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spk01: Good day, ladies and gentlemen, and welcome to SEMA Bay's third quarter 2021 financial results and business update conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open 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.
spk09: Thank you, Operator, and good afternoon, everyone. I hope that you have had a chance to review the press release we issued announcing our third quarter 2021 financial results and business updates. You can access that release on our website under the Investors tab. Joining me on the call today are Sujul Shah, Chief Executive Officer, Dr. Chuck McWhorter, Chief Scientific Officer, and Dr. Dennis Kim, Chief Medical Officer. Following our prepared remarks, we will open up the call for Q&A. Before we begin, I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to SEMA Bay's expected future performance business prospects, events or plans, including clinical plans, regulatory approval, funding and repayment schedules, anticipated timelines and trial enrollment dates, cash runway, and planning for commercialization of any future products are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. Although the company believes that the expectations reflected in such forward-looking statements are based upon reasonable assumptions, actual outcomes and results are subject to risks and uncertainties and could differ materially from those forecast due to the impact of many factors. The company assumes no obligation to update or supplement any forward-looking statements, whether as a result of new information, future events, or otherwise, except as required by applicable law. Participants are directed to the cautionary statements set forth in today's press release, as well as the risk factors set forth in SEMA Bay's quarterly and annual reports filed with the SEC for factors that could cause actual results to differ materially from those anticipated in the forward-looking statements. This conference call is the property of SEMA Bay and any recording or rebroadcast is expressly prohibited without the written consent of SEMA Bay. At this time, I'd like to turn the call over to Sujal.
spk04: Thank you, Paul. Good afternoon, and thank you for joining us today. The third quarter marked another period of significant progress at SEMA Bay toward achieving our mission of improving the lives of patients with the rare autoimmune inflammatory liver disease, primary biliary cholangitis, or PBC. Since restarting CELADELPAR development, we have strengthened and grown our team, and in this quarter have achieved many of our operating plan objectives in clinical development, manufacturing, and commercial planning. Our team is working towards completing what we believe is the most extensive development program for any investigational drug in PBC. In addition to our previously completed phase three enhanced and multi-year open label studies, our program is back on track, and we are currently executing five clinical studies with Celadalpar in more than 20 countries and across five continents in support of our plan for a robust NDA submission. The twin pillars of this effort are 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. Today, our comments will provide a brief summary of our operational progress with our ongoing clinical studies additional data being presented for the first time later this week at the liver meeting sponsored by the American Association for the Study of Liver Diseases, and a summary of our third quarter financials. Before Dennis and Chuck discuss our ongoing studies and upcoming presentations at the liver meeting, I think this is a good time to give those not familiar with CeladalPAR an appreciation for the breadth and depth of our experience in PBC. and the confidence this has given us that Celadelpar has the potential to be a leading treatment option for many patients with PBC. Before discussing the Celadelpar program, let me lay out what we see as the three main unmet needs for patients with PBC. First, many patients need therapies with improved activity against the disease, as evidenced in the incomplete responses commonly observed in their liver 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. It can be argued that offering patients an improved biochemical response and especially the opportunity to potentially achieve the ideal response of biochemical normalization should be a goal 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 puritis. A therapy that can provide symptom relief would improve patients' lives, potentially improving acceptability and adherence to therapy as well. Lastly, the majority of 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 the spectrum of non-cirrhotic and compensated cirrhotic stages of disease. Beginning in 2015, we initiated a series of studies of Celadalpar in patients with PBC that have now included more than 400 participants and has explored a wide range of Celadalpar doses from 2 to 200 milligrams. Over 50 patients in these studies have been treated for two years or more. A remarkably consistent profile has developed across the open-label Phase II studies and the placebo-controlled enhanced Phase III study. The 10 milligram dose emerged as the optimal dose with a pattern of rapid and sustained response with 70 to 80% of patients achieving the primary endpoint, which includes alkaline phosphatase and bilirubin that has been used for accelerated approval of second-line treatment in PBC. Further, up to 30% of patients on Celadalpar normalized their levels of alkaline phosphatase, a potentially significant improvement over available second-line treatment. Significant decreases in transaminases were also found, and we believe that these may be an important difference from other drugs currently in development. As described in our recent publication in the journal Liver International, The 10 milligram dose appears to have improved pruritus, sleep, and fatigue while lowering serum bile acid levels after 52 weeks of treatment. This effect on pruritus was consistent with the data in Enhance, which was measured after three months of treatment using an eDiary collection on the pruritus numerical rating scale. In June, we reported a comparison of the efficacy and safety in a pooled analysis of patients with and without cirrhosis, finding that the biochemical responses and safety profiles were similar in these subpopulations. Taken together, the treatment effects on alkaline phosphatase, bilirubin, transaminases, and puritis across non-cirrhotic and cirrhotic 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 as part of the expected NDA submission package. I'd like to ask Dennis to turn our attention to the progress we've made toward enrolling our phase three response and long-term sure studies. Dennis?
