Good afternoon, and welcome to Cara Therapeutics' 2022 Virtual R&D Day. Before we begin, let me remind you that today's presentation will include forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see slide two of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. We undertake no obligation to update or revise the information provided on this webinar as a result of new information or future results or developments. Participating from Cara today will be Chris Posner, Cara's President and Chief Executive Officer, and Dr. Joana Goncalves, Cara's Chief Medical Officer. We're delighted to also be joined by two highly accomplished key opinion leaders, Dr. Brian Kim and Dr. Jonathan Silverberg. Dr. Kim is the Vice Chair of Research at the Icahn School of Medicine at Mount Sinai in New York, Site Chair at Mount Sinai West and Morningside, and Director of the Mark Lebwohl Center for Neuroinflammation and Sensation. Dr. Jonathan Silverberg is an Associate Professor of Dermatology at the George Washington University School of Medicine and Health Sciences in Washington, D.C., and the Director of clinical Research and Contact Dermatitis. Today's event is expected to run until approximately 2:00 P.M. Eastern Standard Time. At the end of the presentation, Dr. Jo Goncalves will moderate a Q&A session. If you would like to submit a question, you may do so at any time during the webinar by typing your question into the Ask the Question field. A replay of the webinar will be available on the investor section of the Cara Therapeutics website later today. With that, I will turn it over to Chris for his introductory remarks. Thanks, Iris, and good afternoon, everyone. Thank you for joining us for our virtual R&D event. Since I took on the CEO job last November, I have really looked forward to this day when we can detail moving our late-stage pipeline forward. I see this as a step toward enhancing the trust and excitement around our broader long-term strategy and mission, in which our oral KORSUVA platform is a key value driver. Our mission is to be the leader in chronic pruritus. To achieve that, we are commercializing and developing novel first-in-class treatments that change the way this underdiagnosed and underserved symptom is treated across a variety of diseases. We believe a sizable market opportunity, more than 16 million patients in the U.S. alone, is waiting for the right new treatment option. Ten days ago, you heard how we were executing our first strategic priority to maximize the commercial potential of KORSUVA injection, the first and only FDA-approved product for pruritus in chronic kidney disease patients on hemodialysis. Together with our commercial partner, Vifor Pharma, we are prepared and ready for the impending KORSUVA injection launch in the U.S. Today, we will focus exclusively on how we are executing our second priority, initiating pivotal phase III programs to advance oral KORSUVA for chronic pruritus in advanced kidney disease and atopic dermatitis. In a moment, Dr. Jo Goncalves, our Chief Medical Officer, will detail our phase III clinical programs and the background that gives us confidence in our approach and execution. Current treatment algorithms are not satisfying the significant unmet need in pruritus. They are leaving pruritus patients behind. Chronic pruritus in any form can lead to impaired quality of life, including insomnia and depression. 30% of approximately 1.2 million stage 4 to 5 chronic kidney disease patients in the U.S. have moderate to severe pruritus, and in AD, roughly 12 million U.S. patients suffer from pruritus. We believe we have a rare and unique opportunity to significantly alter the treatment algorithm for pruritus in these diseases. Right now, there are no FDA-approved therapies specifically for pruritus in either one, and currently used therapies have long been insufficient. Moreover, in AD, modern standard of care treatments and their mechanism of action do not specifically target pruritus, a central manifestation of the disease. Our oral KORSUVA program aims to change this. You will hear more from the two experts in the field on the scientific rationale underlying our programs, the mechanism of action of oral KORSUVA, and how it might play a role in the clinical practice for AD. We have a well-defined scientific rationale, an anchor approval, and a clear clinical and regulatory path forward for oral programs in advanced kidney disease and in AD. This is a formidable point from which to start our pivotal trials. Today's event is a significant step toward accelerating momentum and reinvigorating the excitement around our phase III programs, as well as our strategy overall. By focused execution on our oral KORSUVA platform, we are building the next key growth driver for Cara. I'd like to turn it over to Jo to present the details of our phase III programs. Thanks, Chris, and good afternoon. It's an exciting time at Cara as we initiate two pivotal phase III programs for oral difelikefalin. I'll start off by reviewing the advanced chronic kidney disease phase III program. We are confident in the success of this program due to our development of work with KORSUVA injection and our study of the oral formulation in chronic kidney disease. Data from our phase III KALM program with KORSUVA injection led to its approval last year in hemodialysis patients. That experience, along with the data from our phase II CKD study with oral difelikefalin, supports the use of difelikefalin as an antipruritic treatment for patients with advanced CKD-associated pruritus. As a reminder, our phase II study with oral difelikefalin was conducted in patients with CKD stages 3-5, as well as patients undergoing hemodialysis. The primary endpoint was met with a 1 mg once daily dose versus placebo at 12 weeks, and the safety and tolerability was consistent with the known safety profile from the IV formulation in the CKD patient population. We presented this data to the dermatology division of the FDA and were pleased with a positive discussion and alignment on the phase III program in patients with advanced CKD with moderate to severe pruritus who are not on dialysis. The phase III program will comprise of two identical 12-week double-blind placebo-controlled studies, KICK 1 and KICK 2. Each study will enroll approximately 400 patients who will be randomized 1: 1 to either oral difelikefalin 1 mg once daily or matching placebo. The study population will include adult patients with advanced CKD stages 4 or 5 who are not on dialysis. We are excluding stage 3 CKD patients who are largely responsible for the high placebo response rates in our phase II study. We also know, based on data from a recent National Kidney Foundation survey, that the itch characteristics in patients with CKD stage 4 and 5 are very similar to the itch characteristics in hemodialysis patients. Thus, we believe that the patient population in the KICK studies should behave more like those in the phase III KALM program. Let me elaborate further on the inclusion criteria. Patients must have pruritus for at least six months prior to entering the study. In addition, there will be a seven-day run-in period by which patients will be required to have an itch score of greater than or equal to five on the worst itch NRS before being randomized. Together, these requirements will help to reduce the variability in itch and further assist in controlling the placebo response rates. Patients will be allowed to continue using itch treatments, including antihistamines and gabapentinoids, as long as they remain on a stable dose throughout the study. KICK 1 will be conducted in the U.S., and KICK 2 will be a global study with sites both in the U.S. as well as outside of the U.S. The primary endpoint is the proportion of patients with a greater than or equal to four-point improvement at week 12 from baseline in the worst itch NRS. Additional endpoints include quality of life assessments such as sleep, as well as safety assessments. The 12-week study period will form the foundation for the NDA filing of difelikefalin in non-dialysis advanced CKD stage 4 to 5 patients. We estimate to have top-line results in the second half of 2024. Now let me review the safety extension period. After the initial 12-week treatment period, patients are allowed to enter the safety extension. At that time, they will be re-randomized to either difelikefalin or matching placebo for up to 52 weeks. A placebo control arm during the extension period will allow for a more robust and