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spk14: Good day, ladies and gentlemen, and welcome to Syma Bay's fourth quarter and full year 2020 financial results and business update conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised that the call will be recorded at the company's request. It is also being webcast live on the investor section at the Syma Bay website at www.symabay.com. Now I would like to turn the call over to Mr. Dan Mendel, Vice President of Finance at Syma Bay. Mr. Mendel, you may proceed.
spk06: 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 2020 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 and plans on the development program for Celadelpar. Chuck will discuss updates to other pipeline opportunities, and I will provide a brief summary of our financials. Following our prepared remarks, we will all be available for Q&A. Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to SEMA-based expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, and anticipated timelines and data release dates, and cash runway, are forward-looking statements as defined under the Private Securities Litigation Reform Act 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 CIMA 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 CIMA Bay, and any recording or rebroadcast is expressly prohibited without the written consent of CIMA Bay. At this time, I'd like to turn the call over to Sujil.
spk07: Good afternoon, and thank you for joining us. We will spend the majority of our time today discussing the significant progress we are making with Celadalpar, our lead Phase III candidate for patients with the rare autoimmune liver disease, primary biliary cholangitis, or PBC, as well as the other promising opportunities we are actively advancing in our pipelines. It is first important to reflect on all that we have accomplished in 2020 and how those efforts position us for success in the coming year and beyond. After reducing our workforce by 60% at the end of 2019, we started 2020 actively closing down all of our clinical studies and winding down all non-essential activities. We did this to aggressively conserve capital and maximize our ability to execute any number of strategic alternatives we evaluated, including potential in-licensing of assets, mergers, and even liquidation. Importantly, we also launched a rigorous independent evaluation of the potential safety concerns in our Phase II study of Celadalpar in patients with non-alcoholic steatohepatitis, or NASH. By the second quarter, the independent safety review conducted at arm's length by a panel of world-renowned liver experts found no evidence of Celadalpar-related injury in our NASH study, and we quickly submitted complete responses to the FDA clinical holds. In the third quarter, the FDA lifted all clinical holds across the Celadalpar program, and one week later, we announced positive top-line results from our enhanced Phase III study of Celadelpar in PBC. Even though ENHANCE was halted prior to completing its planned 52-week treatment period, results were available for 167 patients who completed at least 12 weeks of treatment. These results, we believe, demonstrated that Celadelpar 10 mg provided patients with a statistically significant benefit on the primary and two key secondary endpoints in the trial. The results for the 55 patients on Celadalpar 10 mg at week 12 revealed a nearly 80% response on the primary composite endpoint, an accepted regulatory approval endpoint when measured at 52 weeks, versus 12.5% for the 56 patients on placebo. Further, there was an almost 30% response on ALP normalization versus none on placebo, and a meaningful and statistically significant placebo-controlled effect on reducing puritis in patients with moderate to severe puritis at baseline, as measured by the numerical rating scale, or NRS. As you may know, puritis is a significant and often debilitating clinical symptom of PBC, reported to affect up to 70% of patients. As we closed out the year, these results were highlighted in a late-breaking presentation at the liver meeting, sponsored by the American Association for the Study of Liver Diseases in November. They were also instrumental in the design for response, our global Phase III registration study that mirrors Enhance. Response will study the same optimal 10 milligram dose of Celadalpar versus placebo in the same patient population with the same primary and two key secondary endpoints. Since our last quarterly update in November, we have been focused on the restart of our global development program for Celadalpar in PBC. It is important to highlight that every element of our program had been either shut down or paused in an effort to conserve capital, including clinical studies and drug manufacturing. A restart of the Cell at LPARP program is a result of the extraordinary efforts our teams made in many behind-the-scenes activities in regulatory, CMC, and quality assurance. In parallel, our clinical operations group has been working tirelessly to enable the initiation of response and our open label long-term study, Assure. It is with great pleasure and excitement that I can announce today that both of these studies are actively recruiting patients. I look forward to providing regular updates on these studies as we progress in the months ahead. For the remainder of our call today, we will outline our plans for the remainder of 2021, including first, Our primary focus on execution of response, assure, and other NDA-enabling clinical and CMC activities for Cell at LPAR and PBC. Second, pre-commercial planning and market research to support investments for launch and lifecycle management for Cell at LPAR in PBC. Third, advancement of our early-stage pipeline and business development opportunities. And finally, fourth, continued management of our capital and human resources. Completing the development of Cell at LPAR for patients with PBC is our top priority. Although Enhance was halted early, its results allowed us to optimize the design and size of response and to leverage our prior experience with clinical sites in more than 20 countries around the world. Our goal is to complete enrollment by the end of this year. despite challenges we are facing with the ongoing COVID-19 pandemic and increased competition for patients. We will have a better indication of enrollment timelines as we move past the middle of this year. In the first quarter, we held investigator meetings in North America, Europe, Latin America, and Asia, where we continue to see enthusiasm and support for Cell at LPAR's return to clinical development. The study is now actively recruiting patients, and with increasing numbers of site activations, we expect screenings and randomizations to accelerate in the coming months. For those not familiar with the design, response is a 52-week placebo-controlled randomized global Phase III registration study evaluating the safety and efficacy of Celadalpar in patients with PBC. It is intended to enroll 180 patients with an inadequate response or intolerance to ursodeoxycholic acid in a two-to-one randomization to oral once-daily Celadelpar 10 mg or placebo. The primary outcome measure is the composite responder rate after 52 weeks. in which a responder is defined as a patient who achieves an alkaline phosphatase level less than 1.67 times the upper limit of normal with at least a 15% decrease from baseline and has a normal level of total bilirubin. Additional key outcomes of efficacy will compare the rate of normalization of alkaline phosphatase at 52 weeks and the change in puritis from baseline to six months for patients with a baseline NRS of four or greater for moderate to severe puritis. Puritis will be assessed using the same numerical rating scale and daily electronic diary as we used successfully in ENHANCE. I can't overstate the value of ENHANCE in determining the size and design of response, which, as I mentioned, once again will evaluate the same patient population the same 10 milligram optimal dose of Celadalpar, and the same primary and two key secondary endpoints. In addition to response, we have 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. The study will first enroll patients who have participated in our prior studies of Celadalpar and PBC, including the patients who completed the open-label Phase II study and enrolled into our previous long-term study and enhanced. As patients complete response and potentially other future PBC studies with Cell at LPAR, they will also have the opportunity to enroll in Assure. We expect Cell at LPAR to have one of the most robust safety databases in PBC patients ever submitted for an NDA. In the background of these two significant global clinical studies, our teams have also been executing on regulatory and clinical activities for numerous NDA-enabling studies and CMC efforts required to meet our filing and