Charles A. McWherter; President of Research & Development and Chief Scientific Officer; CymaBay Therapeutics, Inc.
Lewis J. Stuart; Chief Commercial Officer; CymaBay Therapeutics, Inc.
Paul T. Quinlan; General Counsel, Chief Compliance Officer & Corporate Secretary; CymaBay Therapeutics, Inc.
Sujal A. Shah; President, CEO & Director; CymaBay Therapeutics, Inc.
Jay Olson; Executive Director & Senior Analyst; Oppenheimer & Co. Inc., Research Division
Julian Reed Harrison; Director & Biotechnology Analyst; BTIG, LLC, Research Division
Kristen Brianne Kluska; Analyst; Cantor Fitzgerald & Co., Research Division
Mayank Mamtani; MD, Senior Biotech Research Analyst & Group Head of Healthcare; B. Riley Securities, Inc., Research Division
Patrick Edward Dolezal; Senior Analyst; LifeSci Capital, LLC, Research Division
Steven James Seedhouse; MD & Analyst; Raymond James & Associates, Inc., Research Division
Tsan-Yu Hsieh; Senior Research Analyst; William Blair & Company L.L.C., Research Division
Wing Cheung Yip; Research Analyst; H.C. Wainwright & Co, LLC, Research Division
Yasmeen Rahimi; MD & Senior Research Analyst; Piper Sandler & Co., Research Division
Good day, ladies and gentlemen, and welcome to CymaBay's First Quarter 2023 Financial Results and Business Update Conference Call. (Operator Instructions) 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.
At this time, I would like to turn the call over to Mr. Paul Quinlan, General Counsel at CymaBay. Mr. Quinlan, please proceed.
Paul T. 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 first quarter 2023 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 of R&D; 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 or 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 A. Shah
Thank you, Paul. Good afternoon and thank you for joining us today. 2023 continues to be an exciting year for CymaBay with only a few short months before we report results from the RESPONSE Phase III study of seladelpar in patients with primary biliary cholangitis or PBC. Conducted across 5 continents, the seladelpar development program embodies our commitment to advancing care for patients with this rare autoimmune liver disease. In service of their need for improved treatments, we have worked in close collaboration with patient advocacy groups and the world's leading disease experts to ensure that the design of the seladelpar program evaluates those aspects most important for patient needs.
Our early Q1 accomplishments included licensing of rights to develop and commercialize seladelpar in Japan to Kaken Pharmaceutical company and a follow-on equity offering. The capital we raised will fund our operating plan through Q3 of 2024. Our update today will describe our key activities, progress and accomplishments made since our last call and will share catalysts expected in the months ahead.
Last week, we announced the appointment of Harish Shantharam as our Chief Financial Officer. For almost 20 years, Harish led various financial functions in commercial biotech companies with a particular focus on setting strategy and building financial planning and accounting operations to prepare companies for commercial drug launch. Harish spent 11 years at Gilead Sciences, last serving as Vice President and Head of Global Commercial Finance. Prior to Gilead, he served in various roles of increasing responsibility, driving forecasting, commercial analytics and business development at Amgen. Over the course of his career, Harish has supported multiple product launches and brings his operational leadership capabilities as well as his strong strategic finance and commercial experience to CymaBay as we embark on a transformation to becoming a fully integrated commercial biotech company. We are thrilled to have him on our team and look forward to his impact on our mission to deliver seladelpar to patients with PBC.
Since our last update call, we have continued to collaborate with PBC stakeholder communities. In April, we had the opportunity to be a sponsor and participant in the 10-year anniversary meeting of the Global PBC Study Group that assembled experts, advocacy groups, regulators and industry with the theme on the future of treating PBC. Emerging concepts included advancing treatment goals to include normalization of cholestatic and inflammatory markers of disease, addressing clinical symptom burden, particularly fatigue and pruritus, and leveraging inherent knowledge within real-world data to better understand risk parameters and effects of treatments on long-term outcomes.
Thanks to the advances by so many around the world, we are convinced that an important inflection point is at hand for treating patients with PBC. Novel improved treatments and growing investments by the collective community is increasing awareness and diagnosis of PBC. Our goal is to increase the number of patients treated with therapies that for the first time have the potential to both reduce the risk of disease progression while also improving quality of life.
Today, I will ask Chuck McWherter, our Chief Scientific Officer and President of Research and Development, to provide important updates on our clinical progress. Lewis Stuart, our Chief Commercial Officer, will then share a brief summary of our pre-commercial planning activities before handing the call to Dan Menold, VP of Finance, to review our financials for the first quarter.
