Tvardi Therapeutics Inc (TVRD) 2020 Q1 法說會逐字稿

Good afternoon, and welcome to Cara Therapeutics First Quarter 2020 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 2020 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 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 the submission of its first NDA; the potential for the company's product candidates to be alternatives in the therapeutic areas investigated; 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 annual report on Form 10-K for the year ended December 31, 2019, 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 Mr. Rick Makara, VP and Head of Accounting. I'll now turn the call over to Dr. Chalmers.

Thank you, Jack. Good afternoon, everybody, and thanks for joining us today.

So our first quarter and recent progress, in many ways, culminated in positive top line data from our KALM-2 global Phase III trial of KORSUVA injection in hemodialysis patients, which we announced a few weeks ago. We were and continue to be very pleased to observe a robust, sustained antipruritic effect of KORSUVA injection in these patients that was consistent with what we observed in our first U.S. Phase III trial, our KALM-1 trial. With positive results from both our Phase III efficacy trials in hand and a large safety database ready to go, we're now focused on preparing our NDA, and we indeed remain on track to submit that in the second half of this year.

Before we go on, I'd like to commend the entire Cara team for delivering this data set on time during such a challenging period. As the COVID-19 pandemic has evolved, our team has continued to demonstrate great flexibility and dedication in order to advance our clinical development programs and our commercial preparations in keeping with our original time lines.

As a result of the pandemic, we have implemented several 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 studies. These include such measures as adopting SOPs for remote monitoring visits and remote source document verification for our clinical trials.

I will note that, like many other companies, the rate of enrollment in our ongoing clinical studies has been affected somewhat in response to the pandemic. However, almost all of our study sites remain open and are enrolling patients. And we are fortunate. Our projected clinical time lines remain on track. And of course, we will continue to update you should there be any changes to these expected milestones.

Lastly, we do have sufficient clinical supply of both KORSUVA Injection and Oral KORSUVA. We are in close contact with our clinical and commercial manufacturing partners, and we believe that future supply will continue with minimal or no disruption.

On the overall operations side, the Cara team is working very efficiently in a virtual setting. We're continuing to monitor the progression of the pandemic and guidelines from state and federal government so we can quickly adapt our business operations should that be appropriate.

So on today's call, I'll provide an update on each of our programs and our expectations for the rest of this year. But first, I wanted to provide a quick reminder on KORSUVA's broad antipruritic mechanism of action, which is in contrast to other modalities that focus on blocking one specific pruritogen. So the action of KORSUVA on dermal and epidermal immune cells blocks the release of a range of nerve-sensitizing molecules or pruritogens, and KORSUVA directly diminishes the stimulation of dermal sensory fibers or C-fibers, all of this downstream from the action of pruritogens. And it's this dual, neuronal and anti-inflammatory effect that is what we believe provides for antipruritic activity regardless of the initiating pathophysiology, whether that's chronic kidney disease or chronic liver disease or some dermatological condition.

So let's begin with our lead program for KORSUVA Injection in hemodialysis patients with CKD-associated pruritus. This is a patient population where approximately 40% to 50% of patients suffer from moderate to severe pruritus. So a clear, significant unmet need with no therapies currently approved in the U.S. or in Europe. Our pivotal program is presently concluding and that includes 4 Phase III studies, a KALM-1 U.S. efficacy trial, which read out positive top line data last year; KALM-2, our global efficacy trial, which read a positive top line data last month; and 2 open-label safety trials. Both KALM-1 and KALM-2 were designed to investigate the efficacy of KORSUVA Injection at a dose of 0.5 micrograms per kilo versus placebo, administered 3 times per week, so that's after scheduled biopsy sessions over a 12-week treatment period. And each efficacy trial included a 52-week open-label extension phase for safety.

In April, as I've already mentioned, we were very pleased to report positive KALM-2 top line results. Analysis of the primary endpoint demonstrated that KORSUVA Injection significantly reduced itch intensity with 54% of subjects achieving at least a 3-point improvement in worst itch intensity compared to 42% of subjects in the placebo group.

As for the key secondary endpoint, 41% of subjects treated with KORSUVA achieved at least a 4-point improvement in worst itch intensity compared to 29% in the placebo group. And although we didn't achieve statistical significance on our 2 quality of life endpoints, as measured by the Skindex-10 and the 5-D itch self-assessment scales, additional analysis of these results did indicate that itching intensity-related domains in both scales were significantly reduced. So that's consistent with the improvement we reported in both the primary and key secondary endpoints. KORSUVA Injection was generally well tolerated with a safety profile that was consistent with KALM-1 and with our prior clinical trials in this program.

