Therapeutics Meet the KOL Experts Webinar. 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 in 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 in this webinar as a result of new information or future results or developments. Participating from Cara Therapeutics today are 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 three highly accomplished key opinion leaders. Dr. Brian Kim, he is the Vice Chair of Research in the Department of Dermatology at the Icahn School of Medicine at Mount Sinai and the Director of the Mark Lebwohl Center for Neuroinflammation and Sensation. Dr. Kim was previously Co-Director of the Center for the Study of Itch and Sensory Disorders, Associate Professor of Medicine, Associate Professor of Anesthesiology, and Associate Professor of Pathology and Immunology at the Washington University School of Medicine in the Division of Dermatology in St. Louis, Missouri. A recipient of numerous honors and awards, Dr. Kim most recently received the AAD Marion B. Sulzberger Lectureship Award in 2024. Dr. Kim is one of the top researchers worldwide in the study of patients with itch and other skin conditions and has published in many internationally recognized journals. Dr. Gil Yosipovitch, he is a tenured Professor of Dermatology at the Miller School of Medicine at the University of Miami and Director of the Miami Itch Center. Prior to joining the faculty of the University of Miami, Dr. Yosipovitch chaired the Department of Dermatology at Temple University and directed the first translational clinical and research center dedicated to the study of chronic itch in the United States. He is the founder and past President of the International Forum for the Study of Itch and served on the editorial boards of six key specialty journals. He is a recipient of many prestigious awards, including the AAD Marion B. Sulzberger Memorial Award and Lectureship in 2016. Dr. Yosipovitch has published more than 480 articles in books and peer-reviewed journals and has edited five books. He has given more than 500 invited lectures to dermatology groups and organizations around the world and has mentored more than 30 fellows, PhD students, and postdoctoral fellows. Dr. Melinda Gooderham, she is the Medical Director at the SKiN Centre for Dermatology in Ontario, Canada, and the Principal Investigator for the SKiN Research Centre. Dr. Gooderham is an Assistant Professor at Queen's University and also works as a Consultant Physician at the Peterborough Regional Health Centre. She is a Fellow of the Royal College of Physicians and Surgeons of Canada and Vice President of the Dermatology Association of Ontario. Actively involved in teaching, Dr. Gooderham provides medical students, medical residents, nurse practitioners, and physicians with both didactic lectures and hands-on clinical training. As an investigator, she has been involved in over 180 clinical trials to date. A warm welcome to all our esteemed speakers. In a moment, Chris will kick off today's event with a brief overview of Cara’s strategy and focus on notalgia paresthetica, a common yet underserved neuropathy. We will then hear from our experts. Joana will guide us through discussions with Drs. Kim, Yosipovitch, and Gooderham around the epidemiology, diagnosis, and treatment landscape and unmet medical need in the field of neuropathic itch, and more specifically, notalgia paresthetica. Joana will follow with a recap of the impressive results of oral difelikefalin in its proof-of-concept study in NP. As you may recall, this data was published in the New England Journal of Medicine in February 2023. Joana will also review the design of the ongoing Phase II/III study, which is expected to have top-line results of the dose-finding Phase II portion in the third quarter of this year. Chris will close the formal portion of the event, and we will then open up for Q&A. If you would like to submit a question, you may do so at any time during the webinar by typing a question into the Ask the Question field. Today's event is expected to run until approximately 11:00 A.M. Eastern Time. A replay of the webinar will be available on the Investor section of Cara Therapeutics website later today. With that, I will now turn it over to Chris for his introductory remarks. Chris? Thanks, Iris. Good morning, everyone. Thank you for joining our Meet the NP Experts virtual event. Cara is on a path to pioneering innovation in medical dermatology with our high-value late-stage program in notalgia paresthetica. NP ticks all the boxes for a breakout program for a growth-oriented biotech company, a differentiated asset which we believe has a high probability of success targeting a therapeutic area with no FDA-approved therapies. Notalgia paresthetica is an unexplored neuropathy characterized by chronic pruritus, and yet NP is relatively common. We estimate an addressable market of over 650,000 adult patients who are currently in the care of a provider. This does not account for any un- or misdiagnosed patients. Literature suggests that chronic pruritus is often as onerous as chronic pain in terms of the impact on the quality of life of patients. Anecdotal evidence draws the same comparison between neuropathic pruritus and neuropathic pain. And while chronic neuropathic pain has been targeted and studied extensively, chronic neuropathic pruritus has not. Our strategic decision to focus on Notalgia paresthetica is driven by this clear unmet medical need and our belief in oral difelikefalin's high probability of success in this underserved disease. DFK's neuromodulatory mechanism of action is ideally suited for neuropathic pruritus and has already translated into positive clinical proof of concept data in Notalgia paresthetica. This data, which was published in the New England Journal of Medicine, has generated widespread buzz in the dermatology community, attracting significant interest across treating physicians, patients, and other stakeholders. As a result, we saw rapid enrollment in our ongoing Phase II/III study, which tracks to the release of top-line results in the third quarter of this year. I am excited to now turn the discussion over to Joe and our esteemed panel of experts for a deep dive into Notalgia paresthetica. Joe, take it away. Thank you, Chris. A hearty welcome to our panel of experts. To start, I thought maybe we could just have