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

Good afternoon. This is Will Gramig with Stern Investor Relations, and welcome to Cara Therapeutics' 2021 R&D Day. As a reminder, we will be making some forward-looking statements today. We would encourage you to review Cara's most recent SEC filings for a more complete description of our risk factors. Cara management is delighted to be joined on the webinar today by 2 highly accomplished key opinion leaders, Dr. Brian Kim and Dr. Mark Lebwohl. Dr. Brian Kim is an Associate Professor of Medicine and the Co-Director of the Center for the Study of Itch and Sensory Disorders at Washington University School of Medicine in St. Louis. Dr. Mark Lebwohl is a professor of Dermatology and the Dean for Clinical Therapeutics at the Icahn School of Medicine at Mount Sinai in New York. Participating from Cara today will be Dr. Derek Chalmers, Cara's President and Chief Executive Officer; Dr. Joana Goncalves, Cara's Chief Medical Officer; Mr. Eric Vandal, Cara's Senior Vice President of Commercial Operations; and Mr. Tom Reilly, Cara's Chief Financial Officer. Today's event is expected to run until approximately 3:00 p.m. Eastern Standard Time. At the end of the presentations, Dr. Chalmers will moderate a Q&A session. [Operator Instructions] A replay of the webinar will be available on the Investors section of the Cara Therapeutics' website later today. With that, I'll turn it over to Dr. Derek Chalmers for introductory remarks.

Thank you, Will. Good afternoon, everybody, and thanks for joining Cara's 2021 R&D Day. Despite the many significant and obvious challenges that 2020 presented, it has nevertheless been a defining year towards our mission of developing novel, first-in-class therapeutics to transform the treatment of chronic pruritus. And building on that momentum, we do expect to meet a number of very significant milestones across our main development programs throughout 2021, including FDA approval of our lead product candidate, KORSUVA injection, a breakthrough designated treatment for pruritus in hemodialysis patients. If approved, we anticipate commercial launch of KORSUVA injection in the U.S. in the second half of 2021. And we also expect phase 2 data readouts from our Oral KORSUVA program, the first of those being topline data from our dose-ranging trial in atopic dermatitis patients, just a little later this quarter. And finally, we do plan to move oral KORSUVA into Phase III registration trials in the second half of 2021. So a very busy 2021 ahead for the company. We've put together today's agenda to highlight the significant unmet need and the broad opportunity for a novel effect of therapeutic for the treatment of chronic pruritus. We know that pruritus is a prominent symptom of high prevalence across a range of clinical conditions, including systemic diseases such as chronic kidney disease, dermatological inflammatory diseases, including atopic dermatitis, and certain neuropathic conditions. And the negative impact on quality of life and increased propensity for comorbidities is significant for these patients, as you will hear in much more detail this afternoon. When we look at empirical script data for the treatment of chronic pruritus, it's in the region of 20 million scripts annually here in the U.S., and the vast majority of these are generic corticosteroids are centrally acting antihistamines, which are generally ineffective or not appropriate for chronic use. And this is a clinical problem, which is only growing with prevalent U.S. pruritic patient populations exhibiting very significant growth rates. So we've developed KORSUVA or difelikefalin, a first-in-class, really only-in-class, highly selective, peripherally acting Kappa agonist as a novel therapeutic approach to address the clinical pruritus problem. As a result of its unique mechanism of action directly on the pruritus sensory pathway, KORSUVA has the potential to act as a broad antipruritic. Rather than target any individual immune stimulator of pruritus or pruritogen, which vary dependent on the pathophysiology of the underlying disease, KORSUVA stimulates Kappa receptors localized on dermal sensory nerves to directly block sensory afferent activity and downstream from the action of any pruritogens. And a little later this afternoon, Dr. Brian Kim, based on his research work with difelikefalin, will elaborate on how this mechanism of action on classes of sensory neurons may interact with other modalities involved in chronic pruritus, including those implying the JAK/STAT pathway. Additionally on mechanism of action, it's well established that Kappa receptors are localized across immune cells, and KORSUVA can inhibit the release of pruritogenic immune molecules via stimulation of these receptors. So this is key. These 2 complementary mechanisms, neuromodulatory and anti-inflammatory, form the basis for the potential of KORSUVA to act as a broad antipruritic across clinical populations and regardless of the initiating pathophysiology. And we've developed our KORSUVA pipeline accordingly. We have 2 distinct formulations in development. KORSUVA injection, which is an intravenous formulation of difelikefalin for the treatment of CKD-associated pruritus, specifically in hemodialysis patients. Here, our NDA is under priority review with a PDUFA target action date of August 23 of this year. We've already established strategic alliances for commercialization of KORSUVA injection in the U.S. with Vifor Pharma and in the EU and select regions with the Vifor Fresenius joint venture as well as with Maruishi Pharma and Kissei for Japan and CKD pharma for South Korea. Oral KORSUVA is an oral tablet formulation of difelikefalin, in development to treat pruritus across a range of clinical populations, including CKD pre-dialysis patients, atopic dermatitis, primary biliary cholangitis patients and in pruritus of neuropathic origin, specifically in patients with notalgia paresthetica, as we'll hear about today. And Cara retains commercial rights for Oral KORSUVA. Today, we're going to touch on all of these programs with a particular emphasis on CKD-associated pruritus, both in hemodialysis patients and pre-dialysis patients, atopic dermatitis and in notalgia paresthetica patients. So in summary, we've made considerable progress since the filing of our first pruritus-related IND for KORSUVA injection in 2014 with both the NDA and the MAA on the regulatory review. We're currently working closely with our partner, Vifor Pharma, towards planned U.S. and EU commercial launches in 2021 and 2022, respectively. We've also now advanced Oral KORSUVA into Phase II trials in multiple pruritic patient populations, and we're currently working towards end-of-Phase II meetings for both CKD-associated pruritus and atopic dermatitis to allow initiation of Phase III registration programs in the second half of this year. So with that, it's now my distinct pleasure to turn it over to our KOL guest speakers for today. Dr. Mark Lebwohl from the Icahn School of Medicine at Mount Sinai, will be discussing the unmet need in neuropathic-related pruritus, specifically notalgia paresthetica. And firstly, Dr. Brian Kim from Washington University School of Medicine, will cover the physiology of pruritus and some of his own really seminal research work on signaling pathways, mediating chronic pruritus in relation to atopic dermatitis. So over to you, Brian.

