This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk04: Good day, ladies and gentlemen, and welcome to the SEMA Bay second quarter 2022 financial results and business update conference call. At this time, all participants are in a 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. Now, I would like to turn the call over to Mr. Paul Quinlan, General Counsel at CIMA Bay. Mr. Quinlan, please proceed.
spk13: Thank you, Operator, and good afternoon, everyone. I hope that you have had a chance to review the press release we issued announcing our second quarter 2022 financial results and business updates. You can access that release on our website under the Investors tab. Joining me in the call today are Sujil Shah, Chief Executive Officer of Chuck McWhorter, Chief Scientific Officer, 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 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 forward-looking statements are based on reasonable assumptions, Actual outcomes and results are subject to risks and uncertainties 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 Sujil. Thank you, Paul.
spk10: Good afternoon, and thank you for joining us today. I'm excited to start our call today highlighting the achievement of a significant milestone in the development of Celadalpar for patients with the rare autoimmune liver disease primary biliary cholangitis, or PBC. Last week, we announced the completion of enrollment in response. Our global phase three registration study evaluating Celadelpar in PBC patients who have had an inadequate response to or are intolerant to first-line treatment, ursodeoxycholic acid. As a result of the tireless efforts of our team here at SEMA Bay, the commitment of our patients and their family members, the expertise of our investigators and their staff, and the support of our investors, we have been able to bring CELADELPAR a step closer to our goal of improving the lives of patients with PBC. We believe our development program for CELADELPAR is one of the most robust ever conducted in patients with PBC, with over 600 participants, including over 325 currently receiving treatment in our ongoing study. We have explored a broad range of doses between two and 200 milligrams and have studied a wide spectrum of patients, including non-cirrhotics and compensated cirrhotics with and without portal hypertension. Our current experience includes patients who have been on treatment for between three months and up to three years. Today, I'll ask our chief medical officer, Dr. Dennis Kim, to provide an overview of our progress in response, as well as across the entire PBC development program. Over the years, a key element of our development program has been to publish and present our findings at major medical meetings. Since beginning development in PBC in 2015, we have consistently shared data with the medical community And today, our Chief Scientific Officer, Dr. Chuck McWhirter, will review some of our most recent data presented at the International Liver Congress sponsored by Eazl this past June. Finally, as we look forward to completing response and reporting top-line results from the trial in the third quarter of 2023, we will continue our pre-commercial work to identify strategies that maximize the impact Celadelt Park can have in PBC. Our Chief Commercial Officer, Louis Stewart, will briefly discuss the work that is ongoing and that will be expanded on during a virtual investor event we are planning to hold in September. Before taking questions, we will wrap up our paired remarks with our VP of Finance, Dan Minold, reviewing our financials for the past quarter. Let me first turn the call over to Dennis.
spk07: Thanks, Sujal. It's my privilege to discuss the progress we have made in our phase three development program for CellDelPAR and PPC. The completion of patient enrollment in response is an important milestone that enables us to set timelines and plan with more granularity for completion of full study conduct, data analysis, availability of high-level efficacy and safety results, and transition to putting together a high-quality NDA for potential marketing approval of CellDelPAR as a novel treatment option for patients living with PBC. On our road to study enrollment completion, we executed an extensive screening effort at more than 150 active sites in more than 20 countries. Ultimately, we concluded enrollment with a total of 193 patients randomized. Patient recruitment and enrollment is always one of the most challenging operational aspects of any clinical trial, but the response study had some additional challenges related to the worldwide pandemic, which started several months prior to initiating response. COVID-related challenges, such as workplace shutdowns, diversion of clinical and hospital resources to address COVID infections, labor shortages, and some patients' reticence to participate in clinical trials among other COVID-related factors, required us to go further, dig deeper, and get creative with patient recruitment strategies. Other similar studies being sponsored by our competitors targeting a comparable PBC patient profile were also being conducted in parallel to response, and the geopolitical strains in Russia and Ukraine posed additional hurdles to overcome. To meet these challenges, We expanded our footprint with respect to the number of study sites, countries, and patient recruitment partners. We sought to build new relationships with high potential investigators in regions of the world we had not previously conducted trials, and intensified focus on engaging those preexisting relationships and study sites we knew had potential to perform well. Our rich experience in working previously across various CBC clinical studies with many of the same PBC experts, principal investigators, allied health professionals, and patient advocacy groups served us well in being able to leverage these relationships to meet the challenges. Indeed, as Sujal mentioned, our CellDelPAR clinical program represents the most robust and rigorous dataset for drug candidates in development in PBC to date. We have gathered clinical data across more than 600 patients with PVC through our phase two and phase three studies with greater than 100 patients and greater than 50 patients having had at least one year and two year of CellDelPAR treatment experience, respectively. In our ongoing open-label extension study, Assure, there are currently more than 150 patients being dosed every day with CellDelPAR. The 193 patients randomized in the response study will be our flagship data set. supported by the consistent efficacy and safety results we've observed from our prior trials. This gives us additional confidence in being able to deliver life-changing therapeutic options to those living with PBC. Through these data collection and experiences, working with various stakeholders in the field of PBC, we're able to glean important and encouraging information and sentiments from our partners. The ongoing Assure study is a significant differentiating feature of our program. All patients are receiving open-labeled cells Alpar on a daily basis, which will add significant amounts of long-term efficacy data for biochemical response and pruritus in addition to creating large state safety data sets. The Data Safety Monitoring Board for response has allowed it to continue without any changes, The feedback from our investigators on their clinical experience in these studies have been overwhelmingly positive. Many of these investigators were also involved in our prior studies, including our first phase three study, Enhance, which showed encouraging efficacy and safety results at three and six months. As a reminder, 10 milligrams of daily Pseudelpar treatment in our prior open label phase two and long-term extension study demonstrated consistent, sustained, and progressive improvements in alkaline phosphatase in the range of approximately 50% reduction after two years of treatment, with 79% of patients achieving the composite endpoint of ALK-FOS less than 1.67 times upper limit of normal, greater than or equal to 15% reduction in ALK-FOS, and total bilirubin less than equal to upper limit of normal range. We also previously reported progressive improvements in liver transaminases, and in LDL cholesterol over a two-year period. Similarly, an enhanced 10 milligrams of Saldolpart daily over three months resulted in 78% of patients achieving the primary composite endpoint and more than 25% of patients achieving normalization of alkaline phosphatase from mean baseline of approximately 290 units per liter. These biochemical results were accompanied by an improvement in measures of pruritus, an important and meaningful symptom of PBC many patients experience and are hampered by every day. Importantly, cell delpar appears to be safe and well-tolerated across these prior studies. With attention now focused on our current studies, we anticipate sharing top-line data for response in Q3 of 2023. I'll now hand the call over to Chuck to share highlights of some of the most recent presentations we made at EZL in June. Chuck?
