Cara Therapeutics, Inc. (CARA) Earnings Call Transcript & Summary

I do. I do. And I think if you don't let them drive their car home. It's like saying they're not going to get the drug, right? Because people -- that's how they get to dialysis.

Great. And then you've alluded to a direct holiday. Do you think still that KORSUVA is a chronic treatment?

I think for some people, it's a chronic treatment. And I think for some people, it's a bridge until their itching gets better. I think it's a case-by-case basis. And I think the -- my sense is this was a question that wasn't even thought about when they designed the studies and the studies don't answer that question. And so we're kind of like we're in new territory here.

And in terms of the length of the drug holiday, how do you handle that?

Right now, it's 1 month of my patient -- the patient who had the symptoms, couldn't go that long and was -- and a couple of weeks later, we still resume the drug.

Great. Are there any more questions from the room? No. Okay.

Great. So now we will turn the podium over to Dr. Chovatiya to discuss atopic dermatitis.

All right. Perfect. Thank you, guys so much for having me. We're going to be shifting a little different direction to -- the nephrologist topic is complicated for me. So hopefully, this one's a little more of my stream. We're going to be talking a little bit about atopic dermatitis before we move into notalgia paresthetica. And hopefully, a little bit of what we're going to be exploring with atopic dermatitis for disease state that we know is very common, a lot talked about now, a lot happening, maybe a slightly different take on it to make you think a little more broadly about your patients out there. So -- this is taken from real life of patient that I'm actually very specifically thinking of him. And we'll call, [ Hon John. ] He's a 35-year-old with atopic dermatitis. He's been around since he was a kid and he says his trajectories, it's continued to get worse over time. He said when he was younger. He was covered in these thick scaly patches all over his body. But these days, it's not really that so much. He feels like he's overall xerotic or has kind of dry skin. And maybe occasionally get some patches by his hands or his feet or his ankles or his wrists, but itch is really the predominant part of his life these days. And he hasn't slept well in a really long time. It's actually getting worse. And he works as a delivery driver for unnamed company and his atopic dermatitis really gets in the way of focusing on that aspect of his job. And at the moment, his regimen is complex. So a couple of different antihistamines used to different times during the day. A couple of different topical steroids, a topical calcineurin inhibitor. Occasional oral steroids during the year and occasional oral antibiotics as well. So the question that I want you to consider with that entire case is we talk about mild disease, moderate disease, severe disease, and they seem like very simple terms. But is this severe atopic dermatitis. And I suppose the definition here would lie a little bit in the eye of the beholder, right? So what does severe atopic dermatitis actually mean? Believe it or not, this is actually a pretty flexible definition. And you can think about this in a number of different ways. Is the idea of having large plaques all over your skin, what drives the idea of severity. Maybe it's the location, hands and feet are real tough. You're walking around, you're using your hands all day. So that involvement could be really severe. Is it when your skin bright red and super scaly could be potentially. What about just being covered all of your body, body surface area extent? Is that severity could be as well, what about symptomatic burden being super itchier, not being able to sleep or focus? Is that really what's driving severity. Maybe it's the other comorbidities you have. Maybe it's overall trajectory of which direction disease is moving or actual effects on your life, you can't work. Maybe it's the treatments that you're using, if you're using creams, but you've got to move on to an oral or injectable medication or your actual response to past treatment. So you already begin to realize that there's a number of different ways to actually look at this disease based on what's going on. And so this concept really think about atopic dermatitis is heterogeneity. It's actually probably one of the most heterogeneous diseases. We have in dermatology, in part because there's so many different clinical domains to consider based on everything that I just put on that slide before. So severity is, in fact, a multilayered concept, I love asking my residents, my medical students, what would you define a severe disease? Because everyone usually has a slightly different explanation or different answer. But it's probably some combination of where lesions are distributed, what they look like, how broad they are, what's the actual intensity, what are the symptomatic burden? What do things look like over the long run, quality of life burden, comorbidities, kind of some of those elements that I mentioned before. And so these are pictures taken directly from my clinic patients, I've seen probably over the last 6 months. This is all atopic dermatitis actually. So each of these patients has the same disease even though you can see going from top to bottom, what looked like darker patches, deep pigmented scared areas, more nodular areas, round areas, involvement of flexures of the feet or the back, all the same disease. And so even if you just looked at what something looks like on the skin, you could have completely wildly different presentations. And that's not even thinking about those other domains that I was talking about. So when it comes to thinking about actual describing and subsetting our disease, there's patient-centered ways, clinician centered ways and probably combined perspectives that we would use to try to figure out what's going on. So this is kind of combining some of those elements I mentioned before. So from the patient perspective, thinking about what the actual course of disease looks like in terms of persistence and flares. Symptomatic burden, itch being one of the really big ones we think about disease, even burden, you need the patient to be able to explain all this to understand the disease. From a clinical standpoint, this is where a lot of our focus is on disease severity, right? Because it's very much what do we see? What does it look like? What's the extent of disease? And then there's some combined perspective as well when it comes to actual treatments and potentially comorbidities that need to be diagnosed and followed. But it's that middle section right now where we've sort of landed, I'm thinking about as a dermatologist, I love pictures and visual. What I see is what I assess and we won't worry about everything else. And that can be an issue, right? So this is just a really convenient example taken from a paper published a few years ago in American Journal of Clinical Dermatology, where they simply just asked physicians to report severity of what they saw in their patients. And then they ask patients to actually report their overall global assessment of their own severity. And this is just kind of a 3x3 table just trying to say where exactly the agreement lies. So if everyone was 100% in line, you would see when physicians in the column that said mild, look at the row patients and mild, that should be everyone moderate, severe, same thing. But you'll notice in each one of these rows and columns, it's really only about 1/3 of patients that are discordant to each group. And that's what happens when you subset this entire thing out, meaning that take a look at the severe role for a second. For the patients that physicians thought were severe, 61 out of those 99, they perhaps agreed with patients, but there was an entire other subset of another 35 patients out there that physicians thought were severe. Patients felt differently and vice versa. And so I think that the point that I'm trying to make is that when you use just physician ratings, you're probably not catching the number of people that probably agree with the severity of disease. So particularly in people with mild to moderate disease, there's a lot of other aspects to consider and probably different ways that you can subset the disease out. So itch is a really good example. People with milder clinician-assessed disease can still experience severe itch, and we'll talk about that in a few slides. But even quality of life. Somebody that has what you may perceive to be milder lesions, actually believe they have very severe lifestyle limitations on what their disease does. Hands and feet are a classic place for that just because you work with your hands, and it's really hard even with mild atopic dermatitis to go about your day-to-day experience. Mental health is another good one, too. There's actually pretty strong studies that would suggest even people with milder atopic dermatitis based on just what you see on the skin. They actually have a similar mental health burden as people that maybe have even more severe disease on what you see as the skin as well. And it's just that, that question sometimes is not necessarily asked. So what could be a different way to perhaps think about our patients with atopic dermatitis in a way that's more holistic about what's going on. So from a convenience