Tvardi Therapeutics Inc (TVRD) 2021 Q1 法說會逐字稿

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

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 p.m. 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 time line for FDA review and potential approval and commercial launch of KORSUVA Injection for dialysis-dependent CKD-aP; the expected time line 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 time lines 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.

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 is 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 U.S. 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 in U.S. dialysis clinics. We're confident that Vifor'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 KORSUVA Injection in the U.S. 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 U.S. 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 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 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 to 3 tablet strengths of Oral KORSUVA, 0.25, 0.5 and 1 milligram taken twice daily versus placebo for 12 weeks, followed by a 4 weeks of an active extension phase.

While KARE did not meet the main end points in the ITT population in a pre-specified analysis, a statistically significant change in the primary efficacy end point was observed in the mild to moderate patient population, which was evident at week 1 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 end point from which to design Phase III trials. With this in hand, we plan to conduct an end of Phase II 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 3 tablet strengths of Oral KORSUVA: 0.25, 0.5 and 1 milligram once daily and identified the 1-mg 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 pre-dialysis CKD patients, which would allow us to leverage the substantial clinical efficacy and safety data set we've compiled with KORSUVA Injection in hemodialysis patients.

The FDA has indicated the viability of stage V 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 provide an expeditious path to an NDA for Oral KORSUVA in 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 in 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 experience 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 end point 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 antipruritic 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 affects up to 13% of the U.S. population and about 8% of these patients suffer from neuropathic itch, 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 laid 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 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?

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 of $23.7 million, partially offset by proceeds of $0.7 million from the exercise of stock options.

For the 3 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 3 months ended March 31, 2021, compared to $8.1 million during the same period of 2020. Revenue of $1.9 million during the 3 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 3 months ended March 31, 2020, which related to the 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 3 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 3 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 3 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 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 31, 2021, will be sufficient to fund our currently anticipating operating expenses and capital expenses into 2023, without giving any impact to 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.

(Operator Instructions) Your first question comes from the line of Chris Howerton from Jefferies.

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 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 V 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.

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 are 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 in more well defined in the later-stage CKD patients such as stage V. And in fact, if you look at the prevalence rates in pre-dialysis stage V patients is very similar to that in hemodialysis patients. So we do see do this as a population that should respond very well to Oral KORSUVA.

Furthermore, using that population, we also think that stage IV patients should and could be incorporated into that as a viable population for the same program, as we believe these advanced stage IV patients are eventually transitioning into stage V, presenting with a higher degree of pruritus.

So this patient population looks very similar to HD. We want to 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 is acknowledging that there is a 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, if we focus 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 time frame.

Does that answer your question, Chris?

Yes. 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 and -- or would it be more towards efficacy-focused study for those earlier-stage patients?

Yes. 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 IVs are going to be transitioning into stage V 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 IV -- we'd like to include stage IV patients. And as I said, we'll continue in that discussion with the FDA with the idea that we'd like to see both IV and V in that final Phase III program.

Your next question comes from the line of David Amsellem from Piper Sandler.

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 (inaudible) in conclusion (inaudible) for how you think about Parsabiv and IV KORSUVA? That's number one.

Number two, (inaudible) last call is (inaudible) focus 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, the threshold for mild to moderate?

David, I don't know if you're on a cell phone. It's a very terrible line. But I think I've got the gist of 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.

In 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 2 and 3 being mild to moderate and then 4 being severe.

So that is a standard definition and accepted regulatory defined group. And as you know, we certainly have many drugs out there in Derm 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're asking if we can glean 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 -- we discussed this before in terms of the differences between the 2 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 calcimimetic drug. There are already oral generic equivalents out there. But this is an IV drug. It's given 3 times a week. If you look at the population where there is parathyroid dysfunction, it's approximately the same size as the population we are 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 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 its second year.

So we think positioning for us is actually better in that we are 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.

Now I think that was your question. But if I picked it up wrong, David, then let me know.

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

Your next question comes from the line of Annabel Samimy from Stifel.

This is Nick on for Annabel. Just building on Chris' question about the pre-dialysis population, I guess we kind of expected stage IV to V 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 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 V 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?

Great. Thanks, Nick. I think that was 4 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 around about 2 million patients in the U.S. Based on diagnostic AD patients, a minority of these would be stage V. And the median time a patient would remain end-stage V before transitioning to dialysis is a little under 1 year. So they are in stage V 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 V patients and late stage IV 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 III patients, so that's obviously the earlier stage IIIa and IIIb, versus the data we're seeing in stage IV and V, we do see a much greater effect size in the later-stage patients. Perhaps not surprisingly, they have the more severe pruritus. In fact, it's -- on mean NRS change, it's approximately 30 points on late-stage subpopulation versus approximately 50% of that in the very early stage III patients. So there 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 this quite carefully in our Phase II CKD study, the placebo rate is much lower in the stage IV and V patients. And again, we may expect that they have a more consistent pruritus of a higher degree than these earlier-stage IIIa and IIIb patients.

So the advantage here is moving a trial through in potentially stage IV and V 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 that data to make sure we can power that Phase III registration trial for significance on the responder end point.