spk13: Thank you, Sujal. I will remind you that we initiated our global phase three registration study response in the first quarter of this year. randomizing our first patient in April. Response is a 52-week placebo-controlled randomized global phase three registration study evaluating the safety and efficacy of Celadalpar in patients with PVC. The study is intended to enroll 180 patients in a two-to-one randomization to oral, once-daily Celadalpar, 10 milligrams, or placebo as an add-on therapy to patients with an inadequate response or intolerance to first-line ortho-deoxycholic acid therapy. The primary outcome measures is the composite biochemical responder rate after 52 weeks for Aclan, Fositase, and bilirubin, the same endpoint used to register Ocaliba, the only approved second-line treatment alternative for PBC, and the same endpoint from our initial Phase III study, Enhance. Two key secondary endpoints that we also studied and enhanced and will evaluate in response include the rate of normalization of alkaline phosphatase at 52 weeks and improvements in pruritus from baseline to six months in patients with moderate to severe pruritus as reflected in baseline pruritus numerical rating scale value of four or greater. As Sujal highlighted, Our extensive operational experience in TDC continues to be a tremendous asset, particularly in the face of the challenges our entire industry has faced conducting clinical studies during the global COVID-19 pandemic. We have mentioned previously the headwinds we have faced, including longer approval times for investigational review boards and ethics committees required prior to contracting with sites and resourcing challenges at sites. which have increased timelines for site activations and screenings. We continue to offer patients and sites a wide range of alternatives to make it easier on patients to participate in our studies. Years of building relationships with sites, staff, investigators, and patient advocacy groups, and sharing results from our previous studies continues to pay off. On our last quarterly call, we had approximately 40 active sites in 10 countries. Today, we have more than 100 sites in more than 20 countries activated to screen and enroll patients, with more expected to be activated before the end of the year. In a rare disease such as PBC, where it is not uncommon to enroll one to two patients per site on average, hitting this critical mass of activated sites is key to driving an accelerated enrollment which we expect to be completed in the first half of 2022. In addition to making progress in response, site activation and enrollment in our Assure long-term study of cell delpar in patients with PBC also continues to accelerate. Assure is open to PBC patients enrolled in previous studies of cell delpar. Like response, it will be conducted in more than 20 countries and has already activated more than 50 sites with more than 90% of patients completing screening having enrolled. It is understandable that with the emphasis placed on response, Assure is sometimes overlooked. But to our knowledge, CellDelPAR is the only investigational drug in development for PBC that has dedicated and significantly sized long-term study like Assure, providing our value study patients an opportunity to receive chronic treatment with CellDelPAR as well as our investigators with crucial cellular part clinical experience. In our view, not only does this significantly support the approval decisions that regulators will make, but we believe it will provide a rich and significant source of persuasive information to inform practice guidelines, payers, physicians, and patients as they select treatment options. Let me hand the call over to Chuck to discuss upcoming clinical abstracts and presentations that will be featured at the liver meeting this week. Chuck?
spk11: Thank you, Dennis. The extensive clinical program to date continues to give us additional ways to examine and understand cellulose parse profile. Continuing our commitment to research, we were pleased to have two important and revealing analyses to report at the upcoming AASLD liver meeting. An oral presentation will be made by Dr. Marlon Maio, Professor of Internal Medicine, Division of Digestive and Liver Diseases at the University of Texas Southwestern in Dallas, Texas. Dr. Maio, a prominent expert in PBC and an investigator in our studies, will discuss the efficacy and safety of Celadilpar during two years of treatment in patients with PBC. The mean percent change in alkaline phosphatase from baseline was minus 42% at one year. and further improved to minus 50% in the more than 50 patients treated for two years. Over two years, there were sustained reductions in the transaminases ALT and AST that are commonly associated with inflammation and liver injury, and in gamma-glutamyl transferase, a biomarker associated with cholestasis and oxidative stress. In this analysis of two-year data, Soledelpar appeared safe and well-tolerated. These results support an interpretation that long-term treatment with Celadalpar results in continued improvement in markers of cholestasis and risk for disease progression. 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 a second presentation, Dr. Cynthia Levy, Assistant Director for the Schiff Center for Liver Diseases, and Program Director for the Transplant Hepatology Fellowship at the University of Miami in Florida, will discuss a pooled analysis from cell adult PAR Phase II and Phase III studies, examining its efficacy and safety in patients with compensated cirrhosis and evidence of portal hypertension due to PBC. This electronic poster presentation will highlight the effects of cell adult PAR in compensated cirrhotic patients with portal hypertension after three months of treatment. This led to alkaline phosphatase changes of minus 30% in the 5-mg group and minus 45% in the 10-mg group. Total bilirubin, platelets, and albumin either improved or remained stable. Again, in this analysis, Celadolpar appeared safe and well-tolerated. The efficacy, safety, and tolerability in patients with compensated cirrhosis and portal hypertension was comparable to that of non-cirrhotic patients. Portal hypertension in cirrhotic patients with TBC is estimated to comprise about half of all patients who have compensated cirrhosis. Portal hypertension is a significant risk factor for progression to decompensation, which are liver-related adverse events. Patients with cirrhosis and portal hypertension have narrowing treatment options after the recent restriction for their treatment with the FDA's revision to the Ocalavel label. 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. For those who are unable to attend the liver meeting, We will be hosting an encore webcast of these two presentations with Drs. Mayo and Levy on Monday, November 15, at 430 p.m. Eastern Time. Information to access a live webcast of this post-AASLD KOL call is contained in the press release we issued today. And a link will also be available on the events section of the SEMA Bay website. As Sujal mentioned earlier, A peer-reviewed paper was published in August in Liver International, and its co-authors include six leading experts in cholestatic pruritus. It reported that Celadalpar appeared to improve pruritus over 52 weeks, as assessed by three independent questionnaires. Pruritus baseline intensity correlated with serum bile acid levels. And pruritus 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. The study has limitations and that is not placebo-controlled, but this is mitigated by the significant agreement between the different measures of pruritus. and the persistence of the effect through 52 weeks. You can find a link to this publication on our website. The enhanced study provided important confirmation of these pruritus effects, and we will seek to further confirm them in the response study. Once again, CIMA Bay remains committed to sharing and publishing results from our clinical studies. Sujal?
