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spk03: Good day, ladies and gentlemen, and welcome to SEMA Bay's fourth quarter and full year 2021 financial results and business update conference call. At this time, all participants are in listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised that the call will be recorded at the company's request. It is also being webcast live on the investor section at the SEMA Bay website at www.semabay.com. Now I'd like to turn the call over to Mr. Paul Quinlan, General Counsel at SEMA Bay. Mr. Quinlan, please proceed.
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 fourth quarter and full year 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 Sujul Shah, Chief Executive Officer, Dan Minold, VP Finance, Dr. Chuck McWhorter, Chief Scientific Officer, Dr. Dennis Kim, Chief Medical Officer, and Louis Stewart, Chief Commercial Officer. Following our prepared remarks, we will open the call for Q&A. Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session, relating to CIMA Bay's expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, funding and repayment schedules, anticipated timelines and trial enrollment 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 uncertainty and could differ materially from those forecast due to the impact of many factors. The company assumes no obligation to update or supplement any forward-looking statements, whether as a result of new information, future events, or otherwise, except as required by applicable law. Participants are directed to the cautionary statement set forth in today's press release. as well as the risk factors set forth in SEMA Bay's quarterly and annual reports filed with the SEC for factors that could cause actual results to differ materially from those anticipated in the forward-looking statements. This conference call is the property of SEMA Bay, and any recording or rebroadcast is expressly prohibited without the written consent of SEMA Bay. At this time, I'd like to turn the call over to Sujil.
spk12: Thank you, Paul. Good afternoon, and thank you for joining us. Today, we will discuss highlights of our 2021 accomplishments and review recent progress we have made advancing the development of Celadalpar, our lead phase three candidate for patients with the rare autoimmune liver disease primary biliary cholangitis, or PBC. and on the key milestones we believe we are well positioned to achieve in 2022 and beyond. Highlights of our accomplishments in 2021 include many important areas impacting our primary objective of improving the lives of patients with PBC. These include the initiation and advancement of our global phase three clinical development program, presentation and publication of data at important medical meetings and in peer-reviewed journals, execution of two successful financings, and the addition of experienced, dedicated team members across the organization. At the beginning of 2021, we reinitiated what we believe is the most extensive program for any investigational drug currently in development for treatment of PBC. In addition to several NDA-enabling studies, we initiated two global studies in patients with PBC. Response, the primary phase three efficacy and safety study to support marketing approval, and Assure, a long-term safety study to complete a comprehensive patient safety database. These studies draw from the extensive experience we gained from our prior phase two and phase three development, where data has continued to support the potential for Celadalpar to address many of the unmet needs faced by patients with PBC. The presentations and publications we made in 2021 highlight the potential for Celadalpar to address three important unmet needs for patients with PBC. First, many patients need therapies with improved activity against the disease, as exhibited in the incomplete responses commonly observed in their lab tests for cholestasis and liver injury. These tests include levels of alkaline phosphatates, bilirubin, and transaminases, biomarkers that have been associated with histological progression and poor outcomes for patients with PBC. We believe that offering patients an improved biochemical response, and especially the opportunity to achieve biochemical normalization, should be the aspiration of therapy in PBC. Second, many patients with PBC suffer from significant burden of symptoms, including puritis. Currently approved therapies have not addressed this need, and the only approved second line treatment, abetacolic acid, has been associated with exacerbation or worsening of pruritus. A therapy that can provide symptom relief would improve patients' lives, potentially improving acceptability and adherence to therapy. Lastly, PBC patients encompass a spectrum of disease stage, ranging from those without cirrhosis to those with compensated cirrhosis, including with portal hypertension. a leading treatment option should be safe across this spectrum of non-serotic and compensated serotic stages of disease. During 2021, we had the opportunity to present new analyses at the annual meetings hosted by the European Association for the Study of Liver Diseases, or EASL, in June, and the American Association for the Study of Liver Diseases, or ASLD, in November. In one presentation at EASL, we shared a retrospective analysis of data from our prior phase 2 and phase 3 studies that demonstrated Celadalpar appeared to be safe and well-tolerated and showed meaningful and dose-dependent improvement in biochemical response in PBC patients with prior treatment with abetacolic acid, the only approved second-line treatment for PBC, or fibrates. which are sometimes used off-label in patients with PBC. At EASL, we also shared pooled analysis of cirrhotic patients from the open-label Phase II study and a placebo-controlled enhanced study reporting on three-month efficacy and safety of 5 or 10 milligrams of Celadalpar. After three months, the efficacy, tolerability, and safety in patients with compensated cirrhosis had a consistent pattern and magnitude of biochemical response in liver biochemistry to that of non-cirrhotic patients, and importantly, was accompanied by a similar safety profile. As increased attention has emerged on the significance of portal hypertension in cirrhotic PBC patients, we updated this pooled analysis later in the year at ASLD. examining the cirrhotic patients with and without portal hypertension compared to those without cirrhosis. Again, there were comparable profiles for efficacy, tolerability, and safety. Portal hypertension in cirrhotic patients with PBC is estimated to comprise about half of all patients who have compensated cirrhosis and is a significant risk factor for progression to decompensation. Understanding the safety and efficacy of Celadalpar in cirrhotic patients with and without portal hypertension will be an ongoing part of the Celadalpar program with the goal of understanding if Celadalpar is an appropriate treatment option for this currently unserved population. Perhaps the most meaningful dataset last year was the oral presentation at ASLD, where we shared an analysis on