Moving on to our safety studies in the program. We currently have a safety database in line or indeed exceeding ICH guidelines for an NDA submission with over 1,500 total patient exposures, including more than 600 patients having completed 6 months of treatment and over 300 patients completed 1 year of treatment as a therapeutic dose. So we are confident we have sufficient safety exposures to support our NDA submission.

We believe we're well positioned to submit a strong NDA package to the FDA in the second half of the year. As you may recall, we have breakthrough designation for KORSUVA Injection for this indication, so we'll also be applying for priority review.

As you know, we plan to commercialize KORSUVA Injection in the U.S., and we've already established commercial license agreements in other major commercial markets, including Japan, South Korea and the European Union. In the EU, we have a collaboration with Vifor Fresenius, which allows us to leverage the broad reach of Fresenius to dialysis patients across that continent. Working with our partners at Vifor Fresenius, we plan to submit for marketing authorization approval to EMA shortly after we complete the NDA submission.

In the U.S., we've established a co-promotion and profit-sharing agreement with Vifor Fresenius, specifically within Fresenius clinics, which allows us to leverage the nephrology-focused expertise of both Fresenius and Vifor and which we hope will build momentum for the adoption of KORSUVA Injection upon launch.

In terms of our commercial preparations, we've established and continue to execute on our cross-functional launch plan. We already established a national MSL group at Cara, and they've been working hard to increase awareness of the CKD-associated pruritus through disease education. Beyond that, we've begun to prepare all of the necessary steps to potentially launch KORSUVA Injection in 2021, and that includes establishing commercial manufacturing agreements and planning for senior sales, marketing, market access hires as well as laying the groundwork for our sales force activation post NDA approval.

So again, we are very pleased with the NDA-enabling KALM-2 results, and the Cara team is working extremely hard on finalizing our NDA package for submission later this year. And we'll continue to update you on the timing for that and our commercial preparation in the coming quarters.

So let's move on to our pipeline program focused on Oral KORSUVA and start with our lead program in predialysis CKD patients with moderate to severe pruritus. In December last year, we reported positive top line results from our 12-week Phase II trial, evaluating the safety and efficacy of 3 tablet strengths of Oral KORSUVA, 0.25, 0.5 and 1 mg, taken once daily. Based on that data, we identified the 1 mg tablet strength as the dose level to take forward into Phase III.

As with the hemodialysis population, pruritus reflects a significant proportion of predialysis CKD patients. Based on pruritus-related drug prescription data of approximately 7 million people diagnosed with CKD here in the U.S., about 1/3 are currently receiving some sort of treatment for pruritus. And these treatments are typically generic antihistamines or corticosteroids, neither of which effectively alleviate the pruritus burden, certainly not in the long term. So there is a significant opportunity for Oral KORSUVA as a novel therapeutic approach in that population, and we're keen to move to a registration program here as soon as possible. With that in mind, we do plan to hold an end of Phase II meeting with the FDA in the second half of this year to enable initiation of that pivotal Phase III program.

As many of you know, we're also currently evaluating Oral KORSUVA in ongoing Phase II trials for atopic dermatitis and primary biliary cholangitis, or PBC. Atopic dermatitis is, of course, one of the most common chronic inflammatory diseases with prevalence rates of 5% in adults and approximately 25% in children. Pruritus is the defining symptom of atopic dermatitis with a point prevalence estimated at essentially 100%. And in a similar fashion to CKD-associated pruritus, current treatments across the AD patient spectrum, particularly the mild to moderate disease area, fall short, consisting of topical corticosteroids, high-dose antihistamines or indeed antidepressants.

So our ongoing Phase II trial is designed to randomize atopic dermatitis patients across 3 tablet strengths of Oral KORSUVA, again, 0.25, 0.5 and 1 mg, taken twice daily versus placebo. In January of this year, we made 2 adjustments to this trial. We expanded the enrollment size from 240 adult patients with moderate to severe pruritus to approximately 320 patients. And we incorporated an interim conditional power assessment into the design to be conducted after approximately 50% of the targeted patient number complete that designated 12-week treatment period. And I'm happy to report that we're on track to complete this interim statistical analysis in the next number of weeks before the end of the second quarter.