the panel briefly just describe the areas of focus. Maybe we could start with Dr. Yosipovitch, if you could just briefly elaborate on what areas of your focus for you. In terms of everything about itch is in my domains of interest, and it's even my name. It's the suffix of my name. I can't avoid discussing anything. I have to mention the neuropathic itch for many years. I mean, there's an unmet need because around 10% of all chronic itchy patients that come to our clinics suffer from neuropathic itch. Notalgia is one of them. You'll be surprised, I'm actually one of those who suffers a bit from Notalgia. I don't need difelikefalin because it's very limited. But it is related to a lot of pressure on spinal nerves that none of the other drugs, including the sophisticated biologics that work extremely well for a lot of aspects of itch, would help. A drug that targets the neural system would be extremely helpful. And I don't know if the panel knows, more than 20 years ago, I worked on kappa opioids. And I'm a big believer in kind of promoting this area because they are very effective in different treatments. I worked on butorphanol, which is a kappa opioid and mu antagonist. But this field is, and I'll shorten because I can talk a lot, and Brian and Melinda. I would say one important aspect is that when you'll have a drug in the market, hopefully, you'll be surprised to all of you guys analysts that are interested only in atopic eczema. The unmet need here is so big because there's so many types of neuropathic itch that you're maybe not familiar. So Notalgia, this is an open area, but BRP, scalp itch, genital itch, the area that's taboo to discuss mainly is actually neuropathic. I'll end with that, but hopefully, it's an eye-opener this type of approach. Wonderful. Thank you. Dr. Kim, can you describe your area of interest? Yeah. Of course, a dermatologist does also run an NIH-funded laboratory studying basic mechanisms of itch in terms of how the immune and nervous systems interact. And I think, as Dr. Yosipovitch mentioned, that with regard to notalgia paresthetica, we're very interested in how, when the nerve itself is damaged, can trigger itch. And we think that this is and at the end of the day, all itch has to go through the nerves. And in reality, you could probably treat every itch one day by simply targeting the nervous system. But we're not quite there yet. But this is a major step forward in terms of the strategy. And also, the other idea here is that when you're actually going after the nerve, the treatments are actually incredibly limited because none of the agents really that modify nerves in general were ever designed to go after itch. That was not from conception. So any agent that we use, even off-label, is very much repurposed or redeployed for itch. And I think that's where this asset is particularly unique when it comes to neuropathic itch in the context of notalgia paresthetica. And then the last thing I'll say is that we've lived this Dr. Yosipovitch and I have lived this where other conditions, chronic itch conditions that have neuropathic elements like prurigo nodularis, before there was any FDA-approved treatment, the incidence of those conditions were estimated woefully underestimated by at least fivefold, probably more tenfold. We're already learning that now. That with the advent of a new therapy, we see the incidence of the disease go up logarithmically. But that's not because the incidence is actually growing. It's that there's a major woodwork effect that when you have a first tool, a first FDA-approved agent, the disease just comes out of the woodwork. And I think that's something that's just been a recurring theme in chronic itch. And we'll see that continuing to go forward. So whatever estimate, in my opinion, that we have of how prevalent Notalgia paresthetica is, it's probably yet even way off. Thank you. Lastly, Dr. Gooderham, if you could just speak to that a little bit as well. Yeah. So I'm also a general dermatologist. I run general derm clinics all week long. At the same time, I'm doing my clinical research in parallel, which is basically new drug development, looking for new drugs with unmet needs. So I see this from twofold. I was an investigator in both the phase II and phase III program. It was very welcome to have an option for patients. As a general derm, I see everything. All day long, I see itchy conditions, including notalgia paresthetica, brachioradial pruritus. It's something we're seeing every day in clinic in some form multiple times. It's been really great. I feel very fortunate to have been part of the trials to help find something for these patients who, for so many years, has been such a frustrating thing to treat as a physician and frustrating for the patient when you keep giving them treatments that are not helping. On that, Dr. Gooderham, how common do you see NP patients? I mean, in a week, what would you estimate will be the number of patients you see? Yeah. It's funny because some patients are actually referred for itch. But other patients, they'll be referred for a mole check. And when you're examining them, you'll say, "Hey, you've got this patch on your back that looks like you've been scratching. Oh, yeah, I've had this itch for years." So it's something that we're finding in patients who aren't even visiting us for that reason, something that they were probably told years ago there was nothing to do about. So they've been sort of living with it. But it's hard to really put a number on it. I would say probably two or three patients a week that I would see specifically with notalgia paresthetica and probably more that aren't even bringing it up unless we start to ask. And I find that, too, when we have new options, we start to ask patients a bit more about it. Like Brian said, uncover all of these patients who are out there who are just underdiagnosed or undertreated. Yeah. Dr. Yosipovitch, can you talk about your clinical experience with patients you see with NP? How often do you see them? Yeah. Yeah. Yeah. I have a clinic dedicated to itch. So I see a lot of these patients. On a weekly basis, I see more than Melinda just because but it's a bit biased because these patients come as but I can tell you there are more of these patients out there. And part of it is that we, dermatologists, were not aware. Several years ago, I