Good morning. My name is Liz, and I will be your conference facilitator. I'd like to welcome everyone to Cara Therapeutics call to discuss the top-line results of the KOMFORT phase II proof of concept study in NP. All lines have been placed on mute to avoid any background noise. After the speaker's remarks, there will be a question-and-answer session. If you'd like to ask a question during this time, simply press star and the number 1 on your telephone keypad. If you'd like to withdraw your question, press pound on your telephone keypad. Please be advised that this call is being recorded. I would now like to introduce Iris Francesconi, Chief Strategy Officer and Head of Investor Relations from Cara Therapeutics. Ms. Francesconi, you may begin the call. Thank you, Liz, and good morning, everyone. Earlier today, we issued a press release detailing our top-line results for the proof of concept study KOMFORT in notalgia paresthetica. The press release can be found on our website at www.caratherapeutics.com. You may also listen to a live webcast and replay of today's call on the investor section of the website. Participating in today's call are Chris Posner, Cara's President and Chief Executive Officer, and Dr. Joana Goncalves, Cara's Chief Medical Officer. Before we begin, let me remind you that statements made on today's call regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Examples of these forward-looking statements include statements concerning the timing of the company's planned clinical trials, potential results of ongoing and planned clinical trials, the company's planned future regulatory submissions and potential future regulatory approvals, timing of future regulatory and development milestones for the company's product candidates, the potential for the company's product candidates to be alternative for notalgia paresthetica, the size and growth of the potential markets for notalgia paresthetica, the potential for oral Difelikefalin to address additional pruritic indications, and the potential impact of COVID-19 on the company's clinical development and regulatory timelines and plans. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks are described more fully in Cara Therapeutics' filings with the Securities and Exchange Commission, including the Risk Factors section of the company's annual report on Form 10-K for the year ending December 31, 2021, and its other documents subsequently filed with or furnished to the Securities and Exchange Commission. All forward-looking statements contained in this presentation speak only of the date on which they were made. Cara Therapeutics undertakes no obligation to update such statements to reflect any events that occur or circumstances that exist after the date on which they were made, except as required by law. With this, I will now turn it over to Chris. Well, thank you, Iris, and good morning, everyone. You know, Cara Therapeutics' mission, our North Star, is to be the world leader in chronic pruritus. Chronic pruritus is often a severe, intractable, underserved problem for patients in a wide range of diseases. With limited therapeutic options for this condition, we have set out to develop a treatment, oral Difelikefalin, that may provide a clinical benefit independent of the underlying cause of pruritus. Now, due to its novel mechanism of action, oral Difelikefalin, or in short DFK, has the potential to treat pruritus across a spectrum of disease categories, systemic, dermatologic, and neurologic. Our clinical programs are targeted to actively exploring DFK in diseases in all three. Now, today's positive data helps to establish DFK's broad applicability with the potential in pruritus of neurological origin, specifically, notalgia paresthetica. This affirms that our core strategy is on target and on track. Now let me spend a moment on discussing the market opportunity in NP. The patient population is sizable. We estimate about 2.7 million adults have neuropathic itch, including NP. The disease is significantly underdiagnosed. We believe only a quarter of NP patients are under the care of a provider. Lastly, there are no FDA-approved therapies. Moreover, off-label treatments that are currently used have little or no efficacy or safety and tolerability concerns. There is a void. There is a void to fill from a medical perspective and an opportunity to capture from a commercial viewpoint. We believe we have a product candidate that may address both. Now, for a review of the KOMFORT top-line study results, I'd like to turn it over to Joana Goncalves, our Chief Medical Officer. Thank you, Chris. Welcome, everyone. I'm pleased to be able to share the exciting results of our NP KOMFORT study with you today. Before I present the data, I wanted to remind everyone of some of the salient features of Notalgia Paresthetica. Notalgia Paresthetica or NP, is a sensory neuropathy, and in fact, it is one of the most common form of neuropathic itch. It is characterized by a localized chronic