Good morning, and welcome to the CymaBay Therapeutics Analyst Day. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the CymaBay website following the conclusion of the event. I'd now like to turn the call over to your host, Sujal Shah, President and CEO of CymaBay Therapeutics. Please go ahead, Sujal. Thank you, Tara. Welcome and thank you to all who've joined us today. It's really been an exciting time in the field of PBC over the last few years, and it's an exciting time for CymaBay, where we are centrally focused on patients with PBC today. On the heels of completing enrollment in RESPONSE, our global phase III registration study of seladelpar in PBC, it's fitting that we're here today during PBC Awareness Month with an opportunity to talk to you all about a potential near-term opportunity we believe we have to significantly advance the care for patients suffering from PBC. Next. Now, before we begin, I'll highlight that during today's presentations, we may be making forward-looking statements, and as such, I do advise you to review the risk factors inherent in our operations as set forth in our SEC filings. Next slide. Now, our agenda for today is highlighted here. I'll make a few opening remarks before asking Dr. Kris Kowdley to discuss current unmet needs and future treatment goals for patients with PBC. Our Chief Medical Officer, Dr. Dennis Kim, will review some of the unique elements of seladelpar's mechanism, as well as clinical data. Seladelpar is really what we believe is one of the first in a new class of targets called delpars to treat chronic inflammatory liver disease. From there, Dennis will hand the call over to our Chief Commercial Officer, Lewis Stuart, and Lewis will discuss the PBC opportunity and what we believe to be opportunities for seladelpar's success in the patient population as we progress through development with the potential behind success to commercialize and launch seladelpar and put it directly into the hands of patients. We'll close the call with a Q&A session after our prepared remarks. Next slide. Now, our broader mission at CymaBay is really towards a focus around transforming the lives of people suffering with chronic liver, digestive tract, and inflammatory diseases. This focus that we have is really centered around an opportunity for us to leverage internal expertise, external relationships that we've really built over the years, focused in and around metabolic, inflammatory, and fibrotic diseases, where the ultimate goal that we have is to truly transform the lives of patients, give them an opportunity to actually live more fulfilling lives without suffering. This near-term ability for us to achieve our mission overall is really centered around a goal we have today to put seladelpar in the hands of every patient living with PBC who may have a benefit. Next slide. Now, over the years, we've always been guided by the science. We think first about the mechanism of action, we think about the datasets that we generate, and then we think about the unmet needs in particular areas. As it relates to PBC, our first study ever conducted with seladelpar was back in 2016. That showed significant promise around reducing biomarkers of disease. In fact, on normalizing biomarkers of disease and disease progression, as well as on improving symptoms. Now, since 2016, we've run six clinical studies, largely across PBC patient spectrum, including non-cirrhotic PBC patients, as well as compensated cirrhotic PBC patients. We believe we're truly executing on and advancing on arguably the most robust development program in PBC today. When you collectively think about that, the fact that these studies now have resulted in over 600 unique exposures to seladelpar in this patient population. Now, all this work is really only executed not just by the internal folks we have here at CymaBay, but partnerships that we've built across the medical community globally, and importantly, with advocacy groups in PBC globally as well. We're really partnered alongside all of these individuals to advance care for patients with PBC. Where it's taken us to today, and I'm excited for you all to have the opportunity to hear from our broader team today, is really in a place where we believe that the science, the data, the patient experience allows us now not only to address unmet needs for patients, but you'll hear a constant theme today around, importantly, opportunities to really raise expectations and treatment goals for patients in PBC. Next slide. That theme is really the focus of what you see here. You know, clearly there's been a tremendous amount of work done in the field to recognize that reductions in biochemical markers of cholestasis and inflammation can correlate to improved outcomes for patients. We really stand on the shoulders of folks like the Global PBC Study Group, as well as a host of other consortium and even others who have advanced treatment alternatives in the field. Where the expectation we now have around where we take future care is to take it another step beyond. Not just improving biochemical markers of disease, managing PBC symptoms, and improving health, but actually guiding patients towards normalization of biochemical markers of disease and disease progression. Now, actually reducing symptoms of disease like pruritus that can plague patients' quality of life. Really a focus around an opportunity to overall improve quality of life and clearly a focus on continuing to prove improve predicted outcomes. To kick off today's presentations, it's my honor to introduce you now to Dr. Kris Kowdley, who's the Director of Liver Institute Northwest and Professor of Medicine at Washington State University's Elson S. Floyd College of Medicine. Dr. Kowdley is an internationally recognized hepatologist, educator, and researcher who has been and continues to be a leader in supporting the advancement of treatment alternatives for patients with a broad range of liver diseases, including PBC. Kris. Thank you very much. My goal here is to talk about current unmet needs and future goals of PBC treatment. Next slide, please. PBC, or primary biliary cholangitis, is a rare and progressive autoimmune disorder of the liver. It affects one in a thousand women over 40 years of age, and is characterized by a chronic, destructive autoimmune liver injury, that affects the small bile ducts in the liver, the microscopic bile ducts. This immune-mediated destruction of these small bile ducts leads to secondary portal inflammation, cholestasis, and the consequences of cholestasis related to chronic bile acid-mediated toxic injury in the liver microenvironment leads to secondary immune activation and progressive liver fibrosis. We've made a tremendous amount of progress in terms of identifying surrogate markers for disease progression and biomarkers that can help us identify patients with early and late stage and early and greater risk. These elevated serum markers are predominantly alkaline phosphatase and total bilirubin. Shown in the cartoon below is the progression where cholestasis associated with inflammation can lead to progressive biliary fibrosis that ultimately may lead to cirrhosis, end-stage liver disease, and the dreaded complications of portal hypertension, liver failure, liver cancer, and need for liver transplantation and death. Our goals in treating patients are to improve the biochemical response, namely by improving alkaline phosphatase and bilirubin. Hopefully by doing that, we can achieve slowing down of the disease progression and reduce symptoms. The symptoms in PBC can be quite difficult for patients, and unfortunately, we still have a lot of work to do in terms of finding symptomatic relief for patients, particularly with regard to fatigue and pruritus. Next slide. Now, a tremendous amount of work has been done over the past 20 years to identify prognostic models that can help predict which patients with PBC are likely to need liver transplantation in the near future. Shown on this slide are two examples. One is the Rotterdam model, which is elegant in its simplicity. Essentially, patients are classified into early, moderate, or advanced disease based on whether their bilirubin and albumin are both normal, both abnormal, and one of the two tests may be abnormal. We have data from the Rotterdam criteria, if you will, that when you compare Rotterdam criteria to the Dutch population and early, moderately advanced, and advanced PBC, there is some additional granularity with regard to outcomes when compared to the Mayo Risk Score. Clearly, the Rotterdam criteria are associated with significant differences in survival over a 10-15 year period. Shown on the right side is the historically interesting Mayo model, which utilizes a variety of clinical and laboratory tests to plot observed and expected survival in patients treated with ursodeoxycholic acid. Rotterdam and Mayo have been useful in identifying patients with advanced stage. Since the approval of ursodeoxycholic acid in 1999, we've changed the natural history of this disease and shown what is possible with treatment in this chronic progressive disease. Based on approval of urso and long-term use of urso, we've seen evidence that need for liver transplantation is reduced and the course of PBC is changed. There remains a significant unmet need because although the number of patients requiring liver transplantation has decreased over time, the average age at liver transplantation in PBC has not changed at all, suggesting that there is a population of patients who have a significant urgent unmet need and need additional therapies today. Next slide, please. Now, these more recent prediction models are elegant in that they differentiate between stage and risk. The staging models such as Mayo or Rotterdam essentially tells you where the patient is as today, whereas these models, such as the Paris I and II criteria, the Toronto criteria, are all based on future risk of complications and are elegant in their simplicity because we can utilize changes in alkaline phosphatase, bilirubin, with or without accompanying changes in AST levels to determine which patients are likely to be in a lower risk category over time, and which patients are likely to be at higher risk categories over time. These biomarkers have really helped us identify surrogate endpoints for