accurate interpretation of the long-term safety data compared to using historical controls. This brings me to the end of the CKD program. Now moving on to atopic dermatitis and the KIND phase III program. Based on the efficacy and safety profile from the phase II KARE study, we are advancing oral difelikefalin into two pivotal phase III studies. As a reminder, the phase II KARE study demonstrated an improvement in itch with oral difelikefalin at week one, which was sustained to week 12, with the treatment effect more pronounced in patients with mild to moderate AD, that is, patients with a body surface area of less than 10%. Difelikefalin was well tolerated across all doses, with the most favorable benefit risk profile seen in the lower two doses of 0.25 mgs and 0.5 mg twice daily. Both clinical and preclinical data support that the mechanism of action of difelikefalin in AD is predominantly neuromodulatory. Since current therapies for AD are mostly anti-inflammatory, they may improve the rash, but they may not always fully address the itch. As such, we see difelikefalin playing an important role in this patient population and as a complement to current treatment options. Dr. Kim will elaborate further on this point in his presentation. At the end of phase II meeting with the dermatology division of the FDA, we discussed our key phase II data and agreed on a path forward for a phase III AD program for difelikefalin as an adjunctive therapy to topical corticosteroids. Using difelikefalin as adjunctive therapy will mimic real-world clinical practice and the way it would be likely used by dermatologists. The pivotal phase III program for difelikefalin in AD will comprise of two studies, KIND 1 and KIND 2. The KIND 1 study will be composed of two parts, part A and part B. KIND 1 and KIND 2 will be double-blind, controlled, 12-week studies with patients allowed to roll over into open-label 52-week extensions. The studies will include adult patients with pruritus who have not been adequately controlled by topical therapy alone. Patients have to have chronic AD related pruritus for at least six weeks prior to screening, and the pruritus must be rated as moderate to severe with a greater than or equal to five on the itch NRS. Patients must have an IGA of greater than or equal to two and a body surface area less than or equal to 20%. Patients will be washed out of any medication that may impact itch and any medication that may impact their AD prior to screening. We will stratify patients to a body surface area of less than 10% or greater than or equal to 10% with the aim to enroll 85% of patients with a body surface area of less than 10%. As I mentioned, KIND 1 will be composed of two parts, part A and part B. Let me review part A first. Part A will include 280 patients who will be randomized equally to four arms. Difelikefalin 0.25 mg twice daily plus topical corticosteroids. Difelikefalin 0.5 mg twice daily plus topical corticosteroids. Oral placebo twice daily plus topical corticosteroids. Oral placebo twice daily plus vehicle. The dose selection for part A was based on the benefit risk profile of difelikefalin in the KARE study. Part A will be conducted in sites in North America. At the end of the 12-week treatment period in part A, we will have an internal data readout, which will provide key information, specifically the dose and the sample size, to initiate part B and KIND 2. Our decision to determine the dose and the sample size will be based on a four-point responder analysis and safety assessments. To set expectations, part A is not powered to show statistical significance between treatment groups, and part A patients will not roll over into part B. We will not release detailed results from this readout. However, we will disclose the initiation of part B in KIND 2, the selected dose, and the sample size. We estimate to have the readout for part A in the second half of 2023. Part B and KIND 2 will be identical in design. They will be double-blind, controlled, 12-week studies with patients randomized 1:1 to either difelikefalin or matching placebo as adjunct to topical corticosteroids. The difelikefalin dose will be based on the results from part A of KIND 1. The primary endpoint will be the proportion of patients with a 4 or greater than four-point improvement at week 12 from baseline in the itch NRS. As a reminder, a four-point improvement is considered to be a clinically meaningful response and the accepted primary endpoint by the dermatology division of the FDA. Additional endpoints include quality of life assessments such as sleep, as well as safety assessments. The patient population in part B and in KIND 2 will be the same as part A. KIND 1, both part A and part B, will be conducted in North American sites only. KIND 2 will be conducted in sites in North America as well as sites outside of North America. All patients who complete the 12-week treatment period will be eligible to roll over into an open label extension phase for up to 52 weeks. As you can see, our phase III programs in both advanced CKD and atopic dermatitis are designed to accomplish 3 things. Address the unmet need, which is not sufficiently addressed with current treatment options. Focus on the most appropriate patient populations for oral difelikefalin, considering current clinical practice. Execute on the most appropriate study designs with the greatest likelihood of success. Let me conclude by saying, we are thrilled to be initiating these programs, and our clinical teams are working hard on getting these studies started this month. Now let me hand over to Dr. Brian Kim, who will elaborate on the proposed mechanism of action of difelikefalin in atopic dermatitis. Thank you, Jo. I'll be talking today about difelikefalin and its potential mechanism of action in atopic dermatitis. Atopic dermatitis is a classic chronic itch disorder. It has a very high incidence, it's very costly, and itch is the central symptom. Although there is clearly a rash that's chronic and relapsing, itch within this condition is the thing that bothers patients the most and has a tremendously negative impact on quality of life. Therapeutic options have traditionally been very limited in targeting itch or pruritus in atopic dermatitis. Additionally, an increasing number of patients treated for their rash are left with residual itch. The conventional paradigm of atopic dermatitis pathogenesis is as follows. There are immune cells either in the skin or even circulating that come into the skin that then respond to a variety of inflammatory factors referred to as cytokines. These cytokines can activate the immune cells, and in turn, the immune cells or lymphocytes can actually directly produce what we refer to as effector cytokines. These include cytokines like IL-4 and IL-13 that can directly damage the skin and cause a lot of inflammation. In recent years, work from our laboratory has actually identified how these inflammatory factors not only damage the skin, but actually directly communicate with the sensory nervous system to promote itch. In other words, there's a direct link between the immune system and the nervous system in a way that these inflammatory factors act as neurotransmitters to promote itch directly, and these signals work their way all the way up to the brain. We know that blocking inflammatory factors or cytokines represents an anti-inflammatory therapeutic paradigm, not just in atopic dermatitis, but a variety of inflammatory disorders. What we've been proposing in recent years is that we have to actually think of how the sensory nervous system or the nervous system in general represents a direct target of therapeutics as well to block these kinds of signals in inflammatory disorders like atopic dermatitis. If we're talking about the nervous system, we have to actually think about different kinds of signaling pathways such as neurotransmitters. What I'm going to be talking about today here is neurotransmitters such as kappa opioids as well as mu opioids. It's really a careful balance between these two very distinct opioid pathways that results in a healthy, non-itchy, normal skin. What do we know about these opioids? We'll start with mu opioids, which are quite distinct. This includes opiates that actually stimulate this pathway, such as morphine. We know that patients who actually get morphine, there's a high incidence actually of patients developing itch. This is in part because these opioids, the mu opioids, can actually directly stimulate the itch