would see these miserable patients coming with topical steroids, a bag of different topicals, you name it. And it didn't really help them. And dermatologists weren't aware that this is basically not a rash. It's secondary. The scratch marks there are related to just the patient scratching. And by the way, it's one of the most pleasurable things to scratch an itch. So we mapped body areas and diseases. NP patients love to go to a doorknob and scratch themselves because that's the only thing that really relieves them for just minutes. These are common daily aspects. I agree with Brian. When there will be a drug in the market, you'll see that amount of patients will grow very significantly. There is a big unmet need. Dr. Kim, so you mentioned the underreporting. And Dr. Yosipovitch, you just alluded to it as well, that without a drug on the market, it's maybe underreported. But can you speak a little bit more to that, Dr. Kim, and why it is so underreported and underdiagnosed? Yeah. I think, for one, there are a number of layers to it. Most dermatologists are not really viewing itch as a standalone entity. So the idea that, say, someone comes in and their primary issue is notalgia paresthetica is fairly unlikely. It's probably more likely that the patient brings it up incidentally in the course of a visit. As Dr. Gooderham brought up, they might be coming in for something else. Itch is just generally not considered a primary domain actually of any medical specialty, to be completely honest. I think that's the first issue. But then you get into more granular issues, too. The way in which we, as dermatologists, will bill and code for conditions like this are not good. So the data that's actually in our electronic medical records, which we rely on tremendously to look at the instances, is probably not good at all. And then the third domain is if you don't have great treatments, what we essentially do is we bury everything under the rug. That's exactly what we do. And you can actually see how, actually, the great thing about having the internet is you can see exactly there's a direct correlation between, as drugs come to market that work, the incidence goes up, and all the kind of random stuff goes away. So the weird kind of snake oil stuff kind of disappears. We saw that with psoriasis. And I think that's essentially what we'll see as therapies like this come to the forefront that actually work. And there's a number of reasons that drive it. But this is always going to be the case until you have a therapeutic agent. Great. And then, Dr. Gooderham, I just wanted to delve in a little bit more. You mentioned that patients you make the diagnosis incidentally when the patient's there for something else. Do you also see patients referred to you for it? Or is it mostly, as you mentioned, an incidental or due to itch? Yeah. I'd say more cases are found incidentally, for sure. But I have received referrals for an itch to be investigated. And sometimes it's more than just the one patch on the back. Often, sometimes patients will feel the itch. So they'll look in the mirror, and then they'll see something, maybe a seborrheic keratosis somewhere in the vicinity. And they think that that's what's causing the itch. And then they want that spot removed. So you have to really go back and explain that it's not actually the seborrheic keratosis that's itchy. And removing it isn't actually going to deal with the problem. So it really comes from all angles. But I'd say most of patients are not referred for it specifically. Then, Dr. Yosipovitch, how do you make the diagnosis of NP? Can you help explain to the audience how do you? Yeah. So to me, it's quite straightforward. The majority of these patients have localized itch. It's in the subscapular area of the area. Usually, it's not bilateral. It's unilateral. And because of a severe urge to scratch, they pick on their skin. And a lot of times, they have skin signs of what we call hyperpigmentation. And there's no primary rash. So it's quite easy to diagnose. And I think that for dermatologists in the last couple of years, there's a high index of suspicion. So they're more familiar. And that's also, I think, the increase in the incidence is part of knowledge what it is. I want to emphasize something, Joe, if I may, is that for your audience, is that the FDA now understands that itch is not just a symptom. And part of it is work that we coined once that chronic itch is a disease state on its own right. And I think that Notalgia is part of that, that patients need treatments. And you can't solve the spinal stenosis that they have. They don't need that because it's dangerous. And this, I have to mention Brian and myself, I think we did a lot of groundwork there with FDA that they understand that there is a disease entity that is chronic itch. And Notalgia paresthetica is a great example of that. So it's important that they will know because I think it will open our market. Like 40 years ago, pain was part of, okay, it was back pain, migraine headaches, or something. Now people understand you have to treat chronic pain regardless of what the cause is. So we're getting there. Brian, you agree with me? We're on our way for changing that kind of aspect. Yeah. Absolutely. The paradigm has been shifting for the last 10 years. Great. Just to clarify and just so the audience knows, it's a clinical diagnosis. You don't have to do any lab tests or any additional diagnostic assessments. It's really based on your clinical judgment and, as you said, what you see from the history. You mentioned the hyperpigmentation. Can you also just clarify that that's a secondary manifestation from the itching and itching? Yeah. By the way, I mean, Joe, I do recommend in these cases to have some in the majority of these patients, there is spinal stenosis. There is an impingement of the nerve. So I do recommend doing an MRI in the thoracic level of T2 to T6. It's not necessary, in my opinion. But it establishes a and I think it gives a better understanding when we treat. So afterwards, the patient and the caretaker understands that this is not some eczema because they see that there is a specific abnormality. And again, I want to emphasize that there's no data in the literature that correcting that spinal stenosis surgically would be meaningful. And that's extremely important