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spk04: Good day, ladies and gentlemen, and welcome to SEMA Bay first quarter 2021 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 up the call for questions. Please be advised that this call will be recorded at the company's request. It is also being webcast live on the investor section of SEMA Bay's website, at www.semabay.com. Now I would like to turn the call over to Mr. Dan Menel, Vice President of Financial at SEMA Bay. Mr. Menel, you may begin.
spk13: Thank you, Operator, and good afternoon, everyone. I hope that you've had a chance to review the press release we issued announcing our first quarter 2021 financial results and business updates. You can access that release on our website under the Investors tab. Joining me on the call today are Sujal Shah, Chief Executive Officer, Dr. Chuck McWhirter, Chief Scientific Officer, and Clara Dickinson, Chief Regulatory Officer. Sujal will provide an update on recent progress in the build-out of our leadership team to deliver on our value creation strategy. Chuck will discuss an update on our pipeline diversification, and I will provide a brief summary of our financials. Following our prepared remarks, we'll be available for Q&A. Before we begin, I'd like to remind everyone the statements made during this conference call, including the Q&A session relating to CIMA Bay's expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, and anticipated timelines and data release dates, cash runway, and planning for commercialization of any future products 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 upon 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 Sujal.
spk06: Thank you, Dan. Good afternoon and thank you for joining us today. Less than two months ago on our last call, we highlighted the initiation of response. Our global phase three registration study of Stella del Par for patients with primary biliary cholangitis or PVC. And the expansion of our clinical pipeline with MBX 2982 and CB 0406. This past Monday, And then again earlier today, we announced further significant progress with the strengthening of our executive team with the additions of Louis Stewart as Chief Commercial Officer and Dr. Dennis Kim as Chief Medical Officer. These seasoned biotech executives come with considerable talent and energy to apply their leadership and experience as we move into a period in which we plan to complete development and regulatory submissions for CELADELPAR, begin pre-commercial preparations, and continue efforts to diversify our research and development. I am extremely pleased to have Dennis Kim joining CIMA Bay as our CMO. Dennis is a physician scientist trained in endocrinology and with significant clinical development and executive experience in an emerging biotech environment that he acquired during substantial tenures at Amelin, Orexigen, and Zapgen. Dennis will join the executive team reporting to me and will lead all clinical functions, including development, clinical operations, biometrics, and medical affairs. His track record fits precisely FEMA Bay's need to have him lead a highly motivated and productive clinical function that is integrated with research, regulatory, manufacturing, business development, and commercial efforts. I'm confident that many of you will learn that Dennis also brings an acumen well-suited to articulate the science, medicine, plans, and opportunities of our programs to broad audiences, including medical experts, investigators, patient groups, investors, and analysts. I am equally delighted to welcome Louis Stewart as our Chief Commercial Officer. Just a little over two years before CELADELPAR's potential launch, this timing is ideal as we add a recognized commercial leader to implement a thoughtful and efficient build of both a strategy and an organization. Louis comes with deep experience in commercial leadership and product launches in the emerging biotech setting. We were deeply impressed by his knowledge and experience in a variety of situations, including at CV Therapeutics and most recently at MyoVan, both of which required the self-reliant approach of standing up a product launch, but also post-launch, they ultimately involved integrating marketing and sales efforts into much larger entities. Drawing upon this exposure to a broad set of practices, Louis will lead all aspects of the commercial function, including marketing and sales. He will join the senior team reporting to me and will be intimately involved in strategic planning across many functions. There will be many opportunities to get to know Louis as one of our spokespersons as he moves our commercial plans forward. I expect many will gain an appreciation for the energy and enthusiasm he brings that is grounded in his aptitude for acquiring knowledge and using critical thinking. The announcement of these critical C-level hires serves as a capstone to the continued progress we made as discussed in March with the initiation of two studies in patients with PBC, the Phase III Response Study and the Long-Term Safety Assure Study. Our remarks today will be brief, mainly reiterating our guidance on timing for these studies while providing some additional color on study population. We will also describe progress being made on MBX 2982 and CBO 406, our other pipeline projects, for which we expect to be able to provide further updates in the second half of 2021 as we seek to bring additional novel treatment alternatives to patients. We will conclude with key corporate and financial updates. Completing the development of CeladalPAR for patients with PBC remains our top priority. In the first quarter, we initiated response, a 52-week placebo-controlled randomized global Phase III registration study evaluating the safety and efficacy of CeladalPAR in patients with PBC. Response is intended to enroll 180 patients in a two-to-one randomization to oral once-daily Feladilpar 10 milligrams or placebo as an add-on therapy to patients with an inadequate response or intolerance to first-line ursodeoxycholic acid therapy. The primary outcome measure is the composite biochemical responder rate after 52 weeks for alkaline phosphatase and bilirubin, the same endpoint used to register Ocalibum. the only approved second-line treatment alternative for PBC patients. We expect our strategy for differentiation to potentially be significantly strengthened by two key secondary endpoints, the rate of normalization of alkaline phosphatase at 52 weeks and the change in puritis from baseline to six months in patients with moderate to severe puritis as reflected in a baseline puritis numerical rating scale value of four or greater. As many of you will know, the design for response and confidence in the selection of endpoints is significant given the shared population, endpoints, and the safety and efficacy demonstrated by the Celadal PAR 10 