Michael Schaffzin - Stern Investor Relations Derek Chalmers - Chief Executive Officer, President, and Director Joe Stauffer - Chief Medical Officer Joe Schoell - Chief Financial Officer

Charles Duncan - Piper Jaffray Annabel Samimy - Stifel Alan Carr - Needham & Company Arlinda Lee - Canaccord Genuity Chiara Russo - Cantor Fitzgerald Ken Trbovich - Janney Montgomery Scott Jim Molloy - Laidlow

Good afternoon. This is Michael Schaffzin with Stern Investor Relations.

And welcome to Cara Therapeutics fourth quarter and full year 2016 earnings conference call. The news release with our fourth quarter financial results and corporate update became available at 4:01 PM today and can be found on our website at www.caratherapeutics.com.

You may also listen to 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 including statements includes statements concerning the expected timing for the company’s clinical trials and the reporting of clinical trial results.

The potential results of ongoing and planned clinical trials and future regulatory and development milestones for the company’s product candidates. The timing of any company interactions with the FDA or other regulatory authorities, 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 the Cara Therapeutics filings with the Securities and Exchange Commission, including the Risk Factor section of the company’s annual report on Form 10-K for the year ended December 31, 2016 and its other documents subsequently filled with or furnished to the Securities and Exchange Commission.

All forward-looking statements made on today’s call speak only as of the date on which they are 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.

Now, let me turn the call over to Cara President and CEO, Dr. Derek Chalmers.

Thank you, Michael. Good afternoon everybody and thanks for being with us today on the call.

I’m joined here at Cara today by our Chief Medical Officer, Joe Stauffer; and our Chief Financial Officer, Joe Schoell. So, it’s certainly true that during 2016, we have made significant progress and the development of our selective peripherally acting kappa agonist CR845 across our three major clinical programs in uremic pruritus, post operative pain and chronic inflammatory pain.

And today we’d like to focus and walk you through our expected timing for data-readouts in each of these programs over the next few months. Starting with our adaptive Phase 2 / 3 trial of I.V.

CR845 in dialysis patients suffering from moderate-to-severe uremic pruritus. As you know uremic pruritus is and intractable systemic itch condition affecting approximately 60% of dialysis patients with end stage kidney disease.

The disease has a profound effect on quality of life and as we have emphasized on these calls before standard antihistamines, and corticosteroids are not effective in these patients and there are currently no approved therapies for this indication in the U.S. Our Phase2/3 trial is a two part study.

Part A of this trial is a randomized double-blind placebo controlled study to examine the efficacy of three doses of I.V. CR845 administered after each dialysis session that is three times in a week over an eight week treatment period to reduce itch intensity and to improve quality of life measures in approximately 170 hemodialysis patients experiencing moderate-to-severe uremic pruritus.

I’m happy to announce today that we have completed Part A of this study and we expect to report topline data later this month as we previously guided. Data from Part A will inform dose selection for Part B, which is a pivotal double-blind placebo controlled trial of one optimized dose of I.V.

CR845 administered on the same dosing schedule over a 12-week treatment period and after 240 dialysis patients. Also within the UP program, we also expect to finish dosing over a pharmacokinetic safety study of Oral CR845 in hemodialysis patients this month with data-readout in Q2 of this year.

The goal of this study is to define bioequivalent tablet strengths to enable the development of an oral formulation of CR845 suitable for chronic kidney disease associated pruritus. So with that, I’m going to turn the call over to Joe Stauffer, and he’s going to provide an update on progress in both our acute and chronic pain profiles.

Joe?

Thanks, Derek. We are pleased with our execution and progress across all of our clinical programs in 2016 and we are excited to move these programs towards data-readout in the first half of 2017.

First I’ll start with our Phase2b trial of Oral CR845 for the treatment of chronic pain in patients with Osteoarthritis of the knee or hip. This trial continues to dose extremely well and with high patient demand for participation, we’ve increased the patient enrolment over 450 to allow for patient balance across affected joints more reflective of the general OA population.

This study builds off of our Phase 2a data in which we demonstrate statistically significant reduction of both pain and the use of rescue medication over a two week period as well as a relatively clean safety profile absent of the GI side effects in respiratory depression typically seen in centrally [ph] acting mu-opioids. As a reminder this is a double-blind placebo control, multiple dose based 2b design testing three tablet strength of CR845 dosed twice daily over an eight week treatment period in osteoarthritis patients with moderate-to-severe pain.