because, unfortunately, we see sometimes I see even chiropractors promoting that they know how to do maneuvers to improve this disease. And this is actually really bad medicine. That's why you need a pill or a topical treatment for this condition. Yeah. So Brian, can you then maybe just elaborate a little bit on what actually causes Notalgia paresthetica? What's the mechanism that's driving this itch on the back? Yeah. I mean, we don't definitively know. But the idea is that we all, as individuals, especially upright individuals as a species, are undergoing a lot of wear and tear through gravity and also inactivity, bad core, where we actually have susceptibility. These sensory nerves come from our spinal cord and from our spinal column. I think many people appreciate that, but that they go through these little holes. Due to either misalignment or even spurs or wear and tear, what happens is that these nerves get impinged upon at various levels. The idea is that these nerves are actually very electrical. When electricity is interrupted or tampered with, what happens is they fire erroneously, incorrectly. That's why we get a lot of these itch signals. We think they're essentially being triggered from this kind of nerve impingement. There's other. I don't think it's accidental from the standpoint that, A, we're living longer. We're probably living beyond what our bodies can support to some degree. That's part of it. We are also very sedentary. I know, for instance, I'm sitting here at the computer in not a great posture. That's not actually probably good for my spine. We don't do activities that are probably very conducive to actually also having a better core and spine as well. Even if you compare us to our kind of primate counterparts who are hanging and things like that, there's a lot of healthy activities that probably decompress the spine as well. So we're just, in modern day, set up for this to develop this over time. Okay. Thank you. So Dr. Gooderham, you mentioned you're an active trialist. You have a busy clinical practice. In our trials, we typically use the Worst Itch NRS to assess the severity of itch. But clinically, how do you assess severity of itch? Are you using this score? Or how do you determine how itchy the NP patient is? That's a great question because I do think things have changed recently in how we used to just ask if there was itch, yes or no. With newer therapies in atopic dermatitis and prurigo nodularis and that, we're becoming more accustomed to actually asking patients to rate their itch. From a scale from 0-10 so that's usually what I'm doing now for my patients with itchy conditions. I don't know. That's probably a bit of my trialist coming out. I think in a general dermatology clinic, one, they're probably really not asking a lot about itch. As Dr. Kim mentioned earlier, if you just sort of brush it under the rug, then you don't have to deal with it, right, because a lot of dermatologists are busy. When you start talking about itch, it can take up a lot of time. I do think that's one thing we need to go out to the community with to really get people to use the NRS not only for diagnosis but management of the condition and response to therapy. When you see your patients and they complain of the itch, do they also complain about impact on quality of life? What areas does NP impact quality of life? So it's interesting because, as discussed previously, it's not just your regular itch. It's a deeper itch. You can't always satisfy it unless you are using a door frame or a back scratcher or something or your partner if they're willing. So it's the description of the type of itch that also helps with the diagnosis. It's something that's not always satisfied. And because of that, it can be very distracting. It can affect some patients' sleep, especially if they're sleeping in a specific position that is making it flare up and that wakes them up. So that intro video was really great because those are the things that we hear all the time, "Had to buy another back scratcher," things like that. And I just don't want to have to deal with this for the rest of my life. It's one thing to have an itch for a specific time. You got poison ivy, and it's horrible. But you know it's going to go away. But to have this chronic, constant distraction every day can really start to affect your mood, your mental health, how you interact with others. Say you're at work and you're having an itchy day. It can really affect sort of all spheres of your life. Thank you. Dr. Yosipovitch, can you speak a little bit about your treatment algorithm? How do you manage these patients? Yeah. So always, it's important to start with topicals because it's a localized disease. So we do use local anesthetics. There are some topicals that work well. I mean, we developed this formulation that contains a street drug, ketamine, lidocaine, amitriptyline. It's not something common that other dermatologists do. But it really helps numbing that area. And that's very helpful. There have been reports, capsaicin, that chili pepper. There have been Pramoxine. These are topicals. There are some new developments in that field too. But then the second, it's a therapeutic ladder. If itch is more severe or it's not responding, is to use GABAergic drugs. Unfortunately, GABAergic drugs work, as Brian, Dr. Kim mentioned, it's an electric activity of a nerve. And GABAergic drugs really work on inhibiting that oversensitization of a nerve. So unfortunately, these drugs have a lot of side effects, whether they're causing dizziness. Women have more NP than men. Women don't like to increase weight. Gabapentin drugs increase weight and appetite. So it's difficult sometimes to convince these patients. These are the major treatments that we use. So in addition, that's more not in our domain. It's difficult to get insurance-wise. It's only for the rich women, maybe in New York, is Botox injections. Why? Because Botox has an effect not just on cosmetics but has an effect on that neuron, some calcium channels and nerves. It reduces significantly local itch. But again, a practical treatment. Majority of the patients. I see that is coming in mainstream. So I think I covered all the treatments that I use. I mean, the butorphanol because we don't have difelikefalin. It's only for those who have really intractable butorphanol is only an inhaler. It