Good afternoon, everyone. Thank you so much for joining our Piper Sandler Healthcare Conference. I can't tell you how excited I am to have the team from CymaBay Therapeutics here. I remember sitting here about a year ago, and I think the stock was trading at about $2 or so, and I thought it was three or four. It's been an incredible year for you guys in terms of execution, data, and so much more to come. I just want to start off really congratulating you for a very phenomenal 2023 and many more great things coming for 2024. Thank you. So team, I think the first place to start is, given that we just came from AASLD, and you had the chance to share your data from RESPONSE at the late-breaker presentation, could you maybe talk about what were the takeaways and the sentiment for physicians who saw the RESPONSE data that stood out, and what are the key differentiations in terms of seladelpar's data set versus competitor elafibranor? Yeah, happy to dive into that, Yasmeen. You know, first of all, let me just say, the star of the show at CymaBay, without question, has been seladelpar. Mm-hmm. We've been developing seladelpar in the setting of primary biliary cholangitis. Mm-hmm. ... or PBC, since 2015. Perhaps one of the most robust development programs- Mm-hmm. ... in PBC to date. Certainly, as it pertains to a number of clinical studies run at this point, patient exposures, and, you know, the consistency of the data across these studies overall. And, you know, you talked a little bit about where we were last year and where we are today. You know, certainly last year we were fully enrolled in a phase III study- Mm-hmm ... that in large part was a rinse and repeat of a large global study- Mm-hmm ... we had actually run prior to this pivotal study. But when we reflect on what we see in the phase III data set out of RESPONSE that was presented at AASLD, and as we think about the overall landscape, you know, seladelpar really is uniquely set for chronic inflammatory liver disease. Mm-hmm. Part of that comes from the biology, where the target for seladelpar- Mm-hmm ...... PPAR-D elta, as a delpar, seladelpar really drives anticholestatic- Mm-hmm ... anti-inflammatory, and antipruritic effects in the setting of PBC. And so this is a study, cholestatic disease, autoimmune- Mm-hmm ... liver disease, where elevated alkaline phosphatase has been a marker that's been correlated with outcomes. Mm-hmm. And so what we saw in our data set in phase III is six out of 10 patients- Mm-hmm ... meet the primary composite response rate, Mm-hmm ... required for registration, Subpart H, accelerated approval registration- Mm-hmm ... in the setting of PBC. We saw importantly- Mm-hmm ... and in fact, where I think the more central focus was for physicians- Mm-hmm ... to your question, is that one in four patients actually normalized their alkaline phosphatase. Mm-hmm. This has now really become the central view around- Mm-hmm ... how to treat patients, eligible patients- Mm-hmm ... for second-line setting. The target for treatment is really a target that we heard at AASLD in every setting in symposia for PBC as being a target- Mm-hmm ... to normalize biochemistry. Mm-hmm ... and alkaline phosphatase. So again, one in four patients normalizing- Mm-hmm ... on seladelpar 10 mg versus 0 patients in placebo- Mm-hmm ... stacks up quite favorably- Mm-hmm ... to the only existing, approved treatment on the market today- Mm-hmm ... ursodeoxycholic acid, and potentially even to other agents in development today. From there, I think much of the buzz was clearly around an opportunity for the first time to offer patients- Mm-hmm ... some improvement in clinical symptom burden and therefore- Mm-hmm ... potential improvement in quality of life. Mm-hmm. Patients with PBC suffer from fatigue as well as itch or pruritus. Mm-hmm. There is no agent approved for cholestatic pruritus today. Mm-hmm. What we saw in the RESPONSE study was a statistically- Mm-hmm ... significant reduction in itch for both moderate to severe- Mm-hmm ... itchers in the study, as well as the overall population. Mm-hmm. We saw that using three separate scores. Mm-hmm. The numerical rating scale, where we saw the p-value of less than 0.005- Mm-hmm ... relative to placebo. Very consistent drop in itch, upon initiating- Mm-hmm ... treatment, and curves that separated distinctly- Mm-hmm ... from placebo. We see the same pattern- Mm-hmm ... and statistical significance when we look at the 5-D Itch scores- Mm-hmm ... as well as PBC-40. And then finally, to add