Conference Coverage

New hemophilia treatments: ‘Our cup runneth over’



It’s a problem many clinicians would love to have: A whole variety of new or emerging therapeutic options to use in the care of their patients.

In a session titled “Hemophilia Update: Our Cup Runneth Over,” presented at the 2021 annual meeting of the American Society of Hematology, experts in the treatment of bleeding disorders discussed the optimal use of factor concentrates in people with hemophilia, new and investigational alternatives to factor concentrates, and the promise of long-time control or even cure with gene therapy.

Factor concentrates

Prophylaxis – as opposed to episodic treatment – is the standard of care in the use of factor concentrates in patients with hemophilia, said Ming Y. Lim, MB BChir, from the University of Utah in Salt Lake City.

“Effective prophylaxis is an ongoing collaborative effort that relies on shared decision-making between the patient and the clinician,” she told the audience.

As the complexity of therapeutic options, including gene therapy, continues to increase “it is critical that both patients and clinicians are actively involved in this collaborative process to optimize treatment and overall patient outcomes,” she added.

Historically, clinicians who treat patients with hemophilia aimed for trough levels of factor concentrates of at least 1% to prevent spontaneous joint bleeding. But as updated World Federation of Hemophilia (WFH) guidelines now recommend, trough levels should be sufficient to prevent spontaneous bleeding based on the individual patient’s bleeding phenotype and activity levels, starting in the range between 3% and 5%, and going higher as necessary.

“The appropriate target trough level is that at which a person with hemophilia experiences zero bleeds while pursuing an active or sedentary lifestyle,” she said.

The choice of factor concentrates between standard and extended half-life products will depend on multiple factors, including availability, patient and provider preferences, cost, and access to assays for monitoring extended half-life products.

The prolonged action of extended half-life products translates into dosing twice per week or every 3 days for factor VIII concentrates, and every 7-14 days for factor IX concentrates.

“All available extended half-life products have been shown to be efficacious in the prevention and treatment of bleeds, with no evidence for any clinical safety issues,” Dr. Lim said.

There are theoretical concerns, however, regarding the lifelong use of PEGylated clotting factor concentrates, leading to some variations in the regulatory approval for some PEGylated product intended for bleeding prophylaxis in children with hemophilia, she noted.

The pharmacokinetics of prophylaxis with factor concentrates can vary according to age, body mass, blood type, and von Willebrand factor levels, so WFH guidelines recommend pharmacokinetic assessment of people with hemophilia for optimization of prophylaxis, she said.

Factor mimetic and rebalancing therapies

With the commercial availability of one factor mimetic for treatment of hemophilia A and with other factor mimetics and rebalancing therapies such as fitusiran in the works, it raises the question, “Is this the beginning of the end of the use of factor?” said Alice Ma, MD, FACP, of the University of North Carolina in Chapel Hill.

Factors that may determine the answer to that question include the convenience of subcutaneous administration of factor VIII mimetics compared with intravenous delivery of factor concentrates, relative cost of factors versus nonfactor products, and safety.

She reviewed the current state of alternatives to factor concentrates, including the factor mimetic emicizumab (Hemlibra), which was approved by the Food and Drug Administration in 2018 for bleeding prophylaxis in patients with hemophilia A with inhibitors, and is currently the only FDA-approved and licensed agent in its class.

Although emicizumab is widely regarded as a major advance, there are still unanswered clinical questions about its long-term use, Dr. Ma said. It is unknown, for example, whether it can prevent inhibitor development in previously untreated patients, and whether it can prevent intracranial hemorrhage in early years of life prior to the start of traditional prophylaxis.

It’s also unknown whether the factor VIII mimetic activity of emicizumab provides the same physiological benefits of coagulation factors, and the mechanism of thrombotic adverse events seen with this agent is still unclear, she added.

Other factor VIII mimetics in the pipeline include Mim8, which is being developed in Denmark by Novo Nordisk; this is a next-generation bispecific antibody with enhanced activity over emicizumab in both mouse models and in vitro hemophilia A assays. There are also two others bispecific antibodies designed to generate thrombin in preclinical development: BS-027125 (Bioverativ, U.S.) and NIBX-2101 (Takeda, Japan).

One of the most promising rebalancing factors in development is fitusiran, a small interfering RNA molecule that targets mRNA encoding antithrombin. As reported during ASH 2021, fitusiran was associated with an approximately 90% reduction in annualized bleeding rates in patients with hemophilia A and hemophilia B, both with inhibitors, in two clinical trials. It was described at the meeting “as a great leap forward” in the treatment of hemophilia.

However, during its clinical development fitusiran has been consistently associated with thrombotic complications, Dr. Ma noted.

Also in development are several drugs targeted against tissue factor pathway inhibitor (TFPI), an anticoagulant protein that inhibits early phases of the procoagulant response. These agents included marstacimab (Pfizer, U.S.) which has been reported to normalize coagulation in plasma from hemophilia patients ex vivo and is currently being evaluated in patients with hemophilia A and B. There is also MG1113 (Green Cross Corporation, South Korea), a monoclonal antibody currently being tested in healthy volunteers, and BAX499 (Takeda), an aptamer derived from recombinant human TFPI that has been shown to inhibit TFPI in vitro and in vivo. However, development of this agent is on hold due to bleeding in study subjects, Dr. Ma noted.

“It is really notable that none of the replacements of factor have been free of thrombotic side effects,” Dr. Ma said. “And so I think it shows that you mess with Mother Nature at your peril. If you poke at the hemostasis-thrombosis arm and reduce antithrombotic proteins, and something triggers bleeding and you start to treat with a therapy for hemorrhage, it’s not a surprise that the first patient treated with fitusiran had a thrombosis, and I think we were just not potentially savvy enough to predict that.”


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