CymaBay Therapeutics, Inc. (NASDAQ:CBAY) Q1 2019 Results Earnings Conference Call May 8, 2019 4:30 PM ET
Dan Menold – Vice President of Finance
Sujal Shah – Chief Executive Officer
Chuck McWherter – Chief Scientific Officer
Pol Boudes – Chief Medical Officer
Conference Call Participants
Yasmeen Rahimi – Roth Capital Partners
Ellie Merle – Cantor Fitzgerald
Mike Kratky – SVB Leerink
Steve Seedhouse – Raymond James
Jay Olson – Oppenheimer
Ed Arce – H.C. Wainwright
Jeffrey – with B. Riley
Fang-Ke Huang – Robinson Humphrey
Good day, ladies and gentlemen. Welcome to CymaBay’s First Quarter 2019 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call for your questions. Please be advised that the call will be recorded at the company’s request. It is also being webcast live on the Investors section at the CymaBay website at www.cymabay.com.
Now, I would like to turn the call over to your host, Mr. Dan Menold, Vice President of Finance at CymaBay. Mr. Menold, you may begin.
Thank you, operator, and good afternoon everyone. I hope you’ve had a chance to review the press release we issued announcing our first quarter 2019 financial results and business update. You can access that release on our website, under the Investors tab. Joining me on the call today are Sujal Shah, Chief Executive Officer; Dr. Pol Boudes, Chief Medical Officer; and Dr. Chuck McWherter, Chief Scientific Officer. Sujal will provide an update on our financial position and clinical programs and review upcoming milestones before we open up the call for Q&A.
Before we begin, I’d like to remind everyone that statements made during this conference call, including the Q&A session relating to CymaBay’s expected future performance, business prospects, events or plans, including clinical plans and timing are forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. Although the company believes that the expectations reflected in such forward-looking statements are based upon reasonable assumptions, actual outcomes and results are subject to risks and uncertainties, and could differ materially from those forecasted 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.
Good afternoon everyone, and thank you for joining us today. We have continued to build upon our recent accomplishments as we advance the development of seladelpar in multiple inflammatory liver diseases with high unmet medical needs. The progress in the first few months of 2019 positions us well to deliver on our plan for the rest of this year and beyond.
We continue to generate important clinical results at an accelerated pace, and one of our most important objectives this year is to complete enrollment in ENHANCE, our global Phase 3 registration study for seladelpar in PBC. We are also driving towards completion of our ongoing open label Phase 2 study in PBC in the second half of this year, for which we have been regularly reporting updated clinical results at major medical meetings, including at EASL’s International Liver Congress just last month.
In February, we were delighted to announce that the FDA has granted breakthrough therapy designation to seladelpar for treatment of early stage PBC. Also in February, we were gratified to announce the completion of enrollment of our Phase 2b study of seladelpar for patients with biopsy confirmed NASH, well ahead of our original plan. And we now expect to announce top-line date before the end of the second quarter.
Finally, in March, we completed a follow-on equity offering, raising approximately $108 million in net proceeds, a portion of which will fund a Phase 2 dose ranging proof-of-concept study, evaluating seladelpar in Primary Sclerosing Cholangitis, or PSC, an orphan chronic cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts, for which there is currently no approved therapy.
Beginning with seladelpar in PBC, we continue to enroll patients in ENHANCE, as I mentioned, our global Phase 3 registration study. This is a double-blind randomized placebo-controlled 52-week study evaluating the safety and efficacy of 5 milligrams and 10 milligrams of seladelpar versus placebo in patients with PBC, who have had an inadequate response or are intolerant to first-line treatment with ursodeoxycholic acid, or UDCA. The primary endpoint is the responder rate after 52-weeks in which responders are patients achieving an alkaline phosphatase or AP, level of less than 1.67 times the upper limit of normal with at least 15% decrease from baseline in AP, and a normal level of total bilirubin.
We remain focused on completing enrollment by year-end 2019. This would put us in a position to have patients through the 52-week treatment period by year-end 2020 and announce top line data in early 2021.
Our objective in ENHANCE is to confirm seladelpar’s competitive profile observed thus far in Phase 2, in order to obtain regulatory approval in the U.S., Europe, and other markets. We believe that the ongoing Phase 3 study has been substantially de-risked by the 52-week Phase 2 data supporting the potential of seladelpar to provide improved efficacy and better tolerability as a second line treatment for patients with PBC.
In an interim analysis of patients reaching 52-weeks of treatment in the ongoing Phase 2 study, seladelpar 10 milligrams resulted in an over 70% response on the composite responder rate, which is the primary endpoint in the ongoing ENHANCE study. Importantly, seladelpar at 5 and 10 milligram also produced greater than 30% decreases in transaminase levels from baseline, which was sustained through 52-weeks of treatment.
Thus seladelpar has been found to not only address the cholestatic markers reflected in the composite endpoint, but also have effect on lowering transaminases, supporting an anti-inflammatory action that is an important aspect of PBC.
The potential importance of seladelpar in PBC has also been recognized by the regulatory authorities. During the first quarter, the FDA granted breakthrough therapy designations for seladelpar for the treatment of early-stage PBC in combination with UDCA and adult patients with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA. In 2018, seladelpar also received the corresponding prime designation by the European Medicines Agency. We believe that both these designations reflect the significance of the seladelpar clinical data and the potential for seladelpar to be a significantly improved treatment alternative for patients with PBC.