further evidence around the itch benefit of seladelpar- Mm-hmm ... the known inflammatory cytokine, IL-31- Mm-hmm ... that's been known to be pruritigenic. We saw decreases- Mm-hmm ... in IL-31 that correlate with the decreases- Mm-hmm ... in patient-reported itch. So a very consistent set- Mm-hmm ... of data from RESPONSE that mirrors the data- Mm-hmm ... sets that we've generated to date, and I think this is the other key differentiator- Mm-hmm ... coming out of AASLD, that we heard from- Mm-hmm ... many of the physicians that are looking for better treatment alternatives- Mm-hmm ... for their patients. And then the final piece of it, I'd say the third piece, is really just the overall safety. Mm-hmm. You know, now we have north of 500 unique patient exposures- Mm-hmm ... in the setting of PBC with seladelpar, and in the RESPONSE study- Mm-hmm ... overall, a safety profile that we certainly think distinguishes- Mm-hmm ... again, seladelpar, not just from existing treatment- Mm-hmm ... but potentially from other treatments in development. Thank you. That's very helpful. I think we attended many of the sessions, and it was really clear that the PBC community is really bringing awareness to treat cholestatic itch and make physicians aware of it. So the question, given that you showed statistical separation in itch, which was durable at 6 months and 12 months, what's the likelihood of getting that on the label? And in case that it doesn't end up on the label, how could you still utilize, you know, the findings by then RESPONSE will be published to still establish that it has a pruritus benefit. Whether it ends up in the language or not, doesn't matter. What's the likelihood of getting it into the labels? If you could talk about that. Yeah, sure. So, you know, we evaluated as a pre-specified- Mm-hmm. -endpoint that was part of our statistical hierarchy. Mm-hmm. This change in Numerical Rating Scale pruritus- Mm-hmm. at 6 months versus baseline. Mm-hmm. That's where, as you mentioned- Mm-hmm. we get statistical significance. Our expectation is the data, given- Mm-hmm. itch was part of the statistical hierarchy itself. Mm-hmm. should at least exist in the data section of the label. Yeah. I think that is, from our perspective, relatively straightforward. Mm-hmm. Of course, we don't yet have a label- Yeah and we'll be discussing that with regulatory agencies. But that, we think- Mm-hmm ... is fairly straightforward expectation of ours. Mm-hmm. That gives our medical affairs organization- Mm-hmm -our MSLs, our field force, the ability- Mm-hmm to talk about the antipruritic benefits of seladelpar Mm-hmm in the setting of PBC. Our true aim is ultimately to have an indication statement- Mm-hmm ... that includes, treating not just PBC, but also- Mm-hmm cholestatic pruritus and itch in PBC patients Mm-hmm I should say more specifically. Recently, as you're aware, we were issued a revised Breakthrough Therapy Designation- Mm-hmm -where the U.S. FDA granted a broader Breakthrough Therapy Designation that now includes a treatment of PBC- Mm-hmm ... also inclusive of compensated cirrhotics, as well as itch in PBC patients. Mm-hmm. So certainly that gives us some encouragement- Mm-hmm that regulators, one, recognize Yeah -that there is a need, that itch is, significant- Mm-hmm in PBC patients, that there's a need for treatment. Mm-hmm -to actually address, PBC-related itch. Mm-hmm. And I think it at least increases and raises the probability that that we are successful- Mm-hmm -at getting it into, getting it into the indication statement. There's no guarantee, and so it'll- Yeah Of course, be a review issue. But as I mentioned, I think the dataset that we'll be prepared to deliver- Mm-hmm Upon submission is a compelling dataset. Mm-hmm -going from 52-week data in our open label- Mm-hmm phase II, where we saw both the visual analog scores Mm-hmm -as well as PBC-40 and 5-D Itch- Mm-hmm -itch improve, inclusive of two-year extension data- Mm-hmm on the same parameters, as well, again, as our enhanced and Mm-hmm RESPONSE dataset. So I think the case is quite compelling, and it'll be left to the agency to review. But we do think that the break- Mm-hmm The revised breakthrough is encouraging. Thank you. Another question that comes up is timing of the NDA filing. I think competitor, Ipsen has communicated their filing in Europe and the U.S. by year-end. So what is the time gap of how soon could you get your NDA processed and submitted, and time distance between the launch of these two products? Yeah. So, you