Cara Therapeutics Inc (CARA) Q1 2021 Earnings Call Transcript

Cara Therapeutics Inc (NASDAQ:CARA) Q1 2021 earnings call dated May. 10, 2021.

Corporate Participants:

Jack Hildick-Smith — Investor Relations

Derek Chalmers — Chief Executive Officer, President, and Director

Thomas Reilly — Chief Financial Officer

Analysts:

hristopher Howerton — Jefferies — Analyst

David Amsellem — Piper Sandler — Analyst

Nick Rubino — Stifel — Analyst

Chi Tran — Bank of America Merrill Lynch — Analyst

Joseph Stringer — Needham & Company — Analyst

Oren Livnat — H.C. Wainwright — Analyst

Presentation:

Operator

Good afternoon and welcome to Cara Therapeutics First Quarter 2021 Financial Results Conference Call. [Operator Instructions]

I would now like to turn the call over to the CARA team. Please proceed.

Jack Hildick-Smith — Investor Relations

Good afternoon, this is Jack Hildick-Smith with Stern Investor Relations and welcome to Cara Therapeutics’ first quarter 2021 financial results and update conference call. The news release became available just after 4:00 PM today and 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 Investors 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 KORSUVA Injection for dialysis dependent CKD-aP, the expected timeline for conducting meetings with the FDA concerning the company’s product candidates, including Oral KORSUVA for NDD CKD-aP and AD-aP, 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 Cara Therapeutics’ filings with the Securities and Exchange Commission, including the Risk Factors 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, Cara 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, Cara’s President and CEO; and Cara’s Chief Financial Officer, Thomas Reilly.

I will now turn the call over to Dr. Chalmers.

Derek Chalmers — Chief Executive Officer, President, and Director

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 KORSUVA development pipeline in the first quarter of 2021, culminating with the FDA acceptance of our first NDA filing for our lead product candidate KORSUVA Injection. With priority review granted, we look forward to our PDUFA target action date of August 23 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 as planned to date. With our PDUFA date tracking for next quarter, our commercial license agreement with Vifor Pharma in place, we remain focused on preparation for the US launch of KORSUVA Injection in the second half of this year.

As a reminder Cara executed a strategic license agreement with Vifor Pharma in the fourth quarter of last year for the commercialization of KORSUVA Injection and US dialysis clinics. We’re confident that Vifor’s established US nephrology salesforce and relationships with US dialysis organizations, both large and small, will support increased launch momentum in adoption of KORSUVA Injection in the US marketplace. The financial considerations received on entering into the Vifor agreement contribute significantly to the current strength of our balance sheet, further to the terms of that agreement upon US regulatory approval for KORSUVA 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-US commercialization planning. We were also very pleased to announce in the first quarter that the European Medicines Agency accepted the Marketing Authorization Application for difelikefalin injection for the treatment of pruritus associated with chronic kidney disease and hemodialysis patients. The EMA will review the application under the centralized marketing authorization procedure under our 2018 license agreement with Vifor Fresenius. They will be responsible for the commercialization of KORSUVA 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 KORSUVA pipeline. We recently announced top line results from the KARE Phase II dose ranging trial of Oral KORSUVA 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 KORSUVA 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% of patients characterized by moderate to severe atopic dermatitis. Patients were randomized three tablet strengths of Oral KORSUVA 0.25, 0.5 and 1 milligram taken twice daily versus placebo for 12 weeks, followed by a four weeks of an active extension phase.

While KARE did not meet the main endpoints in the ITT population and 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 4-point responder analysis in the mild to moderate patient population with 32% of KORSUVA treated patients achieving a 4-point or greater reduction in NRS at week 12 versus 19% in the placebo group. These KARE 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 KORSUVA CKD Phase II trial, and effect size on the registration 4-point responder endpoint from which to design Phase III trials. With this in hand, we plan to conduct an end of Phase 2 meeting with the FDA to discuss the clinical path forward with the goal of initiating a Phase III program for Oral KORSUVA in mild to moderate AD patients by year-end. We also plan to present additional data analysis from the KARE trial at an upcoming medical meeting.

Moving on to our program in pre-dialysis 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 strengths of Oral KORSUVA 0.25, 0.5 and 1 milligram once daily and identified the 1 milligram tablets 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 pre-dialysis CKD patients, which would allow us to leverage the substantial clinical efficacy and safety data set, we’ve compiled with KORSUVA Injection and hemodialysis patients. The FDA has indicated the viability of Stage 5 pre-dialysis CKD patients as the population for a Phase III program and also indicated the potential to use data from our previous trials of KORSUVA Injection in dialysis patients to support an approval based on a single Phase III clinical trial. We believe this approach could be could provide an expeditious path to an NDA for Oral KORSUVA and pre-dialysis CKD patients, and we currently plan to initiate our Phase III program by year end. We also plan to continue our discussion with the agency on the potential inclusion of earlier stage CKD patients and the same program.

