Okay, so before we dive in, here are some perspectives people have shared on modern hemophilia care.

And I suppose if I was to read one of these out, it would be the top-right one. I think is really on point. Early individualized prophylaxis is recommended – tailored to bleeding phenotype, joint status, pharmacokinetics when applicable and patient preference.

I think this and the other perspectives here really focus on our ability to individualize prophylaxis and bleed treatment and how this can optimize joint health and quality of life for our patients.

[00:11:00]

What Is Hemophilia?

So to make sure we are all starting together on the same page here, hemophilia A and B are rare X-linked bleeding disorders. Hemophilia A is a deficiency in factor VIII and hemophilia B is deficiency in factor IX. Most of the time there is a family history, but up to 30% of hemophilia cases are sporadic, as in there is no known family history, although it is important to offer testing to family members.

Hemophilia A is seen in 1 in about 5,000 male births, and hemophilia B much less common, about 1 in 30,000 male births. And although we historically report incidents in terms of male births, females can also have hemophilia. Most often this is due to having a single factor VIII or factor IX gene variant and being therefore a carrier, but with skewed X inactivation, they can have low levels in the low normal range or in the truly low hemophilia range, and they can be symptomatic with bleeding. Although it is, of course, quite rare, it is also possible for females to have moderate or severe hemophilia.

[00:12:13]

Hemophilia Severity

Hemophilia severity is defined by the baseline factor activity and severe hemophilia is defined as factor VIII or 9 activity, less than 1%. Moderate hemophilia is factor VIII or 9 activity between 1-5% and mild hemophilia greater than 5% and up to 40%.

In the absence of treatment, we know that individuals with severe hemophilia are expected to have frequent and spontaneous deep tissue bleeding, including bleeding into muscles and joints. And these can occur up to 2-5 times per month without treatment.

Spontaneous bleeding is much less common in moderate or mild hemophilia, but we know that bleeding phenotype does not always correlate well with the baseline factor activity. And some individuals, particularly with moderate hemophilia, can have bleeding patterns similar to severe hemophilia and also benefit from prophylaxis.

Prophylactic treatment can be lifesaving by preventing life-threatening bleeds and can also prevent the more chronic joint damage and pain that can come from recurrent joint bleeds as well.

[00:13:19]

Hemophilia With Inhibitors

Of course, the mainstay of treatment and prophylaxis has been the use of factor replacement to make the factor activity level at least temporarily into the normal range. The most feared complication of factor replacement is the formation of inhibitors, that is alloantibodies against factor VIII or factor IX that can occur in response to exogenous factor protein.

The incidence of inhibitor formation is as high as 35% in severe hemophilia A and as high as 10% in severe hemophilia B. And when this occurs, treatment with factor concentrates can become ineffective, particularly in those with a high titer inhibitor. Inhibitor eradication can be possible using immune tolerance induction or ITI, which usually involves high and frequent dosing of factor concentrates, but this is not effective or feasible for everybody and can be effective in about 70% of hemophilia A and maybe only 25% of hemophilia B.

Patients with hemophilia B who develop inhibitors in particular have been shown even in recent studies over the last couple of years to have the lowest reported quality-of-life measures on surveys, basically in all domains. And this is due to the lack of efficacious prophylaxis for this patient population, which has been an area of significant unmet need, and is for these patients in particular, these new medications that we are going to talk about today can really be life-changing because of the lack of really good prophylaxis up until this point.

[00:15:02]

Joint Disease in Hemophilia

Basically, all patients with moderate-to-severe hemophilia have some degree of joint disease. They can present with acute joint bleeds, with joint pain, swelling and warmth. And it is also possible to have subclinical or unrecognized joint bleeds. These too can lead to joint damage over time that can be clinically relevant.

[00:15:24]

Early Identification of Joint Disease

Particularly because subclinical bleeding can occur, it is important to screen for early changes in joint health even in the absence of a high reported bleeding rate. And in our practice, we usually do joint health screening at least once a year at each annual comprehensive visit. This should include at least a detailed history of any recognized or treated joint bleeds and any complaints of joint pain. There are other tools you can use for joint health screening, including standardized tools for assessment of pain, frequency and intensity, joint health assessment scores such as the HGHS, which look at joint range of motion and function that can be trended over time.

