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Hello, my name is Guy Young, and, uh, you see my titles there and um I'm here to talk to you about prophylaxis and mild and moderate hemophilia A. I think a subject that has been um not discussed um enough, especially considering um the data we have as well as the new treatments, uh, that we have. So we'll be going through all of that, um, next. First and important, here are some disclosures. You can see here, uh, disclosures with the companies that produce medications, um, in, um, uh, for hemophilia. Uh, in the second part, we will be discussing, um, some of those medications. In the first part, uh, we will not be discussing any medications, but I, I won't be discussing any non-FDA approved uses of any of the medications. And then, uh, yeah, this continuing education activity is managed and accredited by Affinity CE in collaboration with Metal, and you can read, I think the rest of the disclosure I'll just leave up there momentarily. And then finally and importantly is that monetary support for this activity was provided by Bayer in the form of an independent medical education grant, and so with that we can get started. So we have two modules. Uh, the first one, has the following learning objective initiating timely prophylaxis in patients with mild to moderate hemophilia A to prevent joint deterioration. So that's what we're going to be discussing. So really, the first question is why do we use prophylaxis in hemophilia at all? I mean, what, what actually is the purpose of it? And uh well it seems like a simple question, I think it's uh more nuanced and layered than most people imagine. But for the short presentation, I'm just going to essentially walk you through really what the main objective is. So patients with hemophilia are at risk for bleeding really anywhere in their body, but in particular, something unique about hemophilia is the recurrent joint bleeding events. And here's just one picture, uh, as I think you can quite well appreciate a large bleed in this patient's left knee. Um, if you're looking at the screen, so obviously the knee that's on your right, I don't think it needs any more description than that. And it's not that, you know, uh, we can't treat this joint bleed, we can, and we did, but what can happen is if bleeds continue to occur in one joint is we get to this situation. This is something called synovitis. This is not a joint bleed, albeit the joint looks swollen. I will tell you that this boy had no pain, and he, uh, walked into this, uh, seminar that we were doing or this workshop we were doing, um, and he didn't have, um, any pain at all. And here's one more picture of a different boy. In the same situation, and when you press on this, it really feels spongy. It feels like one of those, uh, you know, soft sort of dish sponges, if you will, and this was not an active bleed, uh, but this is the result of recurring bleeds in the same joint, which leads to inflammation of the synovium, which is the lining of the joint. Which then leads to more bleeding in the joints, which leads to more inflammation, and you enter this vicious circle of bleeding, inflammation, bleeding, inflammation, and ultimately you can end up in a situation, um, like what this boy has. And if we take this further down the line, we end up in this situation with what we call end stage arthropathy or end-stage hemophilic arthropathy. If you look at this boy's right knee, I think you can very well appreciate that you can't see any of the landmarks. So if you look on the other knee, you can see the kneecap or the patella, and you could see the medial condyle, which is the lower part of the, um, thigh bone or the femur. But if you look at the other knee, the one that's on your left or his right knee, you can't see the kneecap, you can't see the typical bony landmarks. And then if you look below the knee, uh, look at the two legs, I think you'll appreciate that there's, uh, much, uh, a lot of muscular atrophy. Uh, underneath that damaged, uh, knee joint, and that's because those muscles aren't being used because when your knee can't straighten any more than this, and that's the most he could, uh, uh, straighten his knee or extend his knee, um, you can't walk, and if you can't walk, you're not gonna use your calf muscles. So really, what is the purpose of prophylaxis? It's to avoid this, uh, final situation. But of course, we want to do more than that. We want to avoid any bleeds at all if possible to improve patients' quality of life. So who gets prescribed prophylaxis? Well, I mean, typically in countries that are well resourced, uh, like the United States and other countries around the world that that are well resourced, you have patients with severe hemophilia, it's essentially an automatic that if you have severe hemophilia, you should be prescribed prophylaxis probably from a very early time in life. Well, not probably, definitely from an early time in life. Um, and starting prophylaxis early early in life, um, uh, has, has been proven that without prophylaxis