We also continue with our Phase II trial of Oral KORSUVA in PBC patients with moderate to severe pruritus. Pruritus is a common symptom of cholestatic liver diseases with 20% to 30% of patients experiencing pruritus but with a prevalence of up to 70% in patients with PBC. So as a reminder, this is a 16-week trial designed to evaluate the safety and efficacy of 1 mg tablet strength of Oral KORSUVA taken twice daily versus placebo in approximately 60 patients.

I'd like to add that nearly all of our study sites for these 2 Phase II trials remain open, and we continue to enroll patients, although the rate of enrollment has slowed somewhat due to the pandemic. We're also expanding clinical sites as we're able, with the aim to report data from both trials before year-end.

So to wrap up, 2020 is off to a very good start with compelling, consistent pivotal data from our KALM-2 trial. We're on track to submit our first NDA for KORSUVA Injection later this year. In addition, we expect major progress with our oral modality of KORSUVA as we work to finalize the Phase III program for predialysis CKD patients and readout data in the Phase II trials in both atopic dermatitis and PBC.

So with that, I'll turn it over to Rick to cover the financial results for the quarter. Rick?

Thanks, Derek.

As a reminder, the full financial results for the first quarter 2020 can be found in our press release issued today after the market closed.

For the first quarter of 2020, we reported a net loss of $28.9 million or $0.62 per basic and diluted share compared to a net loss of $22 million or $0.56 per basic and diluted share for the same quarter of 2019. In the first quarter of 2020, we recognized revenue of $8 million related to the Vifor collaboration agreement compared to $4.2 million during the same quarter in 2019. Revenue from the sale of clinical compound was approximately $100,000 in the first quarter of both 2020 and 2019.

For the first quarter of 2020, we reported R&D expenses of $33.5 million compared to $23.6 million in the same period of 2019. The higher R&D expenses in 2020 were primarily due to a net increase in clinical trial costs, increases in stock compensation expense, payroll and related costs, conferences and travel and related costs. G&A expenses were $4.6 million during the first quarter of 2020 compared to $3.9 million in the same period of 2019. The increase in 2020 was primarily due to increases in legal and accounting fees, stock compensation expense, insurance costs, franchise taxes and payroll and related costs. Those increases were partially offset by a decrease in travel and related costs. Other income was $1 million in the first quarter of 2020 compared to $1.1 million in the same period of 2019.

As of March 31, 2020, our cash, cash equivalents and marketable securities totaled $179.8 million compared to $218.2 million as of December 31, 2019. The decrease in the balance of cash and cash equivalents and marketable securities primarily resulted from $38.3 million of cash used in operations, partially offset by $100,000 received from the exercise of stock options.

Turning to our financial guidance. Based on projected costs for our clinical development plans and timing expectations, we expect that our current cash, cash equivalents and marketable securities as of March 31, 2020, will be sufficient to fund our operations into the second half of 2020, '21, not accounting for any potential milestone payments under existing collaborations.

I'll now turn the call back over to the operator for Q&A.

(Operator Instructions) Our first question comes from Jason Gerberry of Bank of America.

First question for me, just given the COVID dynamics and where you are with your atopic derm and your PBC studies, is either study from a top line perspective at greater risk of getting pushed into 2021? Just any color you can provide on that would be helpful. And then second question is -- pertains to IV KORSUVA. And I'm ultimately wondering how you model and think about patient adherence to therapy with this treatment. And as you think about the RCT and the open-label extension studies, how you think about the proportion of patients who will be lifetime chronic therapy, those that will potentially drop off or get shorter duration therapy? Ultimately, how do you get at a average days of therapy per patient? Just curious how you think about that variable in the model.

Yes. Thanks, Jason. On the first of those, on the COVID effect. So, as I said, we have noticed a slowing in enrollment in post the AD trial and the PBC trial. And in both trials, we are actively moving to enable novel clinical sites that can help make up for some of that. So far, in terms of time lines, we're not going to alter those. As I said, the interim comes when we're 50% through on the AD, 50% through the entire targeted patient population there, and we're going to have that interim in the next, I don't know what, 6 weeks to the end of this quarter. So we're on track for that. And based on that interim, as you know, that's an interim that's somewhat more adaptive than we've used in the past in that we will have the ability to increase sample size on a targeted dose there, specifically. So with the new sites coming on board there and where we are in enrollment which is -- it's slowed, but it's not -- certainly not 0 here in our current sites that we think we can still see top line data later in the year. But clearly, we'll adjust to that. PBC is the same way. We're trying to add novel sites there. That's been hindered a little due to the present environment. But states are opening up, and that should help -- that should help to get these sites up and running. So at the minute, we're still on track to see that data this year.