The trial design incorporates a four week titration period for a response followed by a four week maintenance period. The primary end point will be the difference from base line in pain score and CR845 treated patients versus placebo at the end of the eight week treatment period.

Secondary endpoints include the change from baseline in the Western Ontario and McMaster Osteoarthritis Index amount of rescue medication used and the patient global assessment of PGA of Osteoarthritis. We anticipate completing dosing for this trial in Q2 of this year with data-readout later in the quarter.

Now moving onto our adaptive Phase 3 trial of I.V. CR845 in acute post operative pain.

This trial is a three arm study testing 1 microgram per kilogram and 0.5 microgram per kilogram of CR845 versus placebo in upto 450 patients undergoing various abdominal surgeries. The trial is designed to accommodate an interim assessment for conditional power across doses at approximately 65% enrolment with an adaptation to optimum dose and subsequent progression to complete enrolment.

The trial was enrolling well and we expect to report on our interim assessment next quarter. Additionally, as part of our approach in further establishing the advantageous safety profile of I.V.

CR845 for use in treating acute post operative pain and beyond, we’ve also recently completed subject dosing of a Phase 1 trial to access the effects of I.V. CR845 on respiratory drive after bolus infusion in healthy volunteers.

This was a randomized double-blind three way crossover of two doses of CR845 namely 1 microgram per kilogram and 5 micrograms per kilogram, which is the proposed therapeutic and 5X therapeutic doses compared to placebo. Respiratory drive was evaluated by continuous, quantitative measurement entitled CO2, respiratory rate and pulse oximetry.

We expect to read out data from this trial in Q2. In summary, we continued to be very encouraged by our progress across our three late stage programs where we expect to report data on a total of some 900 patients in the next few months.

And with that, I’ll turn it over to Joseph Schoell for the financials.

Thanks, Joe. And as a reminder, the full financial results for both the fourth quarter and the full year 2016 can be found in our press release issued today after the market closed.

The following is a summary of the fourth quarter results. We reported a net loss of $22.0 million or $0.81 per basic and diluted share for the fourth quarter of 2016 compared to a net loss of $9.5 million or $0.35 per share basic and fully diluted share for the same period 2015.

We did not recognize any revenues during the fourth quarter of 2016 or for the fourth quarter of 2015. Our R&D expenses were $20.3 million in the fourth quarter of 2016 compared to $7.6 million in the same period of 2015.

The higher R&D expenses in the fourth quarter of 2016 were principally due to a net increase in direct clinical trial costs, and an increase in payroll and related costs for R&D personnel. General and administrative expenses were $2 million for the fourth quarter of 2016 compared to $2.2 million in the same period of 2015.

The decrease in the fourth quarter of 2016 was primarily due to a decrease in franchise tax and amortization expense which were partially offset by increases in payroll and related costs. At December 31, 2016 cash, cash equivalents and marketable securities totaled $58.8 million compared to $106.7 million at December 31, 2015.

Turning to financial guidance based on the timing expectations and projected costs for current clinical development, we expect that our existing cash, cash equivalents and marketable securities as of December 31, 2016 will be sufficient for us to fund operating expenses and capital expenditure requirements through the end of the first quarter of 2018 without giving effect to any potential milestone payments under existing collaborations. And now we will open it up to Q&A, operator?

Hi guys, thanks for taking the question and congrats on the progress in the quarter. I have a couple of questions primarily on the uremic pruritus program.

And the first one is really perhaps clarifying some confusion I had. I thought that you folks had completed enrolment by the end of November, so I was kind of doing the calculus thinking that you might have data now, it’s good that you have completed dosing, but could you help us understand the timelines on that program?

And then the other thing is we -- I’d like to confirm what you would think is a clinically meangingful difference, is it 30%, 50% something along those lines?

Yes, thanks Charles. Let me answer the first and then I’ll let Joe Stauffer here to the next on clinical significance but little worry about percentage reductions and what that means for a patient reported outcome.

On the first point on timeline, yeah we did finish randomization towards the end of November last year but this is a two month treatment period Charles and so we were dosing patients into this year and then when we finished our last patient, last visit follow up time point which is actually beyond the two month treatment period, then we are in the mode of data base cleaning at those points. So, but everything is on track.

We are very confident, we are going to see that dataset complete and we’re going to have topline data announced by the end of this month. And then, I’ll let Joe say a little bit about what we are looking for in terms of clinical significance there.

Sure. So for clinical significance as most of you know it’s never been defined anywhere by the FDA or at any certified [ph] textbook that I’m aware of, the pain or itching.