Hello. Thank you for having me. I'm grateful to the Cara Therapeutics for the opportunity to talk about this very important topic of chronic itch, and I'll be talking about the emerging therapeutic landscape in this area. So to begin and put everyone on the same page, the question is what is itch to begin with. Itch is defined as an uncomfortable sensation on the skin that causes a desire to scratch. In contrast, to pain, which has been classically defined as physical suffering or discomfort caused by illness or injury. I think this is one reason for why itch has been so overlooked because by just a sheer definition, we can immediately recognize that one is considered a mere nuisance, while the other is really recognized as a major medical problem. But what we do know is that when itch becomes chronic and it's rather arbitrarily defined as itch that lasts greater than 6 weeks, it affects about approximately 15% of the population as a profoundly negative impact on quality of life, comparable to chronic pain. Many would argue it's much more manding than even chronic pain. For reasons I won't go into greatly today, the incidence of chronic itch is increasing in large part due to the fact that there is a tremendously aging population, and itch is closely tied to the aging process. There are no FDA-approved medication specifically for chronic itch. Almost all therapies are used off-label. The other point I'd like to make, though, is that itch may be the most common medical symptoms. What I'm showing here is only a handful of medical conditions that are associated with itch, ranging from dermatologic inflammatory skin disorders to infections to a variety of cancers, even new conditions, in which patients develop itch secondary to therapies, such as checkpoint inhibitors, in the class of medication-induced itch. There are a variety of neurologic forms of itch. Many, many systemic forms of itch due to metabolic dysregulation as well as idiopathic forms of itch as well. We refer to as chronic pruritus of unknown origin. What I've highlighted for you here is, in red, are essentially the conditions that are emerging, in which there is a lot of therapeutic development just within the last couple of years. So I could not have shown this before even a few years ago, but this is just to highlight how much attention has actually been drawn towards chronic itch conditions just within the last 2 years. There's a huge opportunity in addressing this highly unmet need. There is a very large population of discouraged patients. One thing I often point out to many people is that we often don't know how big the problem is until we actually have a therapy that is very effective. We see this with atopic dermatitis, where there was a lot of questioning of how many patients there really were with moderate-to-severe atopic dermatitis, but only with the advent of new targeted and effective therapies that suddenly everyone says this is a huge market. At minimum, there is an accessible population of at least 50 million in the U.S., I would argue even more. But what's really enhanced are the opportunity and our ability to capitalize on this is there has been the discovery of number of potent itch-specific pathways at the molecular as well as cellular level that had presented as new opportunities. Another point I'd like to highlight that's quite pointing to me is that billions are spent annually on drugs with no proven efficacy. As an example, if we just look at IMS health data, $2 billion -- annually, over $2 billion spent on anti-histamines for itch. We know that antihistamines are very lacking in efficacy for the vast majority of chronic itch conditions, yet we spend over $2 billion a year just naturally for antihistamines. So how does this work? What is the biology of itch? So as much as I noted that antihistamines are not effective, what's been very useful is that histamines as a compound as a tool molecule has been very useful for us to understand itch biology. So the way this works is if you start in the skin, and you inject histamine into the skin, let's say into forearm, what happens is there are neurons that innervate that skin and become immediately activated directly by histamine. These are what we call sensory neurons. These neurons then travel and communicate directly into the spinal cord, where there are another set of neurons called interneurons that they relay the signals and these signals then get transmitted through the spin cord to projection neurons that then go up to the brain. And within the brain, we then ultimately perceive itch. A point that I would like to make here is that histamine causes itch along this kind of electrical circuit. But there are a number of other itch-inducing molecules, which we refer to as pruritogens that can do this on either the same neuron or different neurons, and this is where itch biology has really exploded in the last several years. Additionally, there are a number of different molecules within this circuit that we can block or modulate, which represent future therapeutic targets in chronic itch as well. And which molecules mediate itch are going to be very different potentially across different disorders in that long list that I showed you earlier. Well, what's going on? Why has it been so long? Why are there so few therapeutics in itch? Well, there's another misconception about itch, not only that it's a mere nuisance. But there was a fundamental scientific misconception that was well intentioned, but led to a lot of misdirection in the field. And essentially, what has been known for a long time is that you can cause -- with one stimulus, you can cause pain, and then as that pain resolves, you can actually observe itch. And that primary observation by Max von Frey 100 years ago led to the intensity hypothesis that essentially, with low-intensity stimulation, you get itch. And with high intensity, you get pain. This was a little bit over simplistic in that it implied that if we simply understood pain better that we would get to understand itch. And this led to the idea that if we just simply study pain, we will unravel itch. Well, this was very much debunked in recent years, with the identification that there are, in fact, very itch-specific targets and pathways. And a lot of this work was actually championed by our center. Well, what I want to talk to you about if we're going to talk about itches is a clinical problem of atopic dermatitis, which is a chronic itch disorder. We know that it is high incidence. It's costly. Therapeutic options have always been very limited, and this has only recently been starting to shift, and it has a profoundly negative impact on quality life. But itch is truly the central symptom, whether we're talking about a child or an adult. So how have we traditionally thought of atopic dermatitis? We've really thought about it as a truly inflammatory disorder. In other words, immune cells cause this disease. And if you get those immune cells in check, then everything is fine and even the itch. Obviously, it's a bit more complicated than that. But the way we think about this is that immune cells and their receptors shown here in red, as well as their downstream signaling pathways, such as the JAK/STAT singling pathway, result -- activation of these receptors result in the production of a variety of inflammatory molecules or cytokines, which then directly promote the rash or damage the skin that we see as a rash in atopic dermatitis. Well, in recent years, what we've we've been working on and uncovered is that there's more to it than just the rash or what meets the eye on the skin is that these -- some of these inflammatory factors through these pathways that I've highlighted, namely IL-4 and IL-13 through the receptor in these JAK pathways critically immediate itch within the nervous system. In other words, these immune factors that we thought were largely contained within the immune system, we found directly communicate with the nervous system in a meaningful way to mediate itch, and therefore, this has actually informed therapeutics and our understanding of how these therapeutics, many of which will come in 2021 and likely be FDA-approved this year, how these therapies are not only anti-inflammatory but have also anti-itch effects. So in other words, simply put, all inflammation has to eventually go through the nerves to reach a brain to elicit itch. So if that's the case, why don't we go after the nerves in a targeted fashion and not just develop anti-inflammatory agents, but develop agents that are neuromodulatory. So what I'm highlighting here is on the left, we show that immune cells clearly -- and the pathways that are inherent to them clearly meet inflammation, and that's been well-known and that's where these therapeutics have been largely focused. But what we're proposing is that fortunate to the field, many of these therapeutics also have another mechanism of action, which is it also have neuromodular to our properties, and that is very fortunate for these therapies and, most importantly, for our patients. And this is just a handful of studies showing how itch is now emerging as a central focus or even endpoint of a variety of clinical trials, whether we're talking about drugs like dupilumab, ruxolitinib cream, which is a JAK inhibitor as well as newer agents in development such as omalizumab, which blocks IL-31 pathway and has been largely tailored in the clinical trials to focus on itch as a primary endpoint. And importantly, we are also seeing that drugs that were conceived as neuromodulatory agents such as the Kappa opioid agonist, advanced [indiscernible] therapeutics are useful in potentially other itch conditions and also being evaluated in atopic dermatitis itch. We know that there are a number of primary itch disorders that are becoming increasingly recognized and which -- for which there are trials now on the left. We see Prurigo Nodularis, which is a primary itch disorder. In other words, the nerves are going awry, resulting in these patients scratching, resulting in the lesions that you see here. And we have other conditions, which Mark Lebwohl will talk about later today called notalgia paresthetica where there are misbehaving nerve fibers in the back at least the chronic itching in the back, which is essentially why you get this kind of lesion here because of chronic rubbing and itching and also why the back scratcher was invented. Well, we know that difelikefalin, or DFK, had a major breakthrough for hemodialysis patients who suffer from severe intractable pruritus. And this is further evidence that independent of even rash or inflammation, there are ways in which we can go after these nerves. And treat the itch perhaps no matter what the cost. So I mentioned earlier, there are itch stimuli that trigger this pathway that leads to itch. But -- and we've also, from our laboratory identified how downstream signals, such as JAK can actually be pathways intrinsic to the -- within the nervous system that we can actually target and somewhat inadvertently based on these therapeutics but also what we find now is that there may be other ways that we can more broadly suppress this itch, and how do we do that? And DFK actually represents a potential therapeutic modality. We know and we suspect now that DFK and kappa opioids largely stimulate other sensory nerves of a different class. We've heard of them as beta nerve fibers. And what these nerve fibers do is they often respond to a lot of frictional stimuli. So they're very different from these other nerves that we -- without respond to a variety of itch stimuli and what we think that these nerve fibers can do is actually broadly suppress itch signals that are coming in from the periphery or the environment into the host by way of these itch-specific nerve fibers. So this is a way in which we can essentially stimulate endogenous mechanisms within the individual to suppress the itch by activating other pathways that may be much more itch mitigating. So how is DFK different? We know that what -- as I mentioned, that there are inflammatory forms of itch in which inflammation triggers itch and there a variety of disorders like atopic dermatitis, infestations, insects bites, in which we clearly can target the inflammation and largely ameliorate the itch. But then we have other disorders that are somewhat mixed in terms of the origin of the itch. And then those in the right that are very much neurologically-based such as postherpetic itch where patients get shingles, and they have chronic itch afterwards. I mentioned notalgia paresthetica. There are others like brachioradial pruritus and scalbetic pruritus. And it's very, very important to understand the mechanisms and the ideology of these diseases because therapeutics, such as on the left, were largely conceived as anti-inflammatory agents. Fortunate for some of these, they also have neuromodulatory properties, so they bleed over to the right. But then there are agents that we use off-label, such as gabapen or Neurontin for itch that we know is clearly neurologic in origin, but they're limited in efficacy. Again, they're off-label. So the question is, are there other agents that we can develop and that are in development, as I'm showing here, such as Nalbuphine and DFK, that may actually represent an entirely new mechanism of action where we go after where the itch is really the problem within the host. So I'd like to just hopefully emphasize and underscore and hopefully impressed upon you that itch represents a broad medical landscape for new therapies. It really is a massive frontier that has been long overlooked biologically, medically and pharmaceutically. Thank you for listening.

