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New Era in Hemophilia

Dr. Timothy McCavit, Cook Children's hematologist/oncologist, reveals incredible discoveries taking place in the world of hematology and how the latest clinical research in hemophilia is developing transformative treatments that are opening the doors to a new era not only for how patients are cared for, but for the future that awaits them.

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Meet Timothy McCavit

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Host: Today, we're talking to Dr. Timothy McCavit about some very exciting research with lots of promise for many children and young adults with hemophilia. But before we get to that, just a little bit about Dr. McCavit. He currently directs the Bleeding Disorders program and Hemophilia Treatment Center at Cook Children’s. His work also includes treating children with hemoglobin apathy, including sickle cell disease and thalassemia, as well as the care of children with iron deficiency, anemia, particularly refractory or difficult to treat cases. In addition to his work at Cook Children’s, he has been active on the American Society of Hematology, where he served on the quality committee from 2011 to 2017. Further, he has published numerous works, including a landmark paper, comparing commonly used forms of oral iron for iron deficiency anemia, which was published in the journal of the American medical association in June, 2017. As a forward thinker and a valued member of the Cook Children’s hematology and oncology team. We're so happy that you could take time to visit with us today. Welcome Dr. McCavit.


Dr. McCavit: Thank you. I'm so glad to be with you today.


Host: So, can you start off by telling us a little bit about Cook Children's Bleeding Disorder program and Hemophilia Treatment Center?


Dr. McCavit: The bleeding disorder program at Cook Children’s has been in existence formally for about 25 years. We care for approximately a hundred patients with hemophilia and then probably about 200 patients with a variety of other bleeding disorders. So hemophilia and other bleeding disorders are reasonably common in the population. In fact, we find often that, uh, patients have had them for many years and just not been recognized when we actually make a diagnosis. We are a group that consists not just of me as the physician, but also of a nurse and a social worker, a physical therapist, and then research personnel who are all focused on the care of children with bleeding disorders.


Host: So how does a patient currently receive treatment for hemophilia?


Dr. McCavit: The standard of care for hemophilia has evolved over the years. I should mention that the treatment does depend upon the severity. So there are various forms of hemophilia, mild, moderate, and severe, and in general, patients with mild and moderate hemophilia only receive treatment in the event of bleeding. And so most of the time they live life and don't require regular treatment. Contrast that to the life of a person with severe hemophilia. Historically, before treatments became available in the fifties and sixties, patients with severe hemophilia had frequent, severe bleeding episodes and had a very shortened lifespan. Most patients didn't survive out of childhood. As modern treatments became available in the 1980s and nineties, the use of regular factor infusions became the standard treatment for patients with severe hemophilia. For those patients, what that means is the at home infusion of a factor product. So if there's two common forms of hemophilia. Hemophilia A and B. In hemophilia A you're lacking, what's called factor eight, one of the main blood clotting proteins and in hemophilia B you’re lacking factor nine. Well, what these families do on a regular basis is access the patient's vein actually obtain IV access at home. The parents are trained to do this and then infuse the lacking factor, he factor that the patient is deficient in, at a frequency of up to every other day, potentially as infrequently as every week to two weeks. And that's what the life of a person with severe hemophilia looks like. And that process starts as early as the age of two.


Host: So you recently did a presentation on hemophilia research in which you said a revolution is coming in the way of novel therapies for hemophilia. What are these therapies? What makes them revolutionary?


Dr. McCavit: The current standard of care has greatly improved the quality of life and outcomes for patients with hemophilia, the standard of care, which I just described, which was the regular infusion of factor products has really led to a marked decrease in the severity of joint disease, for instance, because it's in the joints that patients most commonly bleed with hemophilia. So if you look at the overall health of patients with hemophilia today, compared to patients who are in their fifties or sixties, it's much improved, but there's much that can still be improved because the burden of doing those IV infusions all the time is quite significant and bleeding still occurs much too frequently. What we've learned about is that even when there's not what we call clinically overt bleeds or, or a bleeding complication where you can see it, feel it where it's obvious, there's actually the occurrence of what's called micro hemorrhages. So small bleeds that occur into joints or other tissues. And that over time we still see an unacceptable accumulation of joint disease and other complications from having hemophilia, even for patients who are on really rigorous and regular prophylaxis, so what's needed. And what these revolutionary therapies will do is hopefully provide a more regular and steady exposure to factor and protection from even these micro hemorrhages, which we know occur when you're doing regular factor infusions, where your factor level goes up and down dramatically over a two or three or four day period as your dosing.


