This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk06: Good afternoon and welcome to CARA Therapeutics First Quarter 2021 Financial Results Conference Call. All participants are now in a reason-only mode. There will be a question and answer session at the end. Please be advised that this call is being recorded at CARA's request. I would now like to turn the call over to the CARA team. Please proceed.
spk01: Jack Hildik- Good afternoon. This is Jack Hildik-Smith with Stern Investor Relations and welcome to Care Therapeutics first quarter 2021 financial results and update conference call. The news release became available just after 4pm today and can be found on our website at www.caretherapeutics.com. You may also listen to a live webcast and replay of today's call on the investor section of the website. 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 expected timing of the data readouts from the company's planned and ongoing clinical trials, the potential results of ongoing clinical trials, timing of future regulatory and development milestones for the company's product candidates, including the company's projected timeline for FDA review and potential approval and commercial launch of Corsuva injection for dialysis-dependent CKDAP, the expected timeline for conducting meetings with the FDA concerning the company's product candidates, including oral Corsuva for NDD, CKDAP, and ADAP, the potential for the company's product candidates to be alternatives in the therapeutic areas investigated, the potential impact of COVID-19 on the company's clinical development and regulatory timelines and plans, and the company's expected cash reach. 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 care therapeutics filings with the Securities and Exchange Commission, including the risk factor section of the company's most recent annual report on Form 10-K and its other documents subsequently filed with or furnished to the Securities and Exchange Commission. All forward-looking statements made in today's call speak only as of the date on which they were made, CARE Therapeutics undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Participating on today's call are Dr. Derek Chalmers, CARE President and CEO, and CARE Chief Financial Officer, Thomas Riley. I will now turn the call over to Dr. Chalmers.
spk03: Thank you, Jack. Good afternoon, everybody, and thanks for joining us on the call this afternoon. We have continued to make very important progress across our Kursuva development pipeline in the first quarter of 2021, culminating with the FDA acceptance of our first NDA filing for our lead product candidate, Kursuva injection. With priority review granted, we look forward to our PDUFA target action date of August 23rd of this year. Our interactions with the FDA on the NDA review have progressed on schedule, and through the completion of our mid-cycle review, no advisory committee is planned to date. With our PDUFA date tracking for next quarter, our commercial license agreement with V4 Pharma in place, we remain focused on preparation for the U.S. launch of Kursuva injection in the second half of this year. As a reminder, CARA executed a strategic license agreement with V4 Pharma in the fourth quarter of last year for the commercialization of Cursiva injection in U.S. dialysis clinics. We're confident that V4's established U.S. nephrology sales force and relationships with U.S. dialysis organizations, both large and small, will support increased launch momentum and adoption of Cursiva injection in the U.S. marketplace. The financial considerations received on entering into the VFOR agreement contribute significantly to the current strength of our balance sheet. Further to the terms of that agreement, upon U.S. regulatory approval for Cursiva injection, the company will be eligible to receive an additional $50 million common stock investment, and then post-launch be eligible to receive payments of up to $240 million in sales-based commercial milestones. Turning to ex-U.S. commercialization planning, we were also very pleased to announce in the first quarter that the European Medicines Agency accepted the marketing authorization application for difelocephalin injection for the treatment of pruritus associated with chronic kidney disease and hemodialysis patients. will review the application under the centralized marketing authorization procedure. Under our 2018 license agreement with V4 Fresenius, they will be responsible for the commercialization of Trasuva injection across European territories, with CARA eligible to receive tiered double-digit royalty payments based on annual net sales and up to $440 million in tiered commercial milestones all of which are sales related. The EMA is expected to render a decision in the second quarter of 2022. Moving on to progress on our oral Kursuva pipeline, we recently announced top line results from the care phase two dose ranging trial of oral Kursuva for the treatment of moderate to severe pruritus in mild to severe atopic dermatitis patients. The trial was a randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of oral cruciva for moderate to severe pruritus in 401 adult subjects with atopic dermatitis. Patients were stratified across treatment groups by disease severity, with approximately 64% of patients characterized by mild to moderate atopic dermatitis, and approximately 36 percent of patients characterized by moderate to severe atopic dermatitis. Patients were randomized to three tablet strands of oral Cruciva, 0.25, 0.5, and 