An estimated 20,000 people in the U.S. are living with the inherited bleeding disorder hemophilia, and more than 60% of them have moderate or severe hemophilia requiring lifelong treatment with expensive drugs and clotting factors.1
The good news is that these treatments work. During the 1960s, the average life expectancy for a patient with hemophilia was about 12 years; now, people diagnosed with hemophilia can anticipate a near-normal life expectancy.2 The bad news is that successful management of hemophilia is associated with a wide variety of direct and indirect costs, including clinic visits, lost income from missing work, hospitalizations, frequent lab tests, and – the largest contributor – antihemophilic medications.3
"All hemophilia A and hemophilia B therapies, whether it is factor replacement or the newer bispecific antibody emicizumab, cost several hundred thousand dollars per year," Stacy E. Croteau, MD, MMS, a pediatric hematologist and clinical researcher at Dana-Farber/Boston Children's Cancer and Blood Disorders Center told ASH Clinical News. "For an adult patient, that cost is somewhere in the range of $300,000 to $500,000 per year."
Prices for these therapies have been steadily increasing over the years. A 2018 pharmaceutical trend report indicated that, although commercial oncology and oncology support accounted for 43% of monthly spending on health plan members, antihemophilic factor accounted for a disproportionate amount of spending in the commercial arena. The monthly per-member spending for antihemophilic factor increased by 62% over 12 months, from $1.03 to $1.66; for Medicare, that spending tripled, from $0.45 to $1.28.4
As potentially curative gene therapies for hemophilia A and B are poised to enter the market, there is little sign of a pricing slowdown. ASH Clinical News asked Dr. Croteau, other hemophilia specialists, and hemophilia treatment center administrators about the causes of uncommonly high price tags for treatment of this rare disease.
Treatments & Costs
At the moment, clotting factors are probably used more than any other therapy for people with hemophilia requiring treatment, according to Jonathan M. Ducore, MD, MPH, of the UC Davis Hemostasis and Thrombosis Center. The major cost of care for these patients is the factor itself, he said.
For example, the average retail price per prescription of Advate – a third-generation recombinant antihemophilic factor for hemophilia A with a standard half-life of 12 to 14 hours that was first FDA approved in 2003 – is $20,630.5 Eloctate, a fourth-generation antihemophilic factor with a longer half-life (~20 hours) that was approved in 2014, is priced similarly. The out-of-pocket cost varies greatly depending on the patient's insurance coverage and ability to access copay or state-funded assistance programs.
The most recent advance in the treatment of hemophilia A came with the approval of emicizumab, an engineered bispecific antibody that mimics the activity of activated factor VIII (FVIII). The agent was initially approved in November 2017 for patients with hemophilia A and inhibitors; the indication was later expanded to include patients without inhibitors.
Emicizumab works by substituting the co-factor function of activated FVIII by binding activated factor IXa (FIXa) and factor X (FX) on the platelet surface, "which is really what FVIII does," said Kenneth Bauer, MD, professor of medicine at Harvard Medical School and coagulation specialist at Beth Israel Deaconess Medical Center. The wholesale acquisition cost of emicizumab is more than $482,000 for the first year, with a small decrease possible in subsequent years.6
"Newer cost estimates show the price [of emicizumab] coming down slightly," Dr. Ducore said, "but, even if that did happen, it would not be by much."
Because it is administered subcutaneously, "emicizumab also offers an enormous convenience aspect that potentially allows people to avoid regular intravenous infusions," he added. Its half-life is estimated at 28 days, much longer than that of standard plasma-derived or recombinant FVIII products, whose half-lives are measured in hours. To maintain protective factor levels, patients using these standard products may require infusions 2 or 3 times per week.
"All hemophilia A and hemophilia B therapies, whether it is factor replacement or the newer bispecific antibody emicizumab, cost several hundred thousand dollars per year."
â€”Stacy E. Croteau, MD, MMS
Extended Half-Lives, Extended Prices?
New developments in the field of factor replacement products have also lessened the treatment burden for patients, but, unfortunately, have done little to ameliorate the high costs of treatment.
"Over the past few years, a number of extended half-life products have been approved by the FDA," noted Dr. Bauer. "These recombinant FVIII or FIX molecules have been engineered in a number of ways to extend their half-life, which, without modification, is typically about 12 hours for FVIII and 24 hours for FIX."
