Advancing Hemophilia Care—Uniting Expert Insights and Community Voices to Shape the Future of Non-Factor Replacement Therapy

 

Hemophilia A and B are rare X-linked bleeding disorders. Hemophilia A, the more common is due to deficiency in coagulation Factor VIII and is seen in approximately 1 in 5,000 male births. Hemophilia B, or deficiency in coagulation Factor IX, is seen in approximately 1 in 30,000 male births. Although most of our patients with hemophilia have a family history of the disorder, up to 30% of hemophilia cases are sporadic.

 

Although the incidence is usually reported in terms of male births, females can also have hemophilia. Females with a single hemophilia causing genetic variant are usually referred to as carriers, but they can be symptomatic with bleeding and have a low factor activity, although it is quite rare for females to have moderate or severe hemophilia.

 

[00:12:57]

 

Hemophilia Severity

 

Severe hemophilia is characterized by Factor VIII or Factor IX activity less than 1%. In individuals with severe hemophilia who are not on any treatment can have multiple bleeding episodes per month, including spontaneous bleeding into muscles or joints without any identifiable hemostatic challenge.

 

Moderate hemophilia is characterized by baseline Factor VIII or IX activity between 1% and 5%, and individuals not on treatment can also have occasional spontaneous bleeding into muscles or joints, but less often, maybe 4-6 times per year. Of course, we know that baseline factor activity does not correlate perfectly with bleeding phenotype. So some individuals with moderate or even mild hemophilia can have frequent bleeding events and require prophylactic treatment.

 

Prophylactic treatment can prevent life-threatening hemorrhage and can also prevent chronic disability and pain from recurrent joint bleeds.

 

[00:13:58]

 

Disease Burden

 

Joint disease affects most persons with severe or moderate hemophilia and can present with acute joint swelling, pain, warmth and limited range of motion. And bleeding rates for some receiving prophylaxis may still be too high.

 

It is also possible that for patients to have subclinical joint bleeds, so bleeds that are not identified at the time that they are occurring. Recurrence of these joint bleeds can also lead to long-term joint disease.

 

Engagement in physical activity can be limited due to chronic pain from arthropathy or because of perceived risk of bleeding, with activities leading to avoidance.

 

[00:14:41]

 

Disease Burden: Prophylaxis

 

As I mentioned before, in severe hemophilia without treatment, the patients can experience several bleeding events per month, which is an annualized bleed rate as high as 20 to 40. It has been shown that initiation of prophylaxis with standard half-life factor products can decrease annualized bleed rate by as much as 90%, and it can preserve joint function if prophylaxis is initiated early.

 

The newer extended half-life factor products and non-factor therapies can substantially reduce annualized bleed rate compared to the standard half-life factor products. It is important to note that most of the current evidence does not directly compare the outcomes for these newer therapies. So although annualized bleed rates are reported in clinical studies for all of them, it can be challenging to directly compare the ABRs because of differences in study methodology or patient population.

 

[00:15:41]

 

Outcome Measures in Hemophilia: Beyond ABRs

 

How do we decide if our prophylaxis is working? The annualized bleed rate is reported in clinical studies and is 1 of the most important patient-reported outcomes, but it may not be enough. For these newer therapies that we are going to be discussing today, the annualized bleed rate is often low and can be as low as zero to 2. So additional outcomes need to be considered when we are comparing therapies and considering whether prophylaxis is working for our patients.

 

Other patient-reported outcomes include pain frequency and intensity, health-related quality of life which can be measured through quality of life questionnaires, physical exam. There are also objective outcomes, including physical exam scores like the Hemophilia Joint Health Score, factor concentrations for patients who are on factor prophylaxis, and in some cases, global assays like thrombin generation may also be useful.

 

Then joint imaging techniques can be really helpful to detect joint disease early. These imaging modalities include MRI and ultrasound, which can be tricky to have frequent access to. But some hemophilia treatment teams do have team members who are trained in the use of musculoskeletal ultrasound that can be done as a point of care test, and can be really helpful to detect early joint damage before it could be detected by physical examination.

 

[00:17:08]

 

Disease Burden: PROMIS-29

 

I wanted to show a little bit of an example of what we might learn from quality of life questionnaires. This shows some data from a study published earlier this year. The data was collected between April 2022 and April 2023. These are scores on a quality of life questionnaire called the PROMIS-29, which has 7 domains, which you can see along the left-hand side here.

 

In these different columns here are all patients with hemophilia A without inhibitor who are on prophylaxis organized by the severity of their hemophilia. In this study, about half of the patients were on factor therapy and half were on non-factor therapy.

 

You can see there is still burden seen in the domains of physical functioning, pain interference, anxiety and depression, regardless of disease severity and product class in patients with hemophilia A without inhibitors.

 

[00:18:11]

 

Disease Burden: Inhibitors

 

It is really important when we think about disease burden to also think about the subset of patients who have developed inhibitors. Inhibitor formation occurs in response to factor therapy in up to 35% of severe hemophilia A and up to 10% of severe hemophilia B.

 

When this happens, factor concentrates can become ineffective, especially if there is a high-titer inhibitor. And immune tolerance induction, while it can be used and can work, may not always be feasible due to need for frequent IV infusions or necessarily effective for everybody.

 

In a recent non-interventional study, patients with hemophilia B with inhibitor had similar Hemophilia Joint Health Scores and annualized bleed rates, regardless of whether they were on prophylaxis or not. This group of patients had the lowest reported quality of life measures in all domains. This is thought to be due to the lack of efficacious prophylaxis for this patient population, and has been an area of significant unmet clinical need.

 

[00:19:18]

 

Goals of Hemophilia Treatment

 

It is really important when we are thinking about clinical outcomes for our patients that we also think about the patient voice. Here you can see in the red some hierarchy of clinical outcomes or milestones that we might think of for our patients. At the very top is normal hemostasis, which would maybe be achievable if someone was started on prophylaxis or received gene therapy shortly after birth.

 

It is also important to consider those shown in the blue here, which are parallel patient relevant outcomes. If we were able to achieve normal hemostasis, for example, this would only be important if we could also optimize health and well-being for our patients. You can see that patient relevant outcomes include things like participation in work, career, family life in an unrestricted lifestyle.

 

[00:20:17]

 

Treatment Burden

 

When we were using primarily standard half-life factor products, patients needed very frequent IV infusions for their prophylaxis, and in pediatric patients, this was usually about every other day. These frequent IV infusions can be challenging and painful. Although some children can learn how to give infusions at home peripherally, central venous catheters are often required in order to give this frequency of infusions.

 

These central venous catheters carry risk for infection and thrombosis. Treatments would interfere with travel and social activities, and also, importantly, the ability to gain independence in adolescence if the adolescent was unable to do their infusions themselves.

 

The timing of factor activity peaks and troughs can limit spontaneous participation in activities as well, since usually we are trying to time the factor peak with the high-risk activities.

 

[00:21:20]

 

Treatment Burden: Hemo-TEM

 

As far as treatment burden goes, here is another set of quality of life questionnaire data. Again, just to keep us on our toes here instead of to the left, on the right is increased burden. These are answers to the Hemo-TEM questionnaire for patients again with hemophilia A without inhibitor who are on prophylaxis.

 

Even though most patients did pretty well here, there is still burden for both factor and non-factor treatment. Those with non-factor treatment reported a slightly lower treatment burden than those receiving factor replacement therapy, especially in the severe hemophilia A group.

 

[00:22:09]

 

Rapidly Evolving Treatment Landscape for Hemophilia

 

Prior to 2014, we really only had standard half-life factor concentrates, as our tools for prevention and treatment of bleeding in hemophilia, but we now have several tools available, including extended half-life factor concentrates, non-factor therapies, rebalancing agents, Factor VIII mimetics and gene therapy. This can feel at times overwhelming.

 

[00:22:37]

 

Evolution of Hemophilia Treatment: US Approvals From 1988-2025

 

If you look at this figure here, it shows on the top for hemophilia A and on the bottom for hemophilia B, medications that have been approved for treatment of hemophilia between 1988 and 2025. Almost the right third of this slide is just 2022 to 2025 because multiple therapies have been approved in that time span, including gene therapy factor and new extended half-life Factor VIII product and multiple new non-factor therapies.

 

[00:23:08]

 

Gene Therapy for Hemophilia

 

I wanted to touch very briefly on gene therapy for hemophilia. The currently available gene therapy products are liver-directed AAV-based gene therapies, and they have the potential to prevent most or all bleeds with a single infusion, which is pretty incredible. There are limitations, though, including observed decline in factor activity over time, particularly for hemophilia A products. The most common adverse event is transaminitis, which is typically managed with corticosteroids, which of course have their own side effects.

 

The uptake of gene therapy is limited by the inclusion and exclusion criteria for the studies. For example, it is not available to children under 18 years of age, those with a history of Factor VIII inhibitors and pre-existing anti-AAV antibodies may be an exclusion for some as well.

 

[00:23:54]

 

Gene Therapy for Hemophilia

 

Here is a list of the gene therapy products that are currently approved. I am not confident enough to pronounce their chemical names, so I am not going to do that today, instead using their trade names.

 

The first 1 approved was in 2022. This is Hemgenix approved for hemophilia B. Then in 2023, Roctavian was approved for hemophilia A. Then third in 2024, Beqvez was approved. But important to note that this gene therapy product is not being marketed. So right now available on the market are 1 gene therapy for hemophilia A and 1 for hemophilia B.

 

[00:24:34]

 

Pros and Cons of Current FDA-Approved Therapies

 

When we are thinking about all of these newer therapies alongside our patients, it can be really helpful to write down the pros and cons of them next to each other like this, both for ourselves and in discussion with our patients.

 

I am not going to go over all of these different therapies in detail, but just some highlights that, 1 of the advantages of the non-factor therapies, of course, is their subcutaneous dosing, which can be a really big game changer for some patients. The factor concentrates, although they are still given intravenously, are given much less often than they needed to before. Most of them can be done with weekly dosing, or even less frequently, especially in adults.