clinical trials. The prognostic models that I'm showing here and the data derived in terms of outcomes are the basis for acceptance of alkaline phosphatase and bilirubin as surrogate endpoints in pivotal clinical trials. Next slide. Now, recent emerging data suggests that we might be even more, specific and might even fine-tune our criteria for therapy and determine goals for success, in patients with PBC. This is work from the Global PBC Study Group, of which I have been a participating investigator for many years. Shown on the left is data that reflects that any elevation of alkaline phosphatase more than 1x upper limit of normal is associated in a linear manner with increased hazard ratio for liver transplantation or death. In fact, an alkaline phosphatase of one times upper limit of normal and higher is associated with a twofold greater risk of liver transplantation or liver-related death compared to those who have an alkaline phosphatase that is well within the normal range. Similarly, we also have shown that bilirubin levels as low as 0.6 x upper limit of normal and higher are associated with a significantly reduced likelihood of a liver-related survival compared to those who have bilirubin levels that are significantly lower. While alkaline phosphatase and total bilirubin levels have not yet been codified in risk prediction models, there is a growing consensus that normalization of these biochemical markers may be a future treatment goal. Next slide. Now, despite the fact that we've made great deal of progress in terms of improving prognostic models and identifying goals of therapy, patients still remain with significant symptoms, and the symptoms of PBC present a significant burden that existing treatments have not yet been able to effectively address. The common symptoms of PBC are predominantly fatigue and pruritus, and abdominal pain. The pruritus can be extremely severe. The origin of it is unknown. It is associated with a diurnal variation, with the most intense itch reported in the late evening. Localization predominantly in the extremities and exacerbated by contact or hormonal conditions. I can tell you from my personal experience, having been a clinical hepatologist caring for patients for 30 years, I've had three patients over my career who have had pruritus that is so severe that they were suicidal, and liver transplantation was the only treatment that effectively controlled pruritus for these patients. This is a not uncommon and a debilitating symptom for patients, as is fatigue. Fatigue is a symptom that can really leave patients incapacitated and exacerbate depression, decreased quality of life, and poor patient-reported outcomes. Now, our current treatments have not been shown to improve pruritus in a statistically significant or clinically relevant manner. Obeticholic acid may in fact induce or exacerbate pruritus, which provides a challenge in terms of implementing its use uniformly. The American Association for the Study of Liver Diseases has a guidance, and recommends management of pruritus using a stepwise approach, starting with cholestyramine, rifampicin, opioid antagonists, and sertraline. I can tell you from clinical experience that a substantial proportion of patients continue to be troubled by severe pruritus that does not respond to these medicines, or in fact, these medicines may be associated with poor tolerability or toxicity. Next slide. Hopefully, I've convinced you that many patients with PBC need additional therapies beyond urso alone, both for stopping progression of disease and hopefully to reduce symptom burden. Our current approach is to start ursodeoxycholic acid and evaluate the patient after six months or no later than one year of therapy, evaluate their biochemical response and tolerability of urso, and if they remain in a higher risk category based on their serum biochemical markers, then we consider adding a second-line therapy such as obeticholic acid. Or fibrates, which are currently used off-label as second-line treatment. For patients who progress despite these interventions, liver transplantation remains the only option that can provide lifelong improvement, although recurrence of PBC has been reported after liver transplantation. I should point out that there is a label change that has accompanied obeticholic acid last year, and OCA is currently contraindicated in patients with cirrhosis and clinically significant portal hypertension or decompensated liver disease. Use of fibrates is also discouraged in patients with decompensated liver disease. As I mentioned, fibrate use at the present time remains off-label. We have a substantial proportion of patients who may not have a complete response to urso, although many do, and these patients remain at risk for progressive disease. Obeticholic acid, which was approved in 2016, remains an important advance for these patients but has significant shortcomings in terms of inducing or exacerbating pruritus, concerns about safety and tolerability, and contraindications in patients with advanced liver disease. Furthermore, patients who have the greatest unmet need, those who have progressed or are at risk for progressing to cirrhosis, have limited treatment options after urso has been tried. A subset of patients, these are patients who often have diagnosis of PBC at younger age, progress rapidly, and have a ductopenic variant that may require early liver transplantation. These patients are unfortunately not served by any of our current treatment options. Next slide. Thinking about the future, how has our thinking evolved, and what are our treatment goals, and how are they changing over time? Well, for one, I would like to propose that many of us who are leaders in the field are thinking that our goal should be to achieve normalization of biochemical markers, just as we do in autoimmune hepatitis. We don't accept in autoimmune hepatitis that when the ALT is less than 1.6 x the upper limit of normal, that that's an adequate therapeutic response. We would like to achieve a deep or complete biochemical remission. We would like to achieve this in a high percentage of patients. Ideally, we would like a therapy that could resolve symptoms accompanying these biochemical improvements, with the ultimate goal of slowing the progression of disease and be able to offer these therapies across the spectrum from mild to moderate to severe disease. Seladelpar may be a future option to help address these unmet needs. Next slide. Thank you. Thank you, Dr. Kowdley. My responsibility today will be to introduce seladelpar as the first delpar in development or PBC. I will quickly and at a high level go over its mechanism of action and hit on some of the highlights of our clinical data and conclude by describing our near-term clinical development plan for the future. Next slide, please. Seladelpar is a first potent selective PPAR-delta agonist in development for PBC. What you see on the left-hand side is a X-ray co-crystal structure of seladelpar. Shown in blue ribbon is the ligand binding domain of its molecular target, PPAR-delta. In the center there is seladelpar in a tight complex with its target binding domain. What you see on the right-hand side there is demonstration of its potency and its selectivity for PPAR-delta for seladelpar. Even at doses of 200 mg per day, which is about 20 x higher than our optimal dose for PBC, 10 mg, there's really no PPAR-alpha or PPAR gamma activity shown here. Again, seladelpar is once daily 10- mg dose optimized for PBC and is selective, highly selective and potent for PPAR-delta. Having a highly potent PPAR-delta activity, such as we see with seladelpar, is important with respect to beneficial mechanisms well suited for treatment of inflammatory disease such as PBC and avoiding some of the liabilities. Next slide, please. As you see here, as we compare the effects of PPAR-delta against alpha and gamma, which are well-known entities in the marketplace, we see that PPAR-delta agonism is the only PPAR isoform effects that stretch across multiple aspects of PBC disease biology. While PPAR-delta and PPAR-alpha both have effects on cholestasis and lipid metabolism, only PPAR-delta have salutary effects on inflammation and fibrosis. As you can see across the middle here, PPAR delpars have selective PPAR-delta activity and show no gamma effects and avoid some of the liabilities that come with the gamma effects, such as weight gain, edema, heart failure, or fracture risk. Accumulating evidence show us that there's some safety data in patients with compensated cirrhosis with PPAR-delta. Whereas with PPAR-alpha, such as fibrates, as Dr. Kowdley mentioned, sometimes off-label, used off-label in the United States, that would be fenofibrate. It has a contraindication in acute liver disease, including PBC, gallbladder disease, and dialysis. Its warnings consist of myopathy, rhabdomyolysis, and ALT increase in some patients. Again, as I mentioned before, no documented effects on inflammation and fibrosis. Perhaps important long-term benefits of treatment in PBC. Glitazones or PPAR gamma agonists have been around for a long time in the form of rosiglitazone and pioglitazone. These are hardly ever used now and mostly indicated for type 2 diabetes. They're not used very much anymore because now they have black box warnings of causing exacerbation of CHF, edema, and fracture risks. At the cellular level, this translates. Next slide, please. Into several different mechanisms shown here. PPAR-delta is a transcription factor, which many of you know already means that it regulates gene expression and pathways important in the context of liver disease such as PBC. PPAR-delta agonism can repress or upregulate some of the gene expressions and at these four cell types, which are all important in PBC and PPAR-delta receptors are the only ones expressed in all four cell types in these important liver cells, are highlighted here. On the left-hand side, at the level of the hepatocyte and cholangiocyte, seladelpar helps to reduce bile acid synthesis and cholesterol synthesis. It also plays a role in lipid metabolism and energy homeostasis by reducing cholesterol and LDL cholesterol and increasing fatty acid oxidation at the hepatocyte, adipocyte, and musculoskeletal tissues. Reduces inflammation at Kupffer cells and circulating