Increasingly in our practice, we are also using point-of-care ultrasound of the large joints, such as ankles and knees. These are done by a trained team member, in our case, usually a physical therapist. And these ultrasounds, we perform even on young patients without a reported history of bleeds because we may see early joint changes from some subclinical bleeding, and this can be used to guide our discussions about prophylaxis.

MRI is probably the best imaging modality for looking at early joint changes. But of course, this is expensive and not very practical. Mostly in my practice, is being used as part of research studies.

[00:16:56]

Management of Joint Bleeds

So before we talk about prophylaxis, we are going to just talk for a little bit about management of joint bleeds. It is really important to start early and young for patients with hemophilia and their families.

Talking about the signs of acute joint bleeds. This includes pain and swelling. Some patients experience a feeling of warmth or sometimes tingling before the swelling starts. They may have decreased range of motion of that joint. And for very young patients, the parents may just notice reluctance to bear weight on that extremity.

If there is clinical suspicion of a joint bleed or suspicion by the parents of a joint bleed, then treatment initiation should be started immediately before any diagnostic imaging is done, including before ultrasound, which may or may not be accessible to the patient in the moment that they are having a bleed.

The mainstay of treatment for bleeding is factor replacement, but the dosing and frequency really depends on multiple factors, including their inhibitor status and what prophylaxis regimen they are on. We are going to come back to this again in the future part of this talk when we are talking about the new therapies, because for some of the newer therapies, there are significant changes in the factor replacement dosing and frequency because of the mechanism of action of the prophylaxis medication.

In addition to treating with factor replacement, it is also really important to unweight the joint. We usually do non-weight bearing, for example, for the lower extremity with crutches for at least a week after a joint bleed and also the involvement of a physical therapist in order to assess recovery and range of motion and help the patient with a gradual return to activity. This is really key to prevent the early re-bleeding into the same joint and to preserve joint function going forward.

[00:18:56]

Emergency Management of Bleeds: Challenges

Some of the challenges in emergency management of bleeds include that many times patients are going to their local hospital in order to get quick treatment for their bleeds, and not all hospitals can stock factor products.

These medications are expensive and there are many different kinds and versions, and it is just not practical to have these in every hospital. So it is recommended by the National Bleeding Disorders Foundation that all patients with hemophilia should have an emergency supply of their factor at home, either to take to their nearest emergency department with them so it can be infused there, or for self-infusion at home if they are trained and capable of doing this, which many of our patients, including pediatric patients, are.

Patients and parents can also encounter emergency staff who are not familiar with hemophilia treatment because it is a rare disease. And so, it is also recommended that all patients are offered, at least, an emergency treatment plan letter that they can bring with them if they are needing emergency care. And this letter also has an emphasis on urgent treatment for bleeding based on patient or parent report of a joint bleed and not waiting for diagnostic confirmation or lab results.

It is also important for patients and families to have 24-hour access to an on-call bleeding disorder provider and having similarly a knowledgeable provider available on-call for emergency providers if they have questions.

[00:20:36]

Prevention of Joint Bleeds: Prophylaxis

So then we will move on to talk a little bit about prophylaxis. We know, as I mentioned earlier, that in severe hemophilia without treatment, the annualized bleed rate can be as high as 20‑40. And studies have shown that early initiation of prophylaxis can decrease this ABR by more than 90%. And really, early initiation of prophylaxis, meaning in early toddlerhood for severe hemophilia, is really the best way to prevent long-term joint damage and limitations on range of motion of the joints.

The newer medications, that being the non-factor therapies and the extended half-life factor therapies, have been shown to decrease this annualized bleed rate even more in comparison with the standard half-life factor medications. And when we go through the clinical trial data for these new non-factor therapies, you are going to see a lot of graphs that look similar to this.

This is a generalized graph. But it is similar to this, where they are comparing factor prophylaxis to the new therapy. And I think it is important to see that these new therapies decrease the ABR compared to standard half-life factor prophylaxis.