spk06: Thank you, Dennis.
spk03: We believe that our science is not complete until it's been communicated to the scientific and medical community and ultimately then published in peer-reviewed journals. It was at the liver meeting in 2016 that we presented the results of our first study of Celadalpar in patients with PBC. And this was followed soon after by their publication in the Lancet Gastroenterology and Hepatology, one of the premier journals for liver disease. Since 2016, we presented research on Salad Alpar at every AASLD and EASL meeting, with 33 presentations made to date, six of which have been selected for late-breaking presentations, and nearly a third having been oral presentations. This year, we published the results of the 52-week Phase II study of Salad Alpar and PBC in the Journal of Hepatology, one of the foremost journals in the therapeutic area. A secondary analysis reporting improvements in pruritus, sleep, and fatigue was published in Liver International, another journal known for publishing results at the forefront of hepatology. This past June, we continued our commitment to sharing results with three presentations at the EASL-sponsored International Liver Congress in London. The first presentation was a poster describing research led by Professor Bettina Hansen, the leader of the global PBC study group, the group best known for proposing blood tests for alkaline phosphatase and bilirubin levels that are used as surrogates by FDA and EMA as endpoints for approval in PBC. The poster titled, Celadopar Treatment of Patients with Primary Biliary Cholingitis for Two Years Improves the Globe PBC Score and Predicts Improved Transplant-Free Survival utilized a validated risk assessment tool called the GLOBE score. It examined treatment response to Celadalpar over a two-year time period in 50 patients with PBC. The patients were selected based on having an incomplete response or intolerance to frontline therapy with UDCA. The main result was that the addition of Celadalpar led to a predicted reduced risk for liver transplantation or death with a hazard ratio of 0.66, compared to no prior treatment with Celadalpar. The improvement in GLOBE score and predicted survival did not depend on a patient's age. However, an analysis of subpopulations of higher risk patients by GLOBE score revealed that patients while of all ages improved, the younger patients at high risk tended to have greater improvements. This suggested the potential for greater impact by treating earlier in disease with Celadalpar. In an oral presentation by our collaborator, Professor Bernard Schnabel, professor of medicine at the University of California, San Diego, he described an elegant set of studies establishing that Celadelpar acts through PPAR-Delta to suppress bile acid synthesis by upregulation of FGF21 and hepatocytes. This explains the ability of Celadelpar to suppress toxic bile acids that accumulate in the liver because of cholestasis. Importantly, his research established that the suppression of bile acid synthesis is via an entirely different pathway than that of FXR agonists, such as Ocalibus, which is the only second-line treatment for PVC approved today. FGF-19 released by intestinal cells must then travel to the liver to exert its effects on bile acid suppression. The involvement of FGF-21 may be one of several reasons why the cell adelpar mechanism seems to have the ability to produce favorable biochemical responses associated with improvement in cholestasis. The last presentation was a poster from the SEMA Bay Research Team, examining the effect of Celadelpar on fibrosis in mouse livers subsequent to injury caused by repeated low-dose treatment with carbon tetrachloride. Our approach was to allow fibrosis to become established for five weeks. before initiating treatment for three weeks with Celadelpar or vehicle. However, unlike some other fibrosis models, we continued to administer the carbon tetrachloride insult throughout the subsequent three-week treatment period. Celadelpar, unlike comparator FXR or THR beta agonists, was able to reduce fibrosis in the face of continued injury. Molecular analysis using RNA-seq methods was able to establish that Celadalpar treatment changes the signature of genes associated with injury and fibrosis. This is the third animal model in which we have seen that Celadalpar was able to reduce levels of established fibrosis, and we believe that this is consistent with Celadalpar's effects on fibrosis that were observed in patients with NASH. We continue to utilize cutting-edge methods to examine the translation of effects of Celadal PAR on gene transcription to understand its pharmacology in patients. As you can appreciate, we are committed to sharing results of our clinical and mechanistic research, and we expect to participate in the AASLD meeting this fall and other major medical meetings going forward. As we advance Celadal PAR through late stages of development, We are also committed to understanding strategies to maximize the number of patients that may benefit from treatment. I'll hand the call now to our Chief Commercial Officer, Louis Stewart, to discuss our early pre-commercial plans. Louis? Thank you, Chuck.
