Hello. Thank you for standing by, and welcome to the fourth quarter and full year 2021 Intercept Pharmaceuticals earnings conference call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you'll need to press star one on your telephone. Please be advised that today's conference may be recorded. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Nareg Sagherian, Executive Director, Investor Relations. Please go ahead. Thank you. Good morning, and thank you for joining us on today's call. This morning, we issued a press release announcing our fourth quarter and full year 2021 results and business updates, which is available on our website at interceptpharma.com. Before we begin our discussion, I'd like to note that during our call, we will be making forward-looking statements, including statements regarding our approved product and clinical development program, certain regulatory matters, and our strategy, prospects, financial guidance, and future commercial and financial performance. Listeners are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this call, and we undertake no obligation to update such statements except as required by law. These forward-looking statements are based on estimates and assumptions that, although believed to be reasonable, are inherently uncertain and subject to a number of risks and uncertainties. Some, but not necessarily all, of the risk factors that could cause our actual results to differ materially from our historical results or those anticipated or predicted by our forward-looking statements are discussed in this morning's press release and in our periodic public filings with the SEC. Today's call will begin with prepared remarks from our President and CEO, Jerry Durso, our Chief Commercial Officer, Linda Richardson, President of Research and Development and Chief Medical Officer, Dr. Michelle Berrey, and Chief Financial Officer, Andrew Saik. We will then open the call to take questions. Please limit yourself to one initial question in order to allow time for all questions to be addressed. Let me now turn the call over to our CEO, Jerry Durso. Thanks, Nareg, and good morning, everyone. Our performance in 2021 has put us on a solid foundation as we enter this year and embark on the next pivotal chapter for Intercept. In my first year as CEO, we made great strides to achieve our corporate objectives and capitalize on the opportunities to support our future growth. Looking first at our performance in PBC, our team delivered strong double-digit sales growth for Ocaliva and ended the year with worldwide revenue of $363.5 million, despite the challenges associated with the pandemic and the U.S. label update. We now look to 2022 as a year to continue capitalizing on this momentum, as there are still a significant number of people living with PBC globally who could benefit from adding Ocaliva as a second-line therapy to treat their disease. We look forward to expanding our efforts to reach physicians with important data that will support the continued adoption of Ocaliva in the appropriate PBC population. We've also made significant progress towards generating a robust data set that will deepen our understanding of the potential role of OCA in NASH and determine the path forward. After an extensive dialogue last year with FDA, which focused on the REGENERATE study, including the consensus biopsy reading methodology and the scope of an updated safety data set, we have been at work generating what will be the largest data package in the NASH field. The magnitude of this work is unprecedented, and we're looking forward to sharing the new data package from REGENERATE when our work is complete. If the data support it, we continue to target a potential pre-submission meeting with FDA in the first half of this year. Our second phase III trial, REVERSE, is evaluating OCA in patients with compensated cirrhosis due to NASH. Given the magnitude of the data we are generating from REVERSE, as well as complexities associated with reading biopsies in the compensated cirrhotic population with this new method, we now expect that the delivery of these data will move into the third quarter. Michelle will provide more information about the status of our data generation later in the call. As a reminder, REGENERATE remains the only pivotal phase III study in NASH in which an investigational compound has demonstrated fibrosis improvement with no worsening of NASH, and REVERSE remains the only active phase III trial in people living with compensated cirrhosis due to NASH. Taken together, REGENERATE and REVERSE represent the largest and most robust data sets in the field and include more than 3,300 patients across both studies. We look forward to sharing these important data. We also made meaningful advances in our pipeline in the past year as we continue to explore areas of significant medical need in liver disease. We progressed our development program for the OCA and bezafibrate fixed-dose combination and initiated a first-in-human study for INT-787, our next-generation FXR agonist. Advancing these important programs will continue to be a focus in 2022, and Michelle will talk more about that later in the call. I'm pleased to note that we achieved this progress in 2021 while significantly strengthening our leadership team. We've assembled an executive leadership team with the right experience to drive Intercept's next phase of growth and development. Additionally, we successfully exchanged the majority of our near-term debt to address the maturity of 2023 convertible notes. We also remain prudent with our SG&A expenses, which decreased by more than $100 million versus the prior year, resulting in a 30% savings. This, along with our top-line growth, allowed us to maintain a steady cash position for a third consecutive quarter in 2021. With our continued focus on cost management, which Andrew will elaborate on later, we're well-positioned to drive another year of strong performance. 