sensory nervous system. That there is this other counterbalancing pathway, the kappa opioid system, which actually can actually balance this, resulting in normal skin and is actually antipruritic or anti-itch. It's really having less mu opioid signaling and more kappa opioid signaling, and this is a manner in which we can actually restore what we think is non-itchy, healthy skin. How does this work if we actually now look at the nervous system? We know that signals that stimulate itch start in the skin. These activate itch sensory neurons that work their way into what we refer to as a dorsal root ganglia near the spinal cord. The electrical signals from these sensory neurons relay into the spinal cord and onto the brain, and that's how we ultimately perceive itch. As I mentioned already, mu opioids can actually directly stimulate this itch axis zone shown in red. What we also know from a variety of different published work is that kappa opioids can actually directly stimulate other parallel sensory neurons to suppress itch. It's much broader than this because we know that kappa opioids can also activate these itch neurons as well as neurons within the spinal cord to suppress itch. What the operative mechanism is still remains a bit controversial, but what I'm gonna focus on is this particular parallel circuit pathway of the kappa opioids on these other blue neurons, here, shown here. We've actually done some studies in preclinical mouse models of atopic dermatitis. I'm going to show you some of this data and how this plays into some of the biology that I'm talking about. We have a mouse model in which we treat mice with an irritant called MC903, and these mice very reliably develop atopic dermatitis or AD-like disease, clinically with itchy, red, scaly skin. Histopathologically under the microscope as inflammation, that's very distinct. As well as immunologically, if we actually do techniques such as flow cytometry, we can actually look at the inflammatory environment and find that these mice exhibit features very consistent with what's observed in human skin. If we now look at what the genes within the skin actually express by way of RNA sequencing, we find that key cytokines and different inflammatory factors are altered in a way that's very consistent with what has been reported in human atopic dermatitis skin. Importantly for us, because we're talking about itch, we have to look at whether these mice are actually scratching, and in fact, they are. If we look at scratching bouts over time on the Y-axis, as well as over time in days on the X-axis, what we find is that mice, these mice that develop AD-like disease are exhibiting chronic spontaneous itch very robustly as shown in the closed circles. The control vehicle-treated mice do not exhibit much in the way of chronic spontaneous itch, again, shown in the open circles here. What we did was we actually treated mice that develop AD-like disease with difelikefalin or DFK twice a day systemically. By systemic, we mean intraperitoneally to get the drug everywhere into the mouse. What we found is if we actually do perform immunologic analyses in the skin, we don't find any difference in terms of the inflammatory infiltrate based on broad immune cells, CD45 positive immune cells. Key pathogenic cells such as ILC2s or CD4+ T cells, we find no difference in the mice that were treated with DFK or vehicle control. Furthermore, if we actually measure skin thickness over time as a surrogate measurement of the rash, what we find is that the% change is no different. No more thicker or less thick in DFK-treated mice compared to control vehicle-treated mice. However, in stark contrast, if we look at the itch or scratching bouts in these mice on the Y-axis over time on the X-axis, what we find is that in contrast to the vehicle-treated mice, there is a very dramatic and significant reduction in terms of the itch at every time point. What was rather striking was that we saw this right away, even at day zero,one, indicating that the effect is actually quite rapid and does not really require much time to see the effect, despite the fact that the disease is manifesting very robustly. If we go back into the nervous system, there's been great studies, and this is... We've just curated the data that's already out there of single-cell RNA sequencing studies in which we look at each individual neuron within the sensory nervous system, and we can then classify these neurons into different buckets, and that's what these columns are. What we find interestingly in this data is that OPRK1 gene, which is the gene for the kappa-opioid receptor, which is a target of DFK, we find that this gene is highly expressed on touch neurons, shown here on the left. We don't find that much expression on the itch neurons or what we refer to as the C fibers shown on the right. In contrast, if you look at OPRM1, which is the receptor for the mu opioid receptor, we actually find that consistent with what I said before, how these mu opioids stimulate itch fibers, we see the receptors for these actually expressed on the itch fibers. We see again, the kappa opioid gene highly expressed on these touch neurons. I'll come back to that point in a second. If we actually now take these sensory neurons, put them in a Petri dish, and stimulate them with DFK, we use a technique called calcium imaging to see if these neurons actually do respond functionally to the drug. They do. We see these spikes in calcium. That's what we're seeing, these little inflections here. In fact, the neurons do. Which neurons respond to DFK? If we actually compare the compositions of the neurons, we see that it starts to look different. Traditional itch-inducing factors or pruritogens, such as chloroquine, CQ in black, or histamine, which we're all familiar with, in white, tend to activate these small-diameter neurons. So does DFK to some degree. But what we also find is that medium-diameter neurons are highly enriched for DFK, shown here in the red, indicating consistent with the sequencing data I showed you that this DFK seems to activate these larger diameter touch neurons, which we refer to as A beta neurons as well. Now go back to looking at pictures of these mice, they have red scaly rash, no difference whether they're treated with DFK or control. If we look under the microscope, we see no difference as well. Despite this very dramatic reduction in terms of the scratching or itch in these mice, again, we don't really see any clinical features that are different based on DFK in the mouse model. What are we getting at? What we think is actually happening is that there are a variety of different itch stimuli that trigger itch in the skin by activating itch neurons, shown here in red, and this is how you get itch in the mouse or in a human being for that matter. What we're modeling, we think, is that DFK or difelikefalin actually activates another neuron, which is actually a touch responsive neuron, which then is able to suppress itch within the spinal cord by blocking a broad array of itch-inducing stimuli from the skin. This is a very distinct mechanism of action because instead of simply blocking the itch neuron, what we're doing is we're actually activating a touch neuron, the ones that actually respond to scratching, the manner in which we try to alleviate itch, to actually block out these itch signals. The picture I painted for you is that there is an inflammatory paradigm of itch where inflammation leads to itch, but we also know there are many ways in which you can get itch independently of inflammation. We refer to it as primary neurogenic itch. Some diseases fall somewhere in the middle, and we know that conditions like atopic dermatitis are highly inflammatory, and there are a variety of anti-inflammatory agents that are currently available, but many that are emerging to actually treat atopic dermatitis. Traditionally, what we're familiar with is corticosteroids as being an anti-inflammatory mechanism of action. What I'm also proposing is that there are ways in which you can actually block using neuromodulatory agents, the itch within atopic dermatitis. There are different mechanisms of actions that are distinct. Also what we're proposing is could be synergistic, perhaps even in combination, because there's an added benefit to using neuromodulatory agents, particularly when we're talking about atopic dermatitis itch. Thank you very much for listening, and I'll hand it over to Jonathan. Thank you very much, Brian. Good afternoon, everyone. I'll