Okay, let's get started. I think my mic's working. Okay. Well, good afternoon. Day two of the 35th Annual Piper Sandler Healthcare Conference. David Amsellem here from the pharma team, and we have Cara Therapeutics with us and the team, Chris Posner, CEO, Joana Gonçalves, Chief Medical Officer, and Ryan Maynard, Chief Financial Officer. So, lots to talk about and wanted to, as a general question, particularly for those listening in who are not as familiar with the story, let's just go through the milestones for the various clinical programs associated with oral difelikefalin or DFK. Just lay those out, and then we can go into some program-specific questions on the product. So maybe, Jo, I'll turn it over to you. Sure. Yeah. Absolutely. So most exciting, in December, we have the readout about the top-line data for Part A of KIND1, which is the atopic dermatitis study. And then next year, in the second half of next year, we have top-line data for COURAGE, which is a notalgia paresthetica. Mm-hmm. It's the part, first part of that study, and we have the phase three program readout, which is the KICK program for chronic kidney disease. Okay. So I guess let's start with atopic derm. Mm-hmm. And I wanted to get your thoughts on Part A of the study. Well, let's just go through the design- Okay. -of that study first, and then, I want... The question I had was really: Will there be enough there to inform a go, no-go decision on Part B? Okay. Let's go through the design of Part A. Yeah. Yeah. Just as a reminder. Yeah ... KIND1 has a Part A and a Part B. Mm-hmm. Part A is what we will be reading out next month, and that part of the study has four arms. Mm-hmm. It has two doses of difelikefalin added to topical corticosteroid. Mm-hmm. We have 0.25 twice daily and 0.5. Then we have a topical corticosteroid arm and oral placebo, and then we have a pure placebo vehicle arm. Okay. The study is 12 weeks long, and the primary endpoint is a four-point responder analysis for itch. This is Worst Itch? This is worst itch. Okay, got it. Absolutely. And, and so the study was always designed as an informative study to provide us with the information required to move into the Part B and KIND2, which are the pivotal part of the program. So they were designed to have the appropriate number of patients for us to be able to see a signal, a separation from topical corticosteroid, because that's the active comparator here. Mm-hmm. It wasn't designed to show statistical significance- Mm-hmm ... but really to show, for us to get enough information to be able to understand what the sample size needs to be- Mm-hmm and for us to choose a dose. Okay. So I guess... So it's not para for statistical significance. Mm-hmm. Forgive my ignorance here, but how do you use the information from that study? Yeah -to make an informed decision about dosing and sample size- Yeah in the Part B? Yeah. So it's our statisticians will be able to look at what the treatment effect is like in versus the topical corticosteroids- Mm-hmm -and take it from there and power up Part B and KIND2 appropriately. It was always meant to be done that way to de-risk Part B and KIND2. Mm-hmm. Because remember, this is the first time we are looking at it added to topical corticosteroids. Sure. You know, it would have been a bit foolish just going straight into the pivotal program without gathering more information, gathering the data, to be able to understand what the treatment effect was like. Mm-hmm. And so that's exactly what this is for. It's really to de-risk the pivotal program and to give us that additional information needed. So, the idea is, in the pivotal, you will look at DFK on top of topical corticosteroids? Yes. And I guess, is it your view that that's generally a more real-world paradigm- Yeah -or is that something, is that something the FDA communicated that they wanted? Yeah. Just help us understand- Yeah the thought process there. Yeah, we looked at monotherapy in our K phase two study- Yeah Because we just had no idea how the drug was going to work in AD. Mm-hmm. What we understood from that data was that it had a strong neuromodulatory effect. It was able to reduce pruritus, not so much on the skin lesions- Mm-hmm As such, for looking at a patient population with mild to moderate disease, we needed to then... The drug would be able to address the process, but you need something there to address the skin lesions. Okay. That's how it would likely be used in real-life practice. That's why the study was designed this way. It mimics how it will be used. Okay. Can you remind us what the inclusion criteria is in Part A- Yeah - regarding atopic derm severity? Yeah. And just remind us, what subgroups of patients did show that signal- Mm-hmm -that ultimately drove you to move into this, this program? Yeah. In this patient population, what the inclusion criteria is, patients need to have an IGA