Nonfactor agents for hemophilia prophylaxis: A Q&A with Steven Pipe, M.D.

Steven Pipe, M.D., is a professor of pediatrics and pathology and Laurence A. Boxer Research Professor of Pediatrics at the University of Michigan in Ann Arbor, Michigan.

Managed Healthcare Executive (MHE): What are some of the main advantages and disadvantages of factor replacement therapy for patients with hemophilia?

Pipe: Factor replacement therapy was easy to discuss with patients, because, basically, you were communicating that you’re replacing what the patient is missing (factor VIII or factor IX). There are some benefits to factor placement, in that it retains all the natural regulation of hemostasis with those molecules. There’s a wide therapeutic window, and we really had developed an experience of efficacy in almost every clinical scenario possible. We also had the availability of laboratory monitoring.

The challenge with factor replacement is that the peaks and troughs of intravenous (IV) infusion therapy don’t mimic normal physiology. And, because patients end up at low trough level leading up to their next prophylactic dosing, there are real consequences of nonadherence with resultant breakthrough bleeding. There’s also a significant therapeutic burden. Patients were having to get IV infusions multiple times per week, and there was a significant burden of cost.

The other major issue is that about one-third of patients will develop inhibitors to the infused factor VIII. Before the availability of nonfactor therapy, this had life-transforming consequences. Outcomes were worse, bleeding was worse, joint outcomes were worse and overall morbidity and mortality were substantially worse.

MHE: What were the overall goals of nonfactor replacement therapy?

Pipe: We’re trying to get better control of bleeds, and, ideally, zero bleeds — at least zero joint bleeds — to have better joint outcomes. Patients want easier, less frequent administration and to avoid the challenge of the development of inhibitors. The nonfactor therapies also generally modulate hemostasis so that you have a steady-state, hemostatic improvement in the patient, so there are no peaks and troughs between doses.

We’re really trying to improve patients’ overall quality of life and enable them to live active lives, similar to their non-hemophilic peers. The nonfactor agents are also improving overall health equity by leveling the outcomes for patients, regardless of whether they have complications like inhibitors. We can use some of these nonfactor therapies for hemophilia A and hemophilia B, with and without inhibitors.

MHE: Emicizumab, sold under the brand name Hemlibra, was the first nonfactor replacement therapy approved by the FDA. Could you describe its mechanism of action and its use in clinical practice?

Pipe: It is a humanized, bispecific monoclonal antibody. It’s bispecific in that the two arms of the antibody recognize factor IXa and factor X, which is the complex that is key for generating factor Xa and then generating a thrombin burst. Normally, factor VIII in its activated form takes the role of assembling this complex that generates factor Xa, and, of course, when you have severe hemophilia A, you can’t form this complex.

Some people think of this as a substitution therapy for hemophilia A, and emicizumab is sometimes referred to as a factor VIII mimetic. But emicizumab has nothing structurally similar to the factor VIII molecules, so the inhibitors that a patient may have developed in response to factor infusion don’t have a clinical impact. When it was approved initially in 2017, it was approved for people with hemophilia A with inhibitors. That produced almost an unparalleled health equity advance for those patients who really never had a highly effective prophylactic strategy. It was subsequently approved for hemophilia A without inhibitors.

It’s a subcutaneous (SC) therapy with three dosing regimens: once a week, every two weeks or every four weeks. There’s really no key difference between the dosing regimens as far as outcomes.

There are some challenges. Emicizumab doesn’t treat acute bleeding events, so you still have to use factor VIII for treating bleeds or for surgery, and, if you have an inhibitor, you still have to rely on bypassing agents. It was discovered during the clinical trials that activated prothrombin complex concentrate, or aPCC, that we use as bypass agent was associated with thrombotic microangiopathy and some thromboembolic events. As a result, patients either avoided the use of this particular bypass agent or, if it was necessary, were counseled to use it at a lower dose for the minimal duration. We were able to avoid these events subsequently, and, going forward in real-world use, that’s also been quite successful.

The other challenge with emicizumab is that there’s a ceiling effect. It modulates hemostasis to what most would consider to be within the mild hemophilia range, but it doesn’t normalize hemostasis, so patients still have sporadic breakthrough bleeds. For some surgeries, particularly major surgeries, patients are going to require some sort of procoagulant, factor VIII or bypassing agents, to get them through that surgery.

