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So I'm gonna move to module 2. This will be a bit shorter. Uh, this is about personalizing hemophilia, a treatment. Um, and so there are more and more treatment options for hemophilia A. I mean, now we have factor replacement therapies and we've got several different categories of those, 3 actually. We have non-factor therapies for hemophilia A and we also have gene therapy. So how, how do you choose what's the right treatment for each patient? So just a brief overview cause it's a short module, uh, we don't have time to get into the nitty gritty details, but just one sort of comparative slide here is looking at um the drug's mechanism of action and infusions per year. So factor replacement can be once a week in hemophilia A or can even be every other day. So that's where I show you it's 52 to 183 infusions per year and it's only IV. Then we have the factor 8 mimetics, of which only amicizumab is licensed. Those are weekly to every 4 weeks, so 13 to 52 and those are subcutaneous. And then the rebalancing agents, all of which were just recently licensed, Pituaran, concizumab, and marstazumab, and you can see. Uh, the frequency of their dosing, I won't read it off, those are also all subcutaneous. And then there's gene therapy, which is, uh, uh, infusions per year. Well, it's only one infusion period, not per year. It is IV but just one dose with the goal of hopefully not needing to be on prophylaxis after that. So I kind of use analogies. So the treatment options for the last few decades until we've had, um, these newer, newer treatments was just factor replacement. And all the factor replacements essentially work the same, so I kind of equate that to Subway where, uh, you know, the only food you can leave there with is essentially a sub, and there's, you know, some different options of what you might put inside, which is kind of the analogy of the slight differentiations of factor. But now we're in the Cheesecake Factory era, where you've got a menu that's multiple pages, and where you can have any kind of food you want, from salad to pasta, to steak, to, you know, vegetarian to everything. So how do we choose? Well, we use a shared decision making model. Um, this is one model which uses the acronym SHARE where you're going to seek your patient's participation. Um, you're going to help your patient explore and compare treatment options. You're gonna educate them about the different options, sort of like the slide I showed you before, although you, you'll need more detail than that to really discuss the options. Then you assess your patient's values and preferences, and I'll show you some thoughts about that on the upcoming slides. And then you reach a decision. It's, OK, well, with your patient together, we decided we're gonna go with medication A. But then the important part is you have to evaluate your decision. So see the patient back in 3 months or 6 months, how are things going? And if they're not going well, then certainly, uh, you can change and go back to a different treatment option and go through the same cycle again. So what are the patient categories? Well, I break it down like this. By age less than 1212 to 18, and greater than 18, I break it down like this because. We currently have several non-factor therapies that are approved only for patients older than 12, um, so you have to keep that in mind. Also greater than 18 cause gene therapy is only approved for greater than 18. Of course, there's hemophilia A and B, although today we're really focusing on hemophilia A. There's the different severities which we've already discussed in the previous module, and then inhibitor status, that's important because some medications can be used for patients with inhibitors and some cannot. But it goes beyond that. What about other things? And this is where you're assessing your patient through that shared decision making by asking them, how is your venous access? Are you able to access your veins? If it's poor venous access, then an IV therapy is not going to be a good idea for them. That's where some of these decisions come in. What about their adherence? Are they good or poorly adherent? You might decide on a medication that's given less frequently as something that maybe would be better for adherence for patients, although some people argue that it might be better to do something more frequent cause then patients won't forget. So again, thinking about the adherence and what the barriers to adherence are, or is. The patient risk averse? I mean, are they, yeah, I kind of like to stick with my conservative principles in terms of treatment. I kind of like to stick with things that have been around for a long time, or is the patient not risk averse? Like, no, no, I'll take, you know, tell, give me what the latest treatment, the latest best treatment. I don't care if it hasn't been out for that long. So that, that's another category. And then lifestyle of work or play, do they have a high-risk job or do they do high risk sports, for example, or are they sedentary? That might come into your decision making. Other categories come into the age of elderly versus not elderly, so greater than 65 being sort of the cutoff for elderly. I apologize if those of you older than 65, don't consider yourself elderly, that's fine. Uh, but the point here really is that the risk for thrombosis goes up as you get older. And so this is where you might consider issues related to that. What about their joint disease and bleed histories? Is this somebody who's had a lot of joint disease, a lot of joint damage, or