1 milligram, taken twice daily versus placebo for 12 weeks, followed by four weeks of an active extension phase. While care did not meet the main endpoints in the ITT population, In a pre-specified analysis, a statistically significant change in the primary efficacy endpoint was observed in the mild to moderate patient population, which was evident at week one and sustained through the treatment period. A statistically significant improvement was also observed in the four-point responder analysis in the mild to moderate patient population, with 32 percent of Krasuva-treated patients achieving a four-point or greater reduction in NRS at week 12 versus 19% in the placebo group. These care results have provided key information related to a defined patient group that is mild to moderate, an active dose range, which corresponds to that observed in our previous oral Krasuva CKD Phase II trial, an effect size on the registration four-point responder endpoint from which to design phase three trials. With this in hand, we plan to conduct an end of phase two meeting with the FDA to discuss the clinical path forward with the goal of initiating a phase three program for oral cursiva in mild to moderate AD patients by year end. We also plan to present additional data analysis from the CAER trial at an upcoming medical meeting. Moving on to our program in predialysis CKD patients with moderate to severe pruritus. We have previously reported positive top-line results from our 12-week Phase II trial, evaluating the safety and efficacy of the three tablet strands of oral Cruciva, 0.25, 0.5, and 1 milligram once daily. and identified the 1-meg tablet strength to take forward into Phase III. To that end, we recently conducted an end-of-Phase II meeting with the FDA with the goal of defining a Phase III program in predialysis CKD patients, which would allow us to leverage the substantial clinical efficacy and safety dataset we've compiled with Gresuva injection in hemodialysis patients. The FDA has indicated the viability of stage five predialysis CKD patients as a population for a phase three program, and also indicated the potential to use data from our previous trials of Kursuva injection and dialysis patients to support an approval based on a single phase three clinical trial. We believe this approach could provide an expeditious path to an NDA, for oral Krasuva and predialysis CKD patients, and we currently plan to initiate our phase three program by year end. We also plan to continue our discussion with the agency on the potential inclusion of earlier stage CKD patients in the same program. Before moving on to our ongoing trials with oral Krasuva, Let me remind you that due to the ongoing COVID-19 pandemic and in accordance with the FDA's updated guidance for conducting clinical trials, we have implemented numerous clinical and operational measures to prioritize the health and safety of patients, our employees and study investigators, and to minimize potential disruptions to our ongoing clinical studies. Due to the entire CARA team's continued dedication and hard work, We remain on track to meet our main clinical and regulatory goals for the year and continue to enroll patients across oral Cursiva trials. Moving on to our program in patients with primary biliary cholangitis, we're conducting an ongoing proof of concept phase two trial of oral Cursiva in PBC patients with moderate to severe pruritus. As pruritus is a common symptom of cholestatic liver diseases, 20 to 30% of patients experience pruritus, including up to 70% of patients with PBC. Our 16-week trial is designed to evaluate the safety and efficacy of the one milligram tablet of oral Krasuva taken twice daily versus placebo. The primary endpoint is the change from baseline, the weekly mean of the daily 24-hour worst HNRS score at week 16. We aim to report top-line data from this study in the second half of 2021. Finally, with the goal of further establishing the broad antipyretic applicability of Kursuva across patient populations and underlying pathologies, we recently announced the initiation of a Phase II POC trial of oral Kursuva for the treatment of moderate to severe pruritus in patients suffering from Natalgia Parasitica, a nerve disorder characterized by chronic pruritus in the upper to middle back. It is estimated that chronic pruritus affects up to 13% of the U.S. population, and about 8% of these patients suffer from neuropathic itch, including metallurgia parasitica. There is currently no well-defined treatment of NP, and conventional treatments such as antihistamines and topical steroids are largely ineffective treatments. So there remains a significant opportunity for oral Kosova as a novel therapeutic approach here. And I'm happy to report that this trial is currently enrolling very well at over 20 active sites in North America. So overall, our progress through Q1 and recent months has laid the foundation for a very significant second half of 2021. We very much look forward to the projected approval and commercial launch of Cursiva injection. With a strong balance sheet, we're well positioned to support our goal of initiating our phase three programs in both atopic dermatitis and predialysis CKD patients by year end, as well as continue to progress our ongoing phase two trials in PBC and NP patients. And we'll be updating you on all of the progress across each of these programs in the coming quarters. So with that, let me turn it over to Tom to detail the financial results for the first quarter of this year. Tom.