 

As far as the disadvantages, of course, for the factor concentrates, they are given IV. You may need a central venous access device. There is a risk for inhibitor formation.

 

Then for the non-factor therapies, 1 of the major disadvantages is the risk for thrombosis. And thrombotic events were seen in all of the clinical trials for these new therapies. Our next speaker is going to talk in more detail about the safety profile and the clinical trial data for these medications. But for all of them, there are mitigation strategies to prevent thrombosis for patients.

 

[00:26:01]

 

Thrombotic Risk

 

It is really tempting to think of our hemophilia patients as being naturally anticoagulated. But persons with hemophilia have the same degree of atherosclerosis as their peers.

 

US claims database study suggests that persons with hemophilia may in fact have a slightly higher risk of ischemic stroke and DVT when compared to the non-hemophilia population. It is really important to evaluate for and manage early non-treatment-related risk factors, including hypertension, obesity, smoking and potentially inherited thrombophilias, because these also affect patients with hemophilia.

 

As far as treatment-related risk factors go, really any hemostatic therapy could carry risk for thrombosis, including factor replacement therapy if the factor activity is pushed too high. Then for non-replacement therapy, there can be increased risk if factor is needed in the setting of breakthrough bleeding.

 

Then of course, the need for central venous access devices can increase the risk for thrombosis significantly, and especially in our pediatric patients, this is 1 of the most important risk factors that we see.

 

[00:27:14]

 

          Posttest 1

 

That brings us to post-test question 1. This was our 52-year-old man with severe hemophilia A who has a history of obesity and uncontrolled hypertension. He is interested in non-factor therapies but concerned about safety. We will take a pause for everyone to take this question again.

 

I am not sure if we are going to see the answers this time.

 

Dr Pipe: We are supposed to. Why don’t you go ahead and just give your commentary on this one?

 

Dr Maher: Actually, you all did not need me here at all because everyone did very well on this first question. Here we go.

 

[00:29:04]

 

          Posttest 1: Rationale

 

The correct answer was C, to initiate prophylaxis alongside active screening and management of cardiovascular risk factors. As we discussed, patients with hemophilia have the same thrombosis risk factors as the general population. We do not withhold treatment but rather try to mitigate their risk factors so that they can receive prophylaxis.

 

[00:29:31]

 

Thrombotic Risk: Nonfactor Therapies

 

As I mentioned, thrombotic events have been reported in the early trials for all of the non-factor therapies. I am not going to go into these in detail, but they were seen for all of the ones that were newly approved in the last couple of years. So we are going to make sure to address this in the next section of the talk.

 

[00:29:58]

 

Thrombotic Risk: Mitigation Strategies

 

I did want to talk a little bit about generally what mitigation strategies we can use for thrombotic risk. One is of course the screen for cardiovascular risk factors and manage them as appropriate. It may be appropriate to monitor factor activities during intense factor replacement. It may be possible to monitor drug activity for the new non-factor therapies, for example, concizumab plasma levels or antithrombin levels.

 

Then for breakthrough bleeding on non-factor prophylaxis, it is recommended to use the lowest approved dose of factor concentrate or bypassing agent that is effective for treatment of bleeding, and in some cases, there may be specific dose recommendations for breakthrough bleeding.

 

You can also consider, in some cases, holding the non-factor therapy if prolonged factor replacement is needed, for example, in the setting of major surgery.

 

[00:30:52]

 

Personalized Prophylaxis in Hemophilia

 

In summary, early initiation of prophylaxis is standard of care in severe hemophilia and in mild or moderate hemophilia with frequent bleeding events. High treatment burden can lead to delayed or missed doses and increased bleeding. And understanding disease burden and quality of life are necessary for decision-making.

 

Personalized prophylaxis optimizes safety and protection against bleeding, but also important to minimize effort for the patient and improve their quality of life.

 

[00:31:18]

 

Improving Clinical Outcomes With Non-Factor Replacement Therapies

 

With that, I am going to hand over to Dr Croteau, who is going to talk about improving clinical outcomes with non-factor replacement therapies.

 

Dr Stacy Croteau (Harvard Medical School): Thank you. As you highlighted, it has been a very big decade in hemophilia treatment. So we do have a lot to go over.

 

[00:31:45]

 

          Poll 4

 

We will start, of course, this session with a polling question as well. Considering efficacy, safety and patient preferences, which factor most influences your shared decision-making to use a non-factor replacement therapy in a patient with moderate to severe hemophilia?

 

1. Bleed rate reduction;
2. Impact on joint health;
3. Venous access burden;
4. Risk of thrombotic events; or
5. Cost and access to therapies.

 

An excellent spread of considerations that we all take into account.

 

[00:32:45]

 

Non-Factor Therapies: Mechanisms of Action

 

We are going to highlight in this section the non-factor therapies in particular. Here we highlight a few of the mechanisms of action.

 

We start with the anti-TFPI monoclonal antibodies. We have Factor VIIIa mimetics, bispecific antibodies and also antithrombin siRNA knockdown. In the top category of siRNA knockdown of antithrombin, we have now the licensed product, fitusiran. This works to deplete, of course, antithrombin as a subcutaneous therapy.

 

In terms of anti-TFPI monoclonal antibodies, we now have 2 approved therapies: concizumab and marstacimab, also subcutaneous therapies. In aggregate, these 2 categories we refer to often as the rebalancing therapies.

 

Then we also have Factor VIIIa mimetics, bispecific antibodies who perform the cofactor function of Factor VIIIa. We presently have 1 approved therapy, emicizumab. We have another Mim8 that is under regulatory review and another NXT007, still in investigational therapies, and others in these spaces that are in early preclinical and early development.

 

[00:33:55]

 

Overview: MoA of Fitusiran, a Non-Factor Therapy

 

We mentioned fitusiran, siRNA knockdown. This medication was approved by the FDA just earlier this year in 2025, and is presently indicated for severe hemophilia A or B patients who are at least 12 years of age with or without inhibitors. It is administered by subcutaneous injection, with a starting dose of 50 mg once every 2 months.

 

[00:34:21]

 

Fitusiran: Indication, Dosing, and Monitoring

 

You can see here that there is actually a monitoring strategy that is needed. We will review why that is in some of the subsequent slides. This medication does require using an FDA cleared test to monitor antithrombin activity, and then provides dose administration guidelines based on that antithrombin activity and dose modifications, with the idea that the target range of antithrombin for this therapy is keeping individuals in the 15% to 30% range.

 

[00:34:52]

 

ATLAS-INH and ATLAS-A/B: Phase III Trials of Fitusiran in Severe Hemophilia A or B With or Without Inhibitors

 

When we look at the initial fitusiran phase III studies, of which there were 3. Here we have highlighted ATLAS inhibitor and ATLAS A and B. You can see that a dose of 80 mg subcutaneously once per month was used, same population age greater than 12, both in males Hemophilia A or B with inhibitors and on the right-hand side without inhibitors. You can see a marked reduction from 16 to zero in terms of median ABRs in the inhibitor category from nearly 22 to zero in the non-inhibitor category.

 

[00:35:28]

 

ATLAS-PPX: Fitusiran Prophylaxis in Patients With Prior Factor or BPA Treatment

 

In the third phase III, the ATLAS prophylaxis study, using the same characteristics and the same 80 mg per month dosing, marked reduction as well both in inhibitor and non-inhibitor compared to their prior respective prophylaxis.

 

[00:35:45]

 

Fitusiran Safety in Phase III Trials: AEs of Special Interest

 

Unfortunately, there were some safety challenges in this study, notably in the top line with suspected or confirmed thrombotic events. Those thrombotic events correlated with lower antithrombin levels, as I am sure most in the audience will appreciate. This did lead to a series of holds, first in 2017 and then in 2020, with a number of risk mitigation strategies that were put in place, both in terms of how we think about the dosing and frequency of dosing of bleed treatments that are required, as well as the dose-adjusted antithrombin levels that we mentioned on the prior slide.

 

In addition, thinking about safety with fitusiran, there was a higher frequency of liver injury as defined by elevated ALT, AST increases by at least 3 times the upper limit of normal, as well as a frequency of cholecystitis and cholelithiasis. And by dose reducing using a dose-guided antithrombin levels, we mitigated some of those adverse events as well.

 

[00:36:50]

 

Fitusiran Bleed Treatment Considerations

 

You heard in the prior talk that it is important to think about leveraging the lowest effective dose for bleed strategies across the non-factor therapies. Specifically for fitusiran, there are some specific guidelines that are provided, so you can see across different types of bleed management strategies, whether it is Factor VIII, standard half-life Factor IX, extended half-life Factor IX, or use of bypassing agents either aPCC or recombinant VIIa. There is specific single dose recommendations, as well as maximum single dose recommendations and some guidelines around frequency of repeating.

 

You can hopefully recognize, compared to standard bleed dosing that we commonly use with factor concentrates as well as bypassing agents, these represent a dramatic decrease in per dosing, as well as a dramatic decrease in frequency of dosing in many context, limiting repeating to no more than 24 hours, ideally.

 

[00:37:55]

 

Fitusiran: Safety and Revised Dose Regimen

 

The revised dosing regimen that was approved in January of 2021 to mitigate the vascular thrombotic risk looks like this algorithm. This basically recapitulates some of what we saw on the earlier slide, where everyone going into initiation of fitusiran for prophylaxis starts at 50 mg every 2 months. Then we use an FDA-approved antithrombin measurement level at steady state. For those whose antithrombin level is above the goal of 35, we increase the dosing strategy.

 

For those whose level is too low, we modify and reduce the dosing strategy to try to ideally get everyone in this goal, 15 to 35 antithrombin range.

 

[00:38:37]

 

ATLAS-OLE: Fitusiran AT-DR for Hemophilia A/B With or Without Inhibitors

 

When we look at the impact on bleed rates of changing from the 80 mg once a month dosing strategy to this antithrombin modified dosing strategy, you can see we do see some differences in outcomes. These 2 figures represent, on the left, the estimated mean ABR for treated bleeds in participants that had inhibitors in the open-label extension study.