also has some side effects centrally. Just to let you know, the difelikefalin has less of these sites. Butorphanol, it goes into your brain very quickly. So it's not so commonly used. Maybe I'm one of a few that uses it. But I think I covered almost all the treatments that are available. Yeah. Because it's on the back and just with a topical therapy, I mean, do your patients find it challenging to apply it, needing caregivers? Some of them need to be applied multiple times a day. What has been your experience with topicals? That's a limitation. There are some techniques of devices that you could use in application, whether it's like a back scratcher-like with a buff puff or a device that enables you to kind of rub it. But I agree, you need to have two for tango here, someone to apply it. Okay. Wonderful. Dr. Gooderham, can you speak maybe to how you manage patients with NP? What is your treatment algorithm? Yeah. We have different access issues here in Canada. So topical capsaicin is usually the first line. By the time I've seen them, sometimes their family doctor has already tried topical steroids and antihistamines and other things that did not work. So topical capsaicin is something that you can get in some over-the-counter products here. But you say you have to use it five times a day, putting it on. And if you can't reach to put it on that frequently, it's not going to be very effective. It's one of those things that sometimes patients, they just give up after time. But if there is a more severe case, more recalcitrant, then again, I might use something systemic like gabapentin. But it's also 3 times a day. You're increasing the dose. It has some side effects. So it's not a great solution that patients don't love. Yeah. Dr. Kim, if a new therapy were to be introduced, what would be sort of the ideal criteria and the wishlist for that new therapy for NP? Yeah. The ideal would be easy to use, rapid effect, durable effect, low side effect profile, and also that the patient can tailor to their symptoms. Because I think the other thing that is unique about itch is it's not just a fixed rash or something like that that you simply see and treat. But the experience can actually vary a bit throughout the week. So if you have the ability to treat when it's more severe and maybe even back off if you don't really need it, these are all great flexible options. So in my mind, that would be a kind of ideal profile of a medication. And the ability to take it anywhere easily with you. Convenience is a big factor as well. Dr. Yosipovitch, just with our phase II data with difelikefalin, any thoughts on the data that you could share with the audience? Yeah. I think that. Are you changing the dose in the phase III trial? No. Just the phase II proof-of-concept data. What were your thoughts on the effects? Again, for those who are not so familiar with the itch field, you could look, "Okay. Well, there is a difference. But the placebo had an effect." But there's always a placebo effect in drug trials. So I want to emphasize that. But the meaningful itch reduction, which is a bit high standard because it's, in a way, my fault. Several years ago, I did the initial studies. What's a meaningful clinical itch reduction of NRS4 in psoriasis and then in atopic eczema? And I have to tell you, I get attacked very often by my colleagues in Europe that it's because of you, the FDA has caused a challenge because they're asking for an NRS of four and above. And honestly, I tend to agree with my German colleagues that say an NRS of three is also clinically meaningful. The fact that you got it very close shows that you have an antipruritic effect. I want to emphasize something that Dr. Kim also mentioned. Very important is rapid response. So if you look at, I don't have it in front of me. But if the audience would see the slide of reduction, it's extremely important to show that it does work fast because patients want to get immediate response. So it does show that. These are the main important aspects of this type of thing. I agree with Brian. I don't think we need to have this drug long-term use. You could do it on and off. That's where I think would be maybe it wouldn't interest you as a company. But as a patient of mine, patients don't want to be all the time on a drug. If you could show that an on-and-off efficacy works, it's going to be great. Dr. Gooderham, just with the profile of difelikefalin, how could you see it fitting into your treatment paradigm one day if it gets approved as the first approved therapy, really, for notalgia paresthetica? Yeah. Yeah. Well, number one, I agree with what Gil said earlier about topicals always going to be your first line for a localized option. But it's really great to be able to say to patients like, "Hey, we actually have something for this." Because so many years, they've had this chronic condition and been told like, "We'll try this, try that. Might work, might not." But to actually say, "We've studied this. It works in this condition. Try this topical first. If it works, great. Continue on when you need it. But if not, we actually have somewhere to go. And so I would probably use it first thing post-topical. Great. Well, I want to thank you all for a really robust discussion, for your insights. I think it's been very educational, especially for our audience. And thank you for your time. I'm going to now move on to some of the prepared presentation. So thank you again. And we'll come back to questions afterwards. So during this next session, I'm going to review the data from our notalgia paresthetica proof-of-concept Phase II study, the COMFORT Study. But before I actually go through the clinical data, I wanted to briefly remind you of the key features of difelikefalin. So difelikefalin, or DFK, is a selective and potent kappa opioid receptor agonist. Preclinical studies have shown that activation of the peripheral kappa opioid receptor pathway with difelikefalin potently suppresses itch. And this is predominantly by means of a neuromodulatory effect. DFK has unique pharmacological and physicochemical properties. Importantly, due to the high selectivity to the kappa receptor, there's no identified activity at the mu receptor. And as such, it doesn't produce the typical mu side effects of euphoria, addiction, and respiratory depression. It's not a controlled