the efficacy and safety of Celadalpar over two years of treatment in patients with PBC. Treatment of more than 50 patients with Celadalpar over two years appeared safe and well-tolerated and led to sustained and progressive reductions in biomarkers of cholestasis and hepatocellular injury throughout the second year of treatment. Almost 80% of patients achieved the composite endpoint based on ALP and bilirubin and over 40% of patients normalized ALP at two years. We believe that Celadalpar is the only drug in development for PBC as an add-on therapy to UDCA that has safety and efficacy results of this duration. In addition to these presentations, data from a Phase II study demonstrating improvements in measures of pruritus, sleep, and fatigue and decreased serum bile acids in patients with PBC was published as a full manuscript in Liver International last year. Puritis baseline intensity correlated with serum bile acid levels and puritis improvement over 52 weeks correlated with decreases in a specific set of serum bile acids. This paper also reported improvements in patient reported sleep disturbance using two different questionnaires and improvements in fatigue scores using the PBC40 questionnaire. Collectively, these data illustrate CeladalPAR's treatment effects on alkaline phosphatase, bilirubin, transaminases, and puritis across non-serotic and serotic stages, support what appears to be a safe and well-tolerated profile, and is encouraging for our efforts to confirm this in the response and assure studies in support of our planned NDA submission. In the midst of significant challenges in the capital markets of mid to late 2021 that continue to this day, we executed two successful financings that have provided the capital we forecast to support our operating plans through the end of 2023. Under the terms of the non-dilutive risk sharing development funding transaction with Abingworth, we have already received $75 million to support the Celadal PAR development program for PBC since closing of the agreement in July of last year. We have the option to receive an additional $25 million within approximately two months of the completion of enrollment of response. Commonly, Risk sharing funding agreements in biotech are for programs that are commercial or at least have regulatory approval. We believe the strategic funding committed by Abingworth prior to the completion of the phase three response registration study reflects a shared view around the potential for Celadalpar to address unmet needs for patients with PBC. We are excited to have Abingward's support as they have deep scientific, operating, and financial experience in biotech. In November of last year, we also completed a $75 million equity offering that included both existing and new investors. Our balance sheet now lets us fully concentrate on completing the NDA package for Cell at LPAR, including delivering the top line results for response planned for mid-2023. Dan will review our financials later in the call, but we start 2022 with a very strong balance sheet, having brought in multiple experienced quality biotech investors in these two financings. While establishing the value proposition of Cell at Alpar and funding its development were necessary, our future success depends on having a team with the talent and experience to take us through approval and commercial preparation. In 2021, I'm pleased to say we did this up and down the organization, building out functional teams, adding key executives, and adding to our board. In the first half of the year, we appointed Dr. Dennis Kim as Chief Medical Officer and Louis Stewart as Chief Commercial 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 Cell at LPAR and begin pre-commercial preparation. We strengthened the entire organization with the addition of key talent across functions that will form the foundation of our plans to deliver an NDA submission for Cell at LPAR and bring it to the market in order to provide patient access and create value for our stakeholders. At the board level, we were fortunate to bring on biopharma veteran Tom Wiggins and commercial leader Janet Dorling. Tom and Janet bring complementary skills and experiences to the board. and in particular our seasoned biotech executives who have guided teams through development to commercialization. In addition, earlier today we announced the appointment of Dr. Eric Lefebvre to the board. Eric is currently the Chief Medical Officer at Pliant Therapeutics. He has extensive experience in the pharmaceutical industry as an executive focused on clinical development, medical affairs, business development, and lifecycle strategy, and more than 10 years of experience developing drugs and liver disease indication. We look forward to Eric helping guide us through our next phase of development and commercialization. 2021 was a year filled with significant accomplishment and progress, despite multiple headwinds we and others in our industry faced. The pandemic impacted participation in clinical studies, timelines for regulatory and ethics committee approvals of study protocols, and vital resources at clinical sites. Since our last quarterly call in November, we faced new challenges as the Omicron variant has surged more rapidly than any other strain of COVID-19 at the end of the year through the first few months of 2022. Now we find ourselves thinking of the many innocent people impacted by the Russian invasion of Ukraine, including those involved in our PBC clinical studies in both countries. Our primary focus is on their safety, as we hope for resolution and peace. Through all of these challenges, we have worked to focus on those things that are in our control. We expanded our global phase three registration study response to more countries and more sites. We offered services to patients and clinical sites, providing concierge transportation, home health, and temporary staffing where possible. We invested in additional advertising and targeted programs to raise awareness of our study and support screening and enrollment. We have also increased the frequency of our interactions with principal investigators and their staff around the world, both virtually and in person, where permitted. Although we cannot predict new challenges we may face, we remain committed to completing enrollment in response in the first half of this year. Excluding Ukraine and Russia, response is active in 20 countries across more than 120 clinical sites. In parallel to response, our open-label long-term safety study, Assure, has also advanced significantly since the end of last year. As you may recall, Assure is open to PBC patients enrolled in previous studies of Celadalpar. We have seen a high level of interest in Assure, where we have now enrolled more than 120 PBC patients from our prior PBC clinical studies. The progress we have made in both response and assure, despite many global challenges, continues to highlight the significant unmet needs that persist for PBC patients today. Before we open the call for questions, I'll ask Dan to review key financials for the fourth quarter and full year 2021. Dan?
