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spk03: Good day, ladies and gentlemen, and welcome to the CIMA-based third quarter 2023 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 CIMA-based website at www.simabay.com. Now, I would like to turn the call over to Mr. Paul Quinlan, General Counsel at Simabay. Mr. Quinlan, please proceed.
spk16: 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 2023 financial results and business updates. You can access that release on our website under the Investors tab. Joining me on the call today are Sujil Shah, Chief Executive Officer, Chuck McWhorter, Chief Scientific Officer and President of R&D, Louis Stewart, Chief Commercial Officer, and Harish Shantaram, Chief Financial Officer. 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 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 timelines 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 a forward-looking statement are based on reasonable assumptions, actual outcomes and results are subject to risks and uncertainty and could differ materially from those forecast 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 statements 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. At this time, I'd like to turn the call over to Sujal.
spk15: Thank you, Paul, and good afternoon. We appreciate everyone taking the time to listen to our updates at SEMA Bay in the midst of a busy earnings period. 2023 has been a remarkable year for SEMA Bay, And the third quarter was especially momentous with the achievement of multiple significant milestones advancing us towards our goal of improving the lives of people living with PBC. First, Celadalpar met its primary and two key secondary endpoints with high statistical significance in the phase three pivotal response trial for patients with PBC. The consistency and depth of the clinical data set generated from phase two, enhance, and now response, demonstrates that Celadalpar has the potential to be the first ever approved treatment for patients with PBC to significantly reduce both markers related to the risk of disease progression and symptoms. Reaching this milestone required focus, resilience, and perseverance by our team here at SEMA Bay, but it would not have been possible without the commitment of our partners, including the patients who participated in all our clinical trials, their family members and caregivers, investigators and patient advocacy groups who were part of this journey. The reactions from all quarters on the response results have been very positive. and Louis will provide color on some of the feedback we've received from the medical community and patient advocacy groups later in his remarks. Our team is now working with singular focus to deliver high quality regulatory applications for approval as soon as possible and are actively engaged with FDA, MHRA, and EMA. We were very encouraged by the FDA's granting of a revised breakthrough therapy designation for Celadalpar in PBC that now covers the treatment of PBC, including puritis, in patients who are inadequate responders or intolerant to UDCA without cirrhosis or with compensated cirrhosis. The unmet needs for people living with PBC today are for treatments that provide a significantly lower risk of disease progression while also reducing symptoms, across a broad spectrum of patients, including those with compensated cirrhosis. We believe that Celadelpar is the only drug in development for PBC that has received a breakthrough designation that includes puritis and compensated cirrhosis. We look forward to working with the FDA and other regulatory agencies as they conduct their regulatory review post-completion of our submissions. Our commitment to PBC runs deep, and we will continue to add to what we believe is already the largest clinical development program in PBC. The ideal study that we announced earlier in the third quarter targets partial responders to first-line treatment with alkaline phosphatase levels between 1 and 1.67 times the upper limit of normal who continue to have higher risk of disease progression and negative outcomes. We believe that this study has the potential to be transformational for this neglected population, potentially resetting expectations for second-line treatment. In September, we also announced the initiation and design of our long-term outcome study, affirm, that will serve as our post-marketing regulatory commitment. Leveraging years of dialogue with regulators, and work interrogating rich data sets gathered by the global PBC study group, we designed a unique, event-driven, fixed-duration study evaluating CeladalPAR in patients with compensated cirrhosis, assessing its benefits on outcomes relative to placebo. The design of AFIRM attempts to also address the challenges inherent in recruiting placebo-controlled outcome trials in PBC. These studies demonstrate our unwavering commitment to advancing care for people living with PBC. We are too early in startup for us to comment on the timelines for enrollment and results, but Chuck will provide more detail on these studies during today's call. We now have a majority of our U.S. medical field team in place, and they are actively engaging with the community on disease education and Cell at Alpar clinical data. and have initiated additional collaborations with the scientific community to fully understand the potential of Cell at El Par. We have also made significant progress this year with pre-commercial planning efforts and will be accelerating these activities with positive phase three pivotal results now behind us. We are currently determining the size and structure of our commercial field team to optimize its reach for effective coverage of healthcare providers. while also enabling patient activation in preparation for a potential CeladalPAR launch. On the manufacturing and distribution front, we have now established our commercial supply chain and will soon finalize our distribution channel partners in the US. In summary, I'm extremely proud of our achievements to date. With a quality team we have put in place and a strong balance sheet, we are ready to execute on our key near-term deliverables and continue to march towards our goal of helping people with PBC live potentially longer and better lives. With that, I will turn the call over to Chuck.