substance. It is not scheduled. Difelikefalin has demonstrated antipruritic therapy with both the oral and the IV formulation. The oral Difelikefalin formulation has shown positive proof of concept data in the treatment of chronic pruritus and notalgia paresthetica. And in addition, the IV formulation, KORSUVA, is approved for chronic kidney disease-associated pruritus in patients undergoing hemodialysis. We were thrilled that our phase II data notalgia paresthetica was published in the New England Journal of Medicine last year. The Comfort Study was the first robust randomized placebo-controlled study in patients with notalgia paresthetica. In the study, patients were equally randomized to either difelikefalin 2 mg or to placebo twice daily for a period of eight weeks. The study met its primary endpoint with a statistically significant improvement at week eight in the mean change from baseline in the worst itch NRS score. There was a significant reduction in itch compared to placebo occurring here, as you can see on the graph, at week one all the way through to week eight. On this slide, we show now the daily data in the worst itch NRS score. You can see that the drug is effective as early as day one and throughout the first seven days with statistical significance on all days except on day two. This is the four-point response analysis that Dr. Yosipovitch was speaking about and which is the required endpoint in itch studies. When we assess the four-point responder response, we see that 41% of patients versus 18% of patients achieved a four-point response in their Worst Itch NRS. The four-point response was shown to have a statistical significance in the DFK group versus placebo as early as week two and sustained for the eight weeks. We looked at a higher bar. We looked at complete response in Worst Itch NRS. What you see here now is that approximately a quarter of patients treated with difelikefalin experienced this complete response versus 5% of patients on placebo. Patients needed to have a score of zero or one on their Worst Itch NRS score in a week in order to achieve or to be defined as a complete responder. You can see here that patients achieved this complete response, which was statistically significant from placebo as early as week 2 and once again sustained for the eight-week period. The most commonly reported treatment adverse events are shown here in this table. All events in the difelikefalin group were assessed as mild or moderate as assessed by the investigator. Nausea and abdominal pain were the most commonly reported adverse events. This was with equal incidence in the placebo and the difelikefalin group. Then headache, dizziness, constipation, and an increased urine output were reported more commonly in patients on difelikefalin versus placebo. These events are very consistent with what has been reported across studies with oral difelikefalin. It really shows a very consistent safety profile. Moving on to our current program. That's the COURAGE program. As a reminder, the program is comprised of two studies, COURAGE 1 and COURAGE 2. COURAGE 1 has two parts, Part A, which is a dose-finding part, and Part B, which forms part of the pivotal program together with COURAGE 2. As you heard Chris mention earlier on, we were thrilled that patients were swiftly randomized into Part A. This really speaks to the enthusiasm from the investigators but also the unmet need in notalgia paresthetica. 214 patients were equally randomized in the four arms. You can see here the four arms with the 0.25 milligrams, the 1 milligram, and the 2 milligram twice daily of difelikefalin versus oral placebo twice daily for a period of eight weeks. The main objective of the study is to select the dose and to determine the sample size for the pivotal studies. As a reminder, Part A is not powered to show statistical significance between the treatment groups. We eagerly await the top-line data in quarter three of this year. Once we have the data, we look forward to swiftly operationalizing the pivotal studies by the end of this year and anticipate top-line data for Part B in the second half of 2025 and the first half of 2026 for COURAGE 2. In summary, difelikefalin has unique properties. It has a strong neuromodulatory mechanism of action and had robust proof of concept data in our notalgia paresthetica study, thus making it a great candidate for treating patients with NP. Chronic pruritus is the defining feature of NP. Our experts today highlighted the impact that NP has on the quality of life of many of these patients. There's a large underdiagnosed patient population. Currently, there are no approved therapies. Off-label therapies are limited by poor efficacy or tolerability, as you heard from the panel. Difelikefalin has the potential to be the first and only oral antipruritic therapy approved for notalgia paresthetica. I'd like to thank you for your attention. I'm going to hand it over to Chris now. Awesome. Thank you, Jill. Let me first thank Doctors Kim, Yosipovitch, and Gooderham for the engaging conversation. They're really valuable insights. It's certainly become even more clear to me that notalgia paresthetica and possibly neuropathic pruritus more broadly represents a significant unmet need. The therapeutic options available to patients today are neither sufficient nor satisfactory. And as a result, patients continue to endure a significant impact from this really intractable itch on their quality of life. With oral difelikefalin, we believe that we may be able to offer patients a potential solution. Now, data from the proof of concept study were really stellar in terms of both efficacy, safety, and tolerability. We're super excited about the upcoming top-line results of the dose-finding portion of the ongoing phase II/III study in the 1/3 of this year. Now, we'll proceed as swiftly as possible into the pivotal portion of the phase II/III program. Now, like I said earlier, NP ticks all the boxes for a breakout program for a growth-oriented biotech company. We have a differentiated asset, which we believe has a high probability of success targeting a therapeutic area with no FDA-approved therapies. So with that, we'll start the Q&A session. Now, I'll turn it to Iris, who can share the first question, please. Great. Thank you, Chris. All right. We got a number of questions. I'm just going to