And herein lies the speed bump on the prophylaxis innovation highway—the promise of excellent outcomes in children and adolescents has created the imperative to establish a viable health economic strategy for the adoption of bleeding prevention across the lifespan, and into the low- and middle-income countries where 80% of persons with hemophilia reside,35,36 that also incorporates the evolutionary experience with the next generation of EHL therapeutics.
The NHLBI is currently supporting research that may ultimately shape the pathway toward a precision medicine approach to prophylaxis and to the holistic care of individuals with hemophilia. The cornerstone of this effort is the NHLBI-wide program entitled Trans-Omics for Precision Medicine (TOPMed), which endeavors to further study cohorts in heart, lung, blood, and sleep science through genomic and transcriptomic characterization, data that will eventually made accessible to researchers worldwide through dbGAP and other data commons.37 Included in TOPMed is a cohort of 5142 US individuals with hemophilia A who had had baseline FVIII genotyping performed through the national My Life Our Future project. In a separate NHLBI-supported initiative, the PhenX tool, developed by the NIH,38 is being used to develop standardized measures to characterize hemophilia phenomic data.
Furthermore, NHLBI is working with the hemophilia community to establish a national blueprint for the design of prospective cohorts that leverage national data collection and incorporate standard measures for prioritized outcomes, including patient-reported outcomes. Informatics, biobanking, and ethics expertise from within the NIH and the scientific community is being mobilized to create models for direct data transfer from electronic medical records, as well as policies for centralized biobanking, and streamlined data sharing for individual patient-level data. This project is prioritizing the engagement of persons with hemophilia, exploring private-public funding partnerships, and maximizing training opportunities in epidemiology and data science to ensure the long-term role of strategic national data and biospecimen collection in the future precision medicine approach to risk stratification and therapeutic decision making in hemophilia.
While the past few decades have ushered in tremendous progress in the prevention of hemorrhagic and transfusion-transmitted complications of hemophilia and its treatment, they have also seen minimal mitigation, if not intensification, of a complication that has the potential to negatively impact the lifelong healthy outcomes that individuals with even severe disease and access to primary prophylaxis have come to routinely expect. This treatment-related complication is the development of a polyclonal neutralizing anti-FVIII IgG4 antibody that predominantly occurs in 25% to 30% of children with severe hemophilia A after a median number of 14.5 exposures to FVIII replacement therapy at a median age of 15.5 months.39,40 These anti-drug antibodies (ADAs) bind to FVIII with type 1 kinetics, effectively inhibiting infused FVIII activity and, thus, referred to as inhibitors.41 The increased morbidity and mortality associated with inhibitors that cannot be eradicated in a timely way, particularly if high titer (≥5 Bethesda Units [BU]),21 have been well documented.42,43 Neutralizing antibodies also occur less frequently in nonsevere hemophilia, usually in response to intensive FVIII replacement in the setting of trauma of surgery, and impact the phenotype is a significant but distinctive manner.44 The natural history of this phenomenon and associated risk factors have been well documented through the study of the European INSIGHT cohort.45–48 Furthermore, neutralizing polyclonal, predominantly IgG4, anti-FIX antibodies also occur in 2% to 4% of severe hemophilia B patients, and can produce a unique and therapeutically challenging clinical phenotype characterized by anaphylaxis and largely associated with the null genotype.49–52 Due to their high frequency and disproportionate impact on hemophilia clinical outcomes, this article will focus on the scientific gaps, therapeutic innovation, and ongoing challenges related to FVIII antibodies developing in severe hemophilia A.