launch timelines. These efforts are often overlooked outside of the company but are highly valued and resourced to succeed as they play a vital role in ultimately enabling the broadest use of Celadelpar to benefit as many patients as possible. On the topic of bringing Celadelpar to patients, I want to highlight some of the important pre-commercial planning and market research work we have been and will continue to conduct through the course of this year. We have been studying Celadelpar in PBC since 2015. having completed four clinical trials studying five doses of Steladalpar in over 300 patients, including in both cirrhotic and non-cirrhotic patients, and with a subset of these having been treated for two years or longer. The 10 milligram dose has consistently shown anti-cholestatic, anti-inflammatory, and anti-puritic activity and good overall safety to date and suggests the potential of Cell at Alpar to provide patients with improvements in biochemical markers of disease and to reduce symptom burden. Our aspiration is to help as many patients as possible achieve the ideal response of normalizing their alkaline phosphatase. We aim to demonstrate that the potential benefits of Cell at Alpar can translate into improved outcomes and quality of life for many patients with CBC. In the U.S. alone, there are approximately 130,000 patients with PBC, with as many as 20 to 30,000 inadequately controlled by or intolerant to first-line treatment with UDCA. There are many more who are not currently considered eligible for second-line treatment, even though they have elevated alkaline phosphatase and may also be at risk of disease progression. There are also many patients who suffer from the symptoms, such as pruritus, with a significant negative impact to their quality of life. Based on current pricing for second-line PBC therapy and the potential to deliver even greater benefit, our early market research with healthcare providers and payers points to the potential for Celadalpar to be the preferred treatment choice for patients and thus an opportunity that may generate significantly greater long-term revenues than Ocala, which according to recent guidance from Intercept, is currently projected to have $325 to $355 million in annual worldwide net sales in 2021. As we mature our market research, we will be providing updates on specific details of our projections. While our core focus remains on completing development of Cell at LPAR in PBC, we continue to evaluate Cell at LPAR and our other early-stage clinical assets for other indications and development opportunities. Let me turn the call over to our Chief Scientific Officer, Dr. Chuck McWherter, to discuss more. Chuck?
spk13: Thank you, Sujil. Last November, we announced plans to conduct a study to evaluate MBX2982, our GPR119 agonist, as an agent to potentially prevent hypoglycemia in patients with type 1 diabetes. Insulin-induced hypoglycemia in diabetes is a significant cause of morbidity and an important factor that causes many patients to underutilize insulin to control their blood glucose levels. Glucagon, is the counter-regulatory hormone secreted from pancreatic alpha cells under conditions of low, but not normal or high, blood glucose. Glucagon serves to raise low glucose levels caused by insulin back into the normal range. In recently published studies with isolated human pancreatic islets, GPR119 agonists were shown to enhance glucagon secretion in response to low, but not high, glucose levels. And further, they were able to prevent insulin-induced hypoglycemia by increasing glucagon secretion in a rat model. The translation of these findings to the clinic will be evaluated in a Phase II proof of pharmacology study, examining whether MBX2982 can enhance glucagon secretion during insulin-induced hypoglycemia in subjects with type 1 diabetes. While Simabay retains full rights to MBX2982, The study will be led by Advent Health Translational Research Institute in Orlando, Florida, and will be fully funded by the Leona M. and Harry B. Helmsley Charitable Trust. We appreciate the opportunity to contribute to this effort to evaluate MBX 20982 for its potential to treat individuals at risk for insulin-induced hypoglycemia, one of the most challenging and potentially life-threatening complications of insulin therapy and diabetes. Our collaborators who are funding and running the study expect it to be completed this year, although since we are not conducting the study ourselves, we cannot be certain of the timing. Positive results in the study would provide the option to explore monetizing rights in the program through licensing or to advance the compound further into development on our own or with a partner. In 2020, we also began to evaluate CB0406. the active metabolite of the prodrug, or halophenate, that had previously been studied in diabetes and gout. We initiated a single and multiple ascending dose study of CB0406 in healthy subjects to establish its pharmacokinetic safety and maximum tolerated dose. CB0406 is the 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 known NLRP3-dependent pathophysiology of Gaudi 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 and potentially greater efficacy than does the prodrug R-halofenate. Decisions on any future development are contingent on its achieving a favorable profile with respect to safety and exposure. The innate immune system plays a pivotal role in many diseases besides gout, and thus 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 I study. Finally, we continue to explore, via business development discussions, interest in evaluating Celadilpar in combination with other promising agents in NASH. The impact of Celadilpar on fibrosis and NASH pathology in our Phase IIb clinical study together with promising preclinical studies and combinations, suggests the potential for Cella-Delpar to be combined with agents that have effects on weight, liver fat, and insulin sensitivity, and also with other antifibrotic agents. Discussions of this type often take time to mature as other parties evaluate not only Cella-Delpar, but their own portfolio and business interests. We will provide updates when there is significant new information that we are able to share.
spk07: Thank you, Chuck. In addition to the significant momentum behind our efforts to restart and complete development of Stella Delpar for PBC and the advancement of other opportunities in our pipeline, a key highlight of the quarter is the successful management of our overall costs for yet another quarter and throughout 2020, allowing us to start this year with well over a year of cash in our balance sheet. On that note, I'll ask Dan to provide a brief summary of our key financial highlights.
spk06: Dan? 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 CELA DELPAR program, and commenced our response and assure clinical studies and other NDA enabling studies necessary to complete our late-stage development of CELADELPAR and PBC. Overall, our expense management efforts led to cash, cash equivalents, and short-term investments totaling $146.3 million at December 31, 2020. We believe our cash is sufficient to fund our current operating plan, including the reinitiation of the full 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 December 31st, 2020 was $15.8 million or 23 cents per share compared to net loss of $29.4 million or 43 cents per share in the three months ended December 31st, 2019. Net loss for the year ended December 31st, 2020 was $51 million or 74 cents per share compared to a net loss of $102.8 million or $1.53 per share in the year ended December 31st, 2019. Net loss was lower in the three months and year ended December 31st, 2020, compared to the corresponding periods in 2019, primarily due to a decrease in operating expenses, including clinical trial and labor-related expenses. As a result of the termination of our CELADELPAR studies and our cost reduction efforts undertaken in response, to the FDA's clinical holds that were placed on the Cell Adelphi Program in the fourth quarter of 2019. Given the FDA's subsequent lifting of the clinical hold and our restart of the Cell Adelphi Program and further exploration of other clinical development opportunities, our cash expenditures and losses are expected to increase in the future as we advance our restarted clinical development programs and activities. Finally, I'd 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. We will continue to closely monitor pandemic developments and their associated risks to our business, including our restarted clinical development of Cellu-Delpar and PBC, and we will continue to take actions available to mitigate these risks where possible. Further, all our actions will continue to be guided by commitment to ensuring the health and safety of our employees, as well as patients enrolled in our clinical studies. Sujal? Thank you, Dan.