milligram dose in the completed Phase III study, Enhance, which was stopped early. The results for Enhance were presented in a late-breaking presentation at ASLD last November. Celadelpar 10 milligrams achieved a high degree of statistical significance for all three of the same endpoints being used in response after only 12 weeks of treatment. Our approach in the development program for Celadelpar is to collect data necessary to characterize the benefit-risk of Celadelpar across the broadest population of patients with PBC. We have been asked recently about patients with PBC and their underlying stage of disease as it relates to cirrhosis. Broad categories of increasing severity of fibrosis can be described as non-cirrhotic, compensated cirrhotic, and decompensated cirrhotic. Within compensated cirrhotic are sub-stages of patients with and without clinically significant portal hypertension. Clinically significant portal hypertension develops as the fibrotic liver becomes increasingly stiff and is thought to often be a precursor to decompensating liver-related events. Measuring portal hypertension is an invasive burdensome procedure, and so a clinical signature for clinically significant portal hypertension can come from a number of less invasive criteria as recommended in published practice guidelines. Across two significant studies with Celadelpar enrolling more than 360 patients with PBC, there were over 50 patients with compensated cirrhosis, some of which were treated for two years or more. And clinical data from some of these have been highlighted in published abstracts and presentations given at past medical meetings. Due to the identical eligibility criteria and overlap with clinical sites, we expect a majority of patients that enroll in response to also be non-serotic, but would nonetheless expect somewhere around 15 to 20% to be compensated serotics. Patients in this population would eventually be in the target population, and so it is important that they be studied for safety and efficacy. In this quarter, we continue to make headway with our clinical development program for Celadalpar, including activities for other NDA-enabling drug-drug interaction studies and special population studies for patients with renal impairment and PBC patients with hepatic impairment. Results from the hepatic impairment study in particular will provide valuable insights into the exposure and potentially the safety and efficacy of Celadalpar in PBC patients with various degrees of cirrhosis. In the first quarter, we also initiated Assure, an open-label long-term study of CeladalPAR in patients with PBC in order to collect additional safety data to support registration. We expect CeladalPAR to have one of the most robust safety databases in PBC patients ever submitted for an NDA. Our most important focus remains to accelerate site activations, screenings, and randomizations in response over the coming quarters. Our efforts in response with 80 fewer patients are nonetheless on the same scale globally as they were for enhanced. This is being done in an effort to mitigate challenges posed by the pandemic and greater competition for patients. It remains our goal to enroll the study by the end of the year, and we will look to provide additional updates on timelines later this year. Now, let me turn the call over to our Chief Scientific Officer, Dr. Chuck McWherter, to cover updates on our early clinical stage MBX2982 and CB0406 programs. Chuck?
spk08: Thanks, Sujal. I'm pleased to announce that the first patient visit has occurred for the phase 2A proof of pharmacology study with MBX2982 using hypoglycemic insulin clamp procedures in patients with type 1 diabetes. The study is being conducted at AdventHealth Translational Research Institute in Orlando, Florida, and it's fully funded by the Leona M. and Harry B. Helmsley Charitable Trust. Seema Bey retains all rights to MBX 2982. This is a double-blind, randomized, placebo-controlled two-period crossover study that will examine the effect of MBX2982 versus placebo to stimulate the release of glucagon under hypoglycemic conditions in type 1 diabetes. The endpoints will be maximal glucagon release and area under the curve for glucagon concentrations. The study is intended to include about 30 subjects, and the investigator believes it will be complete in the second half of this year. As a brief reminder, MBX2982 is a GPR119 agonist discovered and developed by Simabay. It has completed five previous clinical studies, including in pre-diabetic and diabetic subjects. The product concept being investigated for MBX2982 is as an agent to potentially prevent hypoglycemia in patients with type 1 diabetes, a significant cause of morbidity, and a risk for mortality in individuals with type 1 diabetes. Its action is expected to result from the stimulation of glucose-regulated release of glucagon, the counter-regulatory hormone to insulin, which is secreted from pancreatic alpha cells and which serves to return low blood glucose levels to normal in hypoglycemic conditions. In recently published studies with isolated human pancreatic islets, GPR119 agonists were shown to enhance glucagon secretion in response to low, but not to high glucose levels. And further, they were able to prevent insulin-induced hypoglycemia by increasing glucagon secretion in a RAP model. The translation of these findings to the clinic is being evaluated in this phase two wave proof of pharmacology study. We continue to progress with the phase one single ascending and multiple ascending dose TK study of CB0406, and expect to have results to share later this year. The objective of this study is to establish its pharmacokinetics, safety, and maximum tolerated dose in healthy subjects. As a reminder, we are evaluating CB0406, the active metabolite of the prodrug arachlophenate that had previously been studied in diabetes and gout. CB0406 is a PPAR gamma non-agonist ligand that attenuates the expression of inflammatory genes. It has been shown to block innate immune responses through the NF-kappa B and NLRP3 inflammasome pathways. In published studies, NLRP3, caspase 1, and IL-1 beta were all decreased by CB0406 in response to inflammatory triggers in macrophages. It was also shown to attenuate the NLRP3-dependent pathophysiology of gouty inflammation, when dosed as the prodrug in a mouse model, and also in a Phase II clinical study in gout patients. Based on pharmacokinetic studies in monkeys, we believe that CB0406 may have greater exposure, potentially greater efficacy, than does a prodrug R-halophenate. Decisions on any future development are contingent on its achieving a favorable profile with respect to safety and exposure. We believe CB0406 may have utility in various inflammatory diseases and are currently exploring potential opportunities to advance this development pending the results of the ongoing Phase 1 study. Sujal?
