In this episode, hemophilia experts discuss how they integrate hemostatic rebalancing agents, including an antithrombin agent and tissue factor pathway inhibitors, into their practices for the care of patients with hemophilia. Listen for their insights on dosing, administration, and key differences between the rebalancing agents that inform their personalization of therapy.
In this podcast episode, experts Angela Weyand and Guy Young discuss their experience using hemostatic rebalancing agents for prophylaxis in patients diagnosed with hemophilia. Three rebalancing agents have now been approved, including concizumab, fitusiran, and marstacimab. These new rebalancing agents target the body's natural anticoagulants and provide individualized, convenient options for patients older than 12 years of age.This podcast explores similarities and differences between the rebalancing agents, such as dosing, necessary lab testing, and safety profiles, that are important to discuss with patients and their caregivers.
Presenters:
Angela Weyand, MD
Associate Professor, Pediatric Hematology Oncology
Co-Director, Combined Hematology/Gynecology Program
Pediatric Medical Director, Hemophilia Treatment Center
University of Michigan Medical School
Ann Arbor, Michigan
Guy Young, MD
Director, Hemostasis and Thrombosis Center
Director, Clinical Coagulation Laboratory
Cancer and Blood Disease Institute
Children's Hospital Los Angeles
Professor of Pediatrics
Division of Hematology/Oncology
Department of Pediatrics
University of Southern California Keck School of Medicine
Los Angeles, California
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This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Guy Young (Keck School of Medicine of USC): Hello, we are really happy to be here speaking about hemophilia and the latest treatments in hemophilia. There have been quite a lot of changes. That is what we are going to be discussing today.
When I started taking care of hemophilia, we really just had one option: factor replacement.
Essentially, factor replacement was factor replacement, be it for hemophilia A or hemophilia B. We were always talking about IV therapy. We are always talking about needing to put central venous access devices in younger children in patients with inhibitors, even sometimes in adult patients, those all IV, IV, IV, and that created a lot of problems.
It created problems of needing central venous catheters. It created problems with adherence. It created a lot of other issues. Even if you were adherent and everything went well, it created problems with the treatment burden. We really entered a new era where we have got lots more options, but more importantly, we have got lots of subcutaneous options.
Angela, start with emicizumab and tell us why it is so important that we have these agents.
Dr. Angela Weyand (University of Michigan Medical School): When you first started, there was only factor, and I first started, and then very quickly, we had our first nonfactor product, emicizumab, which was really exciting, especially for inhibitor patients. I think that is also where having different options is most exciting in patients with inhibitors that we cannot just use factor products for.
That was very exciting for hemophilia A. But then I think with that introduction, we were getting a lot of hemophilia B patients coming in and asking, we heard there is these subcutaneous options, or there is options that we do not have to dose as frequently.
We really did not have options for hemophilia B patients outside of factor products. It is really exciting that now we have these rebalancing agents that target our body's natural anticoagulants. Luckily, especially within the pediatric population where people have a lot more issues with intravenous access, as you mentioned, people having to have ports placed which bring all of the different complications having a major surgery.
Even our patients with bleeding disorders can get thrombosis. Having to come in when you are having fever. All of these different things that really impacted patients' quality of life. It is very exciting that they have subcutaneous options. It is very exciting that some of them allow much less frequent dosing than our factor products, where some of the factor products that our patients were on requiring multiple times a week dosing.
Those have been huge improvements in the quality of life. As you mentioned, the treatment burden for our patients. I do not know if you want to talk a little bit about the three products that we now have available, but they are all rebalancing agents, so things where we are not replacing what is missing but rather decreasing our body's natural anticoagulant and trying to balance between bleeding and clotting.
Dr. Young: One of the non-factor therapies is emicizumab that we mentioned earlier. It is only for patients with hemophilia A, and it has been around for quite a few years, so we are not going to talk any more about that option. Really, today, I want to talk about the rebalancing agents with you. These include fitusiran, concizumab, and marstacimab.