spk07: We're now happy to take questions. Operator?
spk14: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions. Thank you. Our first question comes from Yasmine Rahimi with Piper Sandler. Please proceed with your question.
spk15: Hi, team. Thank you so much for sharing all your great progress. A number of questions across various topics. The first one is if you could comment on whether the agency has maybe modified their view on thoracic studies. We recently saw that a label revision would be required for OCA potentially. So we wanted to understand, is the agency changing its perspective on the way we're treating cirrhotic CBC patients? And then the second question is, if you could provide some color on maybe how many patients that were in previous studies have enrolled so far into Assure, and then I have a quick follow-up.
spk07: Sure. Thanks for the question, Yaz. I'll start it off and perhaps invite others to join me here, particularly on the regulatory side. If I miss anything, Clara can chime in. You know, I think first it's important for us to highlight that response, as was the case for enhanced and even intercept phase 3 POI studies, really targeting a large proportion of PBC patients that have either early or mild stage disease. which is actually the case for as many as 80% of the population approximately. And so in that study, we're largely enrolling patients that are non-serotics, although it is possible for patients who are well-compensated serotics to enroll, particularly child's PUA patients. And that is a population, in fact, we've studied, both in our Phase II clinical studies as well as enhanced. In fact, I think it's a key differentiator for us that we have as many as 50 patients, roughly, worth of data in well-compensated cirrhotics, and to date see very good efficacy as well as safety in the same doses we're studying today. in the non-cirrhotic patient population. As it pertains to those patients with more advanced disease, I think one of the advantages we have clearly as Ocaliba has been in the market and as we are able to assess the safety risks and concerns for those advanced patients, we have the opportunity, in fact, in studies for patients with hepatic impairment in our studies potentially alongside response and even thereafter, to have a better overall safety database and even more advanced patients so we have a more clear understanding of the potential risks as well as benefits in that population. So I don't believe, at least from a regulatory perspective, there's any change from the agency's perception at getting a label very similar to what you see with Ocaliba, which is the aim of our study in response, to effectively get a label for second-line treatment, treatment for patients that are either non-responders or inadequate responders to UDCA, I should say, or intolerant. That stance has really not changed. But I think we have a greater view and opportunity, again, to better understand Celadilpar's overall profile in more advanced patients in serotics.
spk15: Thank you so much.
spk07: And then, yeah, and then, Yasmeen, I think you also asked about progress specifically in Assure. And, you know, again, here I'll just say we're incredibly excited that both Response and Assure are now actively recruiting patients. Specifically with Assure, we have, of course, opened up the possibility and opportunity for patients that were in our previous Phase II, most of which, in fact, had enrolled into our prior long-term study, as well as patients from Enhance. And so I think as we continue to offer that to sites and to patients, We're seeing, obviously, a tremendous amount of excitement, particularly on behalf of patients that were previously on Celadelfar. That's a process similar to response that's going to take time to get out to the 20-plus countries that we are enrolling patients, particularly in enhanced. But we continue to do that work. The investigator meetings, as I mentioned, and the prepared remarks that have now covered really all geographies are a key step in getting sites informed as well as ultimately activated. So we'll see progress in Assure enrollment as we see similarly progress in Response enrollment, really mirroring site activations and really accelerating as those sites get on board.
spk15: Thank you. And then a quick one for Chuck. Chuck, can you elaborate a little bit more on CB0406, like in regards to the mechanism of non- What are the potentials of being a non-agonist ligand of P bar gamma? And then also, what are the indications? You don't have to give me the exact one, but what are all the possibilities of areas that you could be potentially interested in? So that could be helpful for us.
spk13: Yes, thank you, Yasmeen. Well, we're really very excited about CB0406. To start with, just for the audience to understand, You know, it's extremely de-risked. The prodrug has been studied in a significant number of patients and a significant number of studies, and it's clinically validated. So as you may or may not know, gout inflammation or gout flares are a strong inflammatory response that's driven by the NLRP3 inflammasome, which is a very exciting drug. area of research in sterile inflammation with many startup companies working actively on this. And it's known because neutralizing biologics to IL-1 beta block gout flares. So our preclinical work with macrophages and mouse models of the inflammation showed that we blocked that pathway, and we did that also in gout patients. So I guess I would just invite you to to consider, you know, the broad landscape that's being described in the literature. If you were to do a PubMed on NLRP3, you're going to return a really large number of indications of interest with a lot of unserved or unmet need that I think interdicting in these pathways could, you know, could make sense for 0406. So just to recap, you know, it's a known pathway. We published a paper in 2018 that's on our website. that describes the mechanism, as well as we published a paper on the gout study. You put those two together with the fact that we believe 0406 will have greater exposure and efficacy, I think it really sets us up with a lot of very delicious menu of opportunities from which to select one of these disorders that you'll find in the literature surrounding NLRP3. And I think the other advantage, just to touch on, you asked what about the non-agonist aspect. You know, PPAR gamma is the target of insulin sensitizers, which, of course, have their own beneficial pharmacology, but they come with a lot of downside with respect to weight gain, increase in adiposity, electrolyte imbalance, edema from action in the kidney, and bone effects. So based upon an extensive clinical program, the fact that we don't activate genes like the insulin sensitizer does keeps the drug, so to speak, out of harm's way with the side effects or the untoward actions of the insulin sensitizer. So that's where another degree of excitement comes from because it's already been de-risked for this clinically.
spk15: Thank you.
spk14: Thank you. Our next question comes from Steve Seathouse with Raymond James. Please proceed with your question.