spk06: Thank you, Chuck. Although this business update is coming only a few weeks since our last earnings call, we would point to significant news. The importance of filling the commercial and clinical leadership roles with Louis Stewart and Dennis Kim is worth emphasizing. Since the lifting of the hold on Celadelpar, we have aggressively filled out the roster of talent up and down the organization, including leadership at all levels and on our executive management teams. In early April, we expanded and strengthened our board as we announced the appointment of biopharma veteran Tom Wiggins and commercial leader Janet Dorling. Tom's experience leading such biopharma companies as Dermira, Peplen, and Kinetics through development to commercialization makes him a perfect addition to guide CIMA Bay through our next phase of business growth. He has a distinguished career, both as an operator and director across numerous pharma companies. Janet knows us well, having been our past chief commercial officer. This gives her unique insights into Celladel PAR's potential opportunity to significantly advance patient care in PBC. This, coupled with her executive leadership as a commercial executive at two of the most successful biotech companies in the world, Gilead and Roche Genentech, should enable her strong strategic and operational contributions to the company in the years ahead. Progress on response, assure, and other NDA-enabling studies for Cellidel PAR in PBC is being made every day. Throughout the company, it is clear that completing the development of Cellidel PAR for PBC is imperative above all else. Even so, we had important progress with the first patient visit for the MBX2982 proof of pharmacology study, and the phase one study for CBO46 is nearing completion. The progress on our portfolio through our people highlighted today is something that we will continue to emphasize. Finally, before we turn to Q&A, I'll ask Dan to provide a brief summary of our financials in the first quarter. Dan?
spk13: Thank you, Sujal. Over the course of 2020, we successfully managed our overall cash expenditures while we completed our NASH study investigation, obtained the FDA's clearance to restart development of the Cell Adelpar program, and commenced our response and assure clinical studies and other NDA-enabling studies necessary to complete our late-stage development of Cell Adelpar and PBC. Our emphasis on operating efficiency continued into Q1 of 2021, albeit balanced against our need to increase our spending appropriately to support our expanding clinical development activities in PBC and other development initiatives. Overall, we completed the quarter ended March 31st, 2021, with cash, cash equivalents, and short-term investments totaling $125.5 million, which we believe is sufficient to fund our current operating plan, including the execution of the development program for Celadelpar and PBC into mid-2022. Turning now to a brief review of our operating results, net loss for the three months ended March 31, 2021, was $17.6 million, or 25 cents per share, compared to net loss of $13.1 million, or 19 cents per share, in the three months ended March 31, 2020. Net loss was higher in the three months ended March 31, 2021, compared to the corresponding period in 2020, primarily due to an increase in operating expenses. including clinical trial and labor-related expenses as a result of our continuing efforts to conduct response, assure, and other late-stage clinical activities associated with our development of Celadalpar and PBC. As mentioned in our prior updates, given the FDA's lifting of the clinical holds on the Celadalpar program last year in July 2020 and our subsequent restart of Celadalpar and PBC and further exploration of other clinical development opportunities, Our cash expenditures are expected to increase in the future as we advance our restarted clinical development programs and activities. Finally, I would like to provide you with a brief update on our current operating environment. Due to the ongoing impact of the global coronavirus pandemic, we continue to conduct operations remotely for all employees, which has allowed business activity to continue as seamlessly as possible. While vaccination progress worldwide in the first quarter of 2020 was encouraging, it is still ongoing. Therefore, we will continue to closely monitor pandemic development and their associated risks to our business, including our ongoing clinical development of Selladel Park PBC, and we will continue to take actions available to mitigate these risks where possible. As always, all our actions will continue to be guided by a commitment to ensuring the health and safety of our employees, as well as patients enrolled in our clinical studies.
spk06: Sunil? As Dan described, we continue to be very capital efficient. Our balance sheet supported the intensive work we completed in 2020, leading to the restart of clinical development of Cell at LPAR earlier this year. allowed us to both accelerate our activities in PVC and expand our pipeline, and has also given us an opportunity to add critical resources across the organization. With cash into mid-2022, we have not been limited in the execution of our operational objectives. As we look to the future, we are grateful for the level of support we are getting from investors interested in continuing to see us achieve our long-term strategic goals, and we believe we have access to multiple potential sources of capital, several of which may be non-dilutive. As we approach the halfway point of 2021, we eagerly look forward to sharing our progress with you in the second half of the year. We're now happy to take questions. Operator?
spk04: Thank you. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. And for participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Our first question is from Yasmine Rahimi with Piper Sandler. Please proceed.
