Hemophilia A and B are hereditary, X-linked recessive bleeding disorders caused by deficiency or absence of coagulation factor VIII and factor IX, respectively. The prevalence of hemophilia is 1 in 5000 live male births for hemophilia A and 1 in 25,000 to 30,000 for hemophilia B.1 Hemophilia classification is based on factor activity levels and range from severe (<1% activity), moderate (1%-5% activity), or mild (5%-50% activity).2 Table 1 outlines characteristics of the disease.
For severe disease, lack of either factor leads to hemarthrosis (spontaneous joint bleeding), which can affect any joint but primarily affects the ankles, knees, and elbows. Additionally, patients with severe disease can develop spontaneous soft-tissue, gastrointestinal, and central nervous system bleeding. Recurrent bleeding can lead to hemophilic arthropathy, which can lead to serious issues with joint mobility, decreasing overall patient function and quality of life. Individuals with moderate disease usually bleed in response to an injury but can experience spontaneous bleeding. Patients with mild disease typically only bleed in response to significant trauma or surgery and can lose excessive amount of blood unless treated.2,3
Burden of Disease
Although hemophilia is designated an orphan disease by the FDA because it affects fewer than 200,000 people in the United States, it imposes a significant burden on patients, caregivers, and society. Individuals with hemophilia have significantly impaired quality of life as a result of pain associated with acute bleeds and arthropathy, disability, and potential exposure to HIV and hepatitis viruses in replacement factor.4
The annual cost of treatment for hemophilia A ranges from $59,101 for those with mild disease to $301,392 for patients with severe disease receiving prophylaxis. For patient a with hemophilia B, the cost ranges from $85,852 to $263,253. Factor replacement products represent up to 94% of total cost for severe disease.5 One study estimated that the overall cost per patient with hemophilia and complications associated with the development of inhibitors at $1 million annually. Indirect costs are also substantial and include individuals’ and caregivers’ lost productivity, caregivers’ unpaid costs, and individuals’ hemophilia-related disability.6
Hemophilia is a complex disease that requires life-long treatment. The cornerstone of hemophilia management is intravenous coagulation factor VIII and factor IX replacement products (recombinant or plasma-derived), administered on-demand or prophylactically. Prophylactic is started early in life, preferably before the onset of hemarthroses, and administered several times per week. Limitations are associated with factor products. Short-half lives of 8 to 12 hours for hemophilia A and 18 to 24 hours for hemophilia B require frequent dosing in the prophylactic setting and repeat dosing in on-demand settings. Factor replacement therapy is not without risk; some patients will develop neutralizing antibodies known as inhibitors that render factor replacement ineffective.3 An estimated 20% to 35% of individuals with hemophilia have inhibitors.5
Patients with high level of inhibitors are treated with bypassing agents (BPAs), which are very expensive—costing as much as $50,000 for treatment of a single bleeding episode—and some patients are treated prophylactically, at a cost of $300,000 to $2.5 million per year. With BPA prophylaxis, many patients continue to have frequent episodes of bleeding. Furthermore, adherence to frequent intravenous therapy can be an issue for patients who are appropriate candidates for prophylaxis. Even in the absence of inhibitors, only 50% to 70% of patients adhere to prophylaxis regimens.7
Great advances in hemophilia have occurred in the past 40 years, with the launch of several new long-acting hemophilia factor drugs in the last few years. In 2018, the FDA approved emicizumab-kxwh (Hemlibra, Genentech, Inc) for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and pediatric patients (aged newborn and older) with hemophilia A with or without factor VIII inhibitors. It was first approved in 2017 for patients with hemophilia A with factor VIII inhibitors. Hemlibra is administered subcutaneously, with multiple dosing options (once weekly, every 2 weeks, or every 4 weeks).8
The approval was based on results from HAVEN 3 and HAVEN 4 clinical trials. Hemlibra prophylaxis led to statistically significant and clinically meaningful reductions in treatment bleeds compared to no prophylaxis (primary end point) and across all other bleed-related end points in the HAVEN 3 study, and it showed a clinically meaningful control of bleeding in the HAVEN 4 study.8
The most common adverse reactions occurring in pooled studies were injection site reactions, headache, and arthralgia. Hemlibra is generally well-tolerated, however, the prescribing information includes a warning that thrombotic microangiopathy and thrombotic events were reported when taking the agent in conjunction with activated prothrombin complex concentrate.8
The wholesale acquisition (WAC) cost for Hemlibra is approximately $482,000 for the first year of treatment and $448,000 for subsequent years; however, it could potentially reduce the need for other costly therapies, according to a pharmacoeconomic report from the Institute for Clinical and Economic Review. The report showed that over a 5-year time horizon, Hemlibra at WAC pricing would reduce the budget by approximately $1.85 million per patient annually for patients aged 12 and older. In patents aged 12 and younger, WAC pricing would reduce the budget by approximately $720,000 per patient annually.7
For the treatment of hemophilia B, the FDA approved coagulation factor IX (recombinant), glycoPEGylated (Rebinyn, Novo Nordisk) in 2017. It is indicated for on-demand treatment and control of bleeding episodes, and the perioperative management of bleeding in adults and children with hemophilia B. It is not indicated for routine prophylaxis or for immune tolerance induction in patients with hemophilia B. Rebinyn is designed to prolong the circulating half-life of factor IX to ensure more sustained protection from bleeding and less frequent infusions for patients.9
Rebinyn was evaluated in in the PARADIGM clinical trial program. In the on-demand arm of the adolescent and adult clinical trial, the therapy was used to effectively treat 98% of patient bleeds with one or two doses. In the surgical clinical study of adolescents and adults, a single preoperative dose of Rebinyn provided a 100% success rate (defined by clinicians as “excellent or good”) in bleeding control during surgery.9
More and more agents in the pipeline are highly complex. Several drugs which use more cutting technology are in clinical trials. For example, fitusiran is an investigational, once-monthly, subcutaneously administered RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B, with and without inhibitors. It is currently being evaluated in the phase 3 ATLAS clinical trial program.10 Gene therapies are also in development (Table 2).