First, we have to discuss rebalancing. What does that mean? What the audience should understand is that these three drugs all work more or less in a similar general way, which is that we have inhibitors to coagulation. For patients with hemophilia, this is the way I think about it. They can generate a small amount of thrombin via the extrinsic pathway Factor VII tissue factor. They generate a small amount of thrombin, but they cannot ever get to the full thrombin burst because they do not have Factor VIII or Factor IX.
Part of the problem is the coagulation inhibitors. Tissue factor pathway inhibitor inhibits the Factor VII tissue factor pathway. Then we have antithrombin, which, obviously, by its name inhibits thrombin but also inhibits other coagulation. Proteins as well. Essentially, we are in a situation where hemophilia patients can generate a small amount of thrombin, but it is immediately inhibited by these coagulation inhibitors.
One way around this is essentially to lower the levels, inhibit, block, reduce, however you want to say it the levels of these coagulation inhibitors. In other words, if we can block or inhibit the function of tissue factor pathway inhibitor, or if we can block or reduce the levels of tissue factor pathway inhibitor or antithrombin, then the small amount of thrombin that hemophilia patients can generate will then be able to feedback on itself and generate more and more thrombin, such that the thrombin burst that is needed to make a blood clot can happen.
That is what we mean by rebalancing. We are essentially saying that the balance is off because we are missing a procoagulant protein, Factor VIII or Factor IX. If you think about it as a scale, we can rebalance by taking away something from the other side. Instead of adding Factor VIII or adding Factor IX, we can take away tissue factor pathway inhibitor, or we can take away antithrombin. That is where that rebalancing comes into play.
Think about three blocks on either side of the scale. You take one block off one side. You can rebalance it by adding that block back, or you can rebalance it by taking a block off the other side of the scale, and that is really what the rebalancing agents are doing.
When we say rebalancing agents, again, just to emphasize, we are talking about fitusiran, concizumab, and marstacimab.
With that, let us maybe start talking about the products specifically.
Dr. Weyand: All three products are only approved for treatment of patients 12 and older. Dr. Young and I both take care of pediatric patients, and there are ongoing studies looking at younger patients, but for now, they are only available for 12 and up. As mentioned with rebalancing agents, they are targeting different things. Marstacimab and concizumab are both targeting the TFPI pathway, whereas fitusiran is targeting a different pathway with antithrombin siRNA knockdown of antithrombin.
The first thing people think about is thrombosis, and so that is something we need to be thinking about.
Marstacimab, as I mentioned, targets TFPI. It is currently only approved, as I mentioned, for 12 and up, and actually only approved for hemophilia A and B without inhibitors. It is subcutaneous, as all three products are, and is dosed once weekly, and there have been multiple trials. Most recently presented at ASH this year, there was a trial for inhibitor patients, and these drugs and specifically marstacimab, and their inhibitor trial, is compared the ABR against patients who have been on on-demand treatment.
There was a huge decrease in bleeding in those patients, a huge decrease in their ABR. It was superior to on-demand treatment. What is also important in a lot of these studies that they are collecting is improved quality of life. More and more in hemophilia trials where you are incorporating quality of life assessments. When I think about my patients, whether it is the patients years ago that got transitioned from factor to emicizumab or now, or thinking about these products, you can look at the ABR, and we always look at the ABR, and we love to see low ABRs, and that is super important.
You can have products that have identical ABRs, and we have so many good products now. We are so lucky where a lot of these trials, the ABRs are so low. Now I think that is the bare minimum. It has to be an effective product. Along with that, it is a very different thing to see an ABR that is very low in a patient who is having to do IV administration three times a week than it is to see a very low ABR in a patient who is able to do maybe a subcutaneous injection every two months. You can imagine the impact on their life and the impact in pediatrics on the rest of their family's lives, where if their mom is having to help infuse the kid three times a week versus doing a subcutaneous injection a couple of times a month, that is a big difference.