spk05: Hi, team. Thank you so much for sharing all the updates. A few questions for you. Maybe the first one is timeline-related. Can you just maybe provide some color if you're still planning to be on track on enrollment completion for end of this year to ensure top line data for late 2022, early 2023? And then I have a regulatory question.
spk06: Yeah, thank you for the question, Yasmeen. You know, we continue to make significant progress every day. You know, all of this effectively is counted by country approvals, followed by site activation, screenings, and randomization. So as we've discussed a bit in the past, you know, here with respect to response, we anchor on the very significant experience of the global clinical study enhanced, where we had randomized 265 patients in just under a year. So our objective remains to enroll response by the end of this year. We're still in that early part of the curve where things continue to accelerate significantly as we get more sites activated. I think we've discussed also, Yasmeen, that there's no question the global pandemic is a factor, is a headwind, as is greater competition for patients today than when we were in rolling enhance. But our efforts for response are on the same scale. as we executed for enhanced despite looking to target a randomization of 80 fewer patients. So fundamentally our strategy remains for this global significant effort to offset those headwinds. I think it'll be important for us as we continue to see this progress we're making every day to reassess on a quarterly basis. As of now, it remains our goal, Yasmeen, to get this study completed by the end of the year, and that would effectively put us in a position of having top-line data by the end of 2022 or very early 2023.
spk05: Thank you, Sudal. And thank you for highlighting that you guys are doing the hepatic impairment study as well as the data on the two-year study of 50 patients that are compensated with, you know, efficacy and clean safety. I just want to understand, do you think that that data as well as the result from the hepatic impairment would be sufficient that the ultimate label would allow you to dose compensated patients with portal hypertension? Or do you think the FDA stance at this moment is that no therapy at this point should be given to this patient population? If you could just drill down a little bit more, that would be helpful for us.
spk06: Yeah, certainly, Yasmeen. I think as we've discussed previously in our prior phase two as well as the enhanced study, we have had patients that have been well-compensated cirrhotics, some actually with portal hypertension. So, this is an area in which we continue to further investigate. It is an area that we expect to continue collecting both safety as well as efficacy data in the population. And I think this question will continue to be answered by the datasets themselves. And perhaps I'll invite Chuck to speak more specifically around what we've learned thus far and what's important for us to evaluate as we go forward.
spk08: Yeah, sure. And thank you for the question, Yasmeen. You know, as Sujal said, we've, across all our studies, we've enrolled more than 360 subjects with PBC. Yeah, roughly about 15 to 20% have cirrhosis. We did find patients that we enrolled that had clinically significant portal hypertension, which in a compensated cirrhotic patient reflects a higher risk for liver-related or decompensation events. Just for background, these could be things like liver bleeds, ascites, or encephalopathy. There are medical complications that themselves require invasive intervention and reflect increasing likelihood for poor prognosis. So the ability to deliver efficacy in that population, there is an unmet need there. So evidence of portal hypertension, measuring portal hypertension is an invasive procedure. And so evidence for it can come from a variety of ways using laboratory findings or non-invasive imaging. This could be things like low platelet counts or typical of a routine ultrasound. can detect an enlarged spleen. And there are some other imaging methods that can detect evidence of portal hypertension without actually having to go through complicated procedures. So we do have some data there. In 2019, at ASLD, we had a poster. I think that's still available on our website. We did a small PK substudy in patients with PBC. And we found that it was reasonably comparable exposure, so there was not a real large difference, just about a two-fold increase in steady-state exposures. And as you can see in the baseline demographics, you can detect that many of these patients had evidence of portal hypertension. So we'll, as Sujal said, we'll continue to expand the study of this important population. We so far feel like the experience has been favorable, but As always, this is something that we have a responsibility to confirm with our both response study and our Assure study.
spk05: Thank you so much, Chuck. And then one last question that we've been getting from clients is, in the past we have spoken with strategic partnership on Stella Delta and NASH, but maybe what would be helpful to understand this is, are the strategic players who are interested in NASH maybe the same players who are interested in and having a therapy such as Salisbury and PBC. If you could just comment on that to the extent you can, that would be helpful for us. Thank you.
spk06: Yeah, sure. Yeah, happy to address that. I think as you're quite aware, NASH and PBC, although both are chronic inflammatory liver diseases, in the one case, you know, you have a highly prevalent disease for which there are no current treatments with respect to NASH. I think some growing level of questions around regulatory hurdles as well as profiles for agents that have been studied to date in that setting. You know, PBC is an area of high unmet need as well, and although there are two approved treatments, there are significant unmet needs for PBC patients. A very straightforward regulatory pathway, of course, in the setting of PBC in an area in which we have significant data that we believe continues to de-risk cell at LPAR. When you ask specifically about strategics, I think there are certainly some who are focused in the liver space in both large unmet need areas and highly prevalent diseases like NASH. as well as an interest in areas like PVC, although there are also some that are more specifically focused on rare and orphan diseases versus others that really are predominantly focused on disease like NASH. So it's a bit of a bifurcation, Yaz. I think there are quite a few players that are solely focused in the area of NASH, and then there are some that have a more holistic approach to treating patients with liver disease.
spk05: Thank you, Sudal, and thank you, Chuck.
spk09: Yeah, thank you.