be discussing the more clinical aspects of atopic dermatitis and some of the heterogeneity and novel phenotypes of the disease. To get started, I think it's important to recognize that atopic dermatitis is a very complex and heterogeneous disorder. I think we often hear this kind of discussion with other diseases, but it is particularly true for atopic dermatitis. Here we see seven different images of atopic dermatitis, and they all look really different, and yet they're all part of the same disease. There's a lot of variability in terms of the clinical signs. Even the most commonly looked for clinical sign, which is the flexural involvement, the involvement of the creases of the elbows, back of the knees, is something that's not universal. In fact, none of the signs are particularly universal. What is universal is the itch. Itch is, you know, the most common symptom. It's also the most burdensome symptom that happens. It turns out that the symptoms of atopic dermatitis go even beyond itch. Skin pain is a newly recognized symptom. A lot of skin pain, though, is secondary to scratch and so is indirectly related to itch. There may be a component of skin pain that's independent of itch. Sleep disturbance, such an important downstream sequelae of itch, and, you know, particularly for nocturnal itch and scratch, such a debilitating issue for patients. Anxiety and depression, major problems that happen with chronic itch, major drivers of health utility decrements and quality of life impacts, and you know become a source of comorbidity in and of themselves. Often or almost always related to the itch. There's other symptoms as well that can impact patients within this disease. Now, when we think about the you know the severity or the prevalence of these different symptoms or of you know how active the disease is, I think it's important for us to recognize that atopic dermatitis is a very variable course, a heterogeneous longitudinal course as well. You know, so sometimes we hear these regulatory definitions, you know, mild disease, moderate disease, and the truth is they kind of don't fully capture what the story is, you know. Patients will bounce around all the time. These are some data from a real-world study that my group conducted looking at the longitudinal course of worst itch and average itch over a two-year period. There's a lot of different ways to measure this, but we used the sort of standard numeric rating scale for average itch or worst itch in the previous week. What we found was that there's a large subset of patients who have, you know, if they started with moderate or severe itch, that a large subset of those will continue to have moderate or severe itch at least one follow-up visit, indicating that there are clearly some unmet needs in the real world. When we looked at patients who had follow-up out for the two-year period, what we found was substantial fluctuation in terms of both the frequency and the intensity of itch, as shown here in these colorful Sankey charts. What you see in these squiggly, you know, less opaque lines, is that they're really, no matter what their baseline severity is, there's just bouncing around and fluctuation of severity that's happening all the time with standard of care therapy, indicating that, you know, patients really have a lot of unmet needs with respect to itch. You know, some patients may not need anti-itch therapies, 24/7, 365 days a year, but it also suggests that all patients really require some anti-itch therapy, at least at some point over that 24-month period of observation. I think when you look at the numbers, it's quite impressive. 65% had persistent itch severity categories over a two-year haul, and 28% had fluctuating severity. Only 6% had sustained improvements in terms of average itch. Very similar results when you look at the worst itch scores as well, with actually even higher rate of persistent worst itch over a period of time. What we're seeing is that for those patients who are following up in the system, a big part of why they're following up and a big part of their unmet needs is that persistent uncontrolled itch. These are just some schematics that I drew up from my own clinical experience of the different longitudinal courses of itch and really not just itch, but atopic dermatitis severity. You could argue that there's many more different combinations or permutations you could come up with, but these are just a few. On the far left, you have an example of a patient who's got overall good control. You see a little background noise there, but by and large, it's a patient who can be managed with some topical steroids here and there and is probably gonna be fine. On the far right, we've got a patient who there's also that noise happening, but the reality is this patient has 365 days a year of bad disease. Then there's everything in between with bouncing up and down of severity groups, and some patients, you know, like the second one from the left, where they get towards mild between flares, but then they're having multiple moderate flares, and you've got patients who are, you know, even when their flare gets better, they're still at that moderate point in time. What this says is that, you know, for a lot of these patients, they're not only going to require, you know, therapies that can control their disease and control their itch during those flares, but also options that they can use to really manage flares, even in sort of those baseline states where they may have more moderate disease that's still quite active and itchy. What about different phenotypes of atopic dermatitis? This is an area I think that's really growing now in terms of its interest. For background, I'm not the biggest fan of some of these expensive biomarker assays, you know, the transcriptomes and other things. I think they provide important information, but they're expensive, they're invasive, they're hard to commercialize, and it's very hard to prescribe a drug based on them at this point. We don't have anything that's really a valid clinical biomarker or theranostic. I'm a big fan of, you know, as clinicians, what can we look at that's cheap and simple and feasible from a clinical phenotyping exercise? We did what I think is a very simple and logical exercise here to say, what if we just looked at the severity of itch and the severity of lesions, and we looked at the combinations of them. We looked at mild to moderate itch versus severe itch, compared that with mild to moderate lesions versus severe lesions. You got, of course, four combinations. We call these MIML, MISL, SIML, and SISL. But I want to draw your attention to the third one, severe itch and mild to moderate lesions or SIML. What we also affectionately refer to as itch-dominant atopic dermatitis in the discussion of the manuscript. This is an important subset 'cause it's something that really was not recognized well until this study. Most patients, perhaps not surprisingly, had MIML, the mild to moderate itch and mild to moderate lesions. Look at this, the second most common subset is the SIML, the itch dominant, which it depends on how you define the lesional severity, whether it's an EASI score or SCORAD, but it's anywhere between 21%-30% of patients who have this itch-dominant disease. This is not an uncommon subset. This is a very common subset that's happening in the real world. Fortunately, those with severe lesions are far less common. The SIML or itch-dominant atopic derm was more common in females. It was also more common in black patients. There are very important characteristics with respect to burden, I think, that we have to think about here. You know, patients who had either severe lesions or severe itch, the itch-dominant atopic derm, describe their atopic dermatitis as being more severe, worse quality of life. They weren't quite as bad as those who had both severe itch and severe lesions, but they still had markedly worse impacts than those who had mild itch and mild to moderate lesions. The patients with itch-dominant atopic dermatitis also had more severe physician's global assessment scores, but they often were missed. The ones who had severe lesions were far more likely to be rated with severe physician's global assessment scores. Now, the patients with, you know, who had the severe itch and severe lesions versus just the SIML, the itch-dominant atopic derm, they had a similar frequency of flares, similar rates in terms of clearance remission. They also had similar rates of itch