spk04: Thank you, Chuck. Before we open the call for questions, let me review some of our key financials for the third quarter. As of September 30th, our headcount grew to 54 employees as we successfully recruited key team members in clinical, regulatory, and medical affairs. Net loss for the three months ended September 30th, 2021 and 2020 was $22.7 million and $11.4 million, or 33 cents and 17 cents per diluted share, respectively. Net loss for the nine months ended September 30th, 2021 and 2020 was $63.5 million and $35.2 million, or 92 cents and 51 cents per diluted share, respectively. Net loss during the three and nine months ended September 30th, 2021, was higher than the comparable periods in 2020, largely due to increases in clinical operating expenses, which were incurred following the resumption of our clinical development of CeladalPAR in PBC during the second half of 2020. In particular, cost increases were primarily driven by enrollment activities associated with Response and Assure, our two active global late-stage clinical trials in PBC. We expect our operating expenses to increase in 2021 as we continue to execute on our clinical development plans in PBC. We completed the quarter ended September 30th, 2021 with cash, cash equivalents, and short-term investments of $113.8 million. As we discussed on our prior quarter call, in July, we signed a non-dilutive risk sharing funding agreement with Abingworth to support the development of CELA DELPAR in PBC. Under the terms of this strategic development funding agreement, we will receive from Abingworth up to $100 million to fund the CELA DELPAR development program for PBC. of which $75 million will be received over approximately six months from execution of the transaction. We received the first installment of $25 million during the third quarter and the second installment of $25 million last week. We believe our existing cash and investments together with the third $25 million installment under the Abingworth Agreement that we expect to receive in early February 2022 will provide sufficient capital to fund our current operating plan into 2023. Furthermore, the additional $25 million of development financing available to us at our option upon the completion of enrollment and response would further extend our runway. We're now happy to take questions. Operator?
spk01: At this time, we will be conducting a question and answer session. If you would like to ask a question, please press star 1 on your telephone keypad. The 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. Our first question comes from Yasmine Ramimi with Piper Sandler. Please proceed with your question.
spk07: Hi, team. This is Jessie on for Yaz. Congrats on your quarter. And we just have two questions on Philadelphia. The first one is, now that we know that enrollment completion for the response study is pushed back to one age 22, can you Please tell us how confident you are that enrollment will remain on track for this timeline on a scale of 1 to 100.
spk04: Thank you, Jessie, for the question. I'm smiling here because I wish I was in the game of giving that kind of precision. But let me address your question this way. You know, we knew on our last quarterly call that the pandemic and evolving situations globally with the pandemic We really put us in a position to keep sites active and enrolling into the first half of next year. So we made that announcement on our prior quarterly call. We continue to make significant progress. We are seeing accelerations. We're seeing increases in screenings. So we've got a tremendous degree of confidence overall in our ability to execute. And I think as you and others know, in 2019, of course, pre-pandemic, we were successful at enrolling a global phase three study enhanced with 265 patients. That study took us just under 12 months to fully enroll. So although we're targeting 80 fewer patients in the response phase three study currently, we're hopeful that that timeline and the challenges of the pandemic effectively offset the smaller patient population that we're enrolling here. But I think at the core of our confidence, Jesse, really comes from the relationships. You know, we mentioned we have over 100 sites now active across 20 countries. That's the type of execution we firmly believe is needed to continue to execute on these timelines. You know, this is a rare disease, as you know. And, of course, we're enrolling patients with alkaline phosphatase levels that are elevated after inadequate response to UDCA largely. And so even pre-pandemic, The most significant screen failure from this population are really patients whose ALKFAS is still elevated, but below that threshold that's required for regulatory approval. Now, when we think a bit about how we've progressed since 2019 in our initial phase three study, as I mentioned, there is much more experience at sites in the medical community for patients with Celadalpar, and that's really where we drive a lot of our confidence. The data that Chuck talked about that we're very excited to share at ASLD at the end of this week, those data sets really underlie the potential benefit for patients, and that's the excitement that we continue to see growing as we execute on this study. So we continue to expect to see significant progress, and we're not really tracking all that different from how we did with Enhance. Enrollment timelines are typically exponential curves as opposed to straight lines as we get a critical mass of sites now active. we really expect to see a conversion from active sites to screenings and eventually to enrollment. So we've done this before. We're confident in our ability to do it again. And all of our focus, of course, is on getting response fully enrolled and really executing, as we described, the most depth of a program in PBC that we think exists.