macrophages by reducing inflammatory cytokines and hsCRP. Importantly, and downstream to inflammation at the stellate cell levels, it reduces collagen synthesis and deposition, thereby reducing fibrosis. Now, clinically, all these effects translate to decreased levels of biochemical markers related to cholestasis, such as ALP, and liver injury, such as liver enzymes. Next slide, please. Thank you. Now, the clinical manifestation of seladelpar mechanism of action have been observed in several large clinical studies that we've conducted, in the form of phase II studies, phase III studies in ENHANCE and RESPONSE, and long-term studies that are ongoing as an open label extension, such as ASSURE. ENHANCE is a phase III study that we've conducted in the past, and RESPONSE is a current phase III study that is ongoing and have been fully enrolled, and the readout is anticipated to be the third quarter of next year. The ASSURE study is an open-label extension study with greater than 150 patients being dosed with active seladelpar on a daily basis, which we believe gives us a lot of exposure and safety data, and stand behind it with confidence and understanding of our disease, of our compound with respect to its efficacy and safety profile. Now, this wealth of data that we've accumulated in PBC with seladelpar also translates to extensive provider experience with seladelpar globally. One such example is Dr. Kris Kowdley, who's with us today. He's one of our lead investigators for RESPONSE, as well as having experience in ENHANCE and having patients in ASSURE. We have an opportunity to discuss seladelpar extensively with PBC experts and treaters prior to commercialization. We also have deep understanding of seladelpar in PBC by way of this wealth of data and allows us to be transparent, publish, and have deeper understanding of peer-reviewed critics on the data itself. Next slide, please. Drilling down on the ENHANCE experience, which represents our most rigorous study results in a randomized placebo-controlled fashion. What you see on the left-hand side here is the three-month data on its primary composite endpoint. This is a phase III study with approximately 250 patients enrolled. We decided to truncate the study early due to a false positive safety signal that we eventually discovered was not related to study drug. One of the silver linings of having this experience is that we do have very robust randomized placebo-controlled trial results at three months with about 55 patients per arm. What's shown here is a primary composite endpoint, often referred to as POISE endpoint. Well, it is the documented accepted endpoint from the FDA perspective for approval of new PBC agents. Specifically, it's al phos, but more than 1.67 x the upper limit normal. At least a 15% improvement in al phos and total bilirubin being in the normal range. At the 10- mg dose, which I've mentioned again is our optimal dose, we have just less than 80% of patients achieving that primary efficacy endpoint versus 12.5% on placebo. On the right-hand side, we have biochemical normalization of al phos of about 27% on 10 mg versus no patients on placebo achieving this endpoint. These are very robust numbers. I would say that even though we don't have any head-to-head trials versus Ocaliva, which is the only other second-line agent approved in the marketplace. If you look at the published literature with Ocaliva in a very similar study design format, you see less than 50% of patients achieving this primary composite endpoint on the left and less than 5% of patients achieving ALP normalization, as shown on the right. Moving on to the next slide, please. As Dr. Kowdley mentioned, one of the most important secondary efficacy endpoints we look at is pruritus or itch. This is a subset analysis of patients in that ENHANCE study at three months who reported having at least moderate to severe pruritus or itch as reported by patients. This is defined by an NRS score of at least 4 or greater, with NRS score of 0 being no itch and 10 being worst imaginable itch. You can see here on the left-hand side, the baseline score was 6.2, and with treatment with 10 mg of seladelpar, we see about a 50% reduction or three-unit reduction in reports of itch versus 1.55 on placebo. The difference is statistically significant even though the numbers are fairly small, implying its robust nature of improvement even in a small number of patients. As another look at the same data, if you see certain patients reaching important thresholds, such as at least a three-point reduction in NRS score or four-point reduction in NRS score, you see 42% and 37% of patients achieving those thresholds on 10- mg dose versus 16.7% and 5.6% on placebo, respectively. An important endpoint that which patients care about quite a bit and something that really differentiates seladelpar from what's existing on the marketplace today. Next slide, please. When we take a step back and also pool our dataset with ENHANCE and some of the previous phase II study patients that are still continuing to take the drug today as a part of the open-label extension, we have accumulated experience in a fairly good number of patients with compensated cirrhosis who are taking seladelpar. When we compare these patients with compensated cirrhosis or without cirrhosis at all, as seen on the left-hand side, patients achieving this primary efficacy endpoint, the composite endpoint is shown here, and it's comparable between patients with compensated cirrhosis versus no cirrhosis. Overall ALP reduction is shown on the right-hand side. Again, very comparable efficacy profile with respect to ALP change and other biochemical markers regardless of the cirrhosis status on seladelpar, which is a big unmet need in patient populations. As has been demonstrated before, as mentioned before, Ocaliva and even off-label usage of fibrates is discouraged in patients with compensated cirrhosis, or cirrhosis in general or especially in decompensated cirrhosis or patients with portal hypertension. Next slide, please. Now you may be wondering about the long-term effects of seladelpar efficacy since all I've shown is at three months. When we look at our group of patients who are continuing to take seladelpar in an open-label fashion every day at 1 mg a day, we have about 100 patients who've taken seladelpar now out to one year and about 50 patients who've now taken seladelpar out to two years. What's shown on the left-hand side is their ALP change over time and ALP normalization on the right-hand side. What you see right away is that as we see near maximal benefit on ALP change on seladelpar by about three months, which is consistent with what we showed in the ENHANCE study results at three months. That effect is sustained, perhaps even progressive out to two years with al phos change being maintained or even getting even better, slowly over the remaining 18-month period. ALP normalization appears to at least be sustained or even improved out to two years, 24% versus 42% respectively at one and two years. You can see the number of patients exposed to the drug within the bar, 24 out of 102 patients reaching normalization at one year and 22 out of 53 patients reaching normalization at two years. Next slide, please. Turning our attention to safety, and I'll hit this at a very high level. This is from, again, our most robust study design, our phase III ENHANCE study, which enables us to compare 5 mg and 10 mg of seladelpar to placebo in about 90 patients per arm. I focus your attention to the third row, starting at the third row with any severe adverse events in the trial being zero across the board. No deaths across all three arms. If you look at serious adverse events in the next row, the numbers are well-matched and any treatment-related SAEs are zero across the board. Perhaps the most important litmus test for tolerability of the drug in patients is the adverse events leading to study drug discontinuation rate, which is well-balanced across the three arms of the study. We have seen consistency in seladelpar safety and tolerability profile across our PBC clinical studies. This enhanced result is entirely consistent with what we've seen in the previous studies as well as in the ongoing ASSURE study. Next slide, please. This also is the case when you look at patients on these safety parameters with and without cirrhosis or compensated cirrhosis. Again, shown here on the left-hand side are patients with cirrhosis. Patients on the right-hand or on the right-hand side of the table are patients without cirrhosis. You can see the numbers of patients exposed to drug in those categories. Again, calling your attention to the third row of this table. A very similar story is played out here. No imbalance or significant imbalance across the arms and across cirrhosis status. Specifically, no treatment-related SAEs and very comparable rates of drug discontinuation due to adverse events across all the columns here. Again, demonstrating that perhaps seladelpar may be a potential good candidate for patients with compensated cirrhosis and with PBC. Next slide, please. This brings us now today to today's situation where we're running the RESPONSE study right now. We've already announced that we fully enrolled this study. We have about 193 patients in the study enrolled. We will have the top-line results sometime in the third quarter of next year. Now, patients finishing RESPONSE, and in fact, all the other previous study participants that we've had, especially in ENHANCE and our previous phase II studies, will be able to or have been eligible to roll over into the ASSURE study, which is our catch-all long-term open label extension safety study. First, before I get there, I'll briefly explain that RESPONSE study design is very similar to the one that we had constructed for ENHANCE. Really, the only difference is that we're focusing our attention to 10-mg dose instead of 5 mg. As shown in previous slides, we believe the 10-mg dose has optimal efficacy and has similar tolerability and safety profile as the 5-mg dose. The primary and secondary efficacy endpoints are identical in RESPONSE as compared to ENHANCE, and we expect to see similar results at one year after RESPONSE is completed. The main advantage of the ASSURE study that we have ongoing, again, greater than 150 patients taking