toss it out to our panel here. So we'll take a little bit of a step back and go back to a little bit talking about the disease. What does a typical patient look like? Maybe Dr. Gooderham, we'll start with you. How would you describe a typical NP patient? It's such a wide range because it can affect so many types of patients. I would say for starters, they're middle-aged. They may be more likely to be female. But I actually have a lot of males who suffer from it as well. And it's just something that's been there. I'm never seeing them for the first time. They've had this for years. You see the scratch marks. You see the depigmentation. And many patients, like I said, have either given up when you ask them about it or are looking for another solution from a new provider. Great. Thank you. Is Notalgia paresthetica progressive disease, Dr. Yosipovitch? Any thoughts? Excellent question. I don't think that it's a progressive disease. It's quite a stable disease in terms of its natural history. What we don't know is the long-term follow-up of these patients. I wish we would have that data. But I don't see it as a progressive disease. And it's an excellent point. Thanks. Dr. Kim, do you have any thoughts on that? Yeah. No, I don't view it as a progressive disease at all in the sense that, for instance, a question people ask is, "Does it expand beyond its boundaries? Will it take over my entire body?" Fortunately, with NP, that does not seem to be the case at all. Great. Thank you. Just a comment. It's interesting because another neuropathy that I think your drug would be extremely well-suited with would be BRP. In BRP, we reported it could become. BRP is on a higher level of obstruction of the spinal. It's on the cervical. That can cause general sensitization. The itch becomes all over the body, but it doesn't seem in NP. I agree with that. Understood. You spoke a little bit about it. You alluded to it. How would you describe the magnitude of benefit you're looking for, independent of sort of the FDA approval hurdles? But what's that benefit you're looking for in a clinical program from any new drug where you say, "This is something I would definitely try for my patients"? And maybe Dr. Kim, we'll start with you. Yeah. I mean, I think you can argue whether a four point reduction is the bar is too high. But what you see in the data here is we've clearly met that. You don't even need to do the math. You just see the separation between the green and the gray. And it's clear-cut, right? So I'm not a big fan of statistics, to be honest. I just like to look at the data. And you see it right there. And a four point reduction is dramatic. So in other words, my patients, they come in at an NRS score of 10. It doesn't matter what the itch is. They drop to a six. And suddenly, they're not happy. They're not doing cartwheels. But they're now actually able to function tremendously more. I mean, they're now able to tolerate it. You go from, say, an itch score of seven to three, it's basically become a much more minor nuisance. They can live with it. This is no longer a centerpiece of their life. At an NRS score anywhere seven or greater, this is a major problem for them. So you're taking it from, "This is all they're thinking about," to now, "This might be the fifth thing they're talking about in their life or thinking about." That's a huge change. As someone who's had also my own personal medical issues, I know what it's like to go from that to the other and toggle between those domains. Great. Thank you. Maybe Dr. Yosipovitch, you can render your opinion on this as well. Yeah. I agree with Brian. So the main issue is really that meaningful clinics and for all these smart analysts in our discussion, the p-values are not so important to me. It's the clinical meaningful because I've seen so many studies where, yes, they were statistically significant. But in real world, they're not what our patients are looking for. So this is clear-cut. You may look and say, "Well, the p-value was not like other studies that you've seen." But it still stands, it's that clinical aspect that you have to understand. And it stands for that, so. Great. Thank you. And Jill, I'll actually pose this question to you as well in terms of you alluded to the fact that the Part A of COURAGE 1 is not meant to meet statistical significance. Having heard our panelists just now and their opinion on that, what is it that we are looking for? Yeah. So as I mentioned in the presentation, the purpose of the study for Part A is really to select our dose and to assess the sample size for the pivotal program. We wanted to do this as rapidly as possible to gather this information to get into our phase III program. We didn't want to have to design the study to be big and cumbersome. We wanted to get the information and move swiftly. What we're looking for is to be able to see separation from placebo and be able to select the dose that has the most favorable benefit-risk profile and to start the phase III program as quickly as possible. Great. Thank you. And moving on to some comments that you all made around sort of the treatment paradigm and maybe starting with localized treatment before you move on to systemic treatment, how do you think about how long you keep patients on these localized treatments? How well do they respond to these treatments? And when do you make a decision to try the next therapy? Maybe we'll start with Dr. Gooderham again. I guess one thing I should have mentioned before, too, is the topical therapies are not really durable. It's something you have to keep putting on. Even at the beginning, if someone does respond, they might get topical application fatigue, if you know what I mean. I mean, even though it may work, after a while, they're just like, "Enough of this. Putting these creams on. It's getting on my clothes," and things like that. Even in patients where topicals are effective initially, it may not be the long-term solution for that patient. But there may be other patients who have a milder condition where, as mentioned before, if you go from a seven to three, then that might be enough that you're happy with that. If you're not getting that benefit and it's something you have to keep applying, then, the patient, it's going to be a shared decision approach there where if the patient's not happy or they're not living