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spk03: Good day, ladies and gentlemen, and welcome to SEMA Bay's third quarter 2022 financial results and business update conference call. At this time, all participants are in listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised that the call will be recorded at the company's request. It is also being webcast live on the investor section at the SEMA Bay website at www.semabay.com. I would now like to turn the conference over to Mr. Paul Quinlan, General Counsel of SEMA Bay. Mr. Quinlan, you may proceed.
spk15: Thank you, Operator, and good afternoon, everyone. I hope that you've had a chance to review the press release we issued announcing our third quarter 2022 financial results and business updates. You can access that release on our website under the Investors tab. Joining me on the call today are Sujul Shah, Chief Executive Officer, Chuck McWhorter, Chief Scientific Officer and President R&D, Dennis Kim, Chief Medical Officer, Louis Stewart, Chief Commercial Officer, and Dan Minold, VP Finance. Following our prepared remarks, we will open the call for Q&A. Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session, Relating to SEMA Bay's expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, funding and repayment schedules, anticipated timeline, and data release dates, cash runway, and planning for commercialization are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. Although the company believes that the expectations reflected in such forward-looking statements are based on reasonable assumptions, actual outcomes and results are subject to risks and uncertainties and could differ materially from those forecasts due to the impact of many factors. The company assumes no obligation to update or supplement any forward-looking statements, whether as a result of new information, future events, or otherwise, except as required by applicable law. Participants are directed to the cautionary statement set forth in today's press release, as well as the risk factors set forth in SEMA Bay's quarterly and annual reports filed with the SEC for factors that could cause actual results to differ materially from those anticipated in the forward-looking statements. This conference call is the property of SEMA Bay, and any recording or rebroadcast is expressly prohibited without the written consent of SEMA Bay.
spk18: At this time, I'd like to turn the call over to Sujil. Thank you, Paul. Good afternoon and thank you for joining us today.
spk17: Although our prepared remarks today will be brief, we made significant progress during the third quarter towards our goal of bringing Selladelpar to patients with PBC. We will cover three key business updates and provide a summary of our third quarter financials before taking questions. In the third quarter, We reported completing enrollment in response. Our global phase three registration study evaluating CeladalPAR in PVC patients who have had an inadequate response to or are intolerant to first-line treatment with ursodiociclic acid. Today, Dennis will provide updates on our progress and plans for the CeladalPAR development program to complete response and announce top-line data in the third quarter of 2023. In September, we shared with investors our view of transforming the future for expectations of treating patients with PBC. Dr. Chris Cowdley, a prominent hepatologist, discussed unmet needs in the management of PBC. Our team then described Celadelpar's clinical profile and its potential to provide a preferred option in second-line treatment including in key segments of the PBC patient population that are either undertreated or not treated at all. Louis will provide a summary of his team's pre-commercial work that we shared during this event in September. Last week, we had the opportunity to share additional analyses and results from our prior clinical studies of Celadalpar in PBC at the American Association of the Study of Liver Diseases annual liver meeting in Washington, D.C. This was the seventh liver meeting at which we've shared results for CeladalPAR. This important congress provided us vital feedback on our program and allowed us the opportunity to meet with patient advocacy groups and thought leaders. Dennis will return to share an overview of our presentations and activities held at this year's LIBOR meeting. To close out our call today, Dan will provide a short summary of quarterly financials.
spk18: Let me first turn the call over to our Chief Medical Officer, Dr. Dennis Kim. Thanks, Sujal.
spk13: Today, I'll provide an update on the progress we have made, as well as our plans going forward in our clinical development program for Cella-Belpar and PBC. As we discussed during our last call, we have fully enrolled our pivotal phase three PBC clinical study response with 193 patient volunteers. And once again, we would like to extend our gratitude to our patients and clinical trial partners in accomplishing this important milestone. The response study is progressing as planned and continues to receive clear signals to proceed without any changes from the data safety monitoring board meetings that have taken place since the start of the study. We continue to project being able to have top line data read out from the response study in Q3 of next year, and thereafter plan on submitting a high quality NDA to the FDA as quickly as possible. In the meanwhile, we are continuing to wrap up clinical pharmacology studies to fulfill the FDA's requirement for a complete NDA. We also continue to evaluate and follow patients and assure our restarted long-term safety study in which qualified patients who participated in one of our prior studies, such as Enhance, can roll over and receive open-label CellDelPAR daily. We continue to gain important clinical experience through this study and will amass valuable efficacy and safety data in a large number of PBC patients exposed to CellDelPAR for months and years. As of last month, we had more than 180 PBC patients in Assure actively taking daily celabalpar. Our duration of exposures include more than 150 patients for at least one year and more than 65 patients for two years. We believe that collecting this degree of long-term safety and efficacy follow-up is a significant differentiating feature of our program. It is intended to substantiate CellDelPAR's long-term efficacy for biochemical response and pruritus, in addition to creating a large safety data set. The CellDelPAR clinical program is expected to yield one of the most robust data sets for drug candidates in development for PBC. We plan to have top-line results from response in Q3 of next year, and then to compile and submit the NDA to the FDA as quickly as possible. I'll now hand the call over to our Chief Commercial Officer, Louis Stewart, to share highlights from our Investor Day held back in September.