spk05: Thank you, Sujal. Over the course of 2021, We carefully managed our expenses as we grew and added new functional depth to our development and administrative teams and made additional progress on our PBC development plan objectives. In clinical development, we made advances in our ongoing efforts to enroll and treat PBC patients and to conduct other required clinical activities in our response, assure, and other NDA-enabling clinical studies that are necessary to complete our late-stage development of CellDelPAR and PBC. We also made continuing progress in manufacturing development, as well as in medical affairs and commercial, where we began early stage efforts to plan for potential future launch of Cellu-Delpar and PBC. In addition to these operational achievements, we strengthened our balance sheet considerably by completing a $100 million non-dilutive risk-sharing development financing agreement with Abingworth, as well as a $75 million public equity offering in November that we believe will be sufficient to support the planned completion of response. Overall, our cash, cash equivalents, and investments totaled $194.6 million as of December 31st, 2021, and included $50 million of funding received to that date from Abingworth. We believe this cash on hand together with additional committed capital available to us under the Abingworth Financing Agreement is sufficient to fund our current operating plan through 2023. I will now turn to a brief review of our fourth quarter and full year operating results. Research and development expenses for the three months ended December 31st, 2021 were $18.4 million compared to $10.7 million in the three months ended December 31st, 2020. Research and development expenses for the full year ended December 31st, 2021, were $64.5 million compared to $35.9 million for the year ended December 31st, 2020. Research and development expenses were higher in the three months and year ended December 31st, 2021, compared to the corresponding periods in 2020, largely due to increases in clinical operating expenses, which we incurred following the resumption of our clinical development of Celadilpar and PBC during the second half of 2020. Specifically, for the full year ended 2021, our contract research organization and investigator site costs for our ongoing clinical trials in PBC increased by $19.3 million to $35 million as these service providers continue to activate sites, enroll and treat patients, and perform other trial execution activities. In addition, contract manufacturing costs increased by $4.2 million to $5.5 million as costs were incurred to acquire raw materials and manufacture drug products for use in our clinical trials and to support registration requirements. Finally, costs related primarily to employee compensation, consulting, and other outside services increased by $7.8 million to $20.8 million as we expanded our clinical development and other research-related teams and activities in support of our late-stage development of Celebel PAR in PBC. Turning now to general and administrative expenses, these costs for the three months ended December 31st, 2021 were $6.1 million compared to $5.2 million in the three months ended December 31st, 2020. General administrative expenses for the year ended December 31st, 2021 were $23 million compared to $16.7 million in the year ended December 31st, 2020. General administrative expense was higher in three months and year ended December 31st, 2021, compared to the corresponding periods in 2020, largely due to higher employee compensation associated with the hiring of additional personnel and an increase in consulting and other infrastructure expenses that were necessary to support our expanding operations following the resumption of CellDelPAR's development in the second half of 2020. In total, net loss for the three months ended December 31st, 2021, was $26.5 million, or $0.34 per share, compared to a net loss of $15.8 million, or $0.23 per share, in the three months ended December 31, 2020. Net loss for the year ended December 31, 2021, was $90 million, or $1.27 per share, compared to a net loss of $51 million, or $0.74 per share, in the year ended December 31, 2020. Net loss was higher in the three months and year-ended December 31, 2021, compared to the corresponding periods in 2020, largely due to increases in clinical operating expenses, which were incurred following the resumption of our clinical development of Soledelpar and PBC during the second half of 2020. 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. Let me now hand the call back to Sujal.
spk12: Thank you, Dan. I couldn't be more proud of our team's persistence and progress over the past year. Despite facing numerous evolving challenges, we have seen improvements in enrollment metrics month after month. In addition to the progress in our clinical development program, we have been actively engaging in dialogue with regulatory agencies, supporting patient advocacy groups, and conducting early market research as we set our planned commercial strategy. We are looking forward to sharing more about these developments in the near future as they advance throughout the year, and we are excited about reaching key milestones ahead in 2022 and beyond. We're now happy to take questions. Operator?
spk03: At this time, we will be conducting a question and answer session. If you'd 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, too, if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions. Our first question is from Yasmine Rahimi with Piper Sandler. Please proceed with your question.
spk08: Good afternoon, team, and thank you so much for your thoughtful remarks. So given that we only have about three and a half months left before the first half of the year is coming to an end, can you maybe help us to quantify what percentage of enrollment is complete or where you are in that enrollment curve? That's one. And then maybe the second one is, it seems like there are seven sites in Russia and two in the Ukraine. Maybe can you comment on so far based on the patients that have enrolled, like what fraction of them are in these two geographies? And thank you again for taking my questions.