spk02: With our clinical team focused on response, our lean commercial team worked diligently throughout last year to conduct a global PBC market assessment. with a specific focus on the U.S., Canada, Europe, Japan, and China. Throughout our primary research, we were gratified by the reception from healthcare providers who reviewed the Celadelpar target product profile. The strong preference for Celadelpar as a next-generation PVC treatment has been consistent across all targeted global geographies. It is clear from our market research and expert advisors that there remain significant unmet needs for enhanced biochemical response and symptom improvement of TBC. Beginning in 2022, our focus turned to several U.S.-based pre-commercial initiatives designed to inform our go-to-market strategy. We began by mapping out the estimated 25 to 30,000 patients in the U.S. that we believe make up the second-line U.S. market. Our analysis demonstrates an immediate opportunity in non-cirrhotic patients that have an incomplete response to UDCA and or have discontinued treatment with the beta-chloric acid, which make up nearly 60% of the second-line target population. In addition, we estimate there are up to another 15,000 cirrhotic patients on first-line treatment, whereby over half experience a partial to incomplete response to UDCA, and could be a distinct population for celadelpar second-line therapy, particularly given the black box warnings for abetacolic acid in this population. Another important consideration across the spectrum of both UDCA-complete and incomplete responders are the over 15,000 patients who experience moderate to severe pruritus and may look to Celadelpar for symptom improvement. Overall, our segmentation analysis shows Celadelpar's product profile could be a preferred choice for the great majority of these distinct patient segments. In the second quarter, we conducted patient-centered research, examining their journey with PBC, and were encouraged by both patients and the families' active engagement in their overall care. Furthermore, we are excited about the overall knowledge of PBC patients and their willingness to learn about new potential treatments. As expected, they were very descriptive of the symptoms they endure, providing distinct details regarding the severe pruritus, fatigue, and or brain fall that is such a significant part of their everyday life. Along with their healthcare provider, they consistently monitor key biochemical markers and are constantly anxious about their overall liver health. At CIMA Bay, we believe that we can provide patient and caregiver education, add to the conversation around quality of life issues, and become a trusted source of information alongside the great work of advocacy groups like the PBCers, PBC Foundation, Canadian PBC Group, and others we've engaged with globally. This past quarter, we also conducted a market access landscape evaluation along with primary market research with payers to identify both opportunities and barriers across the spectrum of health plans, examining both commercial and government coverage. We will utilize these initial findings to inform Celadelpar's value proposition and overall payer and patient support services strategy. Lastly, as Sujo briefly highlighted, we're planning to hold a virtual investor day on September 22nd, where we'll be providing a more detailed review of the global market opportunity for Celadalpar. Included in this agenda will be a clinical review by Dr. Chris Cowley, one of the foremost global experts on the treatment of PBC. We're excited to share more with you on the commercial planning work we continue to conduct and we'll keep you informed of details about the event in the coming weeks. I'd like to now turn the call over to Dan Minow, Vice President of Finance, for a review of our financials in the second quarter.
spk06: Dan?
spk09: Thank you, Louis. As others on the team have highlighted, during the second quarter, we continued to make additional enrollment progress in our Assure Study, and last week we announced completion of enrollment of 193 patients in the Response Study. thus achieving a key milestone in our PBC development plan. We also continue to advance other required clinical activities associated with our response, assure, and other NDA-enabling clinical studies, which are necessary to complete our late-stage development of Celadalpar and PBC. And finally, we made progress in manufacturing development, as well as in medical affairs and commercials, where we continue efforts to plan for a potential future launch of Celadalpar and PBC. Turning to a brief review of our second quarter financial position and operating results, our cash, cash equivalents, and investments totaled $170.8 million as of June 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 June 30, 2022 and 2021, was $27.1 million and $23.2 million, or $0.31 and $0.34 per share respectively. Net loss for the six months ended June 30, 2022 and 2021 was $54.9 million and $40.8 million, or $0.62 and $0.59 per share respectively. Net loss was higher in the quarter and six months ended June 30, 2022, compared to the corresponding periods in 2021, largely due to an increase in clinical trial operating expenses associated with the ongoing late-stage development of CELADELPAR in PBC, as well as an increase in non-operating interest expense accretion related to the Abingworth development financing arrangement. In particular, our operating cost increases were primarily driven by an expansion of our clinical site activation, patient enrollment, and other clinical trial activities associated with Response and Assure, our two active global late-stage clinical trials in PBC, and higher employee compensation associated with the hiring of additional personnel to support the overall PBC development program. 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.
spk06: Let me now hand the call back to Sujal.
spk10: Thank you, Dan. In addition to our primary focus with Celadelpar in PBC, the Phase 2A proof of pharmacology study of MBX 2982 continued to enroll patients in the second quarter. Challenges related to the COVID-19 pandemic continue to impact the pace of enrollment in this study, but we believe our partners who are fully funding and conducting this trial can drive towards completing enrollment by the end of this year. As a reminder, MBX-2982 is a GPR-119 agonist discovered and developed by CIMA Bay. And although this trial is being fully funded by the Leona M. and Harry B. Helmsley Charitable Trust, we retain all rights to MBX 2982. The product concept being investigated for MBX 2982 in the current study is as an agent to potentially prevent or minimize hypoglycemia in patients with type 1 diabetes. In addition to safety and tolerability, The primary goal of the study is to evaluate the levels of counter regulatory glucagon release under conditions of low blood sugar. We look forward to providing more updates on the progress of this study in the coming months. It's been another eventful quarter at SEMA Bay in which we are proud of accomplishing key milestones and more importantly excited about the news flow that lies ahead. We believe the potential for Celadelpar to meaningfully improve the lives of patients with PBC represents one of the most compelling and de-risked late-stage opportunities in our industry. Our goal has always been to put Celadelpar in the hands of as many patients that may benefit globally should we be successful at completing the development program and registering Celadelpar. As part of this, We continue to evaluate alternatives to partner with parties in geographies outside the U.S. where there would be an opportunity to significantly create additional value. Philadelphia remains one of the only late stage opportunities in this area that remains fully unencumbered. With a strong balance sheet, high quality investors, experienced internal teams, and partnerships With the best experts in PBC around the world, we couldn't be in a better position to continue creating value for all of our stakeholders, including patients, who we are focused on every day. We're now happy to take questions. Operator?
