Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education.
Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.
Professor of Medicine and Pediatrics
Department of Hematology
University of Texas Health Science Center
McGovern Medical School
Gulf States Hemophilia and Thrombophilia Center
Miguel A. Escobar, MD, has disclosed that he has received funds for research support from CSL Behring, Genentech, Novo Nordisk, Sanofi, Takeda, and UniQure (paid to institution) and consulting fees from CSL Behring, BioMarin, Genentech/Roche, HEMA Biologics , Kedrion, NHF, Novo Nordisk, Pfizer, Sanofi, and Takeda.
In this commentary, I provide a background for hemophilia A therapy and review promising new agents in clinical development to provide context for new data expected to be presented during the 2021 American Society for Hematology (ASH) annual meeting.
Evolution of Hemophilia A Treatment
The primary challenge in the management of patients with hemophilia A is managing breakthrough bleeding through prophylactic therapy. The mainstay of treatment for hemophilia A has been replacement of the missing factor VIII. For patients with a severe hemophilia phenotype, prophylaxis to prevent joint damage is a standard of care. Hemophilia therapy has evolved over time as the available technology has improved. The initial treatment developed in the 1950s and 1960s to replace factor VIII with plasma and cryoprecipitate was replaced by plasma derived concentrates of intermediate purity in the 1970s, then by plasma derived high purity products in the 1980s. In the 1990s, recombinant factor VIII replacement products became available, all of which have a half life of approximately 8-12 hours. More recently, extended half life (EHL) products have become available for the treatment of hemophilia A. These decrease the number of infusions while effectively preventing bleeding episodes. In the last few years, nonfactor replacement therapy has emerged as prophylaxis for hemophilia A. Today, it is recommended that patients with a severe phenotype initiate prophylaxis at an early age with a standard half life factor, EHL factor, or nonfactor replacement therapy to minimize bleeding episodes.
Current Treatment With Replacement Factors
With standard half-life factor VIII therapies, most patients will need to infuse every other day to prevent bleeding. The EHL products can decrease the number of infusions to 2-3 per week, and substantially lowering the transfusion burden can improve adherence, resulting in fewer bleeding episodes. Of note, there are different technologies used to increase the half life of factor VIII and all were demonstrated to be safe and effective in clinical trials. Development of inhibitors is a concern with factor replacement therapy, and the data for inhibitor development with EHL molecules are quite similar to the standard half life factor replacement products. In addition, all the EHL products are very effective at managing acute, breakthrough bleeding. Most of the EHL products that have been approved for management of acute bleeds and for prophylaxis can also be used for surgical procedures. One consideration when using EHL agents is that different assays (eg, one-stage or chromogenic) may be needed to accurately quantify the factor VIII level.
Nowadays, most patients with hemophilia A on prophylaxis are managed using a personalized regimen that takes into consideration many variables, like age, joint status, activity, adherence, and pharmacokinetic data. A one size fits all approach does not work for prophylaxis because there is so much variability among the patients. For example, different treatments will be required for a patient with advanced joint disease that is minimally or somewhat active compared with a patient who has no or minimal joint damage and is quite active. This is where pharmacokinetic studies can be very helpful.
Nonfactor Replacement in Hemophilia A
Emicizumab is a nonfactor replacement therapy that can help prevent bleeding episodes. It is a humanized bispecific monoclonal antibody that links factor IXa and factor X, thereby promoting hemostasis despite the lack of factor VIII. Emicizumab is effective for both inhibitor and noninhibitor patients. One of the differences from replacement factors is that emicizumab is given subcutaneously and has a half life of approximately 30 days, which avoids the dramatic peaks and troughs commonly seen with factor replacement. In addition, emicizumab can be given once weekly, every 2 weeks, or even once per month.
Results from a series of phase III HAVEN studies clearly showed that emicizumab is very effective in preventing bleeding episodes. However, data are as-yet insufficient to determine whether emicizumab will prevent joint damage over time. Patients receiving emicizumab who develop bleeding episodes will need to be treated with factor VIII or a bypassing agent like recombinant factor VIIa or activated prothrombin complex concentrate. Of importance, concomitant use of emicizumab and activated prothrombin complex concentrate at high doses, and for more than 24 hours, can potentially trigger thrombosis and microangiopathy, as seen in the original clinical trials.