Then concizumab also targeting TFPI the difference with concizumab and marstacimab, they both are targeting TFPI. They both are subcutaneous, which is fantastic. The dosing is a little bit different in that concizumab, instead of being a weekly injection like marstacimab, is a daily injection. With marstacimab, there is no drug monitoring or levels that need to be followed, but with concizumab, it is recommended that a drug level would be checked at four weeks.
Sometimes in clinic, those are things that matter to patients. Do I have to come back? Where can I get that lab drawn? Am I going to have to worry about changing the dose? How do I know that my treatment is in the sweet spot? Especially in hemophilia, where for so long we focused on factor levels, and you could say. For a long time, and still, there are patients and providers where they use the PK data, and they want to know, this many days after prophylaxis, this is where my factor level is.
I feel like I can go and do this activity. We do not really have similar things, but we do have some drug monitoring for these medications.
Do you hear that Guy, that patients struggle with not having that factor level?
Dr. Young: Yes and no. In some respects, patients will take a subcutaneous treatment and accept some of the facts that there is not a specific monitoring to do or things like that. That is not a reason why patients would not switch to these. I have not heard that so much in my clinic.
For all three of these products, they have all been studied in patients older than 12, because they are rebalancing agents, they work in patients with hemophilia A and B, and because they are also not a factor product, they work in patients with inhibitors.
Currently, all three are approved for 12 and older hemophilia A or B with and without inhibitors, with just one exception, which is that marstacimab is not yet approved for patients with inhibitors, but that study was completed, and I anticipate that it will get that approval fairly soon. Just keep in mind for the audience that currently marstacimab is not approved for patients with inhibitors, we do know that that is coming in the near future.
To keep things simple, thinking about these drugs as subcutaneous drugs, all three of them, for hemophilia A or B, all three of them. Currently, for patients older than 12, all three of them, and for patients with and without inhibitors, once marstacimab gets that inhibitor indication. There are trials going on for children. It is going to be some time before these will be approved for children less than 12, so we will not really focus so much on that.
As far as efficacy and safety are concerned, I do believe that these drugs are, generally speaking, effective to very effective, and they are, generally speaking, safe.
There are, of course, risks with any such drugs. I encourage the audience to look at the prescribing information for all the details about the safety issues. Fitusiran, for example, is one that has a boxed warning for thrombotic events and for gallbladder issues, compared to on-demand treatment, these are all highly effective, reducing bleed rates. Compared to clotting factor prophylaxis, all three of them were shown to be at least as effective, if not more effective than clotting factor prophylaxis in the trials where there was a lead-in with clotting factor.
What the audience should take away is that these drugs are effective at preventing bleeding. Now, one other point of emphasis, these are only for bleed prevention. All the patients will still need a prescription for factor replacement or bypassing agents to manage bleeds. You do not give an extra dose of these drugs. If there is a bleed, you then have to give factor. That is the general summary of the efficacy and the safety of these products.
Talk about the implementation issues.
Dr. Weyand: I will just start with marstacimab. As I mentioned, there is no lab monitoring that is required. It is, as I mentioned, weekly subcutaneous injection with a pen device, I do hear things from patients or in the patient community that sometimes the device, that makes a difference to patients more than I would have anticipated.
All three pen devices I should mention. As I mentioned before, the marstacimab is the weekly versus concizumab daily, and fitusiran can be every month or every two months, depending on some of the lab monitoring. For concizumab, there is a recommendation to check the drug level at four weeks. A proportion of patients do require a dose adjustment following that four-week level. That is something that is not just straight dosing that patients would be started on a specific dose and then have that four-week level.
Then fitusiran, similarly, as mentioned, thrombosis is one of the things that we are all very cognizant of as far as a risk for these products, both from just knowing or treating patients with antithrombin deficiency or these things, but then also from the clinical trials. Fitusiran does have that boxed warning about thromboembolism, but they have a very nice mitigation strategy that has been put into place.