Charles A. McWherter
Thank you, Sujal. I'm pleased to report the progress we made this quarter in our 2 global Phase III studies of seladelpar in patients with PBC. The pivotal response study and the long-term safety ASSURE study are together currently active in more than 25 countries and more than 115 research sites and with more than 300 participants. We continue to be encouraged in both studies with patient retention. The most recently quarterly review by the RESPONSE Data Safety Monitoring Board directed that as before, the study can continue without any changes. Our team is collaborating with our partners and the sites to complete RESPONSE and then to analyze data from both studies. Our goal is to share top line results from RESPONSE in the third quarter and then to submit an NDA as soon as feasible.
Our aim for RESPONSE is to confirm the significant and clinically meaningful placebo-controlled results observed in ENHANCE after 3 months. In RESPONSE, the alkaline phosphatase and bilirubin composite and alkaline phosphatase normalization endpoints are at 12 months, and the pruritus endpoint is at 6 months. The ENHANCE results were published online late last month after peer review in the AASLD flagship journal, Hepatology. The article reports results in patients with PBC having persistent elevations in alkaline phosphatase, most of whom are taking, if tolerated, first-line ursodeoxycholic acid. After 3 months in ENHANCE, nearly 80% of patients taking daily oral seladelpar 10 milligrams achieved the alkaline phosphatase bilirubin composite endpoint previously used by regulators for approval. Nearly 1 in 3 of these patients achieved normalization of alkaline phosphatase after 3 months despite having an on-average pretreatment level of 2.5x the upper limit of normal.
The article further reported that in patients with prespecified baseline moderate to severe itch, those taking seladelpar 10 milligrams for 3 months, had significant improvements compared to placebo and their pruritus intensity using a daily electronic diary. ENHANCE is the first study in patients with PBC using a prespecified testing of endpoints of markers of disease activity and symptoms to achieve both significant and clinically meaningful differences on active treatment compared with placebo.
Once again, we will have a significant presence with 3 accepted abstracts to be presented at the EASL Congress in Vienna, Austria from June 21 to 24. Once the EASL embargo is lifted in June, we will be able and eager to share the insights we've gathered in an abstract titled Seladelpar Treatment resulted in correlated decreases in serum IL-31 and pruritus in patients with primary biliary cholangitis, post-hoc results from the Phase III randomized, placebo-controlled ENHANCE study to be presented by Professor, Andreas Kremer of the University of Zurich. The IL-31 pathway is a validated target associated with chronic pruritus in dermatological diseases.
A second clinical abstract to be presented by Professor Gideon Hirschfield from the University of Toronto Liver Center is titled Baseline Characteristics and Risk Profiles of 1,111 Patients with Primary Biliary Cholangitis in Need of Second-line Therapy. CymaBay has acquired considerable experience, having conducted clinical research in PBC since 2015.
The third accepted abstract is titled Novel Pathways Implicated in the Seladelpar Mediated Reductions of Established Liver Fibrosis are identified from RNA-seq data using Plex search and 2 independent mouse pharmacology datasets. Presented by the CymaBay research team, new mechanistic preclinical findings are recorded. The full results of these abstracts and the progress they represent will be available at the Congress.
At this time, I'll turn it over to Lewis.
Lewis J. Stuart
Thank you, Chuck. During our last quarterly call, I shared several themes that are core components of our seladelpar go-to-market strategy. Beginning in January, we began activating numerous work streams from our commercial roadmap that will lay the groundwork for the company's overall launch readiness and set a course for flawless execution of the seladelpar PBC launch. We initiated key commercial infrastructure projects within legal, finance and human resources to support organizational readiness while beginning to evaluate logistics solutions to support our commercial supply and distribution channel strategy. Many of these projects have longer timelines with multi-stage deliverables, all to be enabled in careful alignment with key corporate milestones.
Our primary market research and data analytics initiatives are ongoing and continue to inform our HCP, patient and payer strategies. We recently finalized value messaging research with key U.S. payer organizations, and we're encouraged by their response to seladelpar's target product profile, which will be further strengthened by the results from our pivotal studies and continued evidence generation.
Patient insights were also completed, revealing the deeper, emotional, personal and health care-related needs of people living with PBC. In addition, we interviewed 125 hepatologists and gastroenterologists on their expected attitudes, drivers and behaviors relative to future PBC patient management, which we can then use for future segmentation and targeting efforts.
Finally, we're so excited to have initiated our talent search for key commercial leadership roles scheduled for hire throughout the summer months as we prepare to accelerate our launch readiness plans in the second half of 2023.
I will now turn the call over to Dan.
Thank you, Lewis. As others on the team have highlighted, during Q1 2023, we made additional progress towards completing the patient treatment phase for the RESPONSE study. In parallel, we are preparing for a final data analysis as we focus on delivering top line results in Q3 of this year and submitting our NDA thereafter. We further strengthened our leadership team and enhanced our strategic and operational commercial launch experience by recruiting Harish Shantharam as our new CFO. Overall, our efforts to begin transforming into a fully integrated commercial biotech company are underway as we work to execute on select strategic and operational commercial readiness initiatives to prepare for potential future launch of seladelpar in PBC.
