- Prophylactic regimens have improved outcomes for patients with hemophilia, but barriers to optimal adherence remain a challenge.
- The development of extended half-life (EHL) therapies represents a significant advancement in hemophilia treatment, as these therapies reduce the frequency of infusions and may improve quality of life.
- The decision to switch to an EHL product is an individual choice that must include factors such as cost and access; some patients, such as those who experience frequent breakthrough bleeding, may be better candidates than others for EHL products.
Prophylactic treatment of hemophilia has become the evidence-based standard of care in high-income countries. Further progress in therapeutics has led to the availability of coagulation factors with a longer plasma half-life that allow for wider intervals between treatment, helping reduce the significant burdens on patients that are associated with receiving treatment for hemophilia, such as high costs and the need for frequent injections.
Hanny Al-Samkari, MD, is an assistant professor of medicine at Harvard Medical School and associate director of the Hereditary Hemorrhagic Telangiectasia Center of Excellence at Massachusetts General Hospital in Boston. Dr Al-Samkari discusses innovations in treatment for hemophilia and factors to consider when contemplating whether an EHL product is an appropriate treatment choice.
Frequent intravenous injections are usually necessary due to the relatively short plasma half-life of conventional replacement coagulation factors, but EHL products are changing this paradigm. Can you describe the current obstacles to patient adherence and proper use of conventional factor replacement therapy? What types of venous access problems have you experienced in practice?
The definition of acceptable adherence differs substantially across studies, but in general, excellent adherence is often defined as administering at least 75% to 80% of doses or medication; methods of measuring adherence also vary widely in clinical practice and studies. Barriers to adherence may cross multiple domains and may be related to patient factors, treatment, a poorly coordinated health care system, and/or a patient’s socioeconomic variables.1 For decades, patients with severe hemophilia who need factor prophylaxis have been tasked with home infusion of factor. Most of these patients go to school, work, and live full and busy lives, and so the task of self-infusing with factor at home multiple times per week is a substantial commitment. Anyone who has been prescribed a pill to take each day knows how easy it is to forget to take your medicine or miss doses — now, imagine you had to puncture your veins with a needle and infuse a medication. Patients can be late for work or school and not have time to infuse that morning, or they may be traveling and have difficulty bringing all of their factor and supplies with them. Venous access can be a problem, especially over years to decades of infusion, and we always try to avoid central venous catheters due to infectious risks. Most patients with hemophilia overcome these challenges and become experts at infusing their factor; nonetheless, the ability to infuse less frequently and remain protected, as offered by EHL products, is quite welcome for many patients.
The National Hemophilia Foundation recommends that prophylaxis be considered optimal therapy for individuals with severe hemophilia A or B.2 Should EHL factor replacement therapy be targeted as the new standard of care for bleeding prophylaxis in hemophilia? Are there specific patient populations who would benefit most from adoption of EHL therapy over conventional factor replacement (eg, patients with greater disease severity)?
In my opinion, this needs to be an individualized decision, and many factors, including cost and access to EHL products, play into this choice. For those patients who have EHL products available to them, a discussion of switching to an EHL product and how that could possibly lower infusion burden and offer better overall coverage should certainly be a part of the conversation. Many patients are hesitant to switch from a factor product, especially if they have done well with it for a long period of time and have not developed an inhibitor while receiving it; these concerns need to be balanced with the potential benefits, along with the potential increased cost. A large multinational survey reported that while most patients were generally satisfied with their regimen, nearly 60% said they would be willing to switch to an EHL product if it prolonged their dosing interval while maintaining the same level of safety.3 The majority also reported that they would like more information about its half-life, potential side effects, and efficacy.
Every patient’s factor VIII (FVIII) or IX (FIX) half-life is different. Some patients with hemophilia A and short half-lives of standard factor products still experience frequent bleeding episodes despite infusion 3 times weekly, and these patients may be able to reduce their annualized bleeding rate by switching to an EHL product to increase their factor trough levels. Potentially good candidates who may benefit from switching would include those who experience frequent breakthrough bleeds, patients with target joints, and individuals who are having difficulty adhering to their current treatment regimen. Patients who are being treated with on-demand products, if they are not willing to use prophylaxis with a standard half-life product, may also benefit from EHL prophylaxis. However, those who are experiencing minimal or no breakthrough bleeding and are managing well on their current regimen may not gain a significant clinical benefit from switching.4 Those who are minimally treated may also be less suitable candidates for an EHL product.
Cost has been mentioned as a potential barrier to switching to EHL replacement therapy. Analyses have shown that EHL factor products are more costly than standard products,5 which could be problematic for many patients if they cannot get coverage or have high out-of-pocket expenses. While EHL therapy could actually reduce cost by reducing bleeding episodes, lost days at work, and hospitalizations, higher treatment costs could still be an issue for a patient. Has cost been a barrier to making a switch to an EHL product? Is EHL therapy advocated by medical guidelines at this time?