 

You can see that on bypassing agent prophylaxis, the mean ABR was around 11. On the fitusiran-AT adjusted prophylaxis, there was a reduction to about a mean ABR of 3.

 

When we look on the right-hand side, the mean ABR is for individuals, participants without inhibitors who were previously on clotting factor concentrate prophylaxis compared to fitusiran using a dose adjustment strategy, you can see that there was essentially a net neutral impact on bleed rates, so there did not seem to be a higher frequency of bleeding leveraging this alternative prophylaxis strategy.

 

[00:39:45]

 

ATLAS-OLE: Fitusiran Efficacy With Adjusted Dose Regimen

 

As I mentioned, there was additional impact of leveraging an antithrombin-based dosing strategy on some of the other impacts. In the table to the top left, you see thrombotic events. There were still thrombotic events reported in the AT-based dosing, but they were substantially less than in the original 80 mg per monthly dosing. That is also recapitulated in the figure just below the table.

 

Similarly, when we look at the observed median ABRs with the antithrombin-based dosing regimen in the inhibitor patients in orange, the non-inhibitor patients in black, and the overall group in gray, we see overall an improved median ABR.

 

With this revised dosing, about just shy of 32%, manifested as zero bleed rate in just the 6 months of the primary efficacy period.

 

[00:40:42]

 

TFPI Inhibitors

 

Turning to focus a bit more on TFPI inhibitors.

 

[00:40:49]

 

TFPI Inhibitors: MoA of Non-factor Therapies

 

The 2 licensed TFPI inhibitors: concizumab is a humanized igG4; marstacimab is a human igG1. They do vary a little bit in their construct. Although the overall function serving as an anti-TFPI inhibitor blocking the K2 domain of TFPI is similar, with the goal of inhibiting activated Factor X and bolstering thrombin generation.

 

[00:41:16]

 

Concizumab: Indication, Dosing, and Pharmacokinetics

 

Concizumab was approved in 2024. This is now approved in individuals 12 years of age or greater with hemophilia A or B, with or without inhibitors, for routine prophylaxis to prevent and reduce bleeding episodes. This medication is administered as a subcutaneous injection, ideally in the abdomen or thigh. There is a 1-time day 1 loading dose followed by maintenance daily dosing of subcutaneous 0.2 mg/kg.

 

After 4 weeks of treatment initiation, there is an FDA-approved ELISA to measure plasma concentration of concizumab prior to the next series of doses, again, with an idea of optimizing the concizumab plasma levels. You can see towards the bottom on the left-hand side, for individuals with concizumab levels of less than 200 nanograms per ml, the maintenance dose is increased.

 

If you are in the target range of 200 to 4,000 nanograms per ml, you continue on the 0.2 mg daily. If you are in the higher range of over 4,000 nanograms per ml, a bit of a dose reduction is advised.

 

You can see in the figure to the right when you look over time, overall with maintenance dosing, there is extreme stability in these concizumab levels followed during the maintenance of the clinical trial.

 

In addition to this initial dosing, there is general guidance that routine monitoring with regular follow up just to ensure concizumab plasma concentrations stay within the target range is advised.

 

We will highlight this a bit more as we move on to the next TFPI inhibitor. Just to mention, because you will notice there is a stark difference in dosing strategy between concizumab and the other product in this category, marstacimab. A lot of that has to do with variance in the pharmacokinetics.

 

Both of these TFPI inhibitors have a drug-mediated drug deposition element to their pharmacokinetics. There is a significant non-linear pharmacokinetic component related to the drug and TFPI interaction. Once that interaction is exceeded, we have more of a linear catabolism kinetics.

 

As a result, because of the properties of concizumab, we generally are achieving steady state doses much more quickly, but with holding of concizumab, we have decreased the plasma levels by 90% in 4 days, by 50% in 1 day. So really necessitating that ongoing daily dosing. And we will see a bit of a contrast with regard to the pharmacokinetics with our next therapy.

 

[00:44:01]

 

Concizumab Phase III Trials: Efficacy at 56-Wk Cutoff (Arms 1-4)

 

When we look at the concizumab phase III efficacy trials, this is a 56-week cut off in various arms of the study looking at inhibitors and non-inhibitors. You can see in the explorer7 study, this was the inhibitor study. We had about 76 hemophilia A with inhibitor patients, 51 hemophilia B with inhibitor patients. In explorer8, the non-inhibitor study, we had 80 hemophilia A and 64 hemophilia B.

 

When we look at the combination of treated spontaneous and traumatic bleeds, here presented median ABR as well as mean ABR and min and max ABR. You can see the median ABRs were generally right around 1-3.

 

[00:44:45]

 

Concizumab Phase III Trials: Safety at 56-Wk Cutoff (Arms 1-4)

 

Looking at the safety of these study, you can see that overall relatively well tolerated. Again, we did have some challenges with thrombotic events in the concizumab study, leading to a halting and placement of a risk mitigation strategy. There were fatal events, including in the explorer7 and intracranial hemorrhage, COVID-19, alcohol coma, and 1 intraabdominal hemorrhage in explorer8.

 

[00:45:17]

 

          Posttest 3

 

We will take a pause to do a post-test question, which is the following. A patient with hemophilia B and inhibitors is initiated on daily subcutaneous concizumab prophylaxis. You are developing his long-term management plan to ensure efficacy and mitigate safety risks. Which monitoring strategy is required to minimize the risk of thromboembolism in this patient?

 

1. Weekly monitoring of D-dimer and fibrinogen levels for the first 3 months;
2. Monthly measurements of antithrombin activities to maintain levels of 15% to 35%;
3. Measurement of drug plasma concentrations at Week 4 to adjust maintenance dosing as needed; or
4. No specific laboratory monitoring is required for this fixed dose therapy.

 

Excellent. This is the correct answer. Measurement of drug plasma concentrations at Week 4 to adjust for maintenance dose as needed.

 

[00:46:35]

 

          Posttest 3: Rationale

 

The rationale here is that concizumab does require a loading dose followed by daily dosing. There is a mandatory check of the plasma drug levels at Week 4. If the level is less than 200, a dose increase is required. If the concentration is greater than 4000, a dose decrease is required.

 

Option B the antithrombin levels reflects the treatment protocol for fitusiran, the antithrombin knockdown therapy. And option D describes marstacimab, which is presently a fixed dose with no monitoring.

 

[00:47:11]

 

Marstacimab: Indication, Dosing, and Pharmacokinetics

 

We will talk a bit more now about marstacimab. This was approved both by the FDA and EMA in 2024. Similarly to some of our other non-factor therapies, it is indicated for routine prophylaxis still in that age 12 and older category. Here we are looking at specifically hemophilia A or B without inhibitors.

 

Marstacimab is administered as a subcutaneous injection weekly with a fixed dose, so there is a 1-time loading dose of 300 mg subcutaneously, followed by 100 mg weekly starting the first week after the loading dose. There is no laboratory monitoring required.

 

As you can see by some of the descriptors here of the pharmacokinetics of marstacimab still a target drug-mediated drug disposition in terms of impacting the pharmacokinetics, where we have a mixed non-linear and linear decay element. However, the overall interaction between marstacimab and TFPI is such that the sustainability of levels is longer.

 

Here it takes about a week to get to 50% of marstacimab levels and closer to a month to achieve 90% reduction in levels.

 

[00:48:34]

 

BASIS: Efficacy of Marstacimab in Hemophilia A or B (Noninhibitor Cohort)

 

When we look at the efficacy of marstacimab here, focusing in the non-inhibitor cohort of both hemophilia A and B, you can see the estimated mean ABRs to the right for those who came into the protocol from an on-demand strategy. So during the observation, those that were not treated with standard of care prophylaxis, but instead were just on demand had an estimated mean ABR of around 38. So initiating prophylaxis with marstacimab did reduce during both the active treatment phase and the long-term follow up, the overall mean ABR.

 

This also was observed in those who entered the study on routine prophylaxis. As expected, those on routine prophylaxis had an initial ABR of around 8. During their observation period, certainly less than those treated on demand. You can see a reduction in that bleed rate for those during both the active treatment phase as well as the long-term extension.

 

[00:49:32]

 

BASIS: Safety (Noninhibitor Cohort)

 

From a safety perspective, overall, marstacimab was similarly well tolerated. As you may have noted across all of the subcutaneous therapies and will continue to be true, injection site reactions remain among the more common types of adverse events. There were no thrombotic events during the initial clinical trials with marstacimab, but as you saw during 1 of the long-term follow up extensions, there has been 1 DVT reported.

 

[00:50:02]

 

FVIIIa Mimetics

 

FVIIIa Mimetics Bridge Factor X and Factor IXa

 

Moving on to Factor VIIIa mimetics. This will hopefully be amongst the most familiar to many of you as our first Factor VIIIa mimetic was approved in 2017. This category of therapies represents bispecific antibodies where part of the bispecific antibody recognizes activated Factor IX and the other portion of the bispecific antibody recognizes Factor X. This allows these bispecific antibodies to essentially perform the cofactor function of activated Factor VIII, bringing these 2 important coagulation factors together to generate a tenase complex and then help propagate and improve thrombin generation and ultimately fibrin clot formation.

 

[00:50:47]

 

Emicizumab: Indication, Dosing, and Pharmacokinetics

 

From an indication dosing pharmacokinetic perspective, emicizumab is approved in all ages for routine prophylaxis for individuals with hemophilia A. Practically speaking, really only works for hemophilia A, since it is performing that cofactor function of Factor VIIIa with or without inhibitors.

 

Additionally, off label, I will just mention, one can consider this potentially for von Willebrand disease for acquired hemophilia. So you may start to see possibilities of emicizumab cropping up in other locations, but for an actual labeled indication, congenital hemophilia A only with or without inhibitors.

 

There is a loading phase for emicizumab with 3 mg/kg weekly for 4 weeks, followed by a maintenance dosing strategy of either once a week, once every 2 weeks or once every 4 weeks. The figure to the right helps you take a look at plasma concentrations of emicizumab in each of those dosing strategies longitudinally.