the drug every day as part of participating in this study. It allows us an opportunity to continue to look at the data in a deep, meaningful way so that we can understand the safety and efficacy parameters of seladelpar in a peer-reviewed fashion. Continue to build relationships with our key opinion leaders, investigators, and patient advocacy groups through this data. By the time we file our NDA, we anticipate having a good large-sized number of patients with at least 3+ years of experience, which we believe gives us a leg up on our interaction with the FDA. With that, I will turn things over to Lewis on the next slide. Lewis. Thank you, Dennis. These are truly exciting times at CymaBay. Over the last year, our commercial team has conducted opportunity assessments globally, including patient, payer, and HCP research to gain insights from all of the PBC stakeholders. Today, I wanna share a summary of those insights, mostly focused on the U.S. PBC market as we start our preparation for commercialization and launch readiness. Next slide. I wanna begin with the PBC patient's journey. Our research reflects on their emotions and actions from the onset of symptoms through diagnosis, treatment, and disease progression. We're so inspired by these patients' positive attitude, optimism, and motivation to improve their current health, address quality of life issues, and really lean into their support systems. These are very highly engaged patients, and really they constantly seek new information and are very active within the PBC community. As you can see from the verbatim here below, from the research, just a glimpse here as you see a patient's quote, "I am very proactive about my health." This was echoed throughout our research. Next slide. We also learned about the challenges that PBC patients experience during the chronic management of their disease. As you can see from the row across the top. It may take up to two years for a formal PBC diagnosis to occur. Typically, treatment initiation starts very quickly, though, and continuous management and monitoring are now routine practices in these patients' lives. We consistently heard patients share how debilitating their symptoms were despite being on treatment. We heard stories from specific patients who did not achieve a complete response while on UDCA, with some staying on drug just because they believed there were no safe or tolerable options. Many patients expressed how itching and fatigue dominated their lives and often were being neglected or not adequately addressed by their healthcare provider. As for the providers, too often they were discouraged by the lack of effective treatments that are available to offer to those patients. This all plays a very significant role in the patient's psychological well-being, creating fear and frustration and uncertainty. Despite all of this, though, patients remain hopeful that new treatments will address and potentially solve the challenges they face with PBC. Next slide. I wanted to share these patient observations upfront with you because at CymaBay, we want to develop a commercial strategy that's centered on patients. We want to build a high-touch model that is designed to support patients and their caregivers in navigating the healthcare ecosystem, all while learning from those key stakeholders how to continuously improve the patient experience. We believe that these three pillars, education, coverage support and services, and patient advocacy, really form our guidepost for PBC and PBC treatment. Next slide. We all heard Dr. Kowdley stress that biochemical normalization has a direct impact on disease progression, and improving symptoms may be possible in the future for many of these PBC patients. Given the limitations of current second-line PBC treatment, seladelpar may also offer clinical utility in patients with or without compensated cirrhosis. Dennis shared the seladelpar clinical results to date that support a compelling target product profile. Next slide. When you think about the seladelpar's effectiveness on biochemical response and symptoms, we truly believe we can elevate the goals of PBC treatment and overall liver health. Approximately 60% of patients experience PBC-related pruritus, which has significant downstream effects on the patient's ability to stay treatment compliant. With seladelpar's ability to reduce symptom burden of moderate to severe itching, shown here in the previous clinical studies, we are excited about its potential to significantly impact the overall quality of PBC patients' daily lives. Again, I'll remind you, seladelpar is very easily dosed at one 10-mg capsule once a day. Next slide. In assessing seladelpar's key product attributes, we conducted independent market research with both U.S. HCPs as well as providers in the U.K., EU, and Asia geographies. Irrespective of geography, we observed a consistent reaction from HCPs that seladelpar represents a significant improvement over the current standard of care. In our U.S. survey of 155 hepatologists and health-focused gastros, we found they expressed a clear preference for seladelpar over ursodeoxycholic acid, with second-line preference shares coming in north of 60%. Half of the treaters were willing to consider seladelpar as soon as six months after UDCA, reflecting their enthusiasm for this new treatment, new second-line treatment. They also were complimentary of seladelpar's clinical utility in both compensated cirrhotic and non-cirrhotic patient populations, as is noted by the quotes there in the right, in the lower right-hand corner. In summary, our U.S. PBC experts indicate a strong belief in the seladelpar profile and its impact on PBC outcomes in elevating treatment expectations for patients. Next slide. Next, I want to turn your attention to the addressable second-line market opportunity as we did some extensive work to identify the U.S. opportunity and the size of the key patient segments. Starting with seladelpar's most immediate opportunity, the column here entitled Incomplete Responders, we would estimate that approximately 12,000 patients make up this population, including 3,000 cirrhotic patients. This will be a competitive patient segment where both Ocaliva and, if approved, elafibranor, will be focused. Our existing and future data results suggest that we can extend the benefits of seladelpar beyond the non-cirrhotic population to compensated cirrhotics, which we believe could be a key differentiator in overall clinical utility. To the far right are approximately 9,000 Ocaliva-experienced patients, representing about a third of the second-line market penetration. Of those, we would estimate that two-thirds of these patients, or about 6,000 patients, have experienced Ocaliva therapy but are no longer on treatment. In other words, of the 9,000 who started Ocaliva, only about 3,000-3,500 patients remain on therapy. We believe that seladelpar could be an immediate benefit to these 6,000 patients as a new second-line option. Next slide. In addition to ALP response, there are segments of patients that have moderate to severe pruritus who may also benefit from a change in treatment. This next incremental opportunity reflects patients who continue to experience moderate to severe pruritus, whether they have a complete, partial, or incomplete response to UDCA. Amongst these segments, we conservatively estimate as many as 20,000 patients could benefit from seladelpar. It will likely be a mix of improving biochemical response and pruritus that will drive HCPs to ask, and potentially patients to request, the addition of seladelpar. Before leaving this map, I want to re-emphasize what we heard today from Doctors Kowdley and Kim. The new goalpost should be normalizing ALP. Considering the data you've seen today, there's a large cohort of over 16,000 patients who are partial responders. In other words, their ALP levels remain between 1 and 1.67 times the upper limit of normal. This segment represents a significant market expansion opportunity where seladelpar may play a formidable role in improving overall treatment response. Next slide. We also conducted market assessments in ex-U.S. geographies and have observed a similar second-line opportunity in the UK plus EU markets with the same positive responses to seladelpar as seen in the U.S. Their HCP targets are more concentrated to centers of excellence and treatment rates are a bit higher than the U.S. In Canada, it offers a very similar opportunity to expand treatment. We have KOL experts, investigators, and patient groups who are already excited about potentially adding seladelpar as a new treatment option. We will definitely be seeking a priority review pathway to approval there. From our work with market access experts in the EU4 and U.K., we would expect full reimbursement for seladelpar in these geographies with pricing and parity to Ocaliva's current price point in the EU. In Japan, there's no approved second-line agent, and PBC has a special designation as an intractable disease, clearing the way for smoother reimbursement and lower patient co-pays. Pricing would be expected to be a blended average of the U.S. and EU. China has a very large PBC patient population. While Ocaliva is not available, there are several generic versions of obeticholic acid under development that could result in lower pricing. Next slide. When we examined the U.S. prescriber base, we found a highly concentrated number of PBC treaters. Here in the U.S., we estimate that approximately 7,700 highly specialized hepatologists and gastroenterologists make up the PBC prescriber universe. We would approximate a sales force size of 40-50 representatives to efficiently cover this targeted group and their practice affiliations, along with approximately 10-12 MSLs. We also conducted analysis identifying the patient volume and second-line opportunity at the prescriber levels, as well as those HCPs with seladelpar experience from previous and/or ongoing clinical trials. Next slide. Over the summer, we completed an opening round of market access landscape research, where we examined the payer mix as well as current Ocaliva coverage for both the commercial and Medicare books of business. As expected, Ocaliva is placed on the specialty tier for most payers, requiring a prior authorization to its indicated use, in other words, a