know, we started our phase III study about five to six months behind them. Mm-hmm. We completed enrollment, we believe, just about two months behind them. Mm-hmm. Of course, reported top-line data just about 2 months- Mm-hmm -behind the ELATIVE Phase III data. I think we importantly set an expectation that it would be reasonable to expect about a four to six month timeline post our top line- Mm-hmm would put us into the early part of next year. Okay. Certainly, Q1 is where- Yeah We would want to set an expectation. At the end of the day, we are a company solely focused- Yeah on this opportunity in PBC, and you might imagine. Mm-hmm that our internal resources and processes are really geared towards filing Mm-hmm as quickly as we can. Not sacrificing, obviously. Mm-hmm -quality of that submission, but, you know, we're encouraged. I think we've got a tremendous team- Mm-hmm -that's dedicated and focused to get seladelpar- Mm-hmm into the hands of regulators and therefore, potentially into the hands of patients as quickly- Mm-hmm -as possible. Okay. Do you think once the NDA is filed, and accepted, like, do you anticipate also getting some color on potential outcomes for both products or either product? I think a lot of clients are wondering, just because the agency's gonna review two distinct products. Yeah. So, you know, I think- Like, if one gets an adC om, will both get an adC om, and one get it first? Like, how would that all play out? Yeah. You know, I think it's hard to know today. We certainly are prepared- Yeah in the event that Yeah The agency decides to actually have an advisory panel. Mm-hmm. We'll be prepared for that in any case. It's hard, I think, today to speculate. Yeah. I think the first step is the agency, accepting the submission- Mm-hmm and from there, at some point- Mm-hmm recognizing whether or not they need an advisory panel. And so I think one way- Mm-hmm or another, we'll be prepared in either case. Okay. And then I think the publication is another key priority focus for you guys. I know you guys are working diligently on that. Maybe any update or comment you want to make? I know a lot of clients are going to listen to this fireside chat, so I would love to hear some color on that. Yeah. Well, look, a couple of things. First of all, even at the top-line data release- Yeah We shared a fairly significant amount of information. Mm-hmm ... from response to top-line data. Obviously, the full dataset- Mm-hmm -at ASLD- Mm-hmm -in a late-breaking presentation, all of which are available, all of these materials- Mm-hmm available on our website. It's our goal to have these data published. Mm-hmm as quickly as possible. So I'd just say stay tuned. Yeah. We've worked feverishly to submit what we think would be a high-quality publication representing, you know, the tremendous dataset out of RESPONSE. Yeah. And so, you know, fingers crossed we see that relatively shortly. Thank you. The next question is sort of commercial. I think a lot of investors going into the approval, high POS, the more that they had in terms of high POS for success, is just mapping out the market size. So I guess... You know, I think based on the work that you guys have done, you guys have noted that here in the U.S. are about 21,000 patients here of that are in need for second line. Could you maybe highlight where did these numbers come from? How accurate are they? How many of them OC experienced? And how should we be thinking about sort of, you know, the low-hanging fruit of the first patient getting on the drug out of this market? Yeah. Maybe I'll make a couple of comments, and then- Mm-hmm. And then Harish can dive into the details. Yeah. You know, first of all, as a starting point, we fundamentally believe that the overall patient population in need of second-line treatment. Mm-hmm will be completely recast. Mm-hmm -from that view when obeticholic acid was first launched in 2016. Mm-hmm. Fundamentally, based on the profile of what we're seeing with seladelpar, normalization- Mm-hmm -rates of ALP, the impact- Mm-hmm of seladelpar on pruritus, the overall safety Mm-hmm profile we've seen to date in a broad spectrum of patient population, non-cirrhotics, as well as compensated cirrhotics Yeah We think will be an absolute driving force, along with ultimately changes in treatment guidelines that become explicit. Mm-hmm at some point around treating to normalization Mm-hmm will effectively recast. Yeah How we think about patients in need of second line treatment. Mm-hmm. The 21,000 patients