However, generally when you stoop at positions that are treating these types of patients and when you are looking across clinical trials, what’s clinically meaningful often times can be as low as maybe even 15% to 20% difference or improvement over placebo. We obviously like to see more than that although we are not pre-specified that we have to see that, but I think in a minimum that’s what you are looking for.

You know anywhere 15%, 20% or higher.

And just as a reminder Charles, I know you know the data but the Phase 2a data and that’s an indication which you require a two week treatment period. We saw on approx.

only 54% improvement over the placebo response and infact size that was close to the point 6. So we are fairly confident the molecule has a robust efficacy response and that’s population.

Yes, you’re right. I do know the data but I wouldn’t anticipate a little bit larger study to have quite the same kind of numbers but would like to see a clean result.

The other question I had with regard to that program is, do you think that Part B seeing good efficacy and that could be sufficient or would you anticipate needing to conduct another Phase 3 and then beyond that four week dosing, how would you accommodate chronic dosing would it be in an extension study or do you think the next study would be a little bit longer in duration?

Yes just and I’ll walk you through what we are thinking of in terms of logistics for the program. So you would want to do an extension piece for sure, and as you know we’re required by the FDA because this is a NCE or New Chemical Entity that we are going to have 52-weeks of safety data total, but all of that data obviously doesn’t have to be placebo control.

So at the very minimum you are going to need two placebo controlled trials and then extension for safety after 52-weeks to get the total overall exposures to 1500.

Right. And our plan at the minute Charles as we are going to run those Phase 3 trials obviously after FDA consultation in terms of the agreed optimized dose, but we plan to run both of those simultaneously and in terms of the 52-week safety, that’s a study we are going to start next quarter.

Okay. And then last question for Joe, the CFO the other Joe is regarding R&D spend.

I know you gave good guidance on cash use. Just kind of wondering how much of that is going to be R&D, what’s the pacing of R&D over the course of this year.

I think this quarter was roughly about $20 million that’s a little bit higher but I understand you are investing in clinical trials. Would you see that spend ratchet down over the course of the year?

Certainly as we continue through the year we’ll ratchet down a little bit as we complete the trials. But I think near term it’s going to remain about the same.

Got you. Thanks, I’ll hop back in the queue

Sure.

Thanks, Charles.

Hi, thanks for taking my questions. I have a few.

Just to clarify on the Phase 3 uremic pruritus studies, you are going to consider the Part B of this study, one of the pivotal trials and then do a subsequent Phase 3, correct?

Correct.

Okay, so do you have a sense to the size expectations for the next Phase 3 trial not the 240 Part B but the next phase of the trial and how long you might expect that to take for enrolment?

So a lot – it’s a good question, a lot of that’s going to be driven by discussions with the FDA and what their expectation is on total sample size and what’s clinically meaningful, I’ll get back to Charles earlier question. So, I would expect and I would expect it to be a similar size, it could be a little bit bigger, it could be a little bit smaller, it depends upon what we see coming out of this trial.

Okay and [Indiscernible] wonders considering multiple doses, right?

That’s correct. That’s correct.

Okay. And then switching over to just the oral for a minute, you know for the PKPT [ph] trial in UP, you know maybe you can help us understand what you trying to gather in terms of data study we know it’s a kidney, we know renal comprised population can you talk to us how you are addressing this renal comprised population that’s [Indiscernible] to the kidney.

Thanks.

Yes, now that’s also a good question, Annabel. So there’s two things we are looking at.

That we are dosing in a manner that emulates the I.V. administrations of these.

Those are good for patients who are receiving CR845 orally three times a week, post dialysis and then we also have a second group that are receiving 845 obviously of various doses, once a day and there we are simply looking at the exposure levels we can achieve with both of those types of treatment periods and dose and regimens versus our I.V. exposures and we obviously know which exposure levels are efficacious from our I.V.

study. So I was trying to match up what’s going to be the optimum dosing regimen to emulate what we think is an efficacious exposure based on our I.V.

data.

And Annabel, it’s a – sorry Annabel, it’s not a metabol, it’s not metabolized through the kidney, it’s clear through the kidney and there is a distinction there – we have no active metabolized [ph] unlike other mu-opioids that are metabolized and are back to metabolized.

Okay. And so you don’t expect any problem clearing through the kidney with this population?

I mean it’s something that we have to always anticipate, because right the kidney aren’t working that well. Actually the biggest thing that we want to know is how are they handling it orally because a lot of these people have kind of slowed down in their gut or gastro pruritus because of all their other medical problems and we are just trying to make sure that they can tolerate an oral just as well as they can tolerate the I.V.