"At least in the U.S., many people with hemophilia B have few good alternatives and are switching to extended half-life factor," Dr. Ducore pointed out. However, "the unit prices of extended half-life products are at least double or triple those of standard half-life products."
For example, in 2014, the standard half-life recombinant FIX BeneFix was priced at $1.19 per international unit (IU), while the extended half-life FIX product, Alprolix, was priced at $2.85 per IU.7 Other extended half-life products can exceed $4 per unit, according to Dr. Croteau.
With fewer doses required, one would expect costs to drop accordingly. Still, these extended half-life products require higher doses with each infusion, so, in a best-case scenario, costs would be about the same as with standard products, Dr. Croteau said.
In an analysis presented at the Academy of Managed Care Pharmacy's 2018 annual meeting, researchers found that, for a small number of patients with hemophilia A who made the switch, the average cost of products more than doubled – from $127,168 in the 6 months before the switch to more than $300,000 in the 6 months after the switch.8 Similarly, among 20 patients with hemophilia B who switched to longer-acting factor products, average 6-month costs increased from $116,909 to $230,209.
In her experience, Dr. Croteau noted, extended half-life products have encouraged some patients to finally initiate prophylaxis rather than on-demand use of factors, which can be associated with better outcomes such as joint preservation, so there are limitations to purely considering factor costs in this analysis. Also, the potential for increased costs hasn't dissuaded patients from requesting these alternative products. In a review of factor concentrate use at 138 U.S. hemophilia treatment centers (HTCs) over 18 months, Dr. Croteau and investigators found that use of extended half-life products rose from 10% to 22%.9 Although the authors observed that the median number of extended or standard half-life products prescribed as prophylaxis decreased, the trend did not translate to lower costs.
Costs of Complications
For patients with hemophilia, the costs of treatment do not stop at factor replacement or emicizumab. Those with severe hemophilia – particularly young children – are at risk for developing an inhibitor, which prevents FVIII or FIX replacement treatment from working.
The Centers for Disease Control and Prevention (CDC) estimates that about 1,500 people with hemophilia in the U.S. are living with an inhibitor, and the presence of inhibitors adds more than $800,000 per year to their treatment.10 For the entire population, this amounts to excess health care costs of nearly $1.4 billion per year.
Although some patients with a low-titer inhibitor (<5 BU) can try to overcome the inhibitor with extra factor infusions, those with a high-titer (â‰¥5 BU) inhibitor will have to use bypassing agents, such as FVIII inhibitor bypass activity (FEIBA) or recombinant factor VIIa (marketed as NovoSeven).
"If you have a high-titer inhibitor and have to use bypassing agents, then the cost will jump at least 2 to 3 times higher [compared with factor replacement," Dr. Ducore said.
FEIBA is an anti-inhibitor coagulant complex with the capacity to provide FVIII inhibitor bypassing activity. According to a 2018 analysis from the Institute for Clinical and Economic Review, treatment of a single bleeding episode with FEIBA can cost $50,000 or more.6
NovoSeven is recombinant human activated factor VII (FVII), a hemostatic agent that is similar to human plasma-derived FVIIa. In 2014, the average wholesale price of NovoSeven was $1.71 per mcg. For a patient weighing 70 kg (154 lb) then, the cost of a typical 90 µg/kg dose was $9,480 (rounding to decrease waste).11
In the 2018 pharmacy trend report, FEIBA and NovoSeven were listed as the fourth and fifth most expensive drugs for commercially insured patients, costing $956,408 and $800,490 per patient per year, respectively.4 They also are a boon for their manufacturers: In 2016, sales of NovoSeven and FEIBA hit about $1.36 billion and $800 million, respectively.12
Alternatively, many patients with an inhibitor will attempt immune tolerance induction (ITI), a process that attempts use very high doses of FVIII to overwhelm and teach the body to tolerate FVIII without mounting an immune response. The goal of ITI is to suppress the inhibitor and allow a return to normal factor replacement therapy. The ITI process can take a few months or even years to work.13
According to Dr. Croteau, instead of using factor infusions every other day or thrice weekly for prophylaxis, patients undergoing ITI will infuse factor daily or twice per day, at doses up to 4 times the dose used for routine prophylaxis, amounting to an "astronomical cost."
Dr. Ducore added that he has seen patients "who have burned through a quarter of a million dollars of product over a long weekend."