standpoint, itch is perhaps the defining symptom we think about atopic dermatitis. It affects pretty much everybody with the disease. So maybe one simple way to think about this to move the field forward then would be to actually combine an analysis of a symptom with some of those signs that we actually see in terms of better sub-setting out what our patients might look like. And let's explore that for a second here. Itch. I think we all agree. That's why we're here. That's what we're talking about. And by and large, based on studies, most seem to reflect that something like 90% or more than 90% of people actually complaint of daily itching when it comes to atopic dermatitis independent of severity. So we know that it's an extraordinarily prevalent symptom. Now when you actually take a look at some of the other symptoms that are reported by patients, both in terms of ones that are spontaneous or actual have to be probed, nearly all patients will say that they spontaneously have itch. They bring it up in conversation. You don't actually have to draw that out of them. They're going to tell you that in the office because it's usually the thing that's driving them crazy from a day-to-day basis. Additionally, and this number sort of ranges, but believe it or not, ends up being pretty close to what's on this slide for the study quoted here, but 6 out of 10 atopic dermatitis patients report that their itch is severe or very severe. And considering that we think about severe or very severe clinician-assessed disease being a much smaller portion. There's probably something to it that we need to be thinking a little but more about combining our perspectives when it comes to patients. So very similar to the nephrology talks you saw earlier, itch drives a lot of changes in people's lives and a lot of burden as well. And so in dermatology studies, there's really good ones that show that itch is an important mediator for everything from sleep quality, onset, latency, mental health, anxiety, depression, even distraction, suicidality actually has been reported in some studies as well as, suicidal ideations, health-related quality live overall, itch actually has very strong relationships across all these different aspects of disease that I mentioned kind of that we need to be thinking about when it comes to expanding our perspective. So what happens then if you combine lesional severity then this clinician assessment of how bad somebody is with itch, and make it just a very simple exercise, a 2x2 table, right? Somebody that has mild-to-moderate sort of skin disease and somebody who has severe skin disease and then someone who has mild to maybe moderate itch and then more severe itch in that sense. And that's exactly what's going on in this study that I'll spend a couple of slides talking about the largest of its kind, where it was a real world, about 600 patients undergoing standard of care in a clinical center and really trying to subset out what are some of the differences observed in these populations. And first and foremost, those found in this particular cohort actually that -- most patients had mild to moderate lesions and matching mild to moderate itch severity, yes. But about 1/4 of this subset was individuals who had mild to moderate lesions and severe itch. And this was really one of the first studies to actually report that, in fact, this combination is probably a little more common than people once thought. Because usually, from a dermatology perspective, you come in, you have clear skin, you often to see, hey, things are good. There's not much I need to do. But this actually decided to take a look a little deeper. So in the same study, it tried to unravel then further that if you're taking a look at somebody that has severity assessed in a different way. So the EASI score is kind of the gold standard in the U.S., the regulatory endpoint that's used for those atopic dermatitis trials, EASI, eczema area severity index. You can think about it as a composite measure that combines how much eczema you have, where it's located and the actual severity of disease. So it's a combined number. And even when you take a look at people that have clear disease based on that or mild disease or moderate disease, you actually find that in terms of itch in the past week, there's a lot of people that still have moderate, severe or even very severe itch despite their endpoint, which you're usually gauging for in trials, being on the spectrum of being clear or mild or relatively not so bad at all. So in the same study then, this is simply just looking at Spearman correlation where essentially, you're trying to look at 2 continuous variables, see how well they run together, the closer you get to one, awesome. When you take a look at itch severity and you take a look at lesional severity and extent, you can forget exactly the scores that are on here, but just pay attention to sort of the numbers. Bottom line, there's only really a weak and moderate correlation, meaning that probably there's something very different that's being measured by lesional severity and something very different being measured by itch as well. So they're not the same concept, which logically makes sense. But numerically, this is again some more evidence of that fact and believe it or not, something that hasn't really looked at all that much in the literature either. There we go. So the other point that would be really important to take away is you may ask yourself, okay, that's fine, whether they have severe itch or severe lesions, whatever combination they have something severe. So probably, they're being treated in the same way, no matter what, when it comes to dermatology. And so -- this was broken down in this population. And what you find is that for patients that had severe lesions independent of whether they had mild itch or whether they had sort of severe itch, by and large more than half of them were probably getting some type of advanced systemic therapy. So this would include injectable biologic therapy, some type of oral immunosuppressant, potentially phototherapy. When you actually take a look at that subset with severe itch and milder lesions, less than 1/3, we're actually making it that way depending on what type of scoring criteria that you use, which would argue that, again, we probably are biased to treat based on what we see rather than actually thinking about multiple clinical domains in terms of actual severity of disease. And this argues for the fact that perhaps we're not adequately treating our patients that fall side this pretty sizable subset based on the severity of their symptoms. So what are the implications here for treatment? And I think that's the question we all have in the back of our minds. And I think to understand, you have to understand a little bit about the clinical paradigm behind how we treat for atopic dermatitis. So typically, we think about our treatment as being stepwise and additive usually with baseline foundational care based on optimizing moisturization, bathing, all that good stuff. Then you sort of take a step up to topical anti-inflammatory therapies for your milder and moderate disease. This would be topical corticosteroids, calcineurin inhibitors, PDE4 inhibitor, topical JAK inhibitor. And then as you moderate in severe disease, this is when you start thinking about phototherapy, biologic therapy, oral JAK inhibitors, oral immunosuppressive agents and others. And that's kind of what's evidenced here in the diagram. But I want the big point here to be that there's still a lot of issues with this approach because, number one, it's generally based on this idea of mild, moderate and severe, which hopefully I just convinced you, it's not really clear what that is supposed to be, but that's what you're supposed to be basing it off of. And usually, it has a lot to do with what the clinician is assessing. There's not really a great accepted criteria for how this is determined in terms of severity. So in Europe, they at least tend to use more objective scores as far as the American Academy of Dermatology goes. It's a little more hand-wavy about you use kind of what works for you. There's different treatments and different steps that are more broadly just applied to everybody that fits in those categories. And again, as I mentioned, that's sort of tough when you're thinking that there's not really one singular definition of severity of disease. So the question is, where does this leave this subset that I just spent a few minutes talking about in terms of your people that sort of look milder overall, but actually have more itch dominant. Well, you can see here that, obviously, people that have a lot of itch have a huge quality of life impact. People that have a lot of itch have a lot of different itch triggers, a lot of stuff to really kind of take care of in their life, and they can't avoid 6 or 7 things at any given time, knowing that those things flare their itch. Frequently, these people because their skin seems so mild, they're treated with topical steroids, and this isn't a particularly great treatment for individuals that are generally speaking, itchy. And the data would suggest that these people are probably not getting more adequate systemic therapy they control their symptoms that they actually deserve based on what's going on. So kind of in the final slide before I give you some take-home points in this section, what would I kind of take away here