pay to label, and/or medical exception processing. Payers stated that Ocaliva enjoyed high approval rates and would expect seladelpar coverage to be on par with Ocaliva. Our primary research also revealed a preference by payers for the seladelpar product profile, providing an opportunity for CymaBay to develop an evidence-based value proposition with the goal of obtaining preferred specialty tier coverage. As mentioned earlier, we plan to develop a high-touch patient support service solution aimed at optimizing coverage and minimizing out-of-pocket cost to the patient, all while enhancing the overall patient and provider experience. Next slide. Let me conclude by emphasizing CymaBay's commitment to redefining treatment success for PBC patients. For many patients, UDCA has served them well. However, a large number of patients do not achieve the benefit of a normal alkaline phosphatase level, nor do they experience relief from symptoms. Patients deserve to achieve normal levels of these and other key markers of liver health and relief from debilitating symptoms. Patients should have access to the best of treatments without contraindications or limitations based on their disease status. We believe seladelpar offers the opportunity to treat most patients. HCPs have already weighed in that they can expect more with seladelpar. Patients may also play a role in asking for more options like seladelpar. Widespread reimbursement for seladelpar and support for patients will be a top priority for CymaBay. We believe seladelpar has the profile to be the preferred PBC treatment and opens the door to a new patient experience. This could mean more patients receiving better care, improved quality of life, and better outcomes. I'll turn things back over to Tara for Q&A. Thank you, Lewis. At this time, we'll be conducting a question and answer session with our speakers. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Jay Olson from Oppenheimer. Please go ahead, Jay. Oh, hey, thank you so much for providing this update and introducing the innovative concept of redefining PBC treatment success. We have a couple of questions. What are the remaining steps that need to be taken to make normalization of al phos and ultimately normalization of patients' lives across all outcomes and symptoms the goal according to PBC treatment guidelines? Is the availability of a treatment like seladelpar that can realistically achieve this goal, the only remaining step in updating those guidelines? I had a follow-up question, if I could. Yeah, maybe. Jay, first of all, thank you for the question. I may ask Chuck McWherter, our Chief Scientific Officer, and of course, Kris, to opine on the process around guidelines specifically. I think it's important, first of all, for us to reiterate that the primary efficacy endpoint for accelerated Subpart H approval is the primary endpoint that Dennis really described based on our historical dataset, really measured at 12 months in terms of alkaline phosphatase responders, as well as normalization of bilirubin. That has really been supported by very rich datasets correlating that endpoint and the reduction of alkaline phosphatase and normalization of bilirubin, as Kris described earlier around improved outcomes. That's just simply, you know, I think a reiteration of what the goal is to get onto the market. I think from there, you know, obviously our goal as a sponsor and treatment goals for any treating physician are to improve care as much as you can. It's not simply a matter of registering the drug, but actually getting patients further towards reducing risk of disease progression and having better outcomes. I think the datasets that support the potential for a greater proportion of patients actually normalizing their alkaline phosphatase and the datasets whereby further reductions in alkaline phosphatase into the normal levels are the datasets that we hope to really guide ultimately practice and that treatment goal from practice. I think, Jay, you also asked a specific question around guidelines and perhaps, you know, Kris, if you wanna talk a little bit about, you know, your involvement over the years in guidelines and how that process would unfold. Yeah. Thank you. I think this is a very perceptive question. One of the reasons I think we've been somewhat more circumspect in our treatment goals in PBC is that we've simply not had targeted or rational therapies that could have the goal of normalizing alkaline phosphatase. As we start to think about treating PBC, we really should think of it no differently than any other liver disease, where we look at biochemical markers that are surrogates for what's going on in the liver. At the same time, our goal is to reduce disease stage and halt the progression of the disease. As we start to think about different modes of treatment, you know, one can think about a potential, a backbone, if you will, or a baseline of urso therapy that achieves some level of choleresis, flushes out the toxic bile acids, and then adds on to that more rational therapies that may work by one or more complementary mechanisms with the goal of achieving a complete biochemical remission. Now, there's an important caveat. Although I showed you data that elevation of alkaline phosphatase and bilirubin above 0.6x are associated with worse outcomes, we remain at this point without data to show that normalizing those results will in fact lead to normal clinical outcomes. Confirmatory trials are needed, and we need to harness and use whatever real-world evidence and other databases are out there, along with confirmatory trials. From a guidance perspective, you know, I think, guidelines tend to be the most rigorous because they are somewhat limited by process and by the criteria by which evidence is evaluated. Guidance allows some flexibility. For example, you can see the recent guidance update in AASLD that looks at the possibility of adding fibrates as an alternate second-line therapy after urso. You know, going forward, we look to development of non-invasive tools such as the ELF score or MR elastography or transient elastography to give us information about non-invasive, a prospective measurement of disease stage. In summary, I think we have the ability to achieve biochemical responses that are much better than what we've been able to achieve in the past. Whether that's, you know, best achieved by dual therapy, triple combination therapy, or some sequential add-on therapy, I think remains to be answered. Certainly, the data and common clinical sense would to me as a clinician be that I would like to get the patient's blood tests to be normal. Everybody can relate to what normal means, and determine that their disease progression is stopped using some sort of staging procedure. I think that with the new therapies that are in development, that can be well within hand. Great. Thank you, Dr. Kowdley and Sujal. If I could maybe follow up on one of your comments, Dr. Kowdley, about fibrates and the potential for combinations. I know there's a study underway with bezafibrate and OCA. I was wondering if you could comment on your thoughts about the potential for that combination and any potential combinations with seladelpar that you think would be interesting. Thank you. Yeah. You allude to the study of bezafibrate with OCA for patients who are incomplete responders or intolerant to urso. That, I think, is the way in which we might be thinking about treatment in the future, just as we do in autoimmune hepatitis, where we initiate therapy with corticosteroids, then introduce a steroid-sparing regimen, and if the patient does not achieve a biochemical response, then think about second-line therapies. What's attractive about using different combinations is that if they have different modes of action, then they potentially could have complementary, you know, efficacy. But to this point, we've really had limited ability to achieve deep biochemical response or complete biochemical response just because of the limitations of the treatment available. I think the future would definitely call for possibly dual therapy and maybe for the subset of patients who remain at higher risk and have incomplete responses, multiple combination therapies. Okay, great. Thank you so much for taking the questions. Thank you, Jay. The next question comes from Kristen Kluska from Cantor Fitzgerald. Kristen, you may go ahead. Sorry about that. Good morning, everyone. Thanks for the presentation today. First question is for Dr. Kowdley. While recognizing there aren't many options available now with the heterogeneity of this disease, are there ways for you to potentially predict who may respond from some of these current therapies in advance? If the seladelpar data continues to demonstrate similar benefits when cutting the data in different ways based on these different patient backgrounds, do you think this could support post UDCA usage? Yeah. I think if I understand your question, the first question is, are there predictors that would identify patients who may be in greater need for these therapies and predictors that may identify patients who may be more likely to respond? I think we don't have enough data about response predictors because we are only now starting to accumulate phase III trial information. As I mentioned earlier, clearly there is a subset of patients who have rapidly progressive disease. These are patients that have a very high alkaline phosphatase, potentially the early ductopenic variant. They're generally younger patients who have a more rapidly progressive disease. Those are patients where I would really want to be aggressive as far as everything that we can bring to bear to prevent progressive bile duct loss. Now, there are a variety of, you know, studies that have examined possible cofactors or comorbid conditions. For example, there's some evidence suggesting that patients with anticentromere antibodies, patients with positive antinuclear antibodies, and patients with a disease-specific ANA such as sp100 or gp210 may be patients who have more aggressive disease. I can see that in the future, as we have more effective therapies, we would be more likely to introduce these second-line therapies sooner. In fact, there's some data already in preliminary form showing that patients whose alkaline phosphatase, for