spk08: Thank you, Dennis. During our recent PBC Analyst Day, I shared summary findings from our Saladale Park Global Market Assessment, mostly focused on our U.S.-based research, including recent insights on the PBC patient journey. Our findings reflect on the patient's emotions and active engagement. from the onset of symptoms through diagnosis, treatment, and disease progression. As you know, it is these insights from patients and their care partners that are foundational to the development of our Cilla del Par launch plans. We were so inspired by these patients, their positive attitude, optimism, and motivation to improve their current liver health, their desire to see improvements in their quality of life, as well as how they leaned into their support systems. This is a highly engaged patient population that constantly seeks new information and are active participants within the PBC community. We learned that it may take up to two years for PBC patients to obtain a formal diagnosis, with treatment initiated quickly, followed by continuous management and monitoring. of their overall liver health. We consistently heard patients share how debilitating their symptoms were despite being on treatment. Many patients expressed how itching and fatigue dominated their lives, yet it is often neglected or not adequately addressed by their healthcare provider. In addition to these research efforts, we recently held a patient advocacy forum at the liver meeting attended by leaders of PBC advocacy groups from around the globe. Their commentary and insights validated what we had learned in our market research. During this forum and other liver meeting sessions, patients described their itching as bugs crawling under their skin. Another verbatim heard was, it's relentless. It's like a life sentence of just being uncomfortable. And that scratching barely relieves their itch, sometimes leading to breaks in their skin and scarring. These advocates shared their own research on how physicians' perceptions of their pruritus are often underestimated versus patient reported severity. Most notable was the challenge to their providers to look beyond the numbers. referring to biochemical markers such as ALP and bilirubin, and focus on how their patients are feeling. Clearly, there is an unmet need for more effective disease management of PBC-related pruritus. As a reminder, approximately 60% of PBC patients experience pruritus, which has significant downstream effects on the patient's quality of life and ability to stay treatment compliant. As one PBC patient advocate put it, it's not just that I want to live longer, but I also want to live well. At the PBC Analyst Day, I also shared a summary of the patient segments where Celadopar could experience rapid adoption, which includes 14,000 to 16,000 patients who are either incomplete responders to UDCA or have discontinued second-line treatment of abetacolic acid. Celadelpar's benefit in addressing PVC-related pruritus significantly expands its clinical utility to another 18,000 to 20,000 patients. Moreover, Celadelpar's data set demonstrating normalization of key liver measures in both cirrhotic and non-cirrhotics could support its reach to an even broader patient population with unmet needs. Clearly, we have a unique opportunity to elevate the goals for PBC treatment, effectively addressing not only the patient's overall liver health, but equally important, the quality of their daily lives. At Sima Bay, we want to build a high-touch commercial model that is designed to support patients and their caregivers as they navigate the healthcare ecosystem. We believe our execution should focus on three pillars. medical education on Cellidelpar's unique product profile, optimizing patient access and services, and last but not least, active patient advocacy and engagement. These themes will be our guidepost for supporting PBC patients, providers, and other key stakeholders. I'll hand the call back to Dennis to discuss our recent activities and presentations at the liver meeting in D.C. last week. Dennis? Thank you, Luis.
spk13: As Sujal mentioned, last week we had the opportunity to make two presentations of new analysis of clinical results for celadalpar. The first was a poster presented by Dr. Chris Bolas, the chief of the Division of Gastroenterology and Hepatology at UC Davis, reporting on a post hoc pooled analysis of lipids from the celadalpar open label phase two and phase three enhanced studies in PVC. Dyslipidemia is a common feature in PBC, and so we are interested in understanding how lipids were affected by cell delpar treatment in PBC patients. Changes in lipids were analyzed for 373 patients with PBC receiving daily oral treatment with placebo, five milligram or 10 milligrams of cell delpar at one, three, and six months. At baseline, most patients had dyslipidemia, For example, the average total cholesterol levels was elevated at 238 milligrams per deciliter, with 77% of patients being above normal levels. Similarly, the average LDL cholesterol level was high at 138 milligrams per deciliter, with 54% of patients having levels above normal. At month six, the mean change in total cholesterol from baseline in the 23 placebo patients was minus 4 milligrams per deciliter compared to minus 20 milligrams per deciliter for the 70 patients taking Celadalpar 10 milligrams. The corresponding change in LDL cholesterol for a placebo patient was an increase of 0.5 milligrams per deciliter, whereas the Celadalpar 10 milligram patients' value decreased by 18 milligrams per deciliter. These changes were significant for Celadalpar 10 milligrams versus placebo. Interestingly, These effects were similar for patient groups on background lipid therapy to those without. We expect to continue to collect additional data on lipids in our ongoing studies to support understanding what these changes could mean for patients. A second clinical presentation was made by the SEMA Bay research team describing an analysis of the serum metabolome of 160 patients completing three months of treatment in the enhanced study. This analysis found broad dose-dependent changes in the unbiased survey of 1,474 metabolites. The percentage of measured metabolites with significant changes below the p-value of less than 0.05 levels were 6.6% on placebo, 21% on celadol part 5 milligrams, and 39% on celadol part 10 milligrams. Cell delpar was found to increase serum markers of mitochondrial and proxosomal fatty acid beta-oxidation, indicated by increase in carnitine and acyl carnitines and decreases in dicarboxylates and significant reductions reduced serum levels of inflammatory lipid mediators, including long-chain fatty acids, mono- and diacylglycerol, eicosanoids, ceramides, and sphingomyelins. Measured in our target PBC population, these results provide clinical evidence of cell BelPAR's impact on mitochondrial function as well as reductions in the serum of known inflammatory mediators. These insights have the potential to suggest future approaches to elucidate the underlying reasons for effects of cell BelPAR on cholestasis, liver injury, and inflammation. I'd like to now turn the call over to Dan Mendel, VP of Finance, for a review of our financials in the second quarter. Dan?