no, cause that might figure into your decision making. And then finally, The patient's own values. Are they wanting the treatment that has the highest possible efficacy? What's going to make them the highest likely not to bleed at all, or are they willing to to occasionally have a bleed, but they want the lowest treatment burden because they hate treating. So, you know, and, and there's not necessarily a trade-off. I mean, I've put it here is like you have to do a trade-off of high efficacy versus low treatment burden. You know, there are treatments that are efficacious that have a low treatment burden, but In in some situations there can be some trade-off here as well, so those are other things to consider. And then what about pharmacokinetics to individualize factor therapy? So we really only have data on, on that, and uh I'll just show you a little bit of data on using a tailored PK guided approach to prophylaxis, which can maximize outcomes while minimizing factor utilization. And there's lots and lots of studies on this, but, but we don't have enough time to get into all of it. So just briefly looking here at extended half-life factor 8 in the light blue um bars versus standard half-life. So extended half-life can be dosed about every 3 days, maybe every 4 days worse. Standard half-life is really every other day is the best treatment, and you can kind of see the the the sort of this theorized PK going up and down. And then non-factor therapies you can see at the bottom NFR. We know that with the non-factor therapies, at least, well, I say with memecizumab, which has been around the longest, those patients are probably living around 10 to 15%. I don't think we really know with some of the newer products where patients are living. So that's the non-factor therapy. So here's an example, uh, and what we're showing you here is on the left side, one of the standard half-life factor rates, and then extended half-life factor rate on the right. And this is looking at 3 different subjects like in theorized subjects. So here it's a poor PK subject. So that in other words, they metabolize the drug fairly quickly. And uh so here the dosing is uh Monday, Thursday dosing, and you can see where their levels will end up. But if it's an extended half-life factor, you can see that the levels are substantially higher. Notice that with the poor PK subject, you're going below 1% of the drop levels on the left, and with the uh uh with the EHL, even a poor PK subject, you're staying above 1%. Here we have a normal PK subject where you're dropping close to 1%, but maybe not below 1% on a twice a week schedule, whereas with a normal PK subject, you're staying probably much above, you know, 5%, um, on the lower end. This is a logarithmic scale. And if you have a good PK subject, they might do fine with the standard half-life not dropping much below 10% between doses. And if it's a good PK subject, they may stay above 20% if you're using an extended half-life factor rate. So this is where, you know, uh, doing PK assessments for patients on factor therapies, you can make choices and decisions, and it's definitely recommended to do this to maximize the outcome, as I said earlier, as well as uh minimize the number of doses that need to be given. So another way of thinking about it is adapting treatment by age. So on the top here, I talk about which bleed control issues are, you know, sort of the highlights of the different age groups, and on the bottom, the administration mode. So intracranial hemorrhage, this is a serious concern, particularly in the first year of life. 2 to 5, this is the toddlers, they're always falling, biting their tongue, falling on their head. This is the accident period time. 6 to 12, this is when school, uh, obviously people are in school, away from their parents, doing crazy stuff at recess or PE and kids start playing, uh, sports, uh, or more intensively sports at this age. Teenagers, well, they may do sports and they like to do high-risk activities. We know teenagers like to take risks. And at greater than 18, sports may still be involved, and now high-risk jobs like construction, for example, might be part of somebody's lifestyle. In the youngest age group, subcutaneous is really an advantage because it is hard to do IV therapy and, and for those who really need recurrent IV therapy, you need a port, right? You need a central venous access device, which is something we try to avoid. So subcutaneous administration is really um most valuable I would say in the youngest of ages, not that it's not valuable for older ones, but most valuable at that age. As you get to the school age kids and the and the teenage kids, well, subcutaneous is is still easier, but accessing veins becomes definitely easier at this time. And for those greater than 18, they have the option of subcutaneous therapies, IV therapy, or potentially gene therapy as well. So what drugs are available? Well, for subcutaneous, uh, at this age, the only thing we have available is memecizumab. For hemophilia, because the other drugs that have recently been approved are only approved for older than 12. For this age group, uh, we have amicizumab. We can do IV with factor 8 concentrates, and for those older than 12, uh, marstasimab, concizumab, and feetusuran are all also, uh, licensed for those patients. And if we take it out to the, uh, adults, uh, we can, uh, now add gene therapy as well. So you can see that the choices really start to increase as we increase in age as well, although that will change as, uh, drugs like marstazumab, concizumab, and feetusaran become available.