spk07: Thank you, Sujal. Drug development journey, as we all know, is a marathon littered with many hurdles, but there is no better feeling than entering that final mile with the finish line in sight to deliver on the promise to improve patient care. That's the feeling we had with the positive phase three results from the response study and the evidence it provided on the potential of Celadalpar to benefit patients. By acroceutical sentiments, we are now energized more than ever and our team is dedicated to submitting a high quality application for regulatory review as soon as possible. This quarter has seen many significant achievements on the clinical development and regulatory fronts. Two weeks ago, we announced the FDA granted a revised breakthrough therapy designation for celadalpar. The revised designation specifies celadalpar as a potential breakthrough therapy for the treatment of primary biliary cholangitis, including pruritus in patients without cirrhosis or with compensated cirrhosis child 2A who are inadequate responders to or intolerant to UDCA. The breakthrough designation is for serious, and life-threatening diseases for which the FDA recognizes there is a high unmet need. We're extremely gratified with this revision as it emphasizes the significant unmet need for patients dealing with the impact of pruritus in their day-to-day functioning and underscores the unfulfilled needs of patients across a range of disease severity to include those with compensated cirrhosis. Among the benefits of a breakthrough therapy designation is the opportunity to submit the MDA on a rolling basis and to request a priority review, both of which we intend to do. Our team is moving as quickly as we can to complete and submit a high-quality regulatory application to FDA, MHRA, and EMA for the review. We look forward to working closely with these agencies during the review process to potentially bring CELIDL-PAR to patients with PDC as quickly as possible. Let me now provide highlights of results from our pivotal phase three study response and remind you that additional details will be shared at an oral late-breaking presentation at the liver meeting in Boston next Monday, November 13th. We will present both the time course of the effect seen across multiple endpoints, important supporting results, and additional safety reporting. To remind you, Celadolpar met all the key pre-specified trial endpoints in response. with high statistical significance. The primary composite endpoint, ALP normalization and ALP reductions from baseline on 12, were all meaningful and highly significant. 62% of patients on solid LPAR achieved the primary composite endpoint, and 25% of patients receiving solid LPAR had normal levels of alkaline phosphatase after 12 months of treatment. In patients with clinically significant baseline itch, Celadalpar had meaningful and highly significant reduction in patient-reported pruritus intensity measured with an electronic diary, the mean reduction of 3.2 points using the pruritus numerical rating scale. Overall, safety was comparable between placebo and Celadalpar groups and was consistent with previous studies. Treatment emergent adverse events, serious adverse events, and patient discontinuations were generally balanced across the treatment of placebo arms. There were no treatment-related serious adverse events in the study. The response study also included voluntary paired liver biopsy for a subset of enrolled patients. An expert panel of pathologists with significant experience in cholestatic liver disease, including PBC, have completed a blinded review for these subjects. While we are continuing to analyze these data for intended regulatory submissions and publication, we can now report that the panel concluded there were no findings requiring safety adjudication in any of the biopsies collected. We look forward to sharing more data from response during our oral late-breaking presentation to be delivered by Dr. Gideon Hirschfield, a world-renowned cholestatic disease expert at the Liver Meeting in Boston next Monday. There's more depth from the Solid L-PAR program to share beyond response. Last week, we announced the publication in Alimentary Pharmacology and Therapeutics of the results from our first long-term safety study with two-year open-label follow-up. Treatment of more than 50 patients for two years showed strong improvements in ALP and ALT, with more than 40% of patients normalizing ALP. You should expect more to come as our second long-term safety study, Assure, currently has more than 300 patients taking daily Celadilpar 10 milligrams. We expect Assure to contribute a rich source of important information in the years to come on the long-term impact of Celadilpar treatment on disease and symptoms. Now, turning to the ideal program that we initiated in August, We were making good progress with site activation and initial screening of patients. As a reminder, IDEAL is a phase three randomized placebo-controlled study of patients with a diagnosis of PBC taking a stable dose of UDCA, unless intolerant, with ALP levels between one and 1.67 times the upper limit of normal. In effect, this study targets patients who are partial responders to treatment after being treated with first line and are not currently receiving additional treatment from which they may benefit. These patients would typically be managed by treatment for UDCA in a wait to fail paradigm in spite of the evidence for the risk of progression. We believe IDEAL has the potential to lead the way to gather critical evidence for this overlooked but sizable part of the PBC population. Let me close out the update on the Cell at LPAR program today with AFFIRM, a randomized placebo-controlled confirmatory study to evaluate the effect of Cell at LPAR on clinical outcomes in patients with compensated cirrhosis due to primary biliary cholangitis. The AFFIRM study was initiated to characterize the efficacy and safety of Cell at LPAR in a PBC population with advanced disease. It is designed to fulfill post-marketing requirements for Celadopar to confirm its benefit on clinical outcomes. The affirmed study is planned to enroll approximately 192 patients who have compensated cirrhosis, Child QA or Child QB, based on pre-specified clinical criteria. Patients will be randomized using a two-to-one ratio to oral, once-daily Celadopar or placebo, for a fixed duration of three years. Primary outcome measure is the time from start of treatment to the first occurrence of predefined clinical events, including all-cause death, liver transplant, hospitalization for other serious liver-related events, and progression to child PC decompensated cirrhosis. Additional key outcomes include overall survival, liver transplant-free survival, and time for serious liver-related events. Over the past few years, we had had significant interactions with regulators to develop a study in the backdrop of many known operational and ethical challenges in conducting a placebo-controlled long-term outcome study. Our efficacy and safety data among cirrhotic patients in solid LPAR across Phase II and Phase III enhanced studies that enable us to select this population and design it to establish the effect of cellular power and outcomes within a reasonable timeframe. We remain fully committed to meeting our scientific and regulatory commitments while prioritizing the health of people living with BDC. Now, let me shift gears and provide an update on MBX 2982. The phase two way proof of pharmacology study to assess whether MBX 2982 can enhance glucagon secretion during insulin-induced hypoglycemia in subjects with type 1 diabetes has been completed. This was a placebo-controlled, double-blind, two-period crossover study. Subjects with type 1 diabetes were randomly assigned in period 1 to treatment with daily blinded placebo or MBX2982 for 14 days, followed by 14 days of washout before starting period 2. which consisted of 14 days of daily dosing with the opposite treatment of either MBX2982 or placebo. Each of these two periods ended with hyperinsulinemic hypoglycemic clamps, which were conducted on day 14 and 42. The primary objective was to compare relative to placebo treatment the effect of MBX2982 on glucagon counter-regulatory responses to insulin-induced hypoglycemia in subjects with type 1 diabetes. The study found that there was no change in glucagon secretion during clamps in subjects with type 1 diabetes dose with NDX2092 versus placebo. In contrast, healthy volunteers studied on a single occasion for comparative purposes showed a glucose-dependent increase in their glucagon release during hypoglycemia. Target engagement by MDX2982 was demonstrated by increases in GLP-1 levels in subjects with type 1 diabetes. While disappointing, the results demonstrate a well-designed and executed study that demonstrated pharmacodynamic action of MDX2982, but without demonstrating the pharmacology needed to benefit the type 1 diabetes population. The scientific questions were answered. and CIMA Bay is not planning any further studies with MBX 2982. We would like to thank Dr. Richard Pratley and his team at Advent Health Research Institute in Orlando, Florida, as well as ProSiento, Inc., California, for conducting a well-designed and executed study, and Leona M. and Harry B. Helmsley Charitable Trust for their support of the study through a grant to Advent Health. We are also grateful to the patients with type 1 diabetes and healthy volunteers for their participation in the study. Before I turn the call to Louis, I think it is an opportune moment to mention the deployment of our field medical team and their early impact on KOL engagement, data dissemination, and expanded participation in the regional PBC-related medical conferences. We have gathered a stellar medical affairs team, expertise in PBC and other rare diseases, who will be the core interface facilitating scientific exchange and addressing questions regarding the further understanding of our data. This team will also play a key role in raising awareness of PBC and the key unmet needs that remain for patients today as we interact with the medical community and patient advocates at the liver meeting in Boston next week, and where we look forward Casino Day and Solid Up are being featured prominently. With that, I'll hand the call over to Louis.