about these patients? Well, the question would be, could we potentially be targeting itch better in these people knowing that their lesions are much milder and actually getting to a point of breaking this itch-scratch cycle. You see on the right-hand side, which is this horrible feed-forward loop that people get stuck in with atopic dermatitis. And so by alleviating itch, you very well may stop that, potentially stop some of the [ CPI ] that actually occur related too scratching from itch itself helps sleep, help quality of life and really give people a better shot at resolving their symptoms. So with that, just a couple of big takeaways. Hopefully, in the short little time I had here, you understand that atopic dermatitis is very common. We can talk about how common later, but in general, about 10% of the population has atopic dermatitis. It's heterogeneous. It really can't be fully evaluated by clinician assessment alone because once you start adding other variables on there, you realize that one singular severity measurement probably is not catching everybody. When you start combining it with features and itch is a really good place to start because it's the most common symptom of our patients, you actually get clinically different subsets of patients that have different characteristics. And so it probably then argues the fact that we need better therapies to better target different subsets of patients in atopic dermatitis. You guys are stuck with me for another round. And so I'll just stay up here until someone yanks me off, but we can talk about notalgia paresthetica next and shift gears completely because it's actually a very different disease, but itch being the core, and then obviously, we'll have sort of our Q&A kind of after. But hopefully, let you marinate on atopic dermatitis for a little bit. Okay. So we just saw a very nice slide about different modalities potentially for treatment when it came into itch and renal disease. And that -- it's funny. But in many ways, it's actually very homologous to this slide here where this one is just kind of talking about different etiologies of chronic pruritus. So in my clinic, a lot of patients referred in for just being itchy for a wide variety of reasons. Sometimes it's eczema. Sometimes there's a lot of other things going on. And there's going to be a tough thing to parse through because our actual diagnostics are limited in terms of what we have. But usually, most people fit into one of these buckets, right? And just in case the dictionary definition of chronic pruritus was lost on you. In general, in dermatology, when you add chronic in front of something, 6 weeks is the magical mark. So from chronic pruritus usually somebody that -- something that's giving you this urge to scratch an evolutionary conserve process that goes back to caveman times. The evolution of itch and scratch is actually quite fascinating on its own. Symptoms are present for more than 6 weeks. So we'll get that out of the way. So usually, your inflammatory bucket is the one that we tend to really center on in dermatology because this is where you usually see most characteristic skin changes. A biopsy is going to be helpful. You might be able to visually figure out what's going on. You potentially could have targeted treatments for atopic dermatitis, psoriasis, Lichen planus or Prurigo nodularis, most recently with an approved treatment, it starts to get a little trickier with these other categories, right? So you can have more neurogenic causes of itch. In the case of systemic pruritus, like we talked about with chronic kidney disease, primary biliary cholangitis, hyperthyroidism, things where you may not see much in the way of primary skin signs, but people are still very itchy. There will be lab alterations for sure, but targeted therapy is sort of a bit of a trickier discussion. And then you've got a neuropathic itch, right? So Notalgia paresthetica, brachioradial pruritus, post-herpetic neuralgia, they all fall in this category. These are circumstances where you have things going on with your neurons and glial cells, and that's what we're going to focus on for the next slides. But remember, there's even other etiologies of itch that we don't have a very firm handle on is all very controversial entity, but pruritus in the elderly or whatever you want to call that, is one, we seem to just get each year as we age, and that's not well understood. There's drug-induced forms of itch and then, of course, pruritus of unknown origin, which it's unclear if there's an unknown origin and we just can't figure it out at this point in time. So just thinking about neuropathic pruritus as an entity. As I mentioned, typically, this is an itch that's usually based on the nervous system. So whether it be peripheral or central issues typically some type of neuronal or glial damage, which is causing some type of change in the actual neurotransmission, which is resulting in an itch sensation that you then just kind of go crazy scratching over. And the prevalence of pruritus, actually is fairly common overall in the population. So for the study that have tried to look at this. You're talking about sort of the 10s, 20s, 30s percent kind of worldwide with almost 1/4 of people experiencing some type of itch state. And neuropathic pruritus actually represents about close to 10% cases of chronic pruritus. So it's a pretty sizable chunk. And the tough part about it is that when there's issues with your nerve cells, there's a lot of other symptoms that hop on for the ride. And a lot of this is based on the actual biology of neural transduction. Pain, allodynia, essentially sort of other sensations being interpreted as pain or itch, paresthesias, hyperesthesia or hypothesia, basically heightened sensation, lower sensations just weird altered sensations altogether. A lot of the stuff can accompany. And so even historically, and a lot of the studies we have that look at itch. In neuropathic realms, there's probably a combination of symptoms going on. But in general, we know that certain terms patients really use when it comes to neuropathic itch. Burning, stinging, shooting, tingling. And that usually starts to get you a little heightened that you're dealing with maybe not necessarily your more classic inflammatory itch in dermatology for sure. Now in terms of what are some of the hypotheses here, I mentioned that typically neuron and glional cells are usually what you're thinking about -- but local nerve fiber compression or potentially even localized nerve fiber degeneration in the peripheral central nervous system are really common ones. And so a really good example is, think about some of the symptoms you may have when you have a pinch nerve, a slipped disk, some type of long term -- call out from spinal surgery. And you can think about that as being a very obvious example of local nerve fiber compression. And those are some of the symptoms that people with neuropathic pruritus experience chronically over a long period of time. So when you break down what's happening from the skin to the dorsal root ganglia in the spinal cord, I promise this will be about a science as it gets, but it is actually a very interesting relationship between itch and pain. And evolutionarily, there's a hierarchy your body has. Pain is more important than itch, right? Because if you have a parasite on your arm, itch is actually an evolutionary conserve response to take that boring thing off. If you've got pain like Mastodon or -- something ripped off your arm or something. And that's probably much more important than someone that's itchy. So typically, when you have both signals at once that are interneurons that are in the spinal cord designed to sort of stop itch from happening and make pain more dominant. However, there are a lot of neurons that actually signal both itch and pain. And so this is probably one of the reasons why when things get out of whack, you get a combination of symptoms altogether. But what you're seeing in this little picture is that you have cutaneous afferent sticking out in the skin that are picking up signals, some of them are no susceptive neuron. So these are the ones that are really specialized in pain. And then you have sort of proprioceptive neurons, ones that are specialized in itch. And you have sort of cross talk going on in the course of the spinal cord, then all this going into the brain, having a lot of different evolutionary reserve responses and scratching being kind of one of them. So essentially, any type of trauma or anything going wrong anywhere in this pathway can cause many of those issues that we just talked about in terms of that stinging, burning, itching, you name it, and we'll kind of leave it at that for now. And so typically, the way that our nerves run in the body, you can think of dermatomes being based on anatomy in terms of how you developed and exactly how nerves come out of the spinal cord. And the different areas on this little diagram here that have little letters and numbers or how we think about where different aspects of nerves in the spine cover different parts of the body. So in dermatology or any other physician that might be seeing this, there are certain areas that tend to be much more prone to developing neuropathic itch disorders. Scalp is a very common one. Scalp dysesthesia is what we call it, typically, it's related to some type of issues with nervous in the C2 or C7 distribution. Brachioradial