CymaBay Therapeutics, Inc. (NASDAQ:CBAY) Q3 2022 Earnings Conference Call November 14, 2022 4:30 PM ET
Company Participants
Paul Quinlan – General Counsel
Sujal Shah – Chief Executive Officer
Chuck McWherter – Chief Scientific Officer and President, R&D
Dennis Kim – Chief Medical Officer
Lewis Stuart – Chief Commercial Officer
Dan Menold – Vice President, Finance
Conference Call Participants
Steven Seedhouse – Raymond James
Kristen Kluska – Cantor Fitzgerald
Patrick Dolezal – LifeSci Capital
Ed Arce – H.C. Wainwright & Co
Mayank Mamtani – B. Riley
Jay Olson – Oppenheimer
Sean Kim – Jones Trading
Operator
Good day, ladies and gentlemen and welcome to CymaBay’s Third Quarter 2022 Financial Results and Business Update Conference Call. [Operator Instructions] 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 Investors section at the CymaBay website at www.cymabay.com.
I would now like to turn the conference over to Mr. Paul Quinlan, General Counsel of CymaBay. Mr. Quinlan, you may proceed.
Paul Quinlan
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 2022 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; Chuck McWherter, Chief Scientific Officer and President R&D; Dennis Kim, Chief Medical Officer; Lewis Stuart, Chief Commercial Officer; and Dan Menold, VP, Finance. Following our prepared remarks, we will open the call for Q&A.
Before we begin, I’d like to remind everyone that statements made during this conference call, including the Q&A session relating to CymaBay’s expected future performance, business prospects, events or plans, including clinical plans, regulatory approvals, funding and repayment schedules, anticipated timelines and data release dates, cash runway and planning for commercialization are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995.
Although the company believes that the expectations reflected in such forward-looking statements are based on reasonable assumptions, actual outcomes and results are subject to risks and uncertainties and could differ materially from those forecast due to the impact of many factors. The company assumes no obligation to update or supplement any forward-looking statements whether as a result of new information, future events or otherwise, except as required by applicable law. Participants are directed to the cautionary statements set forth in today’s press release as well as the risk factors set forth in CymaBay’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 CymaBay and any recording or rebroadcast is expressly prohibited without the written consent of CymaBay.
At this time, I’d like to turn the call over to Sujal.
Sujal Shah
Thank you, Paul. Good afternoon and thank you for joining us today. Although our prepared remarks today will be brief, we made significant progress during the third quarter towards our goal of bringing seladelpar to patients with PBC. We will cover 3 key business updates and provide a summary of our third quarter financials before taking questions. In the third quarter, we reported completing enrollment in RESPONSE, our global Phase 3 registration study, evaluating seladelpar in PBC patients who have had an inadequate response to or intolerant to first-line treatment with ursodeoxycholic acid. Today, Dennis will provide updates on our progress and plans for the seladelpar development program to complete response and announce top line data in the third quarter of 2023.
In September, we shared with investors our view of transforming the future for expectations of treating patients with PBC. Dr. Chris Cowley, a prominent hepatologist discussed unmet needs in the management of PBC. Our team then describes seladelpar’s clinical profile and its potential to provide a preferred option in second line treatment, including in key segments of the PBC patient population that are either under treated or not treated at all. Lewis will provide a summary of his team’s pre-commercial work that we shared during this event in September.
Last week, we had the opportunity to share additional analyses and results from our prior clinical studies of seladelpar in PBC at the American Association for the Study of Liver Diseases annual Liver Meeting in Washington, D.C. This was the seventh Liver Meeting at which we have shared results for seladelpar. This important Congress provided us vital feedback on our program and allowed us the opportunity to meet with patient advocacy groups and thought leaders. Dennis will return to share an overview of our presentations and activities held at this year’s Liver Meeting. To close out our call today, Dan will provide a short summary of quarterly financials.
Let me first turn the call over to our Chief Medical Officer, Dr. Dennis Kim.
Dennis Kim
Thanks, Sujal. Today, I’ll provide an update on the progress we have made as well as our plans going forward in our clinical development program for seladelpar and PBC. As we discussed during our last call, we have fully enrolled our pivotal Phase 3 PBC clinical study RESPONSE with 193 patient volunteers. And once again, we would like to extend our gratitude to our patients and clinical trial partners in accomplishing this important milestone.
The RESPONSE study is progressing as planned and continues to receive clear signals to proceed without any changes from the data safety monitoring Board meetings that have taken place since the start of the study. We continue to project being able to have top line data readout from the RESPONSE study in Q3 of next year and thereafter, plan on submitting a high-quality NDA to the FDA as quickly as possible. In the meanwhile, we are continuing to wrap up clinical pharmacology studies to fulfill the FDA’s requirement for a complete NDA.
We also continue to evaluate and follow patients in ASSURE, our restarted long-term safety study in which qualified patients who participated in one of our prior studies, such as ENHANZE can rollover and receive open-label seladelpar daily. We continue to gain important clinical experience through the study and will amass valuable efficacy and safety data in a large number of PBC patients exposed to seladelpar for months and years. As of last month, we had more than 180 PBC patients in ASSURE actively taking daily seladelpar.