spk07: Thank you for the color, Sujal. I have one more question. Looking at the market research that Somavay has done, we know that the recent IVAT approval from Alvareo and Miriam was approved for $380,000 a year. So, obviously, payers see the value and the periodic activity. And on that note, can you guys tell us what work has been done on the payer front for pricing?
spk04: Jesse, thanks for that question as well. So, you know, we've been doing actually quite a bit of work thinking about the addressable patient population for Celadalpar. Of course, it starts with our data sets. And as Chuck and Dennis highlighted during the call, you know, that data set includes a very robust anticholestatic effect, potentially a more meaningful effect than current second-line treatment alternatives, certainly from our Phase II and Phase III experience. It demonstrates a significant anti-inflammatory benefit as well as an anti-puritic benefit. And you mentioned the IBAT inhibitors, of course, for very different indications, ultra-rare pediatric cholestatic diseases where the significant burden of puritis for these young children has a significant impact on their quality of life. Ultimately, in the setting of PBC, You know, today, the only currently approved drug in PBC is priced at about $90,000 a year, and that's a rough estimate, of course. And we think that Celadelpar has the ability to offer patients even greater benefit. We're seeing that in our data sets, and as we continue to do our market research, we continue to have confidence in our ability to really deliver the actual value that would underlie the right pricing at the end of the day. That's how we think about the scenario around thinking about the targeted commercial opportunity and pricing. Obviously, there's work that we will continue to do with the medical community, with the payer community, but we're quite confident in our ability to execute and actually improve upon, again, what's out there today for patients. And I think that's really going to be the key driver. You saw perhaps last week, you know, increases in estimates for betacolic acid, revenue estimates for betacolic acid, now on a run rate north of $350 million a year this year. And I think that really underscores the unmet need for patients. and the significant unmet need to reduce their risk of disease progression. So, you know, we continue to be emboldened and quite confident in that opportunity, and it really builds off of that value per patient as we think about pricing and commercial. But it's still early. We continue to do that work, and we'll continue to progress as our data sets mature.
spk07: Great. Thank you so much. That's all from me, and we're excited to see you guys this weekend at AASLD. I'll jump back in the queue.
spk04: Thank you, Jesse.
spk01: Our next question comes from Steven Seabhouse with Raymond James. Please proceed with your question.
spk08: Hi, good afternoon. Thanks for taking the question. Just on the long-term data for cell adelphi, I was hoping you could comment on how sustained pruritus improvements were and if that's data that will be included in the liver meeting presentation or at your event on Monday.
spk11: Thank you for that question. This is Chuck. We're focused in this particular presentation on biochemical response around liver biochemistry tests, basically, so both cholestatic and inflammatory markers, as well as safety. So, pruritus won't be part of the story, but as I mentioned earlier on the call, we do have, I think, a very impressive study with 52 weeks of data It shows that the pruritus decreases fairly quickly within about four weeks, and then it sustains out through all of the study visits right out to 52 weeks. So we're not going to be presenting that data in this particular opportunity, but I don't think there's any reason that the effects on pruritus would abate given the stability, you know, say from a month all the way through 52 weeks.
spk04: The only other thing I'd add there, Steve, is as Chuck had mentioned, the publication in Liver International that just came out has a significant amount of depth of information overall on symptom burden for patients, pruritus, fatigue, sleep disturbance, as well as the relation of those symptoms to bile acid content. And so, you know, I think we hypothesize effectively that if the effects are there on the bile acids and limiting those bile acids specifically, that that should lead to a confidence around a sustained benefit on these symptom burdens.
spk08: Yep. Okay. Thanks. Thanks for the call there. The other thing I wanted to ask was just on that final $25 million tranche from Abingworth. I mean, it would certainly seem like, you could probably use that money before, even if everything goes well with enrollment happening in first half 22 and launch, et cetera, you can use those dollars at some point. So what would be the potential factors or reasons why you wouldn't draw down on your option there?