spk10: Thank you, Derek. As a reminder, the full financial results for the first quarter of 2021 can be found in our press release issued today after the market closed. Cash, cash equivalents, and marketable securities at March 31st, 2021 totaled $228.3 million, compared to $251.5 million at December 31st, 2020. The decrease in the balance resulted from cash used in operating activities of $23.7 million, partially offset by proceeds of $0.7 million from the exercise of stock options. For the three months ended March 31st, 2021, net loss was 23.3 million, or 47 cents per basic and diluted share, compared to a net loss of 28.9 million, or 62 cents per basic and diluted share for the same period in 2020. Total revenue was 1.9 million for the three months ended March 31st, 2021, compared to $8.1 million during the same period of 2020. Revenue of $1.9 million during the three months ended March 31st, 2021, related to the milestone payment the company earned for Mariushi Pharmaceutical Company's first initiation of a Phase III trial for uremic pruritus in Japan. The company recognized $8 million of revenue during the three months ended March 31st, 2020, which related to license fees earned in connection with agreement with V4 Fresenius Medical Care, Reno Pharma. Research and development expenses were 19.1 for the three months ended March 31st, 2021, compared to $33.5 million in the same period of 2020. The lower R&D expenses in 2021 were principally due to a decrease in costs associated with clinical trials, partially offset by an increase in payroll costs and an increase in stock compensation expense. General and administrative expenses were $6.4 million for the three months ended March 31, 2021, compared to $4.6 million in the same period of 2020. The higher G&A expenses in 2021 were principally due to an increase in stock compensation expense and payroll costs. Other income net was $0.3 million for the three months ended March 31st, 2021, compared to $1 million in the same period of 2020. The decrease in other income was primarily due to a decrease in interest income and a decrease in net accretion income resulting from a lower yield on the company's investments in the 2021 period. Now turning to our financial guidance. Based on timing expectations and projected costs for current clinical development plans, CARA expects that its existing unrestricted cash and cash equivalents and available for sale marketable securities as of March 31st, 2021, will be sufficient to fund our currently anticipating operating expenses and capital expenditures into 2023 without giving any, in fact, any potential milestone payments or potential product revenue under existing collaborations. I will now turn the call back over to the operator for Q&A.
spk06: As a reminder, to ask a question, you will need to press star 1 on your cell phone. To withdraw your question, please press the down key. Please stand by while we compile the Q&A roster. Your first question comes from the line of Chris Howardson from Jefferies. Your line is now open.
spk07: Hi. Thanks for taking the questions. I guess the first question would be just with respect to the Corsuva injection. Is there any CMC site inspection or anything like that that we should be aware of that could be potentially gating going into that PDUFA date? And then the second question was with respect to the oral CKD trial. Just maybe if you could give us a little more color on how we should think about the stage five patient population specifically, you know, how does that relate to drug effect and variability, and perhaps you could put that in light of the recent atopic dermatitis results as well.