Patients have baseline antithrombin levels ordered after each dose for this first six months after starting, and then also after any dose adjustments. Then based on what their antithrombin level is, their dose would be adjusted. Patients are started initially on every two months, but they may end up having to be every one month. That would be the most frequent, the majority of patients, at least so far, end up in that every two-month range based on their antithrombin levels.
That is another one where there is some drug monitoring. There is some possibility, and probably a good proportion of patients for changing dosage based on those levels versus marstacimab, where there is not anything like that.
I have not heard a lot about that being a challenge for patients. For the people I have spoken with, it seems to be going pretty well as far as for concizumab and for fitusiran that not being a huge issue in terms of the monitoring.
Dr. Young: One thing to know about marstacimab is that it is a flat dose. Everybody older than 12 gets the same dose. It does not matter what their weight is. One other point, which is the first dose is a double dose, so it is 300 milligrams.
You get two pens, one pen in one side of the belly or wherever you inject it, one on the other side, and that is how you start. Then, after that, it is weekly. There is an option to double the dose for marstacimab. A small percentage of patients did double their dose in the trial, and that did seem to help. If a patient is on marstacimab and they are having bleeding symptoms, that is an option is to double the dose before you choose to switch them off to something else.
Fitusiran is also flat dosing. Everybody older than 12 gets the same dose. Then, as you mentioned, the dose adjustments happen from there.
In the prescribing information, there is a dosing algorithm. On the website, there is basically a way for you to input your patients' information, your dose like an algorithm again, so you can figure out how to change their dose, if needed, based on the antithrombin levels, because we are targeting levels of 15% to 35%.
Then with concizumab, that is the one that is a little bit different because it is weight-based. The pen for concizumab has a dial in it, and then patients would dial their dose. As you said, you have to get a lab test, and then based on the lab test, you may have to increase the per kilogram dose, or you may decrease the per kilogram dose, which obviously would change the full dose. They all come in these little pens, the marstacimab and fitusiran pens. They are disposable. Use them once, and you throw them out until the following dose.
The concizumab pen is a dial pen, which is multi-dose depending on your dose, and there is different sized pens. Again, on the website in the prescribing information, there is a nice tool that you can use. They are interactive tools that can help you figure out which pen to prescribe for a patient.
The pharmacies help us to do that. I just put the medication in and the frequency, and then they will figure out what size concizumab pen to send to the patients. It is an important point about the monitoring. As you said, marstacimab, no monitoring. Fitusiran monitoring for six months and then once a year, once you get the dose right. Concizumab, there is a requirement to do one test, and then beyond that, it is up to you if you do more tests.
As I think about the practical implementation of which patients might be right for one, I did recently put a patient on marstacimab. It was a young adult patient. He wanted to switch to a subcutaneous drug. He did not really have any specific inclination to one or the other. He was relying on us. One of the things that I learned is that he lives in a rural area, and the closest lab to his house is 45 minutes driving. That is when I started thinking, well, that is going to be a pain to have to do a lab once a month.
The concizumab level is very unique in the sense that you have to go through a special portal. It is not something that could be done in one of those commercial labs out there. As I was thinking about him, I thought, well, I need to figure something out where he does not have to deal with the lab. That is where marstacimab became the natural choice for him.
Not that I felt that it would be any better or worse than the other ones. I feel like they are all effective and safe. But in terms of implementing, that is one thing to think about. If the audience members who are listening to this podcast, if you work in a rural area, if you have patients from a rural area, certainly one consideration is the lab testing.
For those patients for whom lab testing might be a challenge to sort out and figure out how to do it, that is where marstacimab naturally does not require that.
The flip side, though, some patients like to know what their factor level is, and their doctors sometimes like to know where their factor level is. To me, one of the downsides of marstacimab is not only is there no lab monitoring, which is a good thing in many senses, but the flip side of that is that even if I want to do a test, let us say somebody on marstacimab and they are bleeding, and are they adherent? Are they nonadherent? What is their level? There is no way to actually measure a marstacimab level or a TFPI level that is going to be accurate.