spk10: Thank you, Dennis. As others on the team have highlighted, during the third quarter, we directed our resources towards executing the patient treatment phase of the fully enrolled response study and continuing enrollment of the Assure Study. We also worked to close out and summarize the results of certain required clinical pharmacology studies and we continued to advance other required clinical and regulatory activities necessary to complete our late-stage development of Cellidelpar and PBC. Finally, we made progress in manufacturing development, as well as in medical affairs and commercial, where we continued to plan and prepare for a potential future launch of Cellidelpar and PBC. Turning to a brief review of our third quarter financial position and operating results, Our cash, cash equivalents, and investments totaled $153.4 million as of September 30, 2022. We believe this cash on hand is sufficient to fund our current operating plan through 2023. Our net loss for the quarters ended September 30, 2022 and 2021 was $24.5 million and $22.7 million, or 28 cents and 33 cents per share, respectively. That loss was higher in the quarter ended September 30th, 2022, compared to the corresponding period in 2021, largely due to an increase in interest expense accretion related to the Abingworth Development Financing Agreement. This increase was partially offset by a decline in research and development expenses, which moderated following the completion of the enrollment phase of the response trial in July 2022. Net loss for the nine months ended September 30th, 2022 and 2021 was $79.4 million and $63.5 million or 90 cents and 92 cents per share respectively. Net loss was higher in the nine months ended September 30th, 2022 compared to the corresponding period in 2021 largely due to an increase in interest expense and to a lesser extent an increase in research and development and other operating expenses associated with the ongoing late stage development of Cellidel PAR and PBC. Moving forward, we expect our operating expenses to increase in the future as we continue to execute on our clinical development, manufacturing, and commercial readiness plans for PBC.
spk18: Let me now hand the call back to Sujal. Thank you, Dan. It's been another exciting quarter for us here at SEMA Bay.
spk17: as our teams focus on the day-to-day execution of our clinical programs, manufacturing campaigns, and regulatory and commercial preparations. We have been fortunate to add experienced talent across functions and are well positioned for transformational catalysts expected over the next 12 months. In his expanded role as Chief Scientific Officer and now President of Research and Development, Dr. Chuck McWherter, will lead our development functions where his depth of experience and knowledge in PBC can be leveraged across the organization. I have tremendous confidence in our entire leadership team and in all those in the company whose daily contributions are vital to our success in delivering improved treatment alternatives for people with PBC. As we turn the calendar into 2023 in the coming weeks, We will be focused on a broad range of priorities centered around key objectives culminating in releasing top line data from response in the third quarter of 2023 and filing for regulatory submissions as quickly as possible thereafter. We look forward to providing you with updates at future meetings and calls. We're now happy to take questions. Operator?
spk03: Thank you. We will now begin the question and answer session. To join the question queue, you may press star, then 1 on your telephone keypad. You will hear a tone acknowledging your request. If you are using a speakerphone, please pick up your handset before pressing any keys. To withdraw your question, please press star, then 2. We will pause for a moment as callers join the queue. Our first question comes from Yasmin Ramini of Piper Sandler. Please go ahead.
spk04: Hi, thank you for taking my question. This is Lauren on Preyaz. Just a couple questions. The first one, where do you guys stand currently in terms of the patents for Cellidelpar and thoughts on lifecycle management? And then with that, what are the post-marketing requirements based on your FDA interactions? Thanks.
spk17: Yeah, sure. Thank you for that question. So, we actually have issued composition of matter patents on Cellidelpar. one that goes to 2025, and another on the lysine salt form, which is the only form in development that goes to 2026. Neither of those terms actually includes the potential for five-year patent term extension for time in development. There are also a broad range of method of use patents that cover Celadalpar in PBC as well as in other liver disorders. Specific to PBC, once again, those method of use patents go to 2035. Our plan, ultimately, is to continue to develop patents that protect, obviously, Celadelfar as we think about our path forward. You asked a little bit about lifecycle management, and that's certainly part of that process, and we'll speak more about that in the months and years ahead. As part of lifecycle management, we also believe there's some significant opportunities for us to continue, as Louis talked about, exploring Celadelfar for broader patient populations. Once again, we've done a fair bit of this work internally as well as with consultation from thought leaders and patient advocacy groups, really highlighting those unmet needs that continue to exist in underserved populations or patients that are not really treated with adequate treatments today. So, we think there are certainly some lifecycle management opportunities that we will continue to commit to. in order to ultimately achieve the objectives we have of putting Celadilpar in the hands of as many PBC patients that we believe may benefit. You know, some of this we've talked about in terms of those patients that could benefit from full normalization of biochemical markers of disease progression and inflammation, as well as relieving a greater array of the clinical symptoms that patients experience every day in order to improve quality of life. You know, in terms of the last part of your question around post-marketing, I think all here know that in the setting of PBC, we expect that the accelerated approval pathway is, in fact, in the best interest of patients and certainly will remain available to sell Adelphar as it has been for other agents in PBC. That would, of course, put us in a position of really committing to better understanding the long-term outcome benefit of a treatment like Stella Delpar? Should we be successful at gaining registration and being on the market?