spk03: So thanks so much. Great. Thank you, Chris. So on the first question on the site inspection, I do understand that's been an issue for a number of moving PDUFA dates in the last few months. But today, we don't have any indication there is any issue in relation to site inspection. So, as I said in the summary, we're on track for that PDUFA date of August 23rd. Yeah, and then on the oral CKD and the population moving forward there. So, you're correct. So, provide us is more well-defined in the later stage CKD patients, such as stage 5. In fact, if you look at the prevalence rates in predialysis stage 5 patients, it's very similar to that in hemodialysis patients. So we do see this as a population that should respond very well to oral Cursiva. Furthermore, you know, using that population, we also think that, you know, stage four patients should and could be incorporated into that as a viable population for the same program, as we believe these advanced stage four patients are eventually transitioning into stage five, presenting with a higher degree of pruritus. It's a patient population that looks very similar to HD. We understand how that makes sense in terms of referencing the safety database we've already seen and established with Cursiva injection and hemodialysis patients. And the advantage of focusing on that population is the FDA is acknowledging that there's the possibility of moving forward with a single phase three trial. So overall, and as you know, it's been a major goal for us to obtain a label for oral cursiva in prediagnosis patients as expeditiously as we can. Overall, if we focused on this group, it should be possible to have a smaller focused phase three registration program with a single pivotal trial, and we should be able to complete that in a shorter timeframe. Did that answer your question, Chris?
spk07: Yeah. And, you know, I guess if I may, maybe just sneak in a follow-up here. So if you wanted to include the earlier stage patients into the program, is maybe one idea that you include them in any kind of open-label safety study, or would it be more towards efficacy-focused study for those earlier stage patients?
spk03: Yeah, well, it could be both, actually, Chris, because from a logistical standpoint, it's likely we would require a proportion of our patients to be in Stage 4 as they're going to be transitioning into Stage 5 just to get a long enough exposure for the long-term safety group there. So it could be both, both on the efficacy side and the safety side. We're including Stage 4. We'd like to include Stage 4 patients, and as I said, We'll continue in that discussion with the FDA with the idea that we'd like to see both four and five in that final phase three program.
spk07: Yep. Okay. All right. Very good. Well, thanks so much for taking the questions, Jay.
spk03: Thanks, Chris.
spk06: Thank you. Your next question comes from the line of David Absalam from Piper Sandler. Your line is now open.
spk08: Hey, thanks. So just a couple. First, just on the IV, and I realize this is a partnered product, but can you glean anything or any learnings from the experience of parsibiv, aponeurin, and all that kind of stuff? for how you think about . I know the last call is moderate population area above 10% or below 10% threshold. And is that something that's pretty standard or something that the FDA will accept as the definition of the threshold for mild to moderate? Thanks.
spk03: David, I don't know if you're on the cell phone. It was a very terrible line, but I think I got the gist of both your questions. I'll start with the latter one on the care data and our proposal to move forward on the mild to moderate AD population, which is, I think, what you were asking. And that definition we've used there is indeed a standard definition for the agency. Mild to moderate would be a BSA of less than 10, and moderate to severe would be 10 or greater, sometimes with the addition of an IGA designation for two and three being mild to moderate and then four being severe. So that is a standard definition. definition and accepted regulatory defined group. And as you know, we certainly have many drugs out there in Durham that are defined as used in mild to moderate atopic dermatitis patients. So that is standard. On the first one, I couldn't quite make out everything you said, but I think you were asking if we can glean anything from the experience with parsibiv in relation to hemodialysis patients and pricing and the success in terms of uptake of Parsabiv. Look, I think we can, and we discussed this before in terms of the differences between the two drugs, Parsabiv being the first to go through Tdapa and now is in post-Tdapa reimbursement. Parsabiv was reimbursed at a price of approximately $17,000 a year. It's really an additional calcium emetic drug. There are already oral generic equivalents out there, but this is an IV drug. It was given three times a week. If you look at the population where there is parathyroid dysfunction, it's approximately the same size as the population we were addressing with Cursiva injection, approximately 30 to 40% of the hemodialysis population. There was a very fast adoption, presumably because of ease of use of Parziviv in its first year. I think that was a drug that came in at around about $300 million in sales and up to over half a billion in its second year. So we think positioning for us is actually better and that we're a first-in-class breakthrough medication for the primary symptom for hemodialysis patients. There really are no alternatives. So, yeah, we have looked at that and thought that could be a reasonable surrogate for the potential we could see with cruciva injection in that population. Now, I think that was your question, but if I picked it up wrong, David, then let me know.