Seladelpar, was featured in a number of presentations at the International Liver Congress in Vienna, in April. Dr. Marlyn Mayo, associate professor at the University of Texas Southwestern Medical Center in Dallas delivered an oral presentation with results from a cohort of compensated cirrhotic patients from our Phase 2 PBC study.
In an interim analysis of data at 52-weeks, the mean relative decreases in AP in this patient group were minus 36% and minus 43% in the five to 10 milligram, and 10 milligram group respectively.
Treatment with seladelpar also demonstrated anti-inflammatory activity with a decrease in ALT that was comparable to that absorbed in the non-cirrhotic cohort in this study. Importantly, seladelpar continues to demonstrate a favorable safety profile with no transaminase safety signal and no liver decompensation event.
In addition, seladelpar treatment was not associated with drug-induced pruritis or hepatotoxicity in these patients.
Turning to NASH, we announced in February that enrollment of the Phase 2b study of seladelpar in NASH patients was completed approximately one quarter ahead of schedule. This double-blind randomized placebo-controlled study enrolled 181 patients with biopsy confirmed NASH into treatment arms with seladelpar of 10, 20, or 50 milligrams, or with placebo for a planned treatment duration of 52-weeks.
The primary endpoint is the change in hepatic fat content from baseline to 12 weeks as measured by magnetic resonance imaging using the proton density fat fraction method or MRI-PDFF. Effective seladelpar treatment on ALT and marker of inflammation in hepatocellular stress and injury as well as on LDL cholesterol and triglycerides will also be important indicators of early disease activity that will be assessed at 12-weeks.
Thereafter, the study will continue blinded to treatment and culminate with a week-52 biopsy to examine histological improvement in NASH and fibrosis as determined by blinded expert pathologists using NASH CRN scoring. Importantly, the liver biopsy evaluation will permit us to assess histologic endpoints comparable to those used in recent Phase 3 study. They find characteristics of patients in this study revealed significant features of advanced non-cirrhotic NASH, including an average liver fat content of 21.5%, a mean NAFLD Activity Score of 5.2 and 83% of patients with F2 or F3 stage fibrosis.
Also the mean ALT and AST levels were 62 and 46 units per liter respectively, which is above the upper limit of normal. About half of patients enrolled were diabetic and the randomization was stratified on this criteria. Taken together, we believe this NASH population represents an ideal one in which to evaluate the activity of cell seladelpar in this disease setting. Importantly, we believe that population to be optimized for making decisions on Phase 3 development, including selection of doses.
We expect to have top-line results on the primary endpoint of hepatic fat by the end of the second quarter of this year and would expect to report pathology results sometime in mid 2020. It’s worth further highlighting that many additional assessments built into the study including additional MRI-PDFF measurement at weeks 26 and 52, magnetic resonance elastography for liver stiffness at baseline and week 52 and liver multi-scan to assess liver inflammation at several time points.
In addition, the imaging assessments are supplemented by multiple serum biomarkers evaluating fibrosis, inflammation and seladelpar’s mechanism of action. Our goal with this study is to be able to fully profile seladelpar’s activity in NASH to enable a well informed decision regarding its development in this indication. If successful we believe that this would significantly de-risk the development of seladelpar in NASH. As mentioned earlier, an important use of proceeds from our March financing will be to expand clinical development of seladelpar into a new indication, PSC.
PSC is a chronic cholestatic disease of the liver in which chronic progressive degeneration of bile ducts can lead to end stage liver disease. It is characterized by progressive inflammation and fibrosis with consequent obstructions of intrahepatic and extrahepatic bile ducts. Patients are also at a high risk of developing cholangiocarcinoma. Although PSC is an inflammatory cholestatic disease like PBC it has its own set of unique characteristics including being accompanied by a significant degree of comorbidity with inflammatory bowel diseases and challenges related to the obstruction of the large biliary tract. PSC is an orphan indication affecting approximately 40,000 patients in the U.S., currently the only effective treatment his liver transplant.
We have had positive discussions with the FDA regarding our plans to conduct a Phase 2 dose ranging proof-of-concept study of seladelpar for patients with PSC. We are currently finalizing details of the study design with the intent to initiate the study in the second half of 2019. We will provide further details in the near future as our plans are finalized. Turning briefly to our financials, our cash, cash equivalents and marketable securities were approximately $265 million at March 31. Based on current projections, our existing cash is expected to fund the current operating plan into 2021. For a detailed overview of our operating results for the three month period ending March 31, I will refer you to the press release and to our 10-Q filed with the SEC today.
I’d now like to open the call to questions. Operator?
Thank you. At this time, we’ll be conducting a question-and-answer session. [Operator Instructions] Our first question comes from Yasmeen Rahimi with Roth Capital Partners. Please proceed with your question.
Hi, congrats on the continued progress. And the question is for you, Sujal. So maybe you can give us a little bit color as you’re speaking with physicians who are involved in the current NASH study in regards to data expectations. So I guess, most investors are really excited to see the MRI-PDFF data as well as ALT and AST. So when you speak to physician, what matters most of them when they look at a proof-of-concept study in NASH, is it the fat reduction measured by MRI-PDFF or is it ALT/AST, what do they care more about and what is more linked to histological improvement? And then I have one follow-up question.
Sure. Thank you for the question, Yasmeen. I think it’s really important first to just make sure that I have an opportunity to point out that this study in fact is a paired biopsy study, we’ll have the opportunity in this space to evaluate histological improvement at week 52. And this of course, as you know well is the Phase 3 criteria on which to evaluate assets and compounds in the setting of NASH. The study also has a rich set of markers at 12 weeks. And even beyond looking at effects of seladelpar on bile acids, on markers of inflammation as well as fibrosis both wet biomarkers as well as noninvasive imaging.