triggers and a similar longitudinal course over time. What we're seeing is that this itch-dominant atopic derm behaves more aggressively in a sense than the mild to moderate itch, mild to moderate lesions. Many of these patients eventually needed to go on to a systemic or biologic therapy due to you know the poor control that was afforded to them by the current sort of topical therapies that are out there. I can show you the data, but you might say, "Well, but is it real?" Here I show you two example patients that have itch-dominant atopic dermatitis. On the left, we have a patient who, you know, originally the resident walked out of the room saying to me, "Oh, I think this patient just needs some moisturizers." I came out of the room saying, "I think this patient needs a systemic therapy because their itch was so severe." When you look at the lesions, they don't stand out as being so impressive. They're fairly mild-looking. They're quite extensive, but they're fairly mild. But this is a patient who's got a 9-10 out of 10 itch. On the right, we have a similar story. The lesions don't look very impressive. They're mild. They're scattered throughout, but it's a patient who's got a 9-10 out of 10 itch. These are patients that, you know, it's debatable. How should we even manage these? You know, what are you even treating topically with? You can barely even see much in the way of lesions. These are patients who clearly, though, need therapy for their itch. So why should we care? Well, you know, itch-dominant atopic derm is a previously unrecognized subset of the disease. It's a subset that would almost entirely be missed by physical examination alone. We have to ask patients about itch severity in order to make sure that we're not missing them. Then, you know, there may even be differences in terms of race and ethnicity, and certainly a lot of things we have to think about in the real world with respect to measurement. It hasn't been studied well in clinical trials. The regulatory definitions are just starting to catch up to recognize this, which is important. I think most important is that, you know, patients experience a high burden of the disease, and there's a lot of unmet needs, and we still have a lot of unanswered questions. Should we be using topicals? Debatable, because what are you treating? You don't have so many obvious lesions. Should we be using systemic anti-itch? Likely. Possibly systemic anti-inflammatory, but again, you're not seeing profound lesions, so does it make sense to be treating inflammation, or should we be treating itch? I think these are some unanswered questions that we're gonna learn the answers to over time. Very briefly, I'll just highlight here, you know, some of the data from the difelikefalin study just showing this itch-dominant subset or something equivalent, which is those who have less extensive body surface area but who have that moderate to severe itch. What we see is that for those patients, they're able to achieve significant reductions or significant higher response with respect to that moderate, clinically important difference in itch with a four-point reduction in itch at week 12. Not only did I show you that there's a clinical subset that's been recently identified in the real world research, but that now we have therapies that are able to address that. Where would difelikefalin fit in the management? Here I show you a schematic that's taken from the Atopic Dermatitis Yardstick, which uses the conventional step-up approach to therapy. There's you know, how do we treat flares, how do we treat the maintenance part of things, and we stratify by mild, moderate, severe disease. The truth is difelikefalin could be used anywhere in reality. You know, for some patients, they might be you know, certainly the milder lesions. You know, they're optimizing their basic management and topical therapies, but they still need something for their itch. That can be true even for the moderate patients who may be using higher potency topical therapies or even sometimes those who are on systemic therapies who still need some additional boost for their itch. Some patients may require, as I mentioned, you know, 365 days a year, they need to treat that baseline itch. For some patients, they may need it more for during their flares and a little bit more of that intermittent use. I think there's a lot of opportunities, a lot of unmet needs that could potentially be filled with an effective anti-itch therapy. With that, I thank you for your attention, and I turn it over to the Cara team. Thank you, Jonathan. We are now ready for Q&A. Alex, please provide the phone instructions for questions. As a reminder, to ask a question, please press star one on your telephone keypad. Again, that is star one on your telephone keypad. To withdraw your question, press the pound key. Also, for people on the phone line, to help reduce feedback, please don't forget to mute your web. Thank you. Please stand by while we compile the Q&A roster. Thank you, Alex. While we're queuing up phone participants, let's start with some questions that came in on the platform. It looks like the first one goes to Jo and Brian. You didn't study DFK in combination with TCS in the phase II study. How confident are you in the success with this combination in phase III? Thanks so much, Iris. Difelikefalin was used as monotherapy in the phase II KARE study. It was important for us to have a good understanding of the efficacy of the drug as monotherapy. We then took this data to help us design the phase III program, whereby difelikefalin will be used as adjunct to topical corticosteroids. This is likely the way that the drug will be used by dermatologists in clinical practice. The study really will mimic real-world use. We're confident about the design of the study and the potential outcome. Let me hand over to Brian, and he can maybe speak a little bit more to the mechanistic aspect of the combined use of the drugs. Yeah, absolutely. Thanks, Jo. Yeah, I think that the clinical data, the fact that there were pre-specified endpoints of stratifying milder disease and seeing these effects on itch, coupled with the fact that we see in mechanistic preclinical studies that there is a very, very potent and dramatic anti-itch effect that strongly suggests a significant neuromodulatory effect of the drug indicates that there's a different mechanism of action or an additional mechanism of action well beyond the anti-inflammatory properties of and therefore increases our confidence that in on top of any anti-inflammatory agent, including topical corticosteroids, that we would anticipate seeing an effect on itch. Great. Thank you, both. Let's take one more question from the online platform before we go to the phone lines. Will the long-term data from the long-term extension KICK studies be required for registration? Jo, this is another one for you. Yes. As you know, when we're developing a drug for chronic use, we do have to study safety as long-term use with the drug. We will be collecting long-term safety data. That's the objective of the extension study. As per ICH and FDA guidance, you require a certain number of patients with long-term safety data to help to understand the characteristics and the profile of the drug. That will be part of the registration package. Just to highlight, as I presented earlier, that the primary endpoint will be after 12-week period. The efficacy of the drug will be assessed. A lot of interference. I don't know, Jim, can you mute people? I don't know if you heard that. The 12-week treatment period is what will be used to understand the efficacy of the drug and the safety will be assessed and long-term safety will be assessed with long-term use, as we have done even in the CALM program. Thanks, Jo. Let's take some questions from the phone line. Your first question is from Daniel Wolle from JP Morgan. Please go ahead. Hello, everyone. Thank you for taking our question. Two questions, maybe one for the company first. In the CKD trial, what are some of the considerations besides CKD stage, or excluding stage 3 patients you have taken in powering the study to reduce the risk of significant placebo effect you saw? Related to that, in your view, is there any scientific rationale to believe that concomitant treatment to address the underlying CKD could contribute to treatment and therefore potentially be reflected as a high placebo response? I have a follow-up for the doctors on the call. Okay. Thanks, Daniel. The first part was the