And then on the IV KORSUVA for patient adherence, I think we've discussed this before in terms of how the patients view this symptom. There's been numerous studies on this with very large patient samples. And consistently, they rate pruritus as their worst symptom associated with hemodialysis and CKD, which is remarkable on itself. But at that level, where it is moderate to severe, and they have severe effects on quality of life, perhaps understandable. So really, we're going to see patients on this therapy long term. This is a GPCR-related mechanism. When we stop supplying agonists to that target, you're going to see a diminished response biochemically. So they're going to be on the therapy long term to treat that pruritus. And we think it's an advantage. And the feedback we hear from patients and investigators, it's an advantage that we administer this at the point of care, so they don't have to think about another medication. As you know, they're heavily pill burdened. So we think, without getting that 3 times a week, really as a bolus, as they leave out, they finish their dialysis session, they're bolused with KORSUVA. They go home. They get protected from pruritus. They get a decent nice sleep. They stop scratching. They have some sort of social life. I think they're highly motivated to keep that up. And so I think it's going to be a longer-term therapy. And I think the penetration rates into this population would be and will be significantly higher than you'd expect in a normal PBC-type environment, even related to a serious symptom. As you know, these patients really have to come to the dialysis clinic, and they're highly motivated to treat this condition. So I think there'll be a high penetration into that patient population.

And Derek, just as a follow-up, because in the Phase III, we've seen more shorter-term exposure. But is it your sense that the open-label extension should mirror maybe the discontinuation we've seen in the shorter-term RCT trials and that may be a good indicator for the proportion of patients who will go on and be adherent to a chronic therapy regimen?

Yes. That is a possible indicator. That's true. We've certainly seen that a large percentage of patients from the RCT portion have moved into the open label. So there's a motivation there to go on and take the medication, which is always a good sign that people would like to continue that. And the discontinuation rate, I do not have that in front of me in terms of the safety extensions, but I don't recall that being significantly different than what we've seen in the RCT portion of that, which is also a good sign that patients want to maintain their medication for that treatment. So very high percentage moved out of the RCT into the open label, so on both those safety extensions. And I should say, we're winding down all of those safety trials right now and concluding those. So those are wrapping up. And again, getting back to the COVID influence, I think it was a combination of good planning from our clinical group in presciently putting in these SOPs to deal with closing down these databases. And a little bit of good fortune that we were wrapping up many of these trials just as the pandemic was taking off. But we are in good shape for getting all of that data from all the safety trials.

Our next question comes from David Amsellem of Piper Sandler.

So I just had a couple of questions. So I wanted to get your latest thoughts on how you're thinking of -- about pricing and, particularly, wanted to get your thoughts on pricing of Oral KORSUVA here. Just refresh us on how you're thinking about what kind of analogs you're using. And then this is somewhat related to price, but to the extent that you have a real signal in atopic dermatitis and you trying to access that market, how do you think about how that influences your view on the price of the product? And how do you think about step-throughs in terms of what patients are going to go on first and what they could be forced through before they can access the agent?

Thanks, David. Yes. So on pricing, we're still obviously a little early to be thinking about price points. There's going to be a number of variables to consider there as we go out and develop the oral. And these somewhat different markets, of course, I know you're well aware of, on KORSUVA Injection, we're part of the ESRD bundling reimbursement. And as you know there, we're going to have our 2 years TDAPA ASP. And then we're actively engaged, our group is actively engaged with CMS to create some sort of path, some clarity regarding post TDAPA reimbursement there. So that's ongoing, and we're quite confident. We have good engagement there, and we think we'll get some answer as to how that's going to proceed.