spk04: Thank you. Ladies and gentlemen, at this time, we will be conducting a question and answer session. If you'd like to ask a question, you may press star 1 on your telephone keypad. The confirmation tone will indicate your line is 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 two. Our first question comes from the line of Yasmin Ramini with Piper Sandler. Please proceed with your question.
spk01: Hi, team. Congratulations again on the enrollment completion. A number of questions for you. Maybe the first question is, are you able to shed some light whether you have had a chance to look at the baseline demographics from response and maybe help us understand how much it's aligned with the enhanced study? That's question one. Question two is maybe a reminder on the powering assumption of the response study. And then the third question is, Have you started to interact with the FDA in regards to what a post-marketing requirement may look like? I know we have seen from competitor trials that placebo-controlled studies and post-marketing might not be feasible. And thank you so much for taking our questions.
spk10: Thank you guys, appreciate the questions. I'll start off and perhaps ask the team to elaborate on some of these points. I think first of all, with respect to response, we've talked at length in the past about how this is largely, I like to say, a rinse and repeat of what we fully enrolled and enhanced and executed in the enhanced prior phase three study. We're really looking at the same patient population, the same optimal 10 milligram dose of Celadalpar, and the same primary and same two key secondary endpoints. Of course, on a blinded fashion, we have the ability to see some of the high-level baseline demographics. I simply tell you, Yasmeen, we wouldn't expect to see anything really all that different from what we've seen in over 100 patients enrolled in our prior Phase II open-label study, as well as the 265 patients enrolled. that we enrolled in enhanced, so you would see likely very comparable alkaline phosphatase levels in particular at baseline. And again, I think the overall demographics would be very consistent with what we've seen before. I know your second question has to do with in terms of reminder around response powering. I think when you look at the enhanced data in particular that we shared, three-month data on the primary composite endpoint used to register Ocaliba, that would be the registration endpoint for Celadelpar. Particularly, this is the endpoint in which, in order to be a responder, a patient has to drop their alkaline phosphatase levels below 1.67 times the upper limit of normal with at least a 15% drop in alkaline phosphatase and normal bilirubin. And as you may recall in the data that we previously presented at medical meetings, Within even just 3 months of treatment, we saw that 10 milligrams of cell adult are resulted in about a 78% response rate on that primary endpoint versus about 12 and a half percent. for those patients in placebo, and that included just about 55 patients per arm. So on the primary endpoint, that p-value was less than .0001, and so it's a long-winded way for me to tell you that on the primary endpoint, with 193 patients randomized in response, 2 to 1, Celadalpar 10 milligrams to placebo, we are highly overpowered to demonstrate that type of an effect. on the key secondary endpoint with respect to alkaline phosphatase normalization, so well over 90% in each of those cases. Our target initially for 180 patients in response was largely built around some of the assumptions relative to how many patients with moderate to severe itch we believed we would be able to enroll in the response phase 3 study. And so the 180 target largely fills an assumption around 80%, at least 80% powering to show a 20% benefit or two-point benefit on the impact of Celadalpar on the numerical rating scale for worst imaginable itch in the 24-hour prior period. Again, that key secondary endpoint is largely what drove the total target in terms of patients in response. Finally, Asmeen, I think you've asked us a little bit about our dialogue with the agency with respect to Phase 4 outcome study. Of course, approval on this primary endpoint in response as a surrogate endpoint is based on subpart H approval, and so we do have to commit to a Phase 4 outcome study. We've had, in fact, years of dialogue with the agency around various types of study designs He talked a little bit about others in the field having challenges recruiting patients into what ultimately can be long-term placebo-controlled trials in order to evaluate and have enough events to demonstrate this clinical benefit. Our dialogue with the agency has really centered around more novel approaches than what we've seen with other sponsors. That dialogue continues today, and at the point in time in which we complete that dialogue with the agency, we'll share that publicly as we approach completion of the Phase III development program and eventually initiation of a Phase IV outcome study. I will say, Yasmeen, that we as sponsors also recognize the importance of continuing to generate real-world data, registry data around the effects of our potential treatment alternatives for patients with PBC versus those that are not on our treatments. And we've seen others at least generate that data set. Very hard to see if that data set alone is enough for full approval. I think it's important and incumbent upon sponsors like CIMA Bay to really devote time and resources to generating data sets that can potentially point to these outcome results, multiple different strategies on behalf of patients, as that's a key commitment to regulators.
spk01: Thank you so much, Sujal. And again, I cannot be so beyond happy for you on enrollment completion as we're getting closer and closer each month to the data. And thank you again for taking my questions.
spk10: Yeah, absolutely. Thank you, guys.
spk04: Our next question comes from the line of Steve Steedhouse with Raymond James. Please proceed with your question.
spk15: Thank you. Good afternoon. I wanted to ask, I appreciate the rundown of the market research you guys have been doing. It's very helpful. I wanted to just ask about in response, are you comfortable with the sort of sampling you have of the different market segments you outlined? and able to generate and update in each of those ultimately to service a label or detailing to those segments of the market.