spk04: Thank you for those answers. And just a follow-up from what you last said, what is the company doing in terms of commercial preparedness, hiring sales force, et cetera, getting those activities in order? Where do you guys stand right now?
spk18: Sure. Louis, do you want to take an overview on that strategy?
spk08: Absolutely. So, I think certainly our focus as we look to 2023 will be more focused on pre-commercial activities where we'll be getting our MSLs in the field to begin engaging KOLs. We'll also, of course, begin to think about our engagement with payers as part of that pre-commercial strategy. The Salesforce will come a bit later. We would typically time the Salesforce after we've, of course, filed the NDA. But I think our field exposure with KOLs will be an important priority in 2023.
spk18: Thanks so much for taking the questions.
spk02: Our next question comes from Steven Seedhouse of Raymond James.
spk03: Please go ahead.
spk12: Hey, great. Good afternoon. Thank you. lipid analysis data presented at ASLD and specifically, you know, even something as simple as statins, there could be contraindications with active liver disease. There, you know, could be liver function test elevations, transaminitis. And so I'm curious, in these patients with PBC that have dyslipidemia or elevated cholesterol, is there some hesitancy among hepatologists to sort of use just commonly prescribed dyslipidemia medicines? And is this you know, a place where celadop are, you could sort of carve out, you know, a niche that addresses some prevailing hesitancy. Thanks.
spk09: Yeah, Steve, this is Chuck McWhorter. I'll take that question. It's a good observation. There has been in the past quite a bit of hesitancy around using statins, particularly for muscle effects, but also for transaminase elevations. Over time, that hesitancy has abated somewhat. So, for example, in our studies with, you know, hundreds of patients have been screened, we find roughly 20 to 25% of patients are using statins, although they're often not controlled for their LDL cholesterol and total cholesterol levels. So, I'm not sure that I would view it as a replacement for statins, but maybe as an additional feature of the drug that should be considered. In our population, these are typically middle-aged patients. They have a number of risk factors, cardiovascular risk factors. About 30% of them are overweight or obese. Many of them are taking antihypertensive medicines. And as I mentioned, about 20 to 25% are on lipid-lowering therapy. So I think From our perspective, a drug that addresses disease activity for PBC, improves symptoms, but also may have a benefit on lipids for cardiovascular risk for patients for aging, that can only be a benefit. But as we mentioned in our remarks, we'll continue to collect this data in response and assure to build out the story.
spk12: Yeah, and apologies if I missed this, but in response, thanks for that, by the way, Chuck, but in response, do you have a sense of the proportion on these lipid-lowering medicines and proportion with these risk factors is basically similar to the pooled analysis you did in the completed studies?
spk09: Yeah, well, you know, the study's still blind and ongoing, so we haven't, you know, delved into those kind of baseline characteristics quite yet. I'd be surprised to find that there are any differences, you know, given that we've screened over 1,000 patients in our program today, in our PBC program. So we have a very significant PBC patient experience. But time will tell.
spk18: We'll report that out when we've done the analysis. Thanks so much.
spk02: Our next question comes from Kristin Kliska of Cantor Fitzgerald.
spk05: Please go ahead. Hi, good afternoon. Thanks for taking my questions and congrats to Chuck on your promotion. So, there were some presentations on real-world analyses from other therapies in PBC at the liver meeting. Wondering if you have any takeaways from these presentations that further underscore where a therapy like Stella-Delpar could best fit and whether this is from your own interpretation or based off some of the extensive feedback it sounds like you had with numerous engagers at the conference.
spk17: Yeah, thank you for that question, Kristen. You know, we follow very closely the announcement you referred to in some of the presentations and publications on outcome studies in PBC. Our own dialogue, in fact, with the FDA on post-marketing obligations really has included extensive discussion of external control studies. And these discussions we've had with regulators really have taken place over the last several years, in fact. And, you know, we have had input also from many leading experts recently around this topic. Based on this, we believe that we understand both the opportunities as well as the challenges of external control approaches, and ultimately we remain engaged on the topic. Nevertheless, we see that Celadalpar has breakthrough designations and the clinical profile thus far on markers of progression of disease and on pruritus, and if confirmed in response, we believe will fulfill many of the unmet needs for improved treatments for PBC across disease stages. So, as I mentioned before, we still believe the accelerated pathway is available for CIMA Bay. Specific to your question, though, around real-world data and real-world evidence, you know, we continue, in fact, to investigate and we will continue into the future to investigate real-world data from the use of solid LPAR. One of the things I think that gives us some advantage here is, as Chuck had mentioned, the extent of the overall patient population and experience both efficacy and safety database that we continue to collect and assure, which will grow as patients from response continue to roll into that study. Over time, that will give us our own really, I think, you know, closely evaluated data sets that we can continue to compare to real-world evidence and real-world data that exists, of course, as well. And so, I think it's really important given some of the challenges to long-term outcome studies in a setting like PBC for many patients or relatively slowly progressing disease. And so, our commitment remains to continue that work that others have treaded as well around exploring some of these extensive control datasets in comparison to potential real-world data we can collect for Celadelfar, again, through Assure and through our clinical experience.