 

While you can see there is some variability, overall, they all achieve an emicizumab trough of at least 30, which was the goal and have overall overlapping ranges.

 

[00:52:01]

 

Patients With Zero Treated Bleeds With Emicizumab Prophylaxis

 

In addition to looking at mean and median ABRs, another bleed metric that has become increasingly popular, and you will start to see across all of these therapies is a reporting out of proportion of individuals with zero treated bleeds.

 

The HAVEN series, which was the series of clinical trials that looked at emicizumab: HAVEN1, adults and adolescents with inhibitors; HAVEN2, pediatrics with inhibitors; HAVEN3, adults and pediatrics without inhibitors and some additional dosing strategies; and HAVEN4 looking at monthly; HAVEN7 looking at the infants.

 

You can see overall greater than 50% of individuals, and in some populations, even greater with zero-bleed rates. I do think it is important, especially as you start to look across various therapies to remember to look at the duration over which they collected zero bleed data. So is it over 6 months? Is it over a year? Because certainly the duration over which we are looking at zero bleeds becomes important. Across various studies, it is not always the same duration of time. This also extends to some of the other bleed related data that can be captured.

 

[00:53:15]

 

Emicizumab Safety Summary

 

Overall, the safety profile for emicizumab has been quite reassuring, and this has played out nicely in real practice as well. One of the things that we did learn and appreciate early in the emicizumab studies is the actual synergy between aPCCs due to the Factor IX substrate that, of course, comes with infusing aPCCs, the synergistic effect in thrombin generation, and the increased risk of thrombotic-related complications in leveraging aPCCs at standard dosing, along with emicizumab. This would extend, of course, to others in this class as well.

 

While there has not been any specific dose change recommendations for recombinant Factor VIII supplementation, ideally avoidance of aPCCs is advised. But if needed in certain clinical situations, a careful attention to a lower initial dose and real caution with frequency of repeating doses is required to try to avoid thrombotic complications.

 

Additionally, we do have, as I mentioned, HAVEN7, which was our infant clinical study that overall similarly had very excellent safety outcome and allowed us some early insights, potentially into inhibitor risks and a different pattern of how these young infants were seeing Factor VIII concentrate for the first time. And the steady state concentrations in this youngest population did seem to be a bit higher than what we saw in adolescents and adults, but was certainly not correlated with any safety or efficacy differences.

 

[00:54:51]

 

FRONTIER2: Mim8 Efficacy

 

The FRONTIER2 study is looking at Mim8. Mim8 is another Factor VIIIa mimetic with a different design structure compared to emicizumab. So similar in design in that it is still a bispecific antibody with half of the antibody recognizing activated Factor IX, the other Factor X. But the design does lead to a slightly different binding element for where this bispecific antibody binds to Factor IX and has changed the overall potency and the PK characteristics of Mim8 compared to what we have seen for emicizumab.

 

When we look at the FRONTIER2 study, the phase III study conducted in severe hemophilia A and included inhibitor patients, we can see that the mean ABR for treated bleeds in the pre-study on-demand arm in blue to the far right was around 15. When we looked at putting those patients previously on-demand on either weekly Mim8 or monthly Mim8, we saw a marked reduction in the mean ABRs across that group.

 

On the right-hand side, in the other arms, we looked at those individuals who were previously on clotting factor concentrate prophylaxis, and there was a run-in arm here. So we were able to observe the actual bleed rate and monitor that as opposed to just using retrospective data.

 

What you see here is even compared to clotting factor concentrate prophylaxis, the introduction of Mim8 did confer improved bleed control using both every week as well as in every monthly dosing strategy.

 

[00:56:32]

 

FRONTIER2: Mim8 Safety Summary

 

From a safety perspective, we looked at pre-study on-demand treatment group to the far right compared to the prophylaxis group. Overall, it was well tolerated. No thrombotic events were observed in this clinical study. Of course, we had some helpful upfront information again around caution with use of aPCCs. There were no detected neutralizing antibodies for this therapy.

 

As I mentioned, injection site reactions were around 10%. So at or perhaps a bit below some of the other subcutaneous therapies.

 

[00:57:11]

 

          Posttest 4

 

Our post-test question number 4. A 21-year-old man with severe hemophilia A and high-titer inhibitors has experienced traumatic breakthrough bleed events on emicizumab, but is interested in other Factor VIIIa mimetics that might be available in the future. Which statement accurately describes the clinical profile of Mim8 based on phase III data?

 

1. It is an oral therapy intended to mimic Factor VIII activity taken on a scheduled daily basis;
2. It is a monoclonal antibody that targets TFPI and is administered as a once-daily subcutaneous injection;
3. It is an siRNA therapy that reduces antithrombin and is given as a once monthly subcutaneous injection;
4. It is an investigational next-generation Factor VIIIa mimetic antibody delivered by weekly or monthly subcutaneous injection.

 

Excellent. Tremendous work.

 

[00:58:34]

 

          Posttest 4: Rationale

 

D is the correct answer. Mim8 is a bispecific Factor VIIIa mimetic, similar to emicizumab and offers weekly or monthly subcutaneous dosing. Option A is incorrect. It is not oral. Option B describes concizumab, and option C of course describes fitusiran.

 

With that, I will say thank you and turn it over to Dr Pipe.

 

[00:58:56]

 

Individualizing Treatment: Applying Novel Therapies to Clinical Practice

 

Dr Pipe: Thanks so much Dr Croteau and Kristin for setting us up and helping us understand the treatment burden and what some of the core issues are from the patient perspective. We want to try to put this all together now, understanding what our patients deal with, what their challenges are, and then also understanding this clinical trial data, how do we put this into clinical practice?

 

[00:59:30]

 

          Poll 5

 

Another polling question here. What factor most influences your decision to transition a patient from standard prophylaxis approaches to a novel therapy? Is it:

 

1. Efficacy data that you have seen;
2. The overall safety profile;
3. Patients preference for either the route of administration or frequency of dosing;
4. Cost or access issues; or
5. Looking forward to long-term outcomes.

 

Of course, there are no right answers here. We just want to understand how you rank these in their influence and decision-making.

 

Of course, probably all of these come into play, but it seems that people are definitely prioritizing the efficacy data and the overall safety issues.

 

[01:00:41]

 

Personalized Prophylaxis

 

We can still talk about personalized prophylaxis. Maybe some of these non-factor therapies do not allow us the same degree of modulation of dosing. But how we choose the right therapy for the right patient is still in this theme of personalized prophylaxis.

 

Of course, we have to take into account aspects of the hemostatic treatment. We have to understand the underlying status of the patient's joints. Then I think increasingly we are also paying attention to the patient experience, because some of these non-factor therapies are changing the burden of therapy, and they are altering the patient experience.

 

When we are thinking about tailoring treatment regimens, we may be accommodating what we know about individual genetic, physiologic or social factors for the individual. We are also often incorporating their experience with prior therapies and maybe unique responses to those previous therapies.

 

We have to think about both disease-related and treatment-related complications. So disease related would be the status of their joints, accumulating arthropathy, etc., synovitis. But then there may also be treatment-related factors. And of course inhibitors would be the classic treatment-related complication. Patient preferences, as I mentioned.

 

Then increasingly, we are paying attention to the lifestyle that the patient wants to live, their overall activity level. And particularly in pediatric and adolescents, we are talking to boys continuously about allowing them to be able to participate in sports that they are interested in.

 

[01:02:29]

 

Advancements in Hemophilia Therapies Have Enabled More Effective Management for Many People With Hemophilia but They Do Not Suit Everyone

 

Now, what we laid out here is the scope of available therapies that we have. On the far left, we have the Factor VIII and Factor IX clotting factor concentrates. We still talk about the standard half-life and the extended half-life factors. I would say in this part of the world, we are generally not relying on the plasma-based therapies any longer.

 

It is actually a Factor VIII. There is a mistake on that slide here. But we do have a high-sustained clotting factor concentrate, which I will talk about. We still have the bypassing agents. We are relying on 2 different recombinant Factor VIIa: eptacog alfa and eptacog beta, as well as the aPCCs that you heard about.

 

If we look at those 2 categories together, these agents have been indicated for prophylactic use. They can be used for on-demand treatment for breakthrough bleeds. We can also use these for surgery. In practice, most of our patients just have 1 of these products in their home for use. They are only used to administering 1 of these agents.

 

When we now think about the non-factor therapies, these are only indicated for prophylaxis. We still have to rely on all of the other agents which are on the left side. As has been mentioned already, you may be on emicizumab for your prophylactic therapy, but if you need breakthrough bleed management or surgery, you may need Factor VIII concentrate, if you do not have an inhibitor, or you may need a bypassing agent if you have an inhibitor.

 

The same thing is true for the anti-TFPIs and the antithrombin lowering siRNA. These are not indicative for managing acute bleeds or for surgery. So we still have concomitant use together.

 

What we do gain with some of the non-factor therapies is, for the first time, we have a platform of therapy which we can offer to hemophilia A or B with or without inhibitors. So now we have cross-segment utilization of these therapies.

 

[01:04:48]

 

Approved EHL FVIII Products

 

With respect to the available extended half-life Factor VIII products, these are all listed here. They use different methodologies either through conjugation strategies or a fusion technologies in order to enhance their half-life. I would say that even though there is some subtle differences in what their labels say, etc., they are all highly effective when used in prophylaxis.

 

The ABRs are significantly improved vs no prophylaxis, and they can actually improve ABR outcomes depending on how they were used. Generally, these have been well tolerated with no unexpected safety issues.

 

[01:05:27]

 

Approved EHL FIX Products

 

For the extended half-life Factor IX products, 3 primary strategies: 2 fusion technologies, Fc fusion and albumin fusion, and then 1 pegylated strategy. Again, maybe some variabilities in their labels. However, they are all highly effective when used for prophylaxis. The ABRs are significantly improved compared to no prophylaxis.