Before moving on to our ongoing trials with Oral KORSUVA, 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 KORSUVA trials.

Moving on to our program in patients with primary biliary cholangitis, we’re conducting an ongoing proof of concept Phase II trial of Oral KORSUVA in PBC patients with moderate to severe pruritus. As pruritus is a common symptom of cholestatic liver diseases, 20% to 30% of patients experienced pruritus, including up to 70% of patients with PBC. A 16-week trial is designed to evaluate the safety and efficacy of the 1 milligram tablet of Oral KORSUVA taken twice daily versus placebo. The primary endpoint is the change from baseline, the weekly mean of the daily 24-hour worst itch NRS 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 antibiotic applicability of KORSUVA across patient populations and underlying pathologies, we recently announced the initiation of a Phase II POC trial of Oral KORSUVA for the treatment of moderate to severe pruritus in patients suffering from Notalgia Paresthetica, a nerve disorder characterized by chronic pruritus in the upper to middle back. It is estimated that chronic pruritus effects up to 13% of the US population and about 8% of these patients suffer from neuropathic edge including Notalgia Paresthetica. There is currently no well defined treatment of NP and conventional treatments such as anti-histamines and topical steroids are largely ineffective. So there remains a significant opportunity for Oral KORSUVA 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 led the foundation for a very significant second half of 2021. We very much look forward to the projected approval and commercial launch of KORSUVA Injection. With a strong balance sheet, we’re well positioned to support our goal of initiating our Phase III programs in both atopic dermatitis and pre-dialysis CKD patients by year-end as well as continue to progress our ongoing Phase II trials in PBC and NP patients. And we look — and we will 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?

Thomas Reilly — Chief Financial Officer

Thank you, Derek. As a reminder, the full financial results for the first quarter 2021 can be found in our press release issued today after the market closed. Cash, cash equivalents and marketable securities at March 31, 2021 totaled $228.3 million, compared to $251.5 million at December 31, 2020. The decrease in the balance resulted from cash used in operating activities, a $23.7 million partially offset by proceeds of $0.7 million from the exercise of stock options. For the three months ended March 31, 2021 net loss was $23.3 million or $0.47 per basic and diluted share, compared to a net loss of $28.9 million or $0.62 per basic and diluted share for the same period in 2020. Total revenue was $1.9 million for the three months ended March 31, 2021 compared to $8.1 million during the same period of 2020. Revenue of $1.9 million during the three months ended March 31, 2021 related to the milestone payment, the company earned from Maruishi 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 31, 2020 which related to license fees earned in connection with the agreement with Vifor Fresenius Medical Care Renal Pharma.

Research and development expenses were $19.1 million for the three months ended March 31, 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 31, 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 cost for current clinical development plans CARA expects that is existing unrestricted cash and cash equivalents and available for sale marketable securities as of March 31, 2021 will be sufficient to fund our currently anticipating operating expenses and capital expenses 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.

Questions and Answers:

Operator

[Operator Instructions] Your first question comes from the line of Chris Howerton from Jefferies. Your line is now open.

Christopher Howerton — Jefferies — Analyst

Hi, thanks for taking the questions. I guess the first question would be just with respect to the KORSUVA Injection. Is there any CMC site inspection or anything like that, that we should be aware of that could be potentially going into the 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 5 patient population specifically, 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? So, thanks so much.

Derek Chalmers — Chief Executive Officer, President, and Director

Great, thank you, Chris. So on the first question on the site inspection, I do understand there has 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 23. Yes and then on the Oral CKD and the population moving forward there, so, you’re correct. So pruritus is more well-defined in the later stage CKD patients such as such as stage 5. In fact if you look at the prevalence rates and pre-dialysis stage 5 patients is very similar to that in hemodialysis patients. So we do see this as a population that should respond very well to Oral KORSUVA.

Furthermore using that population, we also think that stage 4 patients should and could be incorporated into that as a viable population for the same program as we believe these advanced stage 4 patients are eventually transitioning into stage 5 presenting with a higher degree of pruritus. So this patient population 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 KORSUVA Injection in hemodialysis patients and the advantage of focusing on that population as the FDA as acknowledging there is the possibility of moving forward with a single Phase III trial. So overall, and as you know, it’s been a major goal for us to obtain a label for Oral KORSUVA in pre-dialysis patients as expeditiously as we can. Overall, we’re focused on that group, it should be possible to have a smaller focused Phase III registration program with a single pivotal trial and we should be able to complete that in a shorter timeframe.

