In 1982, the gene encoding factor IX (FIX) was cloned, followed by the cloning of the factor VIII (FVIII) gene in 1984. The events were a turning point for individuals with hemophilia A and B. With the genes now cloned, scientists could make recombinant FVIII and FIX. Clinical trials using recombinant factors rather than human plasma–derived factors were under way several years later, and the first licensed FIX product became available in the U.S. in 1997.
Two decades later, there is a flurry of novel therapies in development for patients with hemophilia. “These therapies represent exciting new opportunities to manipulate the hemostatic system, to improve hemostasis, and thereby, to improve people’s lives,” Margaret Ragni, MD, MPH, told ASH Clinical News. “These new options are more convenient, as they are given subcutaneously and less frequently than standard recombinant FVIII or FIX.” Dr. Ragni is a medical director of the Hemophilia Center of Western Pennsylvania and professor of Medicine and Clinical and Translational Science at the University of Pittsburgh.
Newer therapies in clinical use and in development range from extended half-life recombinant factor products, antibodies that mimic the function of FVIII, agents that target the anticoagulant protein tissue factor pathway inhibitor (TFPI), and RNA interference (RNAi) therapies that target antithrombin. Here, Dr. Ragni and other experts review the new hemophilia therapies on the horizon.
Plasma and Beyond
Both hemophilia A and B are caused by the failure to produce blood clotting factors that are required to prevent bleeding: FVIII in the case of hemophilia A and FIX in the case of hemophilia B. These clotting factors are part of a cascade that results in the formation of thrombin, an enzyme that cleaves fibrinogen to form fibrin, which then forms a blood clot to stop their bleeding.
Initially, patients received infusions of FVIII or FIX to treat an ongoing bleed, but it is more typical now for patients with severe hemophilia to be treated prophylactically with FVIII or FIX infusions at least once weekly and often several times a week. Starting in the 1950s, fresh frozen plasma was infused into patients to deliver clotting factor, and by the 1970s, lyophilized FVIII was derived from pooled plasma, allowing patients to perform at-home infusions.
“For some time now, the standard of care in higher-resource countries has been prophylactic therapy with clotting factor to prevent bleeding,” explained Barbara Konkle, MD, associate director of the Washington Center for Bleeding Disorders at Bloodworks Northwest and a professor of Hematology and Medicine at the University of Washington. “This allows our patients with hemophilia to live normal lives with a normal life expectancy.”
Researchers have been working for decades to improve hemophilia therapies by developing novel treatments that manipulate the coagulation pathway through a number of approaches. These include mimicking or taking the place of missing or inhibited factors, or inhibiting or “knocking down” the inhibitor of clotting proteins – particularly for patients who have developed inhibitor antibodies against the clotting factors. Patients with inhibitors are refractory to standard FVIII or FIX, and have poorly responsive bleeds, which leads to high morbidity and high cost.
Enter emicizumab, a humanized bispecific antibody that mimics FVIII activity by binding to both activated coagulation FIX and factor X (FX), mediating the activation of FX and facilitating blood clot formation. Emicizumab, given subcutaneously, was approved by the U.S. Food and Drug Administration (FDA) in November 2017 to treat patients with hemophilia A who had developed inhibitors to FVIII and could no longer receive FVIII as a therapy, accounting for between 25 and 40% of patients with severe hemophilia A.1 In 2018, the FDA expanded emicizumab’s indication to the treatment of all patients with severe hemophilia A – either with and without inhibitors – including newborns.2
“Emicizumab makes a patient with severe hemophilia more like a patient with mild hemophilia,” said Janice Staber, MD, an assistant professor of pediatrics and hematology/oncology at the University of Iowa Stead Family Children’s Hospital. “These patients still have hemophilia, but not the nonexistent levels of FVIII they would have otherwise.”
The introduction of emicizumab was “great for patients with inhibitors,” Dr. Staber added. “The therapy has revolutionized their care. I have patients who were having multiple bleeds per week. For one patient in particular, after being on emicizumab, he went from 12 or more monthly bleeds to no bleeds and is now able to take part in activities and sports. That is pretty magical.”
Extending the Half-Life
Over the past decade, recombinant clotting factors with extended half-lives, which decrease the number of factor infusions patients require, have been increasingly used to treat hemophilia. These therapies include recombinant factor fused to the fragment of Fc (a protein found in antibodies), recombinant factors conjugated to polyethylene glycol, or the fusion of factor with albumin (an abundant protein in the blood). These novel techniques prolong the half-lives of FIX, which already has a longer half-life than FVIII, by four- to sixfold, allowing for a once-weekly regimen of prophylactic infusion.3 In the case of FVIII, which has a natural half-life of about 12 hours, these products have been able to extend the half-life by 1.5- to twofold, reducing infusion frequency from about three times per week to two.
BIVV001, an investigational FVIII therapy for those with hemophilia A, has been engineered by fusing four proteins together – FVIII, the D’D3 region of von Willebrand factor (vWF), the polypeptide XTEN, and Fc – to overcome the half-life limitations of FVIII. Upon activation by thrombin, FVIII normally dissociates from vWF and acts as a cofactor to promote the activation of the rest of the clotting cascade. BIVV001 includes the D’D3 domain of vWF, which decouples the interaction of FVIII with vWF, breaking the so-called “vWF half-life ceiling.”
“This is the first FVIII product that truly has an extended half-life,” said Dr. Konkle, who presented the updated phase I data on BIVV001 at the Congress of the International Society on Thrombosis and Haemostasis in July 2019.4 The data, from 14 patients, showed that BIVV001 increased FVIII’s half-life to 38 and 43 hours, depending on the dose.