spk05: Thank you, Chuck. Throughout the quarter and leading up to response top-line results, we have been focused on the expansion of our commercial leadership team. We recently added senior commercial leaders in marketing, commercial operations, and market access, all while realizing progress on commercial infrastructure projects that are in alignment with our launch readiness schedule. Our leadership team comes to CIMA Bay with an average of over 20 years' experience, beginning in large pharma, with more recent successes in emerging biopharma, where they each played an essential role in building the commercial capabilities for lead product launches. The arrival of our commercial leaders has been followed by the hiring of key commercial staff positions, including the deployment of our field-based market access team. We're excited to begin scheduling introductory meetings with payers in parallel with the build-out of our specialty pharmacy network and other key patient support deliverables. In addition, our medical affairs team will play an essential role supporting market access in educating payers on the emerging PBC landscape and new goals for treatment. Our commercial operations team has initiated the work of standing up data and analytics platforms to support sales planning, such as Salesforce size and structure, as well as the integration of market intelligence, performance monitoring, and other essential launch readiness components. We are very encouraged by the early impressions from both key opinion leaders and patient advocates, both of whom expressed confidence, and positivity regarding the response data set and its potential impact on Cella-Delpar's target product profile. Many thought leaders expressed excitement over Cella-Delpar offering both biochemical improvements and symptomatic relief. The rate of ALP normalization was particularly highlighted as a key differentiator alongside the statistically significant pruritus reduction. Patient advocates also welcomed the benefit on itch as a key milestone for those living with PBC, given the inability of approved PBC treatments to improve symptoms that they believe play a key role in their quality of life. Given the unique properties of the Delpar class, Celadelpar has consistently demonstrated broad clinical utility across the spectrum of PBC and may prove to be the first and only treatment that both normalizes liver biochemistries and reduces the symptom burden of pruritus. This would be a major advance for patients and their caregivers and lead to a profile that has the potential to position Celadelpar as the second-line agent of choice for PBC. Overall, we are pleased with the progress we've made so far in our pre-commercial planning efforts, which has only accelerated since the reporting of positive top-line pivotal response study results. With that, I will hand it over to Harish.
spk17: Thank you, Louis, and good afternoon, everyone.
spk02: As stated earlier, the third quarter was a very successful one for SEMA Bay and Celadon Park as we achieved significant milestones by delivering strong top-line results from our phase two response trial, initiating two new clinical trials, Ideal and Affirm, and executing an upsized capital raise to strengthen our balance sheet. Operationally, all activities related to NDA preparation, as well as pre-commercial planning, continued to move forward at a brisk pace. In terms of financials, we finished the quarter with a strong balance sheet with cash, cash equivalents, and investments totaling $438.8 million as of September 30, 2023, aided by our upsized public equity offering in September. The net proceeds from the offering were $242.8 million after deducting the underwriting discount and other offering expenses. Following the cash inflow from this offering, we believe that cash investments on hand are sufficient to fund SEMA-based operating expenses into the first half of 2026. Research and development expense for the quarters ended September 30, 2023 and 2022 was $20 million and $15.5 million, respectively. The increase was primarily driven by higher employee count and clinical activities related to initiation of our ideal and affirmed studies. As we continue to progress in the late stage development of Salad Alpar in PBC, we expect our overall research and development expenses to increase in the future. Turning briefly now to a review of general and administrative expenses, these costs for the quarters ended September 30, 2023 and 2022, where $12.2 million and $5.9 million respectively. The increase in general and administrative expenses were primarily driven by commercial and medical affairs organization billed and related spend in preparation for potential commercialization of Celadal PAR in PBC. We expect these efforts to accelerate further in the fourth quarter as we ramp up further our pre-commercial planning efforts. Overall, our net loss for each of the quarters ended September 30, 2023 and 2022 was $33.9 million and $24.5 million, or 32 cents and 28 cents per share, respectively. Net loss for the quarter ended September 30, 2023 was higher than the corresponding period in 2022 due primarily to an increase in operating expenses. Overall, we expect operating expenses to increase in the future as we continue to execute our development and potential commercialization plan for Salad Alpar in PVC. With that, let me hand the call back to Suchil.
spk15: Thank you, Harish. Let me close out this portion of the call by relaying some of the enthusiasm of both the team here in the room and colleagues throughout SEMA Bay. We are eager to continue the positive momentum and are working diligently on our near-term milestones for sell at LPAR and our primary goal of improving the lives of people with PBC. We are happy to now take questions.
spk03: Operator? Thank you. We'll now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your lines in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question comes from Yasmin Rahimi with Piper Sandler. Please go ahead.