pruritus, you can see, is outlining areas of the arm covering another part of C3 to C7. We're talking about notalgia paresthetica which you can see kind of is running right along the upper part of the spine in the back T2 to T6 so the nerves that are really important. But then there's also anogenital pruritus that covers the lower part of the lumbar range and the sacrum as well. So with that little diagram in mind and my little preamble, let's talk about another case. And I feel like this very good representation of a patient that I was thinking of as well with an notalgia paresthetica. So we have Jane here. She's a 55-year-old with chronic pruritus. And she says that she's had itch for the past couple of years, specifically in a region of the upper back. It's never been an issue before. She's never had chronic itch problems, but she feels like she's not able to really focus well because this thing is just bugging her during the day or really kind of sleeping at night as well as being an issue. She's tried a ton of things that all say anti-itch. And if you go to the aisle in the store, everything says anti-itch and dermatologists approve, but rarely both are true. And so she's experienced dry skin, irritation. When she tried these things, so they weren't so good. She's seen several specialists and I hate to say, but this is actually a pretty common thing patients that are itchy get told, including that it was in her head. And she's tried 5 different topical corticosteroids without any improvement from multiple dermatologists. The most recent treatment she tried was an oral medication that made her feel drowsy and lose focus and her important work as an accountant, very relevant as tax season comes up. So with that being in mind, patient did have a diagnosis of notalgia paresthetica. What is this specific type of neuropathic itch? This is actually pretty common, but probably under-recognized neuropathic itch disorder. I mentioned that there's probably this idea that there's some kind of damage to neurons in this T2 to T6 distribution. You can get patients seeing a bunch of different people because the symptoms are so nonspecific and they may not necessarily end up with dermatology per se. But eventually, if the symptoms are bothersome enough, that's where they do end up. And it really tends to be very resistant to most of our therapies. And so whether it be topical, whether it be oral, a lot of what you guys heard about in the case of chronic kidney disease. Very similarly, not really that much help from topical corticosteroids or antihistamines, which people love to use. The antihistamine thing is always fasting to me. Really the only histaminergic itchy process. We have good data for as hives. So just the problem is everybody assumes that everything else has histamine, but from the actual neuronal evolution of studies, most itches non-histaminergic pathways. And believe it or not, this is just kind of a fun tidbit for you guys. Most studies that are non-histaminergic use itching powder actually to induce these things in the lab. And so typically, you think about histaminic itch versus actual itching powder-related itch. So in terms of the clinical presentation, what are you thinking about in the case of notalgia paresthetica? This is a really classic example of an individual who is chronically scratching along the left side of their spinal column, typically recurrent, localized and interscapular and paravertebral. Those are just the fancy words being the top part and the bottom part of this picture. Now typically, I mentioned pain, tangling, burning, hyperesthesia, parethesias, use a combination of neuronal symptoms. This hyperpigmentation is usually one of the only clinical clues you're going to get in dermatology because it's recurrent rubbing and scratching in one area of the body. There isn't usually much of a rash scaling or anything like that, but this is just evidence of kind of chronic touching to the area. And usually, you're thinking about your classic pace from being between 50 and 60 years of age and sort of big more common in women over men. The itch itself is bothersome. I think hopefully, through everyone's talk today is we understood that it bothers our patients, oftentimes more than physicians feel they're necessarily bothered by it. And it can really affect patients' emotions, mood what they do. I mean this is a classic scenario. I love that [indiscernible] story. My patients all have very exotic back scratching things. And it's really hard to touch this part of your body so most people do have some sort of back scratching. Dermatologists always tell people to stop scratching and don't use back scratchers, but it's hard to stop an evolutionarily conserved response. It's like telling someone to stop doing something that you think about doing what that's reflexibly. Patients report difficulty sleeping or staying asleep. This has been shown in multiple studies. Though interestingly, there probably is different types of effects different itchy conditions have on sleep and this one maybe is a little less so than atopic dermatitis where that data is stronger, but my patients still say they find that many itchy things keep them up at night when they're not focusing on much else. Now as far as treatment goes, as I mentioned, there's not really any approved therapies. There's not really professional guidelines. There's no standard approach to working this up. Currently, off-label therapy is much like you heard about, whether they be topical therapies, antihistamines, anticonvulsants like gabapentin, everything is off-label. So nothing is actually approved for this condition. And all of them have some degree of tolerability limitations, meaning that people can't use them very much in the long run, and usually, they're associated with adverse events. The topical part makes this really tricky because many of my patients have nobody to help them regularly put anything on this part of their body in the first place. And so for people that are living alone, impossible when you tell them to figure this out and tie a sponge to a stick and get it back there just like not happening. So in terms of what are the treatment options we have. Usually in the clinic, most people will try the approach of optimizing moisturization and bathing and whatnot. The next thing might be then thinking about a thicker emollient in terms of medicated options, over-the-counter options, things that have menthol, camphor, pramoxine, capsaicin, or all things that people are going to be thinking about. Dermatologists love to use topical corticosteroids for everything. There's really not much of a role for topical corticosteroids here because this is not a primary immune inflammatory process. So you're not really suppressing anything with them. So it's not a surprise that they don't work particularly well. Gabapentin is commonly used just by virtue of the fact that by hopefully slowing down some of that peripheral neuronal signaling you're going to actually end up alleviating some of those symptoms. And then there's other antidotal off-label therapies that are secondary and tertiary options. And this is when you start getting into SSRIs, antipsychotics. If you really want to go down the road of thalidomide or something, most dermatologists are not using these things regularly. And I personally try to avoid a lot of them if I can. But even if you do, it's really hard to have a discussion with the patient coming in with this saying I want to use a psychiatric medication because the moment they hear that, they're like, heck no, I'm not crazy, why are you calling me crazy, and it goes down a very difficult road. So by and large, most of what we have, not great. I'll leave it there before we get into some good stuff and then Jo can kind of take you through. But I hope that in brief few slides, all my joking aside that notalgia paresthetica is a real tough problem in dermatology. We probably don't even understand how common it is because it comes into clinic. Most people are coming in with another condition. People are not putting an ICD code in the chart for it because they feel like they have no actual medication to offer. And it's probably not even popping up in their EMRs, even though we know that people actually have this issue. Because at the end of the day, very selfishly or not, it's not going to be a revenue-generating thing. So why is it going to sort of end up in there. So we don't even know probably how common this is but talk to any dermatologist, they'll tell you that, "Oh, yes, I have patients that are in this age range that complain these issues all the time." we know that the itch is bothering people. It brings them into the office. And clearly, when skin has changes like that, where it's thick-end and darker in color, people have been rubbing their skin for quite some time. Most treatments people are not really that [ plus ] for treatments that come along with a lot of side effects for something that they perceive to be, do I really need to be treating this with something that's going to make manure new problems for me. And I think that just by virtue of that, that's the reason why we need better therapies for people so they can at least have some segment of their quality of life back, particularly considering most of our patients who are in their 50s and 60s and beyond. That's it for me, but I'm happy to pass off the clicker here, but I'll be back. Don't worry.