pruritus in the middle of the back between and below the shoulder blades. The itch is often associated with a well-demarcated hyperpigmented patch, as you can see in these two photos. There's often thickening of the skin. Both the pigmentation and the thickening are due to the intense scratching. The itch is burdensome and can have a significant effect on the patient's quality of life. The treatment of NP is challenging since conventional treatments for pruritus and inflammatory dermatosis, such as antihistamines and topical steroids, are largely ineffective. Treatments like capsaicin cream or gabapentin are limited by compliance and tolerability issues. There are no treatment guidelines, and there are no approved therapies for NP. While the exact etiology of an NP is unclear, hypotheses have centered around a mechanical irritation along the spinal cord, either from localized muscle impingement or from spinal pathology, which then causes disruption of the cutaneous sensory nerves which supply the upper back. KOMFORT is the first robust randomized placebo-controlled study in patients with NP. This phase II proof of concept study assesses the efficacy and safety of oral Difelikefalin on reducing itch severity compared to placebo in patients with NP. Patients were randomized to receive either oral DFK at a dose of two milligrams or placebo twice daily for eight weeks. After the eight-week placebo control period, patients could enter a four-week active extension phase whereby placebo patients were randomized to active drug. The active extension period of the study is still ongoing, so I will only be presenting data from the placebo-controlled period today. Patients needed to have chronic pruritus with a baseline worst itch NRS score of greater than or equal to five. Once randomized, patients continued to report their daily worst itch intensity until the end of the study. Patients were washed out of all anti-itch medication prior to entering the study and were only allowed to take the study drug for their pruritus. The primary endpoint was a change from baseline in the weekly mean of the daily 24-hour worst itch NRS score at week eight. Other endpoints included the proportion of patients achieving at least a four-point improvement from baseline in the worst itch NRS score at week eight, safety assessment and quality of life assessment, including sleep. I will not be presenting the quality of life assessment on the call today as it was not part of the top-line data. Looking at patient disposition, a total of 126 patients were randomized across the two groups. One patient randomized to DFK withdrew consent prior to taking study drug and is not included in the analysis for safety or efficacy. The discontinuation rate was higher in the DFK arm compared to placebo, but the most common reason for discontinuation was due to adverse events. I will provide more details on the AEs leading to discontinuation when I review the safety data later on in the presentation. Based on patient demographics is in line with what we would expect based on the NP epidemiology data. The study enrolled a higher proportion of female patients with a mean age of 60, and the majority were white. Patients were overweight, with a mean BMI of approximately 28 across the groups. Patients had NP for a mean duration of eight to nine years, and the mean worst itch NRS at baseline was 7.6. Very similar to what we have seen across all our previous studies. The study met its primary endpoint. There was a statistically significant improvement in itch observed with oral DFK versus placebo in the mean change from baseline in the worst itch NRS at week eight. Patients treated with DFK had a mean change of -4 versus -2.4 in the placebo arm at week eight. The onset of action started at week one and was sustained through week eight. There was a statistically significant reduction in itch compared to placebo at all time points throughout the study. This pattern of efficacy with early separation from placebo and maintenance of effect is very similar to what has been seen in our other studies with DFK. Similarly, a significantly greater proportion of patients on DFK achieved a four-point improvement in the NRS score compared to placebo. As you know, this is the endpoint that regulators will be looking at in pivotal trials. 41% of patients on DFK achieved a four-point response at week eight, compared to 18% on placebo. Statistical separation from placebo was seen as early as week two and sustained through week eight. Moving on to the safety data. There were similar number of patients reporting at least one treatment emergent adverse event on DFK and placebo. Treatment emergent adverse events were mild or moderate in severity except for one patient randomized to placebo who had a severe event. There were no serious adverse events reported in the study. 