spk17: Hi, team. This is Jingu speaking for Yaz. Thanks for taking our questions. We have two. First, how soon could you get your NDA submitted? And could you provide any thoughts on receiving priority review versus standard review?
spk15: Yeah, happy to take that question. So, you know, I think as we mentioned, this is of course our key and sole focus inside the company with phase three response pivotal data now behind us. It wouldn't be unreasonable as an expectation to assume four to six months roughly to file for regulatory submission. So certainly by the early part of next year, gives you some indication of what might be a standard timeline. Our focus, of course, is to drive as quickly as we can towards filing. And so internally, processes, resources are all geared towards now concluding with our pre-submission meetings with regulators and then getting the filing, a quality filing at that submitted as quickly as possible. Obviously, the breakthrough therapy designation in particular, the revised breakthrough therapy designation now really reflecting some of the added benefits we believe we've seen with the data in hand to date, not just in the ability to treat in a second-line setting for patients that are inadequate responders to UDCA or intolerant, but also being able to deliver improvements, reductions in puritis, and seeing these affect in a broader patient population, both non-serotics as well as compensated serotics. This revised breakthrough therapy designation provides you know, affords us the opportunity to seek an indication, a label that really fully reflects the differentiation of Celadalpar relative to existing treatments and potentially other treatments in development. So as Chuck mentioned, we will of course look to have a rolling NDA submission as well as request priority review. That of course is still up to the agency. But again, the revised Breakthrough Therapy designation encourages us around these paths forward.
spk17: Thank you so much. And then for our second question, what are some key data points you hope to share at the LIVER meeting to establish SolvDelapar's best-in-class second line product profile?
spk15: Yeah, perhaps I'll ask Chuck to give you some overview of, you know, additional information that we think could be helpful as we look towards the end of this week and the presentation Monday.
spk07: Yeah, well, thank you for that question. I think we're quite excited to be able to, you know, finally unveil and share with the delegates to the committee to the meeting what we found so far. Of course, we've already described the demographics of the baseline population quite balanced, really a very good and well-conducted study in our view. We will be sharing, of course, our primary and key secondary endpoints. So that's the composite response previously used to register Ocaliva as well as the normalization. And then, of course, in patients with clinically significant itch, the change in itch at month six. I think the way we think about it is I think folks will be quite interested to see the consistency in those endpoints across the study visits, so right through month 12. I think that's something that we would look to share. You know, additional information on the magnitude of the effects on the composites, you know, the components of the composites, looking at other markers of liver chemistry, things like transaminases and the like. And then importantly, I think a whole broad array of measures of improvements in symptoms. And I think that's really something that we're quite excited to look for. And of course, you know, as we think about the magnitude of effect on disease activity markers and normalizations and symptoms, we're also keenly aware of the interest in safety. Having drugs that can be used safely in a population to reduce risk is vital. It's not just enough to focus on efficacy. So additional safety reporting is something that we look forward to sharing both at the meeting and eventually in a publication. I think that's quite important for all the stakeholders in development.
spk12: Thank you so much.
spk03: Our next question comes from Steven Seedhouse of Raymond James. Please go ahead.
spk01: Good afternoon. Thanks for taking the questions. I just had two lines of questioning, first on Europe versus U.S. I'm curious if you have any sense of whether those regulators are diverging in terms of their expectations for outcomes data and just the quality of data they're looking for, or is it your sense that they're basically aligned still? And then separately, the breakthrough designation language seems to portend a differentiated label in the U.S. I'm curious if it's your expectation that you would get a similar differentiated label in Europe that would include pritis and cirrhotics specifically.
spk15: Great question, Stephen, and I appreciate that. You know, I think first it's important to recognize that alpha phosphatase and bilirubin in the composite endpoint has been used as a regulatory bar for approving obviously the only existing second-line treatment in the U.S. and in Europe today. And I think regulators, of course, are aligned in terms of the need to demonstrate that those surrogates actually correlate to improving outcomes. So I don't think there's any misalignment between US regulators and European regulators in the fact that we as sponsors need to make an attempt to demonstrate that these surrogates are, of course, correlated to outcomes. And I think certainly there can be different views around study design, data sets, one-year, two-year data, for example. But I think in the end, from our perspective, these agencies are, of course, aligned in the need for us to demonstrate some sort of outcome benefit. I think both regulators here in the U.S. and in Europe also recognize some of the inherent challenges in generating long-term outcomes data in PBC. And so I think both have been open to dialogue. around generating the right real-world data and real-world evidence to be alongside these efforts to generate outcomes data. There are challenges with those paths as well, but I think folks should understand that we at SEMA Bay are effectively executing on both. Executing on the AFIRM study that we think is a novel design, certainly relative to others that have been conducted in the past and others that are being conducted today. and we are also looking very closely at generating the right sets of real-world data and evidence alongside and parallel with these activities. You know, in terms of your second question with respect to the breakthrough therapy designation, obviously BTD is a U.S. FDA-specific designation. We have a prime designation with the EMA, but I think as to whether or not The regulators outside the U.S. will look at the data sets that we will look to provide. It will certainly be our intention to have an indication and label in the U.S. that mirrors what we would expect to have outside the U.S. as well. But I think it's a little bit early for us to really come to some conclusion around how regulators outside the U.S. will view these things specific that's in the PTD.
spk01: I appreciate that. Very helpful. And I also wanted to just ask separately on a firm. First, if you're willing to just comment on the powering of that primary endpoint and your comfort there. And then also, since the study is enrolling serotics, which, of course, will let you complete it in an adequate period of time and hopefully ensure success. of completing that study. I just wanted to confirm that FDA is comfortable inferring an outcomes benefit in non-serotics if a firm is successful. Thanks.
spk15: Yeah, great questions. And perhaps I'll ask Chuck to talk a little bit about the data sets that we've really interrogated to come up with the assumptions around a three-year fixed duration study, the populations of patients between compensated serotics, child's PUA and child's PUB, and event rates. I think, again, we probably wouldn't go too far into the detail of the powering per se, but maybe, Chuck, you can talk a little bit about how we approached the study design.