placebo response. Indeed, excluding the stage 3 CKD patients is the biggest factor that will help to contribute to reduce the placebo response, knowing that they were largely the group that added to the higher placebo response in the phase II study. In addition to that, we want to ensure that the patients enrolling will have a more stable itch. When patients come into the study, they will be required to have a chronic itch of at least six months. They will also need to come into a run-in period, whereby we try to ensure that their itch is stable and that they have a moderate to severe pruritus. In addition, recall that our phase II study had a 3-to-1 randomization. This is a 1-to-1, so that will also help to mitigate the placebo response. We have operational factors that we will be implementing to help mitigate that placebo as well. We feel quite confident with all these measures that we should see a lower placebo response. Importantly, just want to bring back to the patient population that this advanced CKD patient population with stage 4 and 5, we know that their itch is much more aligned to the itch of patients undergoing hemodialysis. They should behave more like the patients that we saw on the CALM program. That was your first question. The second question was regarding background medication and whether they're contributing to the placebo response. For sure, we know that patients who are on background meds they come into the study and we know from our CALM program that about 40% of patients had used these meds. Do keep in mind that they're coming in with a score of moderate to severe pruritus. We know that these meds are not really working that well. What is important is that these meds remain that the patients use these in a stable manner. They need to have used them prior to enrolling into the study for a certain period of time, and they're not allowed to adjust it. To try and prevent any influence or impact on that response rate, the placebo response. Great. Okay. For Dr. Kim and Dr. Silverberg, on the primary endpoint of the proportion of subjects with greater than or equal to four-point improvement, worst itch NRS in the KIND 1 part B and KIND 2, what are your expectations, I guess, for a new therapy like oral to be considered clinically meaningful? Will there be a difference based on the severity of the itch? Brian, you wanna take that first or You wanna start? Oh, I was waiting for you, but yeah, no. You know, well, a couple thoughts there. The four-point reduction on the itch, you know, being considered clinically meaningful. I think that's currently kind of the industry standard, but I don't necessarily know that will hold up as the clinically meaningful bar for in perpetuity as we start to think of itch more dynamically and also as we start to think of different populations of patients with itch, whether in atopic dermatitis or other. For example, if we're looking at populations that generally have a milder itch, it's really hard to consider four-point as being dogmatically the most clinically meaningful improvement. That, I think that's the kind of main point that I generally make lately with regard to how we think about itch. How it's gonna play out in terms of the trials, I think, it's an endpoint that you wanna see right now, given what I've said. I think that even if I'm remembering your question correctly, I think that there's still an opportunity for that kind of improvement and effect in adjunctive settings if the itch is actually still remaining significant in the patient. Yeah, those are all excellent points. I think just for context, the four-point reduction in itch is actually not a minimal clinically important difference. That's the way the FDA refers to it because just some technical numbers reasons. It's really a moderate clinically important difference. You can't achieve, and this is what Brian was alluding to, you can't achieve a four-point response if you start with an itch score of two. You know, it's something that is really relevant for those who have more, you know, on the moderate to severe itch at baseline. You know, it's an important regulatory endpoint right now. But certainly, I agree with Brian. There's a lot that's evolving in our understanding of itch and the endpoints of itch. Thanks, both. Thank you very much. Let's go to another phone question. Next question is from the line of Annabel Samimy from Stifel. Your line is now open. Hi. Thanks for taking my question. I guess this is a question directed at Jo. I just want to understand the dosing that you've chosen for the AD trial. I think in the KARE studies, when you did an analysis of the mild-to-moderate patient efficacy, I think it was only the 1 mg dose that showed, you know, a statistically significant change. As far as the four-point improvement, it was all doses. I'm a little bit curious to know why it seems like you're still doing some dose finding at the lower doses 0.25 mg and 0.5 mg in part A of the KIND studies. Maybe you can explain the rationale for having the part A and the part B. I guess that's part of the dose finding as well. Just if you could help us understand that a little bit better, that would be great. Sure, Annabel. Our KARE phase II study, the doses that showed the most favorable benefit-risk profile, and when we looked at the benefit, specifically the four-point responder, was the 0.5 mg, but also the 0.25 mg twice daily. Those are the doses that we are taking forward into part A. Now we know that those are the most favorable doses, when used in monotherapy. Now, adding to topical corticosteroids, we want to assess which of those two doses would have the most favorable benefit-risk profile to take into part B and to take into KIND 2. The reason why we doing part A and part B is indeed to generate data to be able to inform us on part B and KIND 2 on the dose as well as the sample size. We designed the studies this way as a part A and part B. They do fall under one phase III protocol. That's important to note. We designed it this way really to maximize the success of the study. That is to reduce clinical risk and to enhance operational efficiency to be able to get the outcome of that, the data that we're looking for. Okay. I guess the second part of my question is, I think your inclusion criteria is now a BSA of less than 20%. But I think in the pre-specified analysis on the mild-to-moderate patient was a BSA of less than 10%. Does that start to capture some of the patients who are trending to the moderate severe or have more inflammatory component than they did before? I just wanna, I guess, maybe explain how that might have an impact on the placebo response or, you know, patients who are focused more on the inflammatory aspect as opposed to the itch aspect. Great question, Annabel. Indeed, we are conducting the studies across the severity of atopic dermatitis. We still aim to enroll the majority of patients, that is at least 85% of patients, who have a body surface area of less than 10%. As you rightly pointed out, this is where we saw the most pronounced effect of difelikefalin in the KARE study and where we believe the drug will be used most appropriately in the most appropriate patient population. The majority of the patients will still have a BSA of less than 10%. Now as the phase III program, difelikefalin will be added onto topical corticosteroids as adjunct therapy. We believe that difelikefalin will be able to address the itch across the spectrum of disease from mild to severe. We think that it will be able to complement very nicely the effect of the topical corticosteroid, as Brian explained, the different mechanism of action. We feel confident about allowing these patients to be included as well. Okay, great. If I can have a couple of follow-ups for the physicians on the call. As far as, I mean, one of the things that's a little bit more comforting for atopic dermatitis is that it seems like itch is a consistent or persistent characteristic of disease for AD. The placebo responses have been relatively low across the studies we've seen in the immune modulators or anti-inflammatory drugs. But as you look in a mild-to-moderate population, and as you've characterized that some of these patients can be flaring as opposed to persistent, how do you think about what kind of placebo response this particular population might have? Yeah, maybe I'll take a stab at. I think he's best to answer this question, but yeah. Yeah. Okay. You know, we've actually been studying kind of flares and itch