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Hemophilia Prophylaxis
Experts Answer Key Questions on Novel Therapies for Hemophilia Prophylaxis

Released: June 05, 2024

Expiration: June 04, 2025

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Key Takeaways
  • Real-world experience with rebalancing agents, such as fitusiran and concizumab, for hemophilia prophylaxis will help to better define the relationship between efficacy and thrombosis.
  • Alignment in care between hematologists and coagulation labs will be critical to ensure safe and optimal use of hemostatic rebalancing agents as they become available in the United States.

Some of the greatest challenges in managing hemophilia include diagnosis, access to care, and prophylaxis therapy. However, the treatment landscape for hemophilia is rapidly evolving as we understand more about the importance of maintaining the balance of procoagulant and anticoagulant proteins for optimal hemostasis. Novel prophylactic treatments use this paradigm to restore hemostasis through targets like antithrombin (eg, fitusiran), tissue factor pathway inhibitor (TFPI) (eg, concizumab, marstacimib), and activated protein C (eg, serpin PC).

In this commentary, we answer some key questions from a live event at the 2024 Thrombosis & Hemostasis Summit of North America (THSNA) on these rebalancing agents.

When employing rebalancing agents in clinical trials, is it preferable to observe a slight degree of thrombosis, as an indication that homeostasis has been impacted, or is the goal complete absence of thrombosis?

Mark T. Reding, MD:
That is a great question and we are going to be challenged by the lack of head-to-head trial data. We can look at the annualized bleeding rate (ABR) from one study and the ABR from another study, but we cannot compare those directly. We do know that with these drugs we have to find that sweet spot between bringing the regulatory protein of target interest down to a point where we achieve hemostasis, but not so low that we are seeing significant thrombotic events or other severe adverse events. Of note, that ideal spot may differ among patients. For example, in adults, the risk of thrombosis is higher due to age alone. I think it is going to take us some time to fully figure out how best to use these agents and real-world data will help us with that.

There is some validity to the point that if you do not tip homeostasis enough to perhaps see a bit of a thrombosis signal there may not be enough rebalancing. As such, the efficacy may be sacrificed in a way that is unacceptable if the goal is no thrombotic events, considering the other treatment options that will eventually be available. This question will hopefully be sorted out based on real-world experience. I think it is very difficult to be able to answer this question in the clinical trial setting unless there is head-to-head data, which I do not expect us to have.

Based on seeing patients receiving fitusiran with low antithrombin levels in the range that we do not normally observe in clinical samples, how well validated are existing commercial assays for measuring antithrombin levels in the range that would have therapy implications?

Guy Young, MD:
The newer therapies have resulted in a huge emphasis on clinical coagulation labs. There are discrepancies in antithrombin levels when testing people who are receiving fitusiran who exhibit low levels of antithrombin. There are also nuances to testing antithrombin levels; for example, I recently learned that the reagent readout could be bovine or human and the test might evaluate the inhibition of thrombin or Factor Xa. This results in 4 different potential assays—bovine Xa-based, human Xa-based, bovine thrombin, and human thrombin inhibition assays—and each assay may provide different results. In addition, the assays used in each trial may differ from those used in your specific clinical practice.

How will targeting TFPI affect clinical labs that we order?

Mark T. Reding, MD:
When using concizumab, TFPI is not measured directly and this is also not being tested in routine clinical labs, but rather we are measuring drug levels. The broader point here is that with these new therapies, there has been increasing emphasis on the coordination of what is happening in the clinic with what is happening with the clinical lab values to safely use and monitor these drugs. We have had to pay more attention to laboratory assays, even with the new factor products, and I expect that will continue.

This can present a challenge because while some may work in large academic centers with sophisticated labs, the reality is that these drugs will be used in many places that may not have that same capability. It is a good question and more a reminder to us all that the lab component of this is going to be a challenge.

Guy Young, MD:
I agree, and the message here is that we need to talk to each other about these tests because we, as hematologists, have already been asking for more tests from the coagulation labs related to these newer drugs. For example, we need a bovine chromogenic Factor VIII assay because emicizumab impacts the partial thromboplastin time (PTT)-based assays, and Mim8 will have the same impact on PTT-based assays.

As we continue to ask special coagulation labs to do increasingly more, we need to have those conversations where the hematology coagulation team is talking with the coagulation lab. Perhaps we need to have coagulation board, where we have multidisciplinary discussions about which patients are on which drugs and how that affects the lab results. I think that is the only way we are going to learn from each other and fully understand what is needed in these types of situations as these newer drugs enter the clinic.

Your Thoughts?
Hemophilia prophylaxis is continuing to evolve as novel treatments enter the clinic. How comfortable are you in using these newer agents in your practice once they are approved? You can get involved in the discussion by answering the polling question and posting a comment.

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