example, remains greater than 1.9 x upper limit of normal six months after starting urso, that may be a good time to intervene rather than waiting a full year. Finally, I would add that for patients who have this more aggressive type of disease, I think we would want to introduce second- line therapy sooner. I think a question very, you know, that's embedded in your question is, as we get more rational and better therapies, will there be a need for urso? Will urso be required as a necessary first-line therapy? I think that's a question that remains to be answered. Okay, thanks. That actually goes well with my second question here for the CymaBay team. Just talking about that partial responder opportunity and for Dr. Kowdley's comments, when there's very few treatments available, physicians tend to be a little bit more patient, waiting to see if these therapies work. If there's more tools in the toolbox, though that may change. Could you talk a little bit about how you're thinking about that partial responder market opportunity and the specific segment that you chose, believe could be a part of that, and how you might also expect that to change over time as more physicians become aware of the real world experience of seladelpar? Thanks again, everyone. Thanks for the question, Kristen. Lewis, do you want to start? Sure. Absolutely. First of all, just to remind everyone, when we think about the partial responders, we're thinking about patients really with an ALP of between 1x and 1.67 x the upper limit of normal. I think one of the really intriguing parts about introducing a therapy like seladelpar is the fact that you have treatment that not only addresses sort of this notion of normalizing patients, which certainly is a tremendous opportunity, but because you have symptom management, you know, there as well, and the ability to treat patients irrespective of their status of cirrhosis, compensated cirrhosis or non-cirrhosis. We believe that there will be a number of patients that will want to pursue with physicians as well, you know, trying to normalize patients and to get them below that 1.67x level and certainly hopefully below 1x. We think that it's really the profile of seladelpar that will attract a lot more patients into treatment, but also have HCPs considering how to use this particular therapy more aggressively and perhaps more early in the treatment process. Clearly a market expansion opportunity, but one that really hasn't been as much available to the population of HCPs and patients because of all the tolerability issues and of course, the data that hasn't been really that strong in terms of normalization. This is a really important opportunity that we look forward to seeing play out here as we move forward into the marketplace. Thank you. Thanks for the questions, Kristen. Our next question comes from Mayank Mamtani from B. Riley. Mayank, you may go ahead. Mayank, you might be on mute. Can you hear me now? Yes. Thank you. Thanks for taking our questions and appreciate the helpful overview on the delpar development efforts in PBC. Just taking a step back for the CymaBay team first, you know, what do you think is the immediate low-hanging fruit for sort of market segment that you're thinking based on the data we already know in ENHANCE and the RESPONSE kind of design that, you know, doesn't include that initial partial responder population. Can you just comment on that? Would love to also hear from you know, building on the prior discussion, your specific plans to study, you know, the cirrhotic and the partial responder population. Maybe, you know, Dennis can comment on that, existing plans and future plans. Then I do have a follow-up regulatory question. Yeah, sure. Thanks for the questions, Mayank. Sorry, go ahead, Lewis. Why don't you reiterate, as you talked a little bit about during your presentation, you know, really the core immediate population, where the data that we've already generated and certainly potentially RESPONSE data sets would really support the use of seladelpar. Sure, sure. Tara, if you wanna pull up slide 34, I can kind of walk through that low-hanging fruit area again. Fundamentally, I think first of all, starting with those patients that have an incomplete response, these are patients that really, as a definition, are still above 1.67 x upper limit of normal. This is really sort of the immediate low-hanging fruit population. We estimate that to be around 12,000 patients, 3,000 of which are actually in the cirrhotic category. These are low-hanging fruit, frankly, and really the first place we would go when you look at where you would look for second-line support, after a patient's been on ursodiol. The other really important one, though, is to the right there, and that is, you know, we think there are about 9,000 patients that have had experience with Ocaliva. When you think about the fact that only about 1/3 of those patients really remain on therapy, there's about 6,000 patients that have discontinued treatment on Ocaliva, and as a result of that, really provide an immediate opportunity for getting back on a second-line option. We think seladelpar could be a really attractive solution for those patients, particularly given its overall product profile in being able to address both biochemical response as well as symptom improvement. your plans to study as a next step, if Dennis could comment on that before I ask my follow-up on the regulatory stuff. Yeah, sure. Yeah, this is a patient segment that we're interested in. Of course, we haven't done the study specifically in these patients with ALP, al phos, between 1x and 1.67x. It's an ongoing discussion that we're having internally to see how we should address these patient populations. As for your cirrhosis study question, we've accumulated a fairly large number of patients with compensated cirrhosis during our clinical development program. About 10%-20% of our patients fall into this category. We're also conducting an FDA-required hepatic impairment study in patients with PBC. Looking at seladelpar's exposure differences in patients with Child-Pugh A, Child-Pugh B, and Child-Pugh C cirrhosis. The amalgamation of this data that I just mentioned will be going into the FDA in our interaction for the NDA. We think that this should be sufficient to cover off on the efficacy and safety profile in this patient population, but that's up to the FDA to opine. Thank you. Just building on that thought, and as we are hearing live from an ongoing FDA Ad Comm meeting, also building on the New England Journal article that came out overnight on, you know, the importance of accelerated approvals being supported by a confirmatory trial, you know, being well underway. Are you able to comment, you know, your latest thinking on that, you know, the importance of having U.S. sites versus ex-U.S.? Obviously your program, you know, has been very widely sort of done extensively at a lot of major sites globally. Just would help to understand if at all that is a competitive advantage in your mind, and how would you look to do that, you know, confirmatory trial, just your latest thinking on that. Thank you for taking our questions. Yeah, thanks. Thanks for that question, Mayank. We've had a lot of this dialogue internally. Chuck, do you wanna maybe give a part of that response? Yeah, sure. Thank you for the question. You know, we've had a lot of regulatory interactions thinking about confirmatory studies. As you may know, Intercept had conducted an outcome study in COBALT, so-called COBALT study, looking at patients with more advanced disease and was attempting to collect liver-related events, transplant and death. That study was abandoned because of the label change for Ocaliva. Subsequently, they transitioned to try to use so-called one-arm studies to examine effects on outcomes. In essence, the issue is that you can't maintain studies long term for patients on placebo, and the way to get that is to use natural history databases where you basically construct synthetic placebo groups who are matched in the characteristics to patients who are on active therapy. Just two days ago, a paper was published in Gastroenterology, which looked at comparing outcomes in the long-term study of Ocaliva on transplant and death, compared to a matched control cohorts from large registries, the UK-PBC database, as well as the Global PBC Study Group database. They were able to show an effect, a difference in treatment in those matched cohorts. That is one strategy going forward. In our mind, though, we believe that the... We still have an opportunity to conduct an outcome study, which would look at cirrhotic patients on treatment versus placebo, where we have a different strategy that would allow for a successful execution. That's helpful. Thanks for taking our question. Thanks, Mayank. Thanks for the questions, Mayank. Our next question comes from Ryan Deschner from Raymond James. Ryan, you may go ahead. Good morning, everybody. This is Ryan. A couple of questions. Two questions from me. First, what specific areas of differentiation are you anticipating from a potential seladelpar label in PBC versus Ocaliva, in terms of warnings throughout a patient, conditions for line of care, monotherapy usage, dosing, et cetera? I have a follow-up. Yeah, sure. I'll start that off. Thanks for the question. You know, I think fundamentally what you've seen in the data set, and ultimately the label will be guided even by the response data set, of course, at least to date, is a picture around greater efficacy in terms of overall response rate and population of patients that actually meet treatment goals on alkaline phosphatase and bilirubin. Of course, it's, you know, it's our goal to have some demonstration around the benefit, the efficacy benefit, if you will, on reducing clinical symptoms of pruritus in particular. I think fundamentally it's to actually have a label that's supportive of an improved safety profile. Again, of course, the data set would have to support that. As we've developed seladelpar, as you've heard from the team, one of the things that we think is particularly enriching is the population of patients studied, and so particularly including those with compensated cirrhosis with and without portal hypertension. That objective is one in which it's our objective to, of