Agents in Clinical Trials for Hemophilia A
On the horizon, we have more emerging treatment options for patients with hemophilia A.
An emerging treatment option for patients with hemophilia A is Mim8, a factor VIII mimetic bispecific antibody that bridges factor IXa and X in a more potent way than emicizumab. Improved efficacy vs emicizumab has been demonstrated in a hemophilia A mouse model of vascular bleeding. This agent is still quite early in clinical development, but it could represent the next generation of factor VIII mimetic prophylactic treatments for hemophilia A, pending results from later-phase clinical studies due to begin shortly (NCT05053139).
Efanesoctocog alfa (BIVV001) is a fusion of a single recombinant factor VIII protein with von Willebrand factor, plus 2 hydrophilic polypeptides to extend the half life of factor VIII. The mean half life of this molecule after a single infusion has been reported to be between 37.6 and 42.5 hours. This is quite different from a standard factor VIII, which has a half life of approximately 8-12 hours or an EHL product half-life of 19 hours. Efanesoctocog alfa is in late-phase clinical testing (NCT04759131, NCT04644575, NCT04161495), it looks quite promising, and more data are highly anticipated.
Fitusiran is an experimental RNA interference therapy that decreases the synthesis of antithrombin in the liver with the goal of improving hemostasis in patients with hemophilia A. Preclinical data and results from clinical studies provide support that it could be effective in this population. Fitusiran is given subcutaneously once per month. The preliminary data show a decreased annualized bleeding rate in patients with hemophilia A, with and without inhibitors, after an observation period of approximately 28 months. Of note, thrombotic events were reported during the clinical trials, resulting in protocol changes. Several phase III trials of fitusiran are underway (NCT03974113, NCT03754790, NCT03549871).
Concizumab is a humanized monoclonal antibody that binds the Kunitz 2 domain of tissue factor pathway inhibitor (TFPI), thereby downregulating coagulation by preventing TFPI from binding to and blocking factor Xa. Phase I/II data have shown a low annualized bleeding rate in patients with severe hemophilia A, with and without inhibitors, who were treated with concizumab. There were reports of nonfatal thrombotic events in these studies. The phase III EXPLORER7 and EXPLORER8 trials of concizumab in hemophilia (with and without inhibitors) are ongoing (NCT04083781, NCT04082429).
Clinical trials of multiple gene therapies are underway in hemophilia A using several different adeno-associated viral (AAV) vectors (Table). The studies are in differing stages of clinical development and all require a single infusion of a vector (varying doses, depending on the study). The data so far look very promising but there is wide variability in the expression of factor VIII, as well as the duration of expression. Many patients in trials of novel gene therapies for hemophilia have been able to completely stop prophylaxis, whereas other have been able to limit factor VIII to intermittent use for breakthrough bleeding. Early data suggest that expression of factor VIII decreases over time with the gene therapies.
Table. Gene Therapies in Clinical Development for Hemophilia A
Main Challenges in Hemophilia A Treatment
The main challenge in the management of patients with hemophilia A on prophylaxis is that, with all the molecules available, including clinical trials, patients are still having breakthrough bleeding (excluding patients who received gene therapy and maintain higher levels of factor VIII). Why is that happening despite adequate prophylaxis? Is it variable, like adherence, or unique things related to a patient?
In addition, it is unclear whether the newer molecules like Mim8, fitusiran, and concizumab are able to prevent joint disease. If they are approved, long-term studies to look at joint disease will be needed.
At the upcoming ASH 2021 annual meeting, we are anticipating that multiple studies will be presented that will further these investigational agents toward the clinic and make a meaningful difference in slowing the bleeding that plagues patients with hemophilia A. Register here to join me and my colleagues, Mark Reding, MD, and Guy A. Young, MD, on Friday, December 10, 2021, at 7:00 PM Eastern time for a live satellite symposium at ASH 2021 to learn more about managing hemophilia A or register for the live simulcast!
What do you see as the most exciting new developments in hemophilia A? Answer the polling question and join the conversation by posting a comment in the discussion section.