But these current studies do not really compare non-factor therapies to each other. We do not really have any head-to-head comparisons. And so you really have to use caution when you compare ABRs between studies because they look at different study populations and use different study methodologies.

[00:22:24]

Treatment Burden

When we are comparing prophylaxis options, it is really important to consider treatment burden for the patient. And historically, we only had standard half-life factor products. And these factor medications have a half-life of 8-12 hours or sometimes even shorter in very young children. And this means that many patients were doing IV infusions as often as every other day. This can be really challenging and painful. And for some folks, not feasible to do with peripheral venipuncture. And so, they were needing, especially young children, central venous catheters in order to receive their prophylaxis. Central venous catheters, of course, carry a risk for infection, Lyme malfunction and thrombosis. Treatments that are frequent also can interfere with travel or social activities, and an ability to gain independence in their treatment, particularly in adolescents.

There are some recent quality-of-life studies showing that patients receiving non-factor treatment report slightly lower treatment burdens compared to those receiving factor replacement therapy.

[00:23:40]

Thrombotic Risk

Another important thing to consider when comparing prophylaxis options and really starting any hemostatic therapy is thrombotic risk. So we know that individuals with hemophilia can have the same degree of atherosclerosis as their peers, and they can be at risk for ischemic stroke and thrombosis, including DVT in some circumstances, particularly if they have a central venous line.

And so, whenever we think about hemostatic therapies, we also need to recognize early any risk factors, non-treatment-related risk factors for our patients, and see if these can be managed or mitigated in some way in order to improve the safety of their therapy.

[00:24:29]

Personalized Prophylaxis

So as we go forward to talk about the sort of menu of options we now have available for prophylaxis and hemophilia, it is important to step back and think about the patient experience of the treatment. Individualizing prophylaxis includes, of course, consideration of bleeding risks, including the patient's activity level, their desire to participate in sports, the presence or severity of any existing joint damage, or any history of inhibitor or prior treatments.

But it also includes individual social factors, ease of venous access, and patient preferences or needs regarding dosing frequency and the route of administration.

[00:25:13]

Implementing Advanced Therapies in Community Practice

So next, we are going to go forward and talk about these newer advanced therapies, really with a focus today on the non-factor therapies.

[00:25:25]

Evolution of Hemophilia Treatment: US Approvals From 1988-2025

But just to give some context, here is a graphic of the U.S. approvals for medications for hemophilia between 1988 and 2025. And you can see that there have been a lot of new medications in the last 10 years. So up until about 2014, although there are many different versions of the products, they are essentially all standard half-life factor products.

Starting in 2014, we started to see some extended half-life products for both factor VIII and for factor IX. And then starting in 2017, we had the first approval for a non-factor therapy, which was emicizumab or Hemlibra for hemophilia A, which was approved for hemophilia A with inhibitor in 2017 and without inhibitor the following year.

But you can see nearly the full right-hand side of this graphic here is the last 3 or 4 years. In the last 2 years, in 2024 and 2025, there have been multiple non-factor therapies approved. And these are the ones we are going to focus a little bit on today. So there are factor VIII mimetics, which we will talk about. And then there are also TFPI inhibitors and antithrombin-lowering agents. The 2 of those are often referred together as the rebalancing agents because they do not replace or mimic the factor that is missing, but rather work to decrease a natural anticoagulant and rebalance the hemostatic system.

[00:27:19]

Non-Factor Therapies: Mechanisms of Action

Okay, so this picture here is a summary of these non-factor therapies that we are going to talk about and their mechanisms of action.

So in the bottom-left, you can see the factor VIII mimetics. These are bispecific antibodies. And the 1 that was approved first in 2017 is emicizumab or Hemlibra, which most people are familiar with.

There is also a medication called Mim8, which is currently under regulatory review. I think was submitted in September. So we are expecting to hear about that soon. It may be approved soon for hemophilia A. And then there is also an exciting new medication called NXT007, also in this class of medications, which is expected to start clinical trials, Phase III clinical trials soon.