spk12: Thanks for the question, Jasmine. I can address both of these. You know, with respect to enrollment, I think as you know, these studies typically have an enrollment curve that's not really a straight line, but really an acceleration as you get a depth of clinical sites and activated and across the globe. And so we're continuing to see, as I mentioned, real improvement month over month. And I think much of that, again, comes from the kind of prior experience we have. We don't provide any specific numbers on where we are. Obviously, we're reiterating our guidance that we believe we can get the study enrolled within the first half of this year. So obviously, every week here between now and the end of June is quite critical. Our focus is to drive that process as quickly as we can. And we, of course, can't tell you what uncertainties lie in the weeks ahead, but we're quite confident, Yasmeen. You know, I think as most of our followers know, we enrolled a 265 patient global phase three study in PBC in the past. And despite the fact that today, obviously, we're dealing with significant challenges that we weren't dealing with back in 2019, You know, we know the playbook. We know what needs to get done. In fact, even today, our team members are across the globe meeting with PIs, meeting with sites, you know, continuing to find ways to drive screening and enrollment in the study. And we're confident in getting to our finish line. So we're continuing to drive this process, as I mentioned, as quickly as we can. We are seeing the kinds of improvements we would expect to see now that we have more than 120 sites across 20 countries around the world. That's the type of, I think, depth and breadth in this study that we would expect to translate around the kinds of increases we're seeing in terms of enrollment. So we feel good about where we are here. With respect to Ukraine and Russia, we had two sites recently activated in Ukraine. Those sites have not yet screened or enrolled patients. So, of course, everything there is on pause. In Russia, while we are pausing any future screenings, Our focus here is just to address the needs of the patients already enrolled in response, as well as assure our long-term safety study. We're confident around having drug product for those patients already in country, but clearly there's some uncertainties ahead with respect to logistics, and we're monitoring those situations as quickly as we can. I'll just say simply, as we think about the impact here, I think more of it has to do with how we think about overall screening and enrollment, and they're just two countries, again, out of more than 20, excluding Ukraine and Russia. As I mentioned, we have 20 countries where we have over 120 active sites. So that was by intention, because even in the face of the pandemic, absent the conflict in Ukraine at this moment, even in the face of the pandemic, we knew that we'd have to be broad in this effort, and that's exactly the plan that we're continuing to execute on.
spk08: Dr. Hadid, thank you so much.
spk03: Thank you. Our next question is from Steven Seedhouse with Raymond James. Please proceed with your question.
spk14: Hey, good afternoon, everyone. Kudos on what sounds like good execution on the phase three program despite obviously myriad external challenges. I wanted to ask a couple of details on the phase three PBC program. First, are you comfortable with the number of voluntary biopsies you've accrued and are collecting in the study at baseline at least? And then second, has the patient retention throughout the course of the study been good?
spk12: Yeah, thank you for those questions, Steve. First, I can tell you that with respect to biopsies, we are able, at least in a blinded fashion, to observe how many patients are at least volunteering for a baseline biopsy, and we feel good about how we're tracking there. With respect to overall patients, in terms of retention, we're not seeing anything unusual or different than we'd seen before, where we had very good patient retention across our studies I think what we learned in our prior phase two and phase three studies, and even with those patients that had been on treatment for two years or longer, in fact, before we paused development at the end of 2019, is actually very strong retention. I think driven quite a bit by the type of response we were seeing and biochemical markers of disease, but also in particular, the response we're seeing on clinical symptoms of disease. Generally speaking, and we've reported on some of this at medical meetings, you know, we're seeing improvements in fatigue and in particular, as you know, reductions in itch and pruritus that were quite meaningful. So those are the kinds of things that we expect to maintain the type of retention that we've seen in the past and we're seeing thus far here.
spk14: That sounds great. Separately, I wanted to ask, Regarding the last $25 million, I believe, tranche from Admin Works subsequent to enrollment completion, I mean, in what scenarios would you not draw that down versus drawing that down?
spk12: Yeah, it's a good question. You know, we think about our cash runway, and as Dan had highlighted, we have existing cash to get us to the end of 2023, inclusive of the opportunity to bring in that additional $25 million that would take us beyond And so, you know, I think fundamentally, Steve, we think about this as a cost-to-capital decision at the appropriate time. We feel as though the balance sheet is strong today. It allows us to complete the Phase III development program for Cellidel PAR, and it also provides us cushion post when we expect to release top-line data if we continue to hit on the timelines that we're projecting. So we're in a strong position, in fact, starting this year, as we've mentioned. We're actually incredibly encouraged by the fact that we were able to bring in high-quality investors last year. And in the midst of a market that continues to be challenging, I would simply say we have a tremendous number of options, we believe. And so this is really an option from our perspective that we'll evaluate at the appropriate time.
spk14: Great. Thanks for taking the questions. Glad to hear about the positive trends in enrollment as well. Thanks. Thank you, Steve.