spk10: Yeah, sure. I'll start off, and I'm going to ask Louis to actually provide some additional color. I think, Steve, clearly the first objective is in the patient population with the most significant unmet need. The second line setting, of course, are patients who are largely incomplete or inadequate responders to UDCA. effectively highlighting alkaline phosphatase levels, biomarkers of cholestasis that are associated with greater risk of progression. That population, of course, included in our response study are those that have alkaline phosphatase levels above 1.67 times the upper limit of normal, as you well know. That clearly is a strategy to get Celadalpar, again, on the market potentially for these patients in most significant unmet need. What we do see more broadly is an impact of reducing, as a point estimate, the percent reduction in alkaline phosphatase in patients almost independent of baseline levels of alkaline phosphatase. So the types of effects we see in these patients that have ALKPHOS above 1.67 times the upper limit of normal we would expect to see similar percent reductions for those patients that still have elevations above the upper limits of normal that might feed in to how we think about future opportunities to expand the addressable patient population. And perhaps, Louis, I can ask you to add any additional cuddles.
spk02: I think, as I mentioned before, one of the critical areas that we focus on certainly is biochemical response, but we would also sort of focus on two other critical segments I mentioned. I think that notion of being able to address both non-cirrhotic and cirrhotic patients and being able to have data to support that I think will be a very important differentiator And then probably one of the most important areas that we know patients really discuss consistently is this issue around pruritus or quality of life. And I think this opportunity to adjust symptom improvement will be a really important consideration as well.
spk15: And what about patients that have discontinued OCA in the marketplace? It's Sounds like you've done research on that, and it's a very significant chunk of patients. So are you going to have sufficient data from response to speak to those previously exposed to or not OCA? And are these like even pre-specified subgroup analyses, for instance, of the study?
spk10: Yeah, another great question, Steve. So in our experience, even in our prior phase three study enhanced, we did have patients that discontinued treatment with OCA, betacolic acid, we expect and know that we have patients even in response that have discontinued treatment with OCA as well. So we'll continue to gather that data and actually have opportunities to share more of it. As you know, we typically only share data sets when there's a meaningful proportion of patients that can actually provide some potential conclusion around that impact. But, again, we've seen meaningful responses in patients in cell at LPAR, even those that not only are inadequate responders to UDCA, but those that have also discontinued prior treatments such as OCA.
spk02: And just to add in terms of numbers, you know, certainly the manufacturer for OCA has already stated that their penetration in the general marketplace for second line is about 30% to 35%. We have seen, of course, with that 35%, a great number of patients who discontinued therapy with OCA. And we've looked at those numbers. We think that, you know, probably there's about another 5,000 to 7,000 patients that might benefit from Celadep or immediately who have actually discontinued therapy. So we believe that is a very important segment for consideration upon immediate approval. Yeah.
spk15: Okay, last question. I just wanted to check in on the number of volunteers for biopsies in the study. Are you satisfied that you have enough to check the box with the FDA there? I know that was a feature of this study.
spk10: Yeah, thank you, Steve. We do. We do believe that we have a good proportion of patients that have volunteered for biopsy in this trial based on our prior discussions with the agency.
spk06: Perfect. Thanks so much for taking the questions. Absolutely. Thank you.
spk04: Our next question comes from the line of Ed Arcee with HC Wainwright. Please proceed with your question.
spk14: Hello, everyone. This is Thomas Yip asking a couple of questions for Ed. First, congratulations on the response studies complete enrollment. So first question regarding the response study, compared to what you have seen in the past, what are your expectations for response study and reports to the primary composite endpoint and also for key secondary endpoints, such as ALP , and also a prior .
spk10: Yeah, thank you for the question, Thomas. You know, I think one thing to highlight is in our prior experience, not only in the enhanced first phase three study conducted, but again, also in our phase two open-label study that included just north of 100 patients enrolled. we've seen a very consistent response on percent decrease in alkaline phosphatase, on the actual magnitude of alkaline phosphatase reduction, and how those reductions actually translate to the primary composite endpoint. So if you recall in our open-label Phase II study, in fact, through 12 months of treatment, we saw just under 80% of patients actually meet that primary endpoint, very consistent with what we saw at three months in enhanced. We're gratified that even as we've shared some data sets for patients that have gone beyond one year of treatment, we continue to see, in fact, improvements in alkaline phosphatase reductions, and in particular, even normalization of alkaline phosphatase going from about 40% to 50%. 30%, I'm sorry, to 40% between year one and year two. So we've seen a very consistent, continued response across our prior studies, and we'll see what we see, of course, in response. As I highlighted, it really is the same patient population we've studied in these prior trials. It's why we think this program is particularly de-risked at this stage. Our expectation would be to see something similar to what we've seen in the past.
spk05: Great. Thanks. Thanks for asking, Joe.
spk14: And perhaps another question from us. For the ASSURE long-term study, can you discuss what's the rough percentage of patients are for response?
spk05: And also, so far, what's the median and the longest treatment duration of patients in the study?
spk10: Yeah, let me ask Chuck to give you some color, particularly on the second part of that question.
spk03: Yeah, well, thank you, Thomas. So, Assure began its enrollment basically in February of last year. So, the first patients to come in had come from our legacy studies, the low-dose study that we published in the Journal of Hepatology, as well as from Enhance. Those patients have been accruing throughout that period right up to date. And the lion's share, almost all of the patients so far are coming from those legacy studies. As you know, we announced that we began enrollment in response basically in April of last year. And so we do now have a handful of patients who have completed the first year of treatment and are rolling over into into the Assure study. We would expect, based upon our prior experience, we had really good patient retention and quite a significant amount of interest to participate in extension studies. And so we would expect really most of those patients in response to come into Assure. In total, this means that we're looking at, you know, a very large data set with a considerable amount of treatment experience by the time we take the data cut to submit for an NDA. And we think that's really going to be helpful to regulators that need to reach a decision based upon safety, but also the efficacy, the biochemical response, the durability, and looking at the symptom release as well.