Host: So first talk about Hemlibra. Why is this newly available treatment considered a real breakthrough for patients with hemophilia A and especially transformative for the inhibitor population?


Dr. McCavit: Hemlibra, which is also known as Emicizumab appears to be a huge breakthrough, a huge step forward for patients with hemophilia A specifically. It's a treatment that was designed specifically to do the job of factor eight, but it's not actually factor eight. So it's an antibody, a protein that researchers in Japan spent many years working to identify that would have essentially replaced the function of factor eight. But like I said, it's not factor eight. So why is that advantageous? Or why is this a good thing? Well, you mentioned inhibitors in the question. I need to take a step back and explain what an inhibitor is before moving forward. So for patients with severe hemophilia A, where they're not making factor eight, there is a portion of those patients who once they get exposed to factor eight for the first time, their immune system will recognize the factor eight as foreign and attack it.


This is a major problem because when we give those factor eight infusions, they get cleared from the patient's body almost immediately and provide no help. When a bleeding episode occurs, there are treatments that have been available for the last 20 years or so for patients with this problem of an inhibitor, but they're just inadequate. They just didn't work very well. And so for our patients, with this problem of an inhibitor, they tended to bleed extremely frequently. The studies that have been done suggested they tended to bleed somewhere between 15 to 30 times a year. And so there was a huge need for an improved treatment for those patients particularly. And so where Hemlibra comes in for that particular patient population is that it can replace the function of factor eight, like I said, and it's not affected by the inhibitor. And so for those patients, four of whom, for instance, we have had on Hemlibra for nearly a year now,


the treatment just has been transformative. In studies, the bleeding rate for patients with inhibitor decreased from about 25 per year down to about two, our own experience has been that we've had one, literally one single bleeding event and our inhibitor population, since our guys started on this medication, which is really just a remarkable success story. Only recently did the FDA approve Hemlibra also for the treatment of patients who don't have inhibitor. So to gain some understanding about why Hemlibra offers a lot of promise for patients without inhibitor, it's necessary to understand a little bit more about what's involved in their day to day treatment now. I mentioned already that they receive regular IV infusions of factor eight. And that typically is something where they have to give a dose every two to four days. Well, that in and of itself creates a pretty significant burden.


And it leads to a lot of swing in their factor, eight levels, right after a dose, they might have a fairly high level. And then by the time they re-dose, often their factor eight activity is almost zero, and they're really at risk for bleeding at those times. Also, you might imagine that trying to administer an IV dose of anything to a young child creates a lot of difficulty for these families. And so many times we end up having to place a permanent IV and the chest for a time in order for these treatments to be administered. And that in and of itself offers a health risk. So how does Hemlibra improve upon that? Well, it's the first factor product or hemophilia treatment I should say that can be administered subcutaneously, meaning under the skin and doesn't require intravenous access to be administered. So that simplifies the process greatly for our patients.


Also it's so happens that the half-life, which is the amount of time it takes for half of the medicine to be cleared from the body, the half-life of Hemlibra is remarkably prolonged. It's about four weeks, and so the medicine can be administered, the frequency is at most once a week and potentially up to every four weeks for some of our patients. And so those two features in and of themselves really represent a huge step forward for patients with hemophilia A, with severe hemophilia A. The other reality is that because of its prolonged half-life, Hemlibra really provides a much smoother, a much flatter factor eight activity or a replacement of factor eight activity. And so my hope over time is that we'll see that bleeding complications are going to decrease and therefore quality of life and other things will hopefully improve. And so it just is really an exciting time and an exciting thing to consider.