MHE: Please discuss the other category of nonfactor therapy — the rebalancing agents — and their mechanism of action.

Pipe: So the principle here is that we think of our hemostatic balance as a balance between the procoagulants on one side, so this would include factor VIII and factor IX. On the other side, there are the natural anticoagulants, which include antithrombin, tissue factor pathway inhibitor and proteins C and S.When normal amounts of both the procoagulants and the anticoagulants are present, this allows you to get a sufficient burst of thrombin generation that is properly counterbalanced by the action of the natural anticoagulants, which contain the clotting process so that it’s not pathologically excessive.

So how can we leverage these two different mechanisms? We already know from in vitro and clinical data that you can have a deficiency of the procoagulants, including a severe deficiency of, say, factor VIII, yet we can enhance thrombin generation with concomitant impairment of either the activity or the levels of one of the natural anticoagulants — for example, antithrombin. This restores the hemostatic balance, and it can lead to an amelioration of the bleeding phenotype, even though no additional factor is involved.

Because it’s acting on the natural anticoagulant side, rebalancing works the same in hemophilia A or B, with or without inhibitors. We almost have a pan-hemostatic agent to use in the clinics.

Procoagulants are still needed to manage breakthrough bleeding or surgery, and this is part of the risk of these agents. If you’ve already knocked down these natural anticoagulants to enhance thrombin generation, when you have to add in a procoagulant like factor VIII, factor IX or a bypassing agent, there is some risk that you could overshoot, which can lead to a thrombotic complication. This has been observed in essentially all of these clinical development programs.

MHE: Could you discuss the rebalancing agents that have been approved and have been launched?

Pipe: There are two monoclonal antibodies that target tissue factor pathway inhibitor — concizumab [sold under the brand name Alhemo] and marstacimab [sold under the brand name Hympavzi]. Just recently, concizumab was approved for hemophilia A and B, with and without inhibitors. Marstacimab is currently approved for just hemophilia A or B without inhibitors, but there is a clinical development program exploring its efficacy in patients with inhibitors.

Fitusiran [sold under the brand name Qfitlia] has a completely different mechanism of action. It’s a small interfering RNA that gets taken up by the liver. It basically targets the antithrombin messenger RNA, leading to its degradation, so the synthesis for antithrombin is dramatically reduced.

MHE: How has emicizumab changed the hemophilia prophylaxis landscape?

Pipe: Because there was no effective prophylactic option for hemophilia with inhibitors, the vast majority of the U.S. inhibitor population ended up on emicizumab with incredible results. There was also some real longing for relief from the burden of the frequent IV infusions. There were patients who saw advantages just for their lifestyle of having a relatively infrequent SC therapy. And there was also this idea that maybe this is a superior prophylactic strategy because of the steady-state levels that are maintained, avoiding the troughs that we see with factor placement therapy.

The other way that emicizumab has really transformed care from a patient outcome perspective is for infants. IV therapy for prophylaxis is just far too challenging to initiate in small infants at birth with severe disease. We had to delay initiating prophylaxis until infants were somewhere between nine months and 15 months of age, and we know that there is a risk of bleeding when they’re not on prophylaxis. And worse, there’s a risk of approximately 4% of infants who develop intracranial hemorrhage when they’re not on prophylactic therapy. Emicizumab has allowed us to initiate prophylaxis as early in life as possible.

MHE: How have the rebalancing agents changed the hemophilia prophylaxis landscape? How do the three FDA-approved agents compare to one another?

Pipe: From the clinical trial data, they all seem to be effective at producing prophylaxis. There is a thrombotic risk related to using these agents for the reasons we talked about, but risk mitigation, if followed, substantially reduces that risk.

The dosing regimens are quite different among them. With marstacimab, it’s a weekly flat dosing, so anybody over 12 years old gets the exact same dose. There’s no lab monitoring, so a patient can essentially seamlessly transition from their prior therapy to marstacimab. There’s a loading dose, then a weekly SC dose. Patients can still use their factor products for treating breakthrough bleeding or for surgery.