flares recently, particularly in the moderate to severe population. It's really just a kind of a feature of the disease. It's something that's kinda baked into these trials. I don't necessarily know as long as I think you're properly powered. I don't think that's necessarily gonna be more of a problem necessarily in this setting. I think your point about the itch in atopic dermatitis being a little bit more homogeneous is well taken. I think I worry a lot more about placebo effect in if the kind of population that you're looking at ends up having a very heterogeneous origin of itch. As also Jo alluded to before as well, is if the entry criteria for the trial is too liberal about how long you had to have had the itch. Generally, you're looking at durability. You wanna know that the kind of itch is actually falling within a certain kind of category. I think that does clean it up a bit, that you know that these patients started with atopic dermatitis. It may have gotten better, but they still have residual itch. I agree that that's probably a cleaner itch population. Yeah. I would agree with all those points. I think in addition, keeping in mind that when you limit to a patient population with a little bit, you know, more moderate to severe itch at baseline, you're going to be less vulnerable to the placebo responses. One, because the more severe the itch, generally speaking, the more persistent the itch and the more stable it is. Two is, you know, a separate point, but the vulnerability to placebo response is usually greatest when you're looking at, just, you know, least squares mean change. Because you may have a patient who has, you know, as a placebo response, a one to two-point reduction. Generally speaking, as you go to the more rigorous binary endpoints, like a four-point reduction in itch, you're going to see less of that placebo response come up, as a general rule. Great. Thank you. Thank you both. Let's take another question from the phone. Next question is from the line of David Amsellem from Piper Sandler. Please go ahead. Thanks. I had a couple questions on the CKD setting, and I apologize if I missed this earlier, either in the discussion or the prepared remarks. Could you just talk about the mix between stage 4 and stage 5 CKD patients in the studies? Just thinking about the treatment landscape, you know, this might seem like a simplistic question, but when you have these stage 5 patients, you know, these I guess non-dialysis patients, you know, can you talk about just in practice, you know, how the severity of their itch in general compares to what you typically see with the stage 4 patients? I guess where I'm trying to get at is, you know, ultimately, how wide of an audience in stage 4 do you think the product could be appropriate for? Obviously assuming it's, the oral is commercialized. I'll start with that, and then I have a couple of follow-ups. Mm-hmm. Okay. Thanks, David. Jo, you wanna start off? Yes. Thanks, Iris. Let me start with your first point, David. The four and the five, the stage 4 and stage 5 patients. We will be including both stage 4 and 5 patients. We will not be stratifying these patients to stage 4 or five. Based on the epi data, we expect they're likely to be more stage 4 patients than stage 5. You were questioning about the itch in the stage 5 patients. The NKF did conduct a survey last year, and they demonstrated that patients with stage 4 and five itch, the characteristics were very similar. In fact, similar also to the hemodialysis patient population. We believe that the stage 4s will... The itch should behave like the stage 5s, who should also, in turn, behave like the itch in the hemodialysis patient populations. Okay. I guess with that in mind, was that sort of the main reason why you decided not to stratify between four and five because essentially your understanding is that the itch behaves similarly in those patients? Exactly. In other words, we don't have reason to expect, you know, a different kind of response? Exactly. We expect to see the patients behaving the same. Okay. Just, again, I apologize if I missed this, but in terms of background therapies in that study, you know, what are you allowing? In practice, I know I've asked this, Jo, about the IV form, but I guess in practice, you know, I think it applies also to the oral form. I mean, do you expect to see, you know, patients cycling through agents like gabapentin or tricyclics before they get access to oral DFK? I'll address that. They will be allowed to come in as long as they've used a stable course of an antipruritic drug, whether it be antihistamine or gabapentinoid drug. They do need to have used it previously. They need to come in and use it in a stable manner without changing the dose. Importantly, patients need to have moderate to severe itch coming in. If they have that as background and they still have moderate to severe itch, that tells us that the agent is likely not very effective for the itch, and they could be using it, especially the antihistamines, more for assisting with sleep in these patients. As far as, you know, what the label would look like, we did very similar design with our CALM program, and the label has not requested us to step through any antipruritic agents prior. We would expect something similar with the oral label. Okay. Thanks, Jo. Thanks, David. Let's go to the phone lines again. Next is from the line of Oren Livnat from H.C. Wainwright. Please go ahead. Hi, folks. Thanks for the comprehensive presentation today. I just wanted to follow up on a couple of things regarding the AD trial. I'm not sure if you mentioned it. Maybe I missed it. I'm sorry. With regards to the decision to do adjunctive therapy, can you just tell us for certain, was that an FDA requirement that you proceed in that fashion, or was that your decision, aiming for, I guess, the most commercially relevant or real-world, as we'd call it, you know, data set and label? And then I have a follow-up. Okay. Thanks, Oren. As I mentioned, it will be used as adjunctive therapy. This is likely the way that the drug will mostly be used by dermatologists in clinical practice. It was important to mimic the study design to real world. In collaboration with the FDA, we had this discussion, and this was the most appropriate study design for difelikefalin. Okay. It was a collaboration. The dose selection. Pardon me. I think Annabel sort of hit the question about dose selection. Mm-hmm. With regards to the risk-benefit you mentioned a couple times or benefit-risk, can you just remind us in the prior phase II for AD, where the 1 mg dose seemed to have a less robust response, was that due to AEs or dropouts and lower completer rates related to the risk side of that equation? Or is it just that you saw less efficacy there, so you just deduced that all else equal on the safety front, you know, proceed with a lower dose? Good question, Oren. Yes, indeed. When looking at the benefit-risk, you may recall that the 1 mg, the patients they had the most abdominal pain. When we looked at the discontinuations, accordingly had the most discontinuations due to abdominal pain. Very important, we want to obviously try to ensure that patients are able to tolerate the drug and not discontinue, that ultimately could have an impact on the efficacy as well. Indeed, you are correct. It was that safety aspect that really helped us to assess the most favorable profile for the which the other two drugs, other two doses have demonstrated. Okay. Just to piggyback on that, I think I saw it in your sub-10% BSA slide in this deck that showed pretty similar magnitude of efficacy in both the 0.25 mg and the 0.5 mg, albeit only statistically significant with a larger N in the 0.5 mg. Is it that result with, you know, acceptable safety in both of those arms that's leading you to examine both doses again in Part A of KIND? Or am I misunderstanding, and it has to do with the context, you know, with the adjunctive nature of the trial? Exactly. No, you've got it, Oren. It was looking at the four-point responder. Of course, that's ultimately going to be the primary endpoint and so important there. Again, the safety profile. When you looked at the safety profile, the 0.25 mg and the 0.5 mg, you saw how clean that was in those two doses, almost comparable to placebo. Especially, I'm sure you know, Jonathan and Brian can both attest to, as dermatologists, they want a drug that is well-tolerated with very little safety impact for their patients, especially the AD