So it really is a very rich study, not just with respect to the early indicators of disease activity at 12 weeks, but even beyond. Now importantly, as you’ve pointed out at 12 weeks, we’ll have an opportunity to look at the effects of seladelpar in particular at top line on changes in liver fat as well as effects importantly on transaminases and lipid parameters.
So let me just dissect a few of these and I’ll ask Chuck and Pol to chime in as well. First of all, we’ve had an opportunity to really gather input from a wide range of thought leaders in the NASH field. In fact, that EASL had conducted a NASH Advisory Board Panel meeting where this was one of those topics that had been discussed. And given seladelpar really has pleiotropic effects we believe in the setting of NASH, potentially in fact, one of the most exciting targets as a highly selective and potent PPAR-delta agonist, we believe being studied in the entire field in NASH today.
We expect to see improvements across each of these parameters that will observe at the 12 week time point. Liver fat of course is an important metabolic component of NASH. It comes with important consequences including insulin resistance and lipotoxic-driven inflammation and fibrosis. We know that seladelpar, PPAR-delta in particular drives fatty acid oxidation, not just in the liver here but we think one differentiator is that seladelpar in fact has this effect in peripheral tissue.
And this may be a key element of what we see with respect to the early read on changes in hepatic fat at 12 weeks. We also know that PPAR-delta inhibits bile acid synthesis. So when you look at the hepatoprotective nature of a delta agonist in seladelpar, it includes not only reductions in bile acid, motion of fatty acid oxidation and reduction in lipotoxic lipids, also reductions in free cholesterol, which are proinflammatory.
So a variety of effects that will be not only in reductions in hepatic fat, but also potentially in many of these other markers. I’ll also point out that in the setting of PBC, of course, we’ve seen a very robust decreases in transaminase, PBC patients have portal inflammation, although the inflammation can be different in PBC versus in NASH, we have in fact seen what you would expect given the expression of PPAR-delta in Kupffer cells and circulating macrophages as to a potential anti-inflammatory benefit by way of reductions in transaminases.
And of course, as you know, we’ve studied seladelpar in obese patients with mixed dyslipidemia where we’ve seen some meaningful effects on LDL cholesterol, as well as triglycerides. So across the spectrum, really the input we received from thought leaders as well as our own understanding of seladelpar, highlights of both, in fact both changes in hepatic fat as well as transaminases as being really key indicators of early activity in the setting of NASH.
I think independently, each of these parameters as it’s supported in published literature has been associated with improvement in NASH histology above a specific threshold. So we’ll be looking at really, I think each of these two key parameters, liver fat changes as well as transaminase as an early read on what we might be – as we approach biopsy at 52 weeks.
Thank you – yes, please go ahead.
Yes, the only thing else I would add, I think there’s a really calculation. Well, it’s just that in our view liver fat reduction is really the hallmark of one of the positive factors of histological change that continue to drive, so it’s the lipotoxic fat reduction, and general fat reduction accompanying the lipotoxic fat reduction. Whereas transaminase is really a reflection of liver injury, ongoing liver injury both cell death and the regenerative response.
So both of those are two different views into the histological change in the liver and that’s the feedback that we’ve been seeing from publication, for example, by Rohit Loomba, in terms of both fat reduction and transaminase reduction providing a histological change.
Thank you. And then, Pol, quick question for you is congrats on the continued progress on past enrollments. So some competitors are sort of struggling with getting trials enrolled for PBC. Can you tell us what your secret sauce is or is it just what existing dataset that you show? What are so exciting or at least from the physician’s view that are involved? And we’re incredibly impressed. We want to understand the physicians’ perception of seladelpar to get started in the trial.
Yasmeen, it’s Pol. Are you referring to NASH or PBC?
To the PBC Phase 3 study because you have pointed out kind of target for year.
Yes. I would mention one factor, which I think is very important and then I will ask Chuck and Sujal to chime in. I mean, for us the data we have collected so far in the Phase 2 and particularly in the 52-week data where they’re very important because I mean it’s basically for investigators that the drug works well. The safety profile is good. So they’re very excited because they can offer something to their patient. They know that the drug works well. So it’s for them, it’s really the key factor we have to introduce what we’re seeing in the Phase 2 risk benefit profile is so far, the drug is very positive.
I have to add also that the profile of the drug with regard to cirrhosis is very advantages when we speak to investigators, the fact that the drug is not – there’s no drug induced for cirrhosis is viewed very positively. And I think people also extremely interested to figure out what will be the impact of a placebo controlled trials on cirrhosis. So I think the data is really the key factor.
Then the other thing I have to mention is actually we are very close to what’s going on with the investigators. So we develop very close relationship with the side, but that’s more of a subjective criteria.
Thank you team.
Chuck, Sujal, you want to chime in?
No, I think that was – go ahead, Chuck.
Well, I just think Pol is being a little bit modest. There’s a little bit more to the secret sauce, which really relates to the incredible operations team. This is a study that has mobilized from scratch and grew upon a prior experience in a very successful and large 119 patient Phase 2 study, but then expanded out to more than 20 countries, five continents. It’s on the ground logistics with experience and as Pol has said, it’s really leveraging a lot of relationship and making sure that the data is in front and available to the investigators with great access for the investigators and especially the site coordinators to understand what’s needed in terms of implementing the protocol. So I think we need to give a lot of credit to Pol and his team here.
Thank you so much, team.