spk04: Our next question is from Steve Seedhouse with Raymond James. Please proceed.
spk10: Yes, hi. This is Timur Ivankov on for Steve Seedhouse. And so we just wanted to clarify, it sounds like you haven't started dosing in your phase three response study. So if you just can clarify that. And then also in terms of the recruitment in the response study, So we see 11 sites are up in the U.S., and one site is up in Italy. So is this current split driven more by COVID, or is it more by competition? Because I think Jensen is trying to read out around the same timeline as you are.
spk09: Yeah, good question.
spk06: So, you know, first of all, responses has initiated. So we are, in fact, screening and randomizing patients in that study. So randomization has, in fact, begun in response. To address your question around the sites that are updated on clintrials.gov, of course, we try to update those as frequently as we possibly can. They're not seamless in terms of timelines to getting that information uploaded. But, you know, our approach is one in which we're really leveraging the experience that we had, again, for enhanced. That was a study for which we had actually activated sites in 20-plus countries around the world. Of course, in the U.S., Given where we are with vaccinations and the numbers relative to the coronavirus pandemic, there's a real opportunity here to accelerate site activations, approvals here and site activations, and begin screening and randomization most predominantly in the U.S. And then when we look at countries in Europe, you know, these are things that we do really largely in parallel. So what you see as a reflection on CLIN trials is simply where we've been able to accelerate the approval processes from IRBs and ethics committees. In some cases, those take longer timelines just depending on the country. But I simply say that the process internally here is one in which we try to parallel as many of those country and site activations as we possibly can. Of course, they don't all happen instantaneously. It is a process in which we expect these to continue to accelerate through the rest of this quarter and beyond.
spk10: Okay, thank you, Sajil. And then also, in the past, I think you talked about encouraging patients to get a baseline biopsy in response, just like you did in enhanced. And could you remind us what proportion of patients in ENHANCE got baseline biopsies, and is that sort of your goal for response?
spk06: Yeah, it's a good question. So we had about 15% of patients randomized in ENHANCE agree to a baseline biopsy. Once again, in that study, those patients would not have had a second biopsy until perhaps two to three years into the long-term study. And so as we've discussed in the past, the change here with respect to response, the patients that do volunteer to have a baseline biopsy will have a second biopsy at 52 weeks as an additional safety assessment. And although it's voluntary for patients as to whether or not they elect to get a biopsy in this study, it is required for us to have a subset of patients, of course, for an additional safety assessment at the time of NDA submission. We've had a very open dialogue with the agency around this threshold based on the 15% we achieved in enhance. Of course, our goal is to achieve something greater, but we made a proposal to the agency that they accepted based on our significant level of experience here. This was not prescriptive. It was a very constructive dialogue, I would simply say, and we're confident that we can meet the requirement that's set forth for us here.
spk10: Okay, great. Thank you.
spk09: Thank you.
spk04: Our next question is from Patrick Dozal with Lakeside Capital. Please proceed.
spk11: Hi. Thanks for taking the questions. Just to end the response trial and roles, and there's a bit of downtime ahead of data, just curious if you have any further position KWA offers planned to keep the community engaged during this time. And I know it's early considering you just brought on Louis as Chief Commercial Officer, What pre-commercialization efforts, I guess, when will those efforts begin to ramp, and what will those look like?
spk06: Yeah, thank you for the question, Patrick. You know, we're like-minded, by the way, with the suggestion in your question. We've actually already begun some of the work around market research and pre-commercial efforts. So Lewis has, of course, come on board this week and really hit the ground running with It is absolutely our goal to continue to communicate our strategy and our pre-commercial planning and commercial plans ultimately. And I would simply say this, Patrick, I think as Lewis gets integrated to the team here internally and the work that's already been done and continues to effectively help us think about the commercial strategy for Sell at Elkhart going forward, we will in fact look to have an investor day in the second half of the year, perhaps even two, one that I would envision being centered around CELADELPAR for PBC, anchored around some of the opportunities we think with respect to commercial opportunity for CELADELPAR and perhaps even lifecycle management going forward. And then potentially a second that's more centered around the earlier stage pipeline with respect to MBX 2982 and CBO 406. Of course, our goal is to make sure that there's a meaningful amount of update and information for us to share. But I would absolutely envision us doing that in the second half of this year.
spk11: Got it. That's helpful. And, you know, I know you've talked about primary sclerosis and cholangitis before. I would love to hear how you're currently thinking about potential cell delpar in the syndication and kind of ultimately just how you're thinking about a go or no-go decision in pursuing the syndication at the moment.
