Intercept Pharmaceuticals Inc (ICPT) 2013 Q4 法說會逐字稿

Good day, ladies and gentlemen. Thank you for joining Intercept Pharmaceuticals full-year 2013 financial results and business update conference call.

(Operator Instructions)

Please be advised that this call is being taped at the Company's request and a webcast of this call will be archived on the Company's website for two weeks from today's date. At this time, I would like to introduce Senthil Sundaram, Intercept's Senior Director of Corporate Development. Please go ahead.

Good morning and thank you for joining us on today's call. We are reporting on financial results for the year ended December 31, 2013. We will also be providing an update on our development programs, including the positive POISE trial results that were released yesterday and the additional FLINT trial information provided in our 10-K on Friday.

Before we begin, please remember that we will be making certain forward-looking statements on today's call, including statements and forecasts regarding our future financial and operating performance, our POISE and FLINT trials, anticipated timelines for the potential approval and commercial launch of obeticholic acid, and our regulatory clinical and commercial plans, goals, and estimates, as well as other statements which relate to future events. These statements are based on the beliefs and expectations of Management as of today.

Our actual results may differ materially from our expectations. Investors should read carefully the risks and uncertainties described in our reports filed with the SEC, including the Risk Factors section of our most recent annual report on Form 10-K for FY13 that was filed this past Friday, March 14. We assume no obligation to revise or update forward-looking statements, whether as a result of new information, future events, or otherwise.

The format for today's call will include opening remarks from Intercept's Management team and then we'll open up the call to take your questions. At this time, it's my pleasure to turn the call over to our CEO, Dr. Mark Pruzanski.

Thanks, Senthil, and thanks everyone who has joined us on our conference call and webcast this morning. I'm going to provide you with an update on the development of our lead product candidate obeticholic acid, or OCA, and then turn over to Barbara Duncan, our Chief Financial Officer, who will discuss our 2013 financial results, year-end cash position, and cash runway.

As announced in our press release yesterday, we're absolutely thrilled to report that our Phase 3 POISE trial in primary biliary cirrhosis, or PBC, clearly met its primary endpoint, as well as secondary liver function endpoints with very high statistical significance at both doses tested. In fact, not only did both OCA doses meet the primary endpoint at 12 months, the end of study, but also at every time point assessed along the way, starting at two weeks into the trial with p values of at least 0.0001 for both doses at each time point.

In order to meet the POISE primary endpoint, patients had to have a reduction in alkaline phosphatase to less 1.67 times upper limit normal, with at least a 15% decrease from baseline and together with a normal bilirubin. Close to half the patients in both dose groups -- 47% in the 10 milligram group, 46% in the 5 milligram to 10 milligram titration group -- met the endpoint, as compared to 10% in the placebo group.

The robustness of the data in this 217 patient Phase 3 trial underscores the ability of OCA to significantly improve the biochemical health of these patients. As has been previously published and more recently corroborated by the Global PBC study group, or Supergroup, as we've called it, achieving the level defined by the POISE endpoint predicts highly significantly improved liver transplant free survival in patients.

As we had previously reported, the current standard of care in PBC, ursodiol, or Urso, provides an inadequate therapeutic response in up to half of PBC patients. We believe that the results demonstrated by OCA and POISE in our previous Phase 2 trials, both when added to Urso and as monotherapy, support our proceeding to file for approval of OCA [at] the first novel drug therapy in PBC in almost 20 years.

We are excited to continue working closely with FDA and EMA to be in position to file an MDA and an MAA at the end of this year. We believe we are close to finalizing a trial protocol with FDA and plan to initialize our Phase 3 clinical outcomes trial in PBC in the third quarter this year. Given that we're seeking accelerated approval of OCA in the US for PBC, this trial is required to demonstrate clinical benefit on improved liver-related outcomes and will be completed only on a post-approval basis.

Some additional top-line results were provided in the press release yesterday. More data from the trial will be presented in a few weeks at the upcoming 2014 EASL Conference taking place in London in April.

Let me now provide additional details concerning the tolerability and safety profile of OCA observed in POISE. In general, what we've seen is consistent with what we've reported for our previous Phase 2 trials of OCA and PBC, including results in patients on longer-term OCA therapy for a year and with some patients now on monotherapy treatment for more than four years. Of course, the one consistently observed side effect of OCA in PBC patients is pruritus, or itching, the most common symptom of the disease.