From a financial perspective, we finished the quarter with a strong balance sheet with cash, cash equivalents and investments totaling $236.4 million as of March 31, 2023. As a reminder, from our year-end call, in Q1 2023, we enhanced our cash position following the receipt of a $34.2 million upfront license payment from our Kaken collaboration and from the completion of $92.4 million public equity offering. Overall, we believe that our cash and investments on hand as of March 31, 2023, will be sufficient to fund our current operating plan through the third quarter of 2024.
I will now turn to a review of our first quarter operating results. Firstly, while the company received a $34.2 million upfront payment from Kaken, all revenue associated with our collaboration was deferred as of March 31, 2023, pending completion of contractually required tech transfer activities and satisfaction of other future performance obligations associated with the agreement.
As for our operating expenses, research and development expenses for the quarter ended March 31, 2023, and 2022 were $18.5 million and $18.4 million, respectively. Research and development expenses for quarter ended March 31, 2023, were in line compared to corresponding periods in 2022, primarily due to the offsetting impact of lower clinical and CMC costs following enrollment completion of RESPONSE in mid-2022, offset by higher employee compensation as we continue to hire additional personnel to support our clinical studies and other development activities. As we continue to progress late-stage development of seladelpar in PBC, we expect our overall research and development expenses to increase in the future.
Turning briefly now to a review of general and administrative expenses. These costs for the quarters ended March 31, 2023, and 2022 were $8.3 million and $6.1 million, respectively. General and administrative expenses for the quarter ended March 31, 2023, were higher than the corresponding period in 2022 as we continue to add administrative personnel and expand our infrastructure in support of our corporate growth.
Overall, our net loss for each of the quarters ended March 31, 2023, and 2022 was $28.8 million and $27.8 million or $0.29 and $0.32 per share, respectively. Net loss for the quarter ended March 31, 2023, was higher than the corresponding period in 2022, due primarily to an increase in general and administrative expenses, partially offset by an increase in interest income earned on our cash equivalents and investments. Overall, we expect operating expenses to increase in the future as we continue to execute our development and pre-commercialization plans for seladelpar in PBC.
Let me now hand the call back to Sujal.
Sujal A. Shah
Thank you, Dan. While we are thrilled with the progress we have made thus far in the year, we are even more excited about the milestones ahead of us in the coming months. Our team remains laser-focused on delivering seladelpar to patients with PBC, an objective that includes a deeper dive into the unique characteristics of the delpar mechanism, the impact seladelpar may have on both reducing the risk of disease progression and improving quality of life, and raising awareness of how we plan to lead a new frontier in treatment goals. We look forward to sharing more updates with you all at upcoming medical meetings and, of course, when we aim to share top line results from RESPONSE at the end of the third quarter.
We're now happy to take questions. Operator?
Question and Answer Session
(Operator Instructions) Today's first question comes from Yasmeen Rahimi with Piper Sandler.
We are very excited about the upcoming data readout in the third quarter. Two quick questions for you. The first one is, at what junction should we expect to learn about additional studies that you would be conducting with seladelpar in regards to expansion of the PBC opportunity? I know in the past, you have spoken about studies on -- for patients who -- working towards normalization of alkaline phosphate. So any commentary there?
And then second question is, is it premature for us to expect any color in regards to post-marketing commitments and requirements at the time when you report out top line data in the third quarter or whether that will be more likely after the approval? Appreciate color on both of the questions.
Sujal A. Shah
Appreciate the question, Yasmeen. So I'll provide some context. I think first, as we've been describing over the course of our development path with seladelpar in PBC since 2015, we continue to remain committed not just to the current ongoing Phase III study, RESPONSE, and the long-term study, ASSURE, but we continue to be very committed around thinking about really advancing treatment guidelines, really trying to advance the treatment paradigm for patients with PBC. So we're certainly committed to thinking through additional clinical studies, datasets that we think can advance care for patients with PBC and better elucidate where seladelpar may continue to have advantages across disease spectrum for patients.
But I think as we've done historically, what we'd like to do is commit to the first steps in getting those studies started. And then we'll share details around the construct of those studies and the objectives of those studies as we begin. So we look forward throughout the course of this year to sharing more updates with you around additional clinical trials as we continue to think about seladelpar across patients.
With respect to post-marketing commitments, obviously, the approval pathway in PBC, as you've highlighted, and I think as most know on this call, is accelerated Subpart H conditional approval. We will have a commitment for a post-marketing study.
I can tell you that we've had dialogue with regulators over the course of several years and are approaching our commitment to this in somewhat of a novel way given the inherent challenges that exist in running long-term placebo-controlled studies for patients with a rare disease such as PBC. We already have some feedback and key feedback back from regulators. And again, here, I think not just similar for what I just described in your first question. As we make steps forward to committing to that work, we'll share much more of these updates with you in the coming months.