spk08: No, that's perfect, and I apologize for the bad connection.
spk03: Yeah, no problem. Thanks for the question.
spk06: Thank you. Your next question comes from Annabelle Samimi from Stifel. Your line is now open.
spk02: Hi, everyone. This is Nick on for Annabelle. Thanks for taking our questions. Just building on Chris's question about the predialysis population, I guess we kind of expected stage 4 to 5 patients to mostly be on hemodialysis at that point. So can you give us a sense of how many patients that's applicable for? And were there any data cuts in the phase two that you looked at specifically in this population? And then secondly, can you help us think about the oral Corsuba label going forward from this point? So if you use kind of a stage five predialysis population and that goes in the label, will that relatively specific population limit the ability for Corsuva to get that broad antipyretic label. Thank you.
spk03: Great. Thanks, Nick. I think that was four questions. Let me see if I can remember all of those. But in terms of the predialysis patient population, the prevalence rates for late stage, that's four and five patients, is approximately 0.7%. So that's around about 2 million patients in the U.S. Based on diagnosed CKD patients, a minority of these would be stage five. In the median time, a patient would remain in stage five before transitioning to dialysis is a little under one year. So they are in stage five for a significant amount of time, and as you know, there's no approved therapies, and it's clearly a significant unmet need. In fact, the rates of pruritus we see in stage five patients and late stage four patients is actually very similar to those we see in hemodialysis patients. So it's a very significant unmet need. And in terms of looking at these particular stages in our phase two data set, we have looked at that. And based on our phase two data, when we look at an analysis of our NRS change in stage 3 patients, so that's obviously the earliest stage 3A and 3B, versus the data we're seeing in stage 4 and 5, we do see a much greater effect size in the later stage patients. Perhaps not surprisingly, they have the more severe pruritus. In fact, on mean NRS change, it's approximately 30 points on late stage subpopulation patients. versus approximately 50% of that in the very early Stage 3 patients. So there certainly is data we've already generated that that is the most sensitive patient population predialysis. In addition, and importantly, because as you know, we looked at this quite carefully in our Phase 2 CKD study, the placebo rate is much lower in the Stage 4 and 5 patients. And again, we might expect that they have a more consistent pruritus of a higher degree than these earlier stage 3A and 3B patients. So the advantage here is moving a trial through and potentially stage 4 and 5 patients is we'd have a larger effect size and we've already established a more controlled expected placebo response. And of course, we can use this data and frankly are using this data to make sure we can power that phase three registration trial for significance on the responder endpoint. So I think those are all significant advantages of proceeding based on, you know, stage five, and as we're in discussions right now, including stage four in that patient populations, and that would in itself would be, you know, a significant label that's a large opportunity there for the drug. And again, perhaps the biggest advantage in that approach is timeline. So if we can move there with a smaller trial, again, potentially one phase three registration trial, and we can access our already established safety database in hemodialysis patients, that's going to be, you know, the most expeditious path to a label. Did that answer all four of them, Nick, or did I miss anything there?
spk02: No, I think you hit everything. Thanks for handling all the questions, and thanks for the clarity.
spk03: Yep, thanks for the questions.
spk06: Your next question comes from the line of Jason Derberry of Bank of America. Your line is now open.
spk05: Hello. Good afternoon. This is Chi for Jason. Thanks for taking our question. I guess maybe the first one, just a follow-up as a clarity. Sounds like the FDA had assessed stage 5 assay viable patient population, and you're in discussion to incorporate stage 4 CKD patients into the phase 3 program as well. Is stage 3 set up out of the question right now, based on the commentary? And then a follow-up of that would be, you know, do I have to understand correctly or commercially you're alluding to that doctors, you know, the line between stage four and stage five is pretty blurry in such a way that, you know, if you can get approval in stage five, you can leverage doctors to you in stage four patient as well. I guess my second or third question would be, can you talk about how often these patients, stage five fluctuate between predialysis and post-dialysis, and how should we think about sort of the commercialization between oral Corsiva and an IV Corsiva in this particular set of population? Thank you.