spk04: It's a great question. And absolutely, as we mentioned, that final $25 million of the up to $100 million from the Abingworth Clinical Co-Development financing is solely at our discretion at the completion of enrollment. You know, at the end of the day, Steve, I'd say this. You know, we have continued to have multiple avenues of funding our programs and financing the company. I've mentioned this in the past. You know, we are quite grateful for the investors that we have and the interest that we have in CeladalPAR and in CIMA Bay more broadly. Fundamentally, it's just an option. You know, we like to remain and contain that option ourselves. as we think about various ways to fund the company going forward, opportunities to continue to actually show value as our programs progress. And as we continue to have data-driving value events, I think we want to maintain the optionality for ourselves to finance the company in the right way. And we, of course, think about those decisions wearing the lens of our existing investors. You're absolutely right. I think it is a great benefit for us to have that additional tranche. We'll ultimately just make that decision based on the best available information at that time.
spk08: Great. Thanks, Sujal. Appreciate it. Thank you.
spk01: Our next question comes from Patrick Dolezal with LifeSci Capital. Please proceed with your question.
spk03: Hi. Thanks for taking the question. So for the AASLD presentation regarding use of Celadilpar in compensated cirrhotics with evidence of portal hypertension, kind of within the backdrop of the label changes for Acoleva, can you just remind us if this patient subset will be enrolled into response? And if so, could you provide context as to what this would mean for the potential market opportunity there? And then just if you could answer the same question as it relates to the decompensated cirrhotic population. Thanks.
spk11: I'll take the first part, and I'll let Sujit step in for the market perspective. Yes, so patients in enhance as well as in response are expected to have some patients with compensated cirrhosis and portal hypertension. The inclusion criteria would allow for those that the clinical evidence for portal hypertension comes from splenomegaly and platelet thrombocytopenia, some of those considerations. And so we would expect to have probably a comparable representation. Just to remind you that of about 350 patients enrolled in the Phase II as well as an enhanced, about 20% of them had compensated cirrhosis. And somewhere a little south of 50% had evidence of portal hypertension. So there's no reason to believe right now. It remains to be shown that we won't enroll the same population in response. It's something that we feel is very important. You can have a patient with compensated cirrhosis with no portal hypertension. If they progress and that develops, you want to know that your drug is going to be safe. That's an important consideration. Patients with portal hypertension, as I mentioned, are at much higher risk for decompensation events. ascites or peritonitis, ferrocele bleeds, those kinds of things. Once you have an event like that, you're at a much significant risk for dire consequences. You're basically on the downhill slope. In terms of decompensation, they're currently not in our studies. They're excluded. I think The reality is that decompensation is a situation where patients are at much higher risk for progression. It becomes much more challenging to imagine that you'd have a therapeutic intervention that could cause progression, much less reverse, unfortunately. I'll let Sujal talk about their representation in the commercial population, but let's just say it's slow.
spk04: Yeah, and I think, Patrick, you know, some additional comments here that I think are important is, you know, even though it may only be about 10% of those 20% of patients with cirrhosis that Chuck mentioned, or maybe even smaller percentage with portal hypertension, you know, the disease is a spectrum. And so, of course, there's much more work for us to continue to do as we evaluate this patient population in our ongoing response study, expecting, again, similar percentages. But when you're a treating physician, you know that at some point in time, a patient could progress. And so having a data set that shows both efficacy as well as, importantly, safety in the more advanced population, I think drives a comfort level for physicians who have patients even later stage in disease, be it compensated cirrhotics or patients that are perhaps on the cusp of becoming cirrhotic. And so given the fact that it's a spectrum, when you can have a safety data set and efficacy in that population, I think it drives even greater confidence in the more broad population as it pertains to overall safety.
spk03: Super helpful. Thanks again.
spk04: Thank you.
spk01: Our next question comes from Jay Olson with Oppenheimer. Please proceed with your question.
spk10: Oh, hey, thanks for the update, and thanks for taking the questions. Can you talk about what additional steps may be taken to redefine efficacy in the treatment of PBC as the normalization of ALKBOS? And then separately, since Intercept is working on an OCA plus basofibrate combo for the treatment of PBC, can you talk about any potential psilodeltar combinations that you may be considering or potentially have looked at preclinically? Thank you.
spk11: Yeah, thank you, Jay, for that question.
spk04: Yeah, I think initially, Jay, you were asking about just additional steps with respect to the development. The normalization. Yeah, yeah, yeah.
spk11: So just to give you a little bit of color, this is emerging from research that's coming from the Global PBC Study Group, which is an academic consortium that has access to very large patient registry of more than 5,000 patients, where they've made a connection to normalization of alkaline phosphatase and its improvement on outcomes. And so this discussion is ongoing in the academic community. have turned from the previous measures of, let's say, below 1.67 to look to normalization as what we would call an ideal response. Every patient, it can be argued, benefits from lowering of their alkaline phosphatase, but the best benefit comes from normalization. And so we would expect this to be a continued area of discussion both from sponsors, measuring it as endpoints and monitoring patients' disease progression, but also in the academic community. I think that there's already discussion afoot about considering whether practice guidelines should be looked at to address whether normalization should be the ideal goal.