The commitment around the post-marketing study pathway, of course, is one in which we have to have that study initiated and, in fact, make some progress in that study as we look to file for regulatory approval. And so it's very much in the near term for us. And I'd say stay tuned in the coming months. We'll have much more to share on both of these areas.
The next question comes from Steve Seedhouse with Raymond James.
Steven James Seedhouse
I had 2, actually. I'll just ask them together because the first one is pretty quick. Just first on pruritus improvement. Could some of the mechanistic work you've been doing, including the presentation at EASL potentially explain, just mechanistically why PPAR delta specifically seems to improve pruritus so much more relative to pan-PPARs or fibrates?
And then second, on the ENHANCE publication, one of the details is that, that paper sort of confirmed or reiterated was about half of the patients screened for the study were screen failures, and the majority of those were based on alk phos less than 1.67. So it seems to suggest it would be a big demand in theory from those patients that are above upper limit of normal, but below that threshold. And I'm wondering if that's the correct interpretation of that and if you think that there's substantial upside from that sort of middle ground biochemical group of patients ultimately when you get to market.
Charles A. McWherter
Yes. Steve, thank you for that question. This is Chuck. We certainly remain quite interested and committed to understanding the mechanism for pruritus improvement that we've seen first in our 52-week open-label study and then as reported in ENHANCE, after 3 months of treatment in a placebo-controlled fashion with the electronic diary. And of course, we're seeking to confirm that in the RESPONSE study with the key secondary endpoint in patients with clinically significant itch at 6 months.
I think you're tracking down the right idea here. We're fully committed to trying to explain some of the mechanistic features of the delpar and how that's distinguished from other available agents that are used -- either approved or used off-label.
And as you kind of alluded to, really not able to say much more about that at this point, really quite eager to be able to share additional details once the EASL embargo is lifted. And we just have a long-term commitment, not only to improving liver disease, but also the symptoms and really sharing the mechanistic aspects of the delpar mechanism.
Sujal A. Shah
And Steve, I'll answer the second question. As Chuck had mentioned in some of the prepared remarks, one of the other abstracts that will be presented at EASL by Professor Gideon Hirschfield, in fact, does carry much of detail around baseline characteristics and risk profiles for all the patients that we've screened across studies, and that's over 1,000 patients at this point. And you're correct, roughly half patients -- half the patients have screen fail for those that have been trying to be targeted with alk phos levels above 1.67x the upper limit of normal. And it is true, a vast majority of those, in fact, are because their alk phos is somewhere between upper limit of normal and 1.67. This is one of those precursors, in fact, and much of the work that we're doing as we better understand the potential benefits those patients may in fact have.
And there's much more work in the published domain now work from the Global PBC Study Group as well as others really pointing towards the potential benefits of normalization around alkaline phosphatase specifically over the course of disease progression in PBC. And so we're really trying to follow that work and recognize the potential benefits of seladelpar in this broader group of patient populations that we've not really historically studied in clinical trials, be it CymaBay or other sponsors, in fact, as well.
And so we think there's a significant opportunity here. We think there are many more patients, of course, that may potentially benefit from biochemical normalization and, of course, from reduction in symptom burden. And these are some of the things that, again, you'll see us talk much more about in the coming months.
The next question comes from Kristen Kluska with Cantor Fitzgerald.
Kristen Brianne Kluska
Looking forward to some of these upcoming data that you're going to share. So in the past year, and it sounds like heading into these upcoming data, you've done a lot more work relative to understanding the mechanism, going deep into some of the different pathways that are impacted. So I wanted to ask you, how you're thinking about comorbidities in this patient population? And any autoimmunity linked to other indications that are going to further help you to understand the mechanism? And again, while I recognize PBC is the laser focus, just future directions, what that can tell you?
Charles A. McWherter
Yes. Thank you, Kristen. I think with respect to comorbidities related to autoimmunity, remember that PBC is an organ restricted autoimmune disease, which is predominantly described by a dominant autoantigen related to the PDC-E2, basically, the mitochondrial antibody. Related comorbidities in terms of autoimmunity like Sjögren's disease and others really don't have that commonality with respect to the autoantigen. So from that particular perspective, I'm not sure whether there's going to be some low-hanging fruit there.
There are, of course, AIH, autoimmune hepatitis, PBC overlap, which is a disease which does carry in common PBC. And that could be an area that would be something of future interest.
But in terms of other comorbidities, remember that more than half of the patients with PBC have dyslipidemia, strong elevations, and we found in a recent abstract that we presented that in our studies, more than half of them have elevations in total cholesterol and in LDL-cholesterol. About 1/3 of them are on lipid-lowering therapy, many on statins. And we found that so far, seladelpar have lowered both total cholesterol -- LDL-cholesterol and triglycerides to a reasonable effect, and they did that in the presence of background lipid therapy as well. So that's an area that we continue to have a look at an additional benefit in the patient population with this common comorbidity.