you referred to- Mm-hmm are patients in the U.S. that have at least been taking UDCA- Yeah for a minimum of 12 months Yeah whose alkaline phosphatase levels remain above 1.67x Mm-hmm The upper limit of normal, or around 200 units per liter. Mm-hmm. That's effectively the patient population, that Intercept study, that we've studied- Mm-hmm that Ipsen GENFIT have studied for second-line treatment. Mm-hmm. But again, there are patients between 1 and 1 point- Mm-hmm 6x to 7x the upper limit of normal, that are never normalized in their biochemistries on UDCA Mm-hmm that are, in fact, at a greater risk of progression Mm-hmm that are also in need Mm-hmm of improved treatment alternatives. Mm-hmm. We think this is going to fundamentally change and potentially double- Mm-hmm The overall addressable patient population. But perhaps Harish can talk a little bit about Mm-hmm more about the numbers and how that stepwise process Yeah -would occur. Oh, sure, Sujal. Just to layer in on the 21,000- Yeah I mean, these are numbers based on patient claims database. Yeah. Basically, you look at prescription data- Mm-hmm and map the patient level Mm-hmm longitudinal data with, like, the diagnostics information. Yeah. That's how you segment patients- Yeah, okay -based on their lab values. So the 21,000- Mm-hmm reflects the number of patients who, despite being on- Mm-hmm treatment, UDCA, have elevated alk phos level Okay -above 0.67. So of the 21,000, we know about, I mean, about 40%- Mm-hmm have been penetrated by Callebaut, only second line agent today. Yeah. But we also know, in terms of active patients who are continuing- Mm-hmm -on therapy is less, is significantly lower, about 1/3 of that- Okay -which is about 3,500 patients. Mm-hmm. So giving- Yeah leaving a lot of room in terms of an... Yeah opportunity, in terms of, you know, a huge unmet addressable need Yeah even within the existing Yeah defined second-line pool, like before layering in- Mm-hmm double of that market Yeah -once you expand that between 1 and 1 point- Yeah 6x to 7x those patients. So those clearly are- Mm-hmm What I would say is the opportunity at launch, and then, you know- Mm-hmm as the guidelines change Mm-hmm as we generate more data. Yeah All, all of those will be triggers for like- Mm-hmm -you know, payers to, I think, paid payer, formulary status. So that'll enable us- Mm-hmm to kind of go after the broader Yeah patient pool, which is that double the market size. Yeah -that Sujal was just speaking to. Got it. And out of this market size, I think, what if the number of newly diagnosed PBC patients on an annual basis? Do we know that? I mean, there's also different incidence rates- Yeah that would determine. I mean, there are- Yeah data in between 12,000-15,000 patients I see per year is typically what Okay we've seen. But again, these are stuff we'll have more granular as we- Mm-hmm look at different registries and, you know, but based on what some of the global PBC studies Yeah have done, so this is the range Yeah But, in terms of the incidence rates in the U.S. Yeah. The other question that we get is, like, given that I think a lot of investors understand the majority of these patients are in gastros rather than hepatology settings, so that they sometimes worry and say: Well, does that mean my—somebody has to build a really bigger commercial footprint than what we saw versus Intercept, to really go out the gastros versus hepatologists? So could you kind of talk about what work is being done in some way to map out, call it, the high prescribing GI guys and high prescribing hepatologists, and how are you thinking about sort of building your sales force and... Sure. I would say it's... I mean, the treater base is fairly concentrated, if I may say. There's about 4,000-5,000- Mm-hmm -PBC treaters- Mm-hmm -in the U.S., who drive probably 80% of those- Yeah -patients, you know, treat 80% of- Yeah -PBC patients. You know, but of course, between hepatologists and... I mean, most of them- Mm-hmm are actually gastros. Yeah. You know, but hepatologists probably, I would say, maybe are treat the most- Mm-hmm -you know, are the most, I, I guess, high productive ones. If you look at the- Mm-hmm the top layer, where they have, you know- Mm-hmm probably see 5-10x of the patients Yeah -that the, an average, GI- Mm-hmm -would see. So obviously, those are, you know- Mm-hmm But hepatologists are less than 200 in number. Mm-hmm. We think something like a 50-60, you know, Mm-hmm Field size is probably will be what we- Yeah may need to