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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [18]
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Annabel, thanks for that. So you stuck in 3 questions. We'll do the last one first. So the safety exposure levels on the long-term safety trial is through 150 at 6 months and 40% of those are through the 1-year exposure level.
In terms of the clinical relevance on the 3 point. So you recall that part of the condition of breakthrough designation is to satisfy the requirement that the change we see in these patients in terms of reducing their moderate-to-severe pruritus is clinically significant. And we analyzed basically our Phase IIb data using the standard statistical-anchored approach where we look at NRS differences correlated with quality-of-life changes per patient and just a standard analysis to design -- to define clinical meaningfulness. And when we did that, we see a 3-point reduction, actually less than that, as being the threshold for clinical meaningfulness for a CKD-hemodialysis patient with moderate-to-severe pruritus. So in terms of what's a clinically significant reduction of U.S. and the FDA's view would be if we have statistical significance on your primary endpoint, that would be significant for that patient group. So that's where we are in clinical significance. And then I forgot what your second question was, Annabel?
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Annabel Eva Samimy, Stifel, Nicolaus & Company, Incorporated, Research Division - MD [19]
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Just can you remind us what the site overlap is between KALM-1 and KALM-2 and how predictive 1 trial could be for the next?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [20]
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Yes. So the latter part of that -- first of all, there's no site overlap between KALM-1 and KALM-2. We're very careful on that to maximize our enrollment. But the second part of that, of course, we're looking at the same pathophysiology, the same patient class. And so we assume the mechanism is going to be similar there in terms of the antipruritic effect for KORSUVA. So it seems likely that if we see significant effects in KALM-1, there would be good readthrough for KALM-2. We recognize there might be some variability, we're using different countries for KALM-2, we're using more sites. And that's all been built into the power assumptions for KALM-2, which is why, as you know, for KALM-2, we also have an interim conditional power assessment at 50% enrollment. Of course, we're going to guide after we complete that particular interim also. So it should be good readthrough, we recognized there might be variability differences as there are with all clinical trials, but we think we can accommodate that with the powering assumptions we made for KALM-2.
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Operator [21]
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And our next question comes from the line of Alan Carr with Needham & Company.
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Alan Carr, Needham & Company, LLC, Research Division - Senior Analyst [22]
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A couple of them. In the FDA, are there in particular secondary endpoints would you think are particularly critical? I mean behind the obvious one as the primary endpoint. And then also can you give us an update on the commercial prep? What's the strategy and timing around that?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [23]
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Yes. Thanks, Alan. So as you know, primary endpoint is the most important here for the FDA and our label ultimately, so that's the main endpoint for us. We don't anticipate any other quality of life endpoints. We'll make it to the label level. We are looking at a 4-point reduction also since that's been a well-used endpoint in non-CKD pruritus file, so we will have that data to use with the FDA and discussions there. But the main endpoint as always is our primary, and that's the main endpoint we need for our label. What was your second question, Alan?
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Mani Mohindru, Cara Therapeutics, Inc. - CFO & Chief Strategy Officer [24]
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Launch question.
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Alan Carr, Needham & Company, LLC, Research Division - Senior Analyst [25]
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One on commercial?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [26]
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Little early for launch prep. We'd like to get through at least the first Phase III trial and confirm efficacy there. But we have started the very initial stages of that and modeling out what we see as necessary in both sales force and economics to launch this product. And that's something we're going to talk about a little later in the year once that matures a little bit beyond the planning stages.
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Alan Carr, Needham & Company, LLC, Research Division - Senior Analyst [27]
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Can you give us a sense of what commercial prep, I guess, is triggered after a first positive [H3] or after meeting with the FDA? Any guidance around that? Or is it just too early?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [28]
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Yes. It's really logistics preparation and making sure we have everything in line for the necessary implementation of logistics across our various deployments, not just clinical, but we're going to be adding more people on our MSL groups, obviously, and then HR and legal and financial. So it's preparation. The switch from development to commercial organization, that kind of planning initially. And then as we get closer to the NDA and I have talked about this before, we already have ideas on the size of sales force here, we think it's very economical, affordable for Cara. We have some assistance in our U.S. launch with our Vifor Fresenius license arrangement. And so all of that we'll detail a little later in the year once we get past the Phase III data.
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Operator [29]
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And our next question comes from the line of Esther Hong with Janney.