And the other 2 medications on the right-hand side are referred to as the rebalancing agents, are the antithrombin knockdown medication fitusiran, which works by reducing the production of antithrombin. And then the anti-TFPI monoclonal antibodies, so those are concizumab and marstacimab. These medications are both already approved for hemophilia A and B. And they work by blocking the C2 domain of tissue factor pathway inhibitor, which again, can restore thrombin generation in individuals with hemophilia.

[00:29:02]

FVIIIa Mimetics

So let us start by talking a little bit about the factor VIII mimetics.

[00:29:08]

FVIIIa Mimetics Bridge Factor X and Factor IXa

So you may have seen this kind of figure before when emicizumab came out or Hemlibra, which was the first factor VIII mimetic to be approved. The factor VIII mimetics are by specific antibodies that perform the cofactor function of factor VIII.

That is, they form a bridge between factor X and activated factor IX. And although these medications perform this function, they do not look structurally like factor VIII. So they work as well.

They work very well for patients with hemophilia A with inhibitors, even though they have antibodies to factor VIII itself.

[00:29:48]

Emicizumab: Indication, Dosing, and Pharmacokinetics

Emicizumab is used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in both adult and pediatric patients, all the way down to newborns. And the HAVEN 7 study, which is the most recent study for emicizumab, has looked at starting this medication really in newborns down to several days of age.

It is given subcutaneously, starting with loading doses, weekly loading doses for 4 weeks, and then moving into the maintenance phase, which can be, again, a sub-Q dosing that can be weekly, every other week, or every 4 weeks. You can see that the trough concentrations are maintained in similar ranges, regardless of which of these dosing regimens is used.

[00:30:41]

Patients With Zero Treated Bleeds With Emicizumab Prophylaxis

So there have been many clinical trials, looking at emicizumab.

These are the HAVEN, the HAVEN Clinical Trial Program. And HAVEN 1 was the first clinical trial which looked at hemophilia A patients over 12 years of age who had inhibitors. And as I mentioned, the most recent one is HAVEN 7, looking at infants who have been previously untreated with factor and are starting their prophylaxis out their life with prophylaxis with emicizumab.

And so, 1 way that people like to look at the clinical trial data for emicizumab is looking at the percent of patients who had zero treated bleeds. And you can see that this is the majority of patients are really having zero treated bleeds on this medication.

[00:31:40]

Emicizumab Safety Summary

And here you can see the safety summary for emicizumab or Hemlibra.

In the HAVEN 1 study, there were a couple of reports of thrombosis and thrombotic microangiopathy. And these were really associated with the use of activated prothrombin complex concentrates such as FEIBA for treatment of bleeds in patients who had breakthrough bleeding. And again, these were the HAVEN 1 study was patients with inhibitors. So they were not able to use Factor for treatment and were using bypassing agents.

The mitigation strategy for this has been to avoid prothrombin complex concentrates or if they are needed to use them in lower doses than shown here. So to use them in lower doses, less than a cumulative dose of 100 IU/kg/d. We actually typically start with activated Factor VII products for breakthrough bleeding in patients with inhibitors instead if these are effective for them. And since, you know, these mitigation strategies have been put in place, there really have not been significant thromboembolic events on the factor VIII mimetics.

The formation of anti-drug antibodies is very rare, as mentioned here in safety summary, but it is very rare and usually not clinically significant. Although there have been a few cases of anti-drug antibodies that were neutralizing and led to loss of efficacy of this medication. And then there is 1 case report of a patient who developed lupus nephritis associated with this medication, which resolved spontaneously once the medication was stopped.

And there is a note here at the bottom also about infants in the HAVEN 7 study that have been shown to have slightly higher trough concentrations on the same dosing, but they have not had any cases of thromboembolic events despite this higher trough level.

[00:33:44]

FRONTIER2: Mim8 Efficacy

Okay, and then we will touch briefly on Mim8, which is the one, which is the factor VIII mimetic that is under regulatory review. So it is also similar to emicizumab in the sense that it is a bispecific antibody, but it has a novel design compared to emicizumab.

And you can see here are some of these graphs that compare the ABRs in the group pretreatment or after starting. And on the left, you can see for patients who are on on-demand treatment, so, meaning not on prophylaxis, but just receiving factor for bleeds, had a significant reduction in their analyzed bleed rate with, you can see, the mean ABR dropping down to 0.45 for these patients. Similarly, patients who were already on prophylaxis, there was some reduction in their analyzed bleed rates on this medication as well. And this included patients both with and without inhibitors.