And just to clarify Annabel we do have a very long data phase on these patients so you are right at the half way because it’s very long. In fact we can get basically pharmacologically meaningful exposures for two days after a single administration in these patients.

But again, that’s the advantage for these patients that they can receive three times a week dosing and have a robust reduction in pruritus as we’ve measured in our Phase 2 trial.

Okay. And if I can just ask one more question for the oral and the Osteoarthritis condition.

Is there anything that you think might unblind the studies I think that is in, you know some tingling and there is extra thirst that they drink more, is there anything that might possibly unblind this?

No, I mean we’re just not seeing it. I look at the safety data every week and I’m not seeing anything that would lead me to believe that we are unblended one way or the other.

Okay. Great, thank you.

Hi, thanks for taking the questions. I have a couple, Derek, can you go over that, the change in enrolment that you made in the oral Osteoarthritis drive, you said you expanded that.

I wonder if you can give us some more detail on that. And then also, talk a bit about this, the Phase 1 respiratory trial, give us some context around that, and what you expect to learn from it.

The last – I think and I follow up with Charles, I think when you were talking about getting a 52-week safety data, that’s around the uremic pruritus program, right.

That’s correct. So I think you asked, was that the three questions you had there.

Yes, that was my last one that you just answered.

I got it. So I think I answered the third one first.

Yes, it’s 52-weeks and it’s only reimprovises. I’ll go back to your first question on OA.

You know sometimes you get lucky when you are enrolling and in this particular trial there was just a high interest in this trial in Osteoarthritis. And so, when patients are coming actually when they are interested in coming into the trial especially in a Phase 2 trial you take those patients because it just increases your sample size for your enrolment and ultimately as you know we need 1,500 exposures for this trial as well because it’s an -- population.

So you take advantage of the good thing when you can and so that’s why we increased it that way. We also want to replicate and try to look as close to an osteoarthritic population across the population as we can.

So getting those patients would keep away is a good thing to do when those patients come at you. On your second question on the respiratory depression trial, this is one that I was really excited to do and you know so far we are blinded obviously but what we wanted to demonstrate is what our drug would look like in an I.

V push much like someone who potentially might be abusing the drug as a drug abuser or even a patient or someone who is just misuing the drug or even if it’s being used as directed. So we picked what we believe is to be the dose, 1 microgram per kilogram and then five times our dose.

So you know to put that into perspective, if I were to give you say 50 micrograms of Fentanyl I.V. push and then five times 50 micrograms of Fentanyl I.V.

push or 250 micrograms, imagine what that might do to a respiratory drive. And so in a cross over fashion using you know purely quantitative endpoints and the three quantitative endpoints that we measured were I think the three most important what is your respiratory rate as we measure it quantitatively in the clinic, what is your end title Co2 or Carbondioxide because obviously that will go up if you slow down your respiratory rate and then we look at your pulse oximetry or SpO2.

And that’s what we measure and I want to see what does that look like against something that I know shouldn’t affect your respiratory rate which is placebo. And so that is the most pure of assay sensitivity crossover trial you can run as far as I am concerned and we do this observing it in the clinic and observing these subjects overnight to make sure that there is not any other untoward adverse events.

And as I said we’re going to port that out as soon as we can but that was the purpose of doing it, because up until now we had never done that trial and we’ve always believed because of the pharmacology of the drug remember the high charge or the charge and the hydrovelocity of the drug that wouldn’t cross the blood brain barrier, and even if it did we don’t think it hits the respiratory drive anyway because of the pharmacology. But this is a way to prove it, quantitatively.

Now you said it’s a three way question, so I think it is the two doses of 845 versus placebo?

That’s right. So every subject is exposed to placebo, blinded fashion and then each subject is exposed to one microgram per kilo and then five micrograms per kilo.

So there is absolutely zero into a patient variability and again that’s a very pure way, it keeps your sample size down obviously but it’s one of the best ways to observe what is your drug doing and five times your drug doing against placebo because everybody is exposed to each treatment on.

All right. Great, thanks very much.

Thanks Alan.

Hi guys, thanks for taking my questions.

Hey Arlinda.

Hi. On the uremic pruritus program, kind of curious the oral data should be available, I’m too curious is there any possibility that you could use whatever dose you find there for the [Indiscernible] portion of ongoing I.V.

trial?

So let me answer that briefly and then Joe will just elaborate on it. The short answer is no.

We – for that for the HD patient population the idea of formulation there as I indicated earlier is a formulation we could administer at the side of dialysis three times a week, so an I.V. bolus for these patients is a terrific formulation.