I'm Mark Lebwohl. I'm the Dean for clinical therapeutics at the Icahn School of Medicine at Mount Sinai. And for the past 2 decades, I have been Chairman of the Department of Dermatology here at Mount Sinai, and I'm pleased to now be promoted to Dean, and I'm very pleased to be speaking about a condition notalgia paresthetica, which is common for which we have never had a good treatment and hopefully have one on the horizon. So neuropathic itch accounts for approximately 8% of chronic itching cases. And it is something that we see commonly. It involves disturbances at any level of the cervical lumbar or sacral spines and the thoracic spine. And it results in a chronic itch that can't be treated. Of interest, Mu opioid receptor agonist exacerbate itch. So notalgia paresthetica is undoubtedly a mechanical irritation, which occurs anywhere along the spinal column. And there are, of course, patients who have a chronic scalp itch. There are patients who have brachioradial pruritus, which is itching of the arms. But most commonly, what we see is itching under the scapula, usually unilateral, but can be bilateral, and it is thought to be caused by compression of the dorsel branches of the spinal nerves, T2 to T6, which lead to a very sharply demarcated area of pruritus of itching exactly around the scapula. And that is how we make the diagnosis. And it is a condition, which we see commonly. In fact, to give you a little anecdote. When we were ready to get the trial done for notalgia paresthetica, often we'll look for diagnosis by code. But unfortunately, notalgia paresthetica is usually coded as pruritus. So we had to rely on photos that I'd taken of the condition, patients whom I recalled or patients who we saw within the last few weeks. And literally, in a few days, we were able to locate 25 patients. It is a common condition. It is thought to be the reason that the back scratcher was invented. And even though it is that common, there are only a small number of case reports published. It is more common in women than in men and typically occurs in mid- to late adulthood. These are classic photos of notalgia paresthetica, and I have so many of these. It is a chronic, intermittent, paroxysmal itch that occurs usually under the scapula, but anywhere around this scapula or around the vertebra, but again, usually under the scapula. And there can be periods of remission and exacerbation. But these are patients who tell you that several times during a day, they will get up, go to a corner of a wall and start rubbing their back. It can be accompanied by pain, and it can be bilateral but usually unilateral. Typically it lasts for years with the mean duration between 21 months and 3 years, it is a clinical diagnosis. There are other differential diagnostic items, but I'll be frank it is rare for me to need to distinguish notalgia paresthetica from the conditions shown here, which is a pigmented contact dermatitis; parapsoriasis, which is not usually unilateral; neurodermatitis is just an area that you scratch repeatedly; or cutaneous amyloidosis which indeed can be pigmented, which often occurs in notalgia paresthetica as well. Now there are many treatments that have been tried. They all have one thing in common. They don't work. We often will try antihistamines. It doesn't work. I will tell patients, look, my usual first treatment is a topical steroid, but I'm going to tell you in advance, it's almost certain not to work. We then often will go to capsaicin, which is a second-line treatment. But again, often, it doesn't work it often makes the condition worse before it makes it better. If you stop it, when the condition is better, the condition recurs, so you have to continuously use it. Then there's a long list of treatments used here. And the length of the list is simple. The reason it's so long is because we don't have treatments that work for notalgia paresthetica. So with that, I will end my talk here. Thank you very much for having me.