spk06: Yeah, no, another good question, Patrick. Look, I think fundamentally there's no question in our mind that the opportunity for Celadelpar and PBC is of central focus, and one for which, as we've discussed, if we execute appropriately, we have an opportunity not just to be preferred second-line treatment alternative of choice, but potentially to collect data sets that really start to expand the overall addressable patient population, potentially in a very significant way. And so we continue to remain highly focused on that objective. We do believe, based on the profile of Celadalpar in PBC as a cholestatic disease, that there is, of course, promise potentially for the potential of Celadalpar in the setting of PSC. There's no question patients with PSC are more heterogeneous, often with more advanced fibrosis, often with biliary strictures. complications also including comorbidity with inflammatory bowel disease. So it is a more complex patient population. And our approach here, Patrick, is really to think about two things. One, just the early focus for us to make sure that we get response enrolled as quickly as possible, the most near-term de-risk opportunity. And then two, to really reconvene with a set of experts in the setting of PSC, where we're continuing to learn more and more about the disease and about treatment alternatives, and then really put together the right development program in a setting of PSC and communicate that when our plans are effectively set and we're ready to act behind it. But it remains an area of focus. It is an area that we recognize as high unmet need. And when we step forward into PSC, we want to do so with a really meaningful and focused development program that's going to generate the kind of data set to really inform a path forward.
spk11: Appreciate that. Congrats on all the progress. Thank you.
spk04: Our next question is from Mayank Mantami with Beverly Securities. Please proceed.
spk03: Thank you so much for taking my question. This is William Wood on for Mayank Mantami. I was curious, how does the Caliva label update read through to Stella Delaporte?
spk06: Well, I think, you know, again, perhaps I'll invite Chuck to talk more specifically about what we know today. Of course, we only know what's been made publicly available by Intercept to date, and we don't yet have the revised label, of course, for betacolic acid just yet. You know, we recognize that very likely, as Intercept has articulated, that there could be further restrictions, particularly for patients with compensated cirrhosis and clinically significant, perhaps, portal hypertension. As we've discussed, this is a patient population for which we've collected some data. You know, in addition to having a sense of the efficacy, which is comparable in the subset of patients we've studied thus far with compensated cirrhosis as it is with those that are non-cirrhotics, We also see comparable safety to date in those subset of patients. We think that could be potentially a significant differentiator, but there's much more data for us to, of course, collect. But perhaps, again, here I'll pause and see, Chuck, if you'd like to add any additional color.
spk08: I think that's a pretty good summary. Just to reiterate, it's really important that you study a broad population of PBC patients. You would typically expect that if you're safe and effective, that the population you study will be the label that you receive. But even beyond that, there's a potential for patients who are treated once the drug is marketed for those patients to progress. And if they progress into advanced disease that hasn't been studied, that's a problem. So you do have to study those patients even if you're not seeking an indication. But for us, I think right now the inclusion, the eligibility criteria really has been non-cirrhotic and compensated cirrhotic patients with PBC. We have included some patients with clinically significant hormonal hypertension. And if we can confirm the benefits for safety and efficacy, it's a potential path forward for us to have that to be the indicated population. But we'll We'll have to wait and see what response tells us.
spk03: Thank you so much. And then one second question. Could you provide any update on how you were thinking of the next steps in NASH?
spk06: Yeah, sure. Look, I think our strategy is really consistent with what we've outlined in prior calls with our focus on PBC. The plan, fundamentally based on a data set in NASH, is to have conversations with other strategics who particularly have assets that can complement the effects we've seen with Celadalpar. Just as a reminder, we saw significant effects, in fact, on reducing fibrosis. In our Phase IIb study, although the study wasn't designed to show statistical significance there, we did see meaningful effects, 37% of patients at our 50-milligram dose group with a one-point or greater improvement in fibrosis and no worsening of NASH versus 20% on placebo. The overall profile of Celadelpar is an anti-inflammatory, and now with these data showing the anti-fibrotic effects, we think could be quite complementary to a target that otherwise can either cause weight loss or a more significant reduction in total liver fat. And so these are things that we've talked about, we continue to talk about with other strategics. Also very important that any path forward brings with it a partnership with significant resources. Today, we do believe that the most, you know, fruitful and de-risked opportunity for us is to continue to conserve our capital for what is a very near-term significant opportunity. We believe in PBC first and foremost. And so we've articulated that we will not carry forward, once again, in NASH solely on our own, again, without a partner with significant resources and the right complementary assets. So those conversations are ongoing. They continue. Of course, they're never done until they're fully completed. But we do think Salad Alpar has a promising profile here and will continue to carry on those conversations.
spk03: Thank you so much, and thank you for taking my questions, and congratulations on all your efforts.
spk09: Thank you. Thank you.
spk04: Our next question is from Jay Olson with Oppenheimer. Please proceed.
spk12: Oh, hey. This is Matt on for Jay. Thanks for taking our questions. So we were wondering, for CB0406, your P per gamma, we were wondering if this compound has any CNS penetrability and if that's something you're looking at in the phase one study. And then also, which potential indications, I know it's early, but at the moment, could you potentially envision pursuing ultimately with that asset? That would be great. Thank you.
spk08: Yeah, thank you for the question. This is Chuck. I would say fundamentally that we have not seen, we don't believe that this would be a drug that would potentially be targeted towards CNS indications. We do think this pathway, the NLRP pathway we recognize has got a lot of attention with respect to neurodegeneration, but that wouldn't be our focus. In terms of what we might focus on, I will say that we're very excited based upon the clinical validation of the target and a lot of emerging science in inflammatory-driven diseases, including ones that drive fibrosis. We're not really ready quite yet to give any specific guidance, But I think it would suffice it to say that, for us, it starts with the scientific rationale, the medical need. Is there a medical need here? Do we believe that it would be differentiated? Development plausibility, is there a regulatory pathway? Is it feasible to accrue patients and do a trial in a capital-efficient way that gives a meaningful result? And then, of course, there's always the business case. We have to understand the market. what the unmet need is, what the existing therapies, if any, and if there are any emerging therapies so that we have a full view of the landscape before we make a decision. So I think, as we alluded to before, we think that once we have the phase one data in hand and we've completed some of our diligence around making a selection from, honestly, quite a number of opportunities that fit what I've just described, we'll be able to communicate that in the latter half of this year.