of at least two. They need to have some skin lesions. Mm-hmm. And we're capping it at 20% BSA. But importantly, we've enriched it for patients who have a BSA of less than 10%. Mm-hmm. We're really aiming to get the majority of patients, and that's what we landed up with. Okay. It's exactly that. 80% of the patient population have a body surface area of less than 10%. This is the mild to moderate? This is the mild to moderate. Right. But you need to be itchy, right? Right. So the baseline itch needs to be greater than or equal to five... and what we publicly announced just a couple of weeks ago was that the mean pruritus is greater than seven. Mm-hmm. That's exactly what we were looking for, patients with moderate lesions, but who are very itchy, and that's really the itch-dominant patient population. Itchy despite using topical corticosteroids or other modalities? Yeah. Yes. Yeah. An inclusion criteria, which is an important one- Yeah ... was that patients needed to have had an inadequate response- Mm-hmm ... to topical corticosteroids- Mm-hmm in the last three months for the pruritus, right? Okay. And so really not having had an effect with steroids. Okay. We then provided them with a topical corticosteroid for the study to address their skin lesions. Okay. Yeah. Okay. So that's, that's atopic derm. Yeah. I'm gonna continue on. Let's move on to notalgia paresthetica. Yeah. Just, and this is the one where I kind of look at this as having the strongest signal- Mm-hmm ... of the- Mm-hmm of all the clinical programs. So, just walk us through the design of the part A of- Yeah ... of that program. Yeah. So it's a dose-finding study- Yeah ... 'cause you may recall our previous study was a proof of concept. We had one dose. Mm-hmm. Just a high dose, 2 mg. So now we need to understand which dose to take forward into the pivotal program. We're looking at three doses. Mm-hmm. The lowest dose, 0.25 mg twice daily, the highest dose, 2 mg twice daily, and then an in-between dose, so 1 mg twice daily. Mm-hmm. That is given to the patients as monotherapy because these patients have no skin lesions. Yeah. Right? That means the disease is pruritus, and they may get some hyperpigmentation secondary to all the scratching. Sure. So, to use this monotherapy here, and it's also a shorter duration. It's eight weeks because, once again, just neuropathic itch, there's no inflammatory component, which may sometimes take a little longer to address compared to when you have an inflammatory component. That's why the other studies are 12 weeks. Mm-hmm. This is just pure neuropathic, so it's an eight-week study. Primary endpoint, again, a four-point responder analysis. Mm-hmm. At the end of that eight-week period, we'll look at the data and then assess what dose to take forward and what that sample size would look like as well. So, like atopic derm, this is not statistically powered? Not statistically powered. Okay. Yeah. So this will... It's very similar. Yeah ... idea. Strategizing, yeah. Yeah. Okay. Yeah. Okay. Yeah, just to give us information to be able to move swiftly. Otherwise, we'd be here forever trying to, you know- Yeah ... be powering it up, and really what's key is for the pivotal part of the program. Yeah. That will be powered up. So what does enrollment look like in, or pace of enrollment look like in, in notalgia paresthetica? Well, we've been very pleased. Yeah. We've been tracking according to what we had anticipated. The data that we had presented for our- Mm-hmm ... phase two study in the New England Journal, I think, definitely raised the awareness. Mm-hmm. And that certainly has been helpful for sure. A lot of interest in participating- Yeah ... in the study and a lot of interest from patients as well. Just to back up, because I don't think folks know as much about- Okay ... NP as they do atopic dermatitis. So when you think about NP, this is still primarily a dermatologist- Mm-hmm ... focused market. Is that right? Yes, correct. Okay. In terms of diagnosis, though, how difficult is it to ultimately get to a diagnosis, or how long are these patients on average dealing with this before they're saying, "All right, I gotta get seen? Yeah. I mean, it is pretty frustrating and burdensome to the patients because it is an intense itch. Sure. I mean, these patients, again, have a moderate to severe itch, so the intensity is high. It's in a location that they can't reach, so it's not as easily sort of managed just to scratch yourself or... And that's why the back scratcher was actually the thought to be developed for this itch. And you can't even really apply things. So I think the level of going to seek help is pretty low. Mm-hmm. The dermatologist is the doctor that they seek out first, and that is the most commonly- Mm-hmm ... the physician who treats these patients most commonly. And then, as far as diagnosis goes, it's quite a typical history