We already have a very pill burden sometimes upto 20 tablets a day. So we are going to concentrate on the I.V.

formulations for that specific population. What we are interested in with a lot of the modelling we are looking at both the nest study and also we are going to be looking at CKD patients stage 4 and stage 5, so that’s not dialysis patients, not haemodialysis patients, is the idea that we can walk back with the separate formulation one of our oral formulations and to CKD population non-HD.

So that’s why we are interested in the modelling of this point looking at various kidney functions with stage of disease and now -- to predict which tablet strengths would walk back into the population of stage 4 and stage 5 CKD patients.

Great. Thanks, so then that data will be much more granular in terms of by stage of kidney disease.

Exactly. We can model that specifically to kidney function.

Okay. Sorry, I though Joe was going to maybe elaborate a little further.

Oh I was simply going to say you know we’re always going to have these discussions too with the FDA but remember its two different dosing formulations. So technically it would actually be two NDAs, right because you’ve got [Indiscernible] in the oral and it’s a completely different formulation, it’s handled completely differently, one by the gut and the other through the vascular system by patients.

So I would fully expect that the FDA would ask us to demonstrate the safety of that particular dosing regimen and style in this case of till versus it might be different or it might be the same which is likely why they’ll probably – us to two separate pathways there. But it will be discussed I’m sure at our meeting when we meet with them.

Okay. Great.

And since it is two different IND would you also need to do a respiratory drive effect on the oral version two?

No infact if you think about it, right the quickest way to get the drug into the patient is to go I.V. right?

So you know here the we’ve never been asked by the FDA to do any type of respiratory testing involving, therefore we appreciate and understand the pharmacology of the drug. We just wanted to have it, I personally wanted to have it because I thought it was important to demonstrate and in a quantitative fashion what this drug looks like when it’s injected which is the fastest way to get it to the brain if it ever got there in the first place.

Great. Thanks very much.

Yeah hey guys, thank you for taking the question. Just kind of two quick ones.

Are there any sort of experimental arms within the Phase 2b or the Phase 3. I don’t think there are but I just wanted to double check and then secondly, can you talk about sort of what your plans are to sort of highlight the potential enhanced safety profile in terms of incidence of nausea, incidence of vomiting and it looks like we are looking at respiratory depression as well.

Thank you.

Right. So I think were you speaking about the intravenous Post-Op pain program in the Oral Osteoarthritis program or on the UP program.

More on the pain side, More on the pain side.

On the pain side, sure. So no, the only things that we look at in addition to the primary is obviously the secondary’s in the I.V.

pain study and that is nausea, vomiting. And on the oral side, same thing, right.

We are looking at pain, but we are also looking at the WOMAC which is a secondary endpoint. Sometimes people will do clinical trials with the WOMAC as a primary and pain score as a secondary, there is really no right or wrong here, but we want to see that because it helps us understand trends not only in overall pain but the WOMAC as you know has stiffness in function as well as domains within the WOMAC.

Obviously we’ll look at rescue medication there too, and the patient global assessment. So there’s nothing really new under the sun here in terms of something experimental in terms of the design that are out.

Okay. And just in terms of like that whole safety aspect, you should I mean you will be producing data that could potentially be on label that the drug is approved for us.

We would hope so, yes. I mean and I did mention this earlier, but you know we look at chronically even the -- in both these pain trials, we are looking at serum sodium if you remember that issue that we had a few months ago.

We seem none of that problem here in the Osteoarthritis trial. We are dosing people out at eight weeks, you know we look at there, we literally draw blood and check and see.

And we just don’t see those issues like we saw before, we didn’t expect to see it in patients who were taking drugs chronically and drinking and urinating and so we are pretty excited about that. Respiratory depression it’s as I said it’s never been an issue acutely with an I.V.

It’s not an issue chronically either, so I think that kind of highlights again the safety story about the pharmacology, it’s a new pharmacology with a completely unique and non morphing light, non mu-opioid like side effect so far.

All right. Great, thank you.

Thanks for taking the questions. Just wanted to go back to questions on the UP study.

The Part B I know you kind of already addressed the timing with regard to the Part A, but given that the Part B is larger and longer, should we really be thinking about that as a sort of 2018 event in terms of completion?

Yes Ken we haven’t obviously we are still a little too early to talk about completion in the Part B, but the aim here is to with our Part A data in hand in the next few weeks and request the FDA meeting as soon as we can thereafter is to initiate that Part B later this year. And then will guide us to when we think we see data from that as we look at recruitment rates as we normally do.