12 patients on DFK and four patients on placebo discontinued due to an adverse event. The most common reason for discontinuations in the DFK arm were dizziness and nausea. Here you see the most commonly reported treatment emergent adverse events as defined by events that occurred at a frequency equal to or greater than 5% in the group. Nausea was the most commonly reported adverse event in the DFK group, with a similar incidence in the placebo group. Abdominal pain was also reported at a similar incidence across the groups. Headache, dizziness, constipation, and increased urine output were reported more frequently in the DFK group compared to placebo. These events are consistent with what has been reported across all studies with oral DFK. To conclude, oral difelikefalin demonstrated a strong antipruritic effect in patients with notalgia paresthetica. This phase II proof of concept study met the primary endpoint with strong statistical significance. The onset of action was rapid and sustained through week eight. There was a significantly greater proportion of patients on DFK who achieved at least a four-point improvement in the worst itch NRS, historically the regulatory endpoint for registrational studies. DFK was well tolerated with a consistent safety profile and with no new safety signals detected with a two milligram twice daily dose. We are thrilled with the positive result in this NP patient population who have no approved treatment options. The data confirms the potential for DFK to work broadly as an antipruritic agent across disease areas, regardless of the underlying etiology of chronic itch. In addition, it supports our understanding of the mode of actions of DFK, that the antipruritic effect may be strongly driven by a neuromodulatory mechanism. The efficacy and safety data support further development of DFK in NP. We plan to finalize the data analyses and to discuss the path forward with the FDA. Thanks for your attention. Let me turn it over to Liz to open the line for Q&A. If you'd like to ask a question at this time, please press the star then the number one key on your touchtone telephone. To withdraw your question, press the pound key. Our first question comes from David Amsellem with Piper Sandler. Thanks. Just have a couple. First, I guess with the data in hand, is this something where you may explore other pruritic settings where there's a neuropathic origin? I guess more broadly, how do you think about that now, knowing what we know? It seems that there's a much stronger signal here for oral DFK than what you had in the AD setting. Do you now pivot in terms of how you think about DFK going forward? I guess as a corollary to that question, you know, does this data and the stuff that this data make you in any way rethink how you're thinking about the AD program? Thanks. Thanks, David. I think it's an echo. That's better. Thanks, David. Let me first address your first question about other areas. We are focused on our key areas in AD, CKD, and of course now with NP. We'll review the data in totality and discuss further development paths. Regarding other programs, I mean, we remain very confident about our programs, our phase III program in CKD, as well as in atopic dermatitis. They've demonstrated antipruritic efficacy in the phase II studies. We are confident about the design of those programs. Keep in mind that, although we demonstrated that Difelikefalin has strong neuromodulatory properties, it has other antipruritic properties too, and other disease areas have mixed components, neuromodulatory, anti-inflammatory, et cetera. We're confident in the mechanism of action across all the other disease areas as well. Okay. That's helpful. If I may sneak in a follow-up, can you just talk about, you know, other pruritic settings where there is a neuropathic etiology? Maybe just provide specifics on, you know, what other populations might be appropriate. I realize I might be putting the cart before the horse here, but just thought it might be helpful to articulate, you know, the broader populations. Sure. Thanks, David. There are numerous other neuropathic itch and there's one that's quite similar to notalgia paresthetica, which is also a compression-like syndrome, which is brachioradial. Of course, then you get the peripheral neuropathies like the diabetic peripheral neuropathy, post-herpetic pruritus, post-herpetic episode. You get that as well. You get a scalp pruritus as well. There are also pruritic conditions. It's called anogenital pruritus, which is also neurogenic. There is a large group of neuropathic itch, and notalgia paresthetica remains the largest of the neuropathic itch conditions. Okay, great. Thank you very much, Jo. Our next question comes from Annabel Samimy with Stifel. Hi. Thanks for taking my question and congratulations on the data. Now that we have the data for two milligrams in neuropathic pain, I mean, we're seeing clear and early activity. I know you just kind of tried to answer this, but I want to drill down a little bit more. You know, is there any thought to the doses that you've chosen and specifically maybe for