The evolution of hemophilia management, from the treatment of episodic bleeds to prophylaxis, has also caused a surge in the costs of hemophilia treatment. This transition occurred as early as the 1950s in some countries but was delayed in many others during the HIV/AIDS epidemic, Dr. Ducore explained. After pretreated, virally decontaminated factors – and then recombinant factors – became available, the movement began to pick up steam again.
"Individuals with hemophilia can spontaneously bleed in all parts of the body, and bleed easily with minimal trauma," Dr. Croteau said, describing the motivation behind the push to prophylactic treatment. "Bleeds into muscles and skin will heal relatively easily and without consequences, especially with factor replacement, but when patients are bleeding into joints, it causes inflammation and, ultimately, permanent damage."
The number of bleeds it takes for any individual to have permanent joint damage varies. Rather than reacting to bleeds, clinicians shifted their attention to preventing bleeds. This movement was supported by a 2007 New England Journal of Medicine study that demonstrated that young boys with severe hemophilia A assigned to regular infusions of recombinant FVIII had a lower risk of MRI-detected joint damage compared with boys given episodic therapy.14
This shift significantly increased demand for clotting factor, evidenced by a spike in the number of annual supply days per patient for FVIII (160.5 vs. 249.9 days; p<0.003) and FIX (132.8 vs. 214.7 days; p=0.025) products between 2007 and 2012.15
According to Dr. Croteau, while the focus on prophylaxis has increased short-term costs, it likely also has helped to offset some of the long-term costs of the disease, such as treating bleeds, replacing joints, or lost income due to work absenteeism.
The U.S. health care system's use of market-based pricing without any price regulation also means that pharmaceutical manufacturers have little incentive to lower prices. While there are dozens of treatment options available for hemophilia, with plenty more in development, competition has failed to control costs.
"Each drug is its own brand," Dr. Croteau said. "They all keep prices high."
The high pricing may be helped along by the lack of cheaper biosimilar versions available for blood factor products. "Many of these products were licensed in the early 1990s or 2000s, and while there are certainly new variations, especially in the FVIII market, there is not huge variability in characteristics," she added. "Yet, they keep getting more expensive."
Pharmaceutical companies also don't experience much blowback from patients. While patients may experience high annual copays at the beginning of the year before they have reached their out-of-pocket maximum, they often are not exposed to the full price of these high-demand products. The bulk is covered by insurers.
"Because the patient does not see the full costs of the treatments, the average person with hemophilia probably does not think about this often," Dr. Ducore said. "Whether that is a good thing or a bad thing is a philosophical issue."
The 340B Safety Net
In a situation not unique to hemophilia, U.S. payers and patients pay much more for treatments than those in other countries, where national governments have introduced programs to rein in health care spending.
Several countries follow a national tender system or are a part of a multinational tender system – a formal procedure to purchase medications using competitive bidding. In the case of hemophilia, manufacturers of clotting factors propose their best price for a given category of factor concentrate. Officials consider the proposals, then agree to exclusively use one manufacturer's factor product for a given period of time, Dr. Croteau explained. This has resulted in significant savings for participating countries. For example, between 2004 and 2014, Ireland was able to reduce the unit cost of recombinant FVIII by 60% using a tender system.16
"Because the patient does not see the full costs of the treatments, the average person with hemophilia probably does not think about this often. Whether that is a good thing or a bad thing is a philosophical issue."
â€”Jonathan M. Ducore, MD, MPH
The U.S. government also has introduced programs designed to reduce the amount that certain safety net hospitals spend on outpatient drugs, such as the 340B Drug Pricing Program established in 1992. Through the program, drug manufacturers enter into a pricing agreement in exchange for coverage of their drugs by the Centers for Medicare & Medicaid Services (CMS). These agreements require manufacturers to provide discounts on outpatient drugs to covered entities, such as hemophilia treatment centers, or HTCs. This allows these centers to "stretch scarce federal resources as far as possible, reaching more eligible patients and providing more comprehensive services."17
Manufacturers cannot charge covered entities more than the agreed-upon average manufacturer price, reduced by the unit rebate amount, which is 17.1% for clotting factor. These discounted drugs are then dispensed by either an internal specialty pharmacy or by a contracted specialty pharmacy.
"These drugs can only be used for eligible patients of the center, or those with an â€˜established relationship,'" explained Eric D. Gray, CPA, director of finance and business operations of Indiana Hemophilia & Thrombosis Center (IHTC).