Next question comes from Ellie Merle with Cantor Fitzgerald. Please proceed with your question.
Hey guys, thanks for taking the question and congrats on all the progress. Just sort of on the biology of fat reduction, this is obviously an incredible focus into the data in mass. I know you mentioned sort of the peripheral benefits on fat reduction with PPAR delta. But I guess in the context of fat reduction in the liver in particular, could you elaborate on what you would expect based on the biology of the differences between PPAR alpha and PPAR delta. To see between the various mechanisms like what you would expect to see on fat reduction from just the PPAR alpha versus what you would expect to see on fat reduction for just the PPAR delta. Thanks.
Yes, maybe I’ll step in, in and thank you Ellie for that question. I think a key point to be made is it’s not only the difference in PPAR alpha type of that, its also the potency of selling that part of it really needs the, which remain in the forefront of how we think about it. I think the scientific rationale for studying Seladelpar in NASH was really informed by, first of all, pretty substantial literature on the role of delta, both in the liver and the periphery.
And then second of all, our success of our results in two diabetic obese mouse models of NASH. That’s specifically through your question in the liver with respective to PPAR alpha and PPAR delta. We know that PPAR delta drive fatty acid doc patient in hepatocyte has effect on settling of that in the past new state from the periphery in hepatocyte. And in addition the effect are supplemented by a fraction in super cells and macrophages that are recruited into fight the liver injury and subsequently with effects on the inflammatory fibrosis that there is a secondary to that.
But we see strong reduction in fibrosis in collagen content at least in mouse model. I think it’s important to reflect on, I know people are trying to understand how delta in Seladelpar is differentiated from other mechanisms that are accessing alpha. And I think here I would just going to first of all the potency as previously mentioned, but also the potential for peripheral effect. Other agents in NASH currently in development that after alpha are restricted to whether as well as if I point out THR betas are also respected to liver.
PPAR delta has effects on fatty acid oxidation in muscle and adipose as effect on lipolytic activity, which is responsible for the mobilization of fat as that moves through the process of liver. Here we believe that Seladelpar may have an additional effect that maybe important in terms of differentiating. And this is an accident. It’s not expected with PPAR alpha.
Got it. That’s very helpful. Thanks. And then just one quick one on PSC, you mentioned that the discussion of the study design are ongoing. But just curious if you can share any sort of initial thoughts on what end points you might be able to study in PSC and what would be viewed as clinically meaningfulness of the even as SCM, the regulatory path is a little bit more complicated versus PBC, so just curious any sort of initial thoughts there?
Yes. Ellie, maybe I can jump in here first. Yes, I think it is an very important question. I had a couple of things to highlight here. We’re involved with a consortium of other sponsors, regulatory agency and thought leaders in a group called the PSC forum where this is very much active dialogue around endpoint to be evaluated in the setting of PSC. And so this is a bit fluid here internally, but we’ll be looking to finalize what will be effectively a dose ranging proof of concept study of Seladelpar in this setting. It will be important for us to, of course, this is the cholestatic disease. So assessing the impact of Seladelpar and our process we’ve done in the setting of PBC will be a key endpoint that will measure.
I think in addition, recognizing that patients with PSC can have a greater degree of inflammation and even fibrosis, there are some additional elements of the disease pathology that differ from PBC as well in terms of implication of not just the small bile ducts, but of course the large extrahepatic bile duct as well. So we’ll look at in a similar way that we’re doing in the setting of NASH, noninvasive, as well as wet biomarkers of inflammation, fibrosis, liver stiffness. I think these are each elements that can give us some guide around the potential for seladelpar to not only improve cholestate is for really improve overall liver health in the setting of PSC, where today there are really no drugs that are approved in this setting. And so we think it’s a very significant opportunity and we’ll design a Phase 2 study really to give us as many of measures to read and understand the impacts of seladelpar for patients with PSC as we’ve done in the NASH Phase 2b.
Got it. Thank you very much for the color.
Thank you, Ellie.
Our next question comes from Pasha Sarraf with SVB Leerink. Please proceed with your question.
Good morning. This is Mike on for Pasha. Thanks for taking my question. So obviously with this upcoming 12-week interim data, this is just the first readout getting in the NASH side of things. So how much importance are you placing internally on this interim readout versus the full 52-week study, which as you mentioned, is really going to be the gate to ultimately entering that Phase 3 study.
Yes. Thank you for the question, Mike. I’ll start it off and then I’ll ask chuck get the conclusion to chime in as well with some perspective as well as Paul. There’s some things that I don’t cover. I think you really highlighted it. Of course, we recognize as even the FDA guidance and you have an EMA guidance suggests that to do really late stage, proper Phase 2 development and setting of NASH really need to evaluate histology. And so the design of our Phase 2b study without question, while the primary endpoint is a 12-week read on hepatic fat reduction is really anchored on our ability to be able to evaluate histology.
So that really will be the key driver. It will be the key driver in selecting doses and selecting really the clinical development strategy for seladelpar monotherapy and potentially even as combination, as we look to advanced development all be anchored on really histology. I think what the 12-week read on change in hepatic fat and effects on transaminase provide us the ability to be able to potentially think through advancing and perhaps with some success think about front loading our preparation for a strategy to move forward beyond this Phase 2b study in the setting of NASH.