AD, since there's you know, I guess by general standards they're a healthier population and you have two parts to the study? You know, is it possible that you might consider a higher dose? Can you remind us as to how the drug-related discontinuations compare to the prior studies? You know, this higher dose is obviously maybe something that's causing that. Is there anything that you can do to manage the nausea, for example, like a titration schedule? I guess the last question again, and you tried to touch on this, I suppose, and I'm not sure that you're going to have an answer to this, but I know that it's been tossed around for some time. Could you be pursuing a formal pivotal program for NP or just leveraging this to get a broader label for all forms of itch? Thanks. Okay. Thanks, Annabel. First, let me tackle the two milligram dose. As a reminder, we selected the two milligram dose for notalgia paresthetica based on preclinical data in pain models, and it demonstrated that neuropathic pain required higher doses of Difelikefalin. We need to be careful of extrapolating some of these results to the other disease areas. We remain confident about the doses that we have selected in AD and CKD and would not change those doses. Those are the correct doses we believe. As far as the discontinuation rate, the discontinuation rate seen here in fact is very much aligned to what we saw in the atopic dermatitis study. We were anticipating such a discontinuation rate here in the KOMFORT study. We will of course likely need to do some dose finding moving forward, but we are not considering titration as part of at this stage the way we administer Difelikefalin. Regarding clinical studies moving forward, we will review the data in its entirety and we'll be having a discussion with the FDA, and we'll decide on the most appropriate clinical path forward for Difelikefalin in neuropathic itch. Okay, great. Thank you. Our next question comes from Daniel Wolle with JPMorgan. Good morning, guys. Congratulations on the data. A couple of questions here. One is, do you consider the duration of NP between the two arms as balanced, especially considering the standard deviation? Is that a contributing factor to the outcome? Two, what explains the increased urine output and frequent urination observed in the treatment arm? Is it because of an underlying disease? I don't believe we've seen that before. Or is it because of the increased dose? Last but not least, looking ahead, given what we know about Remitch working in PBC, with the same similar mechanism of action and today's positive results, what does this mean for what we should expect as potential outcome when that data reads out in the second half? Thank you. Thanks, Daniel. Let me start with your first question. The study was randomized and we believe that the two groups were equally balanced for a proof of concept study, so we remain confident in the data. The signal is very strong, so I don't think that there's any implications of maybe some small imbalances, possibly baseline characteristics. Regarding the urine output, this is a patient-reported outcome. The patients noticed that they were likely urinating more frequently. This is expected of a kappa opioid receptor agonist. The class of drug has a known aquaretic effect, which is a free water loss in patients with functioning kidneys. This is usually quite mild as we've seen here. These events were mild, and patients just need to drink water and hydrate orally. We haven't seen it reported in the other studies, specifically AD, as the numbers didn't quite meet a 5% threshold. There were a couple of patients, but very few patients. Then your last question regarding PBC, like I said, you know, we always need to be cautious about extrapolating data from one study to another, and, you know, we'll wait eagerly to assess that data at the end of the year. Great. Thank you. Our next question comes from Joseph Stringer with Needham & Company. Hi. Good morning. Thanks for taking our questions. Just one question from us on the placebo response rates. How do these compare These in NP, the phase II NP compare relative to the phase II AD and CKD trials, specifically on just the change in NRS, looks like, you know, 2.4 improvement, and then also the four-point responder analysis, 18% placebo here in the NP trial. How do those compare to the phase II AD and CKD? If you could remind us. Was the placebo response for NP in this trial in line with your expectations? Thanks for taking our question. Thanks. Thanks, Joe. The placebo response rate that we've seen here, I'll start with the last question. We really didn't have great insight into what to expect in the notalgia paresthetica. This is the first robust placebo-controlled study. This was indeed a true learning for Cara. We were very pleased with the response rate, and in fact, when you look across chronic pruritus conditions, very much in keeping with a placebo response. Regarding our other studies, it again, very