[00:34:54]

FRONTIER2: Mim8 Safety Summary

When we are talking about safety, I am going to focus a little bit on the thromboembolic events because I think that is something that people are very interested in understanding as an adverse event of special interest. And here you can see there were none. There were no thromboembolic events in the Mim8 study. And again, this is some benefit of knowledge already from the emicizumab studies and knowing to not use high doses of PCCs. But Mim8 did not have thromboembolic events. There were no neutralizing antibodies detected in this study.

And the most common AE, which was also true for emicizumab, is injection site reactions, which was seen in about 10% of patients, and for the most part, did not lead to discontinuation of these medications.

[00:35:54]

Question 1

All right. So now we are going to come back to question 1. That was a pretest question. So this was the question, which said, which statement accurately describes Mim8 and best differentiates it from other non-factor prophylaxis?

Speaker: The poll is open. Five more seconds.

All right. Thank you. We will close the poll and share the results.

Dr Maher: All right, great. So yeah, the majority of folks are now saying D, which is correct.

[00:36:54]

So Mim8 is a factor VIII mimetic, and it can be given weekly, biweekly, or monthly, a similar dosing schedule to emicizumab. A is incorrect because it is not an oral therapy. There are no oral therapies in trials right now, although there may be in the future, which would be really exciting. It is not a monoclonal antibody against TFPI. It is a different mechanism of action. And then that really, that part B really describes concizumab. And then part C really describes fitusiran. So these are other medications that we are going to talk about today.

[00:37:42]

Question 2

All right. And posttest question 2. A 10-year-old boy has severe hemophilia A with a high titer inhibitor. He has frequent joint bleeds and poor venous access. His family prefers subcutaneous prophylaxis. And what is the most appropriate therapy?

Speaker: Poll is open. Five more seconds. All right.

Thank you. We will close the poll and share the results.

Dr Maher: All right. Great. So most people said emicizumab, which is answer A, which is correct.

[00:38:34]

So this is really, there are 2 parts here. emicizumab is really a great medication for hemophilia A with inhibitor. And also the age of this patient is important in this question because although these others are medications that can be used for prophylaxis and hemophilia A with inhibitor, they are currently only approved for children greater than or equal to 12 years. So they are not appropriate for this 10-year-old patient at this time.

[00:39:06]

Question 4

All right. Another posttest question. This was question 4. A 28-year-old man with severe hemophilia A without inhibitor has 4–5 ankle bleeds per year on on-demand factor and reports morning ankle stiffness. And he is interested in subcutaneous non-factor prophylaxis, but has a history of prior DVT. Which approach best reduces his risk of progressive joint disease?

Speaker: Poll is open. Five more seconds. All right.

Thank you. We will close the poll and share the results.

Dr Maher: All right. Yeah. So most people saying answer B here.

[00:40:06]

So this patient really should be started on prophylaxis, which parts C and D suggest delaying or not starting. But really there is clinical suspicion here, high clinical suspicion for joint damage and ongoing bleeding with an ABR of at least 4-5 per year. And so prophylaxis is appropriate.

And emicizumab is the best choice for this patient because it is indicated for hemophilia A with and without inhibitor. And also we can give factor for a breakthrough bleeding in this patient without an inhibitor.

Answer A suggests that the DVT is not relevant. But of course, a history of thrombosis is relevant in a patient with hemophilia because some of the newer therapies have been associated with thrombotic risk.

[00:41:14]

Antithrombin Knockdown

All right. Then I am going to speed up a little bit here because of the time. But we will talk briefly here about the antithrombin-lowering medication that is now approved.

[00:41:26]

Overview: Fitusiran, Antithrombin siRNA Knockdown

It is fitusiran, also called Qfitlia. It is a small interfering RNA, which you can see here in this figure is a molecule modified with this GalNAc section, and it is depicted by the yellow circles. And it enters the hepatocytes and binds to the mRNA of the SERPINC1 gene, which encodes for antithrombin, leading to the degradation of the mRNA. This leads to decreased antithrombin production, essentially making the patient antithrombin-deficient, the hemostatic rebalancing strategy that leads to less of a bleeding phenotype in hemophilia.