Good afternoon. My name is Joe Goncalves, and I'm the CMO at Cara Therapeutics. I'd like to thank you for joining us today. I'm going to move on to chronic kidney disease-associated pruritus in patients undergoing hemodialysis. CKD-associated pruritus is a serious condition defined by chronic itch that is caused by the patient's underlying dysfunctional kidneys. The pathophysiology is not really fully understood, and it's considered multifactorial with metabolic abnormalities, a disregulated immune and a disregulated endogenous opioid system implicated. The majority of patients undergoing hemodialysis experience pruritus with about 20% to 40% considered moderate to severe in nature. CKD-associated pruritus is underreported and under recognized, leading to an underestimation of both of prevalence and the impact of the condition. CKD-associated pruritus affects patients with CKD across all ages, ethnicities and genders. The itch is distressing and uncomfortable to patients, and it persists during the day and the night. In contrast to pruritus occurring with dermatological conditions, there are no primary skin lesions. However, what may be noted on the skin are excoriations, that is the scratch marks from the patients persistently scratching at their skin, as you can see here on the photos. The pruritus adds to the burden of dialysis patients. And as you know, hemodialysis patients are already heavily burdened by their multiple comorbidities. So having to manage the itch on top of this further negatively impact the quality of life. In addition, patients with severe itch are more likely to miss hemodialysis sessions. They're more likely to have a greater risk of sepsis due to the continuous scratching of their skin, use more IV antibiotics as well. And there are multiple publications, which have demonstrated that patients with severe itching have an increased mortality rate. And this is specifically cardiovascular-related mortality and infection-related mortality. Cara has conducted the largest clinical development program in patients with CKD-associated pruritus undergoing hemodialysis. You may recall our pivotal studies, KALM-1 and KALM-2, and these studies enrolled over 800 subjects in the U.S. and in the ex-U.S. In addition, we conducted another 2 open-label safety studies. So ultimately, our NDA safety package included 1,500 patients undergoing hemodialysis who've been exposed to IV difelikefalin. We were also excited that the FDA recognized the drug as a breakthrough therapy and recently granted us a priority review with our PDUFA date of 23rd of August this year. Let me go into the studies in a little bit more depth. As I mentioned, KALM-1 and 2 are pivotal studies, these were similar studies with the exceptions of the regions where they were conducted in. KALM-1 was U.S. only and KALM-2 was a global study, which included SAP in the U.S., Europe and Asia Pacific. Subject undergoing hemodialysis with moderate-to-severe pruritus were equally randomized to either placebo or IV difelikefalin 0.5 micron per kilogram after each hemodialysis session for 12 weeks. Subjects could then enter a 52-week, open-label, long-term extension study. The primary endpoint was a responder analysis, and that assess the proportion of patients who achieved at least a 3-point improvement from baseline at week 12 and a weakly mean of the daily worst-itch NRS scores. Cara has demonstrated that the 3-point response is the clinically meaningful endpoint for the CKD patient population. Secondary endpoints included the 4-point responder analysis, quality of life and safety assessments. Here, we see the results for the primary endpoint, and it shows that in both KALM-1 and KALM-2, the primary endpoint was met in subject of difelikefalin, showing consistent results across the 2 studies. 51% and 54% of subjects in KALM-1 and 2, respectively, achieved the 3-point response. However, you see that there was some variability with the placebo response across the 2 studies with a higher placebo response seen in KALM-2. And this was anticipated when expanding a clinical study to many more countries than just the U.S. and more clinical sites. It has been demonstrated in the literature that the placebo effect may become more variable when there's greater variability in countries and in sites. Subject to entering the studies, we're allowed to continue on the anti-itch meds, as long as they did not alter their meds during the study. Approximately 40% of subjects use concomitant anti-itch meds, which comprise mainly of centrally acting antihistamines. We see on this slide that regardless if subjects were on anti-itch meds or not, IV difelikefalin showed to be statistically significant compared to placebo. This slide shows us the secondary endpoint of the 4-point responder. And once again, we see similar results as we saw the 3-point response. Here, we demonstrate IV difelikefalin's onset of action. By week 1, you can see difelikefalin separating from placebo, and this is statistically significant at this time point and then at every time point thereafter, with the efficacy maintained throughout the 12-week period across both studies. The daily itch assessment using the NRS tool was only captured during the 12-week double-blind placebo period. However, patients did complete their 5-D itch assessment during the double-blind period as well as the open-label extension period. Just as a reminder, the 5-D itch assessment is a multidimensional questionnaire, which evaluates 5 dimensions of itch. And so by capturing it both in the double-blind phase as well as the open-label extension phase, it gives us an indication of how the drug works over longer durations. So what you see in this slide is the mean reduction of the total 5-D itch. The green line of patients on difelikefalin and the gray on placebo. And so what you've seen in the double-blind phase is that there was a greater reduction of the 5-D itch in subject on difelikefalin, and this was statistically significant compared to placebo throughout the double-blind phase. When patients enter the open-label extension phase, you can see that the efficacy is maintained throughout the 15-month treatment period. But something else also to note on this slide is the placebo response. And what you see, when patients were switched from placebo from the double-blind period to the open-label extension, you see that they have to have a similar efficacy to what we saw for patients who originally were randomized to difelikefalin, and so really confirms the results seen in the double-blind phase. Now moving on to the safety data. This slide shows the incidence of the common treatment-emergent adverse events reported in KALM-1 and 2, and this is pool data. And we show here the incidence of adverse events that occurred at 2% incident rate in the difelikefalin arm and which had a 1% difference versus placebo. The most commonly reported event were diarrhea, dizziness and nausea, and these occurred at least 5% incidence rate. And then in addition, we saw a difference in headache, hyperkalaemia, somnolence and back pain. All these events were pretty well tolerated and that most were reported as mild or moderate in severity and very few led to discontinuation. In fact, dizziness was the most commonly reported event that led to discontinuation and there were 4 subjects out of the 29 who discontinued due to dizziness. In addition, the SAEs reported with the preferred term, seen here, were very low, and that was less than 2%. So when we look at all these factors, this gives us a sense of the tolerability of the drug, and it seemed that it was well tolerated. So that's my last slide for this section. I'm going to hand over to Eric now. Thanks, Eric.