spk07: Yeah, of course. We had a very rich source of discussions with FDA. We had multiple face-to-face meetings going back for several years to discuss various approaches that one could consider to confirm the outcomes and We did settle on this design with their input in the pre-planning phase. And then, of course, after the protocol was drafted, it was shared more than once. And we got their alignment and input before we started to move forward. In terms of the design element, Steve, we're fortunate in this particular rare disease that there's been an international collaboration between investigators called the Global PBC Study Group. which has collected data on several thousands of patients, both in Europe and in North America, including characterization of patients with different severity of disease, including child PUA and child PB. The level of effort to create the quality of data needed in the database to address not only death and liver transplant, but also liver-related events has really matured over the years. So we were able to collaborate with that group to develop an understanding of event rates, incidence prevalence, and to come up with a design that allowed us to estimate, as you allude to, the power of what we would expect to see in a patient population based on not only their natural history and rate of events, but also taking into consideration some thoughts around what we expect to be the risk reduction that we have seen in prior studies with Simabay based upon the surrogates. So you know the surrogates have effects on the composite, for example, and we could factor that in. So we think that we've you know, I guess we could use the phrase thread the needle, a balance between the practical aspects of asking patients to participate in a longer-term placebo-controlled study, but for which they might have benefit. And in this particular advanced population, they're really, in many cases, don't have other treatment options, especially child tube B, there's nothing on label. Child tube A, there's a limitation. And agents that are approved that might be used in that population are not available in every country and in every situation. So I think it's a nice balance to really try to take into account developing a scientific evidence. Placebo-controlled is the gold standard, but also keeping the patient in mind. Having an opportunity, it's a two-to-one ratio active to placebo. There's an opportunity to get benefits They really, in many cases, have no other way to go. And it's a fixed duration. Some of these event-driven trials typically would enroll a patient, they'd go on placebo, and they just go until you collect a total number of events, which could be many, many years, many more than three years in duration.
spk12: Thank you so much.
spk15: Steven, I just ended out. I know you asked about serotics and non-serotics. We do believe that regulators have at least confirmed that showing outcome in the serotic population will portend to the broader population.
spk03: Our next question comes from Kristin Kluska with Kantor. Please go ahead.
spk09: Hi, everyone. Given the unique observations that you've shown with itch, are you planning to do more work around IL-31 in the response study? And if so, when can we see that data? And then second, now that you have a larger N and number of patients you can follow, are there any other analysis you're trying to conduct to further understand what's driving your differentiated benefits? Thank you.
spk15: I appreciate the questions, Chris, and perhaps I can ask Chuck to talk a little bit more about itch and IL-31, and I can answer the second question with respect to additional data sets coming out of Assure.
spk07: Yeah, thank you for that question, Kristen. Of course, we're quite interested in delving into understanding the improvements in symptoms, in particular itch that we've seen, and I think you're probably alluding to poster that we had in Vienna at the EASL meeting, which correlated baseline itch with bile acid levels and IL-31 levels, where we saw that PBC patients have up to 30-fold higher levels of IL-31, a known peritogenic molecule, at least in dermatological diseases. And we do, of course, have an interest, and you can expect us to follow up, on understanding that mechanism, including in response. And as always, our commitment will be to share it at a medical meeting as well as in publications. And we're really trying to understand at the molecular and cellular level, meaning which cells in the liver or elsewhere, what's the driver of IL-31, and can we develop convincing evidence that we've seen to confirm what we've seen so far as to why Celadalpar might be impacting itch in terms of a molecular explanation. So stay tuned. You can be assured that we have a continued interest in this area.
spk15: And then, Kristen, you know, you have some great questions. Sorry, I was just going to say, you have some great questions about number of patients today that are taking Celadalpar north of 300 and Assure. Of course, we're also enrolling patients in the IDEAL study. You know, and I'll just very quickly tell you that our commitment to PBC patients, of course, doesn't end with response or this phase three data set or even our post-marketing commitment in Affirm. It is absolutely our intention to continue to generate data that helps us better understand the advantage of treating patients earlier, treating patients to normal, and better understanding the impacts on symptoms and how they translate to quality of life. And so both ideal and assure, we expect to be very rich data sets to serve for news flow and milestone generation for years to come. Even as we hope to be successful at gaining approval for and launching Cell at LPAR, we'll continue to generate data sets that support the potential for this to be a very differentiated option and a meaningful option for patients.
spk12: Thanks. Looking forward to it. Thank you.
spk03: Our next question comes from Kari Chibbonville with LifeSci Capital. Please go ahead.
spk13: Thanks for taking our questions. A couple from us. We touched upon this a little bit earlier in regard to the availability of existing therapies, but In a firm, how do you plan on tackling some of the feasibility challenges that might emerge, specifically keeping placebo patients on study, assuming cell delpar may likely be approved within that time frame?
spk15: That's a great question. You know, maybe I'll make a few comments and then invite Chuck to share anything in addition. you know, clearly there's no question that long-term outcome studies, as we mentioned, are challenging in this setting. I think part of what's unique around a firm is a target to have a three-year fixed duration study. That's really fed by assumptions with respect to event rates in compensated serotics, again, specifically child's QA and child's QB. We hope that that'll be one factor, Corey, ultimately that, you know, drives to greater feasibility in getting patients to participate. Chuck mentioned the two-to-one randomization, so more likelihood of patients being on treatment. Of course, you asked specifically about placebo. Of course, this is a challenge. You know, we'll look to execute this study, certainly in areas where there may be more limited options for patients. There are already, I'd say, more limited available treatment alternatives for this patient population to begin with. And I think those are the things that we ultimately anchor on with respect to what is a commitment of ours with regulators.