 

I think depending on how you prescribe them and use them in clinical practice, we have all observed better performance and better outcomes for patients compared to standard half-life Factor IX.

 

What we have achieved with the extended half-life Factor IX products is marked improvement in half-life, anywhere up to 3-5 times what we come to expect with the standard half-life Factor IX. I will show you in a few minutes that we have had some limitations with the extended half-life Factor VIII products.

 

[01:06:27]

 

Clinical Impact of EHL Prophylaxis

 

When I talk about how do you leverage the enhanced pharmacokinetics of the extended half-life factors for prophylaxis, there is 2 general ways of using these products. We can absolutely use these to reduce the burden for the patient. So Kristin mentioned at the beginning, with standard half-life Factor VIII, patients often were using every other day for managing prophylaxis. Being able to reduce the number of injections over the course of the week is a clear advantage of these EHL therapies.

 

The other way that you can leverage these technologies is now you have with an EHL Factor VIII or Factor IX, you can actually increase the trough levels with a still reasonable dosing regimen. We have certainly in our clinic had patients with EHL Factor VIIIs who are still using it actually every other day, but they now have substantially higher trough levels. This is allowing them to liberalize their activity levels and really function with a much higher bleed control than we were able to achieve previously.

 

One strategy would be a less burdensome regimen, better for overall compliance and adherence. Then on the other side, enhanced joint protection, particularly for those who may have underlying target joints or are really engaged in an active lifestyle.

 

[01:07:53]

 

Clinical Impact of EHL Prophylaxis

 

I mentioned that we can really think of 3 different categories of EHLs now:

 

• Standard half-life agents;
• Extended half-life agents; and then, this new
• High-sustained factor.

 

[01:08:09]

 

Current FVIII Treatments Are Subject to a VWF-Imposed t_1/2 Ceiling

 

Now why do we consider this maybe a different category? Well, if we look at the innovations that came to the EHL Factor VIII and Factor IX together, we mentioned the fusion technologies and the conjugation strategies with peg.

 

What we observed with Factor VIII that applying the same type of technologies that we used in Factor IX, when they replied with Factor VIII, we had a ceiling effect. Essentially, no matter what the strategy was, we had a limitation of a half-life. We could never really get over about a 14 to 18-hour half-life with these extended half-life factors.

 

Really, this ends up being about a 1.3 to maybe 1.5-fold enhancement of pharmacokinetics over the standard half-life Factor VIII. It was clear that what the limiting factor was is all of these Factor VIII products still bind von Willebrand factor. And von Willebrand factor, then becomes the limitation of the pharmacokinetic profile of the therapy.

 

[01:09:14]

 

BIVV001 (efanesoctocog alfa): The First FVIII Therapy Designed to Break the VWF-Imposed t_1/2 Ceiling

 

The idea is if you decouple Factor VIII from binding to endogenous von Willebrand factor, could you further alter the pharmacokinetic profile?

 

What is depicted on the right is if you look at VWF multimers, it is actually a fragment of the von Willebrand factor molecule. It is the D'D3 portion of von Willebrand factor that confers the stabilization effect on Factor VIII and protects it in circulation.

 

What we have with efanesoctocog is a fusion technology. It is based on the Fc fusion Factor VIII, which we have been using commercially for a number of years. This is then conjugated in a dimer with a recombinant fragment of von Willebrand factor that just the D'D3 domain. That provides the stability and the plasma without the need to bind to endogenous von Willebrand factor. So we are decoupling Factor VIII from binding to endogenous VWF von Willebrand factor.

 

In addition to that, they use this XTEN technology. These are repeating polypeptide sequences. What they do is they help create a watery cloud around the molecule and protect it from binding to clearance receptors.

 

Now upon activation, there is engineered thrombin cleavage sites here. When it gets activated in the course of hemostasis, the liberated molecule is essentially a fully active recombinant Factor VIII Fc molecule, which we have been using for some time.

 

[01:10:59]

 

PK Comparison of Efanesoctocog Alfa to SHL and EHL rFVIIIs

 

You can see here the impact of this decoupling strategy. This is all with a standard dosing administration of 50 IUs per kilo. In the pink, we have a standard half-life of Factor VIII. And you can see a half-life there of about 11 hours.

 

You can see that by about 3 days, patients are falling down to trough levels where ordinarily would be triggering a new dose of prophylaxis.

 

In the blue, we have a pegylated form of extended half-life Factor VIII, and you can see that about 1.3 to 1.5 enhancement of the half-life. Now you can see that somewhere between 3-5 days is where we would be reaching trough levels, where we would need to redose the patient for prophylaxis.

 

In the green, you see the impact of this decoupling of efanesoctocog. You can see the high sustained levels where we are now maintaining factor levels in the non-hemophilic range for about 3-plus days. If you look now, you now are at about a week dosing. The mean levels of Factor VIII are somewhere around 10%. This is a substantially higher trough level.

 

On a weekly dosing strategy, you are getting the best of both worlds that we talked about. You are getting this enhanced pharmacokinetics, a reduced burden, and also improved trough levels for patients.

 

[01:12:33]

 

Phase III Study of Efanesoctocog Alfa Prophylaxis for Patients With Severe Hemophilia A

 

This has had a substantial impact on annualized bleed rates. In their phase III study, we have in the orange is their pre-study Factor VIII prophylaxis. Then after switching to efanesoctocog, the annualized bleed rates were well below 1 for mean ABR, and actually the medians were zero. So overall about a 77% ABR reduction compared to prior factor prophylaxis.

 

In the phase III trial, there was no development of inhibitors that was observed across a pretty substantial cohort of patients. There have been sporadic reports of inhibitors in the real world, but it does not appear that these modifications to the molecule itself have been immunogenic.

 

[01:13:29]

 

Factor Replacement Therapy

 

If we look at factor replacement in general, some of the benefits and limitations. This has been easy to talk to patients for a long time. You are missing a factor. We are replacing it. We are giving it back to you. It was very easy for patients to understand.

 

We took comfort in the fact that these molecules we are replacing retain the natural hemostatic regulation. There is a wide therapeutic window. We have developed experience of efficacy of factor replacement in essentially every clinical scenario: major surgery, major trauma, patients who have all kinds of comorbidities.

 

We also have the availability of laboratory monitoring. What about the risks associated with these therapy or limitations? Well, the peaks and troughs of IV replacement therapy in no way mimic normal physiology. We are basically catching up to factor levels and then every tick of the hour of the clock afterwards, the factor levels are declining until they get to low levels.

 

There are real consequences to non-adherence with factor replacement therapy. If you just miss a dose, particularly with some standard half-life agents, your level is going to go to zero pretty quickly and you are going to increase your risk for breakthrough bleeding.

 

We know from long-term outcome studies that even with optimized factor prophylaxis, we have not been able to abrogate all adverse joint outcomes for patients. There is still a therapeutic burden and cost to these strategies. Of course, the biggest complication with factor replacement is the development of inhibitors.

 

[01:15:10]

 

Replacing or Mimicking the Action of Procoagulants Increases Thrombin Generation in Hemophilia

 

Now if we look at this from a thrombin generation perspective, you can see a healthy control depicted there in orange. You see that nice peak thrombin generation that comes when coagulation is activated. Then in the blue, you see the significant impairment that is familiar for a patient with a severe Factor VIII deficiency.

 

Now if you replace Factor VIII, at least acutely, you will fully normalize the thrombin generation right after that infusion of Factor VIII. However, as you indicated, the pharmacokinetics, you start to lose the benefit of that correction over hours afterwards.

 

What do we achieve with thrombin generation outputs with the Factor VIII mimetics? Well, at least with the first iteration of emicizumab, here again is depicted a healthy control. We do see modulation of the thrombin generation, which for most people, we accept that this is into the mild hemophilia range, but giving more and more emicizumab higher and higher plasma levels does not take you up to a full normalization of the thrombin generation. That is important for patients and clinicians together to understand with this platform of therapy.

 

What the new enhanced products may do is be able to push that thrombin generation closer and closer, or even fully normalize the thrombin generation.

 

[01:16:44]

 

Emicizumab

 

If we look at the benefits and limitations of emicizumab, this is a substitution therapy for hemophilia A. This actually is helpful because it is Factor VIII avoidance. If you have an inhibitor, you now have a prophylactic therapy that can give you excellent prophylaxis.

 

In young infants and neonates, it does allow for Factor VIII avoidance to hopefully reduce inhibitor formation in naive children.

 

I believe the data has supported that it has demonstrated superior bleed protection compared to Factor VIII prophylaxis. It certainly had a positive effect on health-related quality of life and really unparalleled health equity advance.

 

If you think about the stair steps that Kristin showed at the beginning, the inhibitor patients were being left behind with modern therapies until the availability of emicizumab. Now this has allowed them to really enjoy prophylactic benefits, just like their peers without inhibitors.

 

From a limitations perspective, again, it does not treat acute bleeding events, so you still have to rely on factor from time to time. There is this ceiling effect that I mentioned. What that means is it may not provide sufficient hemostasis for all traumatic injuries, and for some surgical interventions, additional factor supports are going to be needed.

 

It certainly reduces the therapeutic burden, maybe does not reduce the costs from a societal level. There is some loss of the natural coagulation because it is an antibody. It is not a clotting factor. We have mentioned the adverse events and the need for risk mitigation.

 

[01:18:24]

 

Novel Therapeutics: Mechanisms of Action

 

Stacy has walked us through the MoA here for the rebalancing agents and the new Factor VIII mimetics. This has given us a new challenge in how we talk to patients about how these therapies work, and it is important for them to understand what the implications are and how this is going to affect their expectations relating to bleed control, how they should manage breakthrough bleeding or how we manage them for surgery.

 

[01:18:53]

 

Fitusiran Dosing Should Be Adjusted to Maintain AT Activity Levels of 15%–35%

 

One thing that we wanted to clarify here is what you saw Dr Croteau go through was the original dosing regimen with fitusiran, which was the 80 mg monthly dosing. Then you saw the dosing strategy for the open-label extension, which was carried out in the clinical trial subjects. This was a starting dose of 50 mg every 2 months. Then there was the range of dosing.