Thanks, Joe. Good afternoon, everyone. My name is Eric Vandal, and I'm the Senior Vice President of Commercial here at Cara Therapeutics. I'm going to take the next few minutes to discuss the commercial opportunity for KORSUVA injection in hemodialysis patients. When discussing the commercial opportunity of a product, let's first start with the relevant patient population in the United States. Currently in the U.S., there are approximately 0.5 million patients that are on hemodialysis, but how many of them itch? Well, it's estimated by several sources that approximately 60% of the hemodialysis patient population has some level of itch. If we focus on the right-hand side of the graphic on the slide, up to 40% of the hemodialysis patient population have moderate-to-severe pruritus. It is this population of 200,000 patients that we will be focused on as this is the population most likely to be treated for their pruritus. It is also consistent with our proposed indication, which will be for hemodialysis patients with moderate-to-severe pruritus. Let's discuss what this moderate-to-severe pruritus is like for the hemodialysis patients who suffer from it. Chronic kidney disease-associated pruritus or, as we call it CKD-aP, is not your average etch that most of us has experienced like an insect bite or mild poison ivy. That type of itch is on the derma layer, localized and will often go away with little or no intervention or treatment. Typically, that itch has no impact on your daily life other than it's perhaps mildly annoying. CKD-aP is, however, completely different. It is a serious intractable systemic itch that can present over large surface areas of the body, typically in dialysis patients on their back, and that's very difficult to scratch. It can be unrelenting to the patient, and most therapies tried provide little or no relief. CKD-aP is so severe in many hemodialysis patients. It is associated with worsening quality of life, sleep disturbance, depressed mood or anxiety, impacting socialization and even an increased mortality risk. Because there are no approved therapies in the products that are tried off-label are generally ineffective, CKD-aP is truly an unmet medical need. Since CKD-aP is considered a serious medical condition and current therapies are generally ineffective, KORSUVA injection was granted by the FDA breakthrough therapy designation for CKD-aP, underscoring the need for such a product. When trying to understand what it's like to suffer from CKD-aP, it is probably best not to listen to me describe the disease, it's probably best to hear directly from the patients who suffer from it. [Presentation]