spk12: Got it.
spk13: And in regard to the breakthrough designation expansion for CellDelPAR, it would be great to hear more about the data package that was submitted to the FDA to attain that expansion. Was this primarily driven by symptom improvement and response? Obviously, you've done quite a bit of work on IL-31 as a biomarker for pruritus in previous studies. We'd love to hear more about what really moved the needle in terms of the FDA's thoughts there.
spk15: Yeah, you know, I think I can comment. Our initial breakthrough therapy designation, in fact, you know, came before we really generated the substantial Phase II data set one year as well as a two-year extension data that was recently published, in fact, and certainly before the subset of data from ENHANCE. And so I think much of the anchoring around the revised breakthrough therapy designation, you know, came from the additional data sets looking at effects of celadalpar on puritis in both our prior phase two long-term extension as well as our prior ENHANCE study. All of these studies, in fact, also included compensated cirrhotic. So, you know, we think that the revision largely came from data sets that continue to mature. And therefore, again, although never guaranteed, we're encouraged by the revised breakthrough therapy designation as it pertains to the indication, the label, given the additional data sets only continue to reinforce these potential benefits.
spk13: Excellent. Thanks. And last one from us. Can you speak a bit more to the ongoing pre-commercialization efforts for CelebDelPAR? Last year, you presented some really great market opportunity data. We'd love to hear more about how or if your commercialization assumptions or strategy has changed post-response. And I guess also on that note, thinking about a potential range for the number of sales reps you're targeting? Do you have a range that you're thinking about?
spk05: Yeah, thanks for the question. I think from a pretty commercial perspective, I would start really with our medical affairs deployment. I think we're right on schedule with where we hoped we would be at this stage in time, you know, coming out of top line readout and being able to engage KOLs and some of the critical accounts here in the U.S. And so I think things are progressing very nicely there. I think we begin now to deploy our market access team and begin to really engage payers. We hope to begin that process here in this quarter and moving into early next year, really based on FEDEMA 114 guidance and being able to really update payers on you know, really the treatment goals for PBC and helping them really understand the opportunity as relates to supporting these patients. Our Salesforce process, we've started a lot of the initial analysis here over the last couple of months or so. I would tell you that generally speaking, Salesforce, somewhere between 50 and 60 representatives is kind of where we would typically see deployment. And I think that generally speaking, This is going to allow us to reach somewhere between 5,000 to 7,000 of the gastroenterology and hepatology target audience. Folks, this is going to get us somewhere around 80% to 85% of the opportunity. So very early on right now in terms of some of that analysis, but that's kind of how we would see some of that at this point.
spk12: Excellent. Thanks so much for taking our questions.
spk03: Our next question comes from Ellie Merrow with UBS. Please go ahead.
spk08: Hi, it's Sam on for Ellie. Earlier you mentioned that the XUS filing preparations are kind of in progress. What is your latest thinking around your strategy with XUS commercialization and whether or not you'd seek a partner?
spk15: You know, I think we're still in the same place, Sam, as we've been for some period of time. We've always had confidence that response as a pivotal phase three study would allow us to register a cell at LPAR both in the U.S. as well as potentially in Europe. And so we're continuing to move forward with a strategy to complete and submit filings ourselves, working these in parallel, in fact, so that we can do so as quickly as possible the closest proximity to one another. We're going to continue at the same time in parallel to evaluate potential interest from licensors that already have infrastructure and capabilities in Europe. I think today the good news for us is with the balance sheet we have, we can keep open broader strategic alternatives for the company and not make that decision too quickly. But I think you'll see us continue to evaluate each of these opportunities in parallel, inclusive of the potential for us to think about a staged commercial launch on our own. So, you know, I think we're fortunate to be in a position where each of these are alternatives we can continue to evaluate in the near term.
spk08: Great. Thank you so much.
spk03: Our next question comes from Jay Olson with Oppenheimer and Co. Please go ahead.
spk04: Oh, hey, congrats on the progress and thanks for providing this update. As we look ahead to the liver meeting, can you just talk about how you'd like investors to compare the results to the response study to the elated results for Elifibinor and maybe compare and contrast those two drugs and Where do you think they'll fit into the treatment landscape assuming they both become approved? Thank you.
spk15: That's a really good question, Jay. It's a little bit challenging for us to really comment because we've seen so little of the top line results for Elifibrin or out of Elative. I think when we look and anchor around the data that we've shared to date from response and obviously an expanded data set we'll look to share a week from today, a week from yesterday, in fact. You know, I think we're really quite anchored around the fact that Felidelpar already appears to be distinguished with respect to normalization rates, which is really where physicians are driving the need to normalize biochemistries in PBC patients and therefore treat a much broader population. set of PBC patients today that remain at risk of progression. We're also anchored on the fact that now response was our second global placebo-controlled study in which we hit statistical significance on reducing itch in patients with PBC. This is not an insignificant milestone. It's something that's been proved to be challenging for other agents and other settings, clearly something that PBC patients have not yet had an opportunity to potentially experience with treatment alternatives This is something that we think is already differentiated from at least the top-line data results we heard from the Elifibinor eletive study, where they did not hit statistical significance on reductions in itch. I think we'll look more broadly to compare and look at the safety profiles of these two agents as well. There are mechanistic differences between Elifibinor and Celadalpar. We continue to think that Celadalpar is well-positioned to be both anti-cholestatic, and anti-inflammatory. Remember, while ALT and transaminases are not part of the primary endpoint for approval, this is a chronic inflammatory fibrosing liver disease. And the impacts we see with Celadalpar on ALT and on inflammation we think are also differentiating with existing data sets to date, and we'll continue to look towards the liver meeting at seeing this differentiation as well. So again, anticholestatic, anti-inflammatory, and now antipyretic with a safety profile that we believe also well-positioned cell with LPARM.