[00:42:07]

Fitusiran: Indication, Dosing, and Monitoring

So fitusiran was approved last year for prophylaxis in patients over 12 with hemophilia A or B with or without inhibitors. And here you can see the starting dose and the dose titration based on measured antithrombin levels. You also need to obtain antithrombin level before initiation to make sure the patient is not already antithrombin-deficient. And this antithrombin activity is performed using an FDA-approved test, which is at least for us, is a send-out, and has to be done on multiple time points.

[00:42:46]

Initial Phase III Trials of Fitusiran (ATLAS Program)

The reason really for this antithrombin-level-based dose adjustment is that in the initial Phase III trials of fitusiran, there were thromboembolic events. The starting dose here is higher than the currently approved starting dose. And the patients who had the significant thromboembolic events, which included cerebral venous thrombosis, were really patients with multiple risk factors for thrombosis, but also were receiving clotting factor concentrates or bypassing agents and also had very low antithrombin levels.

So the risk mitigation strategy here is to adjust the dosing to keep the antithrombin levels within a tighter range and then also reducing the doses of the medicines used for breakthrough bleeding.

The other AEs that were seen with fitusiran were transaminitis, which was seen in up to 20%, around 20% of patients, but was typically modest transaminitis and did not usually lead to the discontinuation of the medication. And then about 11% here of patients developed cholecystitis or cholelithiasis.

[00:44:06]

Fitusiran Bleed Treatment Recommendations

As I mentioned, we are going to adjust the dose based on antithrombin levels, but also there is in the package insert for this medication, a recommended dose chart for different factor medications and bypassing agents in terms of how much should be given and how often it can be given for bleed treatment or for surgery.

And just to give some idea, you could look down the line of factor VIII here. It says the recommended dose for treatment of bleeding is 10 IU/kg, significantly lower than our usual starting dose for a patient with hemophilia A without inhibitor would typically receive 50 IU/kg. So this is significant reduction in the dose of medicines used for breakthrough bleeding.

[00:44:52]

Antithrombin Adjusted Fitusiran Dosing Maintain AT Activity Levels of 15%-35%

And again, here is a more of a graphic that describes the dose adjustment for fitusiran based on antithrombin levels, which may need to be done at multiple time points, depending on what results you get. And the patient will end up on a dose of this medication that is given every 2 months or sometimes monthly. So this dosing frequency is very infrequent, which is 1 thing that is very attractive for some patients that they do not have to take this medication very often at all.

[00:45:32]

Fitusiran: Efficacy and Safety With Antithrombin Adjusted Dosing

With the antithrombin adjusted dosing, you can see here that the annualized bleed rates are significantly lower in patients who were on bypassing agent prophylaxis. So these are patients who had inhibitors. You can see their ABR was as high as 11. And that is, they were on a bypassing agent for prophylaxis and was reduced to 3.4 with fitusiran. And for patients who were without inhibitors and on clotting factor prophylaxis, ABRs were comparable on fitusiran compared to their prior prophylaxis.

And you can see here in the square at the bottom that the risk for thromboembolic events was significantly lower after the antithrombin-based dose titration was introduced compared to the initial trial data, which was done without antithrombin monitoring.

[00:46:31]

TFPI Inhibitors

And then for the TFP, we will move on to talk about the TFPI inhibitors.

[00:46:34]

TFPI Inhibitors

So there are 2 of these approved. These medications block the action of TFPI, which is a natural anticoagulant. So this also restores thrombin generation in patients with hemophilia. The medications are concizumab and marstacimab.

[00:46:58]

Concizumab: Indication, Dosing, and Pharmacokinetics

So we will start by talking about concizumab which was approved in 2024. This is approved for adults and adolescents down to age 12 with hemophilia A or B with or without inhibitors. It is given as a subcutaneous medication, which is daily. Although it is important to note here that the volume of this medication is actually very low, and this will be a slide where we compare these things, as in the frequency and volume of the injection. And so, even though it is a frequent medicine, there are some patients who really prefer this medication because the injections are very much less painful compared to some of their other subcutaneous medications.