Our duration of exposures include more than 150 patients for at least 1 year and more than 65 patients for 2 years. We believe that collecting this degree of long-term safety and efficacy follow-up is a significant differentiating feature of our program. It is intended to substantiate seladelpar’s long-term efficacy for biochemical response and pruritus in addition to creating a large safety data set. The seladelpar clinical program is expected to yield one of the most robust data sets for a drug candidate in development for PBC. We plan to have top line results from response in Q3 of next year and then to compile and submit the NDA to the FDA as quickly as possible.
I will now hand the call over to our Chief Commercial Officer, Lewis Stuart, to share highlights from our Investor Day held back in September.
Lewis Stuart
Thank you, Dennis. During our recent PBC Analyst Day, I shared summary findings from our seladelpar global market assessment, mostly focused on our U.S.-based research, including recent insights on the PBC patient journey. Our findings reflect on the patient’s emotions and active engagement from the onset of symptoms through diagnosis, treatment and disease progression. As you know, it is these insights from patients and their care partners that are foundational to the development of our seladelpar launch plans. We were so inspired by these patients. Their positive attitude, optimism and motivation to improve their current liver health, their desire to see improvements in their quality of life as well as how they leaned into their support systems. This is a highly engaged patient population that constantly seeks new information and are active participants within the PBC community.
We learned that it may take up to 2 years for PBC patients to obtain a formal diagnosis with treatment initiated quickly, followed by continuous management and monitoring of their overall liver health. We consistently hurt patients share how debilitating their symptoms were despite being on treatment. Many patients expressed how itching and fatigue dominated their lives. Yet it is often neglected or not adequately addressed by their health care provider. In addition to these research efforts, we recently held a patient advocacy forum at The Liver Meeting attended by leaders of PBC advocacy groups from around the globe. Their commentary and insights validated what we had learned in our market research. During this forum and other Liver Meeting sessions, patients describe their itching as bugs crawling under their skin.
Another rebate heard was it’s relentless. It’s like a life science of just being uncomfortable. And that scratching barely release their itch, sometimes leading to brakes in their skin and scarring. These advocates share their own research on how physicians’ perceptions of their pruritus are often underestimated versus patient-reported severity. Most notable was the challenge to their providers to look beyond the numbers referring to biochemical markers such as ALP and bilirubin and focus on how their patients are feeling. Clearly, there is an unmet need for more effective disease management of PBC-related pruritus.
As a reminder, approximately 60% of PBC patients experience pruritus, which has significant downstream effects on the patient’s quality of life and ability to stay treatment compliant. As 1 PBC patient advocate put it. It’s not just that I want to live longer, but I also want to live well. At the PBC Analyst Day, I also shared a summary of the patient segments where seladelpar could experience – to experience rapid adoption, which includes 14,000 to 16,000 patients who are either incomplete responders to UDCA or have discontinued second-line treatment of obeticholic acid.
Seladelpar is benefited in addressing PBC-related pruritus significantly expands its clinical utility to another 18,000 patients to 20,000 patients. Moreover, seladelpar’s data set demonstrating normalization of key liver measures in both cirrhotic and non-cirrhotics, could support its reach to an even broader patient population with unmet need. Clearly, we have a unique opportunity to elevate the goals for PBC treatment effectively addressing not only the patient’s overall liver health, but equally important, the quality of their daily lives.
At CymaBay, we want to build a high-touch commercial model that is designed to support patients and their caregivers as they navigate the health care in ecosystem. We believe our execution should focus on three pillars: medical education on seladelpar’s unique product profile; optimizing patient access and services; and last but not least, active patient advocacy and engagement. These themes will be our guidepost for supporting PBC patients, providers and other key stakeholders.
I will hand the call back to Dennis to discuss our recent activities and presentations at The Liver Meeting in D.C. last week. Dennis?
Dennis Kim
Thank you, Lewis. As Sujal mentioned, last week, we had the opportunity to make two presentations of new analysis of clinical results for seladelpar. The first was a poster presented by Dr. Chris Bowlus, the Chief of the Division of Gastroenterology and Hepatology at UC Davis, reporting on our post-hoc pooled analysis of lipids from the seladelpar open-label Phase 2 and Phase 3 ENHANZE studies in PBC. Dyslipidemia is a common feature in PBC and so we are interested in understanding how lipids were affected by seladelpar treatment in PBC patients.
Changes in lipids were analyzed for 373 patients with PBC receiving daily oral treatment with placebo, 5 milligram or 10 milligrams of seladelpar at 1, 3 and 6 months. At baseline, most patients had dyslipidemia. For example, average total cholesterol levels, was elevated at 238 milligrams deciliter with 77% of patients being above normal levels. Similarly, the average LDL cholesterol level was high at 138 milligrams deciliter, with 54% of patients having levels above normal. At month 6, the mean change in total cholesterol from baseline in the placebo – in the 23 placebo patients was minus 4 milligrams deciliter, compared to minus 20 milligrams deciliter for the 70 patients taking seladelpar 10 milligrams.
The corresponding change in LDL cholesterol for placebo patient was an increase of 0.5 milligrams per deciliter, whereas the seladelpar 10-milligram patients value decreased by 18 milligrams per deciliter. These changes were significant for seladelpar 10 milligrams versus placebo. Interestingly, these effects were similar for patient groups on background lipid therapy to those without. We expect to continue to collect additional data on lipids in our ongoing studies to support understanding what these changes could mean for patients.