2022 is poised to be a transformational year in Intercept's history. I look forward to working alongside the dedicated Intercept team as we expand and grow our commercial PBC business where significant opportunity remains. As we deliver important data from our NASH development program that will drive decision-making for our path forward, and as we progress our pipeline opportunities to continue to innovate on behalf of people living with liver diseases with significant unmet need. In summary, I remain confident in the strong foundation we've built and in making data-driven decisions that will define the strategic path for our company's future. I'd now like to turn the call over to Linda, who will talk about our commercial performance for the fourth quarter and the full year of 2021. Michelle will then provide an update on our regulatory and R&D activities, and Andrew will conclude with a review of our financial performance. Linda? Thanks, Jerry, and good morning, everyone. I'm happy to share some of the performance highlights of 2021 as it was another strong year for our PBC commercial business. Despite the ongoing global pandemic, we drove another year of double-digit sales growth, underscoring the strength of Ocaliva's market position as the only second line agent approved for use in PBC. For the full year, we reported $363.5 million in Ocaliva net sales globally, which represents 16% growth over the prior year. For the fourth quarter, we had global sales of $92.4 million, an increase of 11% versus the same period in 2020. Let's review how we were able to drive this growth five years post-launch. First, the U.S. commercial team managed the label update in an exemplary way. Using multiple approaches to communicate the changes to our HCPs, patients, and other audiences in a focused, efficient manner, we were able to fully pivot back to promotional messaging in September. Second, as an organization, we've made excellent and appropriate use of the wealth of data coming from the open label long-term safety extension of our POISE phase III study. We were able to successfully leverage insights from this work throughout 2021. First, we began with highlighting the positive impact Ocaliva has on maintaining ALP and bilirubin levels, important factors in monitoring PBC progression. In the third quarter, we shared data from the same cohort of LTSE patients that showed a stabilization of fibrosis, something physicians have told us is an important consideration in managing PBC. This layering of key messages is creating a more complete picture of how Ocaliva may benefit patients who need second line therapy and that these benefits go beyond lowering ALP. The third thing I'll highlight regarding our strong performance in 2021 is the outstanding growth we see in our international markets, where we achieved annual sales 30% higher than the prior year. Implementation of multi-channel marketing and strong execution of commercial messaging led to an increase in underlying demand. In fact, new patient acquisitions in 2021 surpassed projected targets, and early data in 2022 sees this trend continuing. While Italy and Spain consistently bring strong performance, we are now seeing additional contributions coming from our other markets as well. We know that there remain a considerable number of patients who could benefit from the addition of a second line therapy to manage their PBC. Some estimates have shown that only about a third of eligible U.S. patients have ever received a second line agent. Our focus is to continue to bring education to HCPs on the benefits of actively managing their PBC patients and to reevaluate those that could be appropriate for treatment with Ocaliva. In 2022, we will be creating new promotional campaigns, attending major conferences in person again, and continuing to show the value Ocaliva can bring to appropriate patients, leveraging the data and insights we have from years of being on the market. In closing, I'm proud of the global commercial team's performance, commitment, and passion this past year, and I look forward to sharing updates on our progress in 2022. I'll now turn the call over to Dr. Michelle Berrey. Michelle? Thank you, Linda, and good morning, everyone. I'll be providing a few updates today on our continued work to generate evidence supporting Ocaliva in PBC on our NASH development program and on our pipeline. In 2021, we continued to add to the large evidence base supporting Ocaliva in PBC. We now have more than 20,000 patient years since Ocaliva was first approved for marketing in 2016. We are looking into multiple real-world evidence databases to better understand how to leverage these data to show the clinical benefits of continued therapy with Ocaliva beyond biochemical improvements. We're now expecting to publish our data from the POISE long-term extension study, first presented as a late-breaker abstract at The Liver Meeting last November. These data showed that individuals with PBC treated with Ocaliva had a statistically significant greater transplant-free survival than propensity score-matched controls who were eligible but not treated with Ocaliva. We are submitting the manuscript to a global scientific journal, and we'll disclose details as soon as we have confirmation of the publication. In addition to the publication, we expect these data to be included with other outcomes data as support for our post-marketing study, COBALT. A regulatory submission planned for later this year. As we noted in the third quarter of 2021, we've been closing out our COBALT study because of the challenges with maintaining patients on a multi-year placebo-controlled study, which was designed to confirm benefits in clinical outcomes, but when a therapy is commercially available. We have been discussing options with regulators, and we'll be including the available placebo-controlled data in a broader evidence package that we anticipate submitting to both FDA and EMA in the second half of 2022. We also anticipate presenting these additional data at scientific meetings later this year and are excited about the opportunity to get back to some in-person meetings with our thought leaders and physician advocates. Turning to NASH. Last year, we made substantial progress on our OCA for NASH program. After dialogue with FDA, we implemented a new consensus reading methodology that is in line with the agency's draft guidance. Together, REGENERATE