Host: Can you give an example of Hemlibra success with patients here at Cook Children's?


Dr. McCavit: Yeah, there are several examples I could give you, but I think one that stands out for me is an inhibitor patient of ours. He is a teenager who, in spite of our advice, sometimes didn't always, I think, make the best decisions regarding his activity. So for our inhibitor patients, often we would talk to them about the need to really sort of restrain themselves when it comes to physical activity, because some ordinary physical activity offers real risk for these patients. At least it has historically, and he's a guy who just wouldn't always take that advice to heart. And so for instance, he was pretty prone to riding his bike or a skateboard in a way that just had him here because of bleeding complications pretty frequently. And even when he was doing well, when he would come to clinic, if he hadn't had a joint or a muscle bleed, for instance, his legs would just be covered in bruises, literally just covered in bruises.


So that was really the best that we did before Hemlibra. Well, since then, when he has come to clinic, he just looks like a normal kid. I struggle literally to find a bruise on him and he has not been to our emergency room or had to come to clinic for a bleeding complication since he started on the medication, which has nearly been a year now. And so I think if you could talk to him, you might even get a better vantage for just how impactful this treatment has been in his life. And just how much it's improved his quality of life. He is also a kid who had a, a port in place, a port or a permanent IV in place. And we've been able to remove that. It's just been a huge improvement, I think, overall for him and his quality of life.


Host: So it sounds like ultimately not only does it help the patient, but it also has a big impact on the system itself, by reduced emergency visits and even reduced doctor visits ...


Dr. McCavit: Right. So for Hemlibra in the inhibitor population where the costs of care are astronomical, there is an independent financial or economic sort of health economics entity that evaluates new medications and gave Hemlibra a, A-plus rating. I don't actually know exactly how they term it, but, uh, gave them a glowing review because of the potential positive financial impact. Now it's still an expensive medication, no doubt, but to give you some sense of particularly for the inhibitor population, what the expense of that care could look like. There was a piece in the LA times in the summer of 2016 that spoke about literally a single hospitalization for an inhibitor patient. Now, because of HIPAA, they couldn't go into detail about the complications that the patient experienced, and they must've been significant, but the patient’s factor bill just the treatment that was required for the hemophilia during that hospitalization totaled to $18 million. And so even though this treatment is still fairly expensive on an annualized basis, it makes things like an $18 million hospitalization, a much, much less likely thing to occur. And so in that sense, it is a big financial breakthrough for that particular patient population,


Host: Are there any limitations or drawbacks to this type of treatment. And if so, how do you weigh those against current standards?


Dr. McCavit: So, there are a few instances where we certainly have to give pause. And in general, when we're incorporating a new medication into our armamentarium, we want to be thoughtful about it and make sure that we're not rushing into a new treatment where perhaps certain complications or problems haven't been identified. And I don't want to learn about those in my own patients at the same time with a treatment like this, where it seems like there's so much promise and where the safety profile has been very positive in the clinical trials that have been done. We are fairly open-minded about moving forward in a fairly rapid way. So when it comes to the negatives, there have been some adverse events reported in the inhibitor population uf you use Hemlibra in combination with one of the more kind of historical inhibitor treatments. So when you're on Hemlibra, you can still have a bleeding complication.


And what they learned in the clinical trials was that one of the two mainstays of inhibitor treatment if used in combination was too strong and there were actually some clotting events. And so we've had to exercise caution when it comes to that particular situation, which thankfully is a fairly rare thing. In the non-inhibitor population there are occasionally some reactions at the side of the injections. Like I mentioned, it's subcutaneous, so there's an injection site under the skin, but beyond that, there's really not been much in the way of complications. There are some thought leaders in the hemophilia community throughout the country who also have some concern about whether there may be benefits to regular factor eight exposure that we don't fully understand that we may then lack if we transition to a non-factor rate product like Hemlibra. Now these are for the most part in my mind, somewhat theoretical at this point ...