So I think, for many of the reasons Chuck already highlighted with respect to the pathophysiology and expectation that if you can remove in particular lipotoxic lipid, which are proinflammatory and can instigate the fibrotic process, if you can demonstrate that an agent like seladelpar has really a strong antiinflammatory benefit, by way of reductions in transaminase. I think these early indicators can further encourage us as we have patients progress from the 12-week time point all the way to 52-week. Chuck, is there anything that you think I’ve left out? Mike I think…
Sorry about that. It’s a technical questions, but yes, I think you’ve covered it well, thank you.
Got you. Thanks very much for that. That’s super helpful. And just in terms of a quick follow-up. Obviously, you’ve mentioned a lot about why, certainly you could generate a lot of confidence or at least enthusiasm going into the interim readout. My question is, it might be a little early on, but are you thinking about any thresholds in terms of MRI-PDFF reductions, based on currently available in terms of what a wind might look like?
I think this is a much tougher question and primarily because we know that seladelpar in particular, as I mentioned, PPAR delta has pleiotropic effect, like FXR, we know that we inhibit bile acid synthesis. That’s a key component of the pathophysiology in the setting of NASH, like THR beta and even PPAR alpha, as Chuck mentioned, we know that we drive fatty acid oxidation here. Of course, we know that we do this in the liver as well as externally. I think, the fact that PPAR delta is expressed in the liver and Kupffer cells as well as circulating macrophages. I think supports the hypothesis that we may see a more direct antiinflammatory benefit with this agent as you’ve seen versus other targets and here again, the fact that delta is also expressed in stellate cells as a suggestion for seeing a direct anti-fibrotic effect. We’ve of course seen this in mouse models of NASH. And given all of these different activities of seladelpar, I think it’s important for us to really collectively look at all of these various effects on hepatic fat reduction, transaminases, bile acid in totality to form the right picture around what we consider to be real success.
I think you can have varying impacts across all of these parameters and still see successful biology with respect to changes in histology or improvements in histology. So we’ve got to keep an open mind. I think across, what we may see here early on in the study given the impacts of this target. Again, I think seladelpar is unique to many of the other targets being studied in NASH given the benefits across a variety of these different parameters.
Excellent. That’s very helpful and thanks again. Appreciate it.
Our next question comes from Steve Seedhouse with Raymond James. Please proceed with your question.
Yes. Very good afternoon. Thank you. A couple quick questions on the recent data presentations at EASL. First one, you had some preclinical data combining seladelpar with GLP-1 and ASK1 mechanisms. Can you maybe just talk about any next steps there? It look like the liraglutide combo worked quite well. So is that something you would contemplate just running a clinical study by just purchasing commercially available GLP-1?
Yes, thanks for the question Steve. I think that data is in fact very exciting. From our perspective, I think we like others in the field believe that prominent way to be potentially treating NASH will be to combine various targets. And one of the compelling things for us is some of their known effects of GLP-1 on glucose regulation of course, on weight loss. We think make it a fairly compelling target to potentially combine with seladelpar.
And I’m going to ask Chuck to give a little bit of an overview of what we learned there that may inform us around a potential clinical strategy. But I think you’ve really nailed it there where I think some of the work that’s been done in Chuck’s groups forms the basis for clinical development strategy beyond just thinking about seladelpar as a single agent. And of course, were ardent believers that the data should support our clinical development strategy.
So as we have not just this 12 week data but ultimately biopsy in this study. I think those will be of course key inputs, I’m thinking about not only monotherapy but also combination. But that is the type of strategy that we would potentially look to advance, should we see positive data out of this Phase 2b. Chuck, can I ask you maybe to frame some of that work as well in the context of this question?
Sure, happy to and thank you Steve for the question. And so for those of you listening on the call, you can see a lot of the detail from the work that we presented it’s available in a poster format on our website. As Steve alluded to, we had been conducting an exploration but the scientific rationale for combining seladelpar with a variety of agents and we began with agents that are either metabolic, inflammatory, anti-inflammatory or anti-fibrotic. We want to emerge from the first set of work was really liraglutide and we selected it, because there was good precedence clinically. The lean study was published where it showed in a small set of patients have fairly good effect on resolution of NASH pathology.
Not as much of impact on fibrosis. And this is possibly driven in part by its effect on weight loss. That was recapitulated in the study. This was a biopsy confirmed NASH model where we saw that both a liraglutide and seladelpar when dosed for 12 weeks at the end of the year study both reduced liver fat, improved NAFLD activity score including reductions in ballooning. But where they differed was really the fact that seladelpar maintained a strong anti-fibrotic effect both alone and in combination with liraglutide. So, here I think you have two agents that compliment and reinforce one another on the metabolic side of the equation, if you will, were seladelpar steps in and the inflammation in fibrotic to really add additional benefit.
I think with what’s going on with Ozempic as well as with oral semaglutide coming forward, I think there’s a strong rationale to think about combination with GLP-1 receptor antagonist, especially the long acting one. And as well through rest of it is doing very well, as I have been mention as well. We have additional work that’s ongoing looking at other agents in combination. But I think just to kind of wrap it up completing this work along with confirming the single agent activity of seladelpar were really positioning us very soon to make decisions as Steve, we just alluded to at the potential of doing some small Phase 2 in combination to evaluate the rationale for this combination in the clinical setting to confirm what we’ve seen preclinically.
Okay. Thank you for that. The other data point for me is I wanted to ask about was, the study where you looked at 26 and 52-week treatment with seladelpar on the predicted transplant-free survival. So it looked like the effect of 26 weeks treatment was robust – as robust as 52 weeks treatment. Is that the correct interpretation of what does that suggest about even needing chronic dosing if you get sort of maximal predicted transplant-free survival outcome benefit after just 26 weeks of treatment?