 

Now in the open-label extension, it did allow for patients to go back up to 80 mg monthly if their level allowed them to do that. At the lower end, the lowest dose that was offered in the open-label extension was 20 mg every 2 months. And if they still had too low of an antithrombin level, they were discontinued from participation in the trial.

 

What that meant was somewhere around approaching 20% of the patients actually could no longer continue on fitusiran because of that lower bound.

 

When the FDA reviewed this, they asked for 2 things. The 80 mg monthly dose is no longer an option. The top dose now that you can go up to is 50 mg every month. On the lower bounds, because they saw the potential advantage for fitusiran for patients, they allowed for a new dosing strategy, the 10 mg dose which you saw Stacy indicate.

 

That now allows us at the lower bounds to go down to a 10 mg dose every 2 months. Now if someone still has too low of an antithrombin level below that 15% cutoff, the recommendation would be they should discontinue fitusiran. When we have modeled this with the known pharmacokinetics and formed from the clinical trials, this would be a very small proportion of patients who would actually meet that level.

 

[01:21:02]

 

Rebalancing Agents: Pros and Cons

 

If we look overall the pros and cons of the rebalancing agents, what we can say is, you are using the same medication for hemophilia A and B with and without inhibitors. There is some familiarity that is useful for the caregivers, and also for our treatment teams in managing patients and getting experience with these agents.

 

However, the fact that there are several mechanisms of action, it is possible that this is beneficial. Maybe some patients will perform better on 1 of these rebalancing agents than others. That is something that could be taken into consideration.

 

Will we see patients migrate between different non-factor therapies? I think that is possible depending on what their clinical outcomes are.

 

They have certainly been shown to be efficacious. They are all subcutaneously administered. There is some potential with label expansion coming forward that maybe these will be useful for even some other indications, other rare bleeding disorders, given that they are acting on the natural anticoagulant side rather than on a specific factor replacement.

 

From a cons perspective, all these novel mechanism of action, it is really going to be challenging for treaters and patients. We have to train our own staff about all these therapies, and also we have to have talking points to how we communicate to our patients.

 

Therapeutic drug monitoring with dose adjustments, as you saw, will be required for some of these. Safety concerns, particularly thrombosis does require specific risk mitigation. I am encouraged from the real-world experience to-date, and also some of the long-term extension trials that when the risk mitigation is implemented and followed, first of all, you can follow these risk mitigation strategies. And the outcomes can still be good for patients. And we can avoid many of these adverse events that we are seeing early on in the trials.

 

We also have to accept that there is really a lack of antidote for some of these. Once you are on them and if you decide to switch off for those therapies, you do have to wait for the effect of that therapy to wear off. This has implications for how patients migrate between the platforms of therapies.

 

[01:23:30]

 

Current FDA-Approved Therapies for Prophylaxis

 

Just as a quick differentiator between the 3 rebalancing agents that we have talked about today. They are all subcutaneous, although the rates of administration vary. You saw weekly from marstacimab, daily for concizumab. The majority of individuals on fitusiran will end up on an every other month regimen.

 

It is flat dosing for marstacimab, at least for those in the adolescent and adult category. It is a weight-based dosing for concizumab. It is a flat, not weight based dosing. But it is guided then by antithrombin level for fitusiran. Everyone is going to get initiated on 50 mg every other month, but then their dose and their frequency will be modulated based on the subsequent antithrombin levels.

 

We anticipate that patients over the first 6 months that that will be an accommodation phase. So it will be initial dose. A month later, you will get your level, and then that will inform what your next dose would be. Then over the course of 6 months, almost all patients will be on the set dose that will be going forward.

 

After that, it is anticipated that the monitoring will just be once a year and antithrombin level.

 

[01:24:53]

 

          Posttest 2

 

Here is your next post-test. A 32-year-old man has severe hemophilia B with a high-titer inhibitor. He has got a history of frequent joint bleeds, poor venous access. Then we added this additional modulator here. He has got some moderate hepatic impairment due to steatotic liver disease. But he expresses a strong preference for subcutaneous prophylaxis. What would you recommend for this patient as the most appropriate therapy?

 

Based on everything we have put together for you today, what do you think you would propose would be the best option for him?

 

Okay, there is a mix here. I do think that there is a correct answer, at least, that our faculty here came up with. Let us go through the justification here.

 

[01:26:12]

 

          Posttest 2

 

Our thoughts was that concizumab would be the best choice for this patient. Now some of that is informed by the label indication, as well as a mechanism of action here and how it targets. First of all, he has hemophilia B, so emicizumab is off the table. So A is not correct.

 

Marstacimab currently is only indicated for the noninhibitor population. That could change. As you saw in the clinical trial program, inhibitors were investigated as well, but it is not yet label approved. So we cannot offer that to this patient either.

 

Concizumab, this does meet the label indication. It does meet this person's criteria for seeking to move off of venous access. The issue with fitusiran relates to the liver targeting. This is an individual who has some steatotic liver disease, and the clinician knows that there is some moderate hepatic impairment. Perhaps a liver-targeted agent like fitusiran, this may not be the best choice for this particular patient.

 

Again, I think we should embrace all these tools that we now have in our toolbox and the ability to partner them with the right patient at the right time.

 

[01:27:32]

 

Expanding Options for Prophylaxis in Hemophilia:Current and Emerging Therapies

 

We really have expanding options for prophylaxis in hemophilia. Still, people talk about these as current and emerging therapies. But as time goes on and we are using more and more of the non-factor therapies, they are just going to be part of our routine programs.

 

The gene therapies are continuing to evolve. You saw the 2 approved therapies, which are gene addition or gene transfer strategies, but gene editing and cellular therapies are in active clinical trials right now for hemophilia B as well as for hemophilia A. So you will hear more about these in the future.

 

[01:28:13]

 

The Potential of Gene Therapy for Hemophilia

 

If we look schematically what we are achieving with these different therapies, we can think about the factor levels from a laboratory monitoring and then the corresponding hemostatic effect. For the standard half-life and the extended half-life therapies, this is the same paradigm. A factor level is going to be mirrored by the hemostatic effect in the patient.

 

With the non-factor therapies, what we gain is a steady state hemostatic effect. This is probably part of the benefit for the patient is avoiding the peaks and troughs and having a steady state hemostatic correction is what confers some of the hemostatic protection.

 

What we do not have is, since we are not replacing a factor, we do not have a corresponding level to measure.

 

For the gene therapy, we harmonize the best of both worlds here, because we will get steady state factor levels in the plasma, and there should be a corresponding hemostatic effect. So we have both the monitoring and an expected outcome for the patient.

 

[01:29:19]

 

Beneficial Clinical Outcomes Observed With AAV Gene Transfer

 

If we look at what we have been able to achieve with AAV gene transfer, particularly if we look to the Factor IX approved therapy, we see durable Factor IX activity at therapeutic levels, near normal, that is going to be shown later at this meeting, dramatic reduction in factor concentrate usage, reduced bleeding rates compared to their prior replacement therapy, and overall acceptable safety profiles.

 

[01:29:47]

 

Communicating Realistic Expectations With Patients

 

When we are talking to patients about gene therapy, however, we have some other things we have to communicate realistic expectations about this platform. There are significant post-infusion monitoring requirements. It is not just receive your infusion and then we do not see you in clinic anymore.

 

There is at least weekly visits for several months after receiving this therapy. Then we are watching for evidence of transaminitis, which has been a common occurrence with both the hemophilia A and the hemophilia B protocols. This has required modulation with a course of immunosuppression with oral corticosteroids.

 

How often that is used? It varies. It seems to be a little bit more common in the hemophilia A trials than the hemophilia B trials, but this also opens up to potential other side effects that the patient has to be aware of.

 

The other thing that I think has been vexing for a lot of patients in considering this platform of therapy, is that there is wide interindividual variability. If a patient says, “I want gene therapy but I want to have a normal level”, I cannot really promise that to him.

 

Patients have to accept that they could maybe be into the mild range, or they could be even have supraphysiologic levels. At least for some of the trials, we cannot guarantee that the level they have in Year 1 will still be the level that they have 4 or 5 years later.

 

[01:31:20]

 

Despite Promising Potential of Gene Therapy, Real-World Application Remains Low

 

You saw at the beginning, Kristin shared that, there was a program for hemophilia B that went all the way through phase III, including FDA approval, and then was not marketed. Then if you have also followed the news, you have seen that the company that supports the hemophilia A gene therapy really is not going to continue to promote that as a company, and they are looking for maybe another partner to take over that program.

 

Some have looked at, overall, has there been really poor engagement for gene therapy across the patient community. There has certainly been concerns related to the uncertainty on long-term efficacy and safety, although I think more and more data is coming that I think is encouraging in that regard.

 

What has been underestimated are the clinic resources and institutional barriers that have limited the ability of HTCs to actually offer this therapy to patients. We have certainly seen challenges with reimbursement. I do not mean that you do not get paid for it after you buy the product. I mean, insurance companies have just flat out say, we are not going to pay for this.

 

Then finally, you have seen today all these new therapies that are coming, some of which we have barely started to use in the clinic, and some patients are choosing to pursue some of these other platforms before they consider, if you like, a once in a lifetime choice of gene therapy.

 

There is still some aspects of a lack of understanding of what seems like a complex therapy. This may also be contributing to low uptake of gene therapy as well.

 

[01:33:01]

 

Categories of Therapeutics Available in the Clinic or in Development for Hemophilia

 

One of our colleagues here, Dr Valentino has revised that slide I just showed you to indicate that, yes, I mentioned that this is the optimal outcome from a gene therapy. I believe the hemophilia B trials have mostly replicated this.

 

What we have seen with at least some of the hemophilia A gene therapy programs is those peak activities within the first 6 months or year are not sustainable, and patients fall back to well within the mild range, and a significant proportion of patients actually had to return to prophylaxis because their levels declined too much.