spk09: Good afternoon. Thanks for taking the question. First one, just regarding a SURE long-term safety data you're collecting, what is the target enrollment of that study, and do you need a certain number of patients with longer than 52 weeks follow-up before you submit for approval, or will you essentially just submit what you have when response concludes?
spk03: Hi, this is Clara. We don't have a specific target required by the FDA. Obviously, the more we have, the better to give FDA an assurance of the overall safety and side effects of the drug. So we're trying to just allow as many patients to come back and to assure that we're previously enrolled in the trial as well as those who can participate once they complete the response study.
spk07: I think the only other thing I'd add, Steve, is This is a study that was, in fact, ongoing in parallel, a long-term study, when we were enrolling and conducting enhanced. So we're really just rinse and repeat of the clinical development strategy that we had prior. This long-term study, of course, given enhanced enrolled and randomized 265 patients, is open for those patients in addition to those in our prior long-term study. And I think, as we mentioned, again, in our prepared remarks, it's what really sets us up, even if we get, say, half of those patients to enroll in this study, to have one of the most robust safety databases at time of anticipated NDA in the setting of PBC that any sponsor has actually had at the time of registration. So we're quite confident that this really positions us to have another significant advantage relative to others in the field.
spk09: Yeah, it makes sense. Although the one thing I guess that's not clear is will – assuming that you will apply for accelerated approval on the basis of response, is Assure serving as the long-term outcome study here for full licensure, or is there sort of an extension protocol that's blinded and randomized? Because, of course, as you know, Intercept is communicating some issues with their long-term PBC outcome study, COBOL, and maintaining the blinding and and just completing that study in general?
spk03: Yeah, the Assure study is not intended to be the study to confirm the benefit of Celadal Park as part of our required Phase 4 study. We are in the continued dialogue with the FDA around the design of that study that we're going to propose, so it's not specific to the Assure study.
spk09: Okay. So that study is? also separate from response, it would be a to-be-initiated study?
spk07: Yes, that's exactly correct, Steve. And this is, you know, in fact, a dialogue we've had with the agency for the last couple of years. I think, as you know, the pathway to subpart H approval through the accelerated approval pathway requires us, at least at the time of NDA submission, to have that stage four outcome studied, agreed upon, and initiated effectively at the time of NDA submission. So we're confident, again, at progress we've made in that dialogue. You touched upon some of the challenges that Intercept is facing in enrolling their Phase 4 outcome study. I'll just say here once again, although nothing here is finalized, we once again have the advantage of learning from Intercept some of the challenges they've had and discussing with the agency a study that we would propose to have a best effort of actually enrolling and completing. So it's a challenge in this setting, a slowly progressing chronic disease. But, again, we have the benefit of learning from some of the challenges they've faced and approaching it with some potential advantages as we get there ultimately.
spk09: Very helpful. Appreciate that, Culler. Last question for me just regarding the market research and aspiration. I guess you communicated for greater long-term revenue than what's even indicated by the OCA guidance. How are you thinking about competition like from Elifibronor or generic OCA or even combo OCA plus Bezofibrate, and what impact from those are you assuming in that optimistic long-term outlook that you communicated? Thank you.
spk07: Yeah, it's a great question. So, you know, we've initiated some work, and there's much more for us to do here as we set ourselves up for potential success, and we certainly believe in that. And so, you know, when you look at it fundamentally, Steve, I think it all starts with the profile and the data set. And at least to date, we're seeing a profile of greater efficacy on the composite primary endpoint. Again, I'll simply caution as I make these comparisons, they're not coming from head-to-head data, but just respectively. in the development of these various different targets that you had mentioned. But we're seeing very robust efficacy in biochemical markers of disease that have, in fact, been correlated to improvements in outcomes based on rich historical data sets. As you know, the Global PBC Study Group data, for example. We're seeing significant effects on inflammation. Some of the effects that we're seeing certainly could lead to improvements overall in liver health. potentially liver stiffness and fibrosis, things, again, that long-term have the potential to impact outcomes for patients. We're also seeing not just significant effects on biochemical markers of disease. We're actually seeing a good proportion of patients, up to 30% in our Phase II and our prior Phase III work, actually normalize their alkaline phosphatase. And this is something in the medical community that is becoming ever more important. I think there's a stronger desire in the medical community and PBC to treat patients to normalization. That's not yet something we've seen, certainly to the degree we have thus far in our studies with Celadalpar, necessarily with other agents like Ocalava. You know, of course, the Beezerso study has shown some promising data of Beezofibrate on top of UDCA. Beezofibrate, of course, is not available in the U.S. It is a generic elsewhere. I think fundamentally the Beezerso data once again validates the PPAR mechanism, in fact, as a preferred second-line mechanism, and really only for those patients potentially that need additional biochemical normalization or lowering to reduce risk of disease progression, you might consider adding an FXR for those subset of patients. But we believe, again, based on our data set, that a fair proportion of patients can get to goal and reduce risk of disease progression in a meaningful way, perhaps with Celadalpar really as a preferred choice. So as these other competitors really come online, once again, I think it's the overall profile. And I'll add two other elements to the profile. Obviously, we've seen benefit on reducing the key clinical symptom burden of the disease itself on puritis. We've shown it in a statistically significant fashion versus placebo in the enhanced data set. Once again, I think that's a differentiated data set relative to the many competitors that you highlighted. Even some of those other PPARs that have shown some potential benefit on reducing pruritus, we have no reason to believe they wouldn't. But once again, I think the strength of our data set largely, I think, solidifies CeladalPAR as having this effect. If we're able to show this once again in response, in a meaningful fashion, we think, again, it's a differentiator versus these other data sets. And then finally, overall safety. I mentioned that we've studied not just early stage and patients with mild PBC, if you will, based on biochemical markers of disease and the stage. where we see very good overall efficacy and good safety. We've, of course, also studied patients with compensated cirrhosis, those child 2As, as I mentioned. That's a patient population where, for example, with elefibrinor, we're not aware of any data existing in that patient population. And so when you think about overall safety, we believe that's another key differentiator in potentially positioning cell at LPAR as a preferred treatment alternative. So I think these things matter. Of course, it is true that how the ultimate competitive environment plays out with respect to pricing and generics will also impact future decisions. But we think, once again, CELADELPAR is incredibly well positioned based on this data set and really the opportunity for us to continue investing in in lifecycle management, in additional data sets that may highlight an advantage of Celadal PAR on efficacy, on tolerability, as well as potentially in safety.