I'd like to take a minute to thank [ Jean ], [ Ivan ], [Mavis ], [ Joyce ], [ Michael ] and [ Kenneth ], for not only participating in our clinical trials, which is critically important in helping us get the drug approved, but agreeing to share with us what it's like to suffer from CKD-aP. Hopefully, you all now have a better sense of what it's like to suffer from this terrible disease. So now that we understand from patients that nothing really helps them with their itching, what do nephrologists currently do to try to help their patients even with the limited options they have available to them. To gain a better understanding of this, we conducted a qualitative market research study with a group of nephrologists to find out what they currently do to manage CKD-aP and how they would use a new product like KORSUVA injection. With no approved treatments, nephrologists will try multiple approaches and generally have limited success. First, nephrologists ensure that patients have optimized their dialysis as well as their calcium, phosphorus and parathyroid hormone levels. Although this can help some, it most often does not alleviate the itch in patients, particularly with moderate-to-severe pruritus. Although this is obviously a good clinical practice to optimize both the dialysis and the patient's hormone levels, regardless of whether the patient itches or not. Nephrologists will also recommend emollients, creams, lotions. But as you heard from the patients in the video, that typically doesn't resolve the itch. It helps with the patients' dry skin as most dialysis patients have dry skin regardless of whether they itch or not. Again, this is good clinical practice even if it doesn't help the itch. Nephrologists will then also consider antihistamines for patients who suffer from CKD-aP. Antihistamines are generally ineffective in alleviating the itch, as CKD-aP is not a histaminergic itch. They are, therefore, the wrong pharmacology for this type of itch. When we ask nephrologists about it, they generally say they're useful to help the itching patient sleep. When none of these conservative treatments work, nephrologists will sometimes consider trying other agents like gabapen or less frequently a dermatology consult where they might get UVB light treatment. The efficacy of these agents is considered generally marginal. And since there are concerns over the side effects, particularly in this patient population, they are not frequently used. So given the limited armamentarium that nephrologists have, where do they see a product like KORSUVA injection fitting into their clinical practice? Well, nephrologists do not envision KORSUVA supplanting lower-cost options like emollients and antihistamines, but rather would be added initially to conservative treatments like emollients and antihistamines, as there's little concern over drug-drug interactions or negative outcomes. This treatment approach, expressed by the nephrologist, is, in fact, how we study KORSUVA in our Phase III clinical programs. We did not have patients come off their antipruritic regimen they were on. They were mostly antihistamines. And we added KORSUVA on top of the existing therapy. And as you saw earlier from Joe's presentation, the data were the same, whether the patient was on any antipruritic regimen or not, which underscores the limited benefit of the existing therapies. Additionally, nephrologists mentioned that most CKD-a patients would be appropriate for KORSUVA based on the current product profile. We then asked nephrologists their reaction to the KORSUVA product profile. And when we asked, they were most impressed with the product's efficacy and adverse event profile, elistening very positive response. A couple of physicians even commented by saying there's nothing here to keep me from giving this a try. The side effects are quite low. And someone else said, for someone who is miserable with pruritus, of course, I'm willing to prescribe it. Why would I deny anybody this? When we asked how willing they were to use KORSUVA injection on a scale of 1 to 7, with 1 being very unwilling and 7 being extremely willing, physicians on average scored at a 5.5 or translates to very willing to prescribe KORSUVA. We then asked what percentage of the hemodialysis patients they would try KORSUVA on and nephrologists, on average, said 31% of their patients, which represents roughly half of the patients that itch in this marketplace. So overall, nephrologists had a very positive reaction to KORSUVA injection, and we're excited to be able to finally have a product that could help their moderate-to-severe pruritic patients. Another unique dynamic of the hemodialysis market is that it is a highly consolidated market. In fact, approximately 80% of the patients undergoing hemodialysis in the United States are dialyzed in 2 large dialysis organizations. Another 10% of the hemodialysis patients are dialyzed in the next 4 largest midsized dialysis organizations. Therefore, approximately 90% of the market is consolidated into 6 customers. This presents a unique opportunity to be able to get a quick uptake in this market as it doesn't take a significant reach or lots of sales activity and, more importantly, time to cover the hemodialysis market. Being successful quickly and the top 6 customers can drive rapid uptake of KORSUVA. We have seen this with the most recent launch into the hemodialysis space with Parsabiv. Parsabiv was able to achieve significant sales in its first 2 years of launch, has sold approximately $300 million in its first year and about $550 million in its second year. Therefore, a quick uptake in this market is very, very possible. And finally, we have put in place a partnership in the U.S. market, which we think can maximize the potential of KORSUVA that we've been talking about in my presentation and also to help drive a quick adoption in the key dialysis organizations that we were just speaking about. Last October, we expanded our partnership with Vifor Pharma to lead the launch of KORSUVA for the U.S. Originally, our partnership was just in the Fresenius kidney clinics in the U.S., but now they will lead the charge for all U.S. customers. Vifor as well as Fresenius Medical Care renal therapies group will bring an established nephrology commercial organization with over 200 sales, full-time equivalents. They currently sell key brands like Micera, Velphoro, Venofer and Veltassa. All of these products are used significantly in dialysis patients. They have existing relationships with key U.S., large dialysis and mid-dialysis organizations, which will help us get off to a rapid start that we discussed earlier. And additionally, Vifor has an established market access team plus a supply chain organization to help us launch this brand seamlessly. So in conclusion, because KORSUVA can address a significant patient population that is a true unmet medical need, will get strong support from the nephrology community and is launching into a highly consolidated market with an experienced nephrology partner, which will be able to maximize the benefits of KORSUVA, we feel the KORSUVA injection is in excellent position for a highly, highly successful launch. And with that, I will thank everybody for joining our call today, and I will turn the presentation back over to Joe.

Thanks, Eric. I'm now going to focus on oral difelikefalin. Our strategic aim is that oral difelikefalin will be indicated as a broad antipruritic treatment. FC, a leading pruritus scientific body, has described the etiology of chronic itch. And here, we have extracted the key buckets which cause chronic itch. From the FC classification, and you can see here systemic dermatological or neurological disease that could lead and cause chronic itch. We hope to demonstrate that difelikefalin based on the mechanism of action, as was previously described by both Eric and Brian, that it could work broadly across different disease areas regardless of the underlying pathophysiology. As you know and I've shown earlier, that difelikefalin has shown to be effective in systemic itch due to chronic kidney disease. We hope to demonstrate that it will be effective in an inflammatory dermatological disease in our atopic derm study, and we've recently commenced our study in notalgia paresthetica, which will then assess the efficacy of difelikefalin in a neuropathic-driven itch. This slide is a reminder of the time lines for our clinical program. As I've shown you earlier and mentioned that the NDA for IV difelikefalin is currently under review by the FDA with an August PDUFA date, we're aiming to commence the Oral CKD program later this year, and that's in patients with stage 3 to 5 CKD. We'll have the data for the AD study in the near future and the PBC and notalgia paresthetica Phase II studies are currently ongoing. So let me delve into a little bit more detail on some of the programs. As you may recall, our Phase II study for oral difelikefalin in subject with CKD-associated pruritus, was a dose-binding study with subjects randomized equally to placebo, difelikefalin 0.25, 0.5 milligrams, 1 milligram daily for 12 weeks. The primary endpoint was the change from baseline in the weekly mean of the daily NRS and secondary endpoints included responder analyses, both a 3-point -- as well as a complete responder analysis, quality of life and safety assessments. The study met its primary endpoint with the 1 milligram dose, showing statistically significant versus placebo with a 4.4 mean change versus a 3.3 in the placebo group. We can see here the onset of action, and it was statistically significant at week 2, and they maintained efficacy throughout the 12-week period. And this is a very similar pattern to what I showed you earlier in the IV difelikefalin studies. 72.1% of patients achieved a 3-point improvement versus 57.9% in the placebo group. Although this was not statistically significant at week 12, when looking at the line graph, you can see that at numerous time points, there was a statistical significance compared to placebo, including at week 11. Here, we present the complete responders. Complete response was defined as 80% or greater of the daily NRS scores being equal to 0 or 1 in a week. And the data showed that all difelikefalin doses were statistically significant versus placebo, with almost 40% of subjects on the 1 milligram dose, achieving a complete response compared to approximately 15% of subjects on placebo. So in summary, difelikefalin met the primary endpoint in the weekly mean NRS score. And showed a statistically significant dose-dependent improvement across all doses compared to placebo. As the 1 milligram dose showed to be the most effective, this is the dose that we will be advancing to the Phase III clinical program. Although I didn't show you the safety data here in this presentation, it has been presented before and demonstrate that oral difelikefalin was generally well tolerated with a safety profile that is very similar to what we have seen in the Phase III IV difelikefalin program. We look forward to our end-of-Phase II meeting with the FDA coming up in quarter 2. Okay. Moving on to atopic dermatitis now. Our Phase II dose-binding atopic dermatitis study is assessing oral difelikefalin in subjects with moderate-to-severe pruritus, across the AD disease spectrum, so patients with mild disease and with severe disease. Of note, to keep in mind, patients with mild-to-moderate disease and patients with moderate-to-severe atopic disease, may both experience moderate-to-severe pruritus. So even those subjects may have milder skin lesions, they still make itch extensively and this group of mild-to-moderate patients, as you see here on the slide, make up 80% of the AD patients. And currently, the [indiscernible] systemic agents approved for this group of subjects. These subjects are managed only by topical agents. As you may know, there's only one systemic drug approved for moderate-to-severe AD, and that is dupilumab. I want to remind you of the design of our AD study. 401 subjects were randomized to the 0.25 milligram, 0.5 milligram or 1 milligram dose twice daily or to placebo twice daily. And this was given over a 12-week period during the double-blind treatment period. Subjects could then enter into a 4-week active extension period. The primary endpoint was the change from baseline in the weekly mean daily NRS at week 12. Our key secondary endpoint is a 4-point responder, which has been assessed as a clinically meaningful endpoint in atopic derm subject, and we have also included quality of life assessments, including sleep as well as safety assessments as secondary endpoints. And we look forward to the data in the near future. Lastly then, the last 2 programs are the notalgia paresthetica and the PBC study. We commenced on the notalgia paresthetica study earlier on this year. This is a proof-of-concept study, and we are assessing subjects who will be randomized to 2 milligrams twice daily on IV difelikefalin -- sorry, on oral difelikefalin and randomized -- or randomized to placebo twice daily. And this is subject to NP with moderate-to-severe pruritus. The double-blind treatment period is an 8-week treatment period in the study, and then they can move on to a 4-week active extension period. We are looking to randomize 120 adult patients. The primary endpoint, like the other Phase II subject studies, is the change from baseline in the weekly mean of the daily worst-itch NRS score. And then we have other endpoints, which include quality of life, including sleep, responder analysis and safety assessments. And then lastly, our PBC study is a Phase II study. This is a smaller study as primary biliary cholangitis is an orphan disease. The study is randomizing subject to difelikefalin, 1 milligram twice daily or placebo. And the primary endpoint is, again, a mean change in the NRS at 16 weeks, and we have some additional secondary endpoints and quality of life and safety assessments as well. So this brings me to the end of my presentation. I want to thank you for your attention. And I'll hand over to Tom now. Thanks, Tom.