Cost is a barrier in some clinical situations, and it depends on the patient and their insurance coverage. For example, an analysis of real-world data using US claims databases showed that switching from standard to EHL products was associated with higher expenditures. Increased expenditures rose during the first 3 months after switching and remained throughout the 1-year period of the analysis.5 However, the use of long-acting products may reduce consumption overall and therefore could potentially lead to long-term health savings, although direct treatment costs could increase.4 Additionally, studies have also demonstrated that there are differences between products as far as reducing the frequency of injections, which could affect their economic impact.6,7
Guidelines are a bit open-ended on this topic. For example, World Federation of Hemophilia guidelines highlight that there is no evidence for clinical safety issues with EHL products and offer instructions on the indications and proper use of these products without being excessively prescriptive towards or against their use over standard half-life products.8
As with any area of health care, clinicians and patients may have very different expectations about treatment. Can you discuss the importance of discussions between clinicians and their patients regarding treatment goals for bleeding prophylaxis in hemophilia?
Patients come first, and the best care involves shared decision making. It is important that we educate patients on the potential long-term complications of poor bleeding control but recognize that every patient’s willingness to infuse at certain frequencies and intervals may be different. Ideally, we should work to find the best balance of infusion burden and bleeding prevention for each patient.
EHL factor replacement is a major advancement for hemophilia in terms of reducing treatment burden and increasing adherence, but there is still much room for advancement. Are there other factor replacement products being developed? Can you comment on the role of EHL factor therapy in the era of nonfactor replacement therapies such as emicizumab?
There are other factor replacement products in development, which hopefully will give our patients with hemophilia even more options. Emicizumab, for example, is a humanized bispecific monoclonal antibody that restores the function of missing activated FVIII (FVIIIa) by bridging activated FIX (FIXa) and factor X. This, in turn, mimics FVIIIa cofactor function independently of factor VIII plasma concentration levels and promotes effective hemostasis. Studies conducted in both adult and pediatric patients have demonstrated that emicizumab is an effective treatment; a study in children with hemophilia A and factor VIII inhibitor showed that weekly subcutaneous emicizumab injection decreased annual bleeding rates by 99%.9 Further research in a population with hemophilia A showed that dosing once every 4 weeks was adequate to control bleeding and was well tolerated within the cohort.10 Additionally, there is a great deal of movement in developing approaches to enable endogenous production of FVIII and FIX, including gene therapy or gene transfer, which are now in clinical trials.11 The first gene therapy product for hemophilia B, which consists of a virus vector carrying a gene for clotting FIX, received regulatory approval in November 2022.12
Nonfactor replacement therapies like emicizumab have really led to a revolution in the care of patients with hemophilia, but once again, each patient has different values, concerns, and access to different therapies, and nonfactor products may not be ideal or available for many patients.
This Q&A was edited for clarity and length.
Hanny Al-Samkari, MD, reported affiliations with Agios Pharmaceuticals, Inc; Sobi; Novartis Pharmaceuticals Corporation; Amgen, Inc; Vaderis Therapeutics AG; Forma, Inc; argenx SE; Rigel Pharmaceuticals, Inc; and Moderna, Inc.
1. Thornburg CD, Duncan NA. Treatment adherence in hemophilia. Patient Prefer Adherence. 2017;11:1677-1686. doi:10.2147/PPA.S139851
2. MASAC document 267 – MASAC recommendation concerning prophylaxis for hemophilia A and B with and without inhibitors. National Hemophilia Foundation. Published April 27, 2022. Accessed February 8, 2023. https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-267-masac-recommendation-concerning-prophylaxis-for-hemophilia-a-and-b-with-and-without-inhibitors
3. von Mackensen S, Kalnins W, Krucker J, et al. Haemophilia patients’ unmet needs and their expectations of the new extended half-life factor concentrates. Haemophilia. 2017;23(4):566-574. doi:10.1111/hae.13221
4. Escobar M, Santagostino E, Mancuso ME, et al. Switching patients in the age of long-acting recombinant products? Expert Rev Hematol. 2019;12(suppl 1):1-13. doi:10.1080/17474086.2018.1564032
5. Tortella BJ, Alvir J, McDonald M, et al. Real-world analysis of dispensed IUs of coagulation factor IX and resultant expenditures in hemophilia B patients receiving standard half-life versus extended half-life products and those switching from standard half-life to extended half-life products. J Manag Care Spec Pharm. 2018;24(7):643-653. doi:10.18553/jmcp.2018.17212
6. Batt K, Gao W, Ayyagari R, et al. Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94–9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A. J Blood Med. 2019;10:147-159. doi:10.2147/JBM.S206806
7. Mannucci PM, Cortesi PA, Di Minno MND, Sanò M, Mantovani LG, Di Minno G. Comparative analysis of the pivotal studies of extended half-life recombinant FVIII products for treatment of haemophilia A. Haemophilia. 2021;27(4):e422-e433. doi:10.1111/hae.14313
8. Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020:26(suppl 6):1-158. doi:10.1111/hae.14046
9. Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019;134(24):2127-2138. doi:10.1182/blood.2019001869
10. Pipe SW, Shima M, Lehle M, et al. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol. 2019;6(6):e295-e305. doi:10.1016/S2352-3026(19)30054-7
11. Croteau SE, Wang M, Wheeler AP. 2021 clinical trials update: innovations in hemophilia therapy. Am J Hematol. 2021;96(1):128-144. doi:10.1002/ajh.26018
12. FDA approves first gene therapy to treat adults with hemophilia B. US Food and Drug Administration. Published November 22, 2022. Accessed February 8, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b
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Reviewed February 2023