On the oral, of course, the vast majority of predialysis patients are commercial insurance and certainly in AD. Those are going to be commercial insurance. So that's a slightly different piece there. And as you know, this is the first-in-class. Hopefully, we'll be the first label for treating moderate to severe pruritus with an oral medication here. So I think a reasonable analog might be other long-term symptomatic treatment. And again, I think a differentiated pain drug might be a reasonable analog to look at there. Although there still is an argument. It's a large unmet need, would be a first-in-class, and that usually demands a premium pricing. But highly differentiated, nonabusable or less-abusable pain drugs that are out there in the $8,000, $10,000, $12,000 per year on launch. There hasn't been many recently, not may be the bottom end of that bookmark. And then at the top end, a highly differentiated oral dermatological medication might be (inaudible) and that's getting you in the high teens, $20,000 annually. So that's the conversation, just don't have enough information yet to think about in great detail, but those might be the kind of bookends we'd be thinking of in terms of the AD market. And I think you and I have discussed this a couple of times there. I mean I think that's sorely (inaudible), an oral medication to treat the primary symptom. And as you know, on atopic derm, the vast majority of that population is mild to moderate, and those mild to moderate patients are really not candidates for biologics there, both from a patient perspective and from a payer perspective and paying for that. So I think the only step through, and it's one way to look at it, but it might be a combination here, that's probably topical corticosteroids in the mild to moderate population there. And then, of course, that becomes a practicality to applying that twice daily and then there's a long-term issue with that also. As I said -- I'd imagine that might be the only thing we see ahead of this. And then this easily usable oral medication twice a day to really systemically reduce pruritus would be the next line therapy, we'd imagine.

Okay. That's helpful. And regarding AD, just a quick follow-up. Do you intend to commercialize that yourself? Or is that something you'd look to find a partner for?

Yes. So you're really looking for kind of glass ball projections here, David, right? We're out a few years there. So I think our thoughts on them is we can easily handle -- we can accommodate launching the IV product into the dialysis population. That's something, as you know, is manageable. And we think we've got a good partner in Vifor Fresenius that will help us with that launch, and we think that's something that we can accommodate. We think it's a very attractive product. Of course, when we move to the larger pruritus market and, as you know, there were some 20 million or so scripts broadly in the U.S. annually across all patient populations, that's a bigger nut for the small squirrel that Cara is to crack right now. So at that point, most likely, we'd look for a strategic partnership when we get there, someone with an established sales force would be appealing. And that's some very attractive structures that have been employed on how those commercial relationships have been set up. So I think it's most likely when we get there, we'd look for some sort of strategic arrangement. That really depends where we are in terms of revenues from our launched IV product and how we feel about that. But most likely, we'll look for some strategic alliance on the larger oral market.

Our next question comes from Chris Howerton of Jefferies.

So I think for me it was just a really quick question. So in the past, you've described the aspirations, certainly for Oral KORSUVA to just get a broad antipruritic label. So just curious, again, if you could walk us through potential approvals in single indications and how does that translate to a broad just antipruritic label?

Yes. Thanks, Chris. Yes. Look, as I said at the beginning here, we think we've got a mechanism with this drug, where we're not focused on one specific pruritogen or one specific cytokine that may be elevated in a specific clinical population. It's been widely accepted for many decades that peripheral kappa receptors, when activated, can diminish C-fiber activity, sensory fiber activity very, very effectively. And so as that's the final conveyor of the signal from the epidermis and the dermis, then we should have a mechanism that should be broadly applicable. Now there's some good evidence for that, obviously, we think. And the evidence bears that we're highly effective in CKD-associated pruritus. There's good evidence from the Japanese drug that's on the market there that can treat liver disease-associated pruritus. And obviously, those have different profiles in terms of elevated cytokines within those patients. So that's evidence that perhaps we're thinking the right way.

And then we kind of looked at it the way that people in the past have looked at the pain medication regulatory approach. Now I should say there isn't specific guidance at this point for pruritus. But in pain, as you know, to get that broader label, you would satisfy the division that you had activity across these various subtypes of pain, from inflammatory to neuropathic to visceral. And we thought about it the same way here. And our clinical development group has done a great job in strategically thinking about this in which patient subgroups would be useful to add to that argument. And right now, we have end organ disease, pruritus with CKD and CLD. We're clearly moving into dermatological, if you like, local inflammatory pruritus with atopic, and we may have looked at some other subgroups that provide some information in these other areas that are quite prevalent, perhaps neuropathic pruritus. And so the ultimate case to be made there is with that data on hand that shows activity across all these various pathophysiology has been it would make sense to have the broader label. Now having said that, we think we're in a great position with CKD, as you and I have discussed before. And if we -- when we move that Phase III program forward here, we do have a large number of safety exposures already available from our intravenous KORSUVA Injection program, which would make sense to reference as part of that pivotal registration program.