A second clinical presentation was made by the CymaBay research team describing an analysis of the serum metabolome of 160 patients completing 3 months of treatment in the ENHANZE study. This analysis found broad dose-dependent changes in the unbiased survey of 1,474 metabolites. The percentage of measured metabolites with significant changes below the p value of less than 0.05 levels were 6.6% on placebo, 21% on seladelpar 5 milligrams and 39% on seladelpar 10 milligrams.
Seladelpar was found to increase serum markers of mitochondrial and peroxisomal fatty acid beta oxidation, indicated by increase in carnitine, an acyl carnitines and decreases in dicarboxylates and significant reductions reduced serum levels of inflammatory lipid mediators, including long chain fatty acids, mono and diacylglycerol, eicosanoids, Ceramides and Sphingomyelins. Measured in our target PBC population, these results provide clinical evidence of seladelpar’s impact on mitochondrial function as well as reductions in the serum of known inflammatory mediators. These insights have the potential to suggest future approaches to elucidate the underlying reasons for effects of seladelpar on cholestasis, liver injury and inflammation.
I’d like to now turn the call over to Dan Menold, VP of Finance, for a review of our financials in the second quarter. Dan?
Dan Menold
Thank you, Dennis. As others on the team have highlighted, during the third quarter, we directed our resources towards executing the patient treatment phase of the fully enrolled RESPONSE study and continuing enrollment of the ASSURE study. We also work to close out and summarize the results of certain required clinical pharmacology studies, and we continue to advance other required clinical and regulatory activities necessary to complete our late-stage development of seladelpar in PBC. Finally, we made progress in manufacturing development as well as in medical affairs and commercial, where we continued to plan and prepare for a potential future launch of seladelpar in PBC.
Turning to a brief review of our third quarter financial position and operating results. Our cash, cash equivalents and investments totaled $153.4 million as of September 30, 2022. We believe this cash on hand is sufficient to fund our current operating plan through 2023. Our net loss for the quarters ended September 30, 2022 and 2021 was $24.5 million and $22.7 million or $0.28 and $0.33 per share respectively. Net loss was higher in the quarter ended September 30, 2022, compared to the corresponding period in 2021, largely due to an increase in interest expense accretion related to the Abingworth development financing agreement. This increase was partially offset by a decline in research and development expenses, which moderated following the completion of the enrollment phase of the RESPONSE trial in July 2022.
Net loss for the 9 months ended September 30, 2022 and 2021 was $79.4 million and $63.5 million or $0.90 and $0.92 per share respectively. Net loss was higher in the 9 months ended September 30, 2022 compared to the corresponding period in 2021, largely due to an increase in interest expense and to a lesser extent, an increase in research and development and other operating expenses associated with the ongoing late-stage development of seladelpar in PBC. Moving forward, we expect our operating expenses to increase in the future as we continue to execute on our clinical development, manufacturing and commercial readiness plans for PBC.
Let me now hand the call back to Sujal.
Sujal Shah
Thank you, Dan. It’s been another exciting quarter for us here at CymaBay, as our teams focus on the day-to-day execution of our clinical programs, manufacturing campaigns and regulatory and commercial preparation. We have been fortunate to add experienced talent across functions and are well positioned for transformational catalysts expected over the next 12 months.
In his expanded role as Chief Scientific Officer and now President of Research and Development, Dr. Chuck McWherter, will lead our development functions where his depth of experience and knowledge in PBC can be leveraged across the organization. I have tremendous confidence in our entire leadership team and in all of those in the company whose daily contributions are vital to our success in delivering improved treatment alternatives for people with PBC.
As we turn the calendar into 2023 in the coming weeks, we will be focused on a broad range of priorities centered around key objectives culminating in releasing top line data from RESPONSE in the third quarter of 2023, and filing for regulatory submissions as quickly as possible thereafter.
We look forward to providing you with updates at future meetings and calls. We are now happy to take questions. Operator?
Question-and-Answer Session
Operator
Thank you. [Operator Instructions] Our first question comes from Yasmeen Rahimi of Piper Sandler. Please go ahead.
Unidentified Analyst
Hi, thank you for taking my question. This is Lauren on for Yas. Just a couple of questions. The first one, where do you guys stand currently in terms of the patent for seladelpar and thoughts on lifecycle management? And then with that, what are the post-marketing requirements based on your FDA interactions? Thanks.
Sujal Shah
Yes, sure. Thank you for that question. So we actually have issued composition of matter patents on seladelpar, one that goes to 2025 and another on the lysine salt form, which is the only form in development that goes to 2026. Neither of those terms actually includes the potential for a 5-year patent term extension for time and development. There are also a broad range of method of use patents that cover seladelpar in PBC as well as in other liver disorders. Specific to PBC, once again, those method of use patents go to 2035.
Our plan ultimately is to continue to develop patents that protect obviously, seladelpar as we think about our path forward. You asked a little bit about life cycle management, and that’s certainly part of that process, and we will speak more about that in the months and years ahead. As part of life cycle management, we also believe there is some significant opportunities for us to continue, as Lewis talked about, exploring seladelpar for broader patient population. Once again, we’ve done a fair bit of this work internally as well as with consultation from thought leaders and patient advocacy groups, really highlighting those unmet needs that continue to exist in underserved populations or patients that are not really treated with adequate treatments today.