and REVERSE represent the largest phase III program ever conducted in advanced liver fibrosis and compensated cirrhosis due to NASH, and we initiated a significant amount of data generation using this new methodology in the second half of 2021. We are continuing to generate a new data package from REGENERATE, and as we've previously guided, if the data support it, we're targeting a potential pre-submission meeting with FDA in the first half of this year. We're also continuing to work toward top-line data readout from our REVERSE study, the only active late-stage study in compensated cirrhosis due to NASH. Given the magnitude of the data from REVERSE, as well as complexities associated with reading biopsies in the cirrhotic population with multiple external parties using a new methodology, more time is required to have a top-line data readout. We now anticipate delivering these data in the third quarter of this year. As a reminder, from a regulatory perspective, our efforts continue to be focused on the REGENERATE dataset. Therefore, these shifts in the REVERSE timeline will not impact our ability to hold a potential pre-submission meeting with the FDA in the first half of the year should the data from REGENERATE support it. Overall, the amount of data we're generating in NASH is unprecedented, and upon completion of these analyses from REGENERATE and REVERSE, we will have accumulated the largest dataset in the field. As evidence of that, the REGENERATE safety database will now include an additional 12 months of patient data, and the comprehensive assessment of the safety database will include more than 3.5 times the drug exposure of the prior analyses and submission. In addition, this analysis will now include almost 1,000 subjects who've reached month 48, 4 years of data. Once we have these new data in hand, they will provide a significantly more robust perspective on OCA's benefit risk profile. Despite the substantial amount of work being done across the industry, there are unfortunately still no approved therapies to treat NASH, and we're working to deliver these important data as soon as possible. Moving on to our pipeline. We have several clinical trials ongoing for our OCA plus bezafibrate fixed-dose combination in PBC. In the U.S., our large phase I study to better characterize the exposure data of the fixed-dose combination is ongoing, and we also are beginning to screen patients for our second phase II trial. We are continuing to enroll patients in our international phase II study. These three early phase studies will inform the doses to be included in the fixed-dose combination that we will study in phase III. We believe OCA and bezafibrate have synergistic mechanisms of action that carry the potential to benefit individuals with PBC and other cholestatic diseases when used in combination. Both medications have been shown to help lower the key biochemical markers that predict long-term outcomes in PBC. Bezafibrate has also been associated with improvements in pruritus, a potential benefit we're exploring in our phase II program. In addition, our phase I study of our next generation FXR agonist, INT-787, is ongoing, and we expect to submit an IND in the first half of this year. We're in the process of determining a target indication for 787 and look forward to sharing that information. We are very excited about this compound and its potential applications. I'll now turn the call over to Andrew for a financial update. Andrew? Thanks, Michelle, and good morning, everyone. I would ask that you please refer to our press release that was issued earlier today for a summary of our financial results for the fourth quarter and full year ended December 31, 2021. Beginning with our commercial performance, in the fourth quarter, we recognized $92.4 million in worldwide Ocaliva net sales, up from $83.3 million in the fourth quarter of 2020. For the full year 2021, worldwide Ocaliva net sales were $363.5 million compared to $312.7 million in the prior year. Our full year 2021 Ocaliva net sales comprised of U.S. net sales of $260.8 million and ex-U.S. net sales of $102.7 million, representing growth of 11% and 30% respectively. Our GAAP operating expenses for the fourth quarter totaled $113.3 million, which was a decrease of $10.6 million versus the fourth quarter last year. Non-GAAP adjusted operating expenses were $104.4 million in the fourth quarter, a decrease of $2.2 million versus the prior year period. For the full year 2021, GAAP operating expenses were $419.1 million, and our non-GAAP adjusted operating expenses were $382.3 million. As a reminder, our non-GAAP adjusted operating expenses exclude stock-based compensation and depreciation. Cost of sales for the fourth quarter were $1 million compared to $0.8 million in the prior year period. SG&A expenses were $60.6 million in the fourth quarter, a decrease of $9.4 million versus the fourth quarter of 2020. SG&A expenses were $230.9 million for the full year 2021, a decrease of a $101.6 million dollars from 2020. Our R&D expenses in the fourth quarter were $51.7 million as compared to $51.9 million for the same period last year, and were $185.3 million for the full year 2021, a decrease of $6.2 million from the full year 2020. Approximately two-thirds of our full year R&D spend was related to our NASH programs. Cash, cash equivalents, restricted cash, and investment debt securities available for sale at year-end totaled $429.4 million. Turning to our financial guidance for the year. We expect full year 2022 Ocaliva net sales to be between $375 million and $405 million. This guidance contemplates a significant number of untreated PBC patients globally that could benefit from Ocaliva, the strength of Ocaliva's market position, and the E.U. label change, which we anticipate implementing in the first half of this year. As a reminder, Ocaliva is subject to seasonality in Q1 due to the fact that patients are faced with insurance plan resets and Medicare coverage gaps at the beginning of the year. Therefore, similar to what we've seen in prior years, we expect lower revenue in the first quarter relative to the rest of the year. We expect full year 2022 non-GAAP