You are running a little bit blind with marstacimab. The strength is its simplicity and ease. You do not need lab monitoring, and people live far from a lab, fantastic, and I have chosen marstacimab specifically for patients like that.
The downside is there is not something to test. As you brought up the point about patients want to know, and doctors want to know sometimes where patients are with their meds, what do you think about concizumab and fitusiran, where not only is testing available, but it is required. The downside is it is required. We have to do it, and we have to figure it out. The upside is we have something where we know where patients are.
What do you think of that, as a physician, thinking about these three medications in that situation?
Dr. Weyand: It is a really interesting thought, and I think even you saying that about someone living in a rural area. I was thinking to myself that patient previously was on factor and maybe at times you wanted to get a factor level, and maybe that was not necessarily available or a close lab to him. There is all these intricacies now to how we are measuring things, and that may not necessarily be available in rural places.
It is interesting because I think there is that benefit for patients who want to know. I think of some of the elderly patients, have bad joints, and it is not always totally clear that they are having a joint bleed versus long standing joint damage that is causing them pain.
Sometimes that would give either the patients or the providers a little comfort or reassurance that they could measure that and know that this is where it should be.
\ I still think it is far from where we were with factor levels, where everyone had a lot more decades-long experience, knowing factor levels, feeling more confident about if your factor level is X, that you could do certain activities or go to surgery or these things.
Whereas I feel like if I get a concizumab level back, I do not necessarily have that same comfort level as, okay, the factor is 100%.
Dr. Young: We know that in hemophilia A, the majority of patients in the US are on emicizumab. We know that emicizumab has a long washout time. It is four to six months minimum for a full washout. How would one switch a patient if they are wanting to switch from emicizumab to one of the rebalancing agents?
There are patients on emicizumab who still have more bleeds than they like, but they do not want to go back to an IV therapy. There may be reasons why hemophilia A patient, even if they are doing relatively well, might consider switching to one of these agents. Once they see the hemophilia B patients having these little pens where it is like, boom, I am done in 30 seconds, they might be thinking about one of these drugs as opposed to what they have to do with the injections with emicizumab, which could be large volumes, and they are relatively painful when you have to do them.
We do not really have a way for you to switch. There are studies going on right now for patients to switch from emicizumab to fitusiran to concizumab to marstacimab. There are some very early data that actually I presented at ASH on just a few patients, three patients who switched from emicizumab to fitusiran. Too early to really make any good thoughts or suggestions.
For those of you who have a hemophilia A patient who wants to switch from emicizumab, one option is to let the emicizumab wash out over four to six months. We do not love that idea because then they are open for bleeding. Another option is to pick sometime after stopping emicizumab, say, two months or three months, to then introduce the new medication, but there is no data on that. None of us can vouch for the fact of how safe that would be, or at what point you would need to do that.
There is a bit of a challenge in switching emicizumab patients to one of these drugs until we have more information. You can take this on a case-by-case basis. As I said, there are trials going on. You want to look up the clinical trial and how they are doing it in the trial, and mimic that.
The switch from factor is pretty easy because even the longest-acting factors in about a week pretty much washes out of your system. It is not too difficult to make the switch from factor if it is on a hemophilia A factor or hemophilia B factor, Factor VIII or Factor IX.
In terms of wrapping up, give us a couple of thoughts on that as we get to close.
Dr. Weyand: We used to have patients on factor, and if they were switching to a different factor, it was very clear how to do that. The products were working the same. There was not a lot of education to do because they were still going to be doing intravenous infusion.
These products are very different. There are some centers that have been involved in the trials and have more experience, but all of us are starting with a lot fewer patients that we have experience with compared to what we had when everyone was on factor.