a normal life, they may want to move on to the next step, which would be an oral option. Yeah, Dr. Yosipovitch, what are your thoughts on this question? I agree with Melinda. Just to let you know, by capsaicin, although Melinda, you give it, to achieve results, it takes about four weeks because it doesn't work immediately. It actually initially causes horrible burning sensation. So it's not so practical. But the other topicals that we use, like pramoxine, if it works, it works very quickly. I don't continue using it if in a few days, the patient tells me that it's not working. So the decision is very quick. But again, I would start for milder cases, especially that it's localized with a topical. And I think that in terms of payers, they would ask that you would have that option before receiving an approval to use a more expensive oral drug. Great. Thank you. And Dr. Kim, we have a little bit more of a scientific question here. Is there a possibility for remodeling of neuronal pathways so that in the case of difelikefalin, there could be a longer-lasting effect? And this is obviously, as a reminder, difelikefalin is not an approved therapy. And there is a certain amount of data just available at this point in time. But you certainly studied it extensively. So maybe you have some thoughts on this question. Right. The short answer there is we don't know. Unfortunately, clinical trials are time-limited. So we don't often have that kind of horizon data. My guess is that this is probably not going to be what we call kind of disease-remitting where you're going to go on difelikefalin. That would be my prediction, and that you're on it for six months, and then you're off of it, and you're good to go. By and large, this condition is fairly hardy and chronic. And I know that we're hearing about mild to moderate cases. I'm a bit biased from the standpoint that most of the cases that I do see are not in the mild to moderate range. The horse has kind of left the barn in that regard. So one disclaimer, it's a bit biased in that regard. The patients that I've generally seen are quite refractory as well to the other agents that we've been discussing. Great. Thank you. Jill, maybe we have another question for you. We are studying three different dosage strengths in our ongoing study. What are your expectations in terms of how these three different doses will perform? Are we looking for a dose response? Yeah. So typically, with difelikefalin, we haven't always seen a dose response as far as efficacy goes. And it's really because the drug is so potent, you just need a little bit of it to activate the receptor. So we're not really expecting to see too much of a dose response as far as efficacy goes. What we've typically seen is that there has been a little bit more difference from a tolerability perspective with dosing. And so this is where we will look at the profile and all the data and assess which dose will have the most favorable profile to take forward. Great. Thank you. You've all alluded to the fact that there are no approved therapies. The current therapies are maybe not working as well. At the same time, it sounds like there are no treatment guidelines out there because there is nothing approved. Is there something on the horizon that we can expect to have practitioners then follow the right path in terms of how to diagnose and treat these individuals? Maybe Dr. Kim, we'll start with you. Yeah. I'm sorry. There was a glitch in the feed. What was the question? No problem. Yeah. The question, simply put, is, are there treatment guidelines or some sort of protocols on the horizon for those dermatologists that don't spend all their time on clinical trials and research when maybe not as well-versed as the three of you in the terms of treatment? Dr. Yosipovitch and I just had a draft go back and forth this week. But what's really needed is clearer kind of ladder algorithms for how to treat. We discussed Tvardi Therapeutics, but it's good to know what to try first, second, and third. But full disclaimer, I'm not necessarily a big fan of a lot of these kinds of protocols necessarily because they sometimes get incorrectly interpreted. So for example, the level of evidence for notalgia paresthetica for when we come out and say what's a good ladder is nothing like when we're talking about what's the first, second, third line for hypertension. Those kinds of guidelines are supported by major, huge randomized clinical trials. So the level of evidence for those are in a very different category than when we're talking about notalgia paresthetica. As much as I like to respect my own opinion on this, whatever you want to call it, as a key opinion leader, the opinion is the capital O opinion. The evidence for these are not that great. And that's where I think that the strength of this being a major clinical trial I mean, and I think I want to underscore that the level of evidence for difelikefalin is the highest of anything that's ever been demonstrated in the history of this disease. And so I want to be very clear about that because sometimes I think that these treatment suggestions get wrongly interpreted to say this is really high-level evidence. And that's not it either. Understood. Okay. So we are close to the end of our session today. Chris, I'll have one question for you, and then I'll let you close the session. And that is, we have previously provided financial guidance. Maybe you can speak to what that is and where our current cash balance stands. Yeah. I think the punchline is we were able to solidify our cash balance at the end of Q4 of last year. We guided that we had $100 million in cash that would take us into early 2026. But more effectively, that two years of operating capital allows us to execute these clinical trials for the pivotal trials for oral difelikefalin. That's what we're really excited about. Hearing Brian talk about the body of evidence, we're building that. And we have the cash to do that over the next two years. So we feel like we're in really good shape there. Great. Well, I want to thank everybody, our panelists in particular, for taking time out of their really, really busy schedules to be with us today. Thank you for all the insights that you gave us and our audience. We really appreciate it. We wish everybody a wonderful rest of the day. Thank you all. Thank you. Thank you.