course, avoid contraindications or warning labels, but we've got to have the data sets to support that. To date, we've been encouraged by what we've seen, albeit with relatively smaller subset of patients with compensated cirrhosis. That's ultimately, Ryan, I think what we're trying to achieve when we think about the potential future label. Again, I'll caveat the data sets that we continue to generate, and in particular, RESPONSE and long-term data from ASSURE will have to demonstrate the ability to support that type of label. Maybe I'd just add to that, commentary on the ASSURE, the long-term study, which I think by the time we submit, will be coming close to almost 400 patients, on daily seladelpar. So thinking about following those patients out for their outcomes, for the safety and efficacy, I think that will be an important. I'm not certain that would be in the label per se, but it'll be part of a safety set that will, I think, be very persuasive. Kind of turning back to the comment I made about the Ocaliva long-term study. That study started with just a little over 200 patients, and then was followed out for six years. We'll have, I think, nearly twice that number on active therapy. I think it should be a very robust data set, as Sujal mentioned, also containing probably right around 20% of the subjects with compensated cirrhosis. That's a population that in principle would have higher risk for liver-related events, which is not captured in the gastroenterology paper, by the way. We can look at decompensation, we can look at incidence of transplant, we can look at survival. I think that will be a very robust data set to compare going forward to speak to the issue around outcomes that you discussed, as well as Mayank mentioned in terms of regulatory guidance. You know, Ryan, sorry. The only other thing I'd also add, because I know we've got some questions in the queue around compensated cirrhotics in particular, and I may just invite Kris here to comment. You know, one opportunity certainly is generating data sets that support efficacy as well as safety in that population, and recognizing it's a smaller proportion of the overall PBC population. The other consideration around the potential safety in that population is, you know, this is a progressive disease. Even as you treat patients with earlier stage PBC, you know, again, perhaps Kris can opine, it's always a thought by a clinician around, if I start treatment on one therapy and a patient progresses, if that therapy is not safe in the progressed population, that becomes a question or perhaps a concern. The advantage of having some safety data, you know, having the data sets that we've generated thus far, as well as a larger data set in compensated cirrhotics, you know, in theory, gives a physician some comfort around treating a non-cirrhotic who may, at some point in time, progress. Yeah, I can make a couple of comments. You know, the challenge in PBC is that our current treatments, with the exception of urso, which to me is a nonspecific treatment, are limited by the concern in patients with advanced liver disease. Currently, fibrates have a warning about patients with advanced liver disease and definitely should not be used in decompensated liver disease. OCA with the label change and being not appropriate for patients with cirrhosis and clinically significant portal hypertension, decompensated liver disease, we have this unmet need because we see patients, we take care of patients across the spectrum of disease. Fortunately, we are making more early diagnoses, but we still see patients who are referred late. We see patients who have rapidly progressive disease, and we see patients who have evidence of, you know, progression of histologic stage, even without, you know, much in the way of warnings that we can identify. There's an unmet need because liver transplantation is not a great option for these patients, and in fact, MELD score is somewhat disadvantages patients with PBC. We have the early population where I think we have good data showing that, patients who remain at risk based on alkaline phosphatase would be candidates for second-line therapy. We have really a paucity of data in patients across the spectrum of disease, and especially those patients who have progressed, but not quite, are at the liver transplant stage yet, but still need additional therapies. Having a large safety data set with a prospective open label follow-up, albeit it's not going to meet the criteria from a confirmatory trial standpoint because of not having a placebo arm, is still extremely helpful in determining what the role might be in terms of stopping the progression of disease, and more importantly, in terms of safety and tolerability. As we gain more knowledge with regard to understanding how to use real-world cohorts and real-world evidence, I think we might be in a position to apply these results to a larger population than we're currently doing. Kris, I wonder if maybe you could just add an additional comment. You know, progression to cirrhosis isn't formally used as an event, but it does, I think, cross a threshold for a significant increased risk. Maybe some of the new methodologies, the liver stiffness, either MRE or transient elastography, and how that might be used, for example, in a cohort such as ASSURE to, you know, gain some insight about the ability to maybe arrest progression or slow progression. Yeah. No, these are really valuable insights because we simply do not have the ability to do a liver biopsy every year. But as we get more and more data with regard to the use of vibration-controlled transient elastography, MR elastography, and enhanced liver fibrosis testing and other liquid biomarkers, if you will, we have the ability to do sequential measurements over time, and we have the ability to determine whether, in fact, we're making changes with regard to progression. There are really well-established data sets in Europe, for example, led by Christophe Corpechot and others, showing that in fact, when you look at thresholds of 16.9 kPa for FibroScan or 9.6 kPa or lower, they really predict not only clinical events, but also progression of disease. I think that's an endpoint that will be clearly of interest to clinicians and hopefully also to regulators. Similarly, we have data now with regard to circulating biomarkers, such as FIB-4 or ELF, that repeated measurements over time may help tell us whether the patient is reaching a stabilization of disease or progression of disease. Certainly from a clinical standpoint, progression to cirrhosis is a key endpoint that we hope to avoid, because once a patient has transitioned into cirrhosis, we treat that patient as having cirrhosis even if they have cessation of progression. We see this in hepatitis C, for instance, in patients who have a FibroScan with cirrhosis, they have short-term treatment, the FibroScan improves significantly, but we know that those patients still may be at risk for cancer. The idea is to really prevent the development of cirrhosis and stop the progression to cirrhosis. That would be an endpoint that would resonate with clinicians and those who take care of patients. That's very helpful. Thank you very much. Also, just wanted to quickly ask, do you anticipate initiation of further studies outside of ASSURE in order to get to potential label expansions or to sort of access these patient groups that we're talking about now? And also particularly in the Greater China market, do you see having to initiate another trial in order to access that market to get to authorization there? Yeah, I can answer that. Thanks for those questions. Yeah, I think we always believe it's important, you know, to support the potential use of how we think about seladelpar in the hands of patients and certainly for clinicians to actually do that with subsets of data that support that use. I think you can continue to see us be committed to the PBC population overall and continuing to generate data sets that support its broader use. I think with respect to your question around China, certainly a geography where additional data sets would be necessary. We've talked a little bit about the fact that we are preparing ourselves to at least initially launch in the U.S., and then look outside the U.S. to put seladelpar in the hands of patients as quickly as we can, look outside the U.S. to potentially partner. I think China, in particular, would be one of those regions where we would look to partner. Today, seladelpar remains one of the only unencumbered, very late-stage assets in PBC. We think that provides us clearly with an opportunity to find the right partner that really can help us achieve our ultimate goal, which is, in fact, to get seladelpar in the hands of patients globally. We'll continue conversations that have been ongoing in geographies, particularly outside the U.S., including China. Wonderful. Thanks, Sujal. Yeah. Thank you. Our next question comes from Patrick Dolezal from LifeSci Capital. Please go ahead, Patrick. Hi. Thanks for taking the questions. For Dr. Kowdley, you spoke to the under-treatment of PBC patients, and there are clear treatment attrition issues with OCA as patients work through the paradigm. Is there another cohort of patients that are simply not attempting treatment at all, whether in the first or second-line setting? And if so, kind of what are the main reasons for this? And then for the company, curious how you intend to address this under-diagnosis and under-treatment going into commercialization and, you know, whether there's any key points of differentiation in your planned approach versus what competitors have done historically. Yeah. With regard to what percentage of the population is currently not being treated, you know, I think that's an excellent question. I would say that until we have more routine biochemical screening of patients at risk and until we have good awareness and education, disease state awareness information, we are still gonna have a substantial gap. I would say even more than patients who are not receiving any treatment at all or not being diagnosed. There is some level of apathy in the part of clinicians who don't recognize that these risk prediction models really have a longer-term horizon. A patient that they may see every six months may be progressing, but