All revenues yielded from the program must be reinvested into the center and the patient services it provides. For example, IHTC offers multidisciplinary patient care including access to physicians, nurses, genetic counselors, physical therapists, social workers, a psychologist, a dietitian, insurance coordinators, career and school counselors, and dental hygienists, Mr. Gray said.
At her center, Dr. Croteau said, participation in 340B has meant that staff can offer patients multidisciplinary care from nurses and social workers. The savings also support community outreach and education efforts, as well as emergency funds that can help patients who face extreme financial burden due to the costs of therapy, she added.
Similarly, at Dr. Ducore's center, budget excess as a result of 340B funding can aid patients who may be facing difficulties accessing reimbursement or financial assistance through a state program or other copay assistance programs.
Supporting Hemophilia Research
One justification frequently given for the high price of hemophilia drugs in the U.S. is the use of profits to reinvest in research and development of other lifesaving products. In addition to a number of recently introduced therapies, an estimated 18 new therapies are in various stages of development, including new clotting factor concentrates, bypassing agents, non–factor coagulation products, and multiple gene therapy products.
Gene therapy, which could potentially provide a cure for the disease, is undoubtedly the most enticing of these options. "The hope of gene therapy is to be able to restore the body's ability to make FVIII or FIX," Dr. Bauer explained. "Arguably, gene therapy is to be viewed as a cure or near cure for the disease, with a need for little or any other therapy."
In December 2019, BioMarin Pharmaceutical submitted a biologics license application to the FDA for its investigational gene therapy valoctocogene roxaparvovec for the treatment of patients with hemophilia A. Valoctocogene roxaparvovec is an adeno-associated virus serotype 5 (AAV5) vector containing the B-domain-deleted FVIII gene. It is designed to be delivered in a single dose, as opposed to standard treatments of hemophilia A, which entail frequent intravenous infusions of missing FVIII.
The application is supported by an interim analysis from an ongoing phase III study and updated 3-year results from an ongoing phase I/II study. In the latter trial, treatment with valoctocogene roxaparvovec led to a significant reduction in bleeding events and use of clotting factor, while the phase III interim analysis showed that 8 of 20 patients treated with the gene therapy achieved FVIII levels of â‰¥40 IU/dL.18, 19
BioMarin is not alone in the race to bring a hemophilia gene therapy to market. Spark Therapeutics, Pfizer, and UniQure all have products being evaluated in phase III studies. The BioMarin and Spark products are FVIII gene transfer products and the Pfizer and UniQure products target FIX.
These revolutionary therapies are also, unfortunately, revolutionizing pricing. "Of the numbers that I see batted around, people are estimating that hemophilia gene therapy would cost in the range of $2 to $3 million," Dr. Ducore said. "We don't know yet for sure, though. If one company files and gets approval, it will be the only one on the market and will have to fight out cost issues with insurance companies. If there are five or six companies, then competition may drive cost down to some extent."
The sticker shock is understandable, but Dr. Ducore added that many people are spending at least $250,000 a year on factor, year after year. With a one-time infusion of gene therapy, "their factor requirements will drop to almost zero," he said. "Ten years of no factor pays for gene therapy."
Can Change Happen?
There is no denying that hemophilia is a very expensive disease that affects a relatively small number of vulnerable people. It is important to explore avenues for bringing costs down, but one cannot lose sight of the potential consequences of those decreases, Dr. Ducore said.
"If you look at [HTC] programs, we are pretty much self-supporting based on factor sales," Dr. Ducore said. "If the income from that went away, or let's say was just cut in half, so would our ability to provide comprehensive care [to the bleeding disorders population]."
Mr. Gray agreed, adding that, to the best of his knowledge, many treatment centers nationally rely on the 340B program for most of their center's support.
There also is the other side of the coin to consider: Pharmaceutical companies that profit from the sale of medications to treat this rare disease use that revenue to advance treatment. "Why are all these new drugs and treatments around for hemophilia?" Dr. Ducore asked. "In part, it is because there is money to be made. The engine of innovation is fueled by money."
Whether the U.S. government, its health insurance companies, and its citizens should be underwriting drug innovation and delivery for the rest of the world is a sociopolitical question, Dr. Ducore said, and one without an easy answer. â€”By Leah Lawrence
- National Organization for Rare Diseases. Hemophilia A. Accessed January 8, 2020, from https://rarediseases.org/rare-diseases/hemophilia-a/.