Christopher Howerton — Jefferies — Analyst

Yeah, okay.

Derek Chalmers — Chief Executive Officer, President, and Director

Does that answer your question, Chris?

Christopher Howerton — Jefferies — Analyst

Yeah. And 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?

Derek Chalmers — Chief Executive Officer, President, and Director

Yes, well, it could be both actually Chris, because from a logistical standpoint it is likely we would require a proportion of our patients to be in stage 4, as there 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 5. We’d like to include stage 4 patients and as I said, we’re continuing that discussion with the FDA, with the idea that we’d like to see both IV and V in that final Phase III program.

Christopher Howerton — Jefferies — Analyst

Yes. Okay. Very good. Well, thanks so much for taking the questions Derek.

Derek Chalmers — Chief Executive Officer, President, and Director

Thanks, Chris.

Operator

Thank you. Your next question comes from the line of David Amsellem from Piper Sandler. Your line is now open.

David Amsellem — Piper Sandler — Analyst

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 Parsabiv [Technical Issues] below 10% threshold. And is that something that’s pretty standard or something that the FDA will accept as the definition, the threshold for mild-to-moderate. Thanks.

Derek Chalmers — Chief Executive Officer, President, and Director

David, I don’t know if you’re on a cell phone, it is a very terrible line, but I think I got just both your questions. I’ll start with the latter one on the KARE data and our proposal to move forward in the mild-to-moderate AD population, which is I think what you’re asking. And that definition, we’ve used there is indeed a standard definition for the agency, mild-to-moderate would be 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 and accepted regulatory defined group and as you know, we certainly have many drugs that there are termed, 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 gained [Phonetic] anything from the experience with Parsabiv 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, Parsabic being the first to go through to TDAPA and that was in post-TDAPA reimbursement. Parsabiv was reimbursed at a price of approximately $17,000 a year. It’s really an additional calcimimetics drug. They are already oral generic equivalents out there, but this is an IV drug, which is given three times a week. If you look at the population with the rest parathyroid dysfunction is approximately the same size as the population we were addressing with KORSUVA Injection approximately 30% to 40% of the hemodialysis population. There was a very fast adoption, presumably because of ease of use of Parsabiv and in its first year, I think that was a drug that came in at around about $300 million in sales and up to over $0.5 billion in the second year. So we think Parsabiv [Phonetic] and for us is actually better than that we’re first-in-class breakthrough medication for the primary symptom for hemodialysis patients, there really are no alternatives. So yes, we have looked at that and thought that could be a reasonable surrogate for the potential we could see with KORSUVA Injection in that population. No, I think that was your question, but if I pictured it out wrong David then let me know.

David Amsellem — Piper Sandler — Analyst

No, that’s perfect. And I apologize for the bad connection.

Derek Chalmers — Chief Executive Officer, President, and Director

No problem. Thanks for the question.

Operator

Thank you. Your next question comes from the line of Annabel Samimy from Stifel. Your line is now open.

Nick Rubino — Stifel — Analyst

Hi, everyone. This is Nick on for Annabel. Thanks for taking our questions. Just building on Chris’ question about pre-dialysis population. I guess we kind of expected stage 4 to 5 patients to mostly beyond 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 II that you looked at specifically in this population? And then secondly, can you help us think about the Oral KORSUVA label going forward from this point? So if you use kind of a stage 5 pre-dialysis population and that goes in the label, will that relatively specific population limit the ability for KORSUVA to get that broad anti-pruritic label? Thank you.

Derek Chalmers — Chief Executive Officer, President, and Director

Great, thanks, Nick. I think there was four questions. Well, let me see if I can remember all of those. But in terms of the pre-dialysis patient population, the prevalence rates for late-stage, that’s IV and V patients is approximately 0.7%, so that’s roundabout 2 million patients in the US. Based on diagnosed CKD patients, a minority of these would be stage 5 and the median time patient would remain in stage 5 before transitioning to dialysis is a little under one year. So they are in stage 5 for a significant amount of time. And as you know, there is no approved therapies and it’s clearly a significant unmet need, in fact the rates of pruritus we see in stage 5 patients and late stage 4 patients is actually very similar to those we see in hemodialysis patients. So that’s a very significant unmet need.

And in terms of looking at these particular stages in our Phase II data set, we have looked at that and based on our Phase II 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 and 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 infect is on mean NRS change it’s approximately 30 points on late stage subpopulation versus approximately 50% of the very early stage 3 patients. So there is certainly is data we’ve already generated that that is the most sensitive patient population pre-dialysis.