spk04: Yeah, and I'll address the second part of your question here a bit, Jay. You know, the OCA plus Visa Fibrate Strategy I think is one that makes sense if a patient initially is on OCA or betacolic acid. We know those patients, almost 50% of them, based on the Phase III data for betacolic acid from the POISE study, have an incomplete or inadequate response, and that they can actually have a worsening of their itch. And so adding Visafibrate to gain both greater response on biochemical markers of disease as well as alleviate those symptoms of pruritus I think is a sound strategy. From our perspective, when we look at either the Bezafibrate or, importantly, just the Celadelpar data on top of UDCA, we think that just UDCA plus Celadelpar, in fact, can meet a significant proportion of patient needs around biochemical markers of disease progression as well as on itch. So I think from our perspective, our priority is first to get through this initial data set. which we believe may be the most robust data set and most compelling data set for a preferred second-line treatment alternative of choice, one that can also, as we've talked about, perhaps demonstrate benefit in a much broader patient population, those with still elevated alkaline phosphatase, even if not above 1.67 times the upper limit of normal, who can benefit, as Chuck mentioned, even from normalization. There's no question that at some point down that line, there may in fact be patients whose ALCLOS is still elevated and could use a further decrease in risk of disease progression. I think at that point in time, thinking through combinations for what that patient population may be is something that we'll continue to stay close to. Our goal is to get Celadalpor on the hands of as many patients that will benefit. We've not yet to date, Jay, done any combinations per se preclinically with Celadelpar in this type of setting.
spk10: Okay, great. Thank you. And maybe if I could squeeze in one follow-up question to your comment about portal hypertension. Could you maybe talk about the potential utility of Celadelpar in reducing portal hypertension, either in patients with PBC or perhaps secondary to other forms of liver disease?
spk11: Maybe I can try to sketch out some thoughts that I would qualify to begin with as being somewhat speculative because we don't have any data. One of the first and most compelling data sets that looked at portal hypertension in patients with PBC was a publication that came out of a group in Montreal as well as in Paris that examined the effects of UDCA treatment on patients with PBC and portal hypertension. It's not a study that could be done again. It was a very invasive study where they measured pressures in both the hepatic artery and the hepatic vein, and so they actually measured portal hypertension as opposed to the wedge measures, which are also invasive, that are used today. This study is very interesting, Jay, in the sense that they actually showed that in a significant number of patients that UDCA actually halted progression, and in fact, in some cases, improved portal hypertension. There was a subset of patients in that study, there were about 30, who were studied for two years, placebo versus UDCA, and it did improve their portal hypertension. So it's a bit of an extrapolation at this point, but I think it gives one an example of where an intervention actually affected the portal hypertension. So that's something that I think would be interesting for us to monitor. Of course, we wouldn't do it in the same way this study did. We would probably be examining other clinical surrogates, what you would say, for portal hypertension.
spk10: Great. That's helpful. Thank you very much for taking all the questions.
spk04: Thank you, Jay.
spk01: Our next question is from Mayanka Mampani with B. Riley. Please proceed with your question.
spk12: Hey, team. Good afternoon. This is Sahil Kazmian from MIAC. Thanks for taking our questions. A number of them have been answered, but maybe just one last one related to the abstract coming up at ASLD. Particularly given that you're starting to see sort of similar results in the compensated serotics and non-serotic patients, can you talk about some of the relationships you've established with both the patient and medical community and how you kind of plan on And it's sort of an education campaign on the fact that there can be a real benefit in the cirrhotic population, particularly following the narrowed label of Ocaliba.
spk04: Yeah, thank you for that question, Sahil. Maybe I'll ask Dennis to give some of his perspectives, you know, as our chief medical officer, as he interacts with PIs and patients, giving some of that experience.
spk13: Sure. Thanks, Ujoel. Yeah, that point has not been lost on our PIs or principal investigators already. As we interact and engage our principal investigators involved in response and ASURE, they already appreciate that particular advantage that saladalpar has in patients with compensated cirrhosis, which is something that patients really don't have much of an option at this point. It's actually one of the driving forces for getting patients into our study in those particular patients. So we hope to be able to demonstrate this in response, as well as in Assure, although Assure is an uncontrolled study. And assuming that we are able to have that data in our label in agreement with the FDA, we will certainly be making that an educational point as we roll out cell doll power for patients with TBC.
spk12: Great, thank you. I look forward to the presentation. Thanks for taking the question. Thanks for that, Helen.
spk01: Our next question is from Ed Arce with HC Wainwright. Please proceed with your question.
spk02: Hello, everyone. This is Thomas Yip asking a couple of questions for Ed. First, congratulations on the progress with response on the shore so far. Perhaps the first question regarding the response trial, can you tell us what is the target number of clinical sites in the study and approximately what percentage of sites have enrolled patients past screening stage so far?
