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Experts Answer Questions on Emerging Strategies in Managing Hemophilia A and B

Glaivy Batsuli, MD

Assistant Professor of Pediatrics
Pediatric Hematologist
Division of Pediatric Hematology and Oncology
Department of Pediatrics
Emory University
Pediatric Hematologist
Pediatric Hematology and Oncology
Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta
Atlanta, Georgia

Glaivy Batsuli, MD: independent contractor: Bio Products Laboratories, Kedrion.

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Allison Wheeler, MD, MSCI

Associate Professor
Department of Pathology, Microbiology, and Immunology
Department of Pediatrics
Vanderbilt University Medical Center
Nashville, Tennessee

Allison Wheeler, MD, MSCI: consultant/advisor/speaker: Bayer, Bioverativ, Novo Nordisk, Sanofi, Spark, Takeda.

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Guy A. Young, MD

Professor of Pediatrics
Hemostasis and Thrombosis Center
Children's Hospital Los Angeles
University of Southern California Keck School of Medicine
Los Angeles, California

Guy A. Young, MD: consultant/advisor/speaker: BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Sanofi, Spark, Takeda.

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Released: October 4, 2022

Key Takeaways

  • The differences in half-life and mechanism of action between standard and extended half-life factor replacement and nonfactor therapies must be kept in mind when considering switching between hemophilia treatment options.
  • As novel agents make their way to the clinic, there is a need for studies on how to safely transition patients with hemophilia A or B from one drug to another.
  • Strategies for perioperative management and monitoring are expected to improve as healthcare professionals gain more experience in the use of newer hemophilia therapies.

In this commentary, Guy A. Young, MD; Glaivy Batsuli, MD; and Allison Wheeler, MD, answer audience questions regarding challenges and strategies for the treatment of hemophilia from a recent live symposium titled, “Emerging Strategies in Hemophilia: Restoring the Homeostatic Balance” presented at the 2022 Thrombosis & Hemostasis Summit of North America.

Besides thrombotic events, what are the most significant adverse events with concizumab?

Allison Wheeler, MD:
The most common adverse events are injection-site reactions that are being seen in many patients receiving concizumab. In addition, from a monitoring perspective, healthcare professionals (HCPs) have to keep in mind changes in coagulation proteins, such as D-dimers and other proteins, that are markers of low-level breakdown of blood clots.

Given the recent advances in treatment options for hemophilia A, which patients might be right for factor VIII therapy vs the nonfactor therapies?

Glaivy Batsuli, MD:
Having multiple treatment options is great, but it makes it harder to know what is best for an individual patient. With so many options, the approach at our institution is very much a shared decision-making process that takes multiple factors into account. We consider family lifestyle choices in terms of the priority of preventing bleeds vs the ability to have an infusion where the child is not screaming and running around. This strategy requires a lot of discussion about the priorities of each family. For individuals who have issues with peripheral infusions, particularly toddlers, nonfactor therapies such as emicizumab have the potential to play a significant role. On the other hand, we do not currently have data to know what to do with athletes and others with high physical activity, and that will be an important question to ask for that patient group. The STEP trial (NCT05022459) will be comparing factor VIII with emicizumab prophylaxis in patients with moderate and severe hemophilia who play sports. The trial is not yet recruiting, but I look forward to the results, as they will help us answer the question about which patients are better suited for factor VIII therapy vs emicizumab.

How can we help our patients choose between the different treatment options? Is it possible for HCPs to team up to perform head-to-head comparisons between different products or crossover studies? 

Glaivy Batsuli, MD:
This is a great question, and I think the community is very interested in a direct comparison of the different products for treatment of hemophilia. One thing to be mindful of is the prolonged half-life of many nonfactor therapies, which prevents an immediate switch. For example, emicizumab may remain in your system for 6 months once you discontinue it. We must be very cautious, particularly with rebalancing agents, about switching between products, but we know patients do this. We have patients who have gone from standard half-life factor products to extended half-life products to emicizumab and then off emicizumab. Patients are going to switch, but we need to be very careful with some of the mechanisms of these drugs.

Allison Wheeler, MD:
I also worry about the effect of direct switching when keeping in mind half-life and how drugs could interact. Our registry programs are a place we could collect data, and despite not being a direct comparison, it could potentially inform us about a patient population who should lean toward one drug vs another. I always check in with experienced colleagues when I’m making difficult decisions about newer therapeutic options. One of the reasons I like working with hemostatic rebalancing agents is that the community is great, and I can call whomever I want for advice.