Management Challenges and Strategies
During a session at 2018 Academy of Managed Care Pharmacy’s Managed Care & Specialty Pharmacy Annual Meeting, experts discussed cost and management of hemophilia from the payer perspective.
In addition to the substantial economic burden, payers also face management challenges, including fragmentation of care and lack of uniformity, lack of standardized guidelines or standardized approach to how patients with hemophilia are treated, limited transparency, pharmacy and medical benefit utilization, and navigating the need for reinsurance programs for high-cost members. Among stakeholders, payers have little insight into clinical data outside of factor product cost, and providers may have limited insight into product utilization, dispensed amounts, and total health care resource utilization.11
Stakeholders, however, can take steps to improve management of hemophilia. Utilization management, for example, ensures specific standards of care, improves transparency and data collection, and better care coordination. Pharmacy management should include standardized assay and inventory management, standards of care for patient engagement and clinical contacts, and adherence monitoring and counseling. Data collection and analysis is also critical to determine benchmarks and measure relevant outcomes.11 ν
1. Croteau SE. Evolving complexity in hemophilia management. Pediatr Clin North Am. 2018;65(3):407-425. doi:10.1016/j.pcl.2018.01.004
2. Peters R, Harris T. Advances in innovations in haemophilia treatment. Nat Rev Drug Discov. 2018;17(7):493-508. doi:10.1038/nrd.2018.70
3. The Hemophilia Report. Selected Reports from the 65th Annual Meeting of the National Hemophilia Foundation and 55th Annual Meeting of the American Society of Hematology. Syosset, NY: Direct One Communications; 2014.
4. Escobar MA. Health economics in haemophilia: a review from the clinician’s perspective. Haemophilia. 2010;16(suppl 3):29-34. doi: 10.1111/j.1365-2516.2010.02257.x
5. Rosenberg J. Hemophilia: treatment landscape, costs, and disease management. https://www.ajmc.com/conferences/amcp-2018/hemophilia-treatment-landscape-costs-and-disease-management-. Published April 26, 2018. Accessed August 1, 2019.
6. Dalton DR. Hemophilia in the managed care setting. Am J Manag Care. 2015;21(6):S123-S130.
7. Institute for Clinical and Economic Review. Emicizumab for hemophilia A with inhibitors: effectiveness and value. https://icer-review.org/wp-content/uploads/2017/08/ICER_Hemophilia_Final_Evidence_Report_041618.pdf. Published April 16, 2018. Accessed August 1, 2019.
8. FDA approves emicizumab-kxwh for hemophilia A with or without factor VIII inhibitors. US Food and Drug Administration website. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-emicizumab-kxwh-hemophilia-or-without-factor-viii-inhibitors. Published October 4, 2018. Accessed August 1, 2019.
9. Rebinyn® now available for hemophilia B patients. National Hemophilia Foundation website. https://www.hemophilia.org/Newsroom/Industry-News/REBINYN-Now-Available-for-Hemophilia-B-Patients. Published February 8, 2018. Accessed August 1, 2019.
10. Inacio P. Fitusiran clinical development among 2018 corporate goals, Alnylam Pharmaceutical says. Hemophilia News Today. January 12, 2018. https://hemophilianewstoday.com/2018/01/12/hemophilia-clinical-program-fitusiran-among-2018-goals-alnylam-pharmaceuticals-announces/. Accessed August 1, 2019.
11. Academy of Managed Care Pharmacy. Hemophilia care from a payer perspective. http://amcp2018.amcp.org/daily-report/hemophilia-care-from-the-payer-perspective/. Published April 24, 2018. Accessed August 1, 2019.