adjusted operating expenses to be between $360 million and $390 million. This guidance range reflects our continued investment in our commercial and post-marketing efforts in PBC, our ongoing REGENERATE clinical trial and regulatory efforts in fibrosis due to NASH, our additional pipeline programs, such as the OCA and bezafibrate combination trial, and our phase I study of INT-787, our spend to support NASH data readouts and the subsequent potential regulatory and commercial next steps in NASH, as well as our normal general operating expenses. Cash interest expense for the year is expected to be $23.5 million based on our current capital structure. Even though we managed to reduce SG&A expenses by over $100 million this year relative to the prior year, we continue to find opportunities to manage expenses while ensuring that we invest in the business to meet our company objectives. One example of our continued focus on cost containment is our recent decision to relocate our headquarters to Morristown, New Jersey. Our cost management efforts will continue into 2022 and beyond. Overall, I am very pleased with the progress we made in 2021 and believe that we significantly strengthened our financial foundation. We successfully de-risked the balance sheet by executing an exchange for our convertible notes, and we have materially reduced our spend such that we have had stable cash for three consecutive quarters. We believe that we are well-positioned financially to support the company moving forward and help us achieve our strategic objectives. Now I'll turn it back over to the operator to start the Q&A. Operator? Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key. Our first question comes from Alethia Young with Cantor Fitzgerald. You may proceed with your question. Hey, guys. Thanks for taking my question. You know, congrats on how you're keeping moving forward here. I guess I was just wanting to see if you could give us more color on kind of the timeline shift on REVERSE. You know, is it kind of event-driven or is there something else going on or COVID? Or can you give us any kind of color that you might have on what's going on there? Thanks. Hi. Good morning, Alethia. Good to hear from you. Yeah, maybe Michelle, you can start obviously an important question for us to go into. Michelle? Yep. Good morning, Alethia. First, I wanna be clear that there's no delay in our overall program or in our regulatory interactions. We are still intending to have our pre-NDA meeting in the first half of the year. You remember last year we had discussions with the FDA on the reading methodology and then deployed multiple panels reading the two large studies in parallel. Although our major focus on the regulatory interactions continues to be the REGENERATE study, the delay in REVERSE to the third quarter is not going to impact the pre-NDA meeting. What I can say specifically about the REVERSE study is, it's a large study. It's more complex given the advanced patient population with early cirrhosis. We now expect those data into the third quarter. Great. Thanks. Thanks, Alethia. Thank you. Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. You may proceed with your question. Good morning, team, and thank you for the updates. Just going along the same themes that Alethia raised. Will you be able to share with us when you report out the REGENERATE re-analysis, some safety look into REVERSE? I know that we may still be waiting for the histology analysis, but is there some commentary that's gonna be provided what the safety of Ocaliva looks like in the REVERSE population at the top line? That's maybe question one. Question two is, you know, we're almost done with this quarter. Why not just say the fact that you're not saying it's second quarter, is there any glimpse of hope that this data could come in still onto this first quarter? Thank you for taking my questions. Yep. Thanks, Yas. Again, on the REGENERATE safety database, I think that's a huge question. One of the things that we really wanted to try to pull in was the additional data from REGENERATE. We've now added another year. We've added all of 2021 to our safety database. Compared to what we had submitted with the initial interim analysis, back in 2019, we had about 2,400 patients, so 2,400 total patient years. We're now out to over 8,000, so 3.5 times the number of patient years. Importantly, you know, we now have almost 1,000 patients out to 4 years. That was a really critical point we wanted to pull in. We will pull the safety from REVERSE at the same time that we do the top line for the efficacy, so it's important to lock your database on the same data cutoff. We'll have that safety data coming out around the same time, at the same time, the top line with the efficacy from REVERSE. There won't be too much of a lag between those. Again, our main focus with the FDA pre-NDA meeting would be on the REGENERATE safety database. With regard to the timing, we have a earnings call in May and may have a little more specificity at that point. Speaking from today, I think we expect it to go into the third quarter. Thanks for the question. Thank you. Thank you. Our next question comes from Michael Yee with Jefferies. You may proceed with your question. Hi, this is Yi Chen on for Michael. Thanks for taking my question. Just wanna ask about the REGENERATE study a little more and kind of get an understanding for what are the different scenarios you're thinking of. Is the base case that the phase III data shows at least the same magnitude of effect in hazard ratio, and you view that positive and the study and the safety database is now even larger, and that would drive better risk-benefit then for approval? Yeah, what is your scenario here, and how are you thinking about that? It's a great question, and I think you nailed it. The really important question from the CRL in 2020 was about the benefit risk, and now we will have a much more robust safety database. You know, when we expect patients to be on Ocaliva, on OCA for the rest of their lives for NASH, it's important that we have long-term safety data so that we understand the tolerability, that we make sure there are not new safety