 

[01:33:44]

 

Promoting All Aspects of Health to Reduce Morbidity and Mortality

 

Putting this all together, when we think about what comprehensive care looks like in our clinics, we are certainly focused on the physical health of the patient, trying to improve good outcomes. We are also paying attention to their psychosocial well-being as well as overall quality of life.

 

When we now talk about comprehensive care, all of that holistically should be part of the equation. This comes into play in shared decision-making and talking to patients.

 

[01:34:14]

 

Objective Variables That Guide Treatment Decisions

 

When you are gauging, is my patient well controlled on the therapy? There are certainly some objective variables we look at. We look at their bleeding. We look at their joint status, their treatment adherence, their venous access issues, if that is relevant, and then the overall lifestyle they are choosing to live. That is how we have modulated therapy for patients for a long time.

 

[01:34:37]

 

Select Subjective Variables That Influence Treatment Decisions

 

I also think increasingly we are paying attention to these subjective variables. The patient preference is important here. If they want to be on a subcutaneous therapy, or they want to just have 6 injections over the course of a year to manage their prophylaxis, these are still equally important and valued in that shared decision process.

 

We have to take into account their experience with current or past treatments, any comorbidities, including concomitant medications. What is their support network look like around them? What do we know about their overall psychosocial status? Are there chronic pain issues which also have implications for maybe what therapy they are best suited on?

 

[01:35:16]

 

The Ultimate Goal: A “Hemophilia-Free Mind”

 

Although our focus today was on non-factor therapies, I think thinking about how this is all contributing to this concept of a hemophilia-free mindset is important. This was put forward initially by Dr Hermans in Belgium.

 

This is looking at things that patients may have daily concerns in the gray vs things that might only now be an occasional concern, or in the best possible setting, few or no concerns.

 

As you move between the factor replacement prophylaxis, non-factor and then into gene therapies, we do see that more and more of these components like travel, employment, physical activity, the effect on family members, etc. These become less and less concerning as you modulate through these different platforms of therapy.

 

This idea of hemophilia therapy can reduce not only the treatment burden, but also the disease burden and then also the mental burden of having this condition. We are seeing this in our clinics actually on a regular basis.

 

[01:36:29]

 

Proportion of Participants Achieving Hemophilia-Free Mind Thresholds at Baseline and at Wk 208 Post Valoctocogene Roxaparvovec Infusion (mITT)

 

This was a first attempt at actually depicting this using a spider plot. This was presented at ISTH. This comes from the ROCTAVIAN phase III program. What this is looking at is these are different nodes with a binary variable. Whether there is any impact on physical activity, improvement in the injection schedule, improvement in pain, etc.

 

These were all outcome measures that we could retrieve from the clinical trial program. What you see in the orange is their baseline across each of their nodes. Then as they modulated their Factor VIII levels post gene therapy, we can see how it impacted on the spider plots. We can actually literally visualize this concept of a hemophilia-free mindset.

 

This could really be recapitulated for any of the therapies we have talked about today, and this is an important concept when we are talking to our patients and we are considering different platforms of therapies.

 

[01:37:37]

 

Panel discussion

 

Okay. Thanks for participating with us on all of that. We did want to spend some time together and just see if we could apply some of the principles we talked about this afternoon to some cases. I am going to put Stacy and Kristin on the spot here.

 

[01:37:55]

 

The Active Young Adult

 

Let us start with our first active young adult. This is a 25-year-old man with severe hemophilia A without inhibitors. He has got early signs of synovitis in his left ankle. He is highly active. He plays competitive and recreational basketball on weekends. He is on a standard half-life Factor VIII prophylaxis every other day.

 

The problem is, despite adherence, he is still having about 2 spontaneous bleeds in the last 6 months. These have occurred anywhere from 24 to 36 hours after infusion. He is really frustrated by the need to time his injections around his games. He is really fearful that by having still ongoing bleeding here on a regular basis, what this impact will be on his joints over time.

 

Stacy, what do you think your discussion would look like in the clinic with him?

 

Dr Croteau: Fortunately for him, as a severe hemophilia A without inhibitors, he basically has the full armamentarium at our disposal. So we can start from anything from considering a gene therapy option to the non-factor therapies, or even the ultra-extended half-life or sustained-high activity factor concentrate that you mentioned.

 

For individuals his age that have IV access skills, and who are athletes who really want to normalize their Factor VIII levels, maintain high physical activity, feel protected, I do have a number of individuals who have chosen to stick with factor concentrate therapy, leveraging the high-sustained activity Factor VIII because they are able to easily administer it. It is only once a week. It normalizes their levels for a considerable portion of the week.

 

Unlike in this situation where he is having to dose frequently by the time you get to day 1.5, or certainly Day 2, you are already back in the moderate or severe category, and he is having breakthrough bleedings. That therapy offers better protection normalization.

 

I also have a number of athletes who really appreciate the subcutaneous bispecific antibodies and leverage things like emicizumab, and I am sure will be interested in the next generation of those bispecific antibodies, because moving from the moderate or severe category, even into the mild range, with a lot of recreational type of sports, seems to confer excellent bleed prevention and protection.

 

Then we eliminate the need for regular IV infusions entirely and often achieve no breakthrough bleeding, leveraging that therapy as well.

 

Dr Pipe: Kristin, I think this scenario still would hold up if he was 16, 17-year-old. Does this resonate with you as a real case in your clinic?

 

Dr Maher: Yes, I think we have very few patients in our practice who are still on the standard half-life. We have a couple holdouts on standard half-life Factor VIII prophylaxis. This mention of early signs of synovitis is really important here because even some children who are doing well on standard half-life Factor VIII, if we have imaging evidence or other physical exam evidence of joint damage sometimes, that is enough to have them think again about whether it is working for them.

 

I would say, yes, this is not a common case, but we have a couple still, for various reasons. I would say more often we are talking about whether they are happy with the newer therapy they are already on or have heard about others that might be better. So yes, this is a pretty rare case in my practice at least.

 

Dr Pipe: We would agree that the limitations he is experiencing are absolutely related to the platform of therapies on and the pharmacokinetics. We agree he is clearly not optimized for bleed management, right?

 

If you were going to do a therapeutic switch, can you talk about what you would be discussing with them between, say, an EHL Factor VIII, high-sustained Factor VIII and emicizumab, or any of the other non-factor therapies?

 

Dr Croteau: Yes. So we highlight a lot. We do a lot of drawing in my clinic. I do not know, Kristin, if you do a lot of drawing, but to help try to give a visual representation to the level of hemostatic protection and how that changes over time or does not with the different types of therapies.

 

Then we also review the administration burden and really talk through whether he is able to achieve IV access regularly, if even though he is doing this, is it causing a lot of pain, or are there a lot of additional challenges there, would he really prefer to not have to do any IV access? Is he having difficulty with access and breakdown of some of his venous access and switching to subcutaneous therapies.

 

The need for still thinking about the possibility of bleeds and having bleed treatment available, regardless of what therapy you go through. So we go through the administration logistics, the overall hemostatic coverage logistics, and really try to have a thoughtful conversation to understand what his, or in my case, similar to yours, parent child combination priorities are.

 

Dr Pipe: Kristin, what would your team do from musculoskeletal ultrasound perspective in this particular case?

 

Dr Maher: Yes. We would have started earlier than this in checking ultrasounds. We try to get a baseline on children, at least once they are able to tolerate the exam because it takes a little bit of time and patience. Then I do not think we do them every year in children who are doing well on their prophylaxis, but maybe every couple of years just to check and see if we see any early changes.

 

I would say in children who are on standard half-life Factor VIII, we have seen early signs of changes, even in those who are not much younger than this, even in those who are not reporting any bleeds. It depends on the trajectory, but we would screen them with musculoskeletal ultrasound every couple of years, probably in their comprehensive visits.

 

Dr Pipe: I would say I might have a bias here is that if these were in a 1 particular joint and he was having 2 spontaneous bleeds in the same joint, as a target joint, I would probably prioritize something like efanesoctocog early for some period of time. Then based on how he did on that and improved the bleeding, if he comes back to me and then says, I am really done doing IV injections, and I would really prefer, I think I would feel better going to a non-factor therapy at that point.

 

The clinical trial data supports that target joint bleeding improves even on the non-factor therapies. There is some aspect of me being able to actively treat and see that under control in a short period of time might change the offerings to the patient.

 

Dr Croteau: To normalize those factor levels in a sustained way.

 

Dr Pipe: Yes.

 

Dr Croteau: Agreed.

 

[01:45:03]

 

The “Hard-to-Treat” Patient

 

Dr Pipe: Okay. Let us talk about a hard to treat patient. This is a 32-year-old male. He has got severe hemophilia B, high-titer inhibitors. Comorbidities here, scarring from years of IV access. He has got moderate hepatic impairment. Maybe we did not make this entirely accurate. It is hard to imagine he would be HCV positive at 32 years. But let us assume he came from a geography where maybe that was an issue. Or we could just make him 42, and then that would that would fit. He is post HCV. He is cleared, but he does have some residual fibrosis related to that.

 

His current status, he is using on-demand bypassing agents for bleeds. He has got frequent visits to the ER for venous access issues just to get an acute bleed treated. He is really desperate for subcutaneous prophylaxis option. Kristin, how would you think you would approach?

 

Dr Maher: Yes, this is the patient population, severe hemophilia B with inhibitors that really has been left behind up until very recently. I would definitely want to offer this patient subcutaneous prophylaxis. As in 1 of our earlier questions, hepatic impairment makes fitusiran less appealing. So perhaps concizumab here.

 

Unfortunately, in some of my patients, they are too young, yet it is not approved. If they are young and have hemophilia B with inhibitors. But for this patient, certainly I would be very interested to offer him that option.

 

Dr Croteau: I agree with that. As you alluded to across all of the non-factor therapies, interest in emerging clinical trial data for the inhibitor population as well, presently with licensed therapies. Concizumab is really the only commercial available therapy. It may be true that with marstacimab and other non-factor therapies additionally will have approvals in the future, and echo exactly what you said. This is the highest unmet need population.