Concizumab is quite different due to some aspects of its pharmacokinetics. It has to be given SC daily. You might think that that’s a potential drawback. But, in fact, it’s available in a very nice pen device with a very tiny, 32-gauge needle with an auto-delivery mechanism. Patients have been able to incorporate concizumab into their daily routines. It is weight-based. There’s a single laboratory test that’s obtained four weeks after patients start concizumab. This ensures that they’re within the target range, so patients can either be dosed up or have their dose adjusted down so that they’re in the proper range, and this is part of the risk mitigation. I’ve been surprised, actually, that the daily SC injection hasn’t seemed to be a deterrent for patients to embrace this therapy. Concizumab now has the broadest eligibility for patients, because it’s now approved for hemophilia A and B with and without inhibitors.

Fitusiran was approved by the FDA in May 2025 and is the newest rebalancing agent. It’s administered SC and started on an every-other-month schedule. It does require an antithrombin-guided dosing schedule, but this is not particularly onerous, because when you’re only getting dosed every other month, you’re basically just doing a monthly check of antithrombin level to track your progress of how far the antithrombin has been knocked down. You only have to make adjustments if a patient’s antithrombin activity level is either below 15% (because that could increase your risk for thrombosis) or above 35% (which is going to lead to reduced efficacy for the drug). What we’ve seen from the extended clinical trial program and what’s been modeled based on the pharmacokinetics from that program is that the great majority of patients are only going to need one dose adjustment, if any.

The most common regimen that people will end up on at a steady-state level is at the original starting dose of 50 milligrams every two months. The requirement for the antithrombin testing is a good risk mitigation approach, not too onerous, and something that you just have to discuss with the patient. And then once they’ve been established on their dose, they’re going to maintain steady-state levels for the duration. And this means that, likely, the monitoring is going to be once a year from that point forward.

MHE: What’s the latest evidence about the efficacy and safety of the nonfactor therapies, and what gaps in our understanding are real-world data filling in?

Pipe: From an efficacy perspective, all of them have been shown to be highly effective prophylactic agents. That was by comparing them against patients who came into the trials who were previously only using on-demand therapy, and you see marked reductions in the bleed rates when patients are using these nonfactor therapies. But almost all these trials included a group who came into the study on prophylactic therapy, usually with either factor products or bypassing agents. What we saw is that these nonfactor therapies were, at worst, noninferior to prior standard of care prophylaxis, and, in most cases, showed superior bleed protection than what patients were able to achieve with their prior standard of care prophylaxis. Safety, as we talked about, is primarily related to potential for thrombotic complications and the need for risk mitigation.

What are some of the gaps? When these rebalancing agents were being developed, they were compared to the accepted standard of care, which, at the time, was the factor replacement products and the bypassing agents available in the current era. Now these therapies are going to be compared to what we’ve achieved with drugs like emicizumab. We don’t have head-to-head data comparing emicizumab to any of the other nonfactor agents we talked about today.

The question becomes, how you would even do that trial? There are switching studies, and this is where clinical trial data and real-world data are going to help us understand this. Since emicizumab has become the new standard of care for prophylaxis, many people are studying what that transition looks like. How long do you hold dosing of emicizumab before you initiate these other therapies? How do you safely transition from one nonfactor therapy with a particular mechanism of action to another one with a different mechanism of action? In some cases, it’s just a direct switch.

Along the way, there have also been some new developments with factor replacement products. In the last year, we have had an ultralong half-life factor VIII, efanesoctocog alfa, that was developed and marketed as Altuviiio [antihemophilic factor (recombinant), Fc-VWF XTEN fusion protein]. Its significantly extended half-life has changed the pharmacokinetic paradigm of factor replacement substantially.

These nonfactor therapies now have to compete, if you like, with the new pharmacokinetic profile coming from this ultralong half-life factor VIII. This actually has to be part of our shared decision-making when we’re talking to patients. For those with hemophilia A, we have emicizumab, this new ultralong half-life factor VIII, and then these other nonfactor therapies. We’re having to review all of the characteristics and properties of these agents and outcomes and try to match them to the patient’s personal goals for what they want out of their prophylactic therapy.

MHE: You’ve emphasized patient preference. But are there any lab values or objective tests that would help clinicians decide which patient should be treated with which prophylactic agent?

Pipe: That would be ideal if you had some parameter, based on a lab assay for example, that would determine who is best suited for this particular therapy. We haven’t been able to identify that.

In some cases, for patients who have known family histories of thrombotic complications, or who may have had their own thrombotic complications on their prior therapy, there may be a tendency for clinicians and patients to steer away from the rebalancing agents because of the concern about an increased risk of thrombosis.