Kristen Brianne Kluska
And then looking at the Global PBC Study Group 10-year anniversary conference agenda, it was -- very much it appears to be written and suggesting about how the landscape is going to change and how that could include new therapies such as yourself. So just wondering, since it was such an intimate group of thought leaders, if there's anything that came out of the meeting that was either a surprise to you or something that you walked away with that will be a bigger focus heading into these data or anything in general that you want to share that you felt was important.
Sujal A. Shah
Appreciate it. Thanks for the question, Kristen. It was actually a tremendous event. There's much work that's been going on in PBC, of course, pioneered a number of years ago when obeticholic acid was the first drug approved in 20 years since ursodeoxycholic acid. And I'd simply tell you that the energy surrounding those thought leaders in the field, the patient advocacy groups that were in attendance and participating, regulators as well as sponsors, there was really a palpable sense that there is much more to come in this field.
From our perspective, when we think about seladelpar and the profile we've seen to date, the profile we hope to confirm in response in our ongoing clinical studies, we see real opportunities, as we've mentioned, to treat patients to normalization. That was one of the key themes, of course, during the 2-day set of meetings as well, normalization of alkaline phosphatase, cholestatic markers of disease progression as well as inflammatory markers of disease like ALT, AST. There was a tremendous amount of discussion around these as being really future treatment goals for patients. Those are some of the things that we think are likely to expand the broader addressable patient population potentially significantly. And I think there's a lot of excitement and enthusiasm among all of us focused in the PBC space with respect to these discussions that are ongoing.
There were certainly much more discussion around relieving symptom burden for patients and improving quality of life. Again, when you don't have treatment alternatives that actually have efficacy and benefit in these areas, it's hard to have the discussion with patients.
It's hard to have the discussions with researchers in the field around what you might be able to do and why there should be continued focus in this area. We see that changing now. And some of the data that we've shared and published on with seladelpar, reductions in pruritus, some improvements in fatigue, if you look at our liver international paper, this was another key theme during the 2 days, I would say. And these go -- again, beyond just pruritus, of course, which is a plaguing clinical symptom of the disease, but also into fatigue and really just continuing to get a better sense of treating the patient as a whole and improving not just liver health and longevity of patients, but actually improving quality of life for those patients all at the same time. So just really great themes as we think about where seladelpar might be able to help advance care for patients if we're successful.
And then the last thing I'll mention relative to the meeting, of course, a lot of talk around leveraging real low data sets in demonstrating a potential long-term benefit with treatment alternatives in the setting of PBC. And so we're grateful to have the relationships we've had with the group overall. We've been working in PBC, as you know, as we've articulated since 2015, really just a group of folks that we've developed great relationships with, and we'll continue to work closely with really globally as we continue our efforts.
Our next question comes from Patrick Dolezal with LifeSci Capital.
Patrick Edward Dolezal
So with competitor data on the horizon, perhaps you could provide some thoughts surrounding the importance of not just improving pruritus and alk phos, but even transaminase levels within the context of PBC.
And then on the pruritus endpoint, I know RESPONSE is looking at this metric at 6 months. Curious what the calculus was there in determining the 6 versus 12-month time point?
Charles A. McWherter
Yes. Thank you for that. So with respect to other markers that are important in terms of disease stage and risk for progression, I think the delpar mechanism really lends us out to the potential to harness its effects on inflammation. And associated with inflammation is liver injury and its relationship to fibrosis and outcomes.
There is a paper harkening back to 2010, which was a biopsy follow-up study that related the levels of ALT for the risk of histological progression. The study showed that, in fact, elevated ALT is a risk factor. And so we remain interested in the fact that the delpar mechanism, seladelpar, led to significant reductions in ALT in both our open-label study and its extension to 2 years as well as in the ENHANCE study. For example, in the 2-year extension study, we saw decreases of ALT of up to 40%. And in the ENHANCE study, of those patients who had elevated ALT at baseline, which is somewhat over half, half of those patients have normalized their ALT in a short 3 months.
So to kind of wrap it up, we think that liver injury, which is a consequence of inflammation, the cholestasis, the biliary injury, is related to fibrosis. And we're hopeful to see that the effects of seladelpar on reduction of liver injury will translate in the future into outcomes.
Sujal A. Shah
And then, Patrick, I'll take the second question. You asked a little bit about the decision to have the pruritus endpoint in RESPONSE at 6 months versus baseline. That was actually the original prespecified time point for that endpoint. In ENHANCE as well, of course, we modified that statistical analysis plan before that study was unblinded since we didn't have many patients out to 6 months when that study was stopped prematurely.
When we think and look at our long-term data out to 1 year and even 2 years from Phase II, if you look at the Liver International Paper and the journal of Hepatology paper of our Phase II study, and even as you look at the data around pruritus reduction in ENHANCE, of course, again, out to 3 months for most patients, but continued and sustained out to 6 months, we think 6 months is a really strong time point for demonstrating not just the potential benefit, but sustained effects of that benefit. And again, we see that consistently sustained out to our 6-month time point in prior clinical studies.