it's not so clinically apparent. There is a need for education with regard to adoption of these models and really, you know, socialization of using these predictive models. We're certainly working hard on that with regard to both the UK-PBC and GLOBE score being available through websites that you can put into your EMR. I think we have a ways to go there. I think that a patient case-driven education through continuing medical education and other platforms are really important so that at least we identify those patients who are not currently meeting the criteria for response and utilize second or third-line therapies. There is a lot to be done, I think, with regard to disease state awareness and also to educating people who are treating these patients because they are simply not keeping, you know, they're not up-to-date on these prognostic models and how to use them. The more we can simplify these and get that out there through a variety of different educational efforts, the greater the likelihood that we'll have, you know, earlier implementation of second-line therapies. If I could just jump in, I just want to remind you from what I had shared earlier, we are really focused on an incredibly highly engaged patient population. They're very involved in their treatment. They stay up on all the new information as it comes along. The fact that we're introducing a product that really addresses the symptom burdens that they really experience, I think it's gonna create even more interest in wanting to learn more about new therapies. I'm excited about what the next two or three years will bring for getting patients who might not have normally thought to really, to discuss these issues with their physician, or to maybe talk more openly across the board within their network or ecosystem about improving their overall quality of life, to be able to get more involved in, and to be able to educate them in a way that creates an active and highly engaged population of patients that might not have otherwise been treated. I think we have a really unique opportunity here. I do want to echo that very briefly and say that that's absolutely correct. We saw, for example, when Ocaliva was approved and the advocacy of patients sharing their experiences really highlighted the unmet need at the Ad Comm. I think the patient organizations are really mobilized, and we need to do a lot more, I think, in giving patients agency to advocate for themselves. Because of the fact that healthcare now is increasingly balkanized and there are people practicing in different silos, patients are the ones that need to be encouraged and supported to actually seek out experts who understand these finer points. I think starting with patient advocacy and including that as part and parcel of any effort to bring new therapies to bear is essential. I might just also add that, you know, understanding the magnitude of the issue is important. In that regard, there was just a very nice paper that was published from a U.K.-wide audit that examined the treatment patterns for more than 8,000 patients. This is very, very new data, so it was collected during the pandemic over a one-year period and looked at treatment practices, who was eligible for a second- line treatment but was not receiving it. There was a lot of information there, I think, that helps do the things that both Lewis and Kris are mentioning, but really tells us how well, how much could we get out of that effort. Now, we don't, I think, have that same kind of information in the U.S., but I wouldn't expect that it, you know, it's hard to say how different it would be. I think the role of AASLD, AGA, some of those efforts to also influence understanding, you know, appropriate practice is something that I'm sure Lewis and his team will have, you know, be trying to catalyze, let's say. Great. Thank you. Super helpful. Thanks, Patrick. Our next question comes from Thomas Yip from H.C. Wainwright. Thomas, you may go ahead. It looks like Thomas is having some trouble joining. Thomas, you may go ahead. Hello. Can you hear me okay? Yes. Okay, fantastic. First, thank you for taking our questions. Just taking a couple of questions for Ed. First, looking at the PBC clinical and commercial landscape, how do you look at seladelpar compare with other compounds such as elafibranor and odevixibat? I suppose both in pre-cirrhotic population and also in cirrhotic population as well. Thank you for the question, Thomas. Maybe I'll address it here. I think relatively short answer. You know, there's only limited information that's been shared to date with respect to elafibranor in patients with PBC. The phase II study that they conducted and published had a total of 45 patients across three arms, placebo and two different dose groups of elafibranor out to 12 weeks of treatment. Didn't appear that that study included cirrhotic patients. Once again, you know, hard for us to really give you any sense or answer around the comparison relative to seladelpar and elafibranor. At least as it pertains to alkaline phosphatase, I think seladelpar at 10 mg showed comparable reductions in alkaline phosphatase over a 12-week period to what we saw in their phase II study. That's largely the limits of our ability to really compare. You know, obviously we've generated datasets of patients, as you saw today, out to two years of treatment. In fact, we've had patients even beyond two years of treatment on seladelpar, datasets that we've also shared at medical meetings as well as published some of those datasets. I think it remains to be seen how we view the overall comparison. Dennis talked a little bit about some of the differences between PPAR-delta and PPAR-alpha as it pertains to target in the liver as it pertains to mechanism, elafibranor, PPAR-alpha/ delta, largely with alpha activity and some delta activity. I think again, how those mechanistic differences play out remains to be seen in future datasets. Thank you, Sujal. Perhaps a commercial question. We touched on this briefly earlier. Beyond the U.S. market, China is also another prominent market. Can you discuss what are some other possible markets, both in terms of the market size and also reimbursement as well? Yeah. I think from our standpoint, we've been focusing mostly on the EU4 and U.K. market in terms of looking at, you know, opportunity there. We kinda summarized some of those numbers for you. They seem very, very similar in the E.U., U.K., plus extended European Union and from an epidemiology standpoint as we would see in the U.S. I think their treatment rates are a little bit better than ours just because of the centralized healthcare of those patients. Of course, from our standpoint, I think, you know, you would expect the pricing to be at a different price point than the U.S. We've also explored Japan and the opportunity there. We talked a bit about that opportunity. It's very unique in the fact that, you know, they classify PBC as an intractable disease, and it really helps with the co-pay situation for patients there. Of course, I did describe China. Those are the areas where we've spent most of our time doing our assessments outside the U.S. As I think Sujal has already mentioned, we're really looking to partner those particular opportunities. Great. Fantastic. Thank you again for taking our questions. Looking forward to progress. Thank you, Thomas. This concludes the verbal portion of our Q&A session. I'll now turn the call over to Hans Vitzthum from LifeSci Advisors to read the remainder of the questions. Great. Thank you very much, Tara. We actually really just have one write-in question. I think the others have been addressed. This is for you, Dr. Kowdley. You mentioned a preference for seladelpar's profile and cited seladelpar potentially capturing 60% of the post-UDCA use in PBC. This is from Thomas Smith at SVB. He's asking for clarification, and that is, did your response incorporate profiles for pipeline therapies, or was it simply looking at seladelpar's profile versus currently approved therapies? Yeah. I don't think I made any comment about what percentage of the population would be served by seladelpar as opposed to other therapies. Certainly, I think if you look at the typical proportion of patients that we identify as having an unmet need, that would be about anywhere from 5%-10% of patients are intolerant of urso, so they have an unmet need. Around 40% of patients have been estimated to be patients who are at increased risk after one year of urso therapy. That would be, for example, those patients that have persistently elevated alkaline phosphatase greater than 1.67x or 2x the upper limit of normal after a year of urso. I think those are the patients that would be candidates for seladelpar, and I think maybe I would now defer to Lewis to make some specific comments from a CymaBay perspective. No, you are spot on there, Dr. Kowdley. I think we conducted our research really utilizing both prescription and claims data to really understand really what the available opportunity for in the market was. Of course, we layered that with epidemiology data as well, and it really is as you described it here, how we do the addressable market. We really look at the market based on, you know, historical factors and what we see in terms of overall treatment trends historically. We really haven't taken into consideration any kind of future issues, although we do sort of forecast out what we think the overall market growth is going to be over time. Other than that, those segments are pretty well-defined. Tara, that takes care of the write-in questions. Why don't I turn it back to Sujal for some closing comments. Appreciate it. I know we've taken everyone a little bit long here, but I just wanna fundamentally thank all those for joining again. You know, hopefully, you had an appreciation here today, for this opportunity we all are excited about. As Kris mentioned, you know, relationships with experts as well as the advocacy groups is really vital to the work we do, so I need to thank all of them, certainly Kris for your time, but really the broader group that have really assisted us in trying to position seladelpar, to ultimately be in the hands of those patients that would benefit. Once again, we appreciate everybody's attention and look forward to providing future updates soon.