spk12: Okay, got it. That's really helpful. Thank you. And then we were just curious if you could please remind us, actually, the expected IP expiration on CELA DELPAR. Really appreciate that. Thanks.
spk06: Yeah, absolutely. So CELA DELPAR has composition of matter to 2026. The lysine salt form, which is the only form that's being developed, carries to 2026, and that's without the potential for an additional five-year patent term extension. Importantly, in the setting of PBC, so again, so on the composition of matter could, in theory, be taken to 2031. There are use patents already issued as well for Celadalpar in the settings of cholestatic diseases, PBC, PSC, as well as in NASH and NAPL. Those all go to 2035. And then also we have orphan drug designation in the U.S. and in Europe, so the exclusivity associated with orphan drug designation exists for Celadal for on the setting of PBC as well.
spk12: Okay, awesome. Thank you so much. Congrats on all the progress, and thanks again for taking the questions.
spk09: Thank you.
spk04: Our next question is from Ed Arce with HC Wainwright. Please proceed.
spk02: Hi, thanks for taking my questions and congrats on the recent progress, including the filling of your executive team. Some of the questions I had already been asked and answered, but I did have a couple related to MBX 2982. You had mentioned that your goal is to enroll 30 subjects via the investigator who's doing this by the second half of this year, and the primary endpoint is maximum glucagon release. My two questions around this program are where does that endpoint fit in sort of the regulatory pathway? How well-defined and validated, is there a pathway for this specific indication? And then related to that is what exactly does the landscape for this indication look like and where would you potentially see it fitting in if indeed there are others already on the market?
spk08: Yeah, I'd be happy to take that question, Ed. Thank you. It's a very interesting and important question. Just to emphasize that the study that we've started is a proof of pharmacology study. So as what you've alluded to, it's not actually directed at what you would expect to be a regulatory endpoint. The first thing that we're trying to establish is that we can affect the increase in glucagon secretion in response to the hypoglycemic clamp, so low sugar, low blood sugar conditions. That will be benchmarked. The study includes both type 1 diabetics and healthy volunteers, and we'll be able to benchmark the responses that we see in the diabetics versus what we see in the healthy volunteers. Now, we also do include continuous glucose monitoring in the study. So we'll be able to examine the effects on restoring glucose levels as well. So that's an important aspect to it. In terms of the product concept, there is no product on the market right now that's a preventative for hypoglycemia. And so the challenge for a type 1 diabetic who's using insulin to try to control their blood glucose, there are always concerns. a potential risk of insulin-induced hypoglycemia. Especially, as you know, type 1 diabetes can be something that emerges in childhood or adolescence, so you have families that are concerned about their children. Hypoglycemic episodes can happen nocturnally overnight while you sleep, so there wouldn't be anybody around to help deal with the situation. Now they're typically dealt with, for example, just by taking glucose by mouth. You can take glucose pills. But there are marketed rescue therapies, glucagon, sublingual glucagon. There's glucagon pumps that are being developed as well. But these are all just rescues. They don't actually deal with the unmet need of having a preventative, really providing the patient and their families with the confidence that they no longer have to be concerned by low blood glucose and that they basically can be more intentional about using their insulin appropriately to get better glucose control. I think in terms of regulatory endpoints, I'd just say that this would be a first. So that would, of course, have to come through first developing the concept, conversations with experts, regulatory interactions. But in our mind, in early discussions, it would really be about preventing either moderate or severe episodes of hypoglycemia. And so those have clinical definitions with various levels of glucose, glucose concentrations that define those. And you could use continuous glucose monitors as a way to make the measurements to evaluate the endpoints.
spk02: That's very helpful. Thank you for that. So just as a follow-up, how would you envision moving forward taking over from AdventHealth? Were you to see, you know, significantly positive effects here that would lead you to to want to move forward with this asset?
spk08: Well, I think we would take the approach that we always take, which is we engage with external experts and, you know, develop a deeper understanding of the indication the patient needs, the clinical development, as well as what we would understand to be the regulatory environment. So that would require specific regulatory interactions to help define it. And then of course, importantly, you're not going to make significant investments without doing a deeper dive, a full analysis on the business case. What is the commercial opportunity like? And then finally, we'd have to evaluate what's the strategic fit with CIMA Bay at the time. Where does, where do our other assets lie? What are our aspirations and what does the company want to become? need to make a decision assuming all of those things lined up. You know, what's the best for the asset? What's the best value we can create to deliver both to patients and to, of course, ultimately to shareholders? So we would have, we would take that all in and I think make an objective assessment. Let's say it was extremely positive. Perhaps this would fit well with SEMA-based future plans or perhaps we would come to a determination based upon gaining further understanding that there might be other entities who are maybe more fully vested at the moment in type 1 diabetes who could make more of it than we could.