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Esther Lannie Hong, Janney Montgomery Scott LLC, Research Division - Director of Biotechnology [30]
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So the first question, can you just speak to the severity of the CKD patients on hemodialysis who are enrolling in the study? How long have these patients been on dialysis? And then second, assuming positive I.V. KORSUVA trials, what other studies are expected to be required for ex-U. S. approval? And then along the same vein, under the terms of your agreement with Vifor Fresenius, what's the breakdown of the remaining $470 million in regulatory and commercial milestones?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [31]
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Yes. Esther, just to last one quick because I have it in my mind, it's $470 million. $30 million of that is regulatory. And $440 million is commercial. Obviously, peered by sales ex-U. S. And then as regards to the patients and severity of the pruritus really, from the Phase -- I don't have that data from the ongoing Phase III. But we know it looks similar in terms of their histories and from our Phase IIb data, the average patient was 5 to 6 years on hemodialysis and moderate-to-severe pruritus. So it seems similar patient types recruited and enrolled into our Phase III trial as we'd seen in our Phase II.
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Esther Lannie Hong, Janney Montgomery Scott LLC, Research Division - Director of Biotechnology [32]
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Great. And then for ex-U. S. filings?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [33]
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So European filings, as you know we can file in Europe. There is no approved product in Europe for that. So we don't need a comparator study. So we'd be using the U.S. package. In fact, our partners, Vifor Fresenius, would be using the U.S. package for filing in Europe.
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Operator [34]
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And our next question comes from the line of François Brisebois with Laidlaw.
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François Daniel Brisebois, Laidlaw & Company (UK) Ltd., Research Division - Healthcare Equity Analyst [35]
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Just a couple here. I was wondering you talked about just quickly the dual mechanism, neuronal versus anti-inflammatory aspects to it. Is there -- has there been any evolution understanding of which part might be more important and for which disease you can attack? As just you mentioned NASH, you mentioned PBC. And maybe going after PBC before NASH as a population. Is there any mechanistic reasoning? Or is it really that patient population seems to have an issue with pruritus at the time being?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [36]
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Yes. Frank, thanks for that. So yes, it's really the latter when it comes to liver patient choice, PBC pruritus tends to be more severe, more consistent, and that's the reason we think we could go after that.
We're not the first people to define the anti-inflammatory effect. We have the kappa receptor, there's a great deal of literature at that. We know the cell types involved and mechanistically, we know we can reduce and other compounds had been shown to reduce the pro-inflammatory cytokine pathways there.
So I think that is an important part of the mechanism here. And as you know, we have shown in our Phase IIb trials, we can see sustained antipruritic effects that last through 8 weeks. And we think a lot of that has to do with the anti-inflammatory benefits. There may well be a more immediate benefit from the inhibition the sensory afferents and -- particularly epidermis and dermis that relay the pruritus. But i think ultimately, it's that dual mechanism that's going to be important here. And since we think kappa is on a whole range of immune cells, the point we're making is regardless of whichever cytokine pathway is to the floor and whichever pathophysiology, this should be a mechanism. It should be effective across conditions rather than perhaps a specific biologic, targeting a specific cytokine that we know is elevated in a particular subgroup of patients.
So that's the mechanism that I think the patients can benefit from. It should be pan-antipruritic, if you like. And of course, that's something hopefully we're going to produce more data on in terms of mechanism and the anti-inflammatory effect as we run through these larger trials where we are looking at biologic markers as part of our exploratory measurement. So we hopefully will have that data in future calls to talk about, Frank.
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François Daniel Brisebois, Laidlaw & Company (UK) Ltd., Research Division - Healthcare Equity Analyst [37]
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All right. And I just -- so there's no -- is there for you guys kind of a reason why maybe things wouldn't translate as well from PBC to NASH just because it seems like -- and obviously, drugs aren't approved yet for NASH. But it seems like the pruritic effect is larger than may be expected. So is there any reason when you speak to hepatologists that this might be easier in PBC? Or we'll just have to see for that?
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [38]
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Yes. No. So -- look there's certainly a great need, that's the message we get in speaking to hepatologists and KOLs that there's a great need for effective antipruritics for that patient population. It looks as though we have more consistency in PBC. So for us, that makes sense as the first group we look at. It doesn't mean that ultimately we won't look at other groups within that heterogeneous population, but that consistency of response is important for our first clinical trial, and that's where we're going to focus initially.
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Operator [39]
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And I'm showing no further questions. And I would like to turn the conference back over to CEO, Derek Chalmers, for closing remarks.
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Derek T. Chalmers, Cara Therapeutics, Inc. - Co-Founder, President, CEO & Director [40]
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So thank you, everybody. Thanks for participating in today's call. I'd like to thank particularly the Cara team for all their hard work and commitment. I'd like to thank our investors, our study investigators and, most importantly, the patients who participate in our ongoing large clinical trials. And we look forward to talking to everybody again very soon. So thank you very much, everybody.
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Operator [41]
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Ladies and gentlemen, this concludes today's call. Thank you again for your participation. You may now disconnect. Have a great day.