I will highlight that, again, the measure itself is taken at 6 months as a 7-day average in the 7 days leading up to that 6-month endpoint versus the baseline reading, which is taken as a series of readings in the run-in period before those patients get seladelpar. So again, it's a time point in which we believe that seladelpar has the potential to show the benefit as well as the sustainability of that benefit based on what we've seen historically.
The next question comes from Julian Harrison with BTIG.
Julian Reed Harrison
Congrats on the progress. Assuming a successful result from RESPONSE, can you remind us of the timeline to NDA submission? What will be the gating factors there?
Sujal A. Shah
Yes. Certainly, Julian. Our objective, of course, is to file as quickly as feasible post the top line data readout. I think at the end of the day, our goal is to get seladelpar, if we're successful, in RESPONSE, and confident around regulatory submission, our goal is to get seladelpar in the hands of patients as quickly as possible. So I think you'll look to see us provide a little bit more clarity around specific timelines once that data readout comes out. But overall, again, the urgency is clear. We've continued processes and commitments here along the way. Even as the clinical studies are ongoing, we do have intentions of having rolling work and rolling submission ongoing as we think about the path first to NDA filing and then filing in Europe. So you're going to see us provide a little bit more specificity as we get to top line data. But fundamentally, the urgency is there. And our procedures and processes internally, resource focus is all geared towards this, if successful in RESPONSE.
The next question comes from Andy Hsieh with William Blair.
Harish, congratulations on your new role and look forward to working with you. The EASL abstracts that you talked about is very intriguing. So maybe one question, but a 2-parter for Chuck and Lewis, respectively. In terms of the IL-31, right, called the itch cytokine, I would say, I was just curious, in your view, generally speaking, is that context-dependent? It depends on which cell type that's producing that or you can actually characterize on a global basis based on serum level?
And the second part is basically on IL-31 testing. I'm just curious if that's something that is a part of a normal panel. Or as you think about tracking this cytokine going forward, they'll have to be included and kind of developed independently?
Lewis J. Stuart
Yes. Thank you. Thank you so much, Andy, for that question. I think if you look to the literature, you'll find that IL-31 has been implicated in itch in a variety of different disease settings, whether it be dermatological or uremic or even if you look at the recent paper potentially in cholestatic disease as well.
With respect to the cell type origin, I'm not in a position really to comment on that yet just because of the embargo. We might have more to say on that in June. I would just say stay tuned. It's an interesting and an important question that you've identified. So thank you for that.
In terms of IL-31 being part of the normal panel, know that it's a highly specialized cytokine that's measured, although there are vendors who offer ability to measure that. I think our view is that its relief is first documented and reported by the patient. It's a symptom, not a sign. But having some type of biomarker associated with it would represent in advance, and it's something that we're, of course, keenly aware of.
The next question comes from Ed Arce with H.C. Wainwright.
Wing Cheung Yip
This is Thomas Yip asking a couple of questions for Ed. So perhaps first question, assuming positive headline readout from RESPONSE study, how -- specifically on the composite endpoint, how do you envision cellular proposition against, I believe, both either on the pruritus measurement and also in the ALT normalization as well?
Sujal A. Shah
Yes, appreciate the question, Thomas. I think, of course, if we see the response that we've seen so far from our clinical studies, we think seladelpar's profile demonstrates a greater percent reduction in alkaline phosphatase, a greater proportion of patients meeting the composite primary endpoint, and as you mentioned, also a greater proportion of patients normalizing. Of course, with all the caveats that there's inherent challenges in comparing across studies as opposed to head-to-head, I think the positioning, clearly, we think, is one in which it offers patients -- more patients potentially the ability to get not just a goal, but to actual alkaline phosphatase normalization. Again, one of the areas in which I think the entire field will continue to advance in terms of an actual treatment goal for patients, and that has the ability to potentially position seladelpar as a preferred second-line treatment, and of course, as we've mentioned, a potential to be used in a broader patient population than we might have otherwise originally thought of for second-line setting.
The pruritus impact, clearly, again, as we've mentioned, is really a game changer because today, there are no treatments that have shown real significant benefit on reducing pruritus. First-line treatment with ursodeoxycholic acid, although it's never been shown to cause or worsen itch, it's never been demonstrated to relieve itch either. And so I think this goes without saying that the data that we've generated to date is significant. Having the ability to reconfirm in response to the benefit that we saw in ENHANCE statistically significant for patients with moderate to severe itch, significant proportion of patients seeing a 4-point or greater reduction in the NRS score versus placebo, this is data that we think is quite compelling. And we think the overall story relative to the improvement in overall symptoms for patients is clearly one of those that's positioned seladelpar well, again, assuming that we're successful as we move forward.