The current knowledge about the combination of host and environmental risk factors that trigger the innate immune system in the presence of immune “danger signals” have been studied and frequently reviewed, most recently within the last few years39,40,53,54 (Fig. 2). Predictive modeling of FVIII inhibitor development has been attempted, but has so far been limited by an incomplete understanding of the risk factor landscape.55
There has been significant focus on the contribution of FVIII product type (von Willebrand factor-containing plasma-derived vs recombinant)39,56–64 and recombinant FVIII brand65,66 to the risk of ADAs, much of which has intensified rather than settled the controversy surrounding this issue. Retrospective studies mostly suggest an increased ADA risk with recombinant FVIII; however, the largest prospective cohort study (RODIN) failed to ascertain a difference in risk.39,67 Conversely, the international randomized SIPPET trial of 251 mostly previously untreated pediatric patients (PUPs) with severe hemophilia A did demonstrate a significant 87% increased risk of cumulative incidence (CI) of all inhibitors on recombinant FVIII (rFVIII) when compared to plasma-derived (pdFVIII), as well as a similar trend for high titer antibodies.68 Debate persists about the impact of these results on the complex clinical decision-making process involved in the choice of treatment product type for young hemophilia children, especially given that the CI of all inhibitors was still substantial with the use of pdFVIII (27%), and that the rFVIII product landscape is still rapidly evolving to include novel recombinant biologics that could potentially mitigate inhibitor risk.69–71
However, the SIPPET study outcomes provide the strongest rationale to date for post-translational variation between recombinant and plasma-derived FVIII as potential key determinants of the protein's unique immunogenicity among serine proteases in the coagulation cascade.72–74 Currently, the lack of sufficient actionable knowledge about FVIII immunogenicity constitutes the major remaining speed bump on the innovation highway toward predictably healthy outcomes in severe hemophilia A. Epidemiological and clinical research on FVIII inhibitors has been robust. But future progress may now depend on bringing bedside observations back to the laboratory to inform the mechanistic study of FVIII immunogenicity, the identification of novel druggable targets for inhibitor eradication and tolerance induction, and, ultimately, the rationale design of new biologically active FVIII therapeutics with reduced immunogenicity to minimize or entirely prevent the development of ADAs.75
With this goal in mind, NHLBI convened a group of experts in early 2015 to assist in identifying critical scientific gaps in our mechanistic understanding of FVIII immunogenicity. NHLBI issued a funding opportunity announcement https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-18-014.html in 2017 to stimulate and facilitate the critical science identified by panel of experts from within and outside the field. NHLBI proposed to do this by funding Research Centers of Excellence that would use interdisciplinary teams and bold new approaches to identify FVIII protein-specific triggers and mechanisms underlying the development of anti-FVIII neutralizing antibodies. Applicants in actively engaged disciplines were required to propose basic and translational research that incorporated emerging sciences and technologies that were not yet being exploited in the investigation of FVIII immunogenicity. Collaborations in trans-Omics, glycobiology, the microbiome, and in silico protein design were encouraged. Finally, applicants were required to propose a curriculum to cross train the next generation investigators in interdisciplinary skills development. Teams of interdisciplinary scientists initiated their NHLBI-funded investigation and training activities in 2018.
But even as investigators pursue the science of FVIII immunogenicity, there remains a persistent urgent need to treat individuals with high titer inhibitors with products and strategies that bypass the requirement for FVIII replacement; expediently control acute bleeding in the absence of FVIII; and effectively prevent chronic hemorrhage-associated musculoskeletal morbidity. Bypass therapy with prothrombin complex concentrates (PCCs) was first proven to be effective in the control of acute bleeding in seminal placebo-controlled trials published over 30 years ago by Lusher et al.76,77 Contemporaneously, Hedner and Kisiel reported on the efficacy of recombinant activated factor VII (rFVIIa) as a therapeutic FVIII bypassing agent in 2 hemophilia patients with high titer inhibitors.78 By the 1990s, the principle of procoagulant-driven bypass therapy governed the approach to the treatment and prevention of hemorrhage in the presence of inhibitors. An activated PCC (aPCC) and rFVIIa, intravenously administered alone or in combination, became and remained the mainstay of bleeding control for almost 3 decades, with comparable 80% to 90% efficacy for musculoskeletal hemorrhage,79 and a similar 60% efficacy in bleeding prophylaxis, inferior to the effectiveness of bleeding prophylaxis in the absence of inhibitors.80,81
However, during the past 3 years, a plethora of novel strategies to control hemorrhage in the absence of FVIII or FIX replacement have been proposed (Table 7).82–93 None of these novel agents would be expected to induce or be inhibited by anti-FVIII (or FIX) antibodies. Furthermore, the potential to administer these therapeutics subcutaneously and on a weekly to monthly schedule promises to appreciably improve quality of life in this population in a way that has not been feasible with traditional protein replacement.
The premise underlying most of these approaches is that rebalancing hemostasis would physiologically offset the bleeding diathesis created by a severe deficiency in FVIII or IX, with or without circulating neutralizing antibodies. Two of these novel therapeutics are currently in clinical trials. Phase 3 trials of an antithrombin short interfering RNA (siRNA), Fitusiran (ALN-AT3SC; Alnylam Pharmaceuticals, Sanofi, Cambridge, MA, USA) are ongoing in patients ≥12 years with severe hemophilia A and B, with (ATLAS-INH; NCT03417102) and without (ATLAS A/B; NCT03417245) inhibitors. A patient death from cerebral sinus thrombosis in the preceding Phase 2 trial of this agent required FDA review and replacement dose modification prior to resumption of the Phase 3 trials. Clinical trials of 3 different monoclonal antibodies to tissue factor pathway inhibitor (TFPI) are also ongoing. These include 2 Phase 2 proof of concept studies of concizumab, an IgG4 monoclonal antibody that targets the Kunitz 2 (K2) TFPI domain, in adult hemophilia A and B subjects with inhibitors (explorer 4; NCT03196284, Novo Nordisk A/S, Bagsværd, Denmark) and in adult hemophilia A individuals without inhibitors explorer 5; NCT03196297); a Phase 2 multidose trial of PF-06741086, an IgG1 monoclonal antibody that also targets the K2 TFPI domain, in adult hemophilia A or B participants with or without inhibitors (Pfizer; NCT02974855); and a Phase 1 single escalating and multiple dose study of BAY 1093884, an IgG2 monoclonal antibody that targets both the TFPI Kunitz 1 (K1) and K2 domains, in severe hemophilia A and B with and without inhibitors (Bayer, Berlin, Germany; NCT025571569).