spk04: Yeah, thanks for the question, Thomas. So, you know, in HANCE, we actually had a target that was north of 100 sites. The idea here is the same. In fact, I can tell you we're targeting more sites than we targeted ultimately in Enhance. And not uncommon in this type of setting, we get sites activated and some, in fact, may not enroll by the time the study fully completes enrollment. But that really doesn't stop us from finding places where we believe patients can benefit and sites can actually contribute patients. So it's a number even north of where we sit today. You can see on clintrials.gov, we've got 105 sites that are active now. We expect more to be active between now and even the end of this year. And we think that's a really important testament around our ability to conduct a global study that gives us confidence around getting this study ultimately fully enrolled. So we don't provide granularity around specific sites that have actually enrolled patients thus far. I can tell you this. We interact with sites on a constant basis, up and down the organization here at SEMA Bay. Myself, Chuck, Dennis, many of the others in clinical operations have daily, if not weekly, meetings with sites all around the world. And those are really to try to identify some of the challenges sites have had, whether they're internal resourcing challenges, opportunities we might have to find referrals in and around geographic regions for sites. So there's no question that in some cases there are clearly patients that come in soon after sites are activated, and in other cases where there are sites that may have a few weeks before they bring in a patient for screening. So it's really just a broad effort. And like I said before, we've done this before, so we know the types of things that can help sites at the end of the day. But this is a rare disease. Again, I'll emphasize. I won't, you know, paint a different picture here for you. It's a rare disease. And, you know, in some cases, a physician who saw two patients, you know, in 2019 may not see a PBC patient in 2020. But much of the work that we've done with our CRO really anchors on our prior experience. of understanding centers that have been good contributors to clinical studies, and we'll continue that effort.
spk02: Understood. Thanks for the added detail response. Perhaps one question about Assure, open-label long-term. Can you tell us approximately what is the longest treatment duration among the patients in Assure right now, and is the plan for Assure to report data after a response's top line readout.
spk04: Yeah, so, you know, maybe I'll start off, and Dennis, please jump in here at my conclusion and provide any additional color that I may have missed. So, you know, Assure, Thomas, actually really kicked off earlier this year. I want to say it was February of this year. And so, as sites continue to come on board, that study is for patients that had been on previous studies with Saladalpar. So, our previous Phase II studies as well as our previous enhanced Phase III study. So, there's a bit of a restart for many of those patients because we had paused development and paused our prior long-term study. But I think what's most important is in our prior long-term study, As you'll see at ASLD, about 50 patients that have been through two years of treatment, we actually had a subset of patients even out to three years of treatment. So in terms of continuous treatment, I'd say that we had probably a little over a dozen or so patients that were out to three years, and we continue to see consistent benefit across the biochemical markers of disease, even for those patients. a much smaller subset. So we're focusing this presentation on a good 50-patient subset out to two years. But Assure, you know, will really feed in and continue to contribute to that long-term safety database. We will not only have long-term safety out of Assure by the time we file our NDA at the completion of the response study, but, of course, we'll continue to gather additional data around efficacy and patient benefit So it's a very incredibly valuable data set. And as we mentioned in our prepared remarks, really the only study today of its kind for those programs that are currently in development for PBC. And we think it really adds breadth and depth to the overall Cell Adelpart program.
spk13: Yeah, and not only adding database to the Cell Adelpart program, but also earning the trust of the patients that continue to take the drug in an open-label setting, as well as having principal investigators accumulate clinical experience with the drug, I think will only help us in the long run.
spk11: I'll just maybe add one other thing, Thomas. You're kind of getting at the operational aspects of Assure when you're asking about length of treatment. Just to point out a key distinction between Assure and Response. Assure is really going back to sites we were already operating at, and patients had to be in a prior study. So it's not a matter of going and searching for patients. It's just contacting them, you know, confirming their interests, getting them scheduled in and enrolling. So the ability to get patients back into Assure is a little bit different process, and frankly, it's easier.
spk02: Okay, understood. Perhaps one final follow-up of the response there. So you mentioned, of course, getting patients back into the Assure study after a positive treatment. Is there any plan to look at all... I think we lost Thomas there.
spk13: Yeah, I don't hear him.
spk01: Okay, I can see if I can get him back, but in the meantime, I'd like to introduce Alethea Young with Cantor Fitzgerald for her question. Please proceed.
spk06: Hi, this is Emily Young for Alethea. Thanks for taking our questions. I'm just curious, based on your conversations with physicians who are treating PBC patients, how do you characterize the opportunity for patients currently taking Ocalva and maybe they're not getting benefit from it or could be better served? And how do you think Soledad Park can fit into that population? Thank you.