spk03: Okay. Thanks for the questions, Chi. So, in order then, you're correct. So, the FDA has indicated that In terms of moving forward with the phase three program, we can certainly do that focused on stage five patients. And again, they've indicated there's a potential there to use data from our previous trials in dialysis patients to support that approval. And that's going to allow us to leverage, as you know, over 1,500 exposures in dialysis patients. And the second major advantage would be approval based on a single phase three program. So we are in discussions, and you are correct, when you look at the incidence of pruritus and degree of pruritus in stage 4 and 5, it's actually quite similar. And that's going to be part of our discussions with the agency and further defining that patient population and the characteristics there. And that is quite different than the very early stage 3A and 3B. So at this point, in terms of defining the degree of pruritus and how that relates to, if you like, quality of life burden for the patients. There are certainly two distinct, if you like, populations there, and our current strategy is to focus on the four and the five. So ultimately, we'd like to see both of those stages on the label. It's true that patients transition from particularly late stage four into five in a relatively... defined manner, and then as I said earlier, patients would remain in stage five pre-dialysis on a median range somewhere around just under one year. So there is a significant treatment period there for which oral cruciva would be applicable. You know, another advantage in looking at this commercially, of course, is we would be capturing, if you like, these pre-dialysis patients earlier in the treatment cycle. And, of course, as they move to hemodialysis, there'd then be candidates for Krasuva injection as they move through the dialysis stage of the disease. So, right now, I think we have a defined path forward we can explore in stage five. We'd like to further expand that population into stage four. I think that it seems to make sense when you look at the characteristics of pruritus in those two stages. And as I said earlier, we have good data from our Phase II data set that, you know, we understand the placebo there. There's a large effect size, and we could have, you know, high confidence we should see oral Cursiva efficacy in that particular patient group. Did I get everything there, Chi?
spk05: Yeah, got it very clear. Thanks so much. Maybe just one follow-up from me, just a confirmation that the indication in Stage IV stage five and or stage four CKD prediagnosis patients, they will be reimbursed differently and it will not be, you know, part of the CMS bundle or TADAPA payment consideration. Do I have it correct?
spk03: You have that correct, Chi. The prediagnosis CKD patients would not be part of the ESRD bundle.
spk06: Awesome. Thanks so much.
spk03: Thanks, Chi.
spk06: Your next question comes from the line of Joseph Stringer. from Needham Company. Your line is now open.
spk09: Hi, everyone. Thanks for taking our question. I'll switch it up here and go with PBC provided the Phase II readout coming up in the second half here. You know, maybe help us understand or at least maybe set some expectations around the data readout here and specifically the PBC patient population as it pertains to the three-point responder analysis. How similar would you expect, you know, maybe placebo response rates or effect sizes relative to CKD or AD in this trial? Thank you.
spk03: Thanks, Joy, and thanks for the question on PBC. Of course, I think you remember one of the main reasons we've initiated our oral cursiva trial in that particular patient group is this is a patient group for which that older kappa agonist, now furafine, that's approved in Japan has received a label extension. So we have high confidence that the mechanism itself, that is kappa agonism, should be effective in relation to liver disease-related pruritus. The other aspect of going after PBC, it really relates to consistency in the pruritus. So there isn't a great deal of data out there in terms of pruritus trials. There is one set of data from nalfurophene where it seems as though the placebo is quite well-behaved in liver patients. But with this more consistent pruritus we see in PBC up to 70% of patients have moderate to severe. We do expect that placebo rate to be more controlled in that particular group. The issue with placebo rates seems to relate to the liability in early-stage patients, as we saw in CKD, you know, fluctuating, and that can upset the placebo response and lead to false positives. So we do expect that, based on the data that's out there, in terms of an older kappa agonist, that that placebo response will be much more behaved in a PBC patient. Did I get that, Joey? Yes.
