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Assistant Professor of Pediatrics
Department of Hematology
Boston Children's Hospital
Harvard Medical School
Stacy E. Croteau, MD, MMS, has disclosed that she has received consulting fees from Bayer, Biomarin, CSL-Behring, and Pfizer and funds for research support from Novo Nordisk and Spark Therapeutics.
Innovative bleed treatment and bleed prevention therapies, expanding use of national and multinational data registries, and novel patient-reported outcome tools continue to augment our clinical care of individuals with hemophilia. The 2020 ASH annual meeting captured the progress within each of these domains and offered providers important insights into current best practices for hemophilia management as well as emerging therapies.
Managing Hemophilia and Its Complications Along the Age Spectrum
Early initiation of hemophilia prophylaxis has been difficult due to the need for IV access and the risk of inhibitor development. In 2016, the SIPPET study suggested a reduced immunogenicity of pd-FVIII concentrates compared with rFVIII products; extended half-life concentrates were not included in this trial. The final results of the PUPs A-long study, investigating the use of rFVIII-Fc concentrate in previously untreated patients, did not demonstrate increased risk of inhibitors in the 87 patients who completed the study compared with published inhibitor rates (Abstract 509). Use of emicizumab in the previously untreated patient (PUP) population is also expanding, and clinical trials are ongoing (NCT04030052, NCT04431726). The ASH educational spotlight on emicizumab highlighted clinical considerations for initiating emicizumab in infants, of importance, the potential to prevent life-threatening bleeding such as intracranial hemorrhage as well as early hemarthrosis that sets the stage for hemarthropathy.
As the life expectancy for individuals with hemophilia approaches that of the general population, evaluation of the incidence and clinical impact of age-related comorbidities including hypertension and other cardiovascular risk factors has become increasingly important. Germini and colleagues used the PROBE (patient-reported outcomes, burdens, and experiences) tool to assess the aging hemophilia population and identified a steeper decrease in health status and quality of life in individuals with hemophilia compared with same-age unaffected individuals (Abstract 2529). Nichol and colleagues identified increased depressive symptoms (assessed by SF-12) among adult patients with hemophilia A participating in the Hemophilia Utilization Group studies (Abstract 2530). This was accentuated among those who had less than a high school diploma, were unemployed, had self-reported joint pain, or reported barriers to accessing care.
Emerging Data for Nonfactor (Substitutive and Rebalancing) Therapies
The need for frequent IV infusions to prevent bleeding and the limited prophylaxis options for individuals with FVIII or FIX inhibitors spurred innovation of nonfactor therapies, broadly classified as substitutive (FVIIIa mimetics) or rebalancing (inhibition of anticoagulant proteins) therapies. Escobar and colleagues presented data from the phase IV emicizumab prophylaxis minor procedure study that evaluated periprocedure hemostasis in 13 participants (Abstract 1786). A high proportion of patients (70% of those with inhibitors, and 100% of those without inhibitors) did not experience bleeding requiring factor concentrate or bypassing agent administration. The study was terminated early due to poor enrollment and paucity of surgery types, limited to CVAD removal and dental procedures. This may have been related to the requirement that only reactive use of FVIII concentrates or bypassing agents was permitted. Further investigation of the perioperative hemostatic needs for individuals undergoing other types of minor surgery and major surgical procedures is needed.
Fitusiran, a RNAi therapeutic targeting antithrombin, continues in phase III clinical trials; however, concerns with thrombotic events have resulted in more than 1 clinical trial pause, most recently in the fall of 2020. Post hoc analysis from the phase II OLE study analyzed 258 treated bleeds in 15 participants, most of which were mild, spontaneous, and hemarthroses (Abstract 511). Within the larger study population (N = 34), 2 thrombotic events were reported. It is hypothesized that antithrombin levels of 20% to 30% may represent the ideal therapeutic window, with diminishing improvement in hemostasis and marked increase in thrombotic risk with levels < 20%. Improved health-related quality of life as assessed by the physical health domains of the Haem-A-QoL was reported for patients with hemophilia A or B with inhibitors phase I study participants (Abstract 877).
Two monoclonal antibodies targeting the K2 domain of TFPI, concizumab and marstacimab, are currently in phase III clinical trials. Concizumab is a high-affinity humanized IgG4 antibody with once-daily SQ administration. Safety and longer-term efficacy of concizumab for 22 adult patients with hemophilia A or B with inhibitors who participated in the phase II extension study revealed that it was generally well tolerated; the mean estimated annualized bleed rate was 4.8 (Abstract 2696). Three phase III participants experienced at least 1 thrombotic event, leading to a clinical hold and implementation of a risk mitigation strategy. Marstacimab is a humanized IgG1 antibody administered SQ weekly for prophylaxis (Abstract 1789). Post hoc analysis of the 26 participants in their phase II study investigated whether D-dimer and peak thrombin levels collected within 3 days of each treated bleed event might serve as biomarkers for thrombotic risk. Among the 15 treated spontaneous bleed events that occurred in 8 adult patients, transient increase in peak thrombin levels was detected in 2 patients and no D-dimer elevations were noted. Careful assessment of risk vs benefit for individual patients is needed when considering participation in these trials.
Gene Transfer and Cell-Based Therapeutics in Hemophilia
AAV FVIII and FIX gene transfer programs continue to demonstrate promising results including interim data presented for giroctocogene fitelparvovec (AAV FVIII) for hemophilia A and etranacogene dezaparvovec (AAV FIX) for hemophilia B (Abstracts 671 and 672, respectively). Current challenges include the unpredictable variability in initial response among participants; the acute, transient, asymptomatic immune response prompting need for immunosuppressive agents in many patients; and the uncertain durability of response seemingly more dramatic in hemophilia A programs. Despite the absence of sustained normalization of FVIII or FIX levels, the promise of even achieving levels > 15% to 20% obviating the need for routine prophylaxis and still supporting participation in normal daily activities is enticing to potential participants.
Two first-in-human studies were also presented highlighting novel approaches for gene transfer and cell-based therapeutics for hemophilia. BAY 2599023 using an AAVhu37 capsid vector technology with BDD-FVIII has demonstrated early efficacy with FVIII levels of approximately 2.5% to 45% observed and sustained for up to 18 months (Abstract 1539). SIG-001 is an implantable cell-based therapy using allogeneic cells modified with nonviral vector to express BDD-FVIII that are then encapsulated within a 2-compartment alginate sphere to shield cells from the host immune system and support long-term viability (Abstract 860). SIG-001 is administered interperitoneally via laparoscopy and aims to generate clinically meaningful plasma FVIII levels.
Toward the Future
Currently available hemophilia treatments have outwardly transformed the lives of individuals with hemophilia. Many patients, particularly those in the younger generations, seemingly live normal lives, participating in more sports and physical activities than ever before and actively engaging in school and employment. The “behind the scenes” burden of disease remains high, however. These successful outcomes are only achieved by intensive and time-consuming infusion schedules and, in some subpopulations, cannot be achieved with current therapies, supporting a clear need for the diversity of therapeutic approaches described above.
A comprehensive care model for individuals with hemophilia is more important than ever before to provide thoughtful education and joint decision-making around expanding treatment considerations for PUPs and older patients, screening for comorbidities of aging and guiding appropriate management, and facilitating access to new and emerging therapeutics whose risk–benefit profile must be carefully matched with the needs of the individual.
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