A truly disruptive innovation in effective therapeutics delivery for patients with severe hemophilia A with and without inhibitors has come from the development of emicizumab (ACE910), a bispecific antibody that functions as a FVIIIa-mimetic in the tenase-generating complex with factors IX and X88,90,91,94,95 (Table 7). Despite some limitations in study design, the initial Phase 1/2 trial in a Japanese cohort reported an impressive short-term decrease in annualized bleed rate, regardless of FVIII inhibitor status, in most subjects with historically severe bleeding phenotypes receiving weekly emicizumab prophylaxis at 1 of 3 escalating doses.96 These results were replicated in the subsequent Haven 1 Phase 3 trial of 109 hemophilia A participants with inhibitors aged ≥12 years who received 4 weekly subcutaneous 3 mg kg−1 doses of emicizumab followed by 1.5 mg kg−1 weekly for 24 weeks (NCT02622321).97 The ABR of 2.9 events (95% confidence interval [CI], 1.7–5.0) among participants who were randomly assigned to emicizumab prophylaxis represented a statistically significant 87% decrease compared with those assigned to no prophylaxis.97 The prophylactic efficacy demonstrated in this study was pivotal to US licensure of this therapeutic in November 2017 (Hemlibra, Roche, Genentech, San Francisco, CA, USA)98 followed by European registration in February 2018.
Since its licensure in the United States, the demand for emicizumab has been high among hemophilia A patients with and without inhibitors, despite unresolved issues with laboratory monitoring, and the safety signals (5 episodes of thrombosis and/or thrombotic microangiopathy, including 1 fatality from hemorrhage after the TMA had resolved) associated with the concomitant use of high-dose aPCC administration for breakthrough bleeding noted in the HAVEN 1 trial.97 Although the therapeutic conditions associated with these severe adverse events have led to clinical recommendations for the concomitant use of bypass therapy (https://www.hemophilia.org/sites/default/files/MASAC-Update-on-the-Approval-and-Availability-of-the-New-Treatment.pdf), no pathophysiologic explanation has yet emerged. Furthermore, the development of ADAs to emicizumab, noted in the and original pharmacokinetic studies conducted in healthy volunteers90,91 but of previously uncertain clinical significance, has now been reported in a single HAVEN 2 trial participant in whom the drug was rendered ineffective (https://www.hemophilia.org/Newsroom/Medical-News/MASAC-Safety-Information-Update-on-Emicizumab-HEMLIBRA).
The unprecedented and simultaneous emergence of multiple-novel therapeutics for the prevention of bleeding in hemophilia with and without inhibitors, and their rapid pathway to licensure and subsequent penetration into the standard of care based on short- and medium-term efficacy data, represent the paradigm of the hemophilia innovation highway. But definitive speed bumps are arising from an incomplete and evolving safety profile and an incomplete understanding of how to optimize their incorporation into an individual's comprehensive care plan. In the case of emicizumab, there are many questions with no immediate answers. If proven effective in the longer term, will its early use in primary prophylaxis alter the epidemiology of FVIII inhibitors? If less effective in preventing major hemorrhage from trauma or during surgery, what will be the immunologic consequences of FVIII rescue in an inflammatory state? Should its use for bleeding prophylaxis in inhibitor patients supplant initial attempts at inhibitor eradication, replace bypassing agents during traditional immune tolerance induction, and/or primarily provide a safe alternative to failed immune tolerance? The answers will come in time, but not without strategic data collection from which to develop precise models for individual inhibitor prediction, and well-designed and executed clinical trials to optimize personalized intervention. Consequently, these questions and more have been prioritized in NHLBI's approach to the development of a blueprint for future clinical, translational, and basic science research in FVIII immunogenicity and inhibitor prevention and eradication.
These are both exciting and challenging times in the history of hemophilia. In times of tremendous innovation and therapeutic progress, numerous new questions arise as old problems are solved, and with them, the responsibility to take stock and shape new paradigms through emerging science and technology. There has never been a more critical need to bring substantial data to the table to craft the next generation of solutions, nor a more promising toolkit with which to do so.
The author thanks Drs Lindsey George and Steven Pipe for their critical review of this article.
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