Thank you so much Dr. Chovatiya for laying the foundation now for NP and for my talk. So good afternoon to everybody, and thank you so much for joining us today. I'm really excited to be able to share with you the details of our NP clinical program that we have started operationalizing this quarter. So just as a reminder, oral difelikefalin has demonstrated a robust anti-pruritic effect, together with a consistent safety profile, which was pretty well tolerated by patients with NP in our Phase II proof-of-concept study. In addition, we were extremely excited last week when we saw the data was published in the New England Journal of Medicine. And really just speaks to the credibility and the rigor of the data in this NP patient population. At the end of last year, we had a positive interaction with the FDA, and that's really what has paid forward our path forward for the registrational program in the notalgia paresthetica. So a little bit more about our program. So the program will comprise of 2 studies, KOURAGE 1 and KOURAGE 2. And KOURAGE 1 will have 2 parts: Part A and Part B., with Part A being a dose-finding portion of the program. Part B KOURAGE 2, this will comprise of the 2 pivotal studies, and those will be placebo-controlled and will also include the open-label safety extension portion. The studies will include adult who have clinically confirmed notalgia paresthetica. They need to have chronic pruritus, the pruritus for at least 6 months, and the process needs to be of moderate to severe severity, to at least a 5 on the worst itch NRS score. And patients will not be allowed to use any other anti-pruritic therapy, so they need to be washed out of oral therapy prior to being screened. So let me focus first on Part A. So this is the dose-finding portion of the program. 200 patients will be equally randomized to 4 arms, 3 arms with oral difelikefalin. And the doses that will be taking forward are 0.25 milligrams, 1 milligram, 2-milligram twice daily compared to placebo twice daily. And patients will be treated for 8 weeks. At the end of this Part A period, we will do an internal review of the data and assess the dose as well as the sample size. Our decision will be based on both the efficacy and the safety of the data and specifically looking at the 4-point responder analysis. Just of note, Part A is not powered to show statistical significance, between the treatment groups. Also, in addition, patients from Part A will not be able to roll over into Part B or into KOURAGE 2. And we estimate to have the readout for Part A in the second half of 2024. We won't be releasing detailed results from this readout, but we will disclose the initiation of Part B and KOURAGE 2, the sample size as well as the selected dose. Part B and KOURAGE 2 will be identical in design. These are double-blind, placebo-controlled studies where our patients will be equally randomized to oral difelikefalin or to oral placebo twice daily. And the dose for the oral difelikefalin will be based on the results from our Part A study. The primary endpoint will be the proportion of subjects who have a 4-point or greater improvement from baseline in the worst itch NRS score at week 8. The patient population in Part B and KOURAGE 2 will be the same as in Part A. And both studies KOURAGE 1 and 2 will include patients from North America as well as in Europe. Patients who complete Part B and KOURAGE 2 will have the ability to roll over into an open-label safety extension study. And we estimate to have the results for Part B and KOURAGE 2 in the first half of 2026. So like our AD kind program, we have designed the NP program really to try and enhance our operational efficiency to try and really enroll these patients as rapidly as possible and to ultimately maximize our clinical success. We're really excited about starting this program, as you heard from Dr. Chovatiya that there are no treatments for these patients that have been approved and off-label treatments have limitations. So excited to start the program. And on that note, I think we're opening up for some questions.