- World Federation of Hemophilia. Introduction to hemophilia. Accessed January 8, 2020, from https://elearning.wfh.org/elearning-centres/introduction-to-hemophilia/#hemophilia_faq.
- Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on patient management. Am J Manag Care. 2016;22(5 Suppl):s126-133.
- Magellan RX Management Medical Pharmacy Trend Report 2018 Ninth Edition. Accessed January 9, 2020, from https://www1.magellanrx.com/documents/2019/03/medical-pharmacy-trend-report_2018.pdf/.
- Congressional Budget Office. Prices for and Spending on Specialty Drugs in Medicare Part D and Medicaid: An In-Depth Analysis, March 2019. Accessed January 22, 2020, from https://www.cbo.gov/system/files/2019-03/55011-Specialty_Drugs_WP.pdf.
- Institute for Clinical and Economic Review. Emicizumab for Hemophilia A: Effectiveness and Value. Accessed January 8, 2020, from https://icer-review.org/wp-content/uploads/2017/08/ICER_Hemophilia_A_Draft_Report_012618.pdf.
- Reuters. Exclusive: Biogen prices hemophilia drug on par with older therapies. Accessed January 7, 2020, from https://www.reuters.com/article/us-biogen-hemophilia/exclusive-biogen-prices-hemophilia-drug-on-par-with-older-therapies-idUSBREA3H0KL20140418.
- Bowen K, Borchardt M, Gleason PP. Incremental cost of switching to extended half-life (EHL) coagulation factor products to treat hemophilia among 15 million commercially insured members. Accessed January 10, 2020, from https://www.primetherapeutics.com/content/dam/corporate/Documents/Newsroom/Pressreleases/2018/document-amcpspring18-hemophilia.pdf.
- Croteau SE, Cheng D, Cohen AJ, et al. Regional variation and cost implications of prescribed extended half-life factor concentrates among U.S. Haemophilia Treatment Centres for patients with moderate and severe haemophilia. Haemophilia. 2019;25:668-675.
- Centers for Disease Control and Prevention. Hemophilia. Accessed January 8, 2020, from https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html.
- Risko P. NovoSeven: Cleveland Clinic Guidelines. Cleveland Clinic Pharmacotherapy Update. July/August 2007. Accessed January 10, 2020, from https://www.clevelandclinicmeded.com/medicalpubs/pharmacy/pdf/Pharmaco_X-IV.pdf.
- BiopharmaDive. Disruption of the Year: Long-Acting Hemophilia Drugs. Accessed January 10, 2020, from https://www.biopharmadive.com/news/disruption-of-the-year-long-acting-hemophilia-drugs-2017/510268/.
- National Hemophilia Foundation. Immune Tolerance. Accessed January 10, 2020, from https://www.hemophilia.org/Bleeding-Disorders/Inhibitors-Other-Complications/Inhibitors-for-Consumers/Immune-Tolerance.
- Manco-Johnson, MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357:535-544.
- Eldar-Lissai A, Hou Q, Krishnan S. The changing costs of caring for hemophilia patients in the U.S.: insurers' and patients' perspectives. Abstract # 199. Presented at the 2014 American Society of Hematology Annual Meeting; December 7, 2014; San Francisco, CA.
- World Federation of Hemophilia. Guide to National Tenders For the Purchase of Clotting Factor Concentrates. 2nd Edition. Accessed January 10, 2020, from https://www1.wfh.org/publication/files/pdf-1294.pdf.
- Health Resources & Services Administration. 340B Drug Pricing Program. Accessed January 10, 2020, from https://www.hrsa.gov/opa/index.html.
- Pasi KJ, Rangarajan S, Mitchel N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med.2020;382:29-40.
- BioMarin. BioMarin Announces that phase 3 cohort of valoctocogene roxaparvovec, gene therapy study in severe hemophilia A met pre-specified criteria for regulatory submissions in the U.S. and Europe. Accessed January 8, 2020, from https://investors.biomarin.com/2019-05-28-BioMarin-Announces-that-Phase-3-Cohort-of-Valoctocogene-Roxaparvovec-Gene-Therapy-Study-in-Severe-Hemophilia-A-Met-Pre-Specified-Criteria-for-Regulatory-Submissions-in-the-U-S-and-Europe.