events at year three, year four. Now we have almost a thousand patients, 995 patients through December 31, 2021. That's a really important new set of data. Back in the 2019 interim analysis, we had patients out to month 48, year 4. It's a much more robust safety database, which we feel gives us a much better assessment of the overall benefit-risk for the drug. Okay, great. Thank you. Thank you. Thank you. Our next question comes from Brian Abrahams with RBC Capital Markets. You may proceed with your question. Hi. Good morning. Thanks for taking my question. With respect to REVERSE, I was wondering if you could elaborate a little bit more on some of the key hurdles for the biopsy reads in this cirrhotic population. Is it just a matter of finding readers or variability given the severity of this liver disease that might require any sort of special protocols or extra time? I'm just, I guess, wondering how to think about the overall reliability of the dataset that'll be generated in this population on histology when we see the data. Thanks. Yeah. Thanks for the question, Brian. We're keeping Michelle busy this morning. Hi, Brian. Good morning. I think one of the important things to understand about reading the early cirrhotic patient population is that in clinical practice, it's not really critical to differentiate advanced fibrosis from an early compensated cirrhotic patient population. There's nothing you're gonna do differently clinically to treat that patient. Unfortunately, we still don't have any drug available, approved for NASH. It's never really been that critical to differentiate a high F3 from a low F4. In a clinical trial, however, it is obviously quite critical that these pathologists are differentiating. Yeah, there is some additional elements of training that were involved. We had deployed parallel panels. We had some panels moving forward for REGENERATE and separate panels on the REVERSE study. There was different training for those pathologists to make sure that they were paying special attention to that high F3, low F4 differential. Clearly, that's gonna be important when they progress to reading the month 18s as well. The second element, this is the only advanced trial in advanced fibrosis, early cirrhosis. Third, we're deploying this new methodology. We've learned a lot through these deploying this new methodology and are applying those learnings to the REVERSE trial. Thanks. That's really helpful. Appreciate it. Thank you. Thank you, Brian. Thank you. Our next question comes from Joseph Stringer with Needham & Company. You may proceed with your question. Hi, good morning, everyone. Thanks for taking our questions. Couple on PBCs. Your 2022 sales guide, what percent of that is sort of volume growth as opposed to a price increase? And secondly, you know, 5 years post-launch in PBC, what's your feeling on the market penetration into the addressable PBC patient population at this point? Thanks for the questions on PBC. Obviously, I think, you know, as we said in the prepared remarks, we feel good about the progress we made and the growth in 2021 and look now to push forward. Maybe, Andrew, you start with the question specific to the 2022 view and how we're looking at the sales guidance that we provided. Yeah, sure. Thanks for the question. With regard to PBC growth, we are expecting continued volume growth in both the U.S. and international. I think on the low end of our guidance, it obviously wouldn't take a great deal of volume growth to hit the low end. Obviously, we gave a range. To be on the higher end, we would need to see continued growth in the international and the U.S., which we're enjoying right now. I'll tag onto that if you don't mind. I think there is, you know, really a lot to be said for what we're learning about with the number of years that we've been on the market, our ability, as Michelle noted, to generate new data. Particularly when you're looking at it, the ultimate goal of therapy in PBC is to prevent end-stage liver disease, transplantation, and death. As we're, you know, reading out, as we did at AASLD, some of this information, combined with what we're learning with our five-year LTSE data on not only lowering ALP and bili, but keeping it low and then showing important, you know, stability in fibrosis, we are creating a fuller package of the data that physicians need to take into consideration when choosing to add on a second line agent. This education is, I think, going to very much accelerate with the work that we are doing because of the data we have access to. We know that in Europe, there is a stronger market for second line. It's been more established. Because it's based at institutions, more institutionally treated than perhaps, you know, community gastros as we have to go out and hit them across the land, this is a little bit easier way to penetrate than in the U.S. We did some market research that shows we have really increased the confidence of physicians using Ocaliva to treat second line, and that is, you know, really where the game is being played. Those patients that are appropriate are being intercepted early, and, you know, we're trying to manage that before you get to the point where you're in a hepatology office and very severe. We intend to use new data, new materials, you know, a really comprehensive approach to getting out. We won't have the limitations we've seen, hopefully, with COVID. We've overcome that and move forward with our business. That only a third of patients at all in the U.S. have had second line treatment. We see the next two years as being fundamental to shifting the conversation and really increasing patients getting treated with second line therapy. Great. Thanks so much for taking our questions. Thanks, Joe. Thank you. Our next question comes from Thomas Smith with SVB Leerink. You may proceed with your question. Hey, guys. Good morning. Thanks for taking the questions. Just on REVERSE, it sounds like the gating factors you're pointing to around the complexity of the biopsy slide interpretation. I guess if we turn to the safety analysis, can you just remind us, you know, how much visibility you have into the ongoing safety analyses and the