consistent with the pattern of efficacy that we have seen. The range may differ a little bit, but within the ballpark, this is probably our strongest data. But the others are within the same range of about a one-point difference to placebo in the mean change. In the Atopic Dermatitis, I think you mentioned specifically, for the 4-point responder analysis, specifically in the mild to moderate patient population where we see the greatest, impact of Difelikefalin, in those patients, the placebo response was about the same. It was about 19, it was 19%. Very much in keeping, with this. We were very pleased with the outcome and consistency. Great. Thanks for taking our question. Our next question comes from Sumant Kulkarni with Canaccord. Good morning. Thanks for taking my questions. I have a few here. How would one expect, headache, dizziness, constipation, and increased urine output to change over time with chronic usage of oral KORSUVA? Asked another way, I guess, is how could these be managed in potential real-world usage of this product? How would doctors and patients think about the benefits of the product in treating underlying, NP versus these risks? First, I'd like to say we're very pleased with the safety and tolerability profile of the drug. It's very consistent with what we've seen before. For the two-milligram BD dose, the benefit risk profile was very good. In fact, this profile is very favorable for dermatologists specifically who'd be treating these patients. These events tend to occur early on, and they were mostly mild or moderate, and well-tolerated by patients. We think with the right expectations set by dermatologists to their patients, that this profile should be very acceptable to both physicians and patients. Got it. It's still quite early, but how long do you think a phase three trial in NP could take? Could you potentially get those results prior to obtaining phase three results in atopic dermatitis? We'll be reviewing the data in its totality, and looking at the clinical path, discussing it with the FDA. It's a little early to comment on that at the moment, Sumant. My final question is a two-parter. In the event that the company decides to prioritize NP, for example, would you have enough of a safety database to file in that indication alone? Because you have programs running in CKD, KD, AD, and PBC as well. The second part, specifically, what implications does the increased urine output adverse event in the KOMFORT trial mean for patients with non-dialysis dependent chronic kidney disease? Let me touch upon the safety database. We will always have to meet the required ICH guidance for safety requirements, regardless of which product goes, which disease area goes first. Regarding non-CKD, the aquaretic effect is predominantly an effect that is seen in patients with functioning kidneys. This is not seen in patients with hemodialysis. As patients' kidneys are less functioning than in the non-CKD patient population with advanced CKD, it should be less of an impact on those patients. Thank you. As a reminder, that is star then one to ask a question. Our next question comes from Jason Gerberry with Bank of America. Hello, this is Qi on for Jason Gerberry. Thanks for taking our questions. I guess the first one is you talked about on the slide, you know, over 650,000 addressable patients with NP. I'm hoping you can provide maybe some granularity or segmentation, sort of like within that, you know, what proportion of sort of in that chronic moderate to severe itch that have sort of, you know, already tried. What is sort of the standard of care for these patients, and what proportion of patients have sort of like tried all these standard of cares, topical and oral, and you know, need something else that, you know, that have an unmet need. I have a couple follow-ups after that. Thanks. Yeah, Qi, I'll take that one. So yeah, we believe, you know, from our analysis that the 650,000 is the addressable population. They're currently being seen by a dermatologist. More than likely, you know, they've been using some form of treatment, and Joe mentioned in the prepared remarks that the treatments are typically, you know, either antihistamines, topical steroids, or even to a lesser degree, capsaicin, maybe even a Gabapentinoid. You know, we feel pretty strongly that the 650,000 is the addressable population that would be applicable for this drug. Now, I would also, you know, state that this is significantly under-diagnosed disease, and you can see in the box I presented before, there's roughly 2.7 million patients that have some form of neuropathic itch, including NP. You know, we believe there's a very sizable opportunity, and given the void in treatments, you know, this could really fill that significant void. Great. I guess my second question is, I'm hoping you can contextualize the two-milligram BID dose. What's the systemic exposure of the two-milligram BID dose? How it compares to the one milligram QD dose used for the CKD