spk18: Thank you.
spk02: Our next question comes from Patrick Dolezal of LifeSite Capital.
spk03: Please go ahead.
spk01: Hi. Thanks for taking the question. So, earlier this year, we saw a transaction for XQS rides to acetic acid. Can you just remind us of your plans in regard to commercialization ex-U.S.? Are there any unique perspectives towards marketing in the U.S. versus abroad, whether it be kind of a different treatment paradigm, patient access, et cetera?
spk17: Thanks. Yeah, great question, Patrick. I'll start it out, and perhaps Louis or others can provide any additional color that I may miss. You know, first of all, in terms of our strategy, I think as we continue to articulate, our goal is to get CeladalPAR in the hands of patients globally that we think can benefit. Certainly, the response clinical phase three registration study is one that is a global study. We believe, based on our dialogue, it's a study that would allow us to have an opportunity to register CeladalPAR in the U.S. as well as the U.K. and Europe. When we think about other geographies where additional clinical work would be required, for example, Japan and or China, those are settings in which our goal is to try to partner as soon as possible. So, some of that work, in fact, can continue in parallel with our ongoing clinical activities. As it pertains, I think, to geographies such as the UK and Europe, just as examples, again, given we believe our studies would allow us to register in those geographies. We certainly have the wherewithal to complete our development program in parallel to having discussions with third parties that we may determine might give us both the economics and the ability to really get Celadelfar into a broader set of patients more quickly and more efficiently. So I think I would simply tell you, Stephen, that we're open to that dialogue. It's continued for geographies, particularly outside the U.S. Our strategy fundamentally is to execute on a plan that allows us to launch CeladalPAR at least in the U.S. on our own, potentially other geographies, but at least in the U.S. alone. It is, of course, the majority of the overall commercial opportunity just based on various dynamics, including some of those that you alluded to. a dearth of opportunities and other treatment alternatives for patients and the treatment paradigm fundamentally, as well as other dynamics, of course, including pricing. There are some off-label treatments in PBC that are used and even in guidelines outside the U.S. Those do have some impact in terms of how other treatment alternatives could be used and how Celadelpar could be used. But I think even as we think about global settings outside the U.S., we're incredibly encouraged by the data sets we've generated to date. And if response data confirms the profile of Celadalpar that we've seen thus far, we think even in those geographies that include more off-label use, for example, of drugs like Vesifibrate, there's some very unique characteristics of Celadalpar's profile, both on efficacy, on biochemical markers of disease progression, and clinical symptom burden, as well as on overall safety. that still make it a potential compelling alternative in those various geographies. So, we're excited about those. We talked a bit about the ex-U.S. rights being purchased for betacolic acid. You know, Philadelphia now, as we've also talked about on these calls, remains the only fully unencumbered late-stage program in the setting of PBC today. And so, to the degree that we think there could be alternatives to bring in, you know, significant amounts of non-dilutive capital and also, again, importantly, partners with experienced boots on the ground that can accelerate that work outside the U.S., we continue to have that dialogue and are excited about those potential opportunities.
spk18: Super helpful. Thanks, Sujal. Thank you, Patrick.
spk03: Our next question comes from Ed Arce of HC Wainwright & Co. Please go ahead.
spk11: Hi. Hi, everyone. Thanks for taking my questions. And let me add my congrats to Chuck. A few questions for me. Firstly, just on timing, assuming positive data from response and given your breakthrough therapy designation, would you be applying for priority review? That's one. And two, on Assure, I just wanted to confirm The purpose of this study beyond meeting the minimum number of patients for the NDA safety database. And then thirdly, a quick question on the poster presentation last week on the lipid profile. It was mentioned that their treatment effects were similar whether or not patients were on Um, lipid lowering therapy and so I'm just wondering. Perhaps Chuck could explain how this fits with the known mechanism of people are Delta for cell. Thanks so much.