So we think there are certainly some life cycle management opportunities that we will continue to commit to, in order to ultimately achieve the objectives we have of putting seladelpar in the hands of as many PBC patients that we believe may benefit. Some of this we’ve talked about in terms of those patients that could benefit from full normalization of biochemical markers of disease progression and inflammation as well as relieving a greater array of the clinical symptoms that patients experience every day in order to improve quality of life.
In terms of the last part of your question around post-marketing, I think all here know that in the setting of PBC, we expect that the accelerated approval pathway is, in fact, in the best interest of patients and certainly will remain available to seladelpar as it has been for other agents in PBC. That would, of course, put us in a position of really committing to better understanding the long-term outcome benefit of a treatment like seladelpar should we be successful at gaining registration and being on the market.
Unidentified Analyst
Thank you for those answers. And just a follow-up from what you last said, what is the company doing in terms of commercial preparedness, hiring sales force, etcetera, getting those activities in order? Where do you guys stand right now?
Sujal Shah
Sure. Lewis, do you want to take that overview on that strategy?
Lewis Stuart
Absolutely. So I think certainly, our focus as we look to 2023, we will be more focused on pre-commercial activities, where we will be getting our MS sales in the field to begin engaging KOLs. We will also, of course, begin to think about our engagement with payers as part of that precommercial strategy. The sales force will come a bit later. We would typically time the sales force after we’ve, of course, filed the NDA. But I think our field exposure with KOLs will be an important priority in 2023.
Unidentified Analyst
Thanks so much for taking the questions.
Operator
Our next question comes from Steven Seedhouse of Raymond James. Please go ahead.
Steven Seedhouse
Good afternoon. Thank you. I just want to ask about the lipid analysis data presented at AASLD. And specifically, even something as simple as statins, there is there could be contraindications with active liver disease. There could be liver function test elevations transaminitis. And so I’m curious in these patients with PBC that have dyslipidemia or elevated cholesterol, is there some hesitancy among hepatologists to sort of use just commonly prescribed dyslipidemia medicines? And is this a place where seladelpar you could sort of carve out a niche that addresses some prevailing hesitancy? Thanks.
Chuck McWherter
Yes, Steve, this is Chuck McWherter. I’ll take that question. It’s a good observation. There has been in the past, quite a bit of hesitancy around using statins, particularly for muscle effects, but also for transaminase elevations. Over time, that hesitancy has abated somewhat. So for example, in our studies with hundreds of patients have been screened, we find roughly 20% to 25% of patients are using statins, although they are often not controlled for the LDL cholesterol and total cholesterol levels. So I’m not sure that it – I would view it as a replacement for statins, but maybe as an additional feature of the drug that should be considered in our population. These are typically middle-aged patients. They have a number of risk factors, cardiovascular risk factors. About 30% of them are overweight or obese. Many of them are taking antihypertensive medicines. As I mentioned, about 20% to 25% are on lipid lowering therapy. So I think from our perspective a drug that addresses disease activity for PBC, improve symptoms, but also may have a benefit on lipids for cardiovascular risk for patients aging, that can only be a benefit. But as we mentioned in our remarks, we will continue to collect this data in response and ASSURE to build out the story.
Steven Seedhouse
Yes. And apologies if I missed this. But in response, do you have a sense of the proportion on these lipid lowering medicines in proportion with these risk factors is basically similar to the pooled analysis you did in the completed studies?
Chuck McWherter
Yes. Well, the study is still blinded and ongoing. So we haven’t delved into those kind of baseline characteristics quite yet. I’d be surprised to find that there are any differences given that we’ve screened over 1,000 patients in our program today in our PBC program. So we have a very significant PBC patient experience. But time will tell. We will report that out when we’ve done the analysis.
Steven Seedhouse
Thanks so much.
Operator
Our next question comes from Kristen Kluska of Cantor Fitzgerald. Please go ahead.
Kristen Kluska
Hi, good afternoon. Thanks for taking my questions. And congrats to Chuck on your promotion. So there were some presentations on real-world analysis from other therapies in PBC at The Liver Meeting. Wondering, if you have any takeaways from these presentations that further underscore where a therapy like seladelpar could best fit and whether this is from your own interpretation or based off some of the expenses feedback, it sounds like you had with numerous engagers at the conference.
Sujal Shah
Yes. Thank you for that question, Kristen. We followed very closely the announcement you referred to in some of the presentations and publications on outcome studies in PBC. Our own dialogue, in fact, with the FDA on post-marketing obligations really has included extensive discussion of external control studies and these discussions we’ve had with regulators really have taken place over the last several years, in fact. And we have had input also from many leading experts recently around this topic. And based on this, we believe that we understand both the opportunities as well as the challenges of external control approaches. And ultimately, we remain engaged on the topic.
Nevertheless, we see that seladelpar has breakthrough designations and the clinical profile thus far on markers of progression of disease and on pruritus. And as confirmed in RESPONSE, we believe will fulfill many of the unmet needs for improved treatments for PBC across disease stages. So as I mentioned before, we still believe the accelerated pathways available for CymaBay. Specific to your question, though, around real-world data and real-world evidence, we continue, in fact, to investigate, and we will continue into the future to investigate real-world data from the use of seladelpar.