spk12: Our next question comes from Andy Hisseth with William Blair.
spk03: Please go ahead.
spk14: Thanks for taking our questions. Two, one has to do with DILI. I'm curious if you can share the approach that you're taking as a sponsor to de-risk this potential regulatory risk and, you know, perhaps in-house emulates kind of the deep investigation that the FDA will likely undertake just to prevent any sort of surprises that we have seen in the field.
spk15: Happy to answer the question, Andy. You know, maybe Chuck, if you'd like to give some color here.
spk07: Yeah, of course, it's always important. For any drug in development, the FDA plays close scrutiny to the risk for, you know, liver toxicity. There's a tried and true algorithm that's employed. I believe every sponsor today would be employing that. There's an adjustment to that algorithm that's implemented in the setting of liver disease. And of course, we follow it. There's a published consensus paper and there's very specific guidance about how one evaluates the risk for drug-induced severe hepatotoxicity. And we follow that pattern as well. I think it's really encouraging for me to say that across our program where we've studied 10 milligrams or lower, as we've reported previously, we've had a really solid experience. We feel that in the setting of liver disease, that, you know, that Celadopar really has a really good profile. So there's not any... level of concern that we have at this point. But of course, we do use a protocol, specified methodology, an accepted way to analyze and report any changes, for example, in liver enzymes. And that's all part of the regulatory package that we're putting together and submitting to FDA, as well as other regulators.
spk12: Got it. That's very helpful.
spk14: And as you think about commercialization in speaking with some key opinion leaders, there appears to be some stickiness in patients, obviously, as you kind of think about, you know, wave one, wave two, in terms of perhaps OCA treated and discontinued patients being the easiest to penetrate. As you kind of think about expansion into potentially, you know, currently on OCA but having either high frequencies of pruritus, what's the strategy here to overcome that inertia and really communicate with healthcare providers, you know, convincing them that there is a better option out there?
spk15: You know, Andy, I think it's a good question, first of all, and I'd say, In a setting where you only have one approved second-line treatment, the concept of stickiness may be very different when you have various alternatives. I think the first most important thing for me to call out, as you described, is there are many patients that have been on second-line and have already discontinued. In fact, we think that number is greater than even those that have remained on abetacolic acid as the only second-line approved here in the U.S. And so I think there's clearly an opportunity to serve those patients. Overall, there are many more patients that have still not yet been on second-line treatment as well. And so I think the opportunity is very significant before you even contemplate any patients that may switch over from current second-line treatment. We do expect some of that to occur. Certainly patients that have ultimately tolerability issues may, in fact, seek other alternatives. Those that do not and are actually having an adequate response, we agree with you. We should remain on the treatment they're being given. But again, I think Celadalpar really has the opportunity to completely change the treatment paradigm in the setting of PBC. And so ultimately, you know, we're excited about what we've seen with respect to the efficacy profile. You know, puritis is something that to date has always been talked about as a tolerability issue. And for us with Celadalpar, the effects on puritis are actually an efficacy parameter. The ability to actually reduce puritis is significant in improving the quality of lives for patients. You know, we know with existing second-line treatment, for example, that most patients don't actually up titrate from 5 to 10 milligrams. So, again, I think you're going to see a very different view and approach to giving patients the most optimal treatment. And so right now our focus is to really get through treatment the regulatory process because we do believe Celadal PAR may offer significant advantages to patients if we're successful.
spk12: Great. Thank you very much.
spk03: Our next question comes from Ed Arcee with HEC Wainwright. Please go ahead.
spk11: Hi, good afternoon, everyone. It's Thomas Yip asking questions for Ed. Really appreciate the kind of questions. So just wondering what would be the ballpark figure of incremental U.S. span for a preparation launch in the next 12 months? And then the second question is, I believe EU launch is on the table, as you mentioned. Is that factoring in the first half 2026 cash runway? And if not, what are some major assumptions behind the cash runway estimate? Thank you so much.
spk15: Yeah, thank you. Can you repeat the first question again? I know you asked something related to launch. Were you asking about costs or timeline estimates?
spk11: Cost estimate, perhaps incremental spend in the next 12 months related to our U.S. launch.
spk15: Yeah, I'll ask Harish to answer both of the questions related to the balance sheet and cost.
spk02: Yeah, the way I would answer that question, our cash runway takes into account the investments that we'll see accelerate. Actually, now that we're on the other side of data in all our commercialization efforts, actually, that Lewis alluded to, we have the medical affairs team on board and we're actually building on a commercial organization. The sales piece or FPs probably will come in more closer to the launch timeline once we have a sense of what our producer date looks like. So it's not uncommon, probably about one, two months before. So that's kind of how I would, so that is baked into our assumption in our cash runway. And so you would assume, you know, it'll build now, between now and, you know, as we get to commercialization and all the pre-market planning efforts, and then you would end up having a more of a higher run rate now that we have the, you know, post-launch when we have the full team on board. And to your second part of the question, a full-scale EU commercialization is not included in our cash runway. We are still, again, we're making progress with respect to regulatory filings and some early commercial understanding efforts, but I wouldn't say a full-based commercialization is not in that estimate.
spk11: Understood. Thank you so much for taking our questions.
spk03: Our next question comes from Mayank Kamantani with B. Reilly Securities.
spk12: Please, go ahead. Appreciate you taking our questions.
spk10: This is actually William from Mayank. So, just a couple of follow-ups here. We're curious if there was any indication that the Akalava Article 20 investigation has anything to read into for your review in the EU.
spk15: Nothing that we're aware of, frankly. We know little outside of what everyone knows from the public domain with respect to the Article 20 review for Ocala. To date, we don't believe that this is anything that would affect our discussions and process forward with CeladalPAR.