But certainly we aim to initiate that trial and as pointed out earlier simultaneously the second Phase 3 trial in 2017.

Got it. And then just with regard to the oral dosing in the dialysis patients, were you able to capture enough data from the sort of the I.V.

formulation when you were doing the studies on a PK basis that would inform you that all with regard to food interaction or anything of that nature that you would otherwise see in this population?

I think the short answer to that is yes, and we’ve actually published some of that data Ken in terms of the you recall the original PK data in relation to I.V. administration, and the HD population is something we published in abstract form and so I think most recently kidney week last week, so we have a lot of PK data and how this molecule behaves in that particular patient group.

And is there anything about that process in terms of the oral administration that we need to think of and I guess, I’m just sort of – I guess part of the reason for the question is part of the issue around uremic pruritus and the uncertainties around you know how much of this is a consequence to the condition, how much this is a consequence of dialysis and then obviously when you get in the other factors around you know the PK side I guess. I guess, I’m just trying to better understand if there is anything about that data that gives you reason for pause or perhaps sort of to inform you on the actual patients as you start talking about the modelling effort to walk back into non-dialysis CKD patients.

Nothing on to worry. And as Joe mentioned earlier, obviously a significant proportion of patients that hemodialysis level are diabetic and then one factor we were interested in looking at was gastroparesis and the effect that may have an uptake [ph] so far from what we have seen there is not any significant effects there in terms of effecting the PK or the predicted PK based on our I.V.

exposure. So, so far everything is behaving as planned and as we expected.

Okay. And then just with regard to the OA side in terms of the Phase 2 OA study, can you help us to understand you know from your perspective this change from sort of 330 patients t o 450 patients, you know help us understand how much of that ends up being hip, especially when we are talking about a multi dose study.

It’s not particularly clear how many patients are going to be in each subset and available for analysis and especially you know in a Phase 2 where it’s not necessarily going to be powered for significance in the first place?

You’re correct so, it’s not powered for significance and you get what you get when you enrol. Quite obviously most of the time when you enrol OA trials you wind up with a lot of knees, right because that represents the lion’s share of what people have with Osteoarthritis.

But hip is also a pretty important part of it as well. And so it’s not just hips, it’s also about I always look to the end game as well, right.

Because if you look at OA trials that are pivotal and/or even big Phase 2 trials we got three different doses here. I like having more patients.

If I can get access to more patients particualry in Phase 2, it gives me a lot of things to look at above and beyond the efficacy. I can look at safety as well.

I know the FDA is going to be looking at that. It just gets me closer to the 1,500.

So again, sometimes you get lucky and you catch a break and you take advantage of that, when it’s highly competitive, right. I mean enrolling for trials particularly in Osteoarthritis on competing against the other companies doing OA trials too, so that’s why we do it.

So is it safe to assume then that it hasn’t altered in any way the plan or the design as it is related to the knee portion of the analysis that essentially you would still have as many knee patients as you had originally planned?

Correct.

Okay. And then just back to personal experience here when we talk about these knee patients are we talking about patients who have particular sort of the inclusion,exclusion criteria, how similar would that be when you talk about the difference between knee and hip, is it simply pain scores or other factors that would be involved with regard to mobility?

Right. It’s a pain score.They don’t have to demonstrate X-rays, MRIs things like that, it’s just part of the advantage for us.

This is not about treating osteoarthritis, this is about treating the pain of osteoarthritis, right. And so, we don’t expect or anticipate that we would necessarily be a disease modifying agent nevertheless, if it is and the FDA wants to look at it that way, that would be great.

But for us, this is really all about pain and then WOLMAC as you know which is pain stiffness and function as part of that tool.

Okay. And then just last question for Joseph Schoell I guess on the modelling side, are there any milestones that we should be thinking about with regard to [Indiscernible] in the upcoming year?

Yes, I think we indicate in the 10-K and I think we also had it in the 10-Q that the Phase 3 completion results in a milestone. I think and that’s really from both [Indiscernible]

Okay, terrific. Thank you.

Thank you, Ken.

Hey guys thanks for taking my question. I had a question on – you know [Indiscernible] trials going on, a lot happening and the company will be showing a lot of data coming up.

When you look across the totality of your trials which do you see as your lead oyster [ph] complete and get to a position where you could be filing an NDA?

I mean right now the lead [Indiscernible] in terms of data is the itch trial, right. And I think obviously the I.V.

post [Indiscernible] pain trial and the oral trial in OA reads out later. But a lot of that, a lot of when you submit in NDA is driven by enrolment and is driven by engagement that you have with the FDA.