One of the things I think that gives us some advantage here is, as Chuck had mentioned, the extent of the overall patient population and experience both efficacy and safety database that we continue to collect in ASSURE, which will grow as patients from RESPONSE continue to roll into that study. Over time, that will give us our own really, I think, closely evaluated data sets that we can continue to compare to real-world evidence and real-world data that exists, of course, as well.
And so I think it’s really important, given some of the challenges to long-term outcome studies in a setting like PBC for many patients, a relatively slowly progressing disease. And so our commitment remains to continue that work that others have treaded as well around exploring some of these extensive control data sets in comparison to potential real-world data we can collect for seladelpar again through ASSURE and through our clinical experience.
Kristen Kluska
Thank you.
Operator
Our next question comes from Patrick Dolezal of LifeSci Capital. Please go ahead.
Patrick Dolezal
Hi, thanks for taking the question. So earlier this year, we saw a transaction for ex U.S. rights to obeticholic acid. Can you just remind us of your plans in regard to commercialization ex U.S.? Are there any unique perspectives towards marketing in the U.S. versus abroad? Whether it’d be kind of a different treatment paradigm, patient access, etcetera? Thanks.
Sujal Shah
Yes. Great question, Patrick. I’ll start it out and perhaps Lewis or others can provide any additional color that I may miss. First of all, in terms of our strategy, I think as we’ve continued to articulate our goal is to get seladelpar in the hands of patients globally that we think can benefit. Certainly, the RESPONSE clinical Phase 3 registration study is one that is a global study. We believe based on our dialogue, it’s a study that would allow us to have an opportunity to register seladelpar in the U.S., as well as the UK, and Europe.
When we think about other geographies where additional clinical work would be required, for example, Japan and/or China, those are settings in which we – our goal is to try to partner as soon as possible. So some of that work, in fact, can continue in parallel with our ongoing clinical activities. As it pertains, I think, to geographies such as the UK, and Europe, just as examples, again, given we believe our studies would allow us to register in those geographies. We certainly have the wherewithal to complete our development program in parallel to having discussions with third parties that we may determine might give us both the economics and the ability to really get seladelpar into a broader set of patients more quickly and more efficiently.
So I think I would simply tell you, Steven, that we’re open to that dialogue. It’s continued for geographies, particularly outside the U.S. Our strategy fundamentally is to execute on a plan that allows us to launch seladelpar at least in the U.S., on our own, potentially other geographies, but at least in the U.S., alone. It is, of course, the majority of the overall commercial opportunity just based on various dynamics, including some of those that you alluded to, a dearth of opportunities and other treatment alternatives for patients and the treatment paradigm fundamentally as well as other dynamics, of course, including pricing.
There are some off-label treatments in PBC that are used and even in guidelines outside the U.S. Those do have some impact in terms of how other treatment alternatives could be used and how seladelpar could be used. But I think even as we think about global settings outside the U.S., we’re incredibly encouraged by the data sets we’ve generated to date. And if RESPONSE data confirms the profile of seladelpar that we’ve seen thus far, we think even in those geographies that include more off-label use, for example, of drugs like bezafibrate. There are some very unique characteristics of seladelpar’s profile, both on efficacy and biochemical markers of disease progression and clinical symptom burden as well as on overall safety that still make it a potential compelling alternative in those various geographies.
So we’re excited about those. We talked a bit about the ex-U.S. rights being purchased for obeticholic acid. Seladelpar now, as we’ve also talked about on these calls, remains the only fully unencumbered late-stage program in the setting of PBC today. And so to the degree that we think there could be alternatives to bring in significant amounts of non-dilutive capital. And also, again, importantly, have partners with experienced boots on the ground that can accelerate that work outside the U.S. We continue to have that dialogue and are excited about those potential opportunities.
Patrick Dolezal
Super helpful. Thanks, Sujal.
Sujal Shah
Thank you, Patrick.
Operator
Our next question comes from Ed Arce of H.C. Wainwright & Co. Please go ahead.
Ed Arce
Hi, everyone. Thanks for taking my question. And let me add my congrats to Chuck. A few questions for me. Firstly, just on timing, assuming positive data from RESPONSE and given your breakthrough therapy designation, would you be applying for priority review? That’s one. And two, on ASSURE, I just wanted to confirm the purpose of this study beyond meeting the minimum number of patients for the NDA safety database. And then thirdly, a quick question on the poster presentation last week on the lipid profile, it was mentioned that their treatment effects were similar, whether or not patients were on lipid-lowering therapy. And so I’m just wondering, perhaps Chuck could explain how this fits with the known mechanism of PPAR-delta for seladelpar. Thanks so much.
Sujal Shah
Yes, absolutely. Thanks for the questions. I’ll take through one and two, and then ask Chuck to chime in on number three. Given as you mentioned, we have breakthrough therapy designation in the U.S. and find access into Europe. Certainly, again, as it pertains to U.S., we will, in fact, seek to have priority review. So just to answer to your first question. With respect to ASSURE, there, of course, is the purpose that you described to ensure that we have an adequate safety database at the time of NDA filing and filings outside the U.S., in fact, as well. We certainly, as we’ve mentioned, believe that, that we will have, in fact, a significant number of patients for overall safety and even longer-term safety out to 1 in 2 years and beyond from ASSURE as well as obviously leading in from our prior clinical experience, perhaps, in fact, the most robust safety data set at the time of regulatory filing.