spk06: Fantastic. Thank you again for the kind of questions, and we look forward to the readout next year.
spk04: Our next question comes from the line of Kristin Kluska with Cantor Fitzgerald. Please proceed with your question.
spk08: Hi. Good afternoon, everybody. Thanks for taking my question, and let me also add my congrats on achieving the full enrollment and response. So I saw a recent publication from a study that suggested that pruritus is observed in more patients than previously thought with PBC, over 80%. So I know you're talking about some market metrics for patients who either don't respond or have tolerability issues with other therapies. But in light of some of these statistics, how are you thinking about being an upfront second-line drug?
spk03: Well, maybe I'll start and then Louis can take a crack at it from the perspective of a market. I think I do agree that we continually get feedback about the importance of pruritus in the population. You know, just to share a little bit related to your question, Our team visited over 70 clinical sites in terms of trying to help with recruitment for response. And I can tell you that time and again, anecdotally, we had significant comments from investigators, from study coordinators in particular, from physician's assistants, nurse practitioners that are involved in the study about their patients and the need for something to address poritis. And I think you're seeing this increasingly in the literature that you alluded to, and you may have heard some of the recent roundtable symposia at EASL as well as at AASLD where leading experts really began the discussion about the importance for physicians who were the target audience for these presentations to pay more attention to symptoms. One of the issues really relates to patients reluctant to talk about something that can only be shared by the way they feel. There's nothing currently that can be measured directly. It's only a symptom and not a sign. This can be very discouraging for patients. I'll turn it over to Louis. I think it represents a real opportunity for us to highlight that and kind of help with the entire field, change that dialogue. Because Celadalpart initially seems to have a really nice effect on pruritus, and so that's something that will be important to understand and to take advantage of.
spk02: And Chuck couldn't be more profound in his description as we talked and interviewed a number of patients during our patient journey work. We spent a considerable amount of time listening to them describe how really, really difficult their daily life is in really managing these symptoms, whether that be pruritus, whether it be sleep disturbance, not being able to sleep, particularly at nighttime where the pruritus really becomes a lot more exacerbated. And then, of course, the fatigue that either is an inherent part of certainly their disease, whether they're just not getting a lot of sleep because of the itching and are very, very tired. When we look at the numbers, if you go back, whether you are a complete responder, whether you're a partial responder, whether you're an incomplete responder, all of those patients, whether they're on UDCA or a combination therapy, so many of them really suffer from this moderate to severe pruritus. I would also point out, of course, that cirrhotic patients also have these symptoms as well. So it is a considerable issue, and we're very, very encouraged by what Celadal Park could do to really support this particular population.
spk10: And, Kristen, the only other thing that I would add is, is that we're incredibly encouraged that Celadalpar as a potential treatment alternative has this effect on biochemical markers of disease that may, in fact, improve longer-term outcomes for patients, as well as this impact on improving clinical symptoms. Of course, there are various other approaches being studied towards specifically addressing itch or puritis in PBC patients, The real opportunity here with Cellidelpar is to have a single agent in a very simple manner for both treating physicians, of course, as well as patients, taking a singular treatment alternative that actually does both can be quite compelling, we believe.
spk08: Okay, thanks. I appreciate that. And some of your recent conferences this year, you took your data and cut it in a lot of different ways showing that the results are quite consistent across different parameters. So I'm curious from a physician perspective and the audience you've presented in front of it, there's any components in particular that have really stood out to them that you think are going to be instrumental? Should this be approved in your commercial conversation? Thanks again.
spk03: Well, thank you, Kristen. I would maybe highlight the ability to achieve a biochemical response safely across different stages of disease. And this has been, as I mentioned in the study visits, site visits rather, that is something that's been mentioned time and time again. And that's anecdotal, of course. But really, the ability to see it in not just patients without cirrhosis, but those patients who have compensated cirrhosis or compensated cirrhosis as portal hypertension. And that latter category now, of course, has been excluded from the approved second-line therapy. It's no longer available. That is something that I think has the potential to be an attractive feature. Because if you think about it, you know, patients progress, and they progress at different rates with different risk factors. It would certainly be comforting to know that you can use it in a patient without cirrhosis. If their disease did progress, you wouldn't be, you know, getting into dangerous territory. So we think that's something that's going to be really important to document. We've got a good data set so far, and, of course, we will seek to confirm that with response, which also allowed for patients with compensated cirrhosis.
spk10: And perhaps, Kristen, I'll ask Dennis to add any of his thoughts, having also been with us at EASL most recently, along with us at our ad boards, in terms of impact and responses from many in the medical community.
spk07: Sure. Thanks, Sujal. Yeah, I think, obviously, biochemical response, efficacy, as well as pruritus improvement are very important features of the drug and is well perceived by the prescribers and physicians. The other side of the coin, of course, is safety and tolerability. And I think that's been probably not something that's been talked about very often, but probably something that we need to emphasize because this is something that patients worry about as well as physicians, not only with respect to tolerability and not having annoying side effects or debilitating side effects, but also with respect to patients who can have decompensating events such as cirrhosis or other complications of cirrhosis. And there seems to be a little bit of a halo effect in that we've studied cirrhotic patients in the past, and we're continuing to study these patients. And it appears so far that the drug is being well tolerated in these patient groups. Prescribers recognize that these are sick patients that can have decompensation events at any given moment. So they don't want to use a drug that could, you know, add to that risk. I think we have a drug in cell Belpar that can mitigate some of these risks. We'll see if the data supports that. But I think that's another factor that prescribers appreciate and worry about that I think hopefully we can meet with our database.