spk03: Our next question is from Patrick Dolezal with LifeSci Capital. Please proceed with your question.
spk15: Hi, this is Cory on for Patrick. Quick two from us. So given how well-powered the Assure study is and how Enhance achieves stat sig on the primary endpoint to a high degree in as little as three months, would you consider at all reducing the number of participants in order to meet that first half enrollment criteria? And on the other side of that equation, Are there any considerations for secondary endpoints that might be underpowered if you were to reduce enrollment? Second one from us, you know, has there been any additional dialogue with the FDA in regard to the use of Celadalpar in compensated cirrhotics or patients with portal link retention? You know, to the degree that you can disclose, you know, what has been the response in that regard and how do you envision potentially treating those groups?
spk12: Yeah, great questions, Corey. So, you know, I think you were referring initially to how well-powered response is the phase three registration study relative to our experience in enhanced. So, you're absolutely correct. I think even with a target of 180 patients in response, again, two to one randomization, Celadilpar 10 milligrams to placebo, we remain highly overpowered or well-powered, certainly for the primary endpoint response rate. for registration, as well as the key secondary endpoint on alkaline phosphatase normalization. So, as you mentioned, we hit each of those endpoints at just three months with a high degree of statistical significance in enhanced and are, in fact, well-powered if we were to reduce the size of the overall study and patient target in response. So, that is an option relative particularly to those two endpoints. Importantly, I will note that Enhance provided Celadelpar another key advantage, particularly relative to other agents in development of PBC today. And you know that at just three months, we saw statistically significant reduction in itch at Celadelpar 10 milligrams versus placebo. Quite an accomplishment when you think about the challenges that remain in evaluating itch in PBC clinical studies historically. That's really a key consideration for the 180 patients targeted. Now these are estimates as it pertains to powering, but we have the advantage of having had that enhanced data in order to set the target for 180 patients in response. So this is something we'll continue to evaluate. We think that this could significantly set Celadalpar apart, not just from currently approved treatments, but even potential treatments that are in development today And so it's a consideration that we take seriously when we think about the opportunity to actually demonstrate statistically significant benefit on itch once again in response. And so we'll evaluate as we proceed. It's certainly an alternative and an option, but at present we're continuing to drive towards getting 180 patients randomized into the study by the end of the first half of this year. Now, I'll mention with respect to, I think I gave you some sense there then of secondary endpoints, you know, clearly overpowered on ALK-BOS normalization, and, you know, we'll see where it falls out with respect to itch. You know, in terms of FDA dialogue, our prior enhanced study, as we've shared some of the data, particularly at ASLD and even EASL last year, you know, our studies have, in fact, included compensated serotics with and without portal hypertension. So we haven't had any further dialogue with regulators. That is a population that's eligible based on other inclusion criteria in response. So we continue to expect to see, you know, similar proportions of patients that have compensated cirrhosis, and probably we would estimate a similar split between those with and without portal hypertension in response to what we've seen in prior clinical studies, almost 20% as a rough estimate, if you will. And so that's an expectation we have. At the end of the day, the discussion with regulators will ultimately depend on the strength of the overall data set within response, as well as our prior experience, and also potentially from the Assure long-term safety study. So again, you know, we feel as though this could be a differentiator, particularly for an underserved population today. And so we'll continue to monitor and follow the data as it progresses.
spk00: Excellent. Thanks for taking our questions. Thank you.
spk03: Our next question is from Ed Arcee with HC Wainwright. Please proceed with your question.
spk07: Hello, everyone. This is Thomas Yip asking a couple of questions for Ed. First question, given complete enrollment for response, as you pointed out, SUSHO continues to be online. On target, in the first half, and I believe you said on the call that top line data expected now in around mid-2023, is it reasonable to assume that 52-week top line data are more likely to be in the later half of mid-2023, in other words, third quarter perhaps?
spk12: Well, thank you for the question, Thomas. You know, it's hard for us to provide, you know, the specific timeline. I think once the study is fully enrolled, you know, clearly we'll have a view around the release of top line data based on our target of completing enrollment in the first half of this year. You know, certainly if we're at the back end of that, then top line data would likely be early Q3 2023. So that's why I provide the context around mid 2023 as our target for top line data.
spk07: Got it. And then perhaps for the Assure long-term extension study, and personally as you outlined, 120 patients enrolled so far, can you talk about roughly what percentage is from response or perhaps a big picture, what percentage from other studies as well?
spk12: Yeah, you know, Thomas, I don't have that breakdown in front of me here. You know, I can tell you, as you may recall, in our phase two open label study, we had just north of 100 patients enrolled in that study. And, of course, in response, we had a total of 265 patients randomized into the study. So, you know, that gives you just a breakdown of the total population. I don't have specifics around, you know, the 120 or more that are actually now in Assure. I will just simply say, you know, part of why we wanted to make sure and give some context in terms of what we're seeing, you know, I think it provides, you know, the kind of support we believe that demonstrates how patients responded to Celadalpar in the past and the significant degree of interest many of those patients have had to come back. onto Selladel Park treatment and have re-enrolled in Assure. Certainly some patients over the past two years, as we halted development before we restarted Assure last year, unfortunately progressed. And so there are some patients not eligible to reel into Assure, even if they chose to do so. But we're quite encouraged by having north of 120 patients at this point in time. We continue to expect to see more coming into that study, even as both response and Assure continue to randomize.