you will develop, uh, permanent joint damage. The pictures that I showed you. So prophylaxis does go a long way towards preventing the, um, what you saw in those images that I showed you. Now, in general, most moderate, not all, but most moderate and all mild hemophilia patients really do not start prophylaxis from a young age at this point in time. I say most moderates because there are some moderates that are around 1% and they, they will have a bleeding pattern typically similar to severe hemophilia. So there are moderate hemophilia patients that will start prophylaxis early, but that's a very small group of them and typically just the ones that are around 1% as their baseline factor 8 level. Um, so I guess the discussion then is why is it that we're not starting moderate and mild hemophilia patients on prophylaxis early? I think. Partly it was a misconception that, uh, these patients don't bleed. Um, I mean, they don't bleed as much as a severe patient for sure, but the notion that they don't bleed, that they don't get joint bleeds, and they don't get permanent joint damage, I think that is a misconception. And as we have, uh, better and better medications, um, I think that the, um, idea of starting prophylaxis in moderate to mild patients is very, very important. Um, the second issue is the cost, and yes, it is very costly to use prophylaxis, um, but we cannot use that as an excuse, uh, not to treat patients who really should be on prophylaxis. So let's take a look at some data on moderate and mild hemophilia with respect to bleeding, and I'm going to show you 3 different studies, all of which are fairly recent. In fact, this is the oldest study I'll show you, and it's from 2022, so obviously this is not an old study. Uh, published by a Dutch group and looking at the title, The Bleeding Phenotype in people with non-severe hemophilia, and I'm gonna just show you a few figures and walk you through their data. So on the figure on the left here we're looking at, um, I say for both of these figures, we're looking at the age at the first bleed, so any bleed, but the age of the first bleed. The figure on the left is moderate versus mild, moderate in red, and mild in blue, and then uh figure B on the right side. I'm going to walk you through that in a second. So let's focus on the figure on the left. Again, moderate in red, mild and blue, and I just put an arrow here, so that looks like approximately 2, maybe 3 years of age, and what you'll notice is that 50%, so that's the incidence on the Y axis, that half of the patients with moderate hemophilia, and this is all moderate hemophilia, not just those with 1%, but half of them will experience their first bleed around by the time they're around, you know, 2 to 3 years of age. If we take all the mild hemophilia patients together. About a third of them will experience their first bleed by the time they're 10 years of age. But when it comes to mild hemophilia, it's a very broad category. It includes levels of above 5%, up to 40%, so it's a really wide ranging group. So if we break down the mild hemophilia group further, as we are in the figure on the right side, we're going to break them down into those that's whose baseline factor 8 level is 0.05 to 0.15, so 5 to 15%. In green 15 to 25%, and then those of, you know, sort of the mildest of the mild, if I can say that, uh, is greater than 25%. So if we break down the mild into those three groups, now we see something a little bit different in the sense that the mild at 5 to 15%, so the lowest end of mild hemophilia, now you can see that half of those patients are gonna experience their first joint bleed by around 8 years of age. So we can't think of mild hemophilia as one large group. In fact, probably not even moderate hemophilia as one large group, and I will show you data from other studies that break this down further. Now, looking at the incidence of joint bleeding, what is the age at first joint bleed? Same figures as I showed you before, but this is for joint bleeds. So if we look here, by the age of 10, patients with moderate, uh, half the patients, or a bit more than half, are gonna experience a joint bleed by the age of 10, while they're still relatively young children. Again, this is all the moderates combined. And about a quarter of the patients with mild hemophilia by the time they're about 1314 are gonna experience a joint bleed. And again, breaking down the mild hemophilia as we did in the previous figure, if we look at those at the lowest end of mild 5 to 15%, you can see that about 20% of them by the age of about, looks like 6 years, are going to have a joint bleed by the age of 6. So, so 1 out of 5 will have a joint bleed by the age of 6. And then one last figure from this, uh, paper, um, and I think what's important here, we're looking at annualized bleeding rate on the left. So total bleeds per year, basically annualized bleeding rate, the calculation of that on the right is annualized joint bleeding rate. That's what the J is for in the other figure. And I just want to point out, uh, an inflection.