… but for instance, um, there is some concern that factor eight may have a role in the maintenance of bone health in a way that we don't fully understand. And so we have to give some pause and think about, well, might we be putting a patient who starts on this at some risk for bone issues? That's something we'll keep an eye on, certainly as more and more research has done in that area, but again, in the net, I think the experience and the benefit that Hemlibra offers is so positive that we are in general, you know, moving forward with many of our patients on this treatment.


Host: So let's move on to gene therapy for hemophilia. It sounds so futuristic, but it actually has some history behind it. Can you give us some background?


Dr. McCavit: So gene therapy as a concept has been an idea that has existed for 30 or 40 years for many conditions. And the conditions that are appealing for the potential of gene therapy are those where we know that they are first a genetic disease, and that second it's a single or a common mutation in a particular gene. And that is what hemophilia is. If you have hemophilia A, you have a mutation in your factor eight gene, if you have hemophilia B, you have a mutation of some sort in your factor nine gene. And so the challenging aspects of gene therapy for hemophilia is that these coagulation factors, factor eight and factor nine, are mostly made in the liver. And so for instance, what's been known for some time is if you transplant a patient's liver for, let's say they have liver disease for other reasons, and need that, well, then you actually cure their hemophilia.


That's been reported rarely if a patient with hemophilia also happens to have liver problems. Well, what has been developed over the last 20 or 30 years are viruses that can contain the corrected copy of the factory gene and can be targeted to infect the liver. And there are now clinical trials or experiences where patients with hemophilia have been infected with these viruses that are programmed to go to the liver and essentially insert or unload the corrected form of either the factor eight or factor nine gene. And when that has been done, we see expression of the proper either factor eight or factor nine protein in levels that really can greatly decrease the bleeding complications in these patients.


Host: So we've talked about treating hemophilia A, you just mentioned hemophilia B, Gene therapy has the potential to treat patients with hemophilia A or B. So how does it differ for patients with hemophilia A versus those with hemophilia B?


Dr. McCavit: There are a lot of similarities for the gene therapy treatments for A and B. Gene therapy for hemophilia A, for many, many years was viewed as an impossibility. And the reason is that the factor eight gene happens to be one of the very largest in all of the genome. So meaning all of the genes that humans have. And so for many years, the challenge of packaging that large gene inside of a virus was really insurmountable. Well, thankfully, that challenge has been overcome recently, but it really has only been recently. So a lot of focus early on was on hemophilia B and that gene is somewhat smaller, was more easily packaged inside the virus that they had trained to go to the liver. And so the first clinical trial describing gene therapy for severe hemophilia B patients was published eight years ago in 2011. And so there's really a much longer experience with gene therapy for hemophilia B and as a result, gene therapy for hemophilia B is progressing into later stage clinical trials. And there appears to be the promise that it could get in front of the FDA for approval within the next few years, which would be, uh, obviously very exciting.


Host: So could it possibly be a cure for hemophilia patients?


Dr. McCavit: We have to be careful when we throw the word cure around. I want to be cautiously optimistic and can tell you about some recent information that was presented at the American Society of Hematology annual meeting. Just two weeks ago, there was an update on the first group of patients with hemophilia B severe hemophilia B, who were treated with gene therapy back in around 2010 or so, it was published in 2011. And what they have seen in those patients is not the degree of factor expression that we're hoping for. So in other words, their factor nine didn't go up as much as they were hoping for, but when it increased, that appears to have been stable now for eight years. So these patients who went from making essentially no factor nine to making say 5% of the normal, which doesn't sound that much, but it's actually fairly impactful because many of the patients no longer required regular factor nine infusions to be protected from bleeding. Those patients just continue and continue and continue to produce the factor nine. And so it is looking hopeful that this treatment might be curative, but again, it's too soon to say that definitively at this point.


Host: So with that said, Cook Children’s is opening a gene therapy clinical trial. When is it open, who qualifies and how does it work?