spk07: Thank you so much for taking the questions and we look forward to complete enrollment for response mid-year.
spk00: Thank you.
spk03: Our next question is from Jay Olson with Oppenheimer. Please proceed with your question.
spk04: Hey, congrats on the progress and thanks for taking the questions. Recognizing that you're entirely focused on execution of the response and assurer studies, could you maybe share your latest thinking on opportunities for CELA DELPAR and other indications like PSC or NASH? And related to that, any thoughts you could share on potentially partnering CELA DELPAR either in the U.S. or outside the U.S. or PBC, NASH, or PSC?
spk12: Yeah, thanks for that question, Jay. You know, I think fundamentally, as you mentioned, we are, in fact, focused on what we believe is a very significant near-term driver of value creation for all stakeholders, for patients, obviously for our investors and shareholders. There's no question in our mind that the depth of data that we've amassed in PBC point towards an opportunity potentially to be preferred second-line treatment. also potentially to really meaningfully expand the addressable patient population. You know, we're committed to this population in not only these studies, but even potentially beyond when we think about other populations of PBC patients and an extraordinary opportunity, we believe, to advance Celadelpar as a key treatment alternative for this population. There's no question that, you know, the pluripotent effects of this mechanism, the PPAR-Delta mechanism and Celadalpar set apart as really the only selective and highly potent PPAR-Delta agonist in development in liver disease encourages us around opportunities to explore Celadalpar and other indications. You're going to see us focus on getting through enrollment in response and get to those near-term objectives. But we continue on the sidelines to think about and explore these potential other alternatives. PSC, as a rare disease with significant unmet need, I think is more closely the type of indication we continue to explore for celadilpar, I would say post-PBC, more in the near term. We don't have any ongoing work, of course, in PSC. It is an indication, as we've talked about in the past, that's more heterogeneous in terms of patient population. It is a more complex disease. It's more of a fibrosing cholestatic liver disease than even PBC. And so there are a number of things we continue to better understand and evaluate. We continue to have dialogue with experts in the field. And I'd simply say stay tuned for how we might think about future opportunities for Celadal PAR beyond PBC. But for now, we remain very focused. We talked a bit about NASH, and I think in the past we've also indicated that our data set we thought was very encouraging, particularly around the anti-fibrotic effects of Celadilpar. Effects that may in fact help differentiate even in the setting of PBC, potentially in the setting of PSC. As it pertains to NASH, you know, this is really an indication with probably more questions today than we all in the field had even two or three years ago. So once again, we continue to follow the path of others in this field and how regulatory guidance may or may not change, how endpoints may or may not change. And we've indicated here, again, when we think about the profile of cell at LPAR, in order to treat NASH, which is also a multifactorial disease, The right next opportunity to explore would be to combine it with a complementary mechanism. We don't have one, of course, in-house. And we're going to really stay focused with our capital and be capital efficient in these rare disease indications. Of course, if there are future opportunities to partner, we would explore those opportunities without question. But I want to leave you with really the sentiment, Jay, that we are very focused on a very significant opportunity we believe there is in PBC, certainly potentially other future rare indications for CELA DELPAR or potentially other opportunities within a pipeline as we think about future growth. And then lastly, I think you also, I apologize cutting you off there, Jay. I had this written down. You asked me a little bit about potential partnering of CELA DELPAR for PBC. We explore all alternatives. You know, our goal is to get Celadalpar in the hands of as many patients who could benefit, and that's globally. We certainly are setting ourselves up to be able to put Celadalpar in the hands of patients with PBC here in the U.S. on our own. As we continue to execute on clinical studies, we do believe that response is a study that would allow us to register Celadalpar not just in the U.S., but in other countries, including in Europe. So we'll drive towards that process. We will continue to evaluate market opportunities in the backdrop of what potential partnering could mean for Cell at Alpar. At the end of the day, we'll do the right thing for this program and for all of our stakeholders, and that could involve potential partnering. But once again, you know, the strategy for us is to ensure we have the opportunity to put this drug in the hands of patients ourselves. We certainly believe we have the wherewithal to do so, and that's what we're executing towards.
spk04: Thank you, Sujal. Appreciate you taking the questions.
spk00: Thank you, Jay.
spk03: Our next question is from Alethia Young with Cantor Fitzgerald. Please proceed with your question.
spk11: Hey, guys.
spk03: Thanks for taking my question.
spk11: I think we got some progress. Maybe two. One, can you talk about maybe with a little bit more color, if you did kind of see kind of any disruptions in like let's say the November to January timeframe related to like Omicron and the surge with the global trial?
spk10: Obviously, you know, you sound like you're heading on track, but just any kind of cadence of what kind of occurred there would be helpful. Second question, talk a little bit about populations in PBC that you think you can expand upon and might be potentially low-hanging fruit, you know, as you head toward the completion of the staffing.