spk09: Well, kudos on a remarkable turnaround in 2020 and getting back to phase three. Really, really remarkable. Thanks for taking the questions. Thank you, Steve.
spk14: Thank you. Our next question comes from Alethea Young with Cantor Fitzgerald. Please proceed with your question.
spk02: Hi, this is Naina on for Aletheia. Thanks for taking our questions. We wanted to know a little bit more about the CB0406 program and had a few questions there. We were wondering if this program was discovered in-house or was it unlicensed? Also, how selective is 0406 for gamma versus other isotherms? And last question. what does 0406 need to show in the multiple ascending dose studies for you guys to be comfortable with this profile? Thanks.
spk13: Yeah, those are three great questions. Thank you for that. So, you know, I think with respect, first of all, to the selectivity, we've extensively profiled it, for example, using receptor assays, and it's very specific for PPAR gamma. There is no off-target effects with respect to or isotype effects with respect to PPAR-alpha or PPAR-delta. So it's a very narrow range with respect to that. You asked about what the success factor is. I think if you look at the publication, we had a good effect on gal flares that was a little bit less than the standard of care colchicine. so call it maybe 80%. We think that if we could get a significant improvement in exposure based upon what we understand, we should be able to maximize that effect. And colchicine in the setting of gout flares, which as I mentioned is an NLRP3-driven process, although colchicine acts downstream via a different mechanism, essentially represents the maximal effect that you'll see in the pathway. Okay. So we think if we could get a significant increase in exposure, and I don't want to provide a specific guidance about what that increase in exposure needs to be, but I can say that in the monkey studies where we compared 0406 directly to the prodrug, we saw significantly higher exposure for 0406. So we're just really seeking to confirm that we'll hit that target, and if we do, then we have some very good confidence that that will give us the best chance moving forward. I'm sorry, I missed, I've already lost track of the first part of your question. Someone can remind me.
spk02: Yeah, so was this program discovered in-house or was it in-house?
spk13: Yes, this is an in-house program.
spk07: And I think, Nina, the one other thing I just wanted to add to Chuck's comments, as we think about potential indications, as Chuck mentioned, there are many that are impacted by this pathway. I think fundamentally our focus and priority is in identifying rare diseases and potentially even diseases in which you could gain orphan drug designation. So really fitting into our current strategic focus overall.
spk02: Perfect. Thank you. This was really helpful.
spk12: Thank you.
spk14: Thank you. Our next question comes from Patrick Doledol with LifeSci Capital. Please proceed with your question.
spk10: Hi. Thanks for taking the questions, and congrats on all the progress. Just a couple more on 0406, if I may. You mentioned, you know, some of the safety effects of insulin sensitization. might be averted considering the non-agonist nature of this compound. And I'm just curious, at the same time, does that mean that some of the beneficial effects we've seen with P-par gamma agonists would be lacking? Or do you anticipate some translatability on the efficacy side of things via the NLRP3 pathway? And I obviously totally understand that it's early, and, you know, without an indication selected, this might be a less relevant question. But I'm just curious as we think about potential liver indications. Thanks.
spk13: No, thank you, Patrick. No, it's a question that makes a lot of sense, and so you can find. We had studied Arhalofenate, the prodrug for diabetes, and we were always interested in both the insulin sensitization as well as the anti-inflammatory effect. So I think what we found in diabetes is that the drug was safe. We have completed 17 clinical studies, more than 1,700 studies, subjects were exposed to the prodrug. And we did see some benefits on insulin sensitization, but they weren't competitive commercially. We didn't see the edema. We didn't see weight gain. We don't see effects on bone fracture biomarkers that you see with TZDs. And so for that reason, it just didn't make sense to continue development for diabetes. About that time, we learned about the anti-inflammatory effects. And at some point, if we have an R&D day, it'll be really nice to be able to explain the trajectory of the program and how we moved into inflammation. That's driven by the non-agonist trans-repression of genes. So trans-repressed is NF-kappa-B as well as AP1 inflammatory genes. And, of course, NF-kappa-B drives NLRP3. So it's basically one step upstream from NLRP3, and that also gives, in our mind, an additional degree of selectivity and potential safety. One thing that I didn't mention is that anti-IL-1 beta biologics are effective, and they're registered for a number of indications, including recently, just this last week, Berlonacept, which is an IL-1 beta decoy receptor, was registered for recurrent pericarditis. They come with an infection risk, in fact, even serious and occasionally fatal infections. They depress through the mechanism neutrophil, so you can get occasional grade 3 and grade 4 neutropenia. And we don't see that in any of our studies with the prodrug. So I think being one step upstream gives you a kind of tissue selectivity, but still allows you to get to the anti-inflammatory effect that you'd like to have, you know, without having basically a systemic suppression. So hopefully that helps you give some of the insights around additional excitement we have harnessing this trans-repression in a tissue-specific way.
spk10: Absolutely. Thank you. Thanks, Patrick.
spk14: Thank you. Our next question comes from Jay Olson with Oppenheimer. Please proceed with your question.
spk05: Oh, hey, congrats on all the progress, including getting those two PBC studies up and running. Can you just talk about what impact you expect, if any, from the pandemic on enrolling the response trial and when we should expect to see data from that study? And then separately, if you could comment on how we might extrapolate the shortened enhanced results out to 12 months of treatment for response.
spk07: Yeah, sure, Jay. I'll start off and answer the first part of your question. I appreciate it. You know, there's no question that the pandemic presents challenges not just for us, but I think many enrolling patients in other studies globally as And so, you know, fundamentally it presents challenges often in getting patients to screening and patients that might otherwise enroll in studies. The good thing for us here is during the height of the pandemic, in fact, we were largely in planning stages, getting the protocol approved by regulatory agencies, IRBs, and ethics committees in the various countries in which we are targeting initiating sites, and then even getting site contracts in place. That's really been the crux of the work. at the end of last year and early this year. So it's a heavy lift. And so many don't quite appreciate the fact that when you finally have a protocol for a global study, there's a lot of legwork before you start getting patients into screening and ultimately to randomization. And that's really been the effort that we haven't faced necessarily challenge with for the most part. There are some times in which regulatory bodies and agencies may have delays. Those are some of the things that we absolutely have faced, will face, and will continue to face, hopefully with less severity as things potentially improve as vaccinations themselves are rolled out globally as well. Now, fundamentally, what we're doing in response, although the study is targeting 80 fewer patients Then we had randomized and enhanced. Enhanced, we had randomized 265 patients, as you recall, in just under a year. Given we're targeting 80 fewer patients, the scope of our effort mirrors the scope of the effort that we had in enhanced, if not potentially larger. When I refer to the number of countries and number of sites that we'll target, It'll be a similar, if not larger, number of countries and sites than we targeted in Enhance with an effort, as we discussed in our prepared remarks, to get response enrolled by the end of this year, that would allow us to have top-line data by the end of 2022 or very early 2023. That remains our objective, Jay. And I think even regardless of, or I should say irrespective of the pandemic, in any study of this size and magnitude globally, it would take a couple of quarters for us to really assess how we're tracking on that timeline. It's a hockey stick pattern in clinical studies. As more and more sites come on board, you see an acceleration. That's what we observed in enhanced. It's what we expect to observe in response. And, again, we're excited that we've been able to kick this off, and the study, in fact, is actively recruiting. So we're going to hope clearly to hit those timelines ultimately.
