Alice Ma, MD Beth Warren, MD
For patients with hemophilia, prophylaxis is necessary to prevent bleeding, and in particular, life-threatening or recurring joint bleeding. There are two primary modalities for continuous prophylaxis that a hematologist may prescribe to reduce the frequency of bleeds and improve quality of life: factor prophylaxis and non-factor prophylaxis.
Factor prophylaxis involves the regular infusion of missing clotting factors with the aim of raising the levels and preventing bleeds: factor VIII (FVIII) for patients with hemophilia A and factor IX (FIX) for patients with hemophilia B. At the time of publication, emicizumab is the only product approved in the U.S. for non-factor prophylaxis. This therapy does not replace the missing FVIII in people with hemophilia A but mimics the function of FVIII so that the clotting process can proceed.
In this edition of “Drawing First Blood,” Beth Warren, MD, assistant professor at the University of Colorado Anschutz in Denver, and Alice Ma, MD, professor of hematology at the University of North Carolina in Chapel Hill, discuss the differences between factor and non-factor prophylaxis, explain why a hematologist might select one over the other, and delve into the pros and cons of each modality. Dr. Warren was invited to argue in favor of factor prophylaxis, and Dr. Ma in favor of non-factor prophylaxis.
Dr. Warren: People with hemophilia need prophylaxis because they would otherwise have a higher risk of joint bleeding and long-term joint damage, muscle bleeds, and other bleeding ranging from annoying to life-threatening. It has been well proven that people with hemophilia need prophylaxis. Factor was the original medication used to prove that people with hemophilia need prophylaxis. Traditional factor prophylaxis is intravenous (IV) every other day, depending on the half-life of your product. Those studies were done before any other modalities of treatment were available. Factor prophylaxis is the closest biochemical replacement for what is missing if you have hemophilia, so that is why it might be the preferred treatment modality.
Dr. Ma: Non-factor prophylaxis medications are all of the new fancy biologic therapies that are used to replace factors, such as emicizumab, which is the only non-factor therapy that’s currently approved by the U.S. Food and Drug Administration (FDA) or approved in the European Union for prophylaxis. It’s not approved for the treatment of bleeds and is used for prophylaxis before traditional prophylaxis would even start, especially in babies. It doesn’t require the use of IV access devices, which is much less invasive for little kiddos, and it doesn’t require as much timing for pharmacokinetics either. If you miss a day or don’t give it in the morning before you go off to work or school, it’s much more forgiving. It also allows for a higher “factor VIII-ness,” if you will, so it’s a lot more forgiving, certainly on a pre-damaged adult joint.
To argue Dr. Warren’s point for her, it may be that factor is better for active kids who are playing sports, who might need a higher level around the time of sporting events. Emicizumab might or might not be the very best treatment for them, but certainly for patients with FVIII deficiency with inhibitors, take no prisoners, emicizumab is the best treatment for them. There is no patient with an FVIII inhibitor for whom emicizumab is not superior, unless they’ve developed an inhibitor to it. Absolutely, 120%, I’m going to my grave saying that.
For those who have no inhibitor, I think patients are voting with their feet and their pocketbooks. As of two years ago, 70% — and the number is higher now — of the U.S. market share of patients who are FVIII-deficient without inhibitors had moved to emicizumab, and patients are not switching back. The only people who argue against it are those who work for home care agencies. I think, emicizumab is really the preferred agent? Now we can argue about that. Is it the best agent for surgery? No. Is it the best agent for an inhibitor? If you absolutely need to have activated prothrombin complex concentrate, then yes, use with caution. But for an inhibitor patient, use with caution, but absolutely for prophylaxis, yes, it’s the best agent.
Dr. Warren: What if your patient has a tolerized inhibitor? I worry that a tolerized inhibitor could cause patients on emicizumab to have less exposure to FVIII and they might lose that tolerance until they have some big bleed. Then, you’re going to figure out in the middle of the bleed that these patients have suddenly lost their FVIII tolerance.
If you’ve had an inhibitor, you might want to keep up the FVIII so that you keep your inhibitor tolerance going. As Dr. Ma mentioned before, for sports, FVIII level is way more titratable. So, if you’re doing a high-intensity sport and get injured, your level is probably not going to be high enough if you are only on non-factor prophylaxis.
Full disclosure, we do have a lot of patients doing intense things on emicizumab without extra factor, but theoretically, that’s not enough – you’re not going to get your factor level to 100% on emicizumab.