So that's certainly something we'd like to engage the FDA with, and that would save us a great deal of time in terms of developing that number of exposures and perhaps as an avenue there to have a diminished requirement in terms of efficacy trials also. So it does make sense to push that label quickly. It has a large unmet need that could get us that label as fast as we can. But clearly, if there's a signal as we hope in atopic derm, that's obviously a very large unmet need there that we'd also like to push quite quickly when we get it there. So that's the idea, developing these various patient populations, that the ultimate conversation -- it's probably not the primary conversation, but the ultimate conversation with the oral would be get that broader label there for moderate to severe pruritus.

Okay. And I apologize, I should know this, but I just wanted to -- are you expecting an advisory committee for the IV formulation of KORSUVA?

Well, that's -- I have no information on that. At this point, that's something that they'll decide upon review. I'd imagine it's a novel chemical entity. There might be a higher likelihood for that. But we have no information at this point.

Our next question comes from Annabel Samimy of Stifel.

This is Avatar Jones on for Annabel tonight. Two questions regarding KALM-2. Firstly, have you had an opportunity to pull out any of the additional secondary endpoints, such as the completer response? And secondly, have any of the KALM-2 patients rolled into the open-label or extension studies? And if so, what percent did you see there?

Thank you, Avatar. The answers here are pretty short. We haven't actually done any additional analysis on that. And this is a course of dedicated but smaller force, who've moved on to closing. As I mentioned, some of these safety databases we really need to get done and our team to get done for our NDA submission. So we haven't yet done extensive sub-analysis in all the other secondary endpoints other than, and we mentioned this on the KALM-2 call, we did look in terms of the quality of life secondaries, we did look at the individual domains in there and confirmed that we did indeed have statistically significant reductions in the pruritus-related domains on both those quality of life doses. So that's reassuring and ties in with what we've seen on the primaries. But we haven't had a great deal of time to get through all of that. We will be projecting -- presenting that data later in the year at the nephrology meeting in the fall. So there will be additional sub-analysis that's presented there. And what was your second question, Avatar?

The second was on KALM-2 patients rolling into an open-label, what percentage of patients there had rolled into open-label?

Yes. No, it was high in both KALM-1 and KALM-2. It was a high percentage of patients. I don't have the precise number in front of me, but it was a high percentage that rolled forward into that open-label studies. And both of those studies are wrapping up right now.

Okay. And if I could squeeze one more in there. Just a little -- could you provide a little color on your preparations for commercialization with IV KORSUVA in the dialysis population?

Yes. So yes, that's something we've been working on for a while, actually. So as I said on the call, we've already established -- we're expanding actually our national MSL group here at Cara, under the guidance of our CMO, Jo Goncalves. And we're working to broaden our KOL universe, increase awareness of CKD-associated pruritus. They've been working hard. They're establishing regional and national advisory boards. They're sponsoring strategic education opportunities and putting CME symposia. In fact, we had one recently at the NKF Spring Clinical Meeting in March. And we -- as you know, we're improving and increasing our KORSUVA publication footprint. We published KALM-1 in the New England Journal at the end of last year, and you'll see continuous publications throughout this year in preparation for launch. So our MSL team is established, growing, has been active on the commercial preparation. Say broadly, we've already initiated things like state licensing, processing and application. We have established manufacturing agreements with major CMOs. We've got commercial-scale manufacturing enabled. We are currently screening and hiring senior commercial hires and sales, marketing, market access. So all of this is underway and constantly developing in preparation for our 2021 launch.

Our next question comes from Alan Carr of Needham & Company.

A couple of them. I like to get your latest thoughts on Phase III strategy for the oral formulation CKD, number of trials and that sort of thing and maybe the size, if that's changed any from your previous speculations. And then also around your ex U.S. partnerships. I think you got 1 in Korea, Japan and then over in Europe. What is your expectations in terms of revenue stream from the milestone payments from them in the near term? I think it's -- if I'm wrong, I think it's small single-digit from the 2 Asian ones. But you have some regulatory milestones for Vifor Fresenius, those are tied to a submission or around approval?

Thanks, Alan. Yes. So -- well, let me take the second first, it's probably more -- less speculative, easier to deal with the fact there. So yes, in terms of revenue streams from the various partnerships -- first of all, all of them are designed so we see appropriate royalties, which are obviously tiered by sales, but they're all double-digit starting in reasonable double digits. And all of them, other than the Korean, also have commercial milestones built into them. You're right, in terms of regulatory milestones and completion of the NDA, there are also a set of milestones we've said publicly before for Vifor Fresenius, that's $30 million related to regulatory, and there's approximately another several million in milestones related to our agreement in Japan with Maruishi and with CKD in South Korea. So that's kind of the revenue stream there. In the near term, with Vifor Fresenius, we have approximately $440 million in commercial milestones on top of the royalty there on ex U.S. sales. So that's also significant. And there is a commercial milestone associated with the Maruishi agreement also. So those are all structured very similar.