Yes, we'll invite you and Dr. Chovatiya back to the front. We'll open up to Q&A. And a reminder for those of you just joining us online, if you'd like to submit a question you may do so by typing your question into the Ask a Question field.

We'll start with Joey since he's right there.

Joseph Stringer with Needham & Company. A question is on NP. Just given the distinction of the itch relative to CKD and atopic derm. We're just curious if you think that the placebo effect would be different in terms of a potential itch improvement in NP relative to, say, CKD itch or AD itch?

So I can maybe speak to some of our data that we've seen and we've generated. There are limitations in what's available out there. We've done the largest NP program. And what we saw actually is that the placebo response is quite similar when we look at the 4-point responder analysis even to CKD patients. It's approximately around the 20%. And even so, that's what we saw in our key study. So actually, across all our programs, we've seen around about a 20% placebo response and a 4-point responder analysis. Well, one has to keep in mind as well as become more awareness about the disease, New England Journal publication, et cetera, you do tend to see a placebo response increasing, just with expectations that patients may have that physicians may have now seen that there has been some positive data out there. But I don't know if you want to add anything?

No. I mean I think that's right on. I was going to make the same point, but it's always the first trial that's going to be a little different than everything else as soon as it comes out because expectations are set. So it's hard to see what that means. I was going to make a more of an even general point about the endpoints is that we have these tools that we use broadly across diseases, and we think about this 4-point improvement and whatnot. By and large, this probably is more subtly different across diseases than we really sort of intended to be even though it's what we use. So what is a big change for somebody with NP, might be very different than what are big changes for somebody with actual renal pruritus versus some of the atopic dermatitis. Sometimes you're bound by regulatory endpoints in a sense, but it's important to understand, the more we understand about the disease will probably get a really good idea of what a true important change actually means for somebody.

We'll go to Daniel.

Daniel Wolle from JPMorgan. One question for doctor. You highlighted the difficulty in diagnosis of NP. Is it because there's no defined path for diagnosis? Or is it due to lack of treatment? And the one thing you highlighted, for example, hyperpigmentation and given the different colors of across different variations of states of color, that might be also even a difficult point to look at. So I guess, can you maybe define for us what makes it difficult to diagnose and how it can be a barrier to treatment?

Yes. So I think that the difficulty of diagnosis often lies in itch without rash, right? Because dermatologists tend to inherently be so visual that oftentimes, when they don't see something, it's either -- either I throw my hands up in the air or I'm going to treat as if this is truly an inflammatory disease, and so I'm going to use topical steroids and whatnot. And if that doesn't work, I'm not quite sure what to do. So I think that really from a true algorithm of if you have itch, what's the next thing you're looking at in terms of the tree of all those things I mentioned, that's not really well built out. Additionally, there isn't a specific diagnostic criteria for NP in the sense that if you have had itch for x amount of time in these 2 locations, with these particular findings, you need to have this major amount of criteria, that doesn't exist either, right? And with atopic dermatitis, we were in a similar problem for a long time where without true good treatments, there wasn't much interest in actual codifying a lot of this stuff. But since development happened of actual treatments for the disease, people became much more interested in saying how can we actually sort of define what disease is and what we've actually become to realize is atopic dermatitis is no longer considered to be a thing that starts in childhood generally goes away and doesn't affect people. But 10 years ago, you would have heard a very different story of what atopic dermatitis is. So I think with NP, that's probably going to change a little bit as well. But I think that's what I meant when I said there's not a specific diagnostic criteria, but now there's clinical truck -- clinical clues that can help. To your point about sort of various shades of skin. It's a good one. The hyperpigmentation isn't necessarily in my book to necessarily make the diagnosis. I think oftentimes, it's a constellation of symptoms. Asking specific questions to describe the itch that can really help. And then admittedly sometimes using some of these off-label treatments and looking for a response as well. But I do think that the presence of targeted therapy will change that discussion, especially when it's really hard to do chart-based research or database research when I think that this is being completely underreported because there isn't much to do for that disease and no prescription therapy. The way that reimbursement codes changed this year in 2023, largely everything is based on your ability to talk about complexity of medical management and prescription medications is an important part of the medical recommendations. And largely, if somebody can't do that, it probably ends up not making it to the chart then because it's going to not be worth necessarily the time to even put it in there.

And one more for Joe. Regarding KOURAGE 1, what was the rationale to go down all the way up to 0.25 milligram BID given that you did 2 milligrams for the Phase II trial?

Yes. And so thanks, Daniel. With our Phase II study, remember, it was a proof-of-concept study. So we really wanted to go to sort of a maximum dose to make sure that we didn't miss an effective dose. We have used the range from 0.25 up to 1 milligram in our other dose finding. We believe that this dose range is an appropriate range. With AD, we saw in efficacy at the 0.25, and that's why we've taken that forward. So we believe that it's probably a very good low minimal dose that could be effective.

Annabel?

Annabel Samimy with Stifel. So in terms of the treatment of AD, there's been a few new topicals that have come out, a lot of different atopic dermatitis treatments aside from the systemic. So the JAKs or [ roflumilast ]. And so when you think about -- and these are for more mild to moderate patients.

[ Roflumilast ] isn't approved.

It's not approved yet. Okay. But in terms of thinking about how you're treating AD patients who have more mild to moderate disease and you see lesions. Is there itch still generalized sufficiently? Or do they have enough itch beyond the body surface area of the lesions that would warrant maybe choosing an oral such as DFK? Or would you first gravitate towards topicals like you've done typically in a lot of these patients?

Great question. The short answer is yes, but let me expand. So there's enough study data that suggest that people continue to be itchy beyond where their lesions are, particularly even on uninvolved skin. We know that in patients that have atopic dermatitis, if you serially biopsy involve skin uninvolved skin and compared to somebody healthy, even uninvolved skin actually has changes that are characteristic of the disease, even though it's not overly bad or somebody that has more severe lesions on the skin. I would say that a good number of my atopic dermatitis patients, probably not all have itch that is more general than specifically focused only in the lesions. However, for people with sort of more site limited external disease on the skin, the most severe itch typically tends to be focuses in the areas where they do have sort of more lesional burden. So while I am a big proponent of typically working step-wise and using topicals, most topicals are not that helpful beyond like about 10% body surface area. And most studies would suggest that topical therapy use is associated with higher rates of non-adherence. So some of our best studies to say maybe only about 50% or so. Additionally, it takes people up to 30 minutes to apply their medication twice daily for a topical to their entire body area. And we look at that over a 24-hour period, it's a lot of work. So for somebody that is itchy in more places than maybe just their lesions, even if it's not their entire body. Topicals are wholly impractical to expect somebody to actually use regularly to treat their disease. So for that reason, systemic therapy is actually much more valuable.

Okay. And then a second question, maybe this is putting the cart before the horse a bit. But it looks like the atopic dermatitis program is obviously more advanced than the NP program and you all are very used to off-label treatment. If the oral is approved for atopic dermatitis, you see yourself starting to use thing this drug off-label? Or is this primarily reserved for generic drugs where you don't really get much payer pushback?

Off-label for any specific indication you're thinking or just in general?

Off-label for NP, for example, is such a distinct population.

Yes. So in general, I will do anything to help my patients feel better with the data that I have. And if that means using something that proof for something and trying to see if I can get it covered for something that's not indicated, but I know it has pretty good data behind it. I'll go for it. You saw the same thing happening with oral JAK inhibitors for the long delay they had given that baricitinib and upadacitinib were available already. And tofacitinib for different indications that were being used at low rates off-label. I was one of those people using it as well. You saw the same thing happening for prurigo nodularis and dupilumab as well being used for that disease a long time before the official indication was there. So I think you'll see that happen. In general, I think when people feel that they can have an itch pill that works better than antihistamines or gabapentin with a more favorable sort of risk-benefit profile. People will probably give it a shot if they can get it.

Before we will go to Sumant, I'll take a couple of questions from online since we're on the topic. Is it possible -- and maybe this is for Joe. Is it possible to get a broad label once we see in neuropathic itch once we have NP data?