This medicine requires measurement of the plasma concizumab level at 4 weeks. And this is done again to get the concizumab level within this range, this tight range here, and may require dose titration. Once it is within range, frequent monitoring is not really required as much as the antithrombin levels are for fitusiran. And another important thing about this medicine is that it only takes about 4 days to clear because of the shorter half-life because of the pharmacokinetics.

It is a downside that you need frequent dosing, but there are going to be some situations where a medicine that clears quickly are really helpful. For example, the patient needs a major surgery or something like that, knowing that you can clear this medicine and use high doses of factor concentrates, again, within a short time span, maybe an attractive feature for this medicine.

[00:48:54]

Concizumab Phase III Trials (explorer Program)

So the Phase III trials for concizumab were called the explorer trials. And you can see here that the median and mean ABRs, again, were very low for both hemophilia A and B with and without inhibitors.

[00:49:14]

And if we look at the safety data for this medication, there were some thromboembolic events in the initial trials, and this included DVT and PE. And again, this is what prompted the clinical trial hold in the introduction of this concizumab plasma-level-based dosing.

[00:49:48]

Marstacimab: Indication, Dosing, and Pharmacokinetics

And then marstacimab, which is the other TFPI inhibitor, was approved in 2024, but currently only approved for patients with hemophilia A or B, but without inhibitors. There was data presented on the inhibitor cohort at ASH just a couple of months ago, and that data looks really good. So I would be very surprised if it is not approved soon for patients with inhibitors as well.

This is also a subcutaneous injection, but it is weekly instead of daily and comes with a loading dose and a maintenance dose. There is no laboratory monitoring currently required for this medication, but there is an option for up-titration in patients who have a lot of breakthrough bleeding as judged by their provider. And so there are some patients on the trial who were started on this maintenance dose and then were subsequently increased to a higher maintenance dose, but it was very few.

This medication takes 16-18 days to clear compared to the 4 days for concizumab.

[00:50:54]

Marstacimab Phase III Trials (BASIS Program)

And here you can see, these are the data for patients with hemophilia B with or without inhibitors. And you can see here too the dramatic decrease in the bleeding rate for patients who are getting on-demand treatment in the 6-month observation before the trial medication was started.

And for patients who are on routine prophylaxis, there was also a decrease in ABR.

[00:51:33]

BASIS: Safety (Noninhibitor Cohort)

So for the non-inhibitor cohort, which is the cohort for whom this medication is already approved, there were no thromboembolic events reported in the trial, but there was 1 DVT reported in the open-label extension. And so I think there is also consideration of using lower doses of, again, in a patient who was receiving medicine for breakthrough bleeding.

And so there is consideration of using lower doses of medicines for breakthrough bleeding for the TFPI inhibitors as well, but it is not as prescribed in the package insert as it is for fitusiran.

[00:52:16]

Question 3

All right. That brings us back to question 3, now as a posttest question. So this is a patient with hemophilia B and an inhibitor initiated on subcutaneous concizumab prophylaxis. You are developing his long-term management plan. Which monitoring strategy is required to minimize the risk of thromboembolism in this patient?

Speaker: The poll is open. Please vote. Five more seconds.

All right. Thank you. We will close the poll and share the results.

Dr Maher: All right. So we have a split here between antithrombin activity and drug plasma levels, right? So those are both risk mitigation strategies. But for concizumab, the concizumab medication is a plasma level. And really, I think it is sort of interesting because we really cannot measure TFPI levels in a meaningful way. And so concizumab actually uses a drug plasma level.

[00:53:38]

So the correct answer here is C. Part B, which was another common, which was another popular answer here, is a risk mitigation used for fitusiran though, not for concizumab.

[00:53:54]

Rebalancing Agents: Pros and Cons

All right. So some summary slides here. And I think these are probably the biggest take-home points from today's talk are that we do have these new rebalancing agents. They have pros and cons.