target this physician pool. And of course, we're, we're, we're- Yeah doing a lot of work to understand kind of who these physicians are. Yeah -targeting and, you know, understanding what's the optimal way to look at, you know- Mm-hmm who do we go after at right at launch and over a period of time? Mm-hmm so making sure we have the optimal reach and frequency. So those are work that- Mm-hmm is being done now, now that we Yeah have some of the commercial leadership team in place, and that's being built now. If you can remind investors, what has been, like, Intercept sort of sales force buildup that they had over the first years of launch? I know it's a little complicated- Yeah because they got ready for- Sure NASH, and then they had to reduce it. I think relatively similar. Okay. My understanding is somewhere between 40-50 field reps- Mm-hmm you know, perhaps about 15 MSLs. Mm-hmm. I think in our case as well, in addition to the 50-60 estimated- ... a field force, again, this is sizing that's ongoing now internally, would be about 12 MSLs. The latter have largely already been hired- Okay. - and in fact, are already being deployed given our phase III data set. Mm-hmm. So really high impactful conversations that have been initiated, you know, with key prescribers- Mm-hmm. since our top line data Mm-hmm. readout, and even since AASLD Mm-hmm just a couple of weeks ago, in our activities that our field force Mm-hmm - is already out, discussing, you know, with some of those key prescribers. Then, team, I know that you guys did a really nice job on RESPONSE, in terms of the PIs that were involved in the study. Have you had a chance to look at how many of them have been integral in writing the guidelines for PBC? I think we don't need names, but could you maybe talk about, like, you know, are the individuals that write guidelines, and were they involved in RESPONSE and ENHANCE? Because I think that could be another data point of promoting or wanting to, you know- Yeah, I think, you know, you can go to AASLD and see the committees that are identified- Mm-hmm on some of these guideline committees. And I think if you go there, you'll- Mm-hmm see at least one Yeah. At least one PI that's been involved in our studies historically. As soon as those physicians- Mm-hmm go on to these committees for guidelines. Mm-hmm they can still continue to enroll patients Mm-hmm - for your clinical studies, but of course, they can't be used for advisory purposes. Mm-hmm. I think broadly, we have a good idea around the sentiment. Mm-hmm. And so it's always a mixture of some folks that are, you know, what you might- Mm-hmm - consider KOLs and, you know, running multiple studies in these indications- Mm-hmm as well as others that, again, are very familiar with understanding the disease Mm-hmm and have a significant amount of experience. Mm-hmm. So it'll likely be a mix of folks that have been involved in our studies and others that perhaps have not. Okay, that's very helpful. And then I think, then the next question is targeted on IDEAL. I think a lot of investors recognize it's a very high unmet need, could double potentially your addressable market. And I know you recently initiated the study, but could you maybe talk to us how's enrollment progressing? It's been a few months, start there, and then just, and then just talk to us like, what is the study powered to, to show and, and primary endpoint in this population? Yeah, sure. So just as a reminder, you know, IDEAL is targeting a patient population that's never really been included. Mm-hmm in second-line settings in clinical trials, not really explicitly called out. Mm-hmm even in treatment guidelines. And again, they're patients whose alkaline phosphatase is not normalized on first-line UDCA- Mm-hmm ... and therefore, continue to be at a risk of progression. So I think this is a very novel study. We certainly... Let's start with interest. I would tell you that broadly, investigators- Mm-hmm have had a significant amount of interest. These are patients that, you know, aren't given scripts for second-line treatment- No - even with the singular opportunity that's available today. There's no clinical studies for them, typically, and yet, you know, they're in need of further risk reduction, and then often in cases also need of reducing clinical symptom burden- Mm-hmm - and pruritus. So a significant amount of interest. You know, I'd say it's early days, largely because just getting a study up and running- Yeah sites activated, IRBs, ethics committees, approved