spk09: Thanks for taking our question.
spk03: Thank you.
spk06: Your next question comes from the line of Oren Livna from HEWI. Your line is open.
spk04: Thanks. Can you hear me? We can hear you, Oren. Oh, great. Appreciate it. I'm sorry if I'm not fully understanding some of the language you're using, so just maybe you can make it more explicit. With regards to the oral CKD program going forward and the choice of going with Stage 5, you said the FDA will allow you to do that or accept that. Is that something that you pushed or that the FDA requested?
spk03: So specifically what we were interested on when we went there was the idea that we could leverage our hemodialysis program with Kursuva injection. So there we wanted to access that safety database. We wanted to propose, since we'd already established efficacy in hemodialysis patients with two large Phase III programs, that we proposed that we should have a single registration program to obtain a label. The FDA has indicated that that program could work if it's focused on stage 5 patients. As I said earlier, we understand stage 5 look very similar to hemodialysis patients in terms of the frequency, prevalence of their pruritus and degree of pruritus. And they've also indicated that they'd allow us to use data from our previous trials in dialysis patients and they'd look at approval based on a single phase three trial. So that was the response from the agency. Our response is that stage four patients all really look very similar to stage five. Their degree of pruritus, the prevalence of pruritus there. So our proposal is, and we're in dialogue on this, and we're further defining the characteristics of four with a five, is that that program should include both stage four patients and stage five So the agency has acknowledged the strategy for Stage 5. Our dialogue continues as we want to include Stage 4.
spk04: So I understand you correctly. The primary, the imperative was to use IV data to your advantage, and they said, sure, if you use Stage 5, and you're trying to broaden that a little bit. Yes. Okay. Okay. And great. And then if I can follow up, are we – sure that one phase three then, if you move forward, let's say in stage five alone, just to keep the conversation simple, would suffice? Or are there some other variables with regards to drug effect size or safety out of that study that would, you know, down the road determine whether one or two phase threes are necessary, assuming it works statistically?
spk03: Well, again, I think we have a high degree of confidence based on our phase two data. We already have this, if you like, subgroup analysis of On late stage, stage four or five versus stage three, it's a bigger effect size. Placebo is more controlled. So we have, you know, high confidence as likely Cursiva would have significant efficacy in the late stage predialysis patients. So yes, at the minute, they've acknowledged if we concentrate on stage five, there'd be a path forward for a single phase three trial. We'd like to expand that to include stage four, and that's a dialogue that's continuing. Okay, and if I may, I apologize.
spk04: Just on dosing, in phase two, you settled on, after phase two, you settled on the highest one milligram dose. That was, though, including a population across stage three to five. So if you move forward in stage five or late four to five, how confident are you that you have, that one milligram is the right dose still, given that that theoretically is a different average level of, you know, impairment, renal impairment in that population?
spk03: Right, so... You know, if we look at mean NRS change, which, as you know, is the most sensitive endpoint, the continuous endpoint we consistently use in our stage two dose ranging, in the later stage patients, the stage four and five, and I mentioned this earlier, we do see a larger effect size. So the effect size there is, you know, in the region of 30 points. In the earlier stage patients, that effect size is, you know, approximately 50% of that. So we already have good data in hand from our Phase II trial that there's a large effect size with Cursiva in that late-stage population. But you're also comfortable with the safety profile of that dose? We are. We are comfortable with the safety profile.
spk06: Okay.
spk04: Great. Thanks for the clarifications. Appreciate it.
spk03: Thanks, Oren.
spk06: Thank you. There are no further questions at this time. Turning over back to you, Dr. Chalmers.
spk03: Great. Thank you, Jerome. So thank you, everybody, for participating on the call today. I'd also like to thank the CARA team, our study investigators, and most importantly, the patients who continue to participate in our clinical trials. And we look forward to updating you again very, very soon. Have a great evening. Thank you, everybody.
spk06: Ladies and gentlemen, this concludes today's call. Thank you again for your participation. You may now disconnect. Have a great day.
Disclaimer