Dr. McCavit: We are so excited to be participating in a clinical trial of gene therapy for severe hemophilia A, and, so it is patients with severe hemophilia A who will be eligible for this trial. And, uh, when you think about new therapies and in particular gene therapy, it does have some risks associated with it. And there's some unknown. Uh, when you go doing things like genetic treatments, you always want to be certain about the safety and, uh, historically in the U S and really around the world, these sorts of treatments where possible are not going to be given to children first, just because of the ethical concerns that are created when you're giving a new and potentially risky treatment to children. So for that reason, it's patients who are 18 and older, those who are able to consent, who are going to be eligible for participation in this trial.


And our center does care for a population of patients who are between 18 and 21. And even we sometimes fudge and go a little higher than 21. And so it's those patients in particular, who are going to be eligible for the trial at our center. We hope to have it open here in the near future. What the trial will involve is two stages. In the first stage, you essentially just keep doing what you've been doing. And so if you're doing regular factor infusions or regular factor treatments, you just keep doing that. Um, but you will, uh, for instance, be completing health-related quality of life and bleeding diaries and other measures so that the company or so that those of us who are conducting the trial have a sense of what your life is like in your bleeding complications are like before gene therapy. It will be a subset of patients who are enrolled on that to what we call observational, where we just watch for a time with that observational part, who then move forward and actually receive the gene therapy treatment.


Once that's done, you're essentially followed in some form or fashion for a long time. Uh, and so, uh, because it's such a new and exciting treatment, you know, those patients are watched very carefully. And obviously the hope is, is that we'll see reasonably high levels of expression of factor eight. Hopefully we would see, uh, the need for factor eight infusions, or even if it's Hemlibra the need for that sort of treatment to go away. And that we wouldn't see bleeding complications. That's the hope.

Host: So, are there risks or limitations to the trial and how do they compare with the risks of today's standard treatments?

Dr. McCavit: Thinking about the limitations of the trial, uh, and I'll get to the risks in a moment, but with the limitations, there are certainly limitations. And there are groups that are actively working to try to overcome these limitations. But for instance, the viruses that are commonly used in these trials are viruses that in some form or fashion exist in nature and people get infected with them.


And so it's about 30 to 40% of the population, just in general, who has existing immunity to these viruses before they're ever approached about gene therapy. So they're not able to receive the treatment because if they were to their immune system would immediately or very quickly kill off the virus in the cells that are infected by the virus in it. So it would not prove effective. So that's a pretty significant limitation because then only a subset of the patients are at least as of now eligible for the treatment. And then the degree of increase in the factor activity is variable. So it depends on the trial, and it depends on the gene, whether it's hemophilia A or B, but the increase in some trials has been substantial where their factor activity may increase to 30, 40, 50% high enough where you really would expect that they almost would never bleed unless maybe they needed a procedure or something like that.


But then there are some trials where the increase in the factor activity has only been, has been more modest up to, you know, 5%, 10% maybe. And in those patients, we know that bleeding complications are still going to be a risk. Although the regular infusion of factor would probably be unnecessary if you could get up to those sorts of factor activities. So those are limitations that we have to think about also as a pediatric hematologist, like I mentioned, these trials have only been done in adults, and until it's pretty clear that there's a really nice safety profile, they probably won't be moving forward in children. And so of course I want this treatment to be available as soon as possible for all my kids, but that is another sort of limitation as I see it. My adult hematology colleagues of course, would, uh, would not see it that way.