spk05: Excellent. Thank you for that. And then maybe if I could, just on MBX 2982, can you talk about the registrational pathway there? Is a hypo prevention claim going to require an event-driven trial?
spk13: Well, thanks for that. It's a little early. You know, I think we haven't even had a regulatory discussion yet. So I don't think we, you know, maybe Clara would want to help me answer the question, but Where we are really, Jay, is really establishing proof of pharmacology. You know, do the results that we're seeing with human islets and rats, can we recapitulate that in basically a mechanistic study? You know, then, of course, we would begin to have some dialogue with regulators and would move to a Phase IIb, which, you know, currently you may know that there was just another glucagon approved for a, a rescue therapy. So that's all that's available right now. You know, a safe oral preventative would really be helpful, I think, for a lot of patients who are concerned about how aggressively to use their insulin because of hypoglycemia. There are many patients who are adolescents or teenagers and, you know, their parents worry because a lot of these hypoglycemic episodes occur nocturnally. So having something that they could safely and confidently use and then use insulin appropriately to manage their glucose levels, I think would be a significant step forward. But we're a little early in terms of assessing, you know, what endpoints would be. That phase 2P would probably use continuous glucose monitoring, so it would probably be events of moderate to severe hypoglycemia. I'm speculating here. And then, again, to speculate even a little further than that, of course, I think Phase III would probably seek just to confirm what you learn in Phase IIb. But, you know, it's a pretty intriguing opportunity, we feel. And 2982, which was a homegrown compound, really came out of our efforts through medicinal chemistry and the like, I think is a... One of the best GPR119s that has been studied, we have five clinical studies, more than 200 subjects have been exposed to the drug in a pretty good non-clinical package. So getting some data here should allow us to move forward more quickly.
spk05: Great. Thank you very much for taking the questions.
spk14: Thank you. Our next question comes from Thomas Smith with SVB Learink. Please proceed with your question.
spk11: Hey, guys, good afternoon. Thanks for taking the questions, and let me add my congratulations on the progress. First, just a question on the Phase 3 response study. Can you just clarify the number of study sites you're targeting and how many are activated at this point? And then can you also talk a little bit about your current thinking on Philadelphia Fire Indication Expansion? I appreciate the comments on NASH-DD. but also wondering whether you can speak to how you're thinking about potential CLINs and other rare cholestatic liver diseases like PSC.
spk07: Thanks. Yeah, sure. Thanks for the question, Thomas. You know, as it pertains to the progress in the study, it's obviously very fluid. So every day there's progress. Every week we're making progress. I think there are a number of sites that you can see on CLIN trials, I want to say just under half a dozen thus far. But once again, there's not a seamless timeline as sites get up and running and the information necessarily getting uploaded there. So we've made really good progress in terms of overall sites as we continue to get things up and running. You know, when we talk about a scope as large as we had in Enhance, you know, Enhance we had activated nearly 150 sites, not all of those enrolled patients. In a setting like PBC, you know, We typically see between one to two patients per site. There are some sites we consider super-enrollers with four or five patients Of course, there are some sites that ultimately are not able to enroll patients, just don't meet the enrollment criteria for this type of study. So we feel we've got vast experience now. Of those sites we had enrolled in enhanced, we know those that likely won't have patients, so it will give us some efficiency in not going back to some of those regions and sites specifically where there weren't patients that met the criteria. There were sites that we learned of at the last stages of randomizing enhanced and completing that enrollment that, in fact, had interest. And, unfortunately, we couldn't get them in in that time. And I think that also gives us a little bit of advantage to just know some of the additional centers that we want to ultimately target. But, you know, I think this is going to be, once again, as it was in enhanced, north of 100 sites. that we hope to even be activated into this study and contribute to getting us to this goal, again, hopefully by the end of this year.
spk11: Okay, great. I appreciate that, Carlos. And then maybe if you could just talk a little bit about the business development and I guess how you're thinking about plans in PFC at this point.
spk07: Yeah, no, sorry, good follow-on question. So as we had discussed, you know, we continue to have dialogue around opportunities to potentially study Celadalipar in combination with other treatments for NASH. As Chuck mentioned in our prepared remarks once again, very challenging for us to really pinpoint a timeline on this. It does involve third parties evaluating not just Celadalipar but also their own programs and their own strategy. But to give you an example there really quickly and then move on to other opportunities that we remain excited about, when you look at what Novo and Gilead are doing, for example, combining GLP-1 plus FXR, a collaboration which they've, in fact, expanded, recently announced an expansion of that collaboration. I think in many ways we look at CeladalPAR's profile, and I would argue an even better combination with GLP-1 than SXR could, in fact, be CeladalPAR. So there's much to dig through and discuss there, and we're committed to that ongoing dialogue and potential additional opportunities. Outside of those that we have specifically discussed, decided would only advance with a partner with significant resources on board are, in fact, opportunities you alluded to, other potential indications in rare disease, PFC, clearly potentially one of the most obvious ones with teledelpar. There are others that Chuck and his team have continued to evaluate preclinically as well. We do think this mechanism may lend itself to inflammatory diseases within liver, rare diseases, as well as potentially outside of liver. So those things are early, too early for me to be able to comment on. You know, I can tell you with respect to PSD, obviously this is high unmet need patient population, a smaller patient population than PBC. but a patient population for which there are no approved treatment alternatives. Those patients are more heterogeneous than you see overall in the PBC population, so we continue to have dialogue with experts, with advisors, as we think about the right timelines, the right types of study designs to potentially explore PSE, but certainly that's an area of high interest. The real question right now is timing, and right now we're committed to making sure that we not only get back into the clinic and PBC as we have this quarter, but really drive to a completion there because we think there's a real near-term opportunity to advance care and significantly even grow the patient population, as we've discussed.