There are many other benefits, obviously, from ASSURE. We continue to collect in addition to safety data, efficacy data that we will have the opportunity to continue to mine as we think about patient populations and use as we think more about the potential to address things like longer-term effects on liver stiffness, various parameters that may give us greater insights into the potential longer-term benefit and even potential outcome benefit. I talked a little bit about the potential for ASSURE also to give us just extensive real-world data post potential approval and marketing if we’re successful. And that, I think, is another key benefit from the ASSURE study overall, just a very rich experience in what is obviously a rare disease. So I think there are, in fact, many benefits even beyond just having a minimal number of patients for safety.
And then finally, I’ll let Chuck talk a little bit more about his views around significance of the lipid data in patients that either had been on prior statin or lipid-lowering treatment versus those that did not.
Chuck McWherter
Yes. Thank you for the question Ed. And thank you for your comments. So the mechanisms are really quite distinct. As you know, statins inhibit the synthesis of cholesterol through inhibition of HMG-CoA reductase. We had previously studied seladelpar in hyperlipidemia just draw your attention, there is two papers when it was published in the Journal of Clinical Endocrinology and Metabolism in 2011 and another in atherosclerosis in 2012, where the mechanism was shown to be quite distinct from a statin, it really inhibits synthesis in production of lipoprotein particles, LDL, so apoB100, was inhibited secretion of VLDL, which is the precursor of LDL was also inhibited that was shown in those studies. And in particular, in addition, in patients with PBC, we showed that cholesterol itself, its dietary absorption. Was it inhibited by seladelpar as well as cholesterol synthesis in a mechanism that’s different and doesn’t involve HMG-CoA reductase. So I think it’s a unique and complementary mechanism for seladelpar is reflected in clinical studies, two different populations, and that probably explains some of the observations that we had where we saw decreases both with and without acro lipid therapy.
Ed Arce
Great. That’s helpful. And one follow-up, if I may. Just wondering about the manufacturing and supply chain function. The activities that you mentioned are continue to progress. Wondering if there is anything there that could pose a potential gating factor to the NDA submission? Thanks.
Sujal Shah
Yes. Thanks for highlighting that, Ed. We pay particular attention to ensuring quality in the work that we do with respect to manufacturing and a real focus on ultimate supply chain. We’ve done some of the validation work on drug substance that work will continue on drug product. We don’t see anything as of now, frankly, in terms of anything that would be gating to the time lines that we expect should we be successful in response and successful in being able to register quickly thereafter.
Ed Arce
Thanks so much.
Operator
Our next question comes from Mayank Mamtani of B. Riley. Please go ahead.
Mayank Mamtani
Good afternoon. Thanks for taking our questions. And let me add my congrats to Chuck for an expanded role. So, just a few follow-ups for me. Could you talk to the percentage of RESPONSE patients that you have taken biopsy? And would you look to disclose baseline characteristics in full prior to your third quarter dealer disclosure at some point next year? Should we be expecting that?
Sujal Shah
Yes. So, I will start off. We have not disclosed any specifics around the baseline characteristics, including the percentage of those that have agreed to and volunteer to have baseline biopsies. We certainly feel confident that we have a subset of patients that have agreed to baseline biopsy that we again hope to have a 52-week biopsy around in order for us to gain additional insights and meet regulators’ requirements. So, we don’t see that fundamentally today as any sort of risk based on those that agreed in baseline. We have not traditionally, Mayank, disclosed overall baseline characteristics until we release top line data. That would be our plan here as well. I think in order for investors and others to gain some confidence, given how much clinical experience we have in PBC, both in our Phase 2 as well as our Phase 3 clinical programs. As Chuck had mentioned, we have had over 1,000 patients screened in our clinical trials to-date. I think if you go back to the baselines in the populations in Phase 2 and Phase 3, what we are enrolling in RESPONSE is largely an identical patient population to what we enrolled in ENHANCE based on inclusion and exclusion criteria. And so I think there should be some comfort around those characteristics looking similar to what we had before and then we will release those details at the time we share top line data.
Mayank Mamtani
Got it. Thank you. And could you also talk to the status of the hepatic impairment study? And also ASSURE liver safety or outcomes, whatever info you are able to green there, would you be able to compare that against just external historical controls as some of those are not very unique to a particular company. I mean you are able to also do some of those analysis around the external historical control. So, I am just curious if your long-term studies can do similar kind of analysis real-world evidence-based analysis?
Sujal Shah
Yes. Sure. Good question. So, we continue to execute on the hepatic impairment study in PBC patients. I think as you know, study that’s important for us to understand the exposure as well as safety and even efficacy in patients that are cirrhotic, both compensated cirrhotics as well as those with some decompensation. A very difficult study to enroll given how few patients among the broader PBC populations are in those categories, but something that we continue to be committed to in order to ensure that we have got a good sense of seladelpar. Again, efficacy as well as, in particular, safety and exposure in that patient population, that work continues. And we don’t see it again as being gating to our other activities as we think about our overall timelines. With respect to ASSURE, absolutely, look, I think one of the benefits I described earlier in the Q&A session around collecting a broad set of longitudinal data in that study for, as we mentioned, now north of 180 patients that are in ASSURE. It just gives us that opportunity to compare to some of the external controls. We have in fact, worked very closely with groups that have collected these data sets, that continue to collect these data sets. I think it’s one of those alternatives among other alternatives from – with respect to regulatory options that we believe could be available to us. We have to be committed to regulatory requirements to demonstrate outcomes based on outcome studies. But certainly, in parallel to that, having the opportunity to understand the data sets out of ASSURE and how they compare to external controls will also be important for us to generate in parallel. And I think again, it gives us an advantage given how many patients are in ASSURE today and how many we continue to expect to come into that study.