spk12: Yeah, I heard the second question. Well, I believe that your first question, Alethea, was around some of what we observed in November and December of last year in the early part of this year with respect to Omicron. Yeah, that's it. Okay. So, yeah, you know, look, the last time we all spoke was, in fact, in November of last year in our third quarter call. And we reiterated guidance around enrolling response in the first half of this year. You know, I talked about the fact that that's a wide window. And in particularly, it was a relatively wide window because we never knew what lied ahead with respect to the pandemic. Obviously, about a month later, all over the globe, we dealt with Omicron. And, you know, partially that initiated at a time we would have expected some slowdown around the holidays, but it also lingered through January and February. It really expanded quite rapidly. And so there's no question that that these things have effects on clinical studies. It likely put us in a position where we couldn't get out of the gates in January as quickly as we would have liked to. But again, I'll highlight what we've done throughout the course of this study is try to meet these challenges every way in our control. We've provided clinical sites and patients with access to concierge travel services and reimbursement. Later in the pandemic, as we were seeing sites struggle with resources, we have been partnering with outsourcing agencies to provide those resources to clinical sites where that would be helpful. So we're continuing to do those things, and I think what we're seeing is having more and more sites come online, having, you know, some improvements at least of late in the course of the pandemic, having the ability to address some of these challenges are really translating. They're translating into improvements that we're seeing in terms of overall screening and enrollment, and even our engagement with sites globally. A lot of this is country dependent. And in many cases, different countries peak at different times. And yet again, I think this is an advantage for the response program covering more than 20 countries around the world that we can meet some of these challenges. And then finally, you asked a little bit about other populations in PBC. You know, in order to enroll in response, patients have to have an alkaline phosphatase level above 1.67 times the upper limit of normal. There are a host of patients, despite being on first-line treatment with ursodeoxycholic acid, whose alkaline phosphatase levels are still elevated above normal, but perhaps below 1.67 times the upper limit of normal. Those patients do have a higher risk of disease progression over those patients whose biochemistries are actually normalized. What we've seen with Celadalpar is a tremendous rate of normalization, not just on alkaline phosphatase, but also even on transaminases for patients that, in fact, have come into our prior studies with elevated ALT. This anti-cholestatic and anti-inflammatory effect that we're seeing, the robustness of that effect, encourages us around potential opportunities that we may have to actually normalize biochemistry in many of those patients who otherwise are not eligible to enroll in a traditional second-line treatment setting. That I would consider to be relatively low-hanging fruit, as you described it, Alethea, because we know those patients can potentially benefit not just from the anticholestatic and anti-inflammatory effects of Celadalpar, certainly from the effects on improving clinical symptoms of the disease as well. And that's a population we think about also.
spk10: Great. Thank you.
spk03: Our next question is from Mayank Mantani with B. Riley. Please proceed with your question.
spk02: Hi, good afternoon. This is Sahil Kazmian from MIAC. Thanks for taking our questions and great to see Eric Lefebvre also join the board. Some more questions have been answered, but a few more from us. With the full approval possibility for OCA, you know, potentially based on their fourth quarter filing of poison cobalt, do you sense any risk to the accelerated approval pathway? And then can you also remind us if the breakthrough designation status remains in place?
spk12: Yeah, absolutely. Happy to answer those questions. We still do have breakthrough therapy designation in the U.S., and we continue to have prime access designation in Europe as well. You know, with respect to the full approval possibility of OCA, you know, I think Intercept has clearly disclosed some of the challenges around the cobalt study. Now even populations of patients that are otherwise contraindicated by the new black box warning are I think fundamentally, we don't see a near-term risk around our opportunity to get approved on a surrogate endpoint in response. That has not been a challenge that we faced in our dialogue with regulators. And in fact, we continue to have very constructive dialogue in our own post-marketing environment. outcome study that we would look to execute, perhaps somewhat novel from what Intercept conducted. We'll talk more about that in the future as those discussions fully finalize and we complete enrollment and the process in response. But in fact, I will tell you we're encouraged by where we are now and have had very constructive dialogue with regulators.
spk02: Great. And then maybe a few brief follow-ups. As it relates to response, can you remind us if biopsies are being done at all sites, or are those limited to a select few? And is there a sort of per-site patient number you're targeting for enrollment?
spk12: Yeah, good question. So there isn't a per-site target in terms of those patients that volunteer for baseline biopsy and eventually a 52-week target. paired biopsy. And, of course, most sites, I believe, have the access to biopsy. There may be some that do not. Again, this is a voluntary, you know, in criteria for responses we've mentioned. But I think most sites, in fact, have the ability to biopsy a patient if the patient volunteers for that.
spk02: Okay, great. And then maybe one last quick one. As the data from Assure shows, you know, continues to evolve. Are there any presentations we should expect at any of the, you know, major liver medical conferences this year?