spk06: Thank you.
spk04: Our next question comes from the line of Mayank Mantani from B Reilly Securities. Please proceed with your questions.
spk12: Good afternoon, Dean. Thanks for taking our questions and congrats on over enrolling response. So just maybe a quick follow up for Dennis. Could you comment on the response screening failure rate? I was just curious how much of those are so intolerable or inadequate responders aren't meeting this, you know, clinical trial criteria of ALK-POS, bilirubin, composite.
spk06: Could you just comment on that, and then I have a follow-up for Chuck? Sure.
spk07: So, our screen failure rate has been very consistent from our prior experience. As you can imagine, there are a huge list of inclusion and exclusion criteria for any of the studies. The response study design was almost identical to that of Enhance. So we predicted going in what our screening failure rate would be, and it turned out to be pretty much on line with what we actually saw. It's not inconsistent with general other clinical trials that you may see. They range from anywhere from 40 to 60% screen failure rate. Sometimes it can go up to 75, 80%, depending on the inclusion and exclusion criteria and how much demand there is for these types of comorbidities and biochemical responses or biochemical status. So, you know, Lab results, of course, are usually the most common cause for exclusion, meeting exclusion. And that's what we saw in this response screening effort as well. So that's very consistent with what we've seen in the past and consistent with other trials that we've conducted.
spk12: Got it. Thank you. And Chuck, coming away from the easel data sets, you know, how much of this antifibrotic component do you intend to study further? I also ask, I mean, I ask it for a couple of reasons. You know, obviously your comments on cirrhotic population from a safety standpoint is interesting, but also, you know, getting to that outcomes component and converting the accelerated approval to full approval, is there an evaluation more you could do to understand how good of an antifibrotic drug this is, you know, given your NASH results?
spk03: Yeah, thanks for that question. I think that's really important.
spk06: You know, we're trying to build upon what we learned in the NASH study and take that and apply it.
spk03: It's a little bit different, of course. We do have biopsy in this study, and we may learn a bit there around effects on fibrosis. But it's a relatively short term. It's a year, and of course, not every patient will have a biopsy. There is an emerging approach, though, that was just recently published in the Journal of Hepatology that's getting increasing attention, which looks at liver stiffness using a FibroScan methodology, which is basically transient elastography. that's been correlated with histological stage of disease. So this was a paper coming, led by Christoph Korpischow. And we're including FibroScan measurements in both the response and ASSURE. And we're very interested in understanding how these might be used in clinical research as potential markers for outcomes. Perhaps it's not currently the case, but in the future, it might be that regulators might consider them. But also in medical practice, the fiber scan technology is more and more being widely available. It's really part of general practices, large GI practices, obviously, you know, university or academic medical centers, but even suburban hospitals and the like. And it's also being extensively used in NASH, so we're able to kind of ride the tailwinds for its wide availability. We think that looking at liver stiffness to infer effects on fibrosis, either lack of progression, looking at serial measurements or even hopefully regression could be a wave of the future. And that could be important for a drug like Celadelpar that has anti-fibrotic effects.
spk12: Thank you. And my final question is about the open-label hepatic impairment study you're running. Can you just provide us an update on that? And just confirm, are you just exploring the 10-meg dose level, or are you doing lower doses than that?
spk10: Yeah, let me ask Dennis to provide you some additional color here. This is obviously a study, as you mentioned, a hepatic impairment study in patients with PBC so that we can better understand particularly safety but also efficacy in more advanced patients. And these are those patients that have either Child's Pew A, compensated cirrhosis, and a small subset of patients with Child's Pew B and C, decompensated cirrhosis. And so perhaps I'll let Dennis give you just some high level on this, Mike. This is an ongoing study. And so at the point at which we complete the trial, we'd share updates in terms of data from the trial. But Dennis, perhaps you can give a little bit more color around the trial itself. Sure.
spk07: Thanks for the question, and thanks also, Sujal, for the preamble. Sujal is exactly right. These are the patients that we're looking for in the study. It's an ongoing study for which we don't really make too much detailed comments. Suffice to say, these patients are rare patients, especially CPB patients, and then CPA patients with portal hypertension are also fairly rare. We are making progress in recruiting patients into the study and activating additional study sites. We do have a fairly long timeline before we have to complete the study. So we are planning to be able to include this database into the NDA. We are testing 10 milligram dose, but we maintain the flexibility of going to a lower dose. If we see rate of metabolism and pharmacokinetic exposure in patients with advanced cirrhosis, which would require lowering of the doses. So we do have that flexibility, and we'll let you know how that goes once we finish the study.
spk06: Thanks for taking our questions, Steve. Thank you, Ryan.
spk04: Our next question comes from the line of Patrick Dozol with LifeSci. Please proceed with your question.
spk16: Hi, this is Cory on for Patrick. Congrats on the enrollment, and thanks for taking our questions. So first one from us, you know, you recently had some great data regarding CeladalPAR's effect on GLOBE score. You know, obviously, CeladalPAR has a strong potential for a differentiated label in regard to pruritus, but is there eventually an opportunity for, you know, a label that might include outcomes for GLOBE score? And, you know, to what degree do regulators and clinicians give credence to GLOBE, you know, given that it's a predictive metric.