So I think those are all significant advantages of proceeding based on stage V and as we are in discussions right now, including stage IV in that patient populations. And that would in itself would be a significant label that's a large opportunity there for the drug. And again, perhaps the biggest advantage in that approach is time line. 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 patient, that's going to be the most expeditious path to a label.

Did that answer all 4 of them Nick, or did I miss anything there?

No, I think you hit everything.

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

This is [Chi] on for Jason. I guess maybe the first one is just a follow-up as a clarity. Sounds like the FDA has accepted stage V as a viable patient population and you're in discussion to incorporate stage IV 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 I have the understanding correctly or commercially you alluding to that doctors -- the line between stage IV and stage V is pretty blurry in such a way that if you can get approval in stage V, you can leverage doctors taking in stage IV patients as well?

I guess my second or third question would be, can you talk about how often these patients, stage V, fluctuate 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?

Okay. Thanks for the questions, [Chi]. So in order then, you're correct. So the FDA has indicated in terms of moving forward with the Phase III program, we can certainly do that focus on stage V patients. And again, they've indicated there is a potential there 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 incidence of pruritus and degree of pruritus in stage IV and V, it's actually quite similar. And that's going to be part of our discussions with the agency and further defining that patient population, the characteristics there. And that is quite different than the very early stage IIIa and IIIb. 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 2 distinct, if you like, populations there. And our current strategy is to focus on the IV and the V.

So ultimately, we'd like to see both of those stages on the label. It's true the patients transition from particularly late stage IV into V in a relatively defined manner. And then as I said earlier, patients would remain in stage V pre-dialysis in a median range somewhere around just under 1 year. So there is a significant treatment period there for which Oral KORSUVA would be applicable.

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 we move to hemodialysis, that then be candidates for KORSUVA Injection as we move through the dialysis stage of the disease.

So right now, I think we have a defined path forward we can explore in stage V. We'd like to further expand that population into stage IV. It seems to make sense when you look at the characteristics of pruritus in those 2 stages. And as I said earlier, we have good data from our Phase II data set. We understand the placebo there. There is a large effect size, and we could have high confidence we should see Oral KORSUVA efficacy in that particular patient group.

Did I get everything there, Chi ?

Yes, got it. Very clear. Maybe just one follow-up from me, just a confirmation that the indication in stage IV -- stage V and/or stage IV 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?

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

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

I'll switch it up here and go with PBC pruritus, the Phase II readout coming up in the second half here. Maybe help us understand or at least maybe set some expectations around with the data readout here and specifically the PBC patient population as it pertains to the 3-point responder analysis. How similar would you expect maybe placebo response rate or excises relative to CKD or AD in this trial?

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 is this is a patient group for which that older kappa agonist, nalfurafine, 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 nalfurafine, 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 rate seems to relate to the liability in 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 that's out there in terms of an older kappa agonist that, that placebo response will be much, much more behaved in a PBC patient.

Did I get that Joey or...

Yes.

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

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 V, was that -- you said the FDA will allow you to do that or accept that. Is that something that you pushed or the FDA requested?

So specifically what we were interested, Oren, 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 in hemodialysis patients with 2 large Phase III programs, that we propose that we should have a single registration program to obtain the label.

The FDA has indicated that, that program should work if it's focused on stage V patients. As I said earlier, we understand stage V looked very similar to hemodialysis patients in terms of the frequency and prevalence of the pruritus and the degree of pruritus. And they've also indicated to us they'd allow us to use data from our previous trials in dialysis patients and they look at approval based on a single Phase III trial.

So that was the response from the agency. Our response is that stage IV patients all really look very similar to stage V, the degree of pruritus, the prevalence of pruritus there. So our proposal is -- and we're in dialog on this and would further define in the characteristics of IV with a V is – that, that program should include both stage IV patients and stage V. So the agency has acknowledged the strategy for stage V. Our dialog continues as we want to include stage IV.

So if I'm understanding you correctly, the primary -- the imperative was to use IV data tier advantage and they said, sure, if you use stage V and you're trying to broaden that a little bit?

Yes, okay.

And then if I could follow up. Are we sure that one Phase III then if you move forward, let's say in stage V 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 will be down the road, determine whether 1 or 2 Phase IIIs are necessary, assuming it works statistically?

Well, again, and I think we have a high degree of confidence based on our Phase II data, we already have this, if you like, subgroup analysis on late stage, stage IV or V versus stage III is a bigger effect size, placebo was more controlled. So we have high confidence as likely KORSUVA would have significant efficacy in the late stage pre-dialysis patients.

So yes, at the minute, they've acknowledged if we concentrate on stage V, there would be a path forward for a single Phase III trial. We'd like to expand that to include stage IV and that's a dialog that's continuing.

Okay. And if I may, I apologize. Just on dosing in Phase II, you settled down -- after Phase II, you settled on the highest 1-milligram dose. That was though including a population across stage III to V. So if you move forward in stage V or late IV to V, how confident are you that you have that 1 milligram is the right dose still given that theoretically is a different average level of impairment -- renal impairment in that population?

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 IV and V, 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 in 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 that, there is a large effect size with KORSUVA 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.

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

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.

Ladies and gentlemen, this concludes today's call. Thank you again for your participation. You may now disconnect. Have a great day.