Wing Cheung Yip
Yes. And then perhaps how do you look at both, as I mentioned, pruritus and ALT normalization? Are both measurements of seladelpar against other candidates data in clinic, for example, any other PBC candidates as well?
Sujal A. Shah
I think, Thomas, that's a bit harder of a question to answer to date because we just haven't seen as much data from other agents being developed. Obviously, as we've mentioned a number of times, we've had significant experience in PBC with rich datasets to date. And so I think harder to answer that question today. But obviously, in the coming months, we'll have a much better idea around the impacts of other agents on alk phos and even on pruritus. It's much more to digest relative to seladelpar given our experience, but harder, I think, to compare to others where there's not yet been significant data demonstrating those effects to date.
Wing Cheung Yip
Got it. And perhaps one more question from us, this one is commercial. So with your partnership in Japan, how should we look at other markets, both big and small assets, U.S., ex-U.S., et cetera?
Sujal A. Shah
Yes. It's another good question. We continue to evaluate opportunities either to bring seladelpar ourselves in other geographies or to do so with third-party partners. I would simply tell you that we have ongoing dialogue constantly. And as we get to the other side of Phase III data, I think we're going to have some decision points to make thereafter.
We're not in any sort of specific urgency where company is well capitalized today. We think RESPONSE is a study that will allow us to at least submit for regulatory approval both in the U.S. as well as in Europe, in the U.K. and with the MHRA as well as with EMA. So I think fundamentally, we're going to continue to progress through the conduct of our clinical studies and make the decisions that we think are best in terms of us being able to get seladelpar in the hands of patients broadly.
Our next question is from Jay Olson with Oppenheimer.
Congrats on all the progress, including the addition of Harish to your team. Can you talk about any physician feedback that you've received following publication of the Phase III ENHANCE results in Hepatology?
Charles A. McWherter
Yes. Thank you, Jay. Yes. So I think in general, it's been quite gratifying. There's been a lot of uptake. In fact, I have an application that looks at the number of citations, and it's already jumping up far higher than anything I've seen before. So I think there's a level of interest. I think a large part of that is driven by the fact that it's very closely related and designed to RESPONSE, albeit at a shorter time frame and the fact that it's placebo-controlled with a statistical methodology that looked first at the composite for registration and looking at normalization and, finally, looking at pruritus. That's something that's not been done before. We've combined both placebo-controlled with those 3 particular endpoints. I think it's something that's garnered a lot of interest.
Of course, in addition to that, if you look into the article, you see that we also had a subset analysis looking at cirrhotic patients. We had a number of supportive analysis looking at other measures of itch. We looked at ALT in addition to other liver biochemistry, which was also very supportive in terms of the profile we've seen thus far. And then, of course, the overall safety profile is something that I think is something that's got a lot of attention. People are really looking for an agent that can be used in this population with a safe profile, including across the different stages of disease.
Great. That's super helpful. And then can you talk about any read across or points of differentiation for seladelpar you'll be expecting when the elafibranor Phase III elated study top line?
Charles A. McWherter
I think I would focus on what we know about seladelpar and the delpar mechanism. We think that, that mechanism is unique because PPAR delta activation has found to be important in hepatocytes, cholangiocytes, Kupffer cells/macrophages and in stellate cells. And so if you look at both the clinical profile, clinical markers, improvement in bile acid homeostasis, markers of cholestasis itself, whether it be alkaline phosphatase, GGT or bilirubin, improvements in markers of inflammation and liver injury, ALT, I think that's something mechanism really does quite well at. We have not yet had an opportunity in PBC to look directly at fibrosis, but we did so in NASH as well as in preclinical models. So we think there's a rationale there. And we're looking to confirm that both with liver stiffness measurements in RESPONSE, but probably more appropriately in the long-term ASSURE study where impacts on liver stiffness through effects on underlying fibrosis are probably easier to detect over the long term.
The next question comes from Mayank Mamtani with B. Riley.
Congrats on the progress. So just maybe piggybacking on the prior comments, Chuck, you had on the impressive fibrosis improvement you had in Phase II NASH and the cirrhotic patients in the past you treated. Curious how you're handling a small cohort of patients, which have liver biopsy in RESPONSE? And also, if you could remind us where you are with the hepatic impairment study. I know it's more of a check the box for NDA submission, but would be good to hear if there's anything new that you've learned from that. And then I have a couple of quick follow-ups.
Charles A. McWherter
Yes. Well, thank you for the question. Yes, I'm pretty excited about the opportunity to examine biopsy in this population. It's not something that's normally done in PBC patients. It's not the standard of care. So we put together what we think is going to be a very exciting scientifically-driven program to evaluate both baseline and intervention effects on liver histology in the setting of PBC. Not a lot yet to share about that, but it's our intention to really have a very significant and thorough evaluation. Of course, that will be submitted to the FDA, but we also plan to publish the findings there. So it's something I would just say stay tuned. It's good receiving a lot of energy from the team here.