Pruritus can also be induced by Urso, the standard of care, when patients first begin therapy, so treating physicians will sometimes start patients with lower doses and titrate up to a therapeutic dose. Consistent with this, we decided to include a titration arm in POISE; that is to see if starting patients to lower 5 milligram dose, and titrating OCA up to 10 milligrams at [6] months (company corrected after the call) in those patients who hadn't yet met the primary endpoint and were tolerating treatment, would result in better tolerability without sacrificing much efficacy.

That's exactly what we found. In seven patients in the 10-milligram group, 10% -- seven patients, rather, in the 10-milligram group, or about 10% discontinued due to pruritus, the same proportion as in our previous 12-week Phase 2, trial but only one patient, 1% of total in the titration group, discontinued, and did so only after being titrated up to the 10-milligram dose. Virtually all of the 5-milligram patients who hadn't met the endpoint at six months were titrated up to 10 milligrams, which suggests that 5 milligrams is a generally well-tolerated dose in PBC patients.

Further we did see a lower incidence of pruritus of a little more than half the patients in the titration dose group over the entire year as compared to about 7 in 10 patients in the 10-milligram group and 4 in 10 in the placebo group. This suggests that this titration regime has a better tolerability profile, while giving up very little in efficacy. Another highly encouraging detail, of course, is that as we previously reported, virtually all of the patients who completed the 12-month double-blind phase of POISE opted to continue on in the open label five-year long-term extension phase, which tells us that those who had been taking OCA were generally tolerating therapy well.

PBC patients typically have unusually elevated cholesterol levels, both HDL and LDL, which is associated with the disease, but they've been shown not to be at increased cardiovascular disease risk as compared to the general population. As we saw in our previous Phase 2 trials, patients taking OCA in POISE experienced a modest decrease in HDL, which remained well above the lower limits of normal. There were no changes in LDL cholesterol in either dose group.

Interestingly, in this large cohort of patients, we saw a slight decrease in triglycerides, an effect consistent with FXR activation that we observed in our previous trial in diabetic NAFLD patients who had abnormally elevated triglycerides. Finally, we also saw an increase in VLDL cholesterol.

Other than pruritus, the incidence of all other adverse events was not different amongst the three arms of POISE. Serious adverse events, or SAEs, occurred in 22 patients, about 10% of the total cohort, and although there were more in the two OCA groups than in the placebo group, none were considered to be treatment-related and there was no apparent pattern between the groups.

Given the interest the 10-K aroused in cardiovascular events in patients taking OCA, I can report that there were two cardiovascular SAEs in POISE, one in the placebo group and one in the titration group. I should also say that with chronic OCA treatment to date in more than 400 PBC patients, with some now on therapy for more than four years, we've never observed a drug-related cardiovascular SAE.

It's worth mentioning the SAEs in POISE appear to be of a typical nature in PBC patients over the course of the year of treatment and there are no overlapping SAEs between the two dose groups. We saw several bone fractures, back problems, and osteoarthritis, varicose vein procedures, et cetera. Pretty typical in the patient population that we were studying.

As I mentioned, at EASL, we will be presenting additional details from POISE, including patient demographics and baseline biochemical status; additional details of the primary and many of the secondary endpoints, including proportion of patients achieving certain pre-specified reductions in alkaline phosphatase; and other data. As such, while we welcome your questions, I'm not able to provide any additional information beyond what I've just stated here and what was also included in our press release.

To summarize, it appears that our POISE Phase 3 results are consistent with the effects we observed in our Phase 2 PBC program, which includes patients who have now been on drug for a number of years and in whom we've shown our drug also appears to be safe with a durable therapeutic effect over long-term treatment course. This is important, given that, assuming OCA is approved of course, we will likely become [life time] second line therapy in PBC patients, with either an inadequate response to Urso or inability to tolerate Urso.

This represents the culmination of more than a decade of work, but we are not done yet and remain committed to working diligently to bring our new therapeutic option to the market and help improve health outcomes for PBC patients worldwide. I'd like to thank very much all those who participated in our clinical trials, together with the investigators, and the highly capable team at Intercept.