independent adjudication of safety events there? Are there any types of events that need to be adjudicated as being explicitly defined, or have there been any changes to the types of events that are being evaluated? I guess if you could just confirm if any of the delays in interpreting the data are related to, I guess, adjudication of those events. Thanks. Thanks, Thomas. Michelle? Hi, Thomas. Good morning. Good question. We do have a DMC that is overseeing the NASH trials and is looking specifically at these large patient populations, just to make sure that the ongoing safety, there's no issues there that would require additional monitoring changes in the study design. We continue to have, you know, continue as designed feedback from our DMC. With regard to adjudications, we have had discussions with the FDA and have specific independent committees look at hepatic events, cardiovascular events, and kidney specifically. A large number of these patients are diabetic, so that's something that they wanted to specifically look into. The hepatic safety events is separate, so that's more of a DILI specific re-review of those cases. That's separate than the hepatic outcomes, which will be part of the full approval analysis. Is that helpful? Yeah. No, that's helpful. Thanks, Michelle. I think you alluded to this, but can you just confirm, I guess, do you expect to have any visibility into the REVERSE safety data set as you engage with the FDA potentially in first half 2022 on the advanced fibrotic population? They should be coming in, you know, as I said, in the third quarter, so shortly thereafter, and would certainly be part of our full safety package that would be submitted. The again, you know, we're looking through the DMC and the adjudications, and the DMC has full visibility into the adjudicated cases. If there's any concerns, they could certainly make recommendations to us about altering the study or looking more specifically at any specific kinds of events. Both the patients, the large patient population REGENERATE almost 2,500 patients and just over 900 in REVERSE, are both being reviewed by the DMC. We remain blinded until the database lock for both of those studies. Okay. Got it. Thanks for taking the questions. Thanks, Thomas. Absolutely. Thank you. Our next question comes from Mayank Mamtani with B. Riley Securities. You may proceed with your question. Good morning. Congrats on the progress, notably on the financials trajectory, and thanks for taking my question. On the OpEx guidance, maybe Andrew, it seems like the NASH specific investments just relatively seem to be coming down. Is there anything to read into your level of conviction in the opportunity? Can you just comment on that? I just have a quick follow-up for Michelle. Yeah, sure. Thanks for the question. NASH is one of our key programs, and we are fully committed to funding it through the end of the studies. You will see NASH spend as a percentage of our overall R&D spend continue to decline, but it's mainly a function of REVERSE finishing up. Obviously our spend on NASH overall is gonna reduce. Some of our other programs are gonna increase to kind of pick that up, and that would be notably the combination study in OCA-bezafibrate and INT-787, which hopefully will get going this year. No, absolutely no lack of conviction on NASH. It's just the natural life cycle of our R&D spend. Okay, great. And then for Michelle, just quickly on, you know, on the REVERSE study and thinking about, you know, what you will learn from the REGENERATE biopsy analysis and putting in context the, you know, FDA's posture wanting to go away from biopsy. We've seen other studies also change their primary efficacy endpoint, you know, to a non-biopsy. So is there a remote chance that, you know, you may elevate a secondary endpoint into the primary endpoint analysis? If yes, you know, what might be the NITs that look particularly attractive to you right now? Yeah, no, it's a great question. Certainly we heard at a fireside chat at NASH-TAG earlier this year a lot of interest in the non-invasive tests. FDA at this point is still considering the only validated surrogate endpoint is the biopsy-driven histopathology. We certainly have multiple non-invasive tests, both the wet biomarkers and FibroScan and other non-invasive mechanisms to evaluate the progression, regression of fibrosis in these patients. We'll be pulling in all of those data as well and hope to have as much of that available at the time of our briefing book for the agency on REGENERATE. We have the same non-invasive assessments progressing for the REVERSE study. Thanks for taking our question. Thank you, Mayank. Thank you. Our next question comes from Steve Seedhouse with Raymond James. You may proceed with your question. Yeah. Hi, this is Timur Ivankov for Steve. Just for REGENERATE, wanted to clarify. I'm not sure I heard correctly, but it sounds like you have an internal benchmark in order to proceed with submission and meeting with the FDA. Could you just talk about that benchmark in terms of the safety event rate? And just to clarify for the 48-month safety analysis, is that safety only or will you be adding any type of efficacy in terms of NASH resolution and fibrosis reduction? Thank you. For safety, just wanna make sure we're clear on that. In the initial interim analysis, we actually were still enrolling the study at that time, back at the data cutoff, which was October 2018. We didn't have any patients who had reached month 48. For this data cutoff, we will have almost 1,000 patients, 995 patients out to 48 months or year four. A much larger safety database. We went from 2,400 patient years to over 8,000, almost 3.5-fold increase in patient exposure. A much more robust safety database. We're not looking for this analysis on events. That's not. This is not an event-driven analysis. This is an interim analysis focused on an accelerated approval only. An interim analysis of those month 18 biopsies, not looking at clinical events, progression, et cetera. That would be for the full approval. This is solely focused on an accelerated approval. Yeah. The only thing I would add is, of course, as Michelle indicated