Thank you, Joe, and good afternoon, everyone. My name is Tom Reilly, and I am the Chief Financial Officer at Cara Therapeutics. Today, I will be providing a brief financial summary of Cara Therapeutics. We have a strong balance sheet at Cara. As reported as of December 31, 2020, we had $252 million of cash and marketable securities. We do not carry any debt and had 49.9 million common shares outstanding. We do not provide forward-looking EPS guidance. However, we do expect our clinical trial costs to decline versus our historical trends. As the projected costs for our oral clinical trials are less expense than the historical costs associated with the IV clinical trials. Turning to our financial guidance as stated during the 2020 year-end earnings call, based on the projected costs for our clinical development plans and timing expectations, we expect that our current cash, cash equivalents and marketable securities will be sufficient to fund our operations into 2023. This projection does not account for any potential milestone payments or potential product revenue, under which we could receive under existing collaboration agreements. With that, I will now turn the presentation back to Derek for the closing summary and discuss upcoming milestones.

Thank you, Tom. Let me finish by summarizing our projected upcoming major milestones. With our KORSUVA injection NDA under priority review, we do anticipate approval in Q3 of this year and U.S. commercial launch thereafter. As we announced last month, our EU partner, Vifor Fresenius has successfully submitted the difelikefalin MAA to the EMA, and we anticipate a first half 2022 EU launch. On Oral KORSUVA, we're expecting top line data readout from our Phase II trial in atopic dermatitis, just a little later this quarter and from our PBC trial in the second half of this year. And we're currently on track to initiate Phase III programs in CKD-aP and atopic dermatitis in the second half of this year. So we look forward to updating you on all of our progress towards these milestones throughout the year. And with that, we'll now move to the Q&A session for today.

Okay. Let me see we're going to start with some general questions that have been rolling in. I think actually, this is ideal for you, Brian, and then I would say, Mark, and it's a general pruritus clinical incidence and prevalence question and what is the main patient burden as a consequence to that pruritus. Brian, if you want to go first on that?

Okay. So just to clarify, the question is, what is the prevalence of chronic pruritus burden.

Yes. How frequently do you see pruritus clinically? And what is the main patient burden?

Yes. It's -- in dermatology, it's the most common symptom. So it's very, very common. It's -- a chronic pruritus affects 15% of population. But in a dermatology clinic, I would say it's the vast majority of our visits. Does it mean it's addressed? No, not necessarily. It's a heavily kind of ignored component. So it's highly prevalent, and the burden is very significant as we try to underscore in some of -- in different ways throughout the talks, equivalent to chronic pain, maybe worse. So there's -- and there's also probably a tremendous amount of unmeasured morbidity associated with itch. So for an example, in atopic dermatitis, especially in children, what we often don't capture is that it actually ruins the lives of actually the whole household. The parents often have to take a lot of time off from work. They can't sleep in addition to the child and I think we have to think a little more broadly in terms of itch and its burden as well. I hope that fully I addressed it.

Very good. Mark, would you like to comment on that?

So we -- in atopic dermatitis, it's 100% of patients. Several years ago, we did a survey of psoriasis patients. And it emerged as the most troubling symptom. Admittedly, it's not as severe as the itching of atopic dermatitis, but it was the most single patient-reported outcome of significance. If you look at many of the other conditions that we take care of, and we spoke about some conditions like notalgia paresthetica neuropathic conditions, it is common. Pruritus of the elders, itching of the elderly, extremely common. So it is a very common disorder. And Brian alluded to this, the divorce rate in the parents of children with atopic dermatitis is enormous. There's actually a funny issue, which says the baby's T-shirt says, "If I don't sleep, nobody sleeps." And that is accurate. It ruins the life, not only of the person affected, but family members as well.

