and inclusion in health services research, and implementation science around the health of women, girls and those with the potential to menstruate. For more information, visit hemophilia.org/summit.
Key Recommendations From the NIH Summit
The NIH’S State of the Science meeting on inhibitors yielded a rich array of recommendations in four areas:
- Develop scientific priorities for clinical trials on integrating nonintravenous, nonfactor therapeutics, including gene therapy, into the standard of care for people with hemophilia A and inhibitors.
- Identify scientific priorities for 21st‐century data science and biospecimen collection that could be used for observational studies.
- Determine the scientific priorities for understanding FVIII immunogenicity and the immunology of the person’s response and FVIII tolerance.
- Create prospective pregnancy/birth cohorts to study FVIII immunogenicity, inhibitor development, and eradication.