So it’s a little bit hard right now to predict who’s going to go fastest because just because you read out data first in the Phase 2 trial [Indiscernible] it doesn’t mean that say the post dot pain trial could go quicker and that might. Right, because that’s an acute situation as opposed to a chronic situation.

You know we don’t have to generate 52-week safety data in a post dot pain trail. So a lot of that conversation is driven by which the strength of our data as we read it out in the latter part of this first half of the year an engagement with the FDA.

So I would only speculate as to who is first in terms when we submit. I know who is first in terms of when we read out data and that itching.

If you could hit your idea and have reasonable enrolments and on track for both for I.V. itch and the I.V.

pain, which one of those – what’s the timeframe you think you could be completing in all trials and looking down the throat of an NDA?

So, as you know Jim, we don’t guide the precise quarters for NDA submission when we’re in the midst of trials, but at that point as we said repeatedly if we get it what we expect to see in the Part A trial here in the two months exposure and UP and we pick or optimize those, our aim is to run those Phase 3 as quickly as possible. And again, that’s going to come down to enrolment as Joe knows only too well.

But we’re going to start both of those trials simultaneously this calendar year, that’s our aim, and that’s how we’re modelling everything in relation to UP. And similarly, for Post-Op, we plan to validate again optimal dose here fairly soon, and with that we want to replicate that as quickly as possible, run those trials this year and certainly have data from Post-Op pain in 2018.

So as rapidly as we can get them done, we want to get the NDA obviously it’s in our interest, get that NDA as quickly as we can.

I Appreciate. Not want to get down the quarter.

I’m just trying to figure out years. But when you looking at potential partners for additional programs, any thoughts on where the timing of something like that could potentially happen?

Yes, that’s not something we talk about publicly Jim, but at this point we are much interested in retaining U.S. rates across all of these program.

As you know our strategy has been in terms of non-dilutive finance. We’ve looked to ex-U.S.

territories. We have a Japanese partner.

We’ve South Korean partner and if the deals comes along this attractive enough from an ex U.S. territory than something we’re going to look at.

But at that point we want to retain U.S. rates and all of these.

Okay. The last question of I.V.

pain, one of the challenges has been number new formulation, abuse resistance, there’s been some easier scheduling, obviously you [Indiscernible] would have. How do you – but there’s seems even with that there’s been challenge breaking through the years momentum of using opioids and doctors don't know how to write these generic drug.

Any thoughts on your -- should you guys get to market, have you given any thoughts how to position to sort of breakthrough that?

Yes. it’s a great question and the beautiful part about what we have is that we’re not just another mu opioid, right.

We’re brand new class of compounds, and I think that our safety profile both pre-clinically the evidence is out there, the human abuse liability trial, which I didn’t design to run, but I’m really proud of that trial. I love talking about it.

So I think it’s a terrific trial, as well as when we finally announced it, our respiratory depression trial, I think all those things bode very well for a drug at the very least if it’s scheduled at all would be scheduled five, because the how trial, we won against this schedule IV compound pentazocine. I think that makes it very convenient for hospitals and hospital pharmacies, nurses on the floor, anaesthesiologists in the OR, in the pre-OR setting to use.

It's easy, it's room temperature it's a quick I.V. push.

I mean all these things are benefits for the patient, right? This drug has no active metabolites like other mu opioids to do, and so you know I don't have to worry about age or kidney function of what I'm giving this drug, right because it's clear whole to the kidney.

So I think there's a lot of attributes. I just named a couple there.

But that's how I would position it. Hopefully, it comes out, it's approved as a intravenous Q6 and indeed if it's used along with or as an adjunct to other opioids that are still being used, that's just fine.

Because that's part of enhanced recovery and that's part of the multimodal approach to anaesthesia. One drug can’t fix everyone's problems, and it will be the same for us.

And I fully expect us to be used that way if you are lucky enough to get it approved.

Great. Thank you for taking the questions.

Thanks, Jim.

Hi, guys. Lots of questions so they’ll try to be quick, thanks for taking my follow-up.

I just wanted to ask a couple more questions on your agreement for uremic pruritus program. When you think about the endpoints in which you’ve demonstrated a good activity in the past with visual analog scale.

I hope, we’ve address this, but I'm just wondering what you think about the current employment believe its numeric [ph] rating scale in terms of the ability to capture efficacy and the noise for running scale. I know that you design the trial, but what do you thinking about in terms of the portability of those two?