The pros are that they are effective in reducing bleeding. They are given subcutaneously, which can be really game-changing for a lot of our patients. And they really work, these rebalancing agents work for both hemophilia A and B with and without inhibitors. So it is a medicine that can work for a lot of different patients.

Some of the downsides are that they have a novel mechanism of action. And although this is really, you know, cool from a scientific standpoint, it makes things complicated in the sense that we have to understand and explain to our patients how they work in language that makes sense. And this can be challenging when we are used to saying you have a low factor VIII, we are going to give you some factor VIII to fix the problem. This is a much more complicated thing to explain. And then they also have some safety concerns with thrombosis seen in some of the clinical trials. And these can require specific risk mitigation. And in some cases, this is a lot of lab draws for drug monitoring, which may or may not be attractive to some patients.

[00:55:14]

FDA-Approved Rebalancing Therapies for Prophylaxis

This figure compares some of the dosing regimens. And I think that this is really helpful also, because for some, in many cases, what the patient really wants to know is what does this actually look like for me in terms of how many injections and how many labs am I getting?

And you can see here that marstacimab is flat dosing, does not require lab monitoring, at least as of now. Concizumab is weight-based and daily and does require levels, but potentially just once after initiation and then very infrequently thereafter. And then fitusiran is antithrombin level-driven, and antithrombin level testing is required in order to keep the antithrombin level between 15-35%.

[00:56:04]

Case 1: The Active Young Adult

All right. So I feel like we do not have very much time left. So maybe I will just get through reading 1 of these cases, and then we can open it up for questions. We can either talk about the case or whatever other questions people have.

But this case is a 25-year-old man with severe hemophilia without inhibitors. He is highly active, plays basketball on weekends and is currently on standard half-life factor VIII concentrate prophylaxis, which has to be given every other day. And despite adherence, he is still having bleeds, and he is frustrated by the need to time his injections around games and fears long-term joint damage.

This case is interesting because there are a lot of options for this patient now that would not have been there 10 to 20 years ago. And so it is just to open it up for ideas about prophylaxis and what we might do for these patients.

So that I am going to pause just because of the time, and I am going to have a look in the chat and see if there are questions.

Speaker: Thanks, Dr Maher. I have been monitoring it. I do not see anything on our end so far. So feel free to continue.

[00:57:18]

Collaboration Between Community Providers and HTCs

Dr Maher: I think the last part of this presentation really is just to try and talk a little bit about hemophilia treatment centers or HTCs.

[00:57:30]

Hemophilia Treatment Centers

The HTC system started around 1973 with the Hemophilia Act which provided federal funding for comprehensive hemophilia treatment centers. And there are now more than 140 in the country. Every HTC is a little bit different. And some treat pediatric patients, some adults, and some are lifespan centers. But there is really an emphasis on comprehensive care and bleed prevention for patients. And a lot of resources go into these activities that are really sort of coordination of care and provision of prevention services, physical therapy, social work, nursing. I am lucky to work in an HTC over here in Seattle. And there are many over in your region as well.

[00:58:18]

What Does Comprehensive Care Typically Include?

And these centers are really based on the foundation of providing comprehensive care, what we call comprehensive care.

So this typically includes at least an annual multidisciplinary clinic visit to sort of like a well visit for the patient's hemophilia. It includes providers from hematology, nursing. We have social workers and others. We have a psychologist in our HTC. We have physical therapists who specialize in hemophilia, and these are folks in our center who do musculoskeletal ultrasounds to assess joints. We have a genetic counselor. And many centers also have other dedicated specialists like dentists and gynecologists who have special knowledge in bleeding disorders.

We do telemedicine and in-person visits. We provide emergency after hours access to a bleeding disorder specialist and also do surgery procedure and delivery planning, which is done without additional visits and really as a coordination of care service. We also do outreach and testing for family members.

So I wanted to make sure to get to this slide because HTCs can care for patients with hemophilia but can also act as a resource to and partner with community providers. And especially in patients who are having enough bleeding that they are requiring prophylaxis and consideration of these new non-factor therapies, I would say that hemophilia treatment centers really should be a resource for these patients and planning for them to get these medications safely, and treated for bleeds safely if that is needed.