One problem, or one limitation that they're working to overcome is that when they infect the patient with the virus that has the corrected form of the gene, it only gets taken up in a small proportion of liver cells. And so in that sense, if we could overcome that problem and come up with a virus that was more avidly taken up by more of the liver cells, we think that there would be higher proportion or a higher amount of the factor protein produced, which would then really start to look more like a cure, assuming that it's something that would continue indefinitely. And so just again, at the American Society of Hematology meeting, two weeks ago, the group in London that pioneered this promoted the results, or kind of published the results in abstract form of a new virus that they're using, that certainly seems to lead to greater uptake and therefore greater expression of the factor proteins …


… and it looks like a significant breakthrough in that regard. So it's an exciting thing to see. So thinking about the risks, anytime we were talking about gene therapy, we have to worry about the possibility that the gene that's getting introduced into these cells could somehow disrupt or cause problems in the normal processes in these cells. Unfortunately, that fear is based in some reality because gene therapy, when it was first introduced for instance, about 20 years ago, for a rare immunologic defect, the gene was given in those patients in a way that it inserted into the genome and ultimately disrupted some cancer control genes that led these patients to actually develop leukemia as a complication of the treatment, several of them. And that was a very high profile event. It was a major setback for gene therapy in general, understandably it needs to be a safe therapy.


And so current hemophilia gene therapy includes the corrected form of a gene on a little circle of DNA called plasmid. And I'm not a gene therapy expert per se. But what I have understood is that they have designed this plasmid where the corrected form of the gene is that gets inserted into the liver cell that ultimately makes the protein to not insert into the genome or to not insert. And hopefully therefore not disrupt the normal genes that are there in those liver cells. And hopefully decrease the risk of having this new, uh, gene in the cell.


Host: Do you foresee a day when hemophilia can be cured or maybe even eradicated?


Dr. McCavit: I certainly live with the hope that that is a possibility. And you know, when I talk to the parents of my young patients, I am fairly optimistic with them that whether it's truly curative or in a huge way ameliorative, or, you know, decreasing the complications of the condition, I am hopeful that we are really at the precipice of these sorts of treatments being available. And so I'm cautiously optimistic that these gene therapy treatments will prove to be both safe and effective in a way that ultimately will lead us to refer to them as a cure. But it takes a long time, like we just talked about before, we want to throw that sort of term around, because the last thing I want to do is create false hope, false optimism, but really I am very hopeful.


Host: So considering the revolutionary therapies we talked about today, they're currently fairly expensive, but if they prove to be effective, what do you think the longterm cost savings would be not only to patient families, but the healthcare system in general?


Dr. McCavit: Well, this is a great question. And it's a huge concern because cost of hemophilia care is a huge topic of concern for anyone who's involved with this patient population. And the reason is that the production of factor proteins, which are what have been used historically as the standard treatment, it's a very specialized thing, and it's just a very expensive treatment. So for patients with severe hemophilia, it would not be unusual for the annualized costs of their preventive treatments to cost somewhere in the ballpark of $200,000 in potentially up to half a million dollars. So a year per year. And so when you start thinking about what that looks like over a 30, 40, 50 year life span, it's really, really dramatic as far as costs go. So in that sense where Hemlibra offers maybe a more effective treatment, but not a cure, it doesn't have the same financial promise or impact that gene therapy might have.


So even if they priced gene therapy at what would seem like an astronomical number to anyone who is not versed in this patient population or versed in hemophilia care, like let's say a million dollars. That sounds, that sounds crazy. It does. It does. And yet, if it actually works as a cure, if we can get a form of gene therapy that really leads to a large amount of factor expression, and truly does cause these patients to require factor infusions either never or very, very infrequently, the cost savings at a million dollars a head would be enormous. Absolutely enormous. I mentioned to you already the inhibitor patient that had an $18 million single hospitalization. And so when you start to look at this patient population as a whole, the costs are extraordinarily large. And in that sense, gene therapy, if it really could be a one-time treatment would be a huge step forward.


Host: Well, Dr. McCavit, we really appreciate you taking time away today from your very busy schedule to talk to us about these innovative therapies for hemophilia and for the incredibly important work you're doing for patients at Cook Children’s and for kids everywhere, coping with hemophilia.


Dr. McCavit: Well, I thank you for the chance to talk with you today. And, uh, I'm so happy to be at cook and to take care of this very special patient population.


Host: Thanks for tuning in to physician perspectives recorded in the Child Life studios at Cook Children’s. If you'd like to learn more about our program and research at Cook Children’s visit our website at Cook Children’s dot org.