patients. Great. Very good. Thanks for the clarification. I'm gonna cut you off, Oren. Thank you. Let's take two more questions from the phone lines, if we have them. Please try to limit yourself to one question because we are nearing the end of the session. Next question is from Sumant Kulkarni from Canaccord. Your line is now open. Good afternoon. Thanks for taking my questions. This is gonna be a two-part one question. Sorry about that. For Dr. Kim, from a mechanistic perspective, at what point do we need to start worrying about potential buildup of tolerance to kappa opioid receptor agonists either in the CKD or AD settings? And on atopic dermatitis, for anyone who would like to take it, given these studies will only involve oral KORSUVA as an adjunctive topical corticosteroids, in the real world, how do you expect to tease out the effect of any steroid sparing that might happen with oral KORSUVA use? Yeah, the first question is about is there tolerance to kappa opioids. I'm not aware of tolerance to kappa opioids in the way that we are well aware of tolerance to mu opioids. I'm not so sure that that is necessarily a thing. Based on some of the mechanisms that I highlighted, particularly in the periphery, it seems unlikely that those kinds of nerve fibers would actually result in tolerance. But you know, that's you know, to be proven, I think, if that's the case. I think the second question is related to. You said with the topical corticosteroids and the additional effect of the kappa opioids, the question that you're asking was what. I'm sorry, I'm trying to remember what exactly the concern was there. Yes. It's more of a question. It's not really a concern, but at what point could use of oral KORSUVA result in steroid sparing? That's not using as much topical corticosteroids as one otherwise might. Got it. Yeah. Well, you know that the reality is that steroids are so widely used in dermatology that I think there are a lot of scenarios in which patients will itch and they'll use topical steroids, even if there's not much in the way of inflammation. Certainly a lot of neuropathic itch conditions, people will throw topical steroids at it. I think that's actually not very productive. In that sense, I think it could be very steroid sparing in that people aren't just throwing steroids on areas where there aren't really clear lesions, where really what they need to do is just treat the itch. Got it. Thank you. Great. Do we have any more questions on the phone? Yes, we have last two questions, and next one is from the line of Joseph Stringer from Needham & Company. Please go ahead. Hi. Thanks for taking our question. Just a quick one from us for Doctors Kim and Silverberg. Just curious in your experience, you think about use of topical steroids as it relates to the KIND AD program here. Do you find that there's a difference in use of topical steroids and just in terms of, you know, patient adherence or compliance to those based on BSA, a difference in BSA, for example. You know, do you find patients are more likely to use a steroid on a daily basis, for example, if they have less than 10% versus over 10%? I mean, I think in general, in the real world, the answer would be yes to that question. I think in the clinical trial setting, where you have, you know, pretty well-defined protocols for how to deal with this, I mean, most patients, you know, they're. This is what they signed up for. If the recommendation is to use them in a certain way, then generally speaking, I think they're reasonably good. There are ways of measuring, you know, frequency or quantities of topical steroid application, which you can sort of look at post-hoc to adjust for some of that. I think you know, it certainly can be an issue. I think it's just in the real world, I mean, it's a little bit indirect to your question, but patients who have much more extensive itch, you know, and that's in much larger parts of the body, are ones who are gonna need a systemic option for itch more than those who might just have a localized itch on a, you know, a teeny little area. Yeah. I think that topical steroids are incredibly problematic in the real world. They carry a tremendous amount of baggage, which is often patients don't know how to use them. They're often given wrong tube sizes for the amount of BSA they have. It's not even a compliance issue, it's just a practical. They don't have the right tube size. Oftentimes, you know, they get very mixed messages about how to use them because they say, "Use it very aggressively, but not for too long," and such. There's a lot of issues with topical steroids, I think, in the real world. It's not just a compliance issue. There's just a lot of confusion in terms of how to use them issue. There's a... Yeah, they just have a lot of baggage. Great. Thank you. Let's go to our final question on the phone. Last question is from the line of Chi Fong from Bank of America. Please go ahead. Hey, this is Chi on for Jason Gerberry from Bank of America. Thanks for taking our questions. One question, but maybe a little color from the physician and also a little color from Cara's team. I guess the first part is just curious from the physician perspective, how defined is the CKD stage 5 population. Trying to get at is, you know, what proportion of patients would advance from a non-dialysis to dialysis stage in stage 5 and how, you know, how frequently that can happen, how quickly can that happen. I guess the second part of the top question is for the Cara team. How do you sort of control that dynamic in your phase III. Say, if you have CKD stage 5 patients who sort of progress in their dialysis stage, do they keep on be continued and receive oral KORSUVA in trial, or would they be rolled over to IV KORSUVA given as an approved product for the dialysis population? Thanks. Should I take that first? 'Cause I think I can probably answer. Yeah, please go on. Both of the questions under one. Thanks for the question. Patients with stage 5 CKD, depending on when they come into the study and what their GFR is, the GFR tends to reduce over time, and it can take one or up to two years, depending on how aggressive their kidneys are dysfunctioning. Patients would typically move into that end-stage renal disease within a one to two-year period. It would differ from nephrologists to dialysis centers on when to start them on hemodialysis. In the clinical study, once the patient moves into that end-stage renal disease stage, they will no longer be able to continue in the study and will have to stop being part of the study. Thanks, Jo. Unfortunately, we're gonna have to call it off here. Thanks to you for the questions. With that, I'll turn it over to Chris for his closing remarks. Well, thanks, Iris, and thank you all for joining us today. Let me just conclude briefly by reiterating we are making really significant progress in executing our second strategic priority of advancing our late-stage programs for the oral KORSUVA platform. I wanna emphasize just a few key takeaways. First, we have a robust category-defining phase III trial designs in our KIND atopic dermatitis program and the KICK advanced chronic kidney disease program. The designs capture the right populations, and they seek to differentiate oral KORSUVA from current standard of care, which is often ineffective in controlling pruritus. You know, we plan to initiate these phase III programs this month. Second, there is a strong scientific rationale for oral KORSUVA in these disease states. In atopic dermatitis, pruritus has a neurogenic trigger, and oral difelikefalin has a neuromodulatory mechanism of action, which allows it to potentially address itch in a way that anti-inflammatory mechanisms just cannot. In pruritus associated with advanced kidney disease, we have a very strong scientific foundation stemming from our work with KORSUVA injection in hemodialysis patients and the phase II data with the oral formulation. Third, we have a clear clinical rationale and market opportunity. Current treatment algorithms do not have approved products to specifically control chronic pruritus, and currently used treatments are routinely inadequate, leaving potentially millions of patients still in search of options. We believe we have the potential to bring life-changing options to these patients. I wanna thank you for your participation. We look forward to updating you when appropriate on our progress in these programs and the rest of our oral KORSUVA pipeline in the future. With that, I wanna thank you.