The other thing I worry about is that people could lose their infusion skills on emicizumab because it’s subcutaneous, so they are not using their IV infusion skills. There is currently a problem in Colorado with Medicaid only allowing people to have factor at home if they can prove that they can self-infuse. We have some patients who are seven hours from the nearest emergency room that has factor, so losing the ability to self-infuse is an important consideration. I don’t know if it’s worth it to poke yourself in the vein every other day just to maintain that skill, but it is something we do need to think about.
Dr. Ma: So that’s FVIII. That’s about two-thirds of our hemophiliacs. For everyone else, we’re just waiting, it’s a theoretical thing, because for patients who are FIX-deficient, we’ve got nothing but factor. We’re waiting for two rebalancing therapies, fitusiran and concizumab, to be approved by the FDA, but until then, the options are factor or factor, so I guess we’ll choose factor.
Dr. Warren: For factor prophylaxis, there are a lot of different options. This is not going to be a very popular opinion, but there are too many options for factor products, and they all have subtle differences that drive up the prices. That makes me a little crazy because we’re having trouble getting factor for a lot of people right now, and it would be really nice if that could be solved, in part, by lowering prices. The bigger differences between products are in the modifications to factor that have changed the half-life, which has had a lot more success in FIX than in FVIII. So, on paper, there are about a million options for different factor products, but in practicality there are a couple of classes, and we go with whatever your insurance company would prefer at that time.
Dr. Ma: When it comes to non-factor products being approved, I think fitusiran is at the FDA and concizumab is done with phase III trials, so in the next year or two those therapies should be available for patients who are both FVIII- and FIX-deficient. They’re going to have a hard time breaking into the FVIII-deficient space because emicizumab has been so successful, but everybody’s waiting on what to do for the FIX-inhibitor patients. Those few patients are really where there’s an unmet need.
Dr. Warren: Regarding quality of life for patients, I must flip sides on this. Giving yourself a subcutaneous shot every two weeks is way more convenient than IV every other day.
Dr. Ma: If you’re the parent of three school-age children with hemophilia, your quality of life in trying to do IV infusion every other day, getting it to them before school starts, is going to be exponentially more difficult versus one shot on the weekend. There is no parent who’s going say, “Oh, I really prefer factor prophylaxis.”
Dr. Warren: If you’re looking at patients who are active in sports, I don’t think we know which modality is preferred. Theoretically, there are patients who are involved with sports like skiing or football (which we don’t recommend, but sometimes people feel very strongly), and we don’t feel great sending them into a contact situation with a factor level of less than 100%. Skiing isn’t as bad unless you’re running into a tree, but if you’re going into a contact situation, your factor level really should be 100% because we need to even the playing field due to the risk of a brain bleed. So, if you’re going to do contact sports, which we generally don’t recommend, you should be on factor. That being said, we’re trying to gather a lot of data about what kind of sports you can safely do on emicizumab, but everybody is different and moves differently. Peewee tee ball is very different from varsity baseball, so it’s hard to collect that data, but, anecdotally, a lot of people are doing well on emicizumab and are doing sports.
Dr. Ma: I don’t have anything to add except to say that it’s an individualized decision. When you’re playing soccer, it’s one thing until you start heading the ball. And when you start heading the ball, that’s a very different decision. And when you start heading the ball and you’re on the varsity team, it’s a very different decision than when you’re just playing around.
Dr. Warren: I don’t think it’s possible to achieve zero bleeds. It would be ideal, but things happen. I don’t think you can fully prevent bleeds unless you fully normalize your FVIII or FIX all the time.
Dr. Ma: It depends. If you step in a hole, for example, you’re going to have a joint bleed, even if your FVIII level is 100%. On the other hand, if you are a more sedentary adult, which most of my adult patients now are, our annualized bleeding rates (ABRs) are zero on emicizumab, which they weren’t on factor prophylaxis.
Dr. Warren: Our ABRs on emicizumab are not zero, but our clinic doesn’t have as many sedentary patients.
Dr. Ma: Sedentary adults have less bleed risk, so I think it depends on your patient population.
Ultimately, when it comes to prophylaxis, more options are better. Lower costs are also better, as is more choice for the physicians and less choice in the hands of the pharmacy benefit managers and the insurance companies.
Dr. Warren: I could not have said it any better.
The following positions were assigned to the participants and do not necessarily reflect ASH opinions, the participants’ opinions, or what they do in daily practice.
Kimberly Retzlaff is the managing editor of ASH Clinical News.
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