Guy A. Young, MD:
Even though they would be great, I don’t know if there will ever be head-to-head trials. Perhaps it could happen in academia, but these are tough studies to do. 

One thing that needs to be done is studying how to transition patients between therapeutic products. As more and more patients are receiving emicizumab for prophylaxis, at some point we will be in the position where we may want to switch a patient from emicizumab to another non-factor therapy. In order to safely switch patients from emicizumab (taking into consideration its long half-life) to another drug, we must do studies about how to make that transition in such a manner as not to result in thrombosis or adverse events while maintaining bleed protection. The switch from emicizumab to Mim8 may be straightforward because they have the same mechanism of action, so perhaps they just compete with each other and there is nothing to worry about. But what if you want to switch from emicizumab to fitusiran, or maybe your patient is receiving fitusiran and you are worried about thrombotic risk, so you want to switch them to Mim8? How can we do that in the safest way possible?

These are issues we are all going to have to think about, and we will need industry support for at least some of it. It may never be a head-to-head comparison, but we will need various transition studies so we can learn how to switch treatments safely.

What are the difficulties and challenges of perioperative management and monitoring for the newer hemophilia drugs in patients who need surgery?

Allison Wheeler, MD:
Coagulation factors can be monitored on at least some of these drugs, but I think the more challenging question is not necessarily how we monitor, but rather what drug dose should be given to patients in certain surgical circumstances. We don’t want to give too much drug while in the proinflammatory state of surgery and push patients over into a prothrombotic state. We obviously want to achieve hemostasis, but in patients who are having minor and major surgeries within clinical trial programs, we need to learn how much support they actually need once they get back to the real world. There is a level of monitoring possible using our standard one-stage assays with the rebalancing agents fitusiran and concizumab. A challenge with emicizumab is that HCPs aren’t able to get information from standard one-stage assays that are in use at most institutions.

Guy A. Young, MD:
I think we will learn how to better manage patients who need surgery from experience. There is a huge body of evidence from the phase III HAVEN 1-4 trials, which will be published fairly soon, so we should get more information on exactly what to do. In these trials, even though planned surgery was an exclusion criterion, because some patients were involved for 4 or 5 years, approximately 240 surgeries were conducted during the trials. Obviously, these were not planned surgeries at the time of study entry, but if you are on a trial long enough, normal surgeries that are not hemophilia related—such as dental procedures—are expected, as well as some hemophilia-related surgeries. The Explorer program for concizumab has 8 trials, with almost 500 patients enrolled in total. The fitusiran clinical trial program has almost 300 patients enrolled, and Mim8 is just getting started, but there will be hundreds of patients on these trials, and many will need surgery at some point. That is where we will gain more experience in perioperative management.

Are there any data on using bypassing agents with emicizumab for breakthrough bleeds?

Glaivy Batsuli, MD:
There is a report looking at the use of recombinant factor VIIa with emicizumab, and overall, it’s been very safe at various doses. Early on there was a concern with individuals receiving emicizumab who developed thrombotic events and thrombotic microangiopathies upon high-dose activated prothrombin complex concentrate (aPCC) use, but subsequently there mostly have been in vitro data looking at thrombin generation with lower-dose aPCC use for treatment of bleeding events in these patients. We do many interesting things at our center in Atlanta, but one thing we’ve noticed is that there are patients who just don’t respond to recombinant VIIa before emicizumab treatment and still don’t respond afterward. To treat bleeds in some of those patients, we have achieved hemostatic efficacy using low-dose aPCC. Obviously, monitoring is required, and experience is important for being able to do that, but there is a growing body of evidence for the use of bypassing agents, mostly recombinant factor VIIa. A broad group of people throughout the United States have used low-dose aPCCs safely, and I know there are ongoing trials—including the SAFE trial being led by Dr Robert Sidonio of Emory University—looking at the safety of aPCC following emicizumab prophylaxis (NCT04563520).

Guy A. Young, MD:
We performed a study in our center, with Dr Hande Kizilocak as the first author on the publication, where we looked at in vivo injections of aPCC in patients with severe hemophilia A receiving emicizumab (N = 9). Baseline blood samples spiked in vitro with clinically relevant concentrations of aPCC resulted in very high levels of thrombin generation. Surprisingly, in vivo administration of similar doses of aPCC resulted in normal thrombin generation in 66% of those patients. Our results cast doubt on the validity of previous in vitro spiking studies.

Your Thoughts?
What strategies do you use when helping your patients decide between the many therapeutic options for hemophilia A? Answer the polling question and join the conversation in the discussion box below.

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