What you are saying about the transition, if you are on emicizumab, the case-by-case basis is so important because I feel like we have some patients where I would worry more about overlap because they have other thrombotic risk factors. Maybe they are older versus other patients, where maybe they are young and very healthy, but really are more tenuous when it comes to being at risk for bleeds, and so those patients I really would not want to be off things, and maybe I would feel more comfortable with more overlap between the emicizumab and a new product.
We are all learning. Reiterating what you said, it is always a good idea to see what they did in the trials. In general, they have so much data to base those decisions on and clearly want to do things safely.
Dr. Young: I will just close with some really practical things. I am going to group the patients by hemophilia A, hemophilia B, with or without inhibitors.
Hemophilia B patients with inhibitors. They do not have prophylaxis options. Using bypassing agents for prophylaxis is just too difficult, too challenging, too much treatment burden, and does not even really work well. For hemophilia B patients with inhibitors who are older than 12, you now can and probably should be putting them on either fitusiran or concizumab, and once marstacimab has the indication, then marstacimab could be indicated for those hemophilia B patients with inhibitors older than 12.
I really think that they should be on one of these drugs. You have to have a good reason not to put them on one of these drugs, or you are probably not doing the patients a good service.
Hemophilia B patients without inhibitors. We have extended half-life factor products. They are good. They work well. Patients have generally been very satisfied with them. They are good products, but they are IV.
Most patients are on weekly IV, so that is 52 IV infusions a year. You still get peaks and troughs. For hemophilia B patients without inhibitors who are on a factor product, typically an extended half-life factor product, this is a good option for them and should be discussed. We always do the shared decision-making. How are you doing with your current drug? How is it working for you? Are you bleeding? Are you not bleeding? Is it difficult to administer? Is it not? That discussion.
Then to say, okay, we have other options for you. You do have fitusiran, concizumab, and marstacimab for those patients without inhibitors as an option and discussing the pros and cons of those with a lot of the information we provided here, and more that you can find on your own, and then make a decision for those patients.
I have had patients who have chosen to stay on the factor, and I have had patients who have chosen not to. For hemophilia A, it is a little more complicated because we have emicizumab. For hemophilia A, patients with or without inhibitors, if they are on emicizumab, those with inhibitors probably are.
Many of those without inhibitors are also on emicizumab. Then the calculus is a bit different because they are already on a subcutaneous product. For concizumab, you are going to be giving more subcutaneous injections because it is daily, but it is with a pen, which is pretty easy.
For marstacimab, you are going to give the same amount if it is weekly or potentially more infusions, because most people on emicizumab are not every two weeks or every four weeks, but it is with a pen, so it is pretty easy.
For fitusiran, that is where you have got the advantage of less frequent injections every two months. Although you do need to get labs. For patients with hemophilia A, it is really, again, a shared decision-making approach. How well is the drug you are on working?
These newer drugs, what can they do for you that the other drugs cannot? There is the pen, for example. There is the less frequent infusions for fitusiran. Those are all the things that come into mind as you are talking to your patients. As you learn more about these drugs, as you know about the benefits, the risks, the implementation, the pens, the lab testing, or not lab testing, that will help you to come to a rational decision that you can make for all of your patients.
The last thing I will say is those decisions are dynamic. If you talk to patient in clinic today and they decide they want to stay on whatever product they are on when you see them again, whether it is in three months, six months, or a year, you bring up that discussion again because maybe they have changed their mind, or maybe we have more information to share with them.
There is no point in a patient coming for a clinic visit just for you to say, “Hey, everything is great. You are not bleeding. Here is your physical therapist checking you and take off.” This day and age, every single clinic visit, when we see a patient, every clinic visit, unless it is an acute bleed follow-up, it is a discussion about, what do you want now? How is that working? Here are options for you that are different options.
Really, that is what we do as doctors. We give the patients the different options. Then together we make a decision what is best for them.
Anyway, thank you all for listening. I hope it was a good learning for you. There is a lot more information out there, and we wish you all the best with all your patients.