 

Having this option is really a lifeline because prior to this, historically, we would be thinking about something like a central access or something to allow more effective, potentially even prophylactic bypassing agent therapy for him. So something that improves hemostasis, provides a consistent, improved hemostatic capacity and can be administered subcutaneous is really going to change his life.

 

Dr Pipe: I would say that, although, there were some liver criteria that were applied for eligibility for the fitusiran studies, there were patients who had history of hepatitis C, and there was no indication that they had any differentiating outcomes. You had mentioned at the beginning about the transaminase elevations and the cholelithiasis issues, that also did not seem to be linked related to history of prior hepatitis.

 

It is a dose-dependent effect, which was then shown with the modified dosing regimen that those complications went down. We are still in maybe the learning phase about how much hepatic impairment is an issue with fitusiran. I maybe understand the sentiment of maybe wanting to steer away from a liver-targeted agent. Obviously, it has implications, not that he would have been eligible for gene therapy, but anything that is liver targeted, we are going to pay attention to these kinds of historical things, and we are going to use FibroScans and transaminase elevation screening, etc. I would not say it is completely off the table for this particular case.

 

If you did put him on concizumab, what would that look like?

 

Dr Maher: He would start on daily dosing, and then you would have to get a level at 4 weeks to make sure you are within the acceptable ranges. Then it would also be really important to have a discussion about what we are going to do for breakthrough bleeding or surgeries.

 

At our center, we offer these emergency letters to patients with hemophilia, saying like, if in case they are going to an emergency room and this is what we do for bleeding, we would have to have a really close look at what information they have and what they know, because it is going to change how we think about those scenarios.

 

Dr Pipe: That is what I was thinking is he is having some dosing here, which may be outside the HTC oversight. He shows up in a local ED. Are they going to understand the implications of him being on concizumab? And are they going to be paying attention to the doses of the agents? A lot of centers have maybe had emergency cards that the patients take with them, and they go to the emergency room so that they understand that there may be some risk mitigation related to breakthrough bleed management. So that is good practice as well.

 

[01:50:08]

 

The Quest for a “Cure”

 

One more case here. This is a 38-year-old man with severe hemophilia A without inhibitors. He just has mild non-alcoholic fatty liver disease. Otherwise he is healthy. He is on prophylaxis once weekly with efanesoctocog, and actually his ABR is zero.

 

However, even though he has had zero bleeds, he just finds that the mental burden of having hemophilia, being a patient, weekly IV infusion. He just finds this exhausting, and he is seeking this aspect of a hemophilia free mindset. He is asking for a gene therapy so he can be cured and never see a doctor again.

 

Stacy, maybe you have had this conversation before. How are you approaching this and how are you walking him through what he might consider?

 

Dr Croteau: Obviously, a very potentially reasonable candidate for gene therapy. He checks off a number of boxes that his current therapy is working well. So sometimes this can lead to conversations with the insurance company.

 

But thinking about shared decision-making and what is really important for him and what is limiting him in his need for prophylaxis is really important here. We presently have 1 commercially available Factor VIII gene therapy. We do have to do some baseline work. We have to look for anti-AAV antibodies to see if he is potentially eligible for the therapy.

 

Then we do have to walk through with him. Importance of looking at a bit more detail at his organ dysfunction, investigating that liver and his overall liver health potential fibrosis a little bit more.

 

Then we have to be very realistic, and many of your figures, Steve, really helped outline this about the hopes and expectations of what we can deliver with gene therapy. We have very clearly seen with the currently commercial gene therapy that it is very achievable to get normal levels of Factor VIII for some period of time, but it is not currently achievable to get and maintain for the rest of your life, especially starting at 38 years old. At this moment, with the currently available therapy, a complete hemophilia-free mind and durability of that therapy.

 

Additionally, it is not as easy as coming in for 1 outpatient infusion and then going off into the sunset. As you nicely outlined, getting that first infusion in a lot of ways, is the easiest part of the gene therapy process, and there is a lot of monitoring and careful communication that has to happen after the fact.

 

In many instances, particularly for the Hemophilia A gene therapy, use of immunomodulatory agents, corticosteroids, side effects of steroids, adherence to the steroids or potentially other regimens. There is still an important potential benefit but some burden that goes along with that choice. Having very clear expectations of what it means to get gene therapy and go through those logistics, as well as the likelihood of cure and duration of cure, or at least lack of need for ongoing regular prophylaxis, and the likely durability of that will be really important to be sure he understands. So he does not have unmet expectations moving forward.

 

Dr Pipe: I certainly do not dismiss the sentiment, and I have had guys say this exact same thing to me. The reality is that we are still doing gene therapy too late. By the time we are hitting adulthood, we are offering gene therapy, we have accumulated damage in those joints that is going to have implications down the road and probably progressive arthropathy may be at a reduced rate, but still some issues that will have to be dealt with in their 30s, 40s, 50s.

 

The idea of being able to completely disconnect from the HTC is not good, and maybe not likely either. However, you had mentioned that maybe being able to offer a curative gene therapy to a very small child maybe within the first few years of life. We have normalization of factor levels, no bleeding during childhood. Do you think that there is a possibility of really disengaging from the HTC in that setting?

 

Dr Maher: Yes, that would be aspirational, right? It would be great to have a durable, normal factor activity and essentially not have hemophilia. These patients would still need some touch points and certainly genetic counseling. That would be amazing, wouldn't it? It is still a far way off.

 

[01:54:56]

 

          Poll 6

 

Dr Pipe: Yes. Well, thanks for that. We do have another poll question here based on what you learned today. Do you plan to make any changes in your clinical practice based on what you learned in today's program? You can indicate your response here.

 

Okay, I hope everyone said yes. I hope that you will at least take something away from today that will be valuable in how you engage with patients and how you go through clinical decision making with people.

 

[01:55:53]

 

Q&A

 

Now, we did still allow you to have some time to submit questions through the application there. We will take a few minutes here to try to address these. Let us just go rapid fire.

 

Stacy, do you need to have baseline antithrombin levels before you start fitusiran?

 

Dr Croteau: Yes.

 

Dr Pipe: Okay. If you stop it, when do you no longer have to worry about the risk mitigation strategies?

 

Dr Croteau: As your antithrombin level gets up towards the normal range, so certainly up over 35% and back towards baseline.

 

Dr Pipe: Yes, and we feel that the bleed management guidelines do not have to be followed after you reach 80 level back to above 60%.

 

A question here. I do not know the answer to this. Have seizures been reported with emicizumab? And if so, does an alternative product have to be suggested?

 

Dr Croteau: I do not think I have heard of seizures being reported. I have had some patients who have had headache, particularly during the higher doses, either the loading doses or monthly doses, who have had fatigue, who have had some vague neurologic type symptoms. But I do not think I have heard of any seizures in particular.

 

Dr Pipe: What is the experience with emicizumab in women?

 

Dr Croteau: Very little. They were not included in the clinical trials per se. I would say that post-licensure, of course, we have moderate and severe gals with hemophilia who have adopted this commercially for prophylaxis, and I have not seen any particular worrisome safety data that has emerged. Again, as I alluded to, as we started to use this off label in other domains, von Willebrand disease acquired hemophilia, of course, our XX genotype patients receiving in those regards, but no new emerging safety issues.

 

Dr Pipe: Yes. Of course, since emicizumab is now being evaluated in the von Willebrand indication, there is multiple women that are now part of that program. So we are going to glean some additional data there.

 

Someone asked about the anti-TFPI agents that were just measuring a concizumab level. What does that tell us, really, about thromboembolic complications? We are not measuring anything pharmacodynamic related to TFPI itself.

 

I think we accept that. I do not know any other coagulation parameter that we can measure in routine practice that would really help us there. The decision to keep patients within a range with concizumab was informed from the clinical trial program, and then looking at patients who did have thrombotic complications, whether that was a contributing risk factor. I do not know that there is a better coagulation assay that we will have for following patients in this regard.

 

Dr Pipe: Are there any data about bone health differences in patients who are from the beginning on non-replacement therapy compared to standard or EHL prophylaxis? Since you are probably using emicizumab and maybe now eventually some of these other therapies, what are you talking about with your families and what do you know from the data related to bone health outcomes, particularly in small children?

 

Dr Maher: I do not know of any. There will be emerging data for bone health in children who are started on emicizumab as previously untreated patients. I do not think we have anything yet. We are counseling our older children on bone health, but not as it relates specifically to emicizumab.

 

Dr Pipe: Yes. HAVEN7 which is the young infant study. Those patients are now aging well, and the first wave of patients who enrolled are actually now having their bone assessments. So they are going to be undergoing MRI evaluations. The whole cohort of 55 patients are going to have MRIs starting around age 5 years out from being on therapy.

 

That will give us a first cohort of infants who have exclusively been treated on emicizumab and look at their bone health.

 

From a physiologic perspective, there is no question that bleeding and impacts on joint function and limitations on activity has the greatest negative impact on bone health. So anything that reduces bleeding and improves the activity level for the patient is likely to actually have a positive impact on joint health.

 

Maybe we have to wrap up. So maybe I cannot take the take the question. But what I shared with you about the limitations of the uptake of gene therapy, did any of those points resonate with you, or do you think there are other issues that I did not comment on?

 

Dr Croteau: I think you really captured most of the key issues with gene therapy, that there is a lot of hope and interest in curative options and in leveraging gene therapy, but with the whole platform of various therapies that are available, folks are really weighing the risks and benefits, how that is incorporated into their daily lives and regimens and what that means. So we will continue to see a push and interest in gene therapy, both scientifically and from the patient population.

 

I do not think any of this really reflects lack of interest. I just think it reflects a very easy area of treatment options and people trying to appropriately think about safety and prioritize efficacy and their personal needs.

 

Dr Pipe: I still have confidence that over the coming months and years, patients who have not been treated with gene therapy may still come around, and this may be the best choice for them in the future eventually as well.