spk02: Okay, very good. That's very helpful, Chuck. Thanks for your perspectives.
spk04: Our next question is from Athea Young with Cantor Fitzgerald. Please proceed.
spk01: Hey, guys, thanks for taking my question. Congrats on the progress. Two questions for me. One, can you talk a little bit about alternate financing? Since I think you mentioned there were potential for non-diluted options, just wanted to get your thoughts on that. And then as it relates to 0406, you know, have you specified what might be some interesting other programs to go after? I apologize, one more. Just what are the plans and thoughts around Next Generation Cell at Delphi, I think?
spk06: Yeah, sure. Thanks for the questions, Alethea. So I'll start off with the first and maybe ask Chuck to comment again on 0406 here. You know, I think fundamentally we've had, I would say, you know, proud of having a long track record of successfully financing SEMA Bay with really quality investors. And as we have continued to share data sets that de-risk sell at LPAR, we believe in the setting of PBC, we continue to see significant interest from investors around various different sources of capital. Given how de-risked sell at LPAR is, having phase three data set, albeit from a study that was terminated early, we also think that there are avenues and potential structures available that are, in fact, non-dilutive, typically avenues and structures that would be available for assets that are either approved or approaching approval. So fundamentally, I would simply say that, you know, from our perspective, we always think about capitalizing companies to the best of our ability on behalf of our existing stakeholders and shareholders. And we think evaluating various alternatives, inclusive of some of these that are non-dilutive, is prudent on behalf of our stakeholders. And in fact, we're confident that we can do the right thing for the company at the right time. Chuck, do you want to talk a little bit more about CB0406? Again, there's much of what we'll likely discuss around paths forward that will come after we conclude the Phase 1 clinical study, but I don't know if there's anything more you wanted to say about NLRP3 overall.
spk08: Yeah, just that I think that it's very evident. Even a cursory look in the literature will reveal many, many different opportunities where NLRP3 drives inflammation, which then is linked, for example, to fibrosis. I think our focus is, you know, a company that's really delved into rare diseases, whether it be in the liver or, you know, related therapeutic areas. I think adjacent ones, you know, you think of the GI tract and some others you could easily think of makes a lot of sense. So I think that's the kind of thing that you should think of. We're not going to pursue really large, say, primary care indications that really just don't fit with the kind of company that we are and want to be in terms of capital efficiency. At this point in time, there's a number of ideas that we have that we just really can't comment on yet, maybe because they're not certain, but also we have some IP considerations that we we're currently actively involved in working on.
spk06: And to your last question, Alethea, with respect to cell and LPAR and opportunities to continue to invest in the future, I think when we look at our data sets thus far, we're incredibly encouraged by the potential differentiation around alkaline phosphatase normalization, effects on alleviating the symptoms of puritis, which have not been shown with even first-line treatment alternatives for PBC patients today, nothing approved for treating cholestatic itch and puritis in PBC patients. These are some of the things that we are largely anchoring around. There are patients whose alkaline phosphatase remain elevated above the upper limits of normal, and while classically they've not been defined as second-line treatment patients where alkaline phosphatase is, say, above 1.67 times the upper limit of normal, they remain at a high risk of disease progression. So having an agent that's both effective as well as safe and well-tolerated for that particular patient population is another potential avenue for growing the addressable patient population for celadal PARs. These are some of the areas in particular that we're intrigued in terms of potentially investigating as we move the program forward to completion.
spk01: All right, great. Thank you very much, guys.
spk09: Thank you.
spk04: And our final question is from Derek Artillo with Faithful. Please proceed.
spk07: Hey, thanks, guys. This is Ben Porter. I'm for Derek. Thanks for squeezing us in. Most of mine have been asked, and sorry if I missed this, but just on 2982, have you guys given any thought to how you're going to present the data from the Phase 2A, whether it's at a medical conference or just issue a PR? Any thoughts there would be great. Thanks.
spk09: Yeah, I mean, it's always been our team.
spk08: Yeah, go ahead, Chuck. I'm sure we're going to say the same thing. It's always been our approach to present our data at the appropriate scientific or medical forums. So, of course, we're partnered in this case with an investigator, and we would need to align with them. But I think that's actually the intent and the objective. The Helmsley Foundation is to create new science that speaks to a potential avenue that could meet an unmet need for type 1 diabetics. I feel confident that that's the route that we would go when we get results. We'll seek to share them.
spk09: Okay, thanks. Thank you.
spk04: We have reached the end of our question and answer session. I would like to turn the conference back over to management for closing remarks.
spk06: Thank you, Operator. And thank you all for joining us again today. You know, we spent the majority of our time in Q1 on reinitiating our global studies for Celadal Farm PBC. And thus far in the second quarter, we've made further progress with this key primary focus. We've continued to advance two promising early pipeline programs. As you've heard today, we've made significant additions across the organization with experienced leaders up and down our teams. We look forward to sharing significant updates with you as our activities accelerate in the months ahead. Thank you.
spk04: Thank you. This does conclude today's conference. You may disconnect your lines at this time, and thank you for your participation.
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