Choosing Between Treatment Strategies for Patients With Acquired Hemophilia A

Alice Ma, MD
Professor of Medicine in the Division of Hematology and Oncology at the University of North Carolina School of Medicine in Chapel Hill
Rebecca Kruse-Jarres, MD, MPH
Director of the Washington Center for Bleeding Disorders at Bloodworks NW and associate professor of medicine in the division of hematology at the University of Washington School of Medicine in Seattle, Washington

Acquired hemophilia A (AHA) is a rare bleeding disorder in which patients develop inhibitors against clotting factors – most often factor VIII (FVIII). For nearly 10 years, the standard of care for the treatment of AHA was either recombinant factor VIIa (rFVIIa) or FVIII inhibitor bypass activity (FEIBA), known as a “bypassing agent” because it causes coagulation without the need for FVIII. In October 2014, the U.S. Food and Drug Administration (FDA) approved antihemophilic factor [recombinant], porcine sequence (rpFVIII) for the treatment of AHA, which replaces FVIII, rather than bypassing it. rpFVIII has been effective in clinical trials, however, pricing concerns put this treatment out of reach for some patients.

ASH Clinical News invited Alice Ma, MD, and Rebecca Kruse-Jarres, MD, MPH, to debate the question: “In AHA treatment, should we use rpFVIII or standard bypassing agents?” Dr. Ma will be arguing on the “standard bypassing agents” side, and Dr. Kruse-Jarres will be arguing on the “rpFVIII” side.

Dr. Ma: In general, hematologists have used either rFVIIa or FEIBA for patients with AHA for a number of years and have a lot of experience with them. They are effective in controlling bleeding without substantially increasing thrombotic risk – except for in high-risk patients, like older people with underlying vascular disease. The introduction of rpFVIII has provided us with a new therapeutic option but, in the current economic climate, our hospital administration mandates bypassing agents as first-line therapy for these patients.

Dr. Kruse-Jarres: rpFVIII works differently than bypassing agents such as rFVIIa or FEIBA. It is a replacement product – essentially, it “plugs the hole” and fixes the defect in the coagulation cascade, rather than bypassing the defect. rpFVIII contains a recombinant analogue of porcine FVIII, which is similar enough to human FVIII, but is less likely to be affected by FVIII inhibitors that are present in patients with AHA.

The FDA’s approval was based on results of a multicenter, open-label, controlled phase II/III trial. All 28 patients with AHA treated with rpFVIII had a good response – bleeding stopped or was reduced at 24 hours after the initial infusion. rpFVIII also results in measurable factor VIII activity; being able to check those levels lets us know if the patient is getting enough, but not too much, of the product.

It is thus difficult to compare these products physiologically. They do different things, so how would we determine which one is the “better product?” In my opinion, rpFVIII simply offers more advantages; it replaces what’s missing, and it can be measured.

Dr. Ma: True, that is a concern with the bypassing agents; we cannot monitor their efficacy in a standard, reliable way. Monitoring efficacy is possible, but it requires sophisticated equipment; not all health-care centers have that available, and, even in some hands, the sophisticated monitoring is not reliable.

Most centers will only be able to use crude measures of efficacy. Because we’re not able to monitor its efficacy, we don’t know how much of the bypassing agent to give, when to give it, or if it is effective. I like to say, ‘To measure the efficacy of these drugs, you need a Sharpie marker, a complete blood count, and a tape measure to measure limb girth or the size of a hematoma.’

Again, these agents also can be fairly pro-thrombotic in certain patients with circulating activated platelets and significant vascular disease. These are the patients for whom I worry the most about a potential thrombosis.

Dr. Kruse-Jarres: I agree – considering the thrombogenicity in individual patients is important when we are deciding on a treatment approach. AHA is a rare disease that typically affects older people who do not have a bleeding disorder to begin with. Because of their age and the possibility of an underlying disorder, such as a hematologic malignancy, these patients are at an increased thrombotic risk before treatment begins. When we start these patients on a hemostatic agent, we need to keep in mind that they are also being treated with immunosuppressive therapy that will eventually get rid of the inhibitor. During that time, there is definitely an elevated risk for thrombosis.

We have good hemostatic treatment options available, in the form of FEIBA and rFVIIa – which are both about 90 percent effective when used as a first-line agent for hemostasis – but neither one offers measurable efficacy and both of them have thrombogenic potential.

Dr. Ma: Still, I would say standard bypassing agents are preferable to rpFVIII in a couple of circumstances. The first occurs when you are at a center where FVIII levels cannot be measured in real time; using rpFVIII in this case would completely negate the one great benefit of the agent. In clinical trials, rpFVIII was administered in much higher doses than we would typically use in clinical practice. So, if you are going to use it blind – without measuring FVIII activity – then I think you have to use it on-label. In this case, that means overshooting with FVIII and potentially increasing thrombotic risk.

Dr. Kruse-Jarres: That’s absolutely true. rpFVIII is a drug that not only can, but must, be monitored. Because people have very different recoveries and half-lives in response to it, it is difficult to predict how patients will respond.

Dr. Ma: Secondly, patients vary greatly – some need rpFVIII infusions every three or four hours, while some need an infusion every eight to 12 hours. Also, the same patient can go from needing rpFVIII every three to four hours to every eight to 12 hours with prolonged exposure.

Dr. Kruse-Jarres: Or vice versa. We also have to consider that, because people treated with rpFVIII can develop inhibitors to porcine FVIII over time, the response to rpFVIII can lessen over time. This makes monitoring so important.