Yes, very good point, Mark. There's a follow-up question. I think emanating from your clinical presentation, Mark. And it relates to pruritus and aging. Is the correlation of result of underlying etiology, such as chronic kidney disease, or a result of changes in the inflammatory or neuropathic pathways as we age? Do you want to start on that one, Mark?

So I'm not sure I understood the question, but everything that you said is correct. There are many causes of itch, renal failure clearly is associated with itching. And then as you age, there are changes that happen, both in the way your nerves travel through your muscles and in the spine. So when we take radiographic images, x-rays of the spine of patients with notalgia paresthetica, for example, invariably, we see degenerative changes. We see these changes that you get with aging, which speaks to the cause of those neuropathic changes, which is contingent pressing on those nerves that causes itch. So there are many causes of itching.

Brian, do you want to comment on that?

Might be also getting at whether the reduction in renal function in the elderly might also be a contributory factor for the aging. I'm going to say that's not a major factor. Those are fairly independent events, in my opinion. Of course, elderly people have often mild renal function, but that's not what is driving the itch in the elderly decline. The kind of uremic itch that we [indiscernible] somewhat step up from the aging. Of course, there's some overlap.

Right. Now a couple of questions on atopic. Joe, I think this is probably ideal for you. How do you see oral KORSUVA positioning in atopic dermatitis versus Dupixent and upcoming JAK inhibitors?

Okay. Thanks, Derek. So the study that we are conducting in atopic dermatitis with difelikefalin is conducted as a monotherapy agent in a wide spectrum of patients with atopic dermatitis disease, both mild to moderate and moderate to severe. So quite unique and different to the current systemic agents, which are disease-modifying. We believe that the drug will likely be used more commonly in the mild-to-moderate space, where there's a greater unmet need for systemic agent. Currently, the patients are being treated only the topical agents. But not to say that it couldn't also be used in the moderate-to-severe space. It could likely be an entry drug for systemic therapy for patients with moderate-to-severe atopic dermatitis disease, especially with a more moderate patients. So to answer the question about dupi and the JAKs, they would likely be used prior to those. We think a little bit, I came from Celgene and I worked on apremilast and launched apremilast. It was such a successful drug because of it being sort of an entry into systemic therapy for other biologics. So I see difelikefalin working in the same way. And in addition, just to AD, the profile is likely quite different to the JAK profile we've just heard just again today that the FDA has extended their review period. So that profile -- safety profile may be quite different. And we'll, obviously, wait for the outcome, but that may also indicate where that drug with the JAKs may be used. And then one other thought as well is it could be used synergistically. It could be used in combinations and work synergistically with drugs like dupi. Not as if dupi clear pruritus 100%, so that could be an opportunity as well. So quite a broad range where we could position that.

Brian, would you like to comment on that?

The evolving landscape of how we interpret the burden of disease. So right now, based on clinical trial criteria and how payers would view atopic dermatitis, moderate-to-severe atopic dermatitis is completely determined by your rash and not your itch. But we know that there are patients out there who have very severe itch who would not be classified as severe disease. And that's a hugely unmet group of patients with atopic dermatitis. And I think it's very likely that what we're -- the terms reasonably like mild, moderate, severe may actually change, and we may be able to fill gaps in care through agents like this by addressing the itch much more primarily early.

And Brian, as a follow-up question, which relates to your mechanistic presentation. Why do we assume difelikefalin should work effectively in AD or pruritus associated with AD which is a result of an inflammatory itch. And we know that difelikefalin has a primary neuromodulatory mechanism. I'll let you start with that, Brian.

Yes. So I think what is interesting is that when you hear some of the testimonials for the patients, one of the -- they're saying things when I see in my patients. They say it's not on the skin, it's beneath the skin. What they're saying is they can feel it in their nerves. And what we're saying about atopic dermatitis is that at fundamentally, this inflammation to be translated to itch has to go through these nerves and their skin. And can we choke it off at that level? The drugs that we have right now were not conceived in that manner. And also, the way in which the drugs work are to simply block the stimulus that goes to those nerves. But I think that the way this drug might work is very different, where it would actually stimulate pathways that are actually there to restore you back to normal non-itch state and amplify those pathways in a way to get you back to normal, better. So this is not, in my mind, a way to replicate or just be yet another blocking agent for itch, but it actually works very differently. And I think that's very important. Mechanism of action is very important and diversity of mechanism of action is important because it indicates that you may be able to capture something about the disease that the current pipeline does not. And it would be complementary at minimum.

I thought what was intriguing about your data, Brian, was the importance of the a beta interaction where we know there is Kappa receptors expressed and inhibiting the sensory pathway, and we certainly know we inhibit C fiber activity directly. So there's really a dual neuromodulatory mechanism now that could be important for atopic. There's another gene general question, which I think we know the answer to, Mark, is and I think you may have covered this, but how frequently do you see neuropathic itch in the clinic?

Yes. So there's are no great statistics on the prevalence of neuropathic itch, but we see it very nominally. I told the survey when we had to look for patients for a clinical trial, we had no trouble locating 25 recent patients because we see notalgia paresthetica commonly. When residents start with me, they never heard of notalgia paresthetica. When they're with me for a month, they always see several cases. So it is a very common condition. Unfortunately, in the general population, it's overlooked all the time. Most physicians don't even know the term notalgia paresthetica. But once we have a drug for itch that works when they don't have a good explanation for itch, I think this will get used a lot.

And Mark, can you comment on any drugs you've encountered that have been in any way effective in that condition?

So as I mentioned in the talk, there's a very long list of treatments that have been used for notalgia paresthetica. And topical steroids are always used. They virtually never work. Capsaicin is used, makes the condition worse before it makes it better. And then if it does make it better, you have to keep using it or the condition recurs. So the failure rate is more than 90% for Capsaicin. Occasionally, gabapentin is used. And the dose that is effective in some patients, not most, is close to the dose that knock you out, makes you tired. So we have a long history of treatments that don't work well enough, which is why it's easy to recruit patients for this trial, an enormous unmet need.