So currently, the way that the dermatology division has given us guidance and what they like to see is that each product condition is associated with the disease. So that's what we're doing, and that's why we've designed the clinical studies as we have. So CKD-associated pruritus, atopic dermatitis associated pruritus to an NP. And of course, that's always an aspiration that would be nice to have, but that's a discussion down the road with the FDA.

Great. And Dr. Chovatiya, is NP a progressive disease? Or does it come and go? How does it progress?

Yes. So I would say that most of my patients usually tell me they had like nothing for a long time, and all of a sudden they feel like they have something. And I'm making this completely based on just anecdotal evidence, and I hate doing that, but there is no real good study of what does the longitudinal course of NP look like in terms of somebody who's at it for a long time. Does it actually wax and wane or progress? Most of my patients feel like they tell me a story of they had something. Now they had nothing. Now they have something and it's kind of just sticking around and being very, very persistent. So I don't have the sense clinically that it's as much of a fluctuating course like atopic dermatitis. But I think once it starts bugging people, it kind of then just sticks around, it doesn't go away.

Great. And the question on the AD segmentation, the itch dominant population, is it really well recognized within the physician community? Or do you sort of segment it out just via your treatment paradigm?

Yes. So I think a lot of this just lies with, again, regulatory endpoints for atopic dermatitis, primary endpoints are EASI-75 and IGA 0/1. One is a measure of lesional severity. One is a measure of severity, surface area and location. So there's no actual symptom built into those measures. So therefore, oftentimes people's assessment of what mild moderate disease is, it's just those monolithic groups. And hopefully, from what little I show you, and there's more out there to support this, there's so much else going on in our patients with atopic dermatitis. That's probably one of the reasons why in the real world people aren't necessarily thinking about all the time. Okay, let me sit there and make a little diagram and subset out where my patients fall. However, with itch, it's actually probably the easiest way to do it because if there's any patient reported outcome, you can get people to probably ask someone is how itchy are you from 0 to 10. It takes all of 3 seconds. The educational burden is very low. And by and large, just getting a number, it gives you a pretty good gauge, and it is a well-validated tool. So I get the sense that if there is a therapy that starts to basically work on people with very specific combinations of features, that question you're going to be find is more and more asked. I mean we have one example of it with nemolizumab's approval in Japan for the pruritus associated with atopic dermatitis. Albeit not necessarily what they're going for here based on whatever that reads out. But I think that there is precedent for it. And I think that with the option there, people will perhaps begin to ask the question.

Great. Let's go to Sumant.

Sumant Kulkarni with Canaccord. Dr. Chovatiya, a question for you. You mentioned there's so many nuances in actually characterizing an itch as severe in AD. So given the kappa opioid receptor agonist mechanism of KORSUVA, do you think there is a specific population within atopic dermatitis, mild to moderate patients who have severe itch that this might be most suitable to? And if you had to guess what percentage would that be?

So that's a really good question. And there is not enough data for me to give you a smart sounding answer to that. My hunch is going to be probably just given the heterogeneity of what we already know about even lesional aspects of disease in terms of people that have IL-13 versus various combinations, IL-22, IL-17, whatnot. And many of those drugs that didn't hit their endpoints may actually be worthwhile on a small subset of people even within itch, it probably isn't exactly the same quality in everybody. So we know that when you ask these questions, some people actually do explain that their itch is burning and stinging and stabbing, whereas others have more classic inflammatory nomenclature. Does that mean that those people are going to respond better to something that perhaps is much more of a neuropathic treatment versus not? That's tougher to say, right? Because we know that itch receptors on neurons include not only opioid receptors, but true bona fide cytokines like IL-4, IL-13 and IL-31. And I have a hunch that probably there will be additional subsetting, and it's not going to be a one size fits all. That's kind of my baseline answer for most things atopic dermatitis. I don't have a sense of the percentage because like we just are not close to understanding that.

So based on that, given it's so fuzzy, do you have any specific recommendations for the company as it embarks on the Part B of the KIND trial and the KIND 2 trial in terms of specific inclusion or exclusion criteria?

Yes. So I think that probably at this point in time, just simply dividing people up in terms of where they are for itch actual lesional severity and extent is already so different enough in terms of the way we're looking at atopic dermatitis. That has to be the place that you start. I think for more exploratory long-term aims whether it be through some type of actual profiling of patients or looking at people who optimally responded didn't optically respond, whether it be through actual cutaneous analysis, more in-depth analysis, that might be the place you can start to parse that out, but I think that's going to probably have to be post talk understanding who responds the best. It doesn't respond the best. I don't think that probably changes the trial design, the execution though.

And then a question for the company. Joe, you've decided on 2 trials in NP. Given there's nothing approved, and this could potentially be a supplemental new drug application by the time you get to an application point. Do you think it would be too courageous to ask the FDA if you could get away with one trial?

Nice one.

Of course, we always try to go as fast as we can and ask all those questions. We had a good interaction last year with the FDA. And this is the design that we have that I've presented today is the components that we need to -- to generate the data that we need to generate in the components. We need to do some dose finding. We have pivotal studies and open-label extension. So those components are key.

Okay. Great. So Jo, you'll get a couple more then from online is -- you just alluded to the open label is the full open label required for the NDA submission?

Yes. So remember that an open-label study is there for us to gain a better understanding of what the safety profile of the drug is over time. There are guidance, there's ICH and FDA guidance on how many patients we need to have who have gone through an open-label extension period. So that's what we will be doing as we've done with all our studies. So it's not all the patients need to complete the 52 weeks typically around 100 patients, need 52-week data, and that's what we'll follow.

So along those lines, is there a way to accelerate the timelines?

So absolutely. I mean that's why we have conducted the study and designed the study this way really to try and enhance our operational capabilities here and trying to accelerate the study as fast as we can and trying to get to those 100 patients as quickly as we can. So to try and get to that NDA as soon as possible.

Great. And how do you know that you have the right dose? You alluded to the fact that the first part is not powered for statistical significance?

Of the part A?

Part A, yes.

So yes, so it's not powered for statistical significance, but we have an appropriate number of patients. In Part A, there's 50 per group, and that will give us enough information to be able to make that assessment. Remember that it is going to be based on our benefit risk, which is absolutely key, especially in our dermatology patients who are pretty healthy compared to what we saw earlier with the CKD patients. So that benefit risk is very important. We will look at those 3 doses that we have taken forward. And based on the 4-point analysis and the safety data, we will make that decision. So although not power to show statistical significance, enough patients to give us enough directionality to take order dose.