Mayank Mamtani
Got it. Thank you, Sujal. And then on the Phase 3 PBC study that’s running slightly ahead of you. Are you looking to bring any helpful information from there assuming study designs are identical? And it would be helpful if you can confirm that, in fact the two study designs are actually identical between the two programs.
Sujal Shah
Yes. Sure. And just to be clear, you are referring to the Phase 3 study for Elafibranor. A couple of things I will first mention about RESPONSE. RESPONSE is really, as we described a study that we designed based on our experience in ENHANCE, our prior Phase 3 what had intended to be prior Phase 3 global registration study. What we learned from our prior Phase 2 experience and ENHANCE really was the driver around the design for RESPONSE. In many cases, I describe it as a rinse and repeat, if you will, of the ENHANCE study. So, what we have done in RESPONSE is design a study with really the same patient population we studied and ENHANCE the same optimal 10-milligram dose of seladelpar as well as the same primary and two key secondary end points that we evaluated in ENHANCE. So, to the degree that the Phase 3 study for Elafibranor is similar to RESPONSE. I think it’s similar to even what we have done in ENHANCE when you look at the overall endpoints and the patient population that we are studying. Of course, we have in our experience, also leverage the work that had been done with obeticholic acid in their Phase 3 POI study that’s published. So, I think if you look across these various studies, the Phase 3 POI obeticholic acid study, both our ENHANCE and RESPONSE study as well as the Phase 3 for Elafibranor, you are going to see largely many similarities, if you will, when you think about those study designs. So, I think certainly, we always learn from new data sets that are released. And as you pointed out, at least based on what those sponsors have indicated for those studies, that data may come shortly before our expected Phase 3 top line data. So, we will of course, learn things, but obviously, RESPONSE is really set forth based on the experience we have had to-date in PBC, including in our prior ENHANCE study.
Mayank Mamtani
Got it. Okay. Thanks for taking my questions.
Sujal Shah
Yes. Thank you.
Operator
Our next question comes from Jay Olson of Oppenheimer. Please go ahead.
Jay Olson
Hey. Congrats on the progress and thank you for taking the questions. Can you share any physician feedback on the posters presented at AASLD, especially with regards to how lipid benefits could differentiate seladelpar from OCA in patients with PBC. And I had one follow-up, if I could.
Sujal Shah
Yes. Sure. Maybe I will ask Dennis, do you want to share some of what you learned from many of the thought leader discussions we have had. And then certainly, I can add some additional color.
Dennis Kim
Sure. Yes, I think as Chuck mentioned before, the lipid lowering effect of seladelpar is yet another differentiating feature of the drug. And because many patients with PBC have dyslipidemia. When they are diagnosed, there is – as already has been discussed, there is consternation about whether to treat and if to treat with what medication since there are liver toxicity effects that one has to keep in mind. So, in a position of a hepatologist who is now looking at a newly diagnosed patient or a patient who is being referred to that hepatologist, who may already be on UDCA and have dyslipidemia, we think it’s an easy choice for seladelpar to be the next line of therapy not only because of the efficacy that we have demonstrated with seladelpar, but also the plethora of benefits that you can gain from that choice as a second therapy, not only with respect to pruritus, but also with improvement of dyslipidemia. As opposed to perhaps another second-line therapy that we already know can worsen pruritus as well as cholesterol levels. So, the contrast is fairly striking. And I think it’s an easy one to detect, and that’s what the physicians are telling us.
Jay Olson
Great. That’s super helpful. Thank you for that. And just to follow-up on earlier question about the real-world evidence for OCA treatment of PBC patients that was presented at AASLD showing reduction in relative risk of death, liver transplant and hepatic decompensation, which I think Intercept said would be submitted to support full FDA approval of OCA for PBC. Do you expect that outcomes data to impact your strategy to pursue full approval of seladelpar for PBC?
Sujal Shah
Yes. Jay, here is – I will start off and say this. I think certainly, as we see Intercept strategy and particularly regulators respond to their strategy, I think there certainly could be an impact that will pay very close attention to. We think in fact, that the impact could be favorable depending on how they choose to determine obeticholic acid effects in those real-world evidence studies that have been conducted. At least to-date, we would also say this, however, that we fundamentally believe that committing to demonstrating outcomes is very important for the population of PBC patients as well as obviously for regulators who are acting on behalf of patients. And at least to-date, conducting and collecting real-world data and real-world evidence in parallel to that, we think is likely to be the path forward. There are certainly, we know opportunities and benefits from collecting this real-world evidence. But there are of course, some challenges as they relate to things like biases, missing data sets. I think missing follow-ups. I think there are some challenges that continue to be worked out. But we know that regulators recognize in rare disease settings that these are things that must be evaluated and we certainly are committing ourselves to evaluating both of these paths ultimately in parallel. We are not all that surprised that some of the data that came out of the work with obeticholic acid on real-world data and real-world evidence. I think it’s certainly parallels and/or confirms, if you will, some of the data sets that have been generated, for example, by the global PBC study group that originally looked at alkaline phosphatase reductions and bilirubin normalization as surrogate endpoints from what might lead to improved outcomes. And so again, I think there is a lot of strong rationale around our opportunity to continue following both of these potential paths.