Let me now turn to FLINT and our NASH program. While this is not the focus of today's call, we've received questions on some of the information pertaining to our NASH program, and the FLINT trial in particular, that we provided in the 10-K on Friday evening.

Before I make any comments about the information we disclosed, I want to acknowledge that, while it's unusual for a Company to put out piecemeal information from an ongoing clinical trial, we found ourselves in an atypical circumstance in which the early stop of the treatment phase of FLINT had been announced with limited disclosure made by NIDDK, the trial sponsor, concerning both efficacy and a potential safety concern.

Given the very high visibility of the trial results, and as a results of the Company itself have attained after the announcement in January, we felt it was incumbent on us in our 10-K annual update to disclose additional relevant information we've recently been able to glean from the NIDDK in the course of the series of interactions. With most of the focus thus far on safety-related information, we look forward to being able to supplement what we know with the final set of efficacy and safety results in the not too distant future.

As mentioned in the 10-K, our partners at the NIDDK have committed to providing us with the unblinded final results from the FLINT trial in July of this year, as soon as they become available after the completion of the ongoing 24-week observational phase. This is several months earlier than we previously anticipated and we don't expect to get any additional results prior to the availability of the complete data set. Once we have the data, we will be able to proceed to finalize our Phase 3 program design based on discussions with FDA and EMA, [hail and hail als], of course, with whom we've already begun consultations.

We're extremely enthusiastic about moving our NASH program forward and anticipate initiating our Phase 3 program in the first half of 2015, assuming of course, availability of sufficient funding. In the meantime, we intend to initiate a Study of OCA's lipid metabolic effects in NASH patients in the second half of 2014 and are also considering initiating a Phase 2 placebo-controlled trial in pediatric NASH patients. While pediatric NASH has a lower prevalence than the adult form of the disease, it is still highly prevalent and can result in cirrhosis and liver failure in school-aged children.

We currently anticipate that our NASH Phase 3 program may involve two separate Phase 3 clinical trials. Both will be powered for clinical outcomes, one enrolling precirrhotic NASH patients with advanced or bridging fibrosis. The other would enroll all color cirrhotic patients, including a sizeable cohort with NASH, but also with other chronic liver diseases such as alcoholic liver disease, hepatitis C viral infection, hep B viral infection, and PBC, among others.

Based on commentary from the FDA at the NASH workshop, held in September 2013 last year, we believe that we could incorporate a planned interim analysis in both of these trials that could serve as a basis for accelerated approval on a surrogate endpoint. In the precirrhotic patients, this could be histologic improvement after at least one year of OCA treatment, likely employing a liver-biopsy-based endpoint similar or identical to the one used in FLINT.

In the cirrhotic patients, the surrogate endpoint after a similar timeframe could include in the assessment of hepatic venous portal gradient, or HVPG, the same endpoint we used in our portal hypertension proof-of-concept study that recently read out, as well as histologic improvement shown on liver biopsy taken simultaneously during the same procedure.

Let me turn now to the safety information disclosure we made in the 10-K concerning the cardiovascular events observed in the FLINT trial. I should emphasize that the trial remains blinded so we only have a very limited set of information. As reported, as of the end of December 2013, there had been a total of 10 cardiovascular SAEs, which had occurred in 7 patients across both the placebo and the OCA groups, overall 2.5% of the 283 patients enrolled. While these apparently occurred in more patients on OCA than placebo, the difference in number of events was not statistically significant, and 8 of the 10 events were considered unrelated to treatment.

In addition, the clinical circumstances of the two unblinded serious cardiovascular events that were noted as possibly related, led to a conclusion by us, and in one case, the principal investigator himself, that they were likely unrelated to study drug. It's important to highlight that these cardiovascular events occurred over the course of the trial and the last of them occurred prior to mid-2013, about seven months before the positive interim efficacy analysis lead to the NIDDK's decision to stop the FLINT treatment phase early.

We take adverse event monitoring and reporting very seriously in all clinical trials testing OCA. However, based on our understanding of the mechanism of action of OCA as an FXR agonist, our clinical safety experience with our drug, and the well-documented rates of cardiovascular morbidity and mortality in NASH patients, particularly in those with Type 2 diabetes and other cardiovascular risk factors, we do not currently view the low incidence of the cardiovascular events reported in FLINT to be indicative of a safety signal, and the FDA has not reported any concern to us.

Both the NIDDK and Intercept have been encouraged by early demonstration of OCA's considerable efficacy and getting to the final read-out from FLINT sooner than anticipated. There's a tremendous unmet medical need for novel therapy to treat NASH patients, particularly those with more advanced disease, many of whom progress to cirrhosis and are at real risk of liver-related mortality. I would like to take this opportunity to thank again the NIDDK for their sponsorship of the FLINT trial and continued dedication to identifying effective drug therapies to help NASH patients.

As a final comment, some of you may have heard in the past few days that the NIDDK has committed to providing the FLINT data when available in July in response to FOIA, or Freedom of Information Act requests. I would be remiss if I didn't ask on their behalf -- on NIDDK's behalf, that is -- not to bombard them with such requests in the meantime because they will not be honored. I'll now turn over the call to Barbara Duncan, our Chief Financial Officer, for a discussion of our financial position.

Thank you, Mark. Good morning, everyone. Please refer to our press release that we issued on Friday for our summary of our financial results for the 3-month and 12-month periods ended December 31, 2013. I'll focus my comments this morning on an overview of our financial position as of December 31, 2013.

We ended 2013 with $145 million of cash, cash equivalents, and investment securities available for sale on our balance sheet. Based upon our currently expected level of operating expenditures, we believe that we will be able to fund our operations into the third quarter of 2015, which gets us comfortably past the MDA and MAA filings of OCA in PBC currently anticipated in late 2014.

This expected level of expenditures includes all of the studies and the work necessary for the PBC regulatory filings, as well as the initiation of the Phase 2s in PSC, and the lipid trial in NASH patients, and certain pre-commercialization expenses. However, it would not include additional capital necessary for the anticipated Phase 3 program in NASH patients.

While I won't review all of 2013 results that we shared in our press release earlier today, let me make a few remarks on the accounting treatment related to periodic evaluation of our warrants. In connection with some of our pre-IPO equity financings, we issued warrants that are classified as liabilities and are adjusted to fair value on a quarterly basis with the change in the fair value being included in our net loss.

The amount included in net loss is a non-cash item, as Intercept is not required to expend any cash to settle the warrant liability. The warrant liability is primarily affected by changes in Intercept's stock price during each financial reporting period, which causes the warrant liability to fluctuate, as the market price of Intercept stock fluctuates, as well as remaining terminal warrants and underlying volatility utilized in the fair value calculation.

In general, the warrant liability for the fourth quarter and the year ended December 31, 2013 increased significantly, primarily due to the increase in our stock price since December 2012, offset by the decrease in the number of warrants outstanding. For the full year 2013, the warrant revaluation expense was $28.4 million.

As of the end of this year, there is only one tranche of warrants outstanding, representing approximately 865,000 shares and the expiration date on those warrants is January 2015. Therefore, going forward, the warrant liability will be classified as a current liability. Given the substantial increase in the value of our common stock during the first quarter of 2014, this warrant liability is also expected to significantly increase as of March 31, 2014. Let me now turn the call back over to Mark.

Thanks, Barbara. We're ready now for some questions.

(Operator Instructions)

Our first question comes from Colin Bristow of Bank of America. Your line is now open.

Yes, it's actually Rachel McMinn. Thanks for taking the question.

Mark, a couple of things. Can you talk about how much patient exposure you have? Specifically, on duration, how many patients have been exposed to OCA for one year, two years? And just the broader question of how we should be thinking about extrapolating that safety data from PBC into NASH?

And then two other questions. Just the lipid trial in PBC, is that gaiting for your NDA filing and do you have any sense of how much the NASH studies are going to cost when we think about sketching out Phase 3 cost in our model? Thanks.

Thanks, Rachel. With respect to the first question, which is exposure in PBC patients, I don't have the exact breakdown at my finger tips. I can tell you that we have had 19 patients on monotherapy for approximately four years or longer and a total PBC patient exposure of over 550 patient years at this point.

We had, in our previous so-called combination PBC trial, which was the model for the Phase 3 POISE trial, we had a long-term safety extension that went at least one year and for some patients over 18 months. That had enrolled about 70 patients -- over 60 patients had completed the year of therapy. So I apologize I don't have the exact numbers at my fingertips, but we do have very extensive safety exposure in the PBC population.

With respect to the other question, which was the PBC lipid study, that we will be completing this year. We do intend -- it's an open label study -- we do intend on including data from that trial in the NDA and MAA. I can turn to Barbara in terms of the cost, but to be frank, we've just, as I mentioned in my remarks, we've been sketching out what the Phase 3 program will look like.

We still have quite a bit of work to do with KOLs and with the regulatory authorities to really define these trials, so it would be premature for me to comment about the anticipated cost. I will say, though, as a placeholder and, you, yourself are using this number -- 1,000 thousand patients in total -- we think that that's an appropriate placeholder to think about and model.

Thank you. Our next comes from the line of Jonathan Eckard of Citi. Your line is now open.

Thank you for taking the questions. There's more -- there's [miss] about some of the data that's in the two cases that were unblinded. I'm just not sure if you're -- if you know if there's going to be any additional information that could be used so when you do get it, you can share with regulators.

For example, both of the two blinded cases seem to have missing information which is probably pretty important in assessing what really happened in both of them. In the one, there was a suspect stroke but then deemed that the person didn't have a stroke. The second one seems like the cardiovascular event was diagnosed by the patient's family. I'm just trying to understand what additional information may be available to you so that when you do meet with regulators, these can be looked at, at face value rather than speculation?

Well, thanks, Jon. I appreciate the question. We felt it was necessary, given our disclosure, to provide at least the cogent detail in both cases. Even what we've provided and the underpinning of your question is that the medical history and the clinical circumstances in both of these cases would lead to a reasonable conclusion -- at least it did by us, medically -- that this was unlikely to be drug-related.

This information was gleaned from fairly detailed case report forms that would be available in the context of review with FDA in both cases. As I mentioned, we have not gotten any expression of concern from the FDA about any the SAEs in FLINT, so I'm confident that when we do have the complete data set, which will include of course, the unblinded remaining safety data, that we'll be able to have a fulsome discussion with FDA, with all of the relevant details.

Great and then just a quick second question on the PIVENS trial. The CRN, which -- and I believe it probably consists of a similar group of PIs who were on the FLINT trial -- when they did their adjudication of the data, especially the cardiovascular events from that trial to the final analysis, was there much change in those events? Because again, this is a pretty tight group, if I'm not mistaken. I'm just trying to understand what's happened historically with some of the adjudication of events and so on and so forth from PIVENS, and what therefore, may or may not come out of the final analysis for FLINT?

Yes, it's a good question. I don't know the answer to that. We only know what has been published and there is for PIVENS -- there are supplemental data tables, which include more detail on the AEs that occurred in that trial. They have a bit of a (technical difficulty)--

Hello?

Ladies and gentlemen, please stand by. Your conference will begin momentarily.

Hello?

Jon, we're just waiting for Mark to rejoin the call.

Oh, okay, sorry. I didn't know what was going on. I'm dialing in from a [row] so I didn't know what was going on.

Sorry.

If he doesn't get back, he's answered most of my questions. Congratulations on all of the updates. I'll pass it back so everybody else has a chance to ask a question.

Thank you so much, Jon. I appreciate it. Just everyone, the operator is now redialing Mark in. Just a moment.

Hello?

Party Mark has rejoined.

I apologize. My cell phone dropped, but I just got a couple of e-mails, a couple of other people were dropped as well. I was on hold. Anyway, right back -- where was I lost?

Hi, Mark. You were talking about the AEs in the PIVENS study.

Yes, and just the adjudication of those AEs that we can't know. I mentioned -- I don't know if I dropped before this bit -- if you look at the supplemental tables published for PIVENS, there is a breakout of clinical events and outcomes that are separate from the other AE tables. The other thing I was mentioning is that we want to stress that we are not -- it's not appropriate to directly compare two different clinical trials, but we did want to highlight that PIVENS excluded diabetic patients, whereas FLINT had more than 50% on diabetics who, of course, are ostensibly at more cardiovascular risk and morbidity and mortality and other all-cause mortality.

Thanks Mark. I'll let it everybody else get -- in queue get in. Thank you.

Thank you. Our next question comes from the line of Jim Birchenough of BMO Capital. Your line is now open.

Yes, hi guys. Congratulations on the POISE data and just a few follow-up questions. Just Mark, could you maybe first provide some context for what type of CV event rate we typically see in these type of NASH patients, maybe looking at PIVENS and other studies?

Then second, I'm just trying to get a better sense of what the timeline is for interaction with FDA, following the 10-K disclosure and the POISE data. Could you maybe sketch out when is the next time point you'd talk to FDA and get an updated sense from them on how they might think about this?

Then final question -- just wanted to get a better sense of, when you look at designing your Phase 3 trials, would you expect to try and exclude some upper bound risk for CV events in the way that companies like Orexigen have had to do? And would you have some interim time point to do that or would we have to wait till the final Phase 3 completion to get a sense of relative CV risk? Thanks.

Yes, sure. To your first question, which is what's the normal background cardiovascular morbidity/mortality rate, we did report in the 10-K a recent US study showing over 10-year follow-up period, over 50%. In fact, startling 57% mortality in diabetic NAFLD patients, so not even necessarily patients who had NASH, but just the broader spectrum of NAFLD, as compared to non-diabetic NAFLD patients who had a 27% mortality risk.

So if you take a cue from that, you've got a 5% annual mortality. That's all cause but the primary cause in the general NAFLD patient population, especially a diabetic population, would be cardiovascular. There was another paper I saw recently showing, in NAFLD patients, just over 1% annual cardiovascular event rate so that, that gives you the context you're looking for.

With respect to FDA interactions on the program, we don't comment on specific interactions and it's difficult to predict -- we anticipate having a series of interactions with them. We don't have an ID filed, for example, so that's a first order of business for NASH -- NIDDK does and we will be talking to them and also EMA this year.

As I mentioned in my remarks, we anticipate getting going on a Phase 3 program in the first half. So we think it will take about a year. Of course, once we have the unblinded data set in hand, we'll have a much better leg to stand on and going in and reviewing it with them and nailing down the Phase 3 program.

Your third question about excluding patients at more cardiovascular risks, I can't comment on that. I really think we need to take a look at the data. As I said, given this event rate in this particular population, and given what we know about our drug, we're not particularly concerned.

I would highlight the fact that we do -- we have put a stake in the ground that we initially would like to focus on patients with more advanced disease. We do know that patients who are -- have advanced fibrosis or already have established cirrhosis are at much more relative risk of liver-related morbidity and mortality so that the -- that will also be taken into consideration in terms of the patients we choose, so I'll leave it there.

Great, thanks, Mark.

Thanks, Jim.

Thank you. Our next question comes from the line of Alan Carr of Needham & Company. Your line is now open.

Hi, thanks for taking my questions. Wondering if you could give us a few more details about the lipid metabolic trial that you plan for later this year and also the pediatric NASH, too? Thanks.

I'm sorry, Alan, I missed part of that question.

I was hoping you can give us more details on a couple of the trials that you planned this year. One of them is the lipid metabolic trial for OCA. If you could give us some details on that one -- it sounds like it will be relatively quick? And the other -- and I'm wondering if you can comment on the pediatric trial, as well that you're contemplating?

Yes, the lipid -- as you know, we are currently conducting a lipid metabolic study in PBC patients and you can go to Clintrials and get an idea of all of the different detailed lipid and lipoprotein parameters we're studying there. With the NASH trial, we actually recently had an ad board with an impressive group of NASH and lipidologist KOLs who are helping design a study in NASH.

All I can say right now is that this will be a more complex study. We're going to be asking questions like what are the effects of OCA in NASH patients not on statins, what happens if you add a statin, et cetera. So that, that's obviously a point of interest there and not so much in PBC patients and we will likely look at additional parameters -- not just lipid parameters but also inflammatory parameters, because that's also a very key component of cardiovascular risk.

That said, we need -- David Shapiro and his team need a little bit more time to finalize the design of the study and it will be starting in the second half. I really do not anticipate having data from it until next year. It will take some time to get up and going.

With respect to the pediatric NASH trial, this is something that we've been approached on and are very interested. I want to stress that this is something that is a potential; we haven't decided definitively to do it. We need to discuss more with the proposed PI, but obviously there's a real unmet need in this population as well.

Okay, great. Thanks very much.

Thank, Alan.

Thank you. Our next question comes from the line of Akiva [Fleece] of Oppenheimer. Your line is now open.

Hi, Mark. Thanks for explaining the rationale about disclosing the CV events from FLINT. I'm just wondering, when you receive the full data set from the NIDDK in July, what's going to be the planned disclosure of data from that point going forward? Is the plan still to wait for [AASLD] to see the rest of the data or will there will be some periodic disclosures in between? And then I have just a follow-up question after that?

Well, thanks. This has been the source of a lot of speculation. Just as we've put out top-line information from the trial, which we have an obligation to do, NIDDK understands that once we get the complete unblinded data set, we will need to put out top-line results very quickly. That is our intention.

Frankly, we've now heard that there have been FOIA requests in and there have been -- in response to those FOIA requests, NIDDK has, or at least, someone at NIDDK has communicated that the data set will be available to those making the requests, as well. It's -- we're going to need to spend some time now talking to NIDDK about the appropriate dissemination of the data.

The intention, still -- the next key scientific meeting in which it would make sense for NIDDK and the FLINT investigators to present their data to the scientific community is still AASLD in mid-November this year. I believe that, that remains the intention, which is completely appropriate.

Okay, thanks. Then you also mentioned that once you have the FLINT data in hand, you'll go to the FDA and EMA to finalize the Phase 3 trial design. I'm just wondering if you could maybe tell us what it is that you're looking to see in FLINT -- maybe two or three type pivot data points that could impact the Phase 3 design? Is there anything about the tentative trial design in place that you could tell us about? Thanks.

Yes, look, and I can't -- I'll mention one thing but I don't want to second guess what the data set will tell us. We have a keen interest. We know, obviously, that the drug was highly efficacious in meeting the specified primary endpoint, which was the 2 point improvement in NAFLD activity score with no worsening of fibrosis.

For example, that looking at the individual components there, including histologic -- not just individual components of the NAS, but also NASH resolution itself, looking at fibrosis, looking at what's going on in the later-stage patients, that will inform, or could have [informed] our plans, especially in the more advanced patients. I mentioned that -- it's public out there, because FDA made a comment about this at the workshop and Gilead has also made public comments -- that HVPG, hepatic venous pressure gradient, is likely to be acceptable as a surrogate endpoint in cirrhotic patients.

It will be interesting to see how the data might inform, in addition to HVPG, a histologic endpoint, and that will be subject of some interest in discussions with the regulators. But beyond that, we just have to wait to see what the data set is and how our discussions go with FDA.

In terms of design of the studies, we mentioned as much as we can. We've speculated about -- and other companies have also speculated about -- potentially acceptable surrogate endpoints. In addition to HVPG, we have in the precirrhotic patients a histologic endpoint, which could be either similar to FLINT or it could be a little bit more to the left, as I call it, which is histologic resolution of NASH, a secondary endpoint in FLINT.

Then the other area of great interest to us and other companies and to FDA are the non-invasive modalities that we and others will incorporate in our trials. We have FibroScan, which is approved now, been in the market in Europe for a few years, now is in the US market, and has a very high sensitivity specificity of basically giving you the answer cirrhosis or no cirrhosis. We would be interested employing that as a supportive modality in our trials. Then there are other very interesting serum markers of fibrosis in NASH and quantitative liver function tests.

Great. Thanks for the additional color and congrats again on the positive PBC data.

Thank you. Our next question comes from the line of Jim Molloy of Summer Street Research Partners. Your line is now open.

Thanks for taking my questions. Happy St. Patrick's Day to you guys, as well. Just a quick question on looking at the SAEs versus -- the CV SAEs in the two trial -- 10 in the NASH trial and 2 in the POISE -- in the NASH at 25 milligrams and POISE at 5 to 10 milligrams. Is there anything to be read into the dosing or is it the disease state or the co-morbiditites of the two patient populations that may be driving the higher AE/SAEs in the NASH trial?

Yes, thanks, Jim. I really -- it's apples to oranges, right? It's a very different patient population. As I mentioned, the PBC patients are hyperlipidemic, but don't appear to have increased cardiovascular risk compared to the general population. As I -- not just the cardiovascular SAEs, but all of the AEs we saw in the POISE trial and the PBC patients were typical, as expected, in a population like this over the course of a year.

There is a higher dose, the 25-milligram dose, that we used in the FLINT trial and the NASH patients, but also keep in mind that the BMIs on these patients, especially in the US, tend to be quite a bit higher. Just to give you color on that, in our previous six-week diabetic NAFLD study, the mean BMI was 36 of the patients, versus 27 in our previous Phase 2 PBC trial. I think I recall that correctly.

So on a mgs per kg basis, the gap is not that wide. But I wouldn't want to speculate on any dose effect here. Frankly, again, I'll say this, that we obviously need to see what the unblinded data look like, but given all of our understanding of the mechanism of action of this drug and the normal background rate of cardiovascular morbidity in a population like this in FLINT, we're not concerned that there's any signal here.

Great. And then on the PBC data -- congratulations on the very positive data that you presented.

Thank you.

Any additional color from the FDA on -- these are obviously surrogate endpoints. EMA is on board. Any additional color from the FDA? Should we expect any -- that these will be comfortable for approving?

Good question. As I've always been guiding, this is an unprecedented surrogate endpoint and ultimately will be a review issue, but I will say that I've stated publicly in the past that FDA was very enthusiastic about our [cont] -- our sponsorship of the PBC Supergroup that I discussed during my remarks.

They now have seen the more relevant final data from over 6,000 patients in the database and the correlation of our POISE endpoint with -- long-term with liver-transplant-free survival and it was reported that on our specific endpoint, the p-value was 10 to the minus 34. It doesn't get clearer than that and I'd humbly like to think that we've done everything possible to provide sufficient evidence to support the bar, which is reasonably likely to predict clinical benefit. I hope that FDA feels the same way.

Thank you for taking the questions.

Thanks.

Thank you. Our next question comes from the line of Jim Birchenough of BMO Capital Markets. Your line is now open.

Hello, guys. I just wanted to follow-up on a couple things. One, just in terms of adjudication, Mark, do you expect to have some cardiovascular or cardiologist adjudication, or is this just going to remain adjudicated by the FLINT investigators? And then just second question, can you remind us whether we seen an effect of OCA on inflammatory cytokines and CRPs -- some of the important markers for CV risk? Thanks.

Thank, Jim. The answer to your first question is we certainly would have an interest in that. I believe that most of the people involved in the FLINT trial, understandably are hepatologists, and we've learned a lot in our discussions with cardiologists and, especially with lipidologists, and will continue those discussions, right?

And we are absolutely committed, per our desire to do this detailed lipid metabolic study in NASH patients -- we're absolutely committed to understanding to the level possible, mechanistically, what's going on and what the clinical implications are of the lipid metabolic effects we see. So certainly when we have the FLINT data in hand, we will be interested reviewing it and having it adjudicated by cardiology and lipidology.

With respect to your question about inflammatory markers, yes, we know that -- one of the important mechanisms of action of FXR in both the liver and elsewhere are the anti-inflammatory effects. These have been extensively published on. We do have, in our previous Phase 2 trials, evidence that, for example, CRP, C-reactive protein, does decrease on OCA. Of course, this is a very important marker of inflammation and cardiovascular risk.

In fact, I believe, I read a recent paper that if you were on a statin and you get an LDL decrease, you actually don't get decreased cardiovascular risk unless your CRP also goes down concomitantly. So yes, that's why I mentioned the inflammatory markers, and we have seen them go down with OCA therapy.

Great. Thanks, Mark.

Thank you. I'm showing no further questions in the queue. I'd now like to hand the call back over to Mark Pruzanski for any closing remarks.

Yes, thanks. Again, I want to thank everyone who listened in on this call this morning. This is really an absolutely thrilling time for us. I started this Company over 12 years ago and this is -- the Phase 3 result is really a realization of a long -- that's been a long time coming. I really believe that this sets us on the path to getting OCA forward to filing for approval and hopefully to the market and to patients.

I want to thank everyone -- first and foremost, the patients who have participated in our trials, all of the investigator study coordinators, and everyone else involved out there in our trials, and of course, my extremely capable team. I want to thank Senthil, Barbara, and David Shapiro, listening in, and everybody else in San Diego, Italy, et cetera. It really is a special day for me and we look forward to continuing to work hard to execute as we have, to bring OCA forward. So thank you all.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program. You may all disconnect. Have a great day, everyone.