In addition and importantly, because as you know, we looked at that quite carefully in our Phase II CKD study, the placebo rate is much lower and the stage 4 and 5 patients. So, and again we may 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 in potentially stage 4 and 5 patients is we have a larger effect size, we’ve already established a more controlled expected placebo response. And then of course we can use this data and frankly are using this data to make sure we can power the Phase III registration trial for significance on the responder endpoint. So I think those are all significant advantages of proceeding based on stage 5 and as we are in discussions, right now, including stage 4 in that patient populations and that would in itself would be a significant label as 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 III registration trial and we can access our already established safety database in hemodialysis patients. That’s going to be the most expeditious path to a label. Did that answer all four of them Nick or did I miss anything there?

Nick Rubino — Stifel — Analyst

No, I think you hit everything. Thanks for handling all the questions and thanks for the clarity.

Derek Chalmers — Chief Executive Officer, President, and Director

Yeah, thanks for the questions.

Operator

Your next question comes from the line of Jason Gerberry of Bank of America. Your line is now open.

Chi Tran — Bank of America Merrill Lynch — Analyst

Hello, good afternoon. This is Chi on for. Jason. Thanks for taking our question. I guess maybe the first one just a follow-up as a clarity. It sounds like the FDA had accept stage 5 as a viable patient population and you’re in discussion to incorporate stage 4 CKD patients into the Phase III program as well. Is Phase III sort of out of the question right now based on the commentary. And then a follow-up of that would be, do have they understand correctly or commercially you alluding to that doctors, the line between stage 4 and stage 5 is pretty blurry in such a way that if you can get approval in stage 5, you can [Indecipherable] doctors to stay in stage 4 patients as well. I guess my second or third question would be, can you talk about how often these patients, stage 5 fluctuated between pre-dialysis and post-dialysis and how should we think about sort of the commercialization of between Oral KORSUVA and an IV KORSUVA in this particular set of population? Thank you.

Derek Chalmers — Chief Executive Officer, President, and Director

Okay, thanks for the questions Chi. So, in order, then you are correct. So, the FDA has indicated in terms of moving forward with the Phase III program, we can certainly do that focused on stage 5 patients. And again they’ve indicated, there is a potential we have to use data from our previous trials in dialysis patients to support that approval and that was 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 III. So we are in discussions and you’re correct, when you look at the incidents of pruritus and degree of pruritus in stage 4 and 5 is actually quite similar and that’s going to be part of our discussions with the agency in 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 and there are certainly two distinct if you like populations there and our current strategy is to focus on the 4 and the 5. So ultimately, we’d like to see both of those stages on the label, is true that patients transition from particularly late stage 4 and to 5 in a relatively defined manner. And then as I said earlier, patients would remain in stage 5 pre-dialysis in a median range somewhere around just under one year. So there is a significant treatment period there for which Oral KRUSOVA would be applicable.

Another advantage in looking at this commercially of course, as we would be capturing if you like, these pre-dialysis patients earlier in the treatment cycle, and of course as we move to hemodialysis there will be candidates for KRUSOVA 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 5. We’d like to further expand that population in to Stage 4. 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. We understand the placebo there. There’s a large effect size and we could have high confidence, we should see Oral KRUSOVA efficacy in that particular patient group. Did I get everything there Chi?

Chi Tran — Bank of America Merrill Lynch — Analyst

Yes, got it. It is very clear. Thanks so much. May be just one follow-up from me. Just a confirmation that the indication in stage 4 — stage 5 and/or stage 4 CKD pre-dialysis patients, they will be reimbursed differently, and it will not be part of the CMS bundle or TDAPA payment consideration. Do I have it correct?

Derek Chalmers — Chief Executive Officer, President, and Director

You have that correct Chi. The pre-dialysis CKD patients would not be part of the ESRD bundle.

Chi Tran — Bank of America Merrill Lynch — Analyst

Awesome. Thanks so much.

Derek Chalmers — Chief Executive Officer, President, and Director

Thanks Chi.

Operator

Your next question comes from the line of Joseph Stringer from Needham & Company. Your line is now open.

Joseph Stringer — Needham & Company — Analyst

Hi, everyone. Thanks for taking our question. Switching up and PBC pruritus Phase II readout coming up in the second half here. Maybe help us understand or at least maybe set some expectations around the data readout herein and specifically the PBC patient population as it pertains to the 3-point responder analysis. How similar would you expect maybe placebo response rate there relative to CKD or AD in this trial? Thank you.