Great. And one last quick one is rescue medication alert.

No, rescue medication is not allowed. Patients will be washed out of all medication that may impact on the pruritus.

Great. So now I'll turn it over to Chris for some closing remarks, and we will conclude with management Q&A.

So first, let me thank our guest speakers, Dr. Scherer had to leave, but thank you, Raj, and thank you, Jo. I thought incredibly informative. Clearly, for Cara, I mean, our North Star is really clear, right? We want to be the world leader in the treatment of chronic pruritus. And sometimes what I don't talk about is why, why that's such a noble mission we have as a company, why you see our entire executive leadership team here. The why is exactly what Dr. Topf said and Raj as well as Jennifer around the patients. And they gave you examples of the 88-year-old man that Jennifer brought up, and this patient you had Jo were, they're going to go on hospice. And that's what keeps us up at night. And I get that question, what keeps you up at night. Well, what keeps us up at night is a question that Jo got around urgency. And we have that level of urgency to execute our clinical development programs. We have an expert team. They're pressing on every lever to bring in the studies earlier at the highest of quality -- and that's what we did with KALM 1 & 2 under Fred's leadership as well. So that's our mission. That's our North Star. You heard from the thought leaders today that there is significant unmet need. This is an underserved condition, and that's the devotion we have at Cara to that. And Iris, with that, I'll turn it over to the audience for any questions. We have the entire management team here as well.

Chris, we do have a couple of questions on the same topic from online, and that is how is the launch going?

Well, I mean, I guess that's the question, right? How is the launch going? Well, I won't speak to specifics around the quarter, quarter 4. We'll do that at our earnings call coming up. but we're quite encouraged. I mean what I can tell you is in Q3, Fresenius really invested significantly in activating their network. And now what I can report is that we are seeing a subset of those clinics kind of pulling through that trial stock and now doing repeat orders, which is a great sign. And I would say I look at the product performance as well. Anecdotally, what we hear is very similar to what you said, Jo, the medicine is delivering. And that's what we hear from physicians and patients. And Joel, your comments around your patients. I would say it's fairly ubiquitous as the feedback like Eric and I here as well as Jo and Josh from the medical side. So quite encouraged with that. There's a high level of interest from the physicians again Fresenius invested in activating their clinics. We're seeing that getting pulled through nicely. DaVita is a more -- I would say, more traditional, they identify a patient, they order a product, but we are seeing increases in the number of clinics pulling in that product and utilizing it. I think Annabel has a question. Go ahead, Annabel. I can hear you.

So just on the topic of a launch. Since you opened the door, I guess one of the things that we're hearing is that dialysis centers are being impacted by inflationary pressures. And a drug like KORSUVA could be one of the tools in their box to increase margins. So I know that Fresenius specifically as a partner is very incentivized? Are you starting to see some kind of dynamic like that from DaVita and any kind of increased urgency to start getting KORSUVA down to the dialysis centers?

Annabel, what I could say is I think the urgency is increasing more and more as CSL Vifor with their representatives are out there educating doctors more and more. And the proof points are, we see the number of those clinics you've mentioned DaVita, we see the number of those clinics increasing in terms of their purchasing. And the repeat orders, as I've mentioned before with you at one point that DaVita clinic that is ordered, there's a strong majority of them that are repeat ordering. So it's a good sign. In terms of inflationary pressures, incentive, I mean, clearly, we're reimbursed outside the bundle right now. So there's this kind of organic incentive in terms of financials to some of these dialysis providers. But Joel mentioned the importance of partnering with these dialysis providers. And that's exactly what we're doing from a top down. Obviously, Fresenius with the joint venture is a little different. But the same sort of dynamics are in play with DaVita in terms of our engagement top down in terms of contracting, et cetera.

Just to clarify, when you say repeat orders, do you have the granularity to look at if those are for new patients? Or is it for continuing patients who are on...

It's a great question, Daniel. No, I mean we don't have that granularity. So what I can tell you is, obviously, we look at the number of clinics that order and their repeat ordering. But I don't know we don't have that patient level data. So that's why we've always said the greatest proxy we use in CSL Vifor uses is the orders from the dialysis clinics from the wholesalers is a good proxy for demand, but that granularity right now doesn't exist.

So I have a question on TDAPA. At what point would you expect to learn that you might get an additional year for TDAPA?

Well, a lot of activity is going on with CMS, Sumant. As you know, and that's not something we just engaged with CMS last year. This has been an ongoing thing with us, CSL Vifor as well as other stakeholders. So I mentioned to you before, I mean quite -- we're quite enthused with where we are with CMS and why is last year, they came out with the request for information in their final rule where they actually acknowledge the fact that the post-adapt environment's a bit tricky. It's tricky for patients, it's tricky for physicians and dialysis providers. And that needs to be addressed in some fashion. So they came out with different methodologies. Kind of where we are is, obviously, we're continuing to kind of work on policy initiatives with CMS. We don't expect to hear back from CMS, probably till the end stage renal disease, 2024 rule becomes public, which would probably be in the fall period of this year. And there, we would -- we'd hope to hear something. But again, we're working with the federal government, that's always -- it's an unknown sometimes.

And then what are your latest thoughts on how post-TDAPA pricing may play out, especially given Sensipar Parsabiv is not a really good analog in this case? And getting out of the TDAPA period, do you have any thoughts on what optimal utilization rate might be for you to be part of the bundle in an optimal way?

Yes, there are some specific questions there, Sumant. What I could say is that we're still very encouraged with the durability of this drug even post TDAPA. Depending on which way CMS goes with TDAPA-designated drugs, whether it's put in the bundle or it's funded outside the bundle in some fashion, but we're quite encouraged with the durability of this drug. It won't show the same slope as what happened with Parsabiv. You just nailed it. It's not the right comp to look at, but that's the only comp out there. So I won't speak specifically on the ASP. Clearly, there would be some erosion in the ASP and we saw that -- you see that with a lot of Part B drugs anyways. There'd be some erosion. But where I'm encouraged is the volume would I think would be pretty sticky.

Great. And we have one more follow-up for Jo as well, and it's around since on the topic of updates. It's around the -- any update on enrollment for KIND and KICK.

[indiscernible] as for our expectations and we're still on target for having data read out at the end of this year, the second half of the year and KICK program as well, also doing as per our anticipation and that is on track for second half of 2024.

Great. Well, that concludes today's event. Thank you all so much for joining us, both in-person and virtually. For those of you in-person today, we would invite you to join us for lunch in the [indiscernible] room after this. Thank you so much.

Thanks, everyone.