population? I understand there's some differences in the PK because of the state of the kidney, but I'm hoping you can provide some color. Also, I think the team has talked about potentially doing some dose ranging study. Curious if this is something that the company is planning to do, you know, an additional phase II to sort of figure out the best dose forward, similar to sort of what you have done with oral CKD in the AD setting. Thank you. Okay. Let me start with the dose finding. Yes, it's the proof of concept study with one dose. We would likely have to do some dose finding. The two-milligram dose, you know, obviously a higher dose. When we look at exposures across the doses we've selected across our program, they really fall within the exposures required to activate the kappa opioid receptor agonist. It's within that required exposure to activate the receptor. We'll obviously need to do more work on the dosing to look at potential further doses in NP. This is a discussion internally and with the FDA. I just want to understand it correctly. Is it four times the exposure, two times the exposure, or less than 2 times of the exposure compared to the one milligram QD dose? We will have to get back to you on that. Okay. I guess my other question is interesting data. I guess that's why I have a few questions. Can you talk about these trial subjects before they were enrolled? Presumably they might be on some topical and systemic medications. Can you talk about what these medications are? You know, the patient's responsiveness to these medications, and whether it's a standard practice for an NP trial to exclude background medication once in the randomized control phase? Patients were washed out of all drugs that could have an impact on pruritus, prior to entering the study, and the washout depends on what drugs they were on. This is the first robust placebo-controlled study. There is no precedent on what has been done. Okay. I guess there's a capsaicin trial, but I guess it's not run in a contemporary setting. I guess broadly speaking, do you expect, you know, if you were to move forward with the late-stage development, do you expect the trial will exclude background medications similar to how this phase II is run? Or, if I recall correctly, your non-dialysis AD trials, that study allowed background medications. Good question. Qi, first to comment, we are the first to do a robust placebo-controlled study. There are numerous data out there on capsaicin, gabapentin, et cetera. These are not randomized clinical controlled studies, so one has to keep that in mind when reading that data. Good question regarding background meds. We do not anticipate that we would have to use this on any background meds. First of all, as we said, this is a neuropathic-driven itch and agents such as topical corticosteroids are anti-inflammatory agents, which are ineffective for this type of itch. We do not anticipate that, but of course, this will be a discussion with the FDA. I guess my last question is, can you provide additional color on these dropout rates? Are they pretty early, or do they kind of, you know, happen as the trial goes on? You know, when can we expect an update before follow up period data? Okay. First on the discontinuations, they occur very early, within the first couple of days. The patient is unable to tolerate, that's when they discontinue. Once they're on the study and they haven't experienced those events, they remain on the study. I think that's very good, especially for education that providers can give to their patients that these events occur early on. Your second part of the question was? When can we expect the four-week active? Oh, that's right. extension ongoing study? Yes. The four-week active extension, as I said, is still ongoing. The data is still to come. We'll look forward to that. Do keep in mind that is open label data, so not as robust as a placebo-controlled. Okay. Awesome. Great. Thank you so much for taking our questions. As a reminder, if you'd like to ask a question at this time, that is star then one. I'm showing no further questions in queue at this time. I'd like to turn the call back to Christopher Posner for closing remarks. Well, thank you, Liz. I first wanna thank, you know, the patients that participated in the study. I also wanna thank the investigators. Last but not least, a big thank you to our internal Cara team for their dedication and commitment. Now we're extremely encouraged with the results from this trial and really oral Difelikefalin has the potential to be a truly transformative therapy in notalgia paresthetica. Again, this is a disease area void of any approved therapies. It's a disease area where patients and physicians have really been seeking advancements. Today's data readout marks an exciting and impactful milestone in our journey to become the leader, the premier company in the treatment of chronic pruritus. With that, I'd like to thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.