for clinical studies. Mm-hmm is the early work- Mm-hmm before you really hit a crescendo Mm-hmm - around acceleration. So we'll reserve, providing any guidance- Mm-hmm - around enrollment and data until we hit that crescendo, in terms of activation of sites. But overall interest is- Mm-hmm - is incredibly high. And we're excited about this study, for sure. It's, you know, at the end of the day, we fundamentally believe guidelines will- Mm-hmm at some point shift to be explicit around normalization. Mm-hmm - perhaps even in the near term. Mm-hmm. It's our responsibility as a sponsor to generate- Mm-hmm - datasets that provide patients, investigators, payers- Mm-hmm you know, the ability to understand, you know, the impact that treating a broader population- Mm-hmm can actually have. Is the study similarly powered, and the primary endpoint for ALP normalization or? Yeah. So, you know, to your point, sorry, I didn't answer that initially. You know, the endpoint here is a little different than in response. Mm-hmm. So the endpoint is purely normalization. Mm-hmm. One of the key- Yeah - endpoints, of course, in response, but normalization is the primary endpoint. You know, the percent decrease we see with seladelpar 10 mg- Mm-hmm - on average, is about 42% in ALP- Mm-hmm - from baseline. Mm-hmm. You know, and that's a measure that's independent of baseline ALP. Mm-hmm. So 1.67 is just under 200 units. Mm-hmm - per liter. In our studies, in our reference lab, the upper limit of normal- Mm-hmm - is 116. So, you know, if you assume about a 40%-45% drop in ALP- Mm-hmm You might imagine that Yeah many, if not, a majority of those patients are gonna normalize- Mm-hmm - on seladelpar 10 mg on average. And so I think the study is really powered similarly- Yeah - to ENHANCE and RESPONSE, albeit those were on- Yeah different primary endpoints in a sense. So I think significantly powered to show this difference. Mm-hmm. And so we're confident about what we expect to see relative to patients on seladelpar 10 mg versus placebo in that study. But we're also importantly looking at other endpoints- Mm-hmm including, you know, patient-reported itch- Mm-hmm in IDEAL as well. Do you expect to have also sort of 1/4 or 1/3 of the patients with NRS greater than four? Or would the distribution be different in this population with a different- Yeah - baseline ALP? You know, itch has also been historically independent of baseline ALP. Mm-hmm. Even patients whose alkaline phosphatase is normalized- Mm-hmm - on first-line UDCA, can suffer from itch- Mm-hmm Some of them, significant itch. So you know, our expectation is- Mm-hmm - across our studies, we've consistently seen about- Mm-hmm 30% of patients with moderate to severe itch. And so I think at least going in, our expectation is we have the potential to see something very similar in IDEAL. I know since there's only 20 seconds left, is how do you think about partnership, right? I mean, you have a de-risked asset with really outstanding data, differentiation, a defined market, a defined unmet need, or, you know, very competitive pricing. So at what junction do you feel like it's the right point to contemplate partnering versus execution on your own and commercializing on your own? Yeah, look, I think we're very excited about what we're able to continue to execute around- Mm-hmm. we want to maintain the broadest strategic alternatives- Yeah for the company and for all of our stakeholders. You know, that includes our ability to file- Mm-hmm - not just in the U.S., but in both the U.K. and the E.U. Mm-hmm. We fully intend to do that filing ourselves. Mm-hmm. We have the ability to do that and maintain, again- Mm-hmm the broadest set of strategic alternatives Mm-hmm for the company. We're building an organization to launch seladelpar, at least in the U.S., on our own. Mm-hmm. Europe, I think is yet to be determined. Mm-hmm. Potential opportunity- Mm-hmm - to think about licensing alternatives in Europe. But once again, we also have the ability to think about strategically launching in a staged fashion- Mm-hmm ourselves. I think at least to date, we're gonna maintain the broadest set of strategic alternatives- Mm-hmm for the company, and so are not in a rush- Mm-hmm to partner at this point in time. Great. We have... Well, we have come to the end of the fireside chat. I want to say thank you on behalf of all of us here at Piper Sandler, for being part of our conference, and it's been a pleasure covering you and working with you guys. So thank you again. Thank you.