I would add that patients with relatively mild bleeding probably benefit from being treated with a bypassing agent [rather] than rpFVIII. These patients should be started on a bypassing agent so they aren’t exposed to the porcine FVIII; treating a minor bleed with rpFVIII first could trigger the development of antibodies to the porcine FVIII, so we would want to preserve rpFVIII in case the patient has a more severe bleed later.

Dr. Ma: So, we agree that there are definite situations where bypassing agents would be our preferred first-line therapy. Despite this, I also want to make it clear that I like rpFVIII. I think it is a wonderful drug. Patients respond to it, and I can determine their hemostatic levels based on their FVIII activity. It gives me a level of confidence that I’m achieving a satisfactory FVIII level for my patients.

That being said, it costs $4.56 a unit. A cost-comparison between patients treated with the standard bypassing agents demonstrated that rpFVIII comes out at least twice as expensive as these agents. If the costs were lower, we would consider it first-line therapy for our patients, but because of the pricing strategy, I am forced to use a more physiologic agent that might not be the one I’d like to use.

Dr. Kruse-Jarres: Perhaps, but if you have a patient who may only need rpFVIII at 50 μ/kg every 12 hours, it will be cheaper than the bypassing agents – even at the current price. However, if you have to use 200 μ/kg every four hours, then it definitely becomes much more expensive.

Dr. Ma: I can give you one costly example: Our first experience with rpFVIII was treating an older woman who had not responded to rFVIIa. Our pharmacist eventually allowed us to use rpFVIII, which turned out to be very effective. However, the patient went on to have more bleeding episodes during that same hospital admission – as patients with AHA are prone to do – and she was in the hospital for about six weeks.

The total cost of her rpFVIII during that admission was $6 million. Medicare declined the bill three times. That is a huge financial hit for any medical center. Last year, we treated four patients with rpFVIII and our hospital was charged $12 million. Fortunately, the drug was efficacious and patients are doing well; however, the cost issues are a phenomenal barrier. It sometimes puts me in the position of using my second choice of drug to treat patients until they experience harm before I can use my first choice.

Dr. Kruse-Jarres: Related to the cost issue is the ease-of-access issue. At our center, we are having major issues with getting the drug on time.

rpFVIII is supposed to be delivered to the hospital within six hours, but that has not been the case. With the last patient who needed it, it took more than 24 hours to receive it. In addition, the pharmacist has to execute a contract with the distributor to get the drug; when a patient presents on a Friday night, for instance, getting that contract can be difficult.

Dr. Ma: At our institution we may stock an expensive and uncommonly used drug by buying it on consignment. The pharmaceutical company puts the drug on the hospital’s shelf, but the hospital isn’t charged until the drug is used. In this situation, the price the hospital pays at the time the drug is used is higher than the price for buying it outright, but hospitals pay that higher price for the convenience.

Dr. Kruse-Jarres: We have not yet figured out how to purchase the drug on consignment in our pharmacy. I might not see any patients with AHA for the next year. At that point, the product I bought would already be outdated, and I would have lost $100,000 or $300,000 in product that I am responsible for.

In the clinical trials for rpFVIII, we used it completely differently than how we would use it in real-world practice because we were not hindered by the price. I can recall one trial participant who was receiving massive amounts of rpFVIII – 300 to 400 μ/kg every two to three hours for a month. Eventually, after a month, her inhibitor activity went so high that I couldn’t treat her with rpFVIII anymore. That simply could not happen in clinical practice.

Dr. Ma: Not if you wanted to stay employed!

At our hospital, we have treated six patients. It would have been cost-effective to use rpFVIII in three of these patients because the genetics of their antibodies were such that we did not have to use very much of the drug. In other patients, though, rpFVIII has been overwhelmingly more expensive than a bypassing agent would have been. Again, we only used rpFVIII because bypassing agents were either ineffective or too pro-thrombotic.

Rebate programs might help with this problem, but overwhelmingly, the answer from our pharmacy and physicians at our hemophilia treatment center has been that the drug is too expensive and prohibitive. All patients are different; some patients will end up being more cheaply treated with rpFVIII and some will be more expensive. But, because of the cost of rpFVIII, I cannot have it on my formulary. This is a regulation that has been externally imposed on me solely because of the cost.

Before rpFVIII was approved, we had rFVIIa and FEIBA. They weren’t perfect, but they worked pretty well. When rpFVIII was approved, everyone was excited to have another option, but then we saw the price. As a physician, it’s very frustrating to not be able to use what I would like to use, and what I know would be effective for my patients. If price was not an object, I would be inclined to use rpFVIII upfront and switch to a bypassing agent if the patient developed neutralizing antibodies to rpFVIII.

Dr. Kruse-Jarres: Unfortunately, I don’t think there will be a clinical trial that will definitively prove whether rpFVIII or bypassing agents are the best choice for AHA patients, because there are not enough patients to be able to accrue to such a clinical trial. When we’re thinking about which agent would be the optimal choice for most AHA patients, we have to ask, ‘If we have adequate alternatives, like the bypassing agents, why would we prescribe the more expensive option?’ In my opinion, the answer is simple: rpFVIII fixes the hemostatic defect, and it is the most targeted therapy.

Editor’s note: Since this interview was conducted, the manufacturer of rpFVIII (Obizur; Baxalta) has lowered the price per unit to $3.40. However, Dr. Ma noted that the University of North Carolina pharmacy is “still not willing to place it on its formulary.”