spk03: Yeah, thank you, Corey. So the GLOBE score is a continuous measure of risk that's been validated to predict outcomes. This is based on work from the Global PBC Study Group. It includes the elements that go into it are age and then laboratory parameters, which would be alkaline phosphatase, bilirubin, platelets and albumin levels. And those are all liver parameters that really speak to the health of the liver overall. And so the value of it in clinical research, it's typically used in medical practice. There's a webpage you can go to and a physician can just input the parameters based on the laboratory results and get an idea of what's going on with the patient, maybe look at these measures serially. So it's typically used to kind of be a PDC-specific risk assessment so that the attending physician can make some medical judgments about anything that needs to be done, any adjustments to treatment. The way that we're using it is as a variable to examine treatment response. And it has several advantages, I think, over the categorical variables, you know, the ones that, for example, regulators are using right now. You either respond or you don't respond. And that doesn't really give a lot of granularity. It's very much a blunt instrument, especially in clinical research. So having a continuous variable allows for finer gradations in judging risk. and also for examining treatment differences between two groups. So that's another powerful measure. I think that at the moment, as far as our program is concerned, we're using a precedented endpoint, FDA and EMA accept it. We're not going to change that at this point. The GLOBE score is an exploratory parameter. We can use it to tease out Differences for example between you know post-hoc analysis between subsets I would say though that this paper that I mentioned earlier from Christophe corpus show has proposed combining the liver stiffness with fiber scan with the globe score as a potential for regulators to use as an outcomes measure in studies and We're not prepared to do that quite yet, but I think that could be a direction that the field goes and could be quite important. So, personally, I'm quite excited about the GLOBE score. I think it gives you a lot of insight and information. If you had an opportunity to see our presentation, you can see the different ways we can dissect the parameters of response. And also, it was encouraging that through two years, almost every patient had a response, had an improvement. I think 94% of patients, of the 50 patients in two years, improved their GLOBE score.
spk06: So I think that's something to pay attention to.
spk16: Got it. And last one from us. You know, given that response has enrolled about 193 patients across about 160 active sites, How does the distribution of patients across sites compare to that of Enhance? And, you know, are there any regions or sites that are particularly enriched or deficient for patients?
spk10: That's a good question, Corey. Perhaps I'll just answer that one, and if there's anything I missed, Dennis can add on to it. Not dissimilar from Enhance, first of all, majority of patients, of course, come from the U.S., given the site distribution and the number of sites we have in the U.S., But I actually think we had very good representation globally in Europe, in Asia, as well as in particular, in this case, South America. And so there were certainly some countries in which we saw more of a contribution in enhanced countries, in fact, in response that may, in fact, have been impacted more so by COVID restrictions across the 15 months that we were enrolling responses. those restrictions perhaps were lighter in some other regions. And we continue to build in terms of relationships. There are many overlapping sites from our prior enhanced study, but there are many new sites in relationships and partners that we build even with respect to response. And so I think we actually had very good distribution across all of those regions in particular, Europe, Asia, and particularly South America, in addition to, again, the majority of patients coming from the U.S.
spk16: Excellent. That's all we have.
spk06: Congrats again, and thanks for taking our questions. Thank you.
spk04: Our next question comes from the line of Thomas Smith with SVB Securities. Please proceed with your question.
spk11: Yeah. Hi, everyone. This is Mike on for Tom. Thanks for taking our question. As you start to think about the transition to commercial operations, what kind of information do you hope to present in September at your upcoming virtual investor day? specifically on some of the initial learnings that you found and what metrics you expect to track as you move forward with the launch.
spk02: Yeah, thank you for the question. Yeah, we're looking forward to September. I think one of the things we want to try to do is take a bit more of a global view to all the planning that we've done and share some of the data that we have on both U.S., ex-U.S. geographies. We also are examining the payer landscape here in the U.S. We've already done some work in Europe. We'll share a little bit of that, too. We want to just talk a bit about that. both the commercial and government coverage landscape here and what we can expect around those issues. And I think the other thing I'll say is we're hoping that our go-to-market strategy formation that will stand up here in the second half of the year will go also to inform both not just our commercial, pre-commercial work, but also obviously our medical affairs focus as well. So I think the way we'll look to measure and evaluate things here will have a lot to do with our engagement with KOLs and how we'll go about engaging payers here in the pre-commercial setting to really begin to articulate a value proposition. So more to come on a lot of that, but we're really getting into a bit more detail here in the next few weeks.
spk06: Well, you're good. Thanks very much for all the color. Thank you.
spk04: There are no further questions in the queue. I'd like to hand Nicole back to management for closing remarks.
spk10: Thank you, operator. As we look ahead to the remainder of the year, we'll continue to focus on execution of response and all of the ongoing active studies being conducted to prepare ourselves for future regulatory submissions. Should the efficacy and safety data in our ongoing studies reflect what we've observed in our prior Phase 2 and Phase 3 studies, we believe Celadalpar, as we've mentioned, has the potential to significantly improve the lives of patients with PBC. I think it bears repeating. We continue to believe our development program remains one of the most robust and de-risked in this indication today. We see many opportunities ahead of us to unlock near-term and long-term value from Celadal PAR in PBC and look forward to sharing future updates as we make progress. We look forward to sharing more about our story and this opportunity during our virtual investor day on September 22nd that Louis spoke about. I'd like to thank everyone once again for joining our call today, and we look forward to speaking to you again very soon.
spk04: Ladies and gentlemen, this does conclude today's teleconference. Thank you for your participation. You may disconnect your lines at this time, and have a wonderful day.
Disclaimer