Is the regulatory milestone, the $30 million, is that one or is that multiple milestones? And is it just approval or is it (inaudible) submission?

Yes. No, that's related to approval in the U.S. and approval in Europe. That's the $30 million on Vifor Fresenius. And then on the Phase III oral, yes, I mean, really the same answer as we had last time, the great position we're in now with our Phase II data in hand is that we now have a set of empirical data that we can model to make sure we size that Phase III oral trial appropriately. And we discussed this last time. The unusual aspect of the Phase II oral data was a higher placebo response, certainly higher than we've seen in the IV trials in hemodialysis patients. And our thoughts there were a couple, and we think we can make amendments to the design that can address those couple of thoughts. One was the earlier stage patients. They may have more labile pruritus. So we can have longer run-in periods, be more careful, make sure that pruritus is consistent. We can certainly build that into a design -- Phase III design. And we're going to move from a 3:1 randomization to a straight-out 1:1, so that alone should help in terms of placebo response. And then we're not going to use any sites. And as you know, a reasonable number of the sites we used in the Phase II oral trial had previous experience with KORSUVA either from the KALM-1 trial or the Phase II IV trial. And so we think there might be some expectation bias built in there. So using de novo sites is an obvious solution. And there are a few other things we're going to take into consideration to try and help with that placebo response.

But nevertheless, taking that empirical data and modeling, if you like, a worst-case scenario, which is the beautiful thing about running stage development program is we have data -- real data to model on. So we can take that variability we saw there in Phase II and simply model that out for a Phase III study and assume the worst-case scenario, but hope for the best. And as you know, we like to check our assumptions on these larger trials. At the large trial we've ran for the last 3 years, we've incorporated an interim assessment at 50% completion. And that really is a terrific indicator of whether your assumptions are correct. In fact, in all 3 of the latest of those interim assessments, we have the primary endpoint. And so we -- that's how we're going to deal with it. And size-wise, I think I've said this before, really depends on how conservative we want to be on our power assumptions, but at a reasonable conservative rate, I mean, I don't have the numbers right in front of me, but I do recall this is in the 200 to 250, so very reasonable sample size per group to get a very good powering on that trial. So we're in a great position to design that trial appropriately.

Are you thinking 1 or 2? I think before you thought there might be 2 Phase IIIs, is that...

Well, I'm thinking 1, but it really depends what the FDA is thinking. So I think there's a case to be made for 1 here, but obviously, that's a decision we'd have to have in consultation with the FDA. As you know, we have many, many exposures in CKD patients. And so there may be a case, but that's a conversation for the FDA and an FDA decision on that.

Our next question comes from Esther Hong of Janney.

So with IV KORSUVA potentially launching 2021 followed later by other potential approvals for Oral KORSUVA, can you talk about patent protection, other types of protection? Right now, it looks like current patent expiry is through 2027. And so that gives between 6 to 7 years of current patent protection. So it sounds like applications have been filed. Can you speak about those, the status of those? Have any of those been granted? Are they close to being granted? Any update there?

Yes. Thanks, Esther. Yes. No, you're correct, we have composition of matter patents that do run through 2027, but recall that's without extension on those. So with Hatch-Waxman on that, we go to 2032, which will get us our full 10 years on the market, if you like, both with IV and, I would suspect, with oral for our first label there, which would probably be a year behind the IV. But you're also correct, we have multiple other applications. So we've built several fences around this IP estate related to usage. And there are also patents related to specific formulations as part of that, that run into the 2030s, mid to late. And so we've built as much protection around that as we can. But we will get the benefit of Hatch-Waxman, so we'll get our full 10 years on the IV and the oral.

There are no further questions. I like to turn the call back over to the Cara team.

Great. Thank you, Michelle. So thank you, everybody. Thanks for participating in today's call. I also want to thank the whole Cara team, our study investigators, all of the patients who continue to participate in our clinical trials. We certainly look forward to updating you again very, very soon. So be safe, be healthy everybody. Thank you for calling in today. Take care.

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