and presentation, so it gets diagnosed quite easily, just clinically. Mm-hmm. So, you know, it's usually women in their mid-50s who have a very localized itch. Often it is associated with pigmentation- Mm-hmm ... even, like, thickening of the skin as well. Mm-hmm. Once they're at the dermatologist, the diagnosis is made quite easily. Okay, that's helpful. So CKD. So, just continue- Yeah ... down the list here. So walk us through the design- Mm-hmm ... of that program. Yeah. Yeah. So CKD, it's advanced patients with CKD, so patients with stage four and five- Mm-hmm ... who have as well moderate-to-severe pruritus. So it's two pivotal programs and twelve-week studies compared to placebo. These patients are allowed to be on the background of meds. Mm-hmm. Just like we've done, we did the IVCOM program, and so they're allowed to be on the background. And, it's a 12-week treatment period, and at the end of the 12 weeks, then they go into an open extension. They go into a long-term extension program. And that's tracking as per- Mm-hmm ... our anticipated timeline. Mm-hmm. The two programs, one is U.S., one is U.S. plus ex-U.S., so it's a global study. Just to be clear, these are patients more or less with stage four CKD. Yeah. I mean, you are including some stage threes, if I'm not mistaken. No stage two. No stage two. Yeah. Okay. So based on the phase two study- Okay ... you know, the stage three, the characteristics of the pruritus in stage three is quite different- Mm-hmm ...to the stage four and five. A little bit more labile, responsive to topicals, not as long a duration, and as such, they had contributed a little bit more to the placebo response. Yes. Trying to get more of a pure CKD patient population focusing on the advanced. What portion of patients are stage five non-dialysis in the studies? In the studies? It really tracks according to the Epi Data. Yeah. It's a smaller proportion- They're smaller? -of patients. Yeah, you got one million, 1.2 million total, and most are stage four. So most of the patients will be stage four? Stage four. Yeah. Yeah. Okay. So in terms of the opportunity here, and then I'll sort of, you know, bring the discussion around to KORSUVA a little bit. Mm-hmm. We know that, you know, commercially, things didn't pan out. But I guess to the extent that oral DFK works here, I mean, KORSUVA works, It works great. To the extent that oral DFK works in CKD patients, why would market dynamics turn out to be different than what transpired with KORSUVA? Well, I mean, it goes to the main reason why the KORSUVA injection in the U.S.- Mm ... has not performed like we all thought it would. Sure. That's due to reimbursement. Yep. I think what you really need to understand is that the dialysis reimbursement system is incredibly unique. Yep - unlike any other system in the United States. How it's reimbursed is via a bundle amount, right? Sure. So it doesn't follow the patient in terms of if they get the drug, they get reimbursed. If you turn to our oral, specifically on CKD- Mm-hmm ... you know, that's more in a traditional reimbursement model. Right. Right? With you know, commercial insurance, government insurance, but outside the bundle, there's no bundle system, something we're all used to. I think the critical thing, especially if we're focused on CKD, is nephrologists really like this product. Yeah. So just coming back to the dialysis setting, there is a TDAPA period. Yep. Right. So I guess I'm a little bit confused, because there is the TDAPA period, and the volumes, you know, and it was reimbursed, so the volumes- Mm-hmm. But the volumes weren't there, so is it really just reimbursement? That was the- Yeah, it's the primary reason, David. I mean, we always kinda knew that one of the things that hamstrung this drug, even in the early days- Yeah ... was the uncertainty of the post-TDAPA period. So yeah, you're right. We did get reimbursement under TDAPA for two years. Sure. We're still in that period where it is reimbursed outside the bundle, clearly, and there is a financial incentive, to a degree, for these centers to use it. However, what we heard loud and clear from a lot of nephrologists was this fear of, is funding gonna be available after the TDAPA period? And if there was gonna be no funding, well, if they started patients on therapy, you know, in their mind, they're like, "We're gonna have to be forced to stop patients- Sure - when TDAPA ends." So I think it's always been this overhang. Mm-hmm. You know, clearly, we saw when they came out with the rule a couple weeks ago, right? We already saw one of the implications. I mean, Fresenius- Mm-hmm has been a huge customer. They've got almost 1,600 clinics dosing patients, which is great. That's almost 60% of their clinic base. Right. They took the inventory they had purchased in Q3 of last year. They took the remaining inventory of the 1,000 clinics that