spk17: Yeah, absolutely. Thanks for the for the questions and I'll take through 1 and 2 and then and then ask Chuck to chime in on number 3. You know, given, as you mentioned, we have breakthrough therapy designation in the U.S. and prime access in Europe, certainly, again, as it pertains to the U.S., we will, in fact, seek to have priority review. So, just to answer to your first question. With respect to Assure, you know, there, of course, is the purpose that you described to ensure that we have an adequate safety database at the time of NDA filing and filings outside the U.S., in fact, as well. We certainly, as we've mentioned, believe that we will have, in fact, a significant number of patients for overall safety and even longer-term safety out to one and two years and beyond from Assure, as well as, obviously, leading in from our prior clinical experience. Perhaps, in fact, the most robust safety dataset at the time of regulatory filing, there are many other benefits, obviously, from Assure. We continue to collect, you know, in addition to safety data, efficacy data that we will have the opportunity to continue to mine as we think about, you know, patient populations and use as we think more about, you know, the potential to address things like longer-term effects on liver stiffness, you know, the various parameters that may give us greater insights into the potential longer-term benefit and even potential outcome benefit. I talked a little bit about, you know, the potential for Assure also to give us just extensive real-world data post-potential approval and marketing if we're successful. And that, I think, is another, you know, key benefit from the Assure study overall, just a very rich experience in what is obviously a rare disease. So, I think there are, in fact, many benefits even beyond just having a minimum number of patients for safety. And then finally, I'll let Chuck talk a little bit more about his views around the significance of the lipid data in patients that either had been on prior statin or lipid-lowering treatments versus those that did not.
spk09: Yeah, thank you for the question, Ed, and thank you for your comments. So the mechanisms are really quite distinct. As you know, statins inhibit the synthesis of cholesterol through inhibition of HMG-CoA reductase. We had previously studied Celadalpar in hyperlipidemia. Just draw your attention, there's two papers. One was published in the Journal of Clinical Endocrinology and Metabolism. in 2011 and another in atherosclerosis in 2012, where the mechanism was shown to be quite distinct from a statin. It really inhibits the synthesis and production of lipoprotein particles, LDL, so ApoB100 was inhibited. Secretion of VLDL, which is the precursor of LDL, was also inhibited. That was shown in those studies. And in particular, in addition, in patients with PBC, we showed that cholesterol itself, its dietary absorption, was it inhibited by Celadalpar, as well as cholesterol synthesis in a mechanism that's different and doesn't involve HMG-CoA reductase. So I think it's a unique and complementary mechanism for Celadalpar as reflected in in clinical studies in two different populations. And that probably explains some of the observations that we had where we saw decreases both with and without background lipid therapy.
spk11: Great. That's helpful. And one follow-up, if I may. Just wondering about the manufacturing and supply chain function the activities that you mentioned continue to progress. Wondering if there's anything there that could pose a potential gating factor to the NDA submission.
spk17: Thanks. Yeah, thanks for highlighting that. You know, we pay particular attention to ensuring quality in the work that we do with respect to manufacturing and a real focus on ultimate supply chain. We've done some of the validation work on drug substance. That work will continue on drug products. We don't see anything as of now, frankly, in terms of anything that would be gating for the timelines that we expect should we be successful in response and successful in being able to register quickly thereafter.
spk18: Thanks so much. Thank you.
spk02: Our next question comes from Mayak Mamdani of B. Riley.
spk03: Please go ahead.
spk14: Good afternoon. Thanks for taking our questions, and let me add my congrats to Chuck for an expanded role. So just a few follow-ups for me. Could you talk to the percentage of response patients where you've taken biopsy, and would you look to disclose baseline characteristics, info, prior to the third quarter data disclosure at some point next year? Should we be expecting that?
spk17: Yeah, so I'll start off. We've not disclosed any specifics around the baseline characteristics, including the percentage of those that have agreed to and volunteered to have baseline biopsies. We certainly feel confident that we have a subset of patients that have agreed to baseline biopsy that we, again, hope to have a 52-week biopsy around in order for us to gain additional insights and meet the regulators' requirements. So, we don't see that fundamentally today as any sort of risk based on those that agreed in baseline. We've not traditionally, Mayank, disclosed overall baseline characteristics until we release top-line data. that would be our plan here as well. I think in order for investors and others to gain some confidence, given how much clinical experience we have in PBC, both in our Phase 2 as well as our Phase 3 clinical programs, as Chuck had mentioned, we've had over 1,000 patients screened in our clinical trials to date. I think if you go back to the baseline in the populations in Phase 2 and Phase 3, what we're enrolling in response, is largely an identical patient population to what we enrolled in enhanced based on inclusion and exclusion criteria. And so I think there should be some comfort around those characteristics looking similar to what we had before. And then we will release those details at the time we share top line data.
spk14: Got it. Thank you. And could you also talk to the status of the hepatic impairment study and also, you know, assure liver safety or outcomes, you know, whatever info you're able to green there, would you be able to compare that against, you know, just external historical controls as, you know, some of those are not very unique to a particular company. I mean, you're able to also do some of those analysis around the external historical control. So I'm just curious if your long-term studies can do similar kind of analysis, real-world evidence-based analysis.
spk17: Yeah, sure. Good question. So we continue to execute on the hepatic impairment study in PBC patients. I think, as you know, you know, study that's important for us to understand, you know, the exposure as well as safety and even efficacy in patients that are cirrhotic, you know, both compensated cirrhotics as well as those with some decompensation. A very difficult study to enroll given how few patients among the broader PBC populations are in those categories. but something that we continue to be committed to in order to ensure that we've got a good sense of CELADELPAR's, again, efficacy as well as, in particular, safety and exposure in that patient population. That work continues, and we don't see it, again, as being gaining to our other activities as we think about our overall timeline. With respect to Assure, absolutely. You know, look, I think one of the benefits I described earlier in the Q&A session around collecting a broad set of longitudinal data in that study for, as we mentioned, now north of 180 patients that are in Assure. It just gives us that opportunity to compare to some of the external controls. We've, in fact, worked very closely with groups that have collected these datasets, that continue to collect these datasets. I think it's one of those alternatives, you know, among other alternatives with respect to regulatory options that we believe could be available to us. We have to be committed to regulatory requirements to demonstrate outcomes based on outcome studies, but certainly in parallel to that, having the opportunity to understand the data sets out of the shore and how they compare to external controls will also be important for us to generate in parallel. And I think, again, it gives us an advantage given how many patients are in Assure today and how many we continue to expect to come into that study.