Yes. Steve, maybe I’ll start off and then Paul, if you could add some color as well. I think partially looking at GLOBE score, the difference between 26 and 52 is largely driven by the biomarkers and the levels of those biomarkers that we observed at each of those time point. I think in the end, you still need chronic dosing because in order to sustain those anti-cholestatic and anti-inflammatory effects, largely those effects on cholestasis with respect to Alk Phos and bilirubin, in order to sustain those levels, you ultimately need to in fact those chronically. So the really the analysis is just looking at the levels of those reductions in the levels of Alk Phos and bilirubin to give you some guide that if they remain there over long term dosing, what those impacts would then be on overall transplant-free survival. Pol?
No. I think you’re making a very good point, Sujal. This is the chronic dosing and then PBC is a very long term study, so unique chronic dosing and pull up the patient over a long period of time to figure out the impact on clinical events including transplantation.
Okay. Thanks. Thanks for clarifying that. The last question, I had was just on MRI-PDFF, do you get a sense that investors are maybe too focused on MRI-PDFF just based on the pleiotropism you’ve been highlighting, because I know, I think it was the last call you mentioned like a 20% or 30% placebo adjusted reduction is a reasonable expectation. Obviously, it was a few data sets like NGM, and liking in particular that get closer to 50%. So are you confident that The Street will look at the two digits you report for liver fat reduction, and look beyond it to assess the efficacy here?
Yes, I think it’s a good question. Obviously, this is a parameter that has an association with the progression of the disease. So it’s of course important, if not the only parameter of course then I think the important thing for us here internally as well as folks externally to be able to evaluate, of course of the effects of seladelpar across the variety of different parameters. You highlighted a couple of agents and their reductions in hepatic fat as well as we know the results of MRI-PDFF that’s for a variety of other targets as well be at ACC inhibitors, other THR betas, that are being evaluated. Some of the data exists for other targets not yet mentioned as well. And so I think there really is a spectrum. There’s a range, certainly 20% to 30% relative reduction hepatic fat at 12 weeks could improve, as you see a patients continue as we’ve seen with other agents improve over longer terms of dosing, well correlated with seeing some effects on overall histology.
In particular, in fact, when you just think about the proportion of patients, for example, with at least of 30% relative reduction, I think these are numbers early on that are providing positivity and encouragement around what we ultimately would be with respect to histology. So I think the framework around various other targets being studied have pluses and minuses in many cases. And I think our case will be the same as to think about the various impacts on different parameters holistically in setting of the entire patient population.
Thanks so much. Appreciate the question.
Our next question comes from Jay Olson with Oppenheimer. Please proceed with your question.
Hi, thanks for taking my question. I have to, follow-up on some other data at EASL you spoke earlier about the relative strengths of PPAR-delta versus PPAR-alpha in NASH. And, I’d like to ask about some PPAR-alpha data in PBC. That was at delta – that was at EASL. And specifically there was data for PPAR-alpha, where it did not show, ALT reductions in PBC patients. And I was wondering, if you thought that would provide a competitive advantage for PPAR-alpha agonists. Sorry, PPAR-delta agonists, specifically versus PPAR-alpha?
I’ll start off. I don’t think there’s any question at all. I mean PBC in fact is an inflammatory autoimmune liver disease and of course, while reductions in alkaline phosphatase, normalization of bilirubin it has been correlated towards transplant-free survival and are really the key elements – the two only elements in the primary endpoint for registration. Patients in fact do have inflammation as we saw in our Phase 2 study, patients at 10 milligrams mean baseline is actually above the upper limits of normal. And having an agent that actually can reduce inflammation and lower transaminases, we think there’s no question that this is a preferred profile for of course patients and, and even the way I think physicians would think about treatment alternatives in this setting. Pol, do you want to add some additional color?
Well, what I can add is that the – transaminases digitization is part of the PBC disease if you want it just goes to show that the inflammation goes from the auto space, then invade the lobular portion of the liver. So having a decrease in transaminases that particularly in patients with elevated the transaminases, that baseline that can normalize this parameter. I think is very important, and also is that, if you wanted to clinical translation of the implant, anti-inflammatory effect of seladelpar. So I think for us it’s an important part of the efficacy of the drug, of course, then you have the safety side of the equation.
Then I have to say that the data presented at EASL for [indiscernible] that was an update, of course, but it was also a huge valuation in the transaminases, then there was, you might remember that there was one patient that was actually more on the autoimmune arthritis side of things, which means in fact that there was the motivation in transaminases. And a lot of patients with PBC transaminases elevation patients. So it’s really part of the disease then and taming the inflammation that you see with transaminases with certain new positive factor.
Great. Thank you. And then I also, if I may wanted to ask about the efficacy signal, you’ve seen for seladelpar in PBC patients with cirrhosis. And is there any recross to cirrhotic patients with other causes of cirrhosis outside of PBC and specifically, would you expect to see efficacy for seladelpar in NASH cirrhotic patients?
Yes, Pol, perhaps you can maybe address Jay’s question here.
Yes, I think you have to progress step-by-step here. What you want to see is first you start with PBC and you want to see whether the drug is safe and whether the drug was in cirrhosis patients. And you need to answer this question with data. So the data we have, we presented EASL at where important than that in patients with the compensated growth, if it seems that the response to save much patients that do not have cirrhosis and the safety profile was did also, which is really important. Now, I think this kind of information, you can potentially translate that. So, as we said, we’re going to learn, we’re going study PSC. PSC is another cholestatic disease. So, this data that we have in PBC are certainly encouraging for the PSC side of things. Now, if you go to NASH, we also – that’s also an important question, because you want to study the efficacy and the safety in patients with NASH cirrhosis. So, the information in PBC patients, is resetting the importance also for NASH. you’re asked although to remember that this is not exactly the same type of cirrhosis, the fibrosis, they do not stop exactly in the same place in the liver.