weren't using it- Mm Put it right into the clinics that were, meaning that basically telling people, "Don't start new patients on therapy. Right. Okay. Let's come back to oral DFK now. So just looking at the asset strategically- Mm, mm ... just, how are you thinking about it in terms of, possibly partnering it out or, you know, other strategic options, particularly given the state of the capital structure? Well, I mean, listen, all three oral programs have- Mm a lot of value. That's why we've invested dollars in it. You know, our narrative has changed slightly, obviously. We thought the funding for those programs was gonna be on the backbone of IV KORSUVA, specifically- Milestones, the milestones. Right. Right. So, you know, we've had to adjust, and one thing we did to, you know, kind of add to our balance sheet was, you know, what Ryan alluded to in the Q3, we did a royalty monetization deal, and we basically gave our royalties to Healthcare Royalty Partners for about $40 million. That's for ex-U.S. and Japan. Mm-hmm. So as we think about these programs, I mean, you know, we're in late stage programs. We now could fund these programs through key data milestones into 2025. Mm-hmm. So I could get the readout for AD. I could turn over the data card for CKD. In the second half of next year, I could turn over the data card for the COURAGE study for notalgia paresthetica. Yeah. All three of those are very important value inflection milestones for us. Mm-hmm. We're able to do that within the capital structure we have now. We certainly, you know, to kind of complete the AD study, specifically, we're gonna need to look for other, you know, capital raises. Now, one thing you mentioned about partnerships- Mm-hmm ... I've been very public about, you know, we don't have an intention to commercialize outside the United States. Sure. Those discussions are ongoing with other companies. Look, you know, again, our oral, you know, franchise is unencumbered. We own all the economic rights to that. Mm-hmm. So we're clearly looking for partners outside the U.S. that can maximize the value of this brand. U.S., you know, it's a different story. Our intention is to go at this. Just given the where you are in terms of the capital structure and the business, is there one indication for oral DFK that you would prioritize over another? And that maybe that's a venture event or- Yep. Yeah, I'm not sure, but, you know, you've got two dermatology-focused indications. Sure. You have one nephrology-focused indication. You know, is there one that you would look at and say, "Okay, that's, that's- Yeah We're gonna... That's the horse we're gonna ride? Yeah, you know, I get this question a lot, and I always start, I always start by saying, I don't have a favorite child. Sure. I mean, they're all incredibly valuable in their own right, and we are straddling nephrology and medical dermatology. Clearly, as we progress, and that was our strategy, as we progress these, you know, thinking about commercialization in both areas becomes challenging for big and small company. Right. You know, at this point, you know, our goal is to turn over these data cards. Mm-hmm. You know, and then we have some optionality if indeed we deem we wanna do that. Okay. Okay, that's fair. Maybe a white space question- Right ... if you will. If capital wasn't a constraint in sort of a perfect world, this is a question for Jo maybe. Are there other clinical settings that look interesting outside of dermatology or just a different call audience together? I know this drug has had a long journey. Yeah. This molecule, I should say, has had a long journey. What other settings, if any? Yeah ... you know, have or could be worthy of exploration? Yeah, I mean, I think we, you know, targeted what we wanted to do, and it was to demonstrate that it has broad efficacy. Yeah. We've gone after the big buckets. Yeah. I think that's definitely demonstrated, you know, that the neuropathic, the inflammatory, and the systemic. Sure. I think, you know, with a longer runway, you could, you know, just do some additional studies down those areas into other disease areas, within those buckets. But, these really are the ones, the diseases we've chosen really reflect the biggest sort of disease areas within those buckets. And then it's just nice to generate more data. Mm. But I don't think there's anything that we're really missing. We look- No, I'd say they define chronic pruritus- Yeah ... which you said, and that's what we focused on. Yeah. Yeah. When you say it, you mean broadly speaking? Yeah. Broadly speaking. Right. I mean, there's certainly a lot of other conditions where pruritus is implicated. Sure. We obviously, we were working on a program in PBC. Right ... right, if you remember, and Mm-hmm. Mm-hmm Mm-hmm ... We made a strategic decision to stop that program. It was really hard to recruit. Mm-hmm. A lot of