Derek Chalmers — Chief Executive Officer, President, and Director

Thanks. Joe. And thanks for the question on PBC. Of course, I think you remember, one of the main reasons we’ve initiated our Oral KORSUVA trial in that particular patient group as this is a patient group for which that older kappa agonist now 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 than 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 [Indecipherable], 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. And the issue with placebo seems to relate to the liability and early-stage patients as we saw on CKD fluctuating and that can offset the placebo response and lead to false positive. So we do expect that based on the data set there in terms of an older kappa agonist that placebo response will be much more behaved than PBC patients.

Joseph Stringer — Needham & Company — Analyst

Yes. Thanks for taking our question.

Derek Chalmers — Chief Executive Officer, President, and Director

Thank you.

Operator

Your next question comes from the line of Oren Livnat from H.C. Wainwright. Your line is now open.

Oren Livnat — H.C. Wainwright — Analyst

Thanks. Can you hear me?

Derek Chalmers — Chief Executive Officer, President, and Director

We can hear you Oren.

Oren Livnat — H.C. Wainwright — Analyst

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, was that — you said the FDA will allow you to do that or accept that, is that something that you pushed or that the FDA requested?

Derek Chalmers — Chief Executive Officer, President, and Director

So specifically what we were interested are and when we went there was, the idea that we could leverage our hemodialysis program with KORSUVA Injection. So there, we wanted to access that safety database, we wanted to propose since we had already established efficacy and 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 was very similar to hemodialysis patients in terms of the frequency, prevalence of the pruritus and degree of pruritus and they’ve also indicated that they would allow us to use data from our previous trials and dialysis patients and they look at approval based on a single Phase III trial. So that was the response from the agency. Our responses at stage 4 patients all really look very similar to stage 5, degree of pruritus, the prevalence of pruritus there. So our proposal as and we’re in dialog on this and would further define in the characteristics of 4 with a 5 as it that program should include both Stage 4 patients and stage 5. So the agency has acknowledged the strategy for stage 5, dialog continues as we want to include stage 4.

Oren Livnat — H.C. Wainwright — Analyst

So if I’m understanding correctly the primary — the imperative was to use IV data to your advantage and they said sure, if you stage 5 and you’re trying to broaden that a little bit?

Derek Chalmers — Chief Executive Officer, President, and Director

Yes.

Oren Livnat — H.C. Wainwright — Analyst

Okay, great. And then if I could follow-up. Are we sure that one Phase III then if you move forward let’s say and stage 5 below and just to keep the conversation simple, would suffice or there is some other variables with regards to drug effect size or safety out of that study that will — down the road, determine whether one or two Phase IIIs are necessary, assuming it works statistically.

Derek Chalmers — Chief Executive Officer, President, and Director

Well, again I think we have a high degree of confidence based on our Phase II data. We already have this if you’d like subgroup analysis on late stage 4 or 5 versus stage 3, so a bigger effect size, placebo is more controlled. So we have high confidence slightly KORSUVA, we’d have significant efficacy in the late stage pre-dialysis patients. So, yes, at the minute they’ve acknowledged if we concentrate on stage 5 there would be a path forward for a single Phase III trial. We’d like to expand that to include stage 4 and as a dialog that’s continuing.

Oren Livnat — H.C. Wainwright — Analyst

Okay, and if I may, I apologize. Just on dosing in stage — in Phase II, you settled on — after Phase II you said on the highest 1 milligram dose that was including a population across Stage 3 to 5. So if you move forward in stage 5 or late 4 to 5. How confident are you that you have that 1-milligram is the right dose still given that theoretically as the different average level of impairment renal impairment in that population?

Derek Chalmers — Chief Executive Officer, President, and Director

Right. So 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 II dose ranging. In the later stage patients the stage 4 and 5, and I mentioned this earlier, we do see a larger effect size. So the effect size there is in the region of 30 points and the earlier stage patients that effect size is approximately 50% of that. So we already have good data in hand from our Phase II trial. There’s a large effect size with KRUSOVA and that late stage population.

Oren Livnat — H.C. Wainwright — Analyst

So you are also comfortable with the safety profile of that dose.

Derek Chalmers — Chief Executive Officer, President, and Director

We are comfortable with the safety profile.

Oren Livnat — H.C. Wainwright — Analyst

Okay, great, thanks for the clarifications. Appreciate it.

Derek Chalmers — Chief Executive Officer, President, and Director

Thanks, Oren.

Operator

Thank you. There are no further questions at this time. Turning over back to you Dr. Chalmers.

Derek Chalmers — Chief Executive Officer, President, and Director

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.

Operator

[Operator Closing Remarks]