before, the challenge of the CRL was about overall risk benefits. The opportunity to assess this total, the totality of this larger data set inclusive of all the safety data that she outlined, the efficacy, I think, is gonna put us in a good position to assess and reengage if the data supports us. Again, we look forward to getting to the end of that data generation for REGENERATE and defining the next steps. Okay. Thank you very much. Thank you. Thank you. Thank you. Our next question comes from Brian Skorney with Baird. You may proceed with your question. Hi, this is Luke on for Brian. Thanks for taking the question. Just a quick one, and apologies if you've covered this. On REGENERATE, have you had any progression in discussions with the FDA regarding the scheduling of a pre-submission meeting? Or is that something that you'll wait to do once you have data in-hand? That's a good question, and our only disclosure to this today is that we continue to plan for that meeting in the first half of 2022. Great. Thanks. Thank you. Thank you. Our next question comes from Jon Wolleben with JMP Securities. You may proceed with your question. Hey. Thanks for taking the question. A follow-up on safety from me. Following your withdrawal of the MAA, I saw the EMA's, you know, abridged response mention also a potential concern about an effect on kidney function, which I don't think I've heard discussed before. So I was hoping you could provide a little more color on that potential safety signal. Yeah. You'll recall the MAA and the NDA, we were not able to align on the timing of those analyses. As I just mentioned, we're just now pulling in the data for the end of 2021, December 31, 2021, which will be the new data cutoff. Obviously we weren't able to pull those data in to respond to any of the questions from the EMA. Those data are being adjudicated as one of the requested focus areas. Again, those data have been being reviewed by the DMC, but the final adjudications will be coming in together with the rest of that safety data package. Unfortunately, as we've said before, we just weren't able to align on the timing to pull all those data in to respond to their questions. Okay. Maybe a follow-up, if I may, on OpEx. With the jumps in the fourth quarter in R&D and SG&A, how should we expect that split to move forward in 2022 given the guidance you guys gave us today? Andrew? Yeah, sure. No, thanks for the question. Look, when we give guidance, we typically don't break it out between R&D and SG&A, and we're not expecting to at this point in time. As I said, I mean, we're gonna continue funding the pipeline as we've described. You know, REGENERATE is gonna continue on into the year. REVERSE spend will back down a bit. Then some of our other program spend, as those programs get off the ground, will pick up. Other than that, we've given the guidance on OpEx, and we expect to continue to look at our expenses every day and manage them as low as we can while still meeting our objectives. Got it. Thanks for the color. Sure. Thank you. Our next question comes from Ed Arce with H.C. Wainwright. You may proceed with your question. Hi, good morning, everyone. This is Thomas Yip asking a couple of questions for Ed. First, you touched on it briefly earlier regarding your discussions with the EMA for Ocaliva and for full REGENERATE. Are we waiting for REGENERATE data to go ahead, or is it a separate process from the FDA? Not sure I understood the question. We went through the MAA. If the data supported it, we could go forward with a resubmission, as we're doing in the U.S. The procedures in Europe require a full withdrawal and resubmission. You can answer questions for a while, but unfortunately, we had used up all of the time, and their procedures didn't allow us to have any other clock stops. It was that. In the U.S. similarly, we are resubmitting with this now much more robust, larger safety database, plus the additional biopsy data that we'll have in hand this spring. I see. I guess what I meant to ask was, is the EMA also looking for the data package that you plan to submit to the FDA, some time first half this year? Once we have those data in hand, we could consider a resubmission to the EMA as well. It would be a similar data package, yes. Okay. Got it. We'll assess any potential next steps with data in hand. Okay. Sounds good. Perhaps one more question from me. Can you tell us what the next milestones for the OCA plus bezafibrate combination study in this year? When should we expect the first data set? Yeah. We hope to present some data later this year. We are conducting, as I mentioned, one large phase I study, so in healthy subjects looking at the exposure data for multiple different doses and combinations, as well as different doses in combination in a PBC patient population with one phase II study continuing to enroll in Europe and kicking off a phase II study in the U.S. Our next big milestone for us is determining the optimal combination. As we've alluded to, we believe that there's a potential synergistic interaction between these two drugs, potentially decreasing pruritus and synergistic mechanisms of action that could make for a really great combination for patients with cholestatic liver disease, for PBC and beyond. I see. Got it. Thank you again for taking our questions, and looking forward to your progress this year. Thank you very much. Thanks, Thomas. Thank you. Our next question comes from Ellie Merle with UBS. You may proceed with your question. Hey, guys. Thanks for taking the question. Just on the REGENERATE biopsy reads again, can you give us any color, I guess maybe on the proportion of biopsies you've read so far, maybe the proportion remaining both as sort of the reread from the initial biopsies as well as the new patient samples, just any update in terms of where you are in that process or additional color you can give. Then maybe just, you know, kind of like discuss a little bit more your confidence that you'll have this data read in time to support the you know meeting, the potential pre-submission meeting with the FDA in the first half, just in light of the REVERSE you know update in terms of the timing. Just you