MHE: From a health system or payer perspective, are there cost or access challenges influencing the prescribing decisions for nonfactor therapy?

Pipe: Emicizumab was the first nonfactor therapy to be priced against factor products, and from what I have seen in the U.S., its annual cost is roughly what it would be for a patient taking an extended half-life factor VIII agent for prophylaxis. It’s probably considerably more cost-effective than attempts at prophylaxis with bypassing agents. Across the payers, both private and commercial plans, and also for the state Medicaid plans, we haven’t had restricted access to putting patients on emicizumab. It clearly has an advantage for patients with hemophilia A with inhibitors, and there’s accumulating evidence of its benefits for hemophilia A without inhibitors, as well. The pricing on the newly approved nonfactor therapies is in the same ballpark. None of these agents have really made themselves inaccessible, related to price.

What’s a challenge is the stepped approach that payers use in some therapeutic areas. In some cases, payers are asking for evidence of a failure on a prior therapy before you can get access to these agents.

For the rebalancing agents that are used for hemophilia B and hemophilia B with inhibitors, I think it’s been pretty straightforward to get access. But I think it can be variable based on how the insurers structure their access for the hemophilia A patients. So we’re still working this out. Some of these agents are so new. In some geographies, the access for prior authorization isn’t entirely clear yet, so we’ll have to sort of see over the coming months and years what this actually looks like in common practice.

MHE: Are there any practical obstacles to access?

Pipe: It’s a pretty big commitment to start on these therapies because of how long they last; it’s less so with concizumab and marstacimab. With fitusiran, once you reach your steady state, even if you don’t take any more fitusiran doses, your levels of antithrombin are going to be very low for anywhere from three to four months afterwards. So once you’ve made a commitment to initiate this therapy, if you choose to switch to something else, there has to be a real plan on how to do that safely.

Patients who have been treated with emicizumab have evidence of emicizumab still being on board three to five months after they stop getting the drug.

The long duration of effect of these drugs can be a barrier, because if a clinician and a patient are concerned about transitioning from one platform of therapy to another, they have to consider the effect and make sure they have a proper plan in place for how to do that transition.

MHE: Are side effects from administration an issue with the nonfactor replacements?

Pipe: I was taken a little bit aback by the switch from IV to SC therapy. I thought, naively, that SC administration would be no big deal for patients who’ve been used to IV administration. But in some cases, needle phobia still is a significant issue even with SC dosing. We learned this with emicizumab. We’ve been using this for many years now, but some families talk about the anxiety that their child may have leading up to that SC injection, even if they’re only dosing it every four weeks.

We’ve also noticed that some older patients who became very adept at doing their IV accesses — it really doesn’t bother them anymore — but the switch to the SC actually was causing more discomfort for them. In some cases, it was enough of a dissatisfier that they actually stopped doing the SC therapies.

If you look at the clinical trial programs, up to 20% of patients report infusion-site reactions. They are probably related to the volume that’s being injected into the skin and also the formulation of the drug itself. The second-generation mimetics are going to have substantially lower volume, so they will likely be less irritating when injected SC.

MHE: Are there near-term research or policy developments that could significantly affect the uptake and prescribing of nonfactor therapies?

Pipe: The patients were well selected for suitability in the clinical trial program. Many of these trial programs excluded patients who had either a prior history of personal thromboembolism or a strong family history of thromboembolism. In the real world, we’re not advocating for screening thrombophilia assessments. But after these roll out in a less selected population, I think it remains to be seen whether there are some patients who may have more side effects on these drugs. I think we need more research and real-world data to help us understand.

As far as policy, all of these therapies have been achieved with really strong basic research and deep pockets funding the clinical development programs; some of these programs were in clinical trials for 10 years to get to the approval process. So I’m concerned about policy decisions that could be implemented that would reduce basic research, because that’s going to reduce our ability to develop these kinds of innovations.

I’m also concerned about policies that might limit the pricing of biologic agents; some of these could fall under this pricing. If the pricing power for these agents isn’t there because of policy decisions, I worry about access for patients. Drugs will be withdrawn from marketing or will only be available in certain geographies.

I don’t think policies related to state Medicaid plans are really going to be the biggest risk going forward. These nonfactor agents have all been priced similarly to agents that have already been approved and covered by these plans. All hemophilia products are highly costly. I don’t think these nonfactor therapies