According to Dr. Konkle, the observational portion of a phase III trial is now underway, with the interventional study to begin in late 2019.
“The initial recombinant FVIII extended half-life therapies only improved the half-life a bit. These were not as exciting as we hoped they would be,” Dr. Staber said, “but BIVV001 is exciting, with the potential for a once-weekly or every-10-day infusion.”
Generating Thrombin Generators
Additional therapeutic approaches aim to restore the generation of thrombin, but not to replace the patients’ missing FVIII or FIX. Dr. Staber likened the process to patching a hole in a brick wall with mortar, which is the fibrin. “You can make the fibrin a few different ways, but what really matters is the end goal of patching the hole.”
Emicizumab is one such approach already in the clinic. Another, still in clinical trials, is concizumab, a humanized, monoclonal antibody that targets TFPI, which is the primary inhibitor of the coagulation cascade. Targeting TFPI can, in theory, modulate the severity of hemophilia. According to phase II data presented at the 2019 ISTH Congress, subcutaneous administration of concizumab raised no new safety concerns and restored thrombin generation to near-normal range in patients with hemophilia A and B.5 It also substantially reduced the annual bleeding rate in patients with inhibitors on prophylaxis compared with on-demand treatment. Two additional antibodies targeting TFPI are in development: BAY-1093884, which is currently in phase I trials, and PF-06741086, which is about to be tested in a phase III trial of adolescents and adults with hemophilia A and B.
Another approach targeting the natural inhibitors of the clotting cascade is an RNAi which binds to antithrombin mRNA in hepatocytes, attaches to and silences it, preventing synthesis of the antithrombin. This molecule, fitusiran, is currently being tested in phase II/III clinical trials in patients with hemophilia A or B, with or without inhibitors. The RNAi therapy is delivered subcutaneously once a month. So far, phase II data in 34 patients have shown that fitusiran leads to a dose-dependent lowering of antithrombin levels and improved thrombin generation.6 “The drug is potent and, if confirmed to be safe, would be a simpler way to treat patients,” commented Dr. Ragni, who was involved in the early-stage fitusiran clinical trials.
Standard of Care: A Moving Target
“With these new therapies, it is getting more difficult to define a real standard of care because there are so many options now that even highly educated clinicians who encounter patients with hemophilia may not understand the nuances of the treatments,” said Dr. Staber. In her opinion, the questions surrounding treatment choice include appropriate prophylaxis for patients with severe hemophilia and whether some patients with moderate hemophilia should be receiving prophylactic therapy.
“I am curious how patients with moderate hemophilia will be treated in the future,” she commented. “We expect better longer-term outcomes for our patients with severe disease, increasing the levels of FVIII to between 10% and 20% or higher, but those with moderate disease have less than 5% factor levels. So should we also be giving prophylactic therapy to patients in the moderate category?”
The debate is not whether hemophilia specialists need therapies that provide better outcomes for their patients, she continued, but how those outcomes should be achieved. “Hemophilia clinicians need to come together as a community and design clinical trials to answer these questions,” Dr. Staber said.
An advantage of the increasing number of investigational therapies, according to the experts who spoke with ASH Clinical News, is that clinicians will be able to tailor their patients’ therapies to suit their needs. “This needs to be a discussion between the clinician and the patient. If you are not talking to your patients, you are likely not going to give them the right treatment,” Dr. Ragni said. “The optimal treatment for each patient depends on his individual goals and lifestyle, personal choice, and unique response to the novel therapy.”
“All of these therapies have the potential to benefit patients with hemophilia. We need to work with each patient, assessing risks and benefits, and optimize therapeutic choice,” she added. “We need to understand the risks and benefits of each novel therapy and listen as our patients tell us what works best for them.” —By Anna Azvolinsky
- U.S. Food and Drug Administration. FDA approves emicizumab-kxwh for prevention and reduction of bleeding in patients with hemophilia A with factor VIII inhibitors. November 16, 2017. Accessed September 4, 2019, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-emicizumab-kxwh-prevention-and-reduction-bleeding-patients-hemophilia-factor-viii.
- U.S. Food and Drug Administration. FDA approves emicizumab-kxwh for hemophilia A with or without factor VIII inhibitors. Accessed September 4, 2019, from https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-emicizumab-kxwh-hemophilia-or-without-factor-viii-inhibitors.
- Graf L. Extended half-life factor VIII and factor IX preparations. Transfus Med Hemother. 2018;45:86-91.
- Konkle B, Shapiro A, Quon DV, et al. BIVV001: the first investigational factor VIII (FVIII) therapy to break through the von Willebrand Factor (VWF) ceiling, with potential for more optimal, extended protection in hemophilia A. Abstract OC 11.1. Presented at the 2019 ISTH Congress, July 7, 2019; Melbourne, Australia.
- Astermark J, Angchaisuksiri P, Benson G, et al. Subcutaneous prophylaxis with the anti-TFPI monoclonal antibody concizumab in hemophilia A and hemophilia A/B with inhibitors: phase 2 Trial Results. Abstract LB 01.1. Presented at the International Society of Thrombosis and Haemostasis 2019 Congress, July 9, 2019; Melbourne, Australia.
- Pasi KJ, Lissitchkov T, Georgiev P, et al. Fitusiran, an RNAi therapeutic targeting antithrombin to restore hemostatic balance in hemophilia: interim analysis from the open-label extension study. Abstract OC 11.3. Presented at the International Society of Thrombosis and Haemostasis 2019 Congress, July 7, 2019; Melbourne, Australia.