know, any chance that, you know, this meeting could potentially get moved to the second half if, say, the FDA wants to have some more of the full biopsy data from the, you know, the full REVERSE biopsy reads for this meeting, and if this could perhaps, you know, get this timeframe shifted at all. Thanks. On the REGENERATE study, again, back to the initial interim analysis, with a little over 900 patient biopsies that we had both at baseline and at month 18, that was F2, F3s, and we have an additional 500 or so that we are bringing in. Those have been being read using the same panel methodology. The REVERSE patient population, we have just baseline and end of study, majority of those are 18 months, and those are all being read, again, using the same methodology. As we've talked about previously, though, there were more challenges in this patient population given the importance of differentiating those high F3s or low F4s. We presented some of those data at The Liver Meeting last year, talked about the large number of patients who were screened in order to identify those patients with compensated cirrhosis, both clinically and on their biopsies. Again, all of those safety and efficacy data will be pulled in with the same data cutoff, and will provide us with a good assessment of the benefit risk, again, which we look forward to sharing, a little later on this year. It's a big year for us. Thanks for the color. Great. Thank you. Thank you. Our next question comes from Salveen Richter with Goldman Sachs. You may proceed with your question. Thanks for taking the question. This is Andrea on for Salveen. Just wondering if you could discuss further when you do see this expanded safety database, what you're looking for, what you'll be focused on. Is it primarily the cardiometabolic AEs? Remind us what would be acceptable in terms of cholesterol and triglyceride level increases as well as the rates of pruritus. Thanks so much. Sure. Yep. The overall safety, if you think about it from a regulatory perspective for a therapy that we anticipate would be these patients will be requiring for the rest of their lives, it's really important to make sure that we understand the tolerability, that things like pruritus in general, looking at their lipid profiles, given that these patients are in general have higher rates of obesity and type 2 diabetes than the general population. Just look at those general tolerability issues. Also wanna look out now that we have 1,000 patients out at year 4, it's important to make sure that there aren't any new adverse events that are popping up at year 3 or year 4. Those will be the specific things that we're looking at. Again, the DMC has been looking at unblinded data throughout and is continuing to watch that. We remain blinded now, but we'll be pulling those data in shortly. Great. Thanks so much. Thank you. Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. Our next question comes from Geoff Meacham with Bank of America. You may proceed with your question. Hey, guys, it's Aspen on for Geoff. Thanks for the questions. I guess first off, it's clear that most of the REGENERATE reanalysis focus is on the robust safety database, but maybe you can help us understand if you expect to or if you think you need to show any additional delta versus placebo in the fibrosis endpoint. Then for REVERSE, maybe just remind us, after you get that data in 3Q, what does the regulatory pathway look like for that subset. Do you need to generate any additional data to file that with FDA or even talk to the FDA? Lastly, really quickly, just help us understand what are the gating factors for dosing that first patient in the U.S. in the OCA-bezafibrate study. Thank you. Okay. First on the NASH program, if we look at REGENERATE, again, it's a large study, and that's interim analysis. We do have alignment with the FDA that that would be based on a fibrosis endpoint for an accelerated approval, and that is the focus of our discussions with the agency. Again, at the first initial interim analysis, that was also the focus, and we did show statistically significant reduction in fibrosis. There were a number of patients who had regression of at least one stage without any worsening of the NASH activity score, so no worsening of inflammation or steatosis. We now have a much more robust safety database against which to compare that. Overall, a much better opportunity to assess benefit risk. The REVERSE patient population because it is an advanced, more advanced fibrosis, early cirrhosis, initially the agreement was for looking at fibrosis. All the subsequent trials in this patient population, the FDA has stated that they wanna look at the clinical outcomes. Because we had already begun the study, we are grandfathered in on that one. This will be the final endpoint for the REVERSE study is looking at fibrosis. Obviously, we are pulling in, as I mentioned earlier, all those non-invasive tests for both REGENERATE and REVERSE, and I think those are gonna be playing obviously a much larger role as we go forward. Hopefully the FDA are continuing to look at those data, but at this point, those are considered supportive of the primary endpoint of reduction in fibrosis, reversal of cirrhosis in that advanced patient population, and comparison there against the large safety database. With regard to the fixed-dose combination, we do have sites open in the U.S. and are actively screening, so we look forward to announcing our first patient in that fixed-dose combination in the U.S. in our phase II study, and presenting some data from that later on this year. Thanks for the question. Thank you. Thank you. I'm not showing any further questions at this time. I would now like to turn the call back over to Jerry Durso for any further remarks. Thanks everybody for joining us today. I really believe that the work that we did and that really the team did across the business in 2021 puts us on a strong foundation. It's clear we're embarking on what's gonna be a transformative year for Intercept, and we definitely look forward to sharing more updates as things progress. Thanks, and have a great day. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.