headwinds from the COVID days, you know, kind of persisted in the academic centers. And I think, you know, good companies gotta make those decisions, right? Yeah ... if we had all the money in the world, I still... the strategy is really solid, what we embarked on. Got a lot more work to do to kinda complete, you know, these phase III programs to get on the market. Outside of pruritus, though, I mean, this molecule has been evaluated in pain. Mm-hmm. Pruritus, broadly speaking. Outside of pruritus, I mean, are there other settings where you'd say, "Okay, maybe that makes sense, or maybe that's worth exploration with doing animal work? Yeah. Yeah. Can't think of anything. I mean, as you said, you know, we started off with pain. Yeah. It definitely works in the pain setting as well. Yeah. But I think for now, you know, pruritus is what we focused on, and that's, I think, our main goal. Okay. So in terms of cash flow runway- Mm-hmm ... I mean, there's the Healthcare Royalty Partners deal. You talked about potentially getting cash infusions from ex U.S.- Mm-hmm ... partners. Are there other ways that you could extend the cash flow runway beyond those, those things that we talked about? Yeah, I'll take that. And I wanna just add one- Yeah ... kind of clarifying point to your question- Yeah ...of, are you really sure that reimbursement is the reason that KORSUVA launch didn't go well? And why we're so confident in that, also, is the fact that, and this dovetails into the Healthcare Royalty deal, the drug is doing amazing in Europe. It's absolutely doing great. Mm-hmm. Part of the reason why Healthcare Royalty bought the royalties for that. The Japanese partner, Meiji Seika and Kissei, are also ecstatic about the launch. Mm. We were able to bring $40 million into Cara- Mm-hmm ... upfront, and so it certainly is reimbursement because there is no reimbursement issue in those countries. So the good news for us, and it's a relative kind of position, is that we can at least get through these next cards that we've discussed. Mm-hmm. You know, getting into 2025 is not exactly where I wanna be. I'd like to get much further than that, but we do have three value inflection points that are coming to us- Sure ... that hopefully will generate value for the company and kind of expose that value to the investor community. Are there any other ways in which you could extract value out of IV KORSUVA, in any way? I mean, the reimbursement dynamics- Right ... in the dialysis setting are certainly very unique. But once you take it out of that setting, you know, then it's much more, You can't really, you can't really take it out of the setting. Yeah. So, I mean, it's indicated- Always gonna be- Yeah, it's indicated. It's indicated, yeah. For dialysis patients, right? So it's- So you're with- It's almost straight. ... you're with the label, but that was- You're straitjacketed, essentially. Well, but that was- Yeah ... that was the idea of the oral, right? Right. That really opens up... That's the value unlock for this molecule- Right ... and for patients. You know, when you add up those three opportunities, you're looking at roughly four million addressable patients- Right ... across those three indications. But, I mean, to your question, I mean, listen, I mean, we, we have extracted value for IV KORSUVA outside of the U.S. I think it was a great deal we did. Shows the value of this drug. In the U.S., no, there's- you know, unfortunately, with the funding or lack thereof from CMS, you know, this, this product is going to... You know, we anticipate that demand and sales are gonna suffer. And I think the major thing, not to get on a soapbox, is patients are gonna suffer. That's why there's not a lot of innovation in the dialysis space. Mm-hmm. These patients are going to revert back to potentially antihistamines, which we know doesn't work. Mm-hmm. Gabapentin. So there's gonna be a lot of limitations there. And, you know, I think it's really a sad day for patients in this space, clearly, 'cause the patients that are on the product, we're hearing extremely positive feedback. And then you look at the reorder rates in the U.S., that confirms kind of what we're hearing from the sales reps and patients themselves, that this product is absolutely providing value. Last question, and we're out of time. Yep. Just overall strategic options for the company. How are you thinking about that? Well, we have... I mean, listen, our mission is to become the world leader in chronic pruritus. We haven't changed- Mm-hmm ... off of that North Star, David. Mm-hmm. We have three incredibly valuable programs that are in late-stage development. We've improved our cash runway with that deal to turn over those data cards that we think could be highly motivating to our shareholders and potential investors. Okay, great. Well, we're out of time. Thanks, everyone. Thank you. Thank you. Thank you.