spk10: Okay. Appreciate that. And then one quick follow-up. What do you think we should focus on when your full safety adverse event table info is disclosed, since that wasn't really part of the top line release? Should you be needing to show improvement on paritis A's? I'm sure this is a differentiating attribute that is also included or will be included on the label. Any extra color?
spk15: Yeah, I think, you know, the statements we made at top line were that the safety we observed in response in the treatment arm with Celadalpar 10 milligrams was comparable to what was observed in placebo. We also made a statement that the safety was, in fact, consistent with what we've seen in previous studies. I think for Celadalpar, that's a fairly significant data set. The phase two north of 100 patients out to a year, 50 plus of which went out to two years, and then the enhanced study that had actually randomized 265 patients, all of which are in the published domain. And so I think there's a very rich safety data set to interrogate in the published domain for Celadalpar already. And so what we'd observed in response is very consistent with the safety profile that we've now published on in multiple studies. And so I think that should garner some level of confidence, and we'll look towards next week again, to share more of that data out of response. You asked specifically about AEs with respect to puritis. Again, remember, perhaps up to 70% of patients with PBC can experience puritis in the course of their disease, so not uncommon in the setting of clinical studies to observe AEs of puritis. The more important tool to assess whether or not you actually have an impact on reducing itch, of course, are the NRS tool that we've incorporated in response, as well as our prior enhanced study, other PROs, including 5D itch, as well as PBC40 puritis domains. I think interrogating these tools really gives you the best sense of whether or not you have an impact on reducing itch. So I think all of these collectively are insightful, and we'll look forward to sharing more of this data next week.
spk10: Awesome. Appreciate that. Congratulations again, and thank you for taking our questions.
spk03: Thank you. Our next question comes from Thomas Smith with Lering Partners. Please go ahead.
spk06: Hey, guys. Good afternoon. Thanks for taking our questions. Just wanted to clarify, now that you have the revised breakthrough therapy designation in the U.S., are there plans to engage the EMA in a similar conversation around the scope of the prime designation? Is that something you think could be valuable to either your regulatory path in Europe or perhaps securing more favorable reimbursement or access there?
spk15: Chuck, would you like to make some opening comments?
spk07: Yeah. So, thank you, Thomas. A very logical question. You know, I think our focus now is on submitting our application and then having the kinds of, you know, pre-submission meetings that you have rather than opening up once again, you know, the regulatory path for Prime. Prime is, Celadopar's position with respect to Prime is very unique. Most of the Prime designated products in Europe are, in the EU, are actually oncology products or other more, not more, but different types of serious diseases. So we think with the benefits that come to us From the prime designation, it provides us with close access and interactions with rapporteurs. We're able to have a frequency and a quality of regulatory interactions. So I think I would not be guiding you towards thinking that we're going to just repeat the same process that we did in the US. Even though I think it's logical that people kind of think that breakthrough designation and prime are the same thing, they do have some semblance, but they're not exactly the same thing. So we think the most important thing for us to do is to share the data sets, to move forward towards submission and get into regulatory review as soon as we can. As Sujo mentioned earlier, I think it's one of the strengths of our program is that You know, we've had more than 500 patients with PBC dosed with Celadalpar. We have more than 300 ongoing as we speak now. The size of the data sets and the consistency around the features that came with the revision, namely pruritus in two placebo-controlled studies, also pruritus effects in the open label study, and then the totality of patients that we've treated that have cirrhosis is something that is, you know, it's an opportunity. We have more than just response. We've got the other studies to supplement those experiences in the subpopulations.
spk06: Got it. That's helpful. And if I could just sneak in a quick follow-up here. I know you collected some paired liver biopsy data in the response study based on guides from the FDA. I was just wondering if there's any requirement or... if you were conducting any optional collection of paired liver biopsies in the AFIRM trial with the compensated cirrhotic patient population.
spk12: Chuck?
spk07: Yeah, so we've collected, we just, once we started response, we, for most studies, not all of them, we've continued on that commitment, we think, to be able to characterize histology with disease status is a unique and differentiating feature of the Cellidel PAR program. So we've actually collect paired liver biopsies in Assure, and we will be collecting biopsies also in Affirm. Now they're optional, so it's not a requirement because it's not part of standard care in PBC. But for those patients who are interested and willing to understand the status of their histology for their liver and to help us gain an understanding of what might happen in treatment responses, we think that's an important effort to be making.
spk06: Got it. That makes sense. All right, guys. Thanks for taking the questions. Looking forward to seeing the data next week at ASLD. Thank you, Thomas.
spk03: There are no further questions at this time, so that concludes our Q&A session. I would like to turn the floor back over to the company management for closing comments.
spk15: Thank you, Operator. You know, as we've discussed to date with positive pivotal Phase III data now in hand, our team is accelerating each of the activities necessary to get Celadal part to patients as quickly as possible. Just a few weeks ago, we were fortunate to have several people living with PBC share their stories with all of us here at the company. They remind us of the need they and others have for us to advance a potential treatment alternative that has the potential to treat earlier, to treat to normalization, and to treat to reduce symptoms and improve quality of life. Their daily struggle continues to inspire us to be focused, to be driven, and sincere in the work that we do here every day. We could not be more excited, as we've mentioned again today, about the liver meeting in Boston starting later this week. Again, as Chuck mentioned in his remarks, fortunate to have Dr. Gideon Hirschfield on behalf of all of the study investigators present a more detailed summary of the response phase three results in a late-breaker presentation on Monday, November 13th. This will be our most significant presence at the liver meeting since we began development of Celadalpar in PBC in 2015. And we expect CimaBay and Celadalpar to be featured prominently at the Congress as we meet with healthcare professionals as well as patient advocates, many of which have been our valued partners for many years. And again, as we discussed in today's Q&A session, our commitment to people with PBC continues beyond response with our ongoing studies to assure ideal and affirm, and we expect to share much more of our progress with you in the months and years ahead. Thank you again for joining.
spk03: This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.
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