spk12: Yeah, you know, I think, look, with respect to this year's medical meetings, you know, as we've done in the past, we think it's very important to be transparent and share data at medical meetings, to share them at peer-reviewed settings and even in peer-reviewed publications. So you're going to see us continue to do that. You know, I think we've set a very strong track record of doing so when we have, in fact, a meaningful amount of data. That's a key criteria from our perspective. And so we don't often share or publish or present data on only a handful of patients. So I think the most important criteria for us is to think about where we have new information that's helpful to for patients, for the medical community as we think about the profile of Celadal PAR. We will do that through the course of this year with the data sets we already have in hand. You know, as it pertains to Assure, I can't tell you a specific timing around sharing some of those data sets. I think, once again, we're driven by ensuring that we have enough data to really drive towards any kind of meaningful conclusion. So I think we'll look towards future opportunities as that data set matures and look to share data as we've done historically.
spk02: Excellent. Thank you. That's it from us. Congrats on all the progress. Thank you.
spk03: Our next question is from Tom Smith with SVB Lering. Please proceed with your question.
spk09: Hi, everyone. This is Mike on for Tom. Thanks for taking our question. Can you provide an update on the timing of the proof of concept study of MBX 2982 being conducted by AdventHealth When would you expect to get top-line results from that study, and how are you thinking about a potential path forward from a development standpoint?
spk12: Yeah, thank you for those questions. I'll address the first one, and then I'll ask Chuck to talk a little bit about MBX 2982 and thinking forward from the current Phase 2A proof of pharmacology study. As folks may recall, this is a study that's being fully funded by the Helmsley Charitable Trust, We retain all the rights to sell it to MBX-2082, my apologies, even post their commitment to fund this Phase 2A study. Because the study is being funded outside of SEMA Bay, and in fact, as you mentioned, conducted by AdventHealth, TRI, CRO in Florida, once again, outside of SEMA Bay, it's a little harder for us to be precise around timelines. We have talked in the past about the fact that even that study has met some of the challenges or headwinds that many of us in the industry have faced with respect to recruitment. We are in good dialogue and close dialogue, in fact, with both Helmsley as well as AdventHealth, trying to work creatively around making progress in that study. And we're seeing progress in that study. We would hope to see that data set by the end of this year. But again, I'll highlight that's harder for me to commit to just based on the fact that it's happening outside of our walls. But fundamentally, we would like to, we'd be excited about seeing that data likely by the end of this year. Chuck, do you want to talk a little bit about the rationale and potential paths forward?
spk01: Well, sure, I can do that. But I'll also invite Dennis to join me as well to fill in any gaps. So, you know, the concept we're testing is the ability of 2982 as a GPR119 agonist to promote secretion of glucagon under conditions of hypoglycemia. And the glucagon, of course, then restores, tends to restore glucose release from the liver, raising levels and basically taking the patient out of a potentially harmful situation due to the low blood glucose. And in type 1 diabetics, there's known to be a dysregulation in the ability of the pancreas to secrete glucose. And of course, it's lost the ability to secrete insulin. And so that's really the first step is, can we prove that we do see an effect that's been seen with isolated human islets? as well as been seen in rodent models. If that were to be seen, then the concept would be that this could be a safe oral preventative medication. As type 1 diabetics use insulin, they can inadvertently cause, you know, hypoglycemic conditions, which are a cause of morbidity and potentially even mortality. And it becomes a psychological limit. They don't want to be aggressive in their glucose control. because they're concerned about these hypoglycemic episodes. So let's say that we see an effect that, you know, we would call successful. We do have healthy subjects in the study so that we can get an idea what would be, quote, normal or maximal in this mechanism. We would then think about what would a Phase IIb study look like to really prevent hypoglycemic episodes in patients with prior experience of these episodes. And that's going to take some planning. It's going to take some regulatory interactions. It would take, you know, consultation. We typically would use an advisory board to help us design and execute, you know, develop a protocol and think about a full development path. That will also take some analysis of the commercial opportunity, understanding a little bit about the competitive landscape. There are rescue medications available, but there's no preventative that's made it to the market yet. So that's a little bit how it would play out. Of course, there's more work to be done. I don't know, Dennis, if you wanted to add any commentary on that from your perspective.
spk06: No, Chuck, I think you said it very nicely. I think the result of the ongoing study right now would be primarily informing how we would handle the next phase of study and even what population within the indication we would target. I would say stay tuned other than what Chuck has elaborated. I don't have much else to add.
spk09: Got it. Really appreciate all the helpful commentary.
spk03: We have reached the end of the question and answer session, and I will now turn the call over to management for closing remarks.
spk12: Thank you, Operator. Our focus here at SEMA Bay has been unwavering throughout the many challenges we've all faced globally. We know what needs to be done to complete enrollment and response to complete our full development program and drive to filing and approval. We're confident that 2022 will be another year of inflection for SEMA Bay and importantly for the patients we serve. I'd like to leave you with a final thought to all of those who are suffering in Ukraine. We hope for an end to the attack on the lives of the innocent people in Ukraine and anywhere else in this world. We will always do our part to ensure the safety of the patients we serve and all those who make our work possible as we pray for peace. Thank you.
spk03: This concludes today's conference and you may disconnect your lines at this time. Thank you for your participation.
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