Jay Olson
That’s helpful. Thanks for taking the questions and congrats Chuck.
Operator
Our next question comes from Tom Smith of SVB Securities. Please go ahead.
Unidentified Analyst
Hi everyone. This is Mike on for Tom. Thanks for taking our question and again, congrats to Chuck. There has been some recent commentary from competitors highlighting the importance of changes in bilirubin is the most predictive element leading to longer term improved outcomes for PBC patients relative to something like alk phos. And just curious if you tend to think of one being more important than the other between bilirubin and alk phos just as they relate to longer term outcomes in PBC.
Dennis Kim
Maybe I can try to answer that for you. So, it really depends upon disease stage. So, if you look at both alkaline phosphatase and bilirubin and the predictions for outcomes. In early-stage disease, alkaline phosphatase shows up as cholestatic parker that projects the most comprehensive difference in risk profile. Bilirubin itself, it’s true, becomes an important predictor. But it shows up generally when patients become ductopenic that is they have lost their bile ducts. And then in the later stage, you get a very sharp rise in increases in bilirubin. So, in that sense, I think you could say both are correct. Both have some role in predicting risk in different time courses or different aspects of the natural history. There is another feature of bilirubin that’s emerged as a very interesting aspect of predictor. And that is patients who have bilirubins, which were in the normal range, but in the upper end of the normal range, that is between 0.6x and 1x upper limited normal. Those patients are at – still at elevated risk for progression. And it’s believed if you can bring patients down into the lower echelon, say, below 0.6x with a normal alk phos that you can essentially stop progression of disease all together. And so that’s another aspect that we continue to monitor, seladelpar. Now, as others are looking at patients in that strata of still higher risk between 0.6x and 1x upper limit of normal to see if we can decrease that. And in fact, in our 2-year data that we presented at The Liver Meeting in 2021, we showed that about half of the patients who had bilirubin at baseline between 0.6x and 1x upper limit of normal, were put into the lower strata by 2 years. So, we think that’s a different twist to maybe the question you were asking.
Unidentified Analyst
Got it. I really appreciate the color. Thanks for taking my question.
Operator
Our next question comes from Sean Kim of Jones Trading. Please go ahead.
Sean Kim
Yes. Hi. Thank you for taking my questions. First, a quick question. What’s the statistical powering for the RESPONSE trial? And my second question is based on the biology of seladelpar, would you expect the RESPONSE to deepen between month 6 and month 12, or would it – or less stabilized during that time period? Thank you.
Sujal Shah
Yes. Sean, thank you for those questions. I think when you look at overall powering, particularly I would guide folks towards the ENHANCE three months data set that’s available on our website, both in terms of presentations at medical meetings as well as in our corporate deck. And you can see there with as few as 55 patients, around 55 patients in placebo and around the same in the 10-milligram dose group, we hit the primary composite RESPONSE rate at three months with a p-value of less than 0.0001. So, I think when you look at 193 patients enrolled in RESPONSE two to one seladelpar 10 milligrams versus to placebo, we are highly, highly overpowered on the primary outcome measure. The target, which had been 180 patients was really on powering with at least 80% power on itch. But both the primary and then the key secondary on alkaline phosphatase normalization are well over 90% powered just based on the total number of patients that we have brought into the study and the expected treatment effects. In terms of what we would expect between month 6 and month 12, here I would guide you towards looking at the percent reductions in alkaline phosphatase in our Phase 2 experience north of 100 patients out to a year and north of 50 patients out to 2 years of treatment, between month 6 and month 12, you really see a very consistent and leveling percent reduction in alkaline phosphatase. And so we would expect that to really be somewhat consistent between month 6 and month 12 that there may be some increase. I think typically, you see relatively small increases over time. I think what was particularly interesting in some of that data is we continued to see an increase between year one and year two for those patients that have been on treatment out to 2 years. So, encouraged by those data sets that we have, again, for patients out to about 6 months as well as 12 months and even out to 2 years.
Sean Kim
Great. Thank you.
Operator
This concludes the question-and-answer session. I would like to turn the conference back over to Sujal for any closing remarks.
Sujal Shah
Thank you, operator and thank you all once again for joining us today. A highlight of our time at ASLD last week in D.C., included a meeting we had with patient advocacy groups supporting people with PBC from around the world. Having the opportunity to speak to them and importantly to learn from them, there has always been a vital part of our process here at CymaBay. It was exciting for us to provide them with many of the updates we have shared with you all today and to continue partnering with them to make sure we are focused over the coming year and executing with patients in mind. We are a company with a singular focus, but with many upcoming transformational catalysts ahead that we are excited to share with you throughout the coming year. Thank you.
Operator
This concludes today’s conference call. You may disconnect your lines. Thank you for participating and have a pleasant day.
Be the first to comment