spk14: Got it. Thank you, Sujal. And then on the Phase 3 PBC study that's running slightly ahead of you, are you looking to glean any healthy information from there, assuming study designs are identical And it would be helpful if you can confirm that, in fact, that, you know, two study designs are actually identical between the two programs.
spk17: Yeah, sure. And just to be clear, you're referring to the Phase III study for Elefibrenor. You know, a couple things I'll first mention about response. You know, response is really, as we describe it, a study that we designed based on our experience in Enhance, our prior phase three, what had intended to be prior phase three global registration study. What we learned from our prior phase two experience in Enhance really was the driver around the design for response. In many cases, I describe it as a rinse and repeat, if you will, of the Enhance study. So what we've done in response is design a study with the, you know, really the same patient population we studied and enhanced the same optimal 10 milligram dose of Celadalpar, as well as the same primary and two key secondary endpoints that we evaluated in enhanced. So, you know, to the degree that the phase three study for Elifibinor is, you know, similar to response, I think it's similar to even what we had done in enhanced when you look at, you know, the overall endpoints and, you know, the patient population. that we're studying. Of course, we, in our experience, also leveraged the work that had been done with abetacolic acid in their Phase III poise study that's published. So, I think if you look across these various studies, the Phase III poise abetacolic acid study, both our enhanced antiresponse study as well as the Phase III for elefibrinor, you're going to see largely many similarities, if you will, when you think about those study designs. And, you know, I think, you know, certainly we always learn from new data sets that are released. And as you pointed out, at least based on what those sponsors have indicated for those studies, that data may come, you know, shortly before our expected Phase III top-line data. So we'll, of course, learn things, but obviously response is really set forth based on the experience we've had to date in PBC, including in our prior enhanced study.
spk18: Got it. Thanks for taking our questions. Yeah, thank you.
spk02: Our next question comes from Jay Olson of Oppenheimer.
spk03: Please go ahead.
spk07: Oh, hey, congrats on the progress, and thank you for taking the questions. Can you share any physician feedback on the posters presented at AASLD, especially with regards to how lipid benefits could differentiate Celadilpar from OCA in patients with PBC, and I had my follow-up, if I could.
spk17: Yeah, sure. Maybe I'll ask Dennis. Do you want to share, you know, some of what you learned from many of the thought leader discussions we had? And then, certainly, I can add some additional color.
spk13: Sure. Yeah, I think, you know, as Chuck mentioned before, the lipid-lowering effect of CELDAPAR is yet another differentiating feature of the drug. And because many patients with PBC have this dyslipidemia when they're diagnosed, you know, there's, as already has been discussed, there's consternation about whether to treat and if to treat with what medication since there are liver toxicity effects that one has to keep in mind. So in a position of a hepatologist who's now looking at a newly diagnosed patient or a patient who's being referred to that hepatologist who may already be on UDCA and have dyslipidemia, we think it's an easy choice for Celadalpar to be the next line of therapy, not only because of the efficacy that we've demonstrated with Celadalpar, but also the plethora of benefits that you can gain from that choice as a second therapy, not only with respect to pruritus, but also with improvement of dyslipidemia, as opposed to perhaps another second-line therapy that we already know can worsen pruritus as well as cholesterol levels. So the contrast is fairly striking, and I think it's an easy one to detect. And that's what the physicians are telling us.
spk07: Great. That's super helpful. Thank you for that. And just to follow up on earlier question about the real-world evidence for OCA treatment of PBC patients that was presented at ASLD showing reduction in relative risk of death, liver transplant, and hepatic decompensation, which I think Intercept said would be submitted to support full FDA approval of OCA for PBC. Do you expect that outcomes data to impact your strategy to pursue full approval of Celadalpar for PBC?
spk17: Yeah, Jay, you know, here's, I'll start off and say this. I think certainly as we see intercept strategy and particularly regulators respond, to their strategy. I think there certainly could be an impact that we'll pay very close attention to. We think, in fact, that the impact could be favorable depending on how they choose to determine that acolic acid's effects in those real-world evidence studies that have been conducted. At least to date, we would also say this, however, that we fundamentally believe that committing to demonstrating outcomes is very important for the population of PBC patients, as well as obviously for regulators who are acting on behalf of patients. And at least to date, conducting and collecting real-world data and real-world evidence in parallel to that, we think is likely to be the path forward. There are certainly We know opportunities and benefits from collecting this real-world evidence, but there are, of course, some challenges as they relate to things like biases, missing data sets, I think missing follow-ups. I think there's some challenges that continue to be worked out. But we know that regulators recognize in rare disease settings that these are things that must be evaluated, and we certainly are committing ourselves to evaluating both of these paths ultimately in parallel. You know, we're not all that surprised that some of the data that came out of the work with the beta-cholic acid on real-world data and real-world evidence. I think it certainly parallels and or confirms, if you will, some of the datasets that have been generated, for example, by the Global PBC Study Group that originally, you know, looked at alkaline phosphatase reductions and bilirubin normalizations as surrogate endpoints. for what might lead to improved outcomes. And so, again, I think there's a lot of strong rationale around our opportunity to continue following both of these potential paths.