In the end, of course, the cirrhotic patient that decompensated cirrhotic patient – the decompensated cirrhotic patient and the etiology is a bit less important. But this data in PBC cirrhotic patient are very encouraging. So of course, we need – we will have more data and we continue to accumulate data, but that’s also important for the other liver disease that we want to evaluate.
Great. That’s very helpful. Thanks for taking the questions.
Thank you, Jay.
Our next question comes from Ed Arce with H.C. Wainwright. Please proceed with your question.
Hi, Sujal. thanks for taking my question. And just wanted to offer my congratulations also as well for all the recent progress including your breakthrough designation.
So, I wanted to ask about what appears to be that continuingly evolving and expanding profile of seladelpar and PBC, which of course, remains your lead program. The first one you’ll go to market with – the study in particular at last month that at EASL that showed the comparable affects in both non-cirrhotic as well as early cirrhotic Child-Pugh A gives you comfort in that area of PBC patients. And I know that as well, we’ve discussed how your previous data showing significant numbers of patients that actually normalize. ALP gives you the opportunity to look beyond the 1.67 times upper limit of normal as well. And so as you look at sort of the expanding patient – overall patient population of PBC, perhaps you could discuss how that is informing the ultimate commercial approach with the two or three others that would be approaching the market around the same time.
Yes. I’m happy to address that, Ed. Thanks for the question. We’re doing a fair bit of work in fact closely with the global PBC study group, Bettina Hansen in particular and as well as Gideon Hirschfield. As we look at historical data and better understand the impacts of reducing and alk phos and bilirubin and thresholds in fact of each of these markers across disease progression and how they’re related to transplant free survival. And we’re going to continue to do this work in order to better evaluate the potential for patients, really that that may benefit from seladelpar treatment. And of course, our prime focus in enhanced as a second line treatment patients that remain at a high risk of disease progression despite being on UDCA.
I think here the data initially demonstrates that there’s really a log linear relationship between alk phos and transplant-free survival. And so the lower you can bring alk phos, the closer you bring it into the normal range of course, is a benefit for patients. And part of what will be important for us, it’s really just to be able to identify the ability for seladelpar, which has the potential not only to be efficacious, as you mentioned, even with a significant number of patients getting into the normal range, but also very well tolerated and with the potential in fact, as we’re looking to confirm and enhance the potential to even improve on a key clinical symptom of the disease.
So, elements of a quality of life for patients that, in the end, in many ways, can be considered an outcome, I think will be very important parameters to be able to assess the ability to really expand the overall patient population. So, this is ongoing work that’s largely driven by both the efficacy as well as the tolerability profile of seladelpar that may allow us to really continue to expand the overall patient population.
great. That’s helpful. And the other question I had was just around PSC, it’s intriguing to me that clearly with the success you’re seeing with enhanced and with the rapid enrollment that you have now with your NASH study. It would lead us to believe that you can leverage a lot of those experiences, relationships, sites and so forth with a closely related cholestatic disease like PSC and so wondering, other than the end points, which as you mentioned is still a little bit fluid, how does all of this help to inform your timelines then and move forward with this third indication?
Sure. Yes. So we’ll be able to provide more specifics around the timelines with respect to the PSC study when we finalize the plans to move forward. But you really captured the essence of it here internally with our most recent financing completed in March. We’ve really accelerated internal activities here to get ourselves prepared to initiate this Phase 2 study in the second half of the year. the dataset in the setting of PBC as we eventually have some of the data – early data in NASH that each of these things can be key drivers and our ability to really move forward quickly in this study.
Additionally, we have team members; Steve Rossi, who is our VP of Early Clinical Development, has had a tremendous amount of experience in hepatology and most recently running a PSC study himself at his prior company really has given us the opportunity to be in front of all the key individuals, many of which we already have relationships as we’ve developed seladelpar on the setting of PVC. So, we’re going to have an opportunity to move quite quickly. It’s a really key unmet need in that patient population. And so what we’ve seen thus far with respect to seladelpar, I think really fuels our ability to move efficiently into PSC. And so we’ll give you some updates here again as they’re finalized really in the coming, probably weeks to months here.
Okay, great. And then perhaps if I may one last question around, one of the posters you just announced today to be presented at DDW, the work being done in collaboration with other groups around pruritus and PBC, how does that work continue to help with ultimate discussions with regulators and labeling?
Yes, sure. Pol, do you want to start on Ed’s question and I can add some color in the end.
Yes. Can you repeat the question?
Yes. I just wanted to see if you could give some details around how you are thinking with more data coming forward on pruritus, in PBC from other groups including the poster you’re presenting at DDW and how that informs you are going forward?
Yes. So the poster we are seeing at DDW actually, it’s interesting, because it’s a collaboration with patients’ organization. And this goes to show the real – really impulsive feature of pruritus for patients. So, what we did was to try to evaluate the impact of pruritus on patients and also to try to evaluate that is the best way to measure pruritus for these patients. So, it was very good to have a bad feedback that collaboration for this exercise. So, we also try to better understand what is significant for them in terms of a change in pruritus. So that’s also important information and this topic of pruritus is important, because the – potentially, it can also inform, it’s coming back to the question about the expansion of seladelpar that could be also a very important aspect, but you have to realize that that some patients that are itching and having a problem of itch with PBC actually do not have elevated alkaline phosphatase in the lab, very limited elevation of alkaline phosphatase. So while in general there is a correlation between pruritus and the severity of the disease is not always the case. So we were very happy to be able to work with patient and to see [indiscernible].
