Evolving treatment paradigms in hemophilia: A written recap

In this Managed Healthcare Executive K-Cast video series, Annette von Drygalski, M.D., Pharm.D., discussed the evolution of hemophilia care from factor replacement to nonfactor replacement and how the nonfactor therapies have transformed hemophilia care. Von Drygalski is director of the Center for Bleeding and Clotting Disorders at UC San Diego Health in California.

Factor replacement

Hemophilia A is a deficiency in coagulation factor VIII, and hemophilia B is a deficiency in factor IX, von Drygalski explained. Together, the incidence of the two kinds of hemophilia is approximately 1 in 5,000 live male births, with hemophilia A accounting for approximately 80% of the cases. Clinicians may suspect a child has hemophilia if there is spontaneous bleeding and if there are joint bleeds and bruising.

Prophylactic care of hemophilia used to depend on plasma-derived concentrates of clotting factors, von Drygalski said. In the ’70s and ’80s, people with hemophilia became infected with HIV and hepatitis virus through transfusions with contaminated plasma-derived concentrates. Transfusions were made safer with viral inactivation procedures, and then, in the ’90s, recombinant clotting products were developed. They were safe, said von Drygalski, with a drawback being a relatively short half-life that meant frequent infusions. Factor VIII has a relatively short half-life of eight to 12 hours, so people with hemophilia A needed to infuse themselves every other day. Factor IX has a half-life of 24 hours, so people with hemophilia B had to infuse themselves two or three times a week.

The next advance in hemophilia prophylaxis came with techniques that extended the half-life of factor VIII and factor IX. But von Drygalski explained that coagulation from factor VIII is dependent to some extent on von Willebrand factor, which has a short half-life, whereas the action of factor IX is independent of von Willebrand factor. The dependence on von Willebrand factor puts a limit on clotting factor extension for factor VIII. Yet another advance occurred that circumvented the problem of von Willebrand factor’s relatively short life. As a result, hemophilia A patients could be treated with once-weekly infusions.

“However,” said von Drygalski, “it still remains an intravenous infusion. It is still relatively frequent — once weekly. It still requires a lot of setup, needles and equipment.” For parents or caregivers, it can be difficult to find veins suitable for infusion in children. For older adults, a life of infusion may have “destroyed their veins in essence.” Von Drygalski added, “This is where innovative, new treatments that may be subcutaneous — or even gene therapy — could really be helpful.”

First nonfactor therapy

Hemlibra (emicizumab) was approved by the FDA in 2017. Von Drygalski explained that it is a bispecific antibody, which, by bringing factor IX and factor X together on the surface of platelets, mimics the principal action of factor VIII and is therefore called a factor VIII mimetic. But von Drygalski said Hemlibra “leaves room for improvement” in two important respects. First, it achieves a factor VIII equivalency level of just 10% to 20%. (Factor VIII equivalency is how much blood clotting a treatment provides relative to someone without hemophilia A.). Second, it is not a treatment for hemophilia B.

Rebalancing agents

The concept behind the rebalancing agents is to boost blood coagulation by removing or limiting the action of natural anticoagulants, thereby tipping the balance toward the clotting factors and coagulation. These agents also are an advance as the first nonfactor replacement for hemophilia B, not just hemophilia A, she noted. Concizumab [sold under the brand name Alhemo] and marstacimab [sold under the brand name Hympavzi] are monoclonal antibodies that target tissue factor pathway inhibitor. Fitusiran [sold under the brand name Qfitlia] has a different mechanism of action that uses small interfering RNA to “knock down” antithrombin III production in the liver, von Drygalski said. “The principle for all three is the same — remove the natural anticoagulant to make the clotting propensity better. All three are administered subcutaneously, which von Drygalski said is a decided advantage of the intravenous route of administration of the clotting factors. Moreover, the volume of the injections is lower than the volume of Hemlibra.

One major difference with the rebalancing agents is the dosing interval, von Drygalski noted. Concizumab is a daily injection, marstacimab a weekly one and fitusiran is administered every two months. At first glance, the daily dosing of concizumab would seem to be a drawback, but von Drygalski said that isn’t necessarily so. “It’s very fast, it’s painless, it’s a small volume and it almost goes into your routine, like brushing your teeth,” she said.

One issue that needs studying is switching from Hemlibra to a rebalancing agent, because Hemlibra has a half-life of approximately 20 days.

The dosing interval of fitusiran is an advantage, von Drygalski said, but its side effect profile includes thrombosis, elevated liver enzymes (a class effect of the small interfering RNA medicines), and some gallbladder disease. The side effects need to be discussed with the patients.

‘They all work’

Concizumab, marstacimab and fitusiran all work to reduce bleeding in people who were on on-demand treatment, von Drygalski said. “Clearly, if you put them on any of these medications, [they] will pretty much eliminate bleeding,” said von Drygalski.

Von Drygalski continued, “The proof of the pudding is more in what is happening to those who are already on prophylaxis, which is our Western world experience, and if they switch from their standard prophylaxis," she said. Results hinge to some extent on the study population. In some patients, bleeds are harder to control. Some bleeds are not adjudicated — no ultrasound was done — so the joint pain is only patient-reported and might be due to arthritic pain, she said. Whether the studies were done in Europe or the United States, or in countries where clotting factors are not available as prophylaxis, may also make a difference, she noted. Von Drygalski described all these considerations as “hair-splitting.” She added, “The idea is they all work.”

Access issues

The rebalancing agents are new, so the obstacles to access that might arise remain to be seen, said von Drygalski. Although documentation for the reason for switching a patient to one of the new agents will be necessary, von Drygalski said she didn’t foresee “huge, major obstacles to prescribing them,” adding the qualification that it depended on the price. As far as patient acceptance, von Drygalski said she expected patients to prefer the subcutaneous injection route of delivery. “Subcutaneous [injection] is a shot, yes, but it is much easier than finding a vein and doing self-infusion of intravenous therapies,” she said.

Switching

Switching from a clotting factor to one of the nonfactor rebalancing agents should be relatively easy because the clotting factors have a relatively short half-life, von Drygalski observed. The nonfactor agents could be started approximately a week or even sooner after administration of the clotting factor has stopped. With Hemlibra, “we have a challenge” as far as switching is concerned, she said, because it is unclear how great a risk there is if Hemlibra is still present and one of the new rebalancing agents is added. More research is needed, von Drygalski said, and she noted that there is a study of marstacimab underway.

Achieving ‘hemophilia-free mind’

Von Drygalski said that in addition to subcutaneous administration, the new nonfactor rebalancing agents have the advantage of establishing an even level of hemostasis that may relieve patients of the worry associated with peaks and troughs. “How would that affect a patient? I would hope as a game changer. I would hope in a very positive fashion to facilitate or foster that hemophilia-free mind that people talk about quite a bit.” But von Drygalski said it remains to be seen, if patients with hemophilia become very active, how many breakthrough bleeds occur. She was optimistic about adherence to the new replacement factors relative to replacements that require intravenous injection, as they are administered subcutaneously. Reminders might not be necessary for concizumab because it is a daily medication, but von Drygalski said patients may benefit from advice about how to remember to administer the nonfactor rebalancing agents that are taken less often.