spk12: Got it. Got it. Okay, great. Thank you, Bill. I appreciate the color. Yeah, thanks, Thomas.
spk14: Thank you. Our next question comes from Mayank Mamthani with B. Riley Securities. Please proceed with your question.
spk08: Good afternoon. Thanks for taking my questions, and congrats on an incredible turnaround. So just maybe, Sujil, if you could comment on what you said in your prepared remarks, you know, the overlooked NDA enabling activities and TBC. I mean, are there any drug-drug interaction studies that you may have to do? And maybe just thinking about combinations here, If you could comment also, you know, just summarize your work you may have done in NASH to date from a combination standpoint with CeladalPAR, I think that could be really helpful.
spk07: Yeah, certainly. So I'll start off with the first part, and then I'll invite Chuck to more specifically talk about potential NASH combinations. You know, the NDA-enabling studies that Clara and all the teams here internally are really spearheading are really the standard ones, so looking – across PBC at the treatments that patients are typically on. ensuring that we look at drug-drug interaction studies for those commonly prescribed medications that this patient population can be on as well. They include renal impairment, hepatic impairment studies, so just a lot of blocking and tackling, nothing outside of the norm fundamentally than what would be expected in this setting. So those are just ongoing activities as we drive towards Looking forward, if we're able to meet the timelines that we've set forth, we would anticipate being in a position to file an NDA potentially in mid-2023. And so making sure that we have these things completed by the time of that NDA submission is also a priority, of course, alongside the Phase III study and the long-term study as well. Maybe, Chuck, do you want to talk more specifically about the second part of my next question?
spk13: Yeah, sure. Happy to do that. So if you have an opportunity, you can look on our website. We have some posters that we presented looking at some combinations in a pretty aggressive fibrotic model in mice. And we've looked at a variety of agents. We've looked at GLP-1 receptor agonists. We've looked at salonsertib because it was in Phase III. We've looked at some antidiabetic agents and the like. I think what's really emerged for us is so far, is the agents that have effects on metabolic features. So, for example, if you look, you'll see that we looked at loraglitide, which has its own human data, where there's some good effects on NASH pathology, but limited to no effects on fibrosis. You probably know that semaglitide also has recently released some NASH data as well, which has pretty much a similar pattern, some very convincing data on NASH pathology, but really nothing available on fibrosis, at least for the duration of the studies that have been examined to date. In mice, at least, with the caveat of the difficulties of translation, we see a very strong complementarity. So celadelpar has a metabolic effect, but it has some strong antifibrotic effects. Those metabolic effects of celadelpar added very nicely to the effects of the GLP-1 receptor agonist, while maintaining the anti-fibrotic effects. So the thinking is that you have two agents, you put it together, you take away some of the disease driving from the metabolic side, and you supplement that with the known histological feature that drives liver-related outcome. You basically stop that in its tracks. You'll have an early effect on events. Those two together could be quite intriguing to study. And I think that's probably the similar approach concept that Gilead and Inovo are looking at. We just think that if you look at our NASH clinical data where we had 26% NASH resolution and 37% one-stage fibrosis improvement in NASH patients, we believe Celadalpart would be a very strong player in that kind of combination. And with the caveat that it's not head-to-head, I think it really suggests at least one should think about that combination with the GLP-1 receptor agonist.
spk08: Thank you. A very helpful overview on both those topics. And quickly, Chuck, on 0406, I understand the mechanism very well, but on the attributes on the specific molecule, it seems like a lot of dose, like almost you're going up to one kilo. Can you just maybe comment on why is that, and When you think about your next study, is your mid-2022 cash runway include, you know, whatever you may do next with this molecule? Just curious.
spk13: I'll handle the first part, and then Sujil can help you understand the balance and the capital allocation. So in gout, we studied an 800-milligram dose. And, of course, I've already mentioned that we expect that 0406 would be a lower dose because of its higher exposure. The other thing to appreciate is that 0406 is basically the intermediate right before the synthesis of the prodrug. So all of the CMC has been worked out under GMP at the half metric ton scale, and the molecular mass of 0406, of course, is smaller than our halophenate. So the total overall dose, you know, could well be less. And, of course, there will be some cost of goods advantages because there's one less step in the process.
spk07: And, Mike, as it pertains to the forecast on the cash runway, it includes completing the Phase I. It does not yet include, you know, thinking through any number of potential Phase II studies that we would look to execute. I think, again, here we want to make sure and understand that. the indication that we think merits further investment. You know, I will say one thing as it pertains to obviously the balance sheet. You know, we're quite pleased with the fact that we've been very cost efficient through the last year and a half, continue to have, as I mentioned, well over a year's worth of cash on the balance sheet. We feel that There's nothing we're restricted from accomplishing throughout the rest of this year. We also firmly believe that we have access to capital through various means. And we've been evaluating these periodically, as we always do, even in years past. Continue to see a lot of support from investors, again, through various different vehicles. And fundamentally, you know, we'll make the right decision at the right time. around ensuring not only our ability to get Celadal PAR through Phase 3, but to NDA filing and subsequently prepare ourselves for at least a U.S. commercial launch. We continue to evaluate potentially other geographies and whether or not we may out-license rights to other geographies, and that may come down the road in the future. But, of course, again, we'll make sure that we have the balance sheet necessary not just to move Celadal PAR through to completion, but obviously these other programs should we see a real opportunity to create significant value there. And, again, near term, at least with 2982, as you know, the Phase 2A study that's ongoing is being funded fully, as we mentioned, by the Helmsley Charitable Foundation. And so that's not actually taking capital from our balance sheet today.
spk01: Thank you. It's, again, incredible what you've been able to do with what you had a year ago. Thanks for taking my questions.
spk12: I appreciate it. Thanks, Mike.
spk14: Thank you. Our last question comes from Ed Arcee with H.C. Wainwright and Company. Please proceed with your question.