Thank you, Ed.
Our next question comes from Mayank Mamtani with B. Riley. Please proceed with your question.
Hello, everyone. Thank you for taking my question. This is Jeffrey Tan dialing in for Mayank. First could you point to any reference points comparing seladelpar to prior generations of PPAR delta agonists such as GlaxoSmithKline GW501516? Was there any liver fat reduction data ever report in the molecule? I realized the same MRI-PDFF modality might not have been available back in the day, but any color would be helpful.
Yeah. I think unfortunately there really isn’t a data that allows us to really compare on this element. GSK conducted a very small study, only six patients. In fact, they were patients that didn’t have a vastly elevated liver fat only in the 5% to 7% liver fat percent range. So, quite a different profile of patients where they did see 20% reduction in 2-weeks, but I think very important for me to point out that it’s a very few – a small number of patients, and, and those in particular that didn’t really have elevated liver fat. I think more meaningful when we think about the potential seladelpar in this parameter, in fact as the fundamentals of the mechanism itself at seladelpar, it’s really very similar in terms of overall potency and selectivity to that GSK compound.
And so as Chuck has mentioned various points on this call, the key driver around promoting fatty acid oxidation in the liver as well as in peripheral tissue, I think are what really encourage us around seeing some real key benefits on this particular endpoint. And, of course, this marries well with some of the work that we’ve done albeit in mice, but in mouse models of NASH, where we’ve also seen some meaningful reductions in hepatic fat with seladelpar. I think those are really the things I’d anchor on more than looking for comparative data with GSK because it is in fact very limited and again, a different population of patients.
Great. And I have one follow up question. So how are you guys preparing as an organization for the two watershed data readouts in 2020, namely the Phase 2 histology readout in NASH, Phase 3 pivotal readout in PVC. Do you think you would need some sort of partner along the way?
That’s a good question. In the setting of PBC, we’ve really built a team here internally that can help us not only execute the Phase 3 studies, file the NDA and start to prepare us for being able to really launch in the setting of PBC on our own, when you think a little bit about the requirement there and the profile of seladelpar overall. We feel very confident that we have the ability to take seladelpar all the way to the hands of patients in the setting of PBC. The Phase 2b data this year as well as next year in NASH I think will further inform us of our ability to carry forward in clinical development. Here we’ll be pragmatic. I think we certainly have a team and the capabilities to continue advancing development of seladelpar par beyond Phase 2 in the setting of NASH, but we are always thoughtful around strategies to expand clinical development in every setting and NASH is really no exception
Thanks for taking my questions, and congrats on a successful quarter.
Thank you, Jeff.
Our next question comes from Edward Nash with Robinson Humphrey. Please proceed with your question.
Hey, congrats to team for the progress for the quarter, and this is Fang-Ke Huang for Edward. Thank you for taking our questions. Just a quick one for the PTST and for the ENHANCE Phase 3 study, are you realizing as long as study exclusion criteria is basically, can any real subject will be inadequate to response to OCA – in program to OCA. Just wondering whether you have any data point – point to income fill? What percentage of patient are currently not on OCA? And who – what percentage and who are on OCA, but are willing to switch to enrol the trial. And maybe you don’t have data for the intent 3 enrolment, but maybe other data point and point to that percentage, it could be very helpful. Thank you.
Sure, Fang. So let me first clarify as your ENHANCE enrolling patients that are inadequate responders or otherwise intolerant to UDCA, ursodeoxycholic acid or urso, that’s the basis for the population and the basis for second-line treatment effectively. We can have patients that come into the study who have been on OCA in the past, of course they need to wash off OCA treatment. We’ve had some of those patients in Phase 2 very small subset. We expect to see some – and ENHANCE as well. But I still think – believe that the vast majority, certainly particularly outside the U.S. of patients that we have are likely to see come into ENHANCE, in fact, will have only been on UDCA and have not yet tried a better cholic acid.
So hard for me to give you any specific numbers. But I wanted to make sure and clarify that the real enrolment criteria and ENHANCE is to bring in patients that are either inadequate responders to UDCA or intolerant to UDCA.
Yes. Thank you for that. And actually I realizing in the [indiscernible] here must be 20 or 30 days prior to treatment. So yes, I forgot to mention that part. Thank you.
Yes. Thanks, Fang. Thank you for the question.
Ladies and gentlemen, we reached the end of the question-and-answer session. At this time. I’d like to turn the call back to Sujal Shah for closing comments.
Thank you, operator. I’d like to thank you all once again for joining us on today’s call. We’ve had a busy year thus far already and are excited about new data this quarter our first patient data for seladelpar in the setting of NASH. And of course the start of PSP in the second half of this year. And we believe seladelpar really is one of the most promising compounds in active development for inflammatory liver diseases, including PBC as well as NASH. And of course are excited now to expand into PSC.
We look forward to continuing our pioneering work in these indications, and I think it’s important for me to make sure and point out that this work is only made possible by tremendous efforts of everyone here at CymaBay and of course by the generosity of our patients, their families and their caregivers. And we look forward to providing you with updates once again here very soon. Thank you.
This concludes today’s conference. You may disconnect your lines at this time, and we thank you for your participation.