spk04: Yeah, look, I think it's a great question, Emily. And once again, at the conclusion of this remarks, Dennis, please jump in with any of the experience you've had thus far. You know, I think the challenges with Ocaliva are fairly well known. But putting that aside just for a moment, for those patients that, of course, are experiencing biochemical benefit and response and are not actually experiencing itch, you know, it's unreasonable to have a physician really move that patient off of treatment that's actually providing them benefit without further challenges. Now, we know if you look at the data sets from Ocala phase two and phase three studies that a fairly significant number of patients that actually do either experience itch or have an exacerbation of itch. That's really one of the key issues. But even beyond that, there are patients that nevertheless also have an inadequate biochemical response. And we've seen patients either on prior treatment with Ocala or off-label fibrates come on to Celadelpar and actually have an improved benefit on biochemical markers of disease. And so at Eazl, for example, we actually had an abstract that demonstrated a number of the patient's efficacy as well as overall tolerability data. Those are patients that had prior experience with abetacolic acid or fibrates, where we see a very comparable effect with Celadalpar in those patients as we've seen with patients that haven't tried those treatment alternatives before. You know, anecdotally, I'll emphasize that this is anecdotal, but, you know, we do see physicians who have patients as inadequate responders or intolerant to beta-cholic acid, you know, look to move those patients. They have to wash off before they come into response, but they can, in fact, enroll in response, wash off treatment for 90 days, and we do actually see PIs enrolling those patients into our current Phase III study.
spk13: Yeah, and I'll add to that, Bryce. by saying that, you know, one of my recent interactions with a clinician taught me something interesting, which is that the pruritus may be something that patients don't talk about very actively with their clinicians or their healthcare providers. This physician told me that, you know, the patient never mentioned pruritus, that place in Ocala, but later on down the road, the clinician, the physician learned that the patient did in fact have pruritus, some fatigue and sleep disturbance. And had he known, maybe he wouldn't have made that decision to place the patient on Ocaliva and perhaps the patient would have been a better candidate for a response study. So it's a long way of saying that we need to educate patients as well as physicians on this particular aspect of cell delpar. and how it can be very divergent from the profile that Caliba has.
spk01: Okay, our next question is from Tom Smith with SVB Learing. Please proceed with your question.
spk05: Hi, everyone. This is Mike. I'm for Tom. Thanks for taking your question. Just curious, do you have a sense of what portion of patients in the Phase II response study have opted to receive a liver biopsy? And just as a follow-up, could there be a scenario in which you can only enroll patients that are willing to receive a liver biopsy after a certain point, you know, just you're able to be aligned with the amount of biopsies that the FDA is expecting to see?
spk04: Mike, I didn't quite get the second part of the question, but maybe Chuck, let me at least first address your first question. So, you know, we, of course, recognize which patients are volunteering for biopsy at the outset. You know, that's not a number, again, that we would report. I will say that, you know, in our enhanced study, we had at least 16% of patients volunteer for a biopsy. Going into response, we further emphasize the benefit for patients to learn about the stage of their disease and progression of their disease. So fundamentally, we're confident that we're going to get the patients we need to volunteer for a biopsy in this study because it's been much more of a conscious effort for us as we've enrolled responses when we did even enhance. So I think things continue to track well in those conversations, but we don't specifically report those numbers as we're enrolling the study, but we're quite confident in our obligation to patients as well as to regulators as we look to complete response.
spk11: And I'll just, to your second part of your question, just reinforce what Sujal said. I personally don't believe there's going to be any problem with meeting the threshold that we'll need to deliver to the regulators. But, you know, I suppose theoretically, if it turned out that we thought there was an issue, we might... basically take the approach to where we could consider requiring it. But I just don't think that's going to come to pass. I think we're not anywhere close to that situation right now.
spk05: Got it. That's really helpful. Thanks. And then just a quick one. In terms of the investigator-sponsored Phase 2 study of MBX 2982, could top-line results still come before year-end, or is that something where more likely to maybe be early first half 2022?
spk04: Yeah, so good question, Mike. We expect that study to complete and ultimately have data sometime next year. So once again, that's a study that's being fully funded by the Helmsley Charitable Trust conducted by a single site CRO in Florida, AdventHealth TRI. We're, of course, in close contact with them, and the study continues to progress. We're excited about that potential data. potential opportunity to do something quite novel for patients with type 1 diabetes who are suffering from hypoglycemia. But I think fundamentally that data set would come at some point as the study is completed next year. Got it. Thanks very much. Okay. Thank you.
spk01: Ladies and gentlemen, we have reached the end of the question and answer session, and I would like to turn the call back over to Shujil Shah for closing remarks.
spk04: Thank you, operator. I hope today you walk away with an appreciation for our focus executing what we believe is the most robust development program in PBC today, and our excitement around the opportunity Celadalpar has to be a leading impactful treatment alternative to a broad population of patients with PBC. We have enrolled multiple global phase two and phase three studies in PBC in the past and are confident in our ability to do it once again. We know the need for patience is now, and all of our efforts and focus is on this execution. We also couldn't be more excited to have another meaningful presence at the liver meeting at the end of this week, and believe the data we have to share will continue to differentiate Celadelpar in the setting of PBC. Thank you once again.
spk01: This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.
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