spk04: Hi, everyone. Thanks for taking my questions. And let me add congratulations on a remarkable turnaround throughout all of last year with CELDELPAR across your programs. Some of the questions I had have already been been answered, but I do have a couple. One is with regard to response, your pivotal study. Clearly, you're leveraging many of the sites that you had previously used for enhanced, as well as optimizing the study design and everything from the enhanced data But I'm just wondering if perhaps just qualitatively you could discuss, in addition to the ongoing pandemic, what potential obstacles or challenges do you see with enrollment? And I'm just wondering, although this may be unlikely to really affect anything, but I'm just wondering if perhaps while there are a lot of patients that had good experiences in prior studies, if there was any sense that you're hearing of hesitancy from either patients or physicians given the clinical hold and everything during that episode. And then I have a follow-up. Thank you.
spk13: Yeah, thank you for that, Ed. Well, let me first just start out, and I think just to say that, you know, in terms of mitigation for COVID, we're able to kind of leverage a lot of experience that has emerged, you know, for other sponsors and with our partner, CRO, as we've gone through various waves and surges around the world. So there have been a lot of experiences developed that allowed us to put in place various things that you can do to mitigate, things like home health visits where needed, things like being able to dispense drug directly to patients in their homes so they don't have to travel to the site, things like offering transportation, you know, if patients were uncomfortable using public transportation, things of that nature. So there's a lot that we've learned and we've put in place, and we're able to incorporate this into the protocol. So if we need it as an option, we can use it. It's not to say we are going to use it. It's just they're in all territories. So that's kind of one question. The second you're asking about is, you know, is there some kind of lingering concern, some trailing issues, concern about the experience, and I can just say unreservedly no. Our approach really has been to be in close contact not only with key opinion leaders, but really with investigators who've been in all of our studies. There's not a week that goes by that I'm not speaking with them, talking about them. You know, I think our best tool really for enrolling the study is the data from Enhance. And the enthusiasm that I received, the comments that I received, the discussion that we've had with KOLs around what we found as a result of the investigation had really been heartening. And from the patient perspective, for example, I just had an email last night, you know, a site that really has many patients that are just really excited, hopeful that they can come back into treatment with Celadal Park. So I think I really have no reservations about, you know, about a concern that we move through with respect to what happened in Nash.
spk04: Okay, great, fantastic. Glad to hear that. Second question is with regard to the two key secondary endpoints. You've talked before in the past. certainly about what you would like to see in terms of potential labeling. Were you to see significant reductions in puritis? But also wondering about ALP normalization, given that there is data to certainly support the idea that you could see significant normalization, how should we think about, you know, the options that you may pursue in terms of labeling, especially from a differentiation marketing perspective there?
spk07: Yeah, Ed, thanks for the question. Really thoughtful. I'll start it off and invite, you know, Clara and Chuck perhaps to chime in. I think fundamentally with respect to ALFOS normalization, there really isn't necessarily a regulatory pathway to recognize ALFOS normalization from a labeling claim perspective. We do think that the data set itself and having the ability to have data sets from enhanced and even response demonstrating a good proportion of patients that actually experience normalization nevertheless is a key differentiating feature. certainly from the only existing second-line treatment alternative, Ocaliva, and potentially even others that are being evaluated. So, you know, it's of prime interest not only to us but really the entire medical community, and we think could be a key factor in driving, you know, potential use should we be successful in getting Celadel PAR registered, of course. With puritis, I think it's a bit more straightforward than even outclass normalization. You know, this is a known clinical symptom of the disease. It affects quality of life quite significantly. I think in many ways you might consider symptom burden to be an outcome of the disease itself. And so here, of course, we have aspirations. We think there are various ways to win here. You know, clearly having a data set strong enough that the regulators would view as being able to provide, you know, some indication on a label of treating patients with PBC, treating pruritus for patients with PBC is probably at the top of that win list. But there are others, you know, having the data set itself in the label, a strong data set, continuing to be able to invest in evaluating patient-reported outcomes, be it pruritus or even fatigue. just something we've done consistently in our clinical studies. All of these data sets, we think, as we look to publish and continue to invest in lifecycle management to really have data to support broader use of Cellidel PAR, I think can be quite valuable overall as we continue to progress, even in the absence of a specific label claim. Of course, You know, we continue to be hopeful that we'll be successful here and show a kind of effect as we've shown in HANF and continue to think about opportunities even beyond the Phase III study to invest in these types of data sets.
spk04: Okay, great. Final question then for me is, if you could, perhaps this is a question for Dan, but if you could help us understand think through the potential trajectory or cadence of OPEX spending throughout this year and perhaps into early next year, both GNA and R&D, especially perhaps later this year as you look to get readouts from your early stage pipeline and think about pursuing further development with those compounds.
spk06: Yeah, thanks for the question, Ed. You know, certainly as we highlighted in the remarks, we are seeing an uptick in our spending as you would clearly expect as we reactivate these programs across a number of trial fronts and initiatives. And so we're projecting a $20 million and growing to sort of $25 million per quarter sort of run rate and a little bit more towards the back half of this year and less so towards the first half. So that's sort of the progression. And as we discussed a little bit earlier on this particular call here, you know, if you consider some of these other programs, Like the CB0406, for example, we've got funding in the budget for those, but we'll take a look at, you know, where the data leads us there and consider, you know, the capital needs beyond that. And I think I'll just turn it over to Sujal as well for any other color.
spk07: Yeah, no, I think that, as Dan mentioned, if you look back at historical OpEx when we were enrolling enhancement, I think it mirrors what we're projecting here with respect to $20 to $25 million per quarter, and it won't get to the high end of that range until we get much deeper into enrollment. And that's what really provides the cash runway guidance to mid-2022 and the strength of the balance sheet that we have here today. Obviously, we'll evaluate opportunities to continue advancing the pipeline programs as we progress and certainly look to do so in the future.
spk04: Great. That's helpful. and congrats again. Thank you, Ed.
spk14: Thank you. There are no further questions at this time. I would like to turn the floor back over to management for any closing comments.
spk07: Thank you, Operator. I'll just leave everyone here with one sentiment. One year ago today, we had shut down all clinical activities while we took on the important work of ensuring patient safety before dosing another patient with Celadalpar. And today we have four active clinical studies ongoing across three different programs and multiple significant opportunities to create value for patients and our shareholders. We would not have accomplished what we accomplished in the past year without the grit, resolve, hard work, and dedication really by everyone at FEMA VA, by our partners, our expert advisors, and, of course, the patients that continue to inspire us in our most challenging days. I thank all of them. I thank you for joining us today, and I look forward to providing you with many more updates in the month ahead. Thank you.
spk14: This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation. Have a wonderful evening.
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