It’s a good question. This whole conversation I believe Charles has been put to rest between the visual analog scale and the numeric rating scale.

They're basically one and the same thing. But when I used to work at the FDA the range was the VAS, the Visual Analog Scale when it came to pain and nowadays, numeric rating scale seems to be the way they like it and it's easier to administer that particular scale, it’s easier to understand for patients because they can see and appreciate, understand the zero to 10 scale.

That's much easier for patients in pain and it's also much easier for patients in itch, particular since itching patients on dialysis, remember their vision is also somewhat impaired as well. And so these are validated scales.

You can use them virtually interchangeable you can use them interchangeably and that in addition to the skin deck which is our secondary endpoint or quality of life and point which we are also significant on certain parts of it anyway in the phase 2 trial would be important for the FDA. So, the primary endpoint is -- but the secondary endpoint is important as well.

We don't believe we necessarily need to be statistically significant in the secondary endpoint of Skindex. If we are that’s great.

But if we’re not is always a trends in our direction that’s just fine.

That makes sense. So, it show there’s energy for trial readouts, I mean, you have in each year [Indiscernible] minister state-owned, they have more patients, you have a longer dosing period, does that argue for an even cleaner result than what you saw in Phase 2?

The longer is good for us, right. I think the longer patients are exposed first of all to more meaningful if we’re talking about UP and I think we’re still are.

A longer exposure is a good thing, right, because we know it’s a chronic drug. In their first trial, it was only two weeks.

So longer is better for us not only in term, I think demonstrating efficacy but also for the safety profile that we’re going to have to demonstrate to the agency not only in this trial but in another. And again no there is a reason why we met with this division at the FDA, they preferred the numeric rating scale.

So we would have been using it anyway and we’re glad they preferred it.

It’s a very good question because I think you know for chronic use and pruritus for this population, chronic kidney disease and we also believe extrapolating to others that if we can confirm we have sustained efficacy across a two-month period and I think we’re really defined we have a very useful medication now.

So last question is around that word useful, just maybe stepping back and assuming clear results coming up here. Derek , could you kind of share with us your perspective on the value clinical utility, treating uremic pruritus in a dialysis patient population, so what I'm really interested in is hearing your thoughts as to whether you uremic pruritus is a problem for the patient or is it problem that dialysis center, and how you would capture the value and look in the environment that exist for a dialysis patient?

That’s a great question, Charles. It’s actually, the short answer is it problem for both because for the patient and there been a number of studies on this for the patient in terms of their main concerns clinically their main symptoms and what they are asked in the surveys around usually number one and number two in those surveys is pruritus, intractable pruritus.

And the reason for that is, it’s so severe in these patients that it dramatically affects the quality of life. So this is a sleeping issue.

This is a social interaction issue. This is an issue that’s un-addressable by a anything that’s on the market at this point.

So certainly an issue for the patient we know that and we hear a many anecdotal reports, some of which we have shared for our trial phase that patients are very much appreciative of the release of this clinical symptomlogy, for the actual provider themselves. This is also an important aspect of the pharmacoeconomic argument here and we’ve talked about this before.

There are been a number of studies both for the [Indiscernible] here in the U.S. and Europe that have looked at the cost of these pruritic patients to the providers and it's clear from multiple endpoints that on average we see an increased cost of the patient that to the provider from a pruritic patient of somewhere around $50 or $60 per session and that relates to enhanced use of e-port to achieve the same effect, increased use of antibiotics in some cases where they have infections also relates to mess dialysis sessions.

So, there is certainly a pharmacoeconomic benefit for the payor to diminish the percentage of the patients they are creating. They are actually are suffering from this particular condition.

So this is an advantage in both ends, for the clinician, for the patient and also for the provider.

Super gel there. Thanks for that added information, very helpful.

Thanks, Charles.

Hi, guys. Thanks for taking my follow-up and let me just apologize for making this call any longer?

Just one question on the Oral. I was surprised to hear that it’s not powered for statistical significance, did I hear that correctly?

So what exactly are we going to see from the oral study to indicate efficacy and the other things is what exactly, what exactly do, you what time powering do you need for it to be statistically significant?

I wasn’t clear on that. I’m talking about the secondary endpoint and so I’m trying there [Indiscernible] if I misspoke, I wasn’t clear on that, that’s what I mean, right.

So, yeah its powered on primary just not on the secondary.

Okay. All right.

Great. Thank you.

Yes. Sorry about that.

So, thank you very much everybody for calling in today and we look forward to updating you again in the next few weeks. Thank you everybody.