spk18: That's helpful. Thanks for taking the questions and congrats to Chuck.
spk02: Our next question comes from Tom Smith of SVB Securities.
spk03: Please go ahead.
spk16: Hi, everyone. This is Mike on for Tom. Thanks for taking our question. And again, you know, big congrats to Chuck. There's been some recent commentary from competitors highlighting the importance of changes in bilirubin as the most predictive element leading to longer-term improved outcomes for PBC patients relative to something like ALKFOS. And just curious if you tend to think of one being more important than the other between bilirubin and ALKFOS.
spk18: just as they relate to longer-term outcomes in PBC? Yeah, maybe I can try to answer that for you.
spk09: So it really depends upon disease stage. So if you look at both alkaline phosphatase and bilirubin and their predictions for outcomes, In early stage disease, alkaline phosphatase shows up as a cholestatic marker that projects the most comprehensive difference in risk profile. Bilirubin itself, it's true, becomes an important predictor, but it shows up generally when patients become ductopenic, that is, they've lost their bile ducts. And then in the later stage disease, you get a very sharp rise increases in bilirubin. So in that sense, I think you could say both are correct. Both have some role in predicting risk in different time courses or different aspects of the natural history. There is another feature of bilirubin that's emerged as a very interesting aspect of predictor, and that is patients who have bilirubins, which are in the normal range, but in the upper range, end of the normal range, that is between 0.6 and 1 times upper limit of normal, those patients are still at elevated risk for progression. And it's believed that if you can bring patients down into the lower echelon, say below 0.6, with a normal ALK-FOS, that you can essentially stop progression of disease altogether. And so that's another aspect that we continue to monitor. Celadalpar now, as others, are looking at patients in that strata of still higher risk between 0.6 and one times upper limit of a normal to see if we can decrease that. And in fact, in our two-year data that we presented at the liver meeting in 2021, We showed that about half of the patients who had bilirubins at baseline between 0.6 and one times upper limit and normal were put into the lower strata by two years. So we think that's a different twist to maybe the question you were asking.
spk18: Got it. I really appreciate the color. Thanks for taking our question.
spk03: Our next question comes from Sean Kim of Jones Trading. Please go ahead.
spk06: Yeah, hi. Thank you for taking my questions. First, a quick question. What's the statistical powering for the response trial? And my second question is, based on the biology of cell delpar, would you expect the response to deepen between month 6 and month 12, or would it less stabilize during that time period? Thank you.
spk17: Yeah, Sean, thank you for those questions. I think when you look at overall powering, particularly I would guide folks towards the enhanced three-month data set that's available on our website, both in terms of presentations at medical meetings as well as in our corporate deck. And you can see there with as few as 55 patients, around 55 patients in placebo and around the same in the 10 milligram dose group, We hit the primary composite response rate at three months with a p-value of less than 0.0001. So, I think when you look at 193 patients enrolled in response to the one cell at LPR 10 milligrams versus receivo, we are highly, highly overpowered on the primary outcome measure. The target, which had been 180 patients, was really on powering with at least 80% power on itch. But both the primary and then the key secondary on alkaline phosphatase normalization are well over 90% powered just based on the total number of patients that we've brought into the study and the expected treatment effects. In terms of what we would expect between month six and month 12, you know, here I would guide you towards looking at the percent reductions in alkaline phosphatase in our phase two experience north of 100 patients out to a year and north of 50 patients out to two years of treatment. Between month six and month 12, you know, you really see a very consistent and leveling percent reduction in alkaline phosphatase. And so we would expect that to really be somewhat consistent between month six and month twelve. There may be some increase. I think typically you see relatively small increases over time. I think what was particularly interesting in some of that data is we continue to see an increase between year one and year two for those patients that had been on treatment out to two years. So, encouraged by those data sets that we have, again, for patients out to both six months as well as 12 months and even out to two years.
spk18: Great. Thank you. Thank you.
spk03: This concludes the question and answer session. I would like to turn the conference back over to Shu Zhao for any closing remarks.
spk17: Thank you, Operator, and thank you all once again for joining us today. A highlight of our time at ASLD last week in DC included a meeting we had with patient advocacy groups supporting people with PBC from around the world. Having the opportunity to speak to them and importantly to learn from them has always been a vital part of our process here at SEMA Bay. It was exciting for us to provide them with many of the updates we have shared with you all today. and to continue partnering with them to make sure we are focused over the coming year on executing with patience in mind. We're a company with a singular focus, but with many upcoming transformational catalysts ahead that we are excited to share with you throughout the coming year.
spk18: Thank you.
spk02: This concludes today's conference call.
spk03: You may disconnect your lines. Thank you for participating and have a pleasant day.
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