In terms of hepatic impairment and studies in cirrhotic patients, just first say that we do have already completed traditional hepatic impairment study, which recruits patients with either Child-Pugh A, B or C compared to normals regardless of the ideology of the impairment. So that's been completed and submitted to FDA.
In addition, we're conducting this study in patients where PBC is the cause of the impairment. That includes patients with A, with portal hypertension B and C. That study is ongoing. I can say that I think we're pleased that it's proceeding well. We expect it to be able to support the submission. It's predominantly a study that, first of all, establishes the relationship of dose to exposure and to identify whether there's any dose adjustment needed with more severe liver disease or stage.
And then secondly, we're also looking at treatment response, although over a short duration. So we expect to be able to share those results when the study is completed.
Got it. And maybe just a quick follow-up on the discussion around the alk phos. Increased discussion of using complete biochemical response as an endpoint. I was trying to do some internal modeling work of, for example, how seladelpar monotherapy stacks up again, say, using combination of sequencing approaches of FXR, PPAR. Has that been done internally? And do you have a view on that endpoint, complete biochemical response, which includes not just alk phos, but also other transaminase and biochemical markers?
Charles A. McWherter
Yes. Well, thank you for that question. Of course, normalizing liver biochemistry is, of course, a goal that we feel is increasingly considering. The only study that's been published that looked at that carefully was, of course, the BEZURSO study, it was published in the New England Journal in 2018. That study was challenging. Not -- it was a well-conducted study -- well conceived and well conducted. But the eligibility criteria were relatively lower than it's been seen with other studies. For example, employees or, for example, in ENHANCE or RESPONSE or even what's posted on clinicaltrials.gov for ALT. So consequently, it's a little bit easier to achieve biochemical normalization in that setting. Some parameters are easier to normalize than others, I would say.
With respect to the triple therapy and how that might play into normalization, if you look at the (inaudible) paper, which I think you're probably familiar with, this is a study that has a very select population, patients who failed dual therapy or second-line therapy with either OCA or with a fibrate and then go on to receive triple therapy. In that particular case, I think it was interesting in patients who failed a dual therapy on OCA, but then added (inaudible) fibrate on average, they had about a 42% reduction in alk phos, indicating that the fibrate mechanism had potential additional significant reductions. If you look at the inverse group, those patients on a fibrate who failed second-line therapy, and you add OCA, you only get an 11% reduction.
It says to me, and I think it's really consistent with what we've seen in ENHANCE or the open-label Phase II, and hopefully, we'll see in RESPONSE, is that those kinds of mechanisms, the delpar mechanism and potentially even fibrates, seem to have more of an alk phos lowering effect than an FXR agonist. So it really raises the question in a future state where you have multiple approved drugs, what would you start with? Could you start with a drug that has greater effect and then add one, if needed, that's the lesser or the reverse? I think it really suggests to us a drug that could improve liver biochemistry, improve symptoms would be the first agent you would reach to look for. And then, yes, of course, if there's something left that the patient needs, then you might look for, for example, for an FXR agonist.
Yes. That makes sense. And my final question on the strategy to get pruritus on the label beyond the RESPONSE study. I was curious, generally, mechanisms like the IBAT inhibitors that do target itch as the primary condition do have a crossover design. Are you also thinking of doing an additional study like that? Or do you think the effort that you have currently is sufficient to make sure pruritus is going to be on the label?
Charles A. McWherter
Thanks for that question, of course. Our study design was based upon close conversations with regulators, including with the FDA, both in advance of ENHANCE and for RESPONSE, where we discussed our desire for indication as well as the endpoint and the method of measuring the endpoint and the statistical methodology to be used.
I think from our perspective, the study design is you could call nested design, where, first of all, we look at composite endpoint and normalization. These are factors that are related to outcomes. And as well because it's a rare disease, and of course, it's difficult to mount large studies, it makes sense to add in pruritus since it's a common feature. 70% of patients have a history, and in our studies, 30% or more have moderate-to-severe itch at baseline. And so in that case, looking for a secondary endpoint where we get the symptom relief makes a lot of sense.
And then finally, with respect to other agents that might be used to treat cholestatic pruritus, our feeling is, once again, if you have an agent that has improved biochemistry that's related to -- as risk factors for prognostic outcomes as well as improved symptoms, that makes the most sense for the patient, makes the most sense for the physician. And I think that gives us the best opportunity for a patient to get what they need in a single agent.
At this time, we are showing no further questioners in the queue. And this concludes our question-and-answer session. I would now like to turn the conference back over to Sujal Shah for any closing remarks.
Sujal A. Shah
Thank you all once again for joining us today. As we've mentioned a few times, it's been a fast start to the year with much more ahead of us in the coming months. We look forward to sharing data at EASL at the end of June, top line data from RESPONSE in the third quarter and additional clinical and regulatory updates with you throughout the year. Thank you.
The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect.