Q3 2019 Earnings Call

Good day, ladies and gentlemen, and welcome to Cymabays third quarter 2019 financial results Conference call. At this time, all participants already listen only mode. Following the formal remarks, we will open the call for your question. Please.

Please be advised that the call will be recorded at the company's request. It is also being webcast live on the Investor section at the Cymabay website at Www Dot Cymabay Dot com.

Now I would like to turn the call over to Mr., Dan Minolta, Vice President Finance at Cymabay Mr. Mittal. Please proceed.

Thank you operator, and good afternoon, everyone I hope that you had a chance to review the press release, we issued announcing our third quarter 2019 financial results and business updates.

You can access that release on our website under the investors tab.

Joining me on the call today are just Shah Chief Executive Officer, Dr., Chuck Mcwhirter, Chief Scientific Officer.

I'll provide an update on our financial position in clinical programs and review upcoming milestones before we open up the call for queuing it.

Before we begin I'd like to remind everyone that statements made during this conference call, including the Q and a session relating to cymabays expected future performance business prospects events or plans, including clinical plans and anticipated data release dates and cash runway or forward looking statements as defined under the private.

Securities Litigation Reform Act of 1995.

Although the company believes 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 both 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 Cymabays quarterly and annual reports filed with the FCC 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 a rebroadcast it's expressly prohibited without the written consent seem a bag at this time I'd like to turn the call overseas.

Good afternoon, and thank you for joining us.

I begin our call today with several exciting updates related to sell a dalbar are highly selective and potent PPR Delta agonist currently in development for multiple inflammatory liver diseases, including primary biliary, calling giteau score PBC.

Primary sclerosing, cholangitis, or P.S.C., and non alcoholic steatohepatitis or Nash.

Yesterday, almost one year to the day since its initiation, we announced that we had reached target enrollment of 240 patients earlier than expected and enhance our global phase three registration study of Philadelphia are in patients with PBC.

We now expect to complete randomization by the end of this month and to report topline phase three data in early 2021.

As a reminder, enhance is a double blind randomized placebo controlled 52 week study evaluating the safety and efficacy of five and 10 milligrams obsessed with L. part versus placebo in patients with PBC, who had had an inadequate response or our intolerant to fee.

First line treatment with you do you see a.

Importantly, the doses of Citadel par being studied the treatment duration and the primary efficacy endpoint is being evaluated and enhance our identical to those from our phase two study.

In case, you are not familiar PBC is a rare chronic inflammatory liver disease, primarily affecting women over the age of 40.

It is characterized by impaired bioflo or call it status and the accumulation of toxic bile acid, then the liver leading to inflammation and destruction of the intrahepatic bile ducts, which can result in fibrosis cirrhosis and liver failure.

Common clinical symptoms of the disease include potentially debilitating fatigue and pure riders.

I cannot overemphasize the significant achievement of our team working together with our partners investigators their staff and patients to get this study enrolled ahead of schedule.

Enrolling that study of this size in a rare disease in which there is already in approved therapy is in our minds a statement about the unmet need that still exists for patients as well as a testament to the reputation of cell Adele par based on its profile today in phase two.

Speaking of our ongoing open label dose ranging phase two study.

We expect to release full topline data early next year.

As you may recall, various interim datasets from that study have been presented in late breaking presentations at three consecutive A.S.L.D. meetings over the past three years and most recently at ease off this past April .

These results supported our breakthrough therapy and prime access designations for cell Adele par in PBC.

And serve to establish the potential of cell Adele par to offer patients improved efficacy and better tolerability over existing second line treatment.

To date, Philadelphia has demonstrated a pattern of anti call a static and anti inflammatory effects.

Importantly, we observed these effects without a worsening of pure right is a key potential advantage over current second line treatment for patients with PBC.

This study randomize, a total of 119 patients.

With 104 out of 106 eligible patients electing to continue celadon far treatment.

And one year.

Our long term study.

Our safety experience would sell Adele par in patients with PBC continues to grow and there are now over 45 patients in the long term study well I've been on treatment for over two years.

Finally, as our PBC program continues to achieve key milestones will be presenting new clinical and preclinical data for cell Adele part at the upcoming liver meeting hosted by yes, L.D. in Boston from November nine through the 12.

The first presentation examines the pharmacokinetics of cell Adele par in PBC patients with or without compensated cirrhosis.

For those of you attending this abstract is number 13 28 and will be presented on Saturday November nine from 515 to 615 PM Eastern time.

It focuses on the exposure of celadon par in PBC patients with confirmed cirrhosis and area of increasing interest for both clinicians and regulators.

It builds upon our presentation at EASL last April in which we observed similar anti call a static and anti inflammatory treatment effects.

Non cirrhotic and compensated cirrhotic patients without any new or overall safety signals in this challenging population.

As our PBC program advances, we believe it is vital to understand the effects of cell Adele par across the spectrum of bid PVC disease severity and communication of these results reflects our commitment to broadly share what we learn.

The second abstract number 20 to 53 will be presented on Monday November 11th from 12, 30 to 130 PM Eastern time.

It explores the structural and bio physical characterization of the origins of and differences in the selectivity of cell adult par and Ellis ever nor a dual p. par Alpha Delta agonists.

This poster will highlight at the structural level, how and why sell Adele par is able to achieve its potency and selectivity and give insight at the target level of the potential origins of differences in clinical doses of these agents.

As we discussed last quarter, we're committed to expanding our development of cell Adele par for rare orphan call a static liver diseases.

In the third quarter, we made significant progress on this objective with the initiation of a phase two proof of concept study and sell it apart in patients with P.S.C.

Yes. He is a rare chronic call a static liver disease that is characterized by diffuse inflammation and fibrosis of the bile ducts.

The disease affects approximately 40000 patients in the U.S. and share some underlying pathology with PBC. Although it is generally a more heterogeneous disease.

As with PBC, many patients suffer from pure writers.

And there is also a high co morbidity of inflammatory bowel disease in this population.

There's a significant unmet need and PSC with no approved pharmacologic treatment.

The only effective option for patients is liver transplant.

We recently completed investigator meetings in the U.S. and Europe and site initiation and patient screenings are now underway.

In this phase two study, we'll be evaluating three doses of seller Dalbar 510, and 25 milligrams versus placebo in a one to one to one to one cell Adele part dose group to placebo ratio.

And are targeting enrollment of approximately 100 patients at 60 sites globally.

The primary efficacy endpoint will be the relative change in alkaline phosphatase AIDS from baseline to 24 weeks as a proof of concept endpoint for potential pharmacologic activity.

Key secondary endpoints will include liver stiffness by fiber scan.

Imaging evaluations, including MRI with contrast, and M. RCP.

Measurements of pure write us and patient quality of life.

And other exploratory measures, including serum biomarkers of inflammation and fibrosis.

The study will also include an interim assessment of safety and efficacy after approximately 10 patients in each dose group.

Each 12 weeks of treatment.

We will provide guidance in the coming month unanticipated timelines for interim and final topline data as we progressed further with enrollment.

As you can see our development of cell Adele par in inflammatory liver diseases is focused in areas of high unmet medical need.

This is not only true for our call a static disease program in PBC and P.S.C.

But also in our evaluation of Philadelphia for patients with Nash.

Let me ask Chuck to provide updates with our ongoing phase Twob study in Nash Chuck.

Thank you so Joel we remain focused on completing the ongoing phase Twob study attached to the 52 week histology endpoints.

With results expected in the second quarter of 2028.

As a reminder, the study remains blinded and we reported 12 week topline interim results. This past June that revealed clinically meaningful and dose ordered reductions in liver enzymes known to be associated with inflammation and liver damage, but unexpectedly showed minimal changes in liver fat content use.

MRI proton density fat fraction.

As I mentioned sell adult par treatment resulted in robust clinically meaningful and dose dependent reductions in several key markers and these included Alan Dean amino transferase or a LTV with decreases in the cell Adult Park 50 milligram group at 12 weeks of 32 units per liter or 37.

1.5% versus nine units per liter decreasing in the placebo arm.

Underscoring the consistency of the liver enzyme pattern reductions changes were seen in a S. T G T and LP and they included a 43% reduction in the plasma elevated GGP levels that 50 milligrams.

These dose dependent improvements in liver enzyme markers and their potential association with histopathology has generated considerable interest and understanding if the effects seen at 12 weeks will translate into histological improvement at 52 weeks.

To put these results into context and analysis published at the beginning of this year examining histological responses in the one study of a better cholic acid.

Found that decreases in LTL 17 units per liter or greater we're correlated to an improvement in histological response.

Data published from other last studies have also supported the association to bail to productions with through improvements in Nash histology.

Other key results at 12 weeks included decreases in the inflammatory marker high sensitivity C reactive protein and decreases in LDL cholesterol triglycerides supporting a favorable cardiovascular risk profile.

So at a par appeared to be safe and well tolerated at doses of up to 50 milligrams through 12 weeks.

The majority of the treatment emergent adverse events were mild to moderate and severity and deemed unrelated to study drug.

There were two serious adverse events that occurred after randomization through week 12, neither of which were deemed to be related to study drug.

Since reporting these results we have completed some additional assessments of Pharmacodynamic markers again done in a matter, where we can report group means but in which we maintain the blinding of the study.

The first marker is a measurement of seven alpha hydroxy for coal esteem three own or see for a key circulating intermediate of the bile acid synthesis pathway and whose level exclusively reflects action end up out of sight.

Levels the C for our modulated by regulating the gene Sip seven a one which expresses the enzyme responsible for the rate limiting step in bile acid synthesis.

We have previously shown that sell Adele par suppresses Sip seven a one in primary hepatic sites and decreases C in patients with PBC.

In this study we once again observed dose dependent reductions in see forward at 12 weeks with a median decrease of 55% at 50 milligrams.

These results confirmed target engagement and the activity of cell adult par and suppressing bile acid synthesis in patients with Nash a potential benefit given the role that elevated bile acids may play and the pathogenesis of Nash related liver injury.

Another area of interest has been to try to gather mechanistic insights related to the known effects of del Pars and Lippincott capitalism.

Therefore, we evaluated a second set of markers of target engagement that were directed to confirming sell Adele pars effects on promoting fatty acid oxidation add mitochondrial respiration.

We analyze samples at baseline at 12 weeks for levels of card a team and short chain estill carnitine in plasma.

These metabolomic analytes reflect fatty acid turnover at the level of the mitochondria the side of fatty acid oxidation and are known to accumulate in the plasma from tissues, including liver peripheral fat and muscle.

At 50 milligrams. After 12 weeks of treatment increases from baseline, we're seeing encarta team asset fuel carnitine and beautiful carnitine levels of 36.1, 34.7, and 38.5% respectively. While corresponding placebo changes were 2.5 12 into.

2.9%.

Effects on these three markers were also dose dependent.

We interpret this to me, let's sell adult par retains the beneficial effects on liberty metabolism that we expected despite not seen a meaningful effect on reducing total liver fat at the 12 week time point.

Finally, we also evaluated effects at 12 weeks on L. score, a biomarker of fibrosis and corrected T. One noninvasive MRI method designed to explore effects on inflammation.

Neither measure showed any a treatment effect at 12 weeks.

Although other targets have shown effects on these markers in this timeframe, we remain interested to discover it longer treatment times, maybe needed with the Dell par mechanism.

A robust panel at these and other assessments are being collected in the study at various time points added 52 weeks.

We remain blinded and we'll report them along with topline histological results in the second quarter of 2020.

Let me now turn the call back to suit Joe for a review of our financials and closing comments so Joe.

Thank you Chuck.

Our cash cash equivalents and marketable securities were $218.6 million at September Thirtyth.

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 and nine month periods ending September thirtyth.

I will refer you to the press release and to our 10-Q filed with the FCC today.

The third quarter has been one of our most productive periods, culminating in reaching target enrollment and enhance our global phase three registration study of cell Adele par in PBC earlier than originally projected.

We expect a complete randomization and enhanced by the end of November and remain on track to report topline data from this 52 week study in early 2021.

We also made significant progress in our efforts to expand development of sell it apart into a second rare call the static liver disease with the initiation of our phase two dose ranging proof of concept study and PSC.

We look forward to providing future updates to timelines for expected interim and final topline data as the study progressive.

In the coming month, we look forward to topline data from our completed open label Phase two study in PBC and topline 52 week biopsy data from our phase Twob study in Nash in the first and second quarters of 2020, respectively.

I'd now like to open the call to questions operator.

Thank you we will now be conducting a question and answer session. If he would like to ask a question. Please press star one on your telephone keypad.

Information told will indicate your line is another question Q.

You May press Star too if you would like to remove your question from the Q for participants using speaker equipment. It may be necessary to pick up your handset before pressing the star keys.

Our first question comes from Yasmeen Rahimi with Roth Capital. Please go ahead.

Hi team. Thank you for taking my question I have two went out nationally went on PBC. So congratulations on.

Completion enrollment so.

He.

I hear your thoughts on would you be required to do a long term outcomes PBC trial and how do you think your thoughts are in regards to building out potentially commercially or that werent core or positioning Uppsala dalbar indicates that cobalt results become available.

And it potentially there Paul positive and then the second question in regards to now says given that there are no changes CNN, Oh, and Biomarkers, so fibrosis as because it just a function of short duration or does the jeopardize your thought that that we're going to biopsy result, and then when should we.

Be expecting the 26 week data point of view is that something that we're going to either here or later next year. Thank you again.

Thanks to ethane I'll address your first question I'll ask Chuck to specifically talk a bit about our impressions with early 12 week additional analyses and the Nash study. So first of all in PBC. Let me once again highlight the tremendous accomplishment fundamentally by everyone here internally that partners that weve.

Worked with for enhancing including folks in the medical community and their staffs patients of course, and what I think as a tremendous achievement for us to conclude the full enrollment in enhanced by the end of this month and having hit already target enrollment specifically to your question Yasmeen.

As as you know approval in PBC based on.

The composite endpoint inclusive of Alpha in Foster, Jason total believe room and as a surrogate endpoint for subpart H accelerated approval. So we would in fact have to make a commitment to having and conducting a long term outcome study in this setting and this is effectively the past that that intercept is forward.

Ahead of Us and we would follow that same path.

I think you asked the question around what with what would change and the potential scenario in which cobalt read out I think it's hard to predict today. The long term study that intercept is conducting with about a cholic acid is one for which I think enrollment timelines are quite long even projections from their site.

Include timelines that extend beyond seven years.

Conversations with the agency have really been honed in on conducting a confirmatory study effectively a similar to two what intercept has been doing for about a cholic acid and that's effectively are intact. We think there's an opportunity clearly with cell Adele par post the potential subpart H approval should we be successful with enhance.

And an anda filing to execute a confirmatory study that also I think strengthens the positioning of solid alpha relative to its potential and having both improved efficacy as well as better tolerability.

Oh, Hi, Hi, Yasmeen. This is Chuck so.

Great to have your question on health and try to help you with our perspective in terms of how to interpret it I mean first first of all just recognize that elfas enhanced liver fibrosis score test the commercial test as you know as originally developed and has been Ben.

Good measure for viral hepatitis, so hep B Hep C HIV, especially for severe fibrosis. It's also been news and some other some other liver diseases as exploratory measure call a static diseases like DSC.

But has begun to be adopted in used as I'm sure you know and Nash as an exploratory marker.

And of course, it reflects because it has three.

Components hyaluronic acid.

The and terminal.

The Pro College, and then terminal peptide as well as the temp the tissue inhibitor of Matala protease various processes. Both fibrogen assess that is the deposition a matrix as well as well as its its turnover.

There are other measures for example, proceeds three which some feel has some some advantages and around sensitivity, but it comes with cost.

And because there is there's really only one provider for that assay.

You have to manage manage getting in the Q.

Now to well what we think about the result, thus far it's really for US were hampered by in the sense that this study is blinded. So we don't have.

You know patient level data to begin to look at subsets of patients for example, patients with elevated parameters, either histological score or even elevation in transforming basis at baseline nor can we look at subsets of responders to begin to tease tease out but the results might mean.

I think for US, it's really a matter of staying the course I think that as we thought about the results that we had in June .

Just the pattern of effects.

That we think are.

Good sign there proximal to liver injury, Thats really what the pathology us about and that if we were just to let the data ripen, we will collect data additional data as you mentioned that we 26 as well as on through to two week 52.

We will have an opportunity to understand whether many of the parameters that we've collected whether it be be elf proceeds three.

The MRT elastography them right pdfs as well as the attractive T. One will really give us.

It really robust data set by which to make the decision about how we believe so that part should go forward go forward and Nash.

And yes, I mean, I'll just simply add I think it's a very reasonable hypothesis that when you think about histologic change, particularly effects on fibrosis.

That you would need longer time on treatment in order to see those effects. In fact of course, the histologic assessment itself is typically done as you know at 52 and 72 weeks. So it's not all that surprising to us that even early markers of fibrosis would need more time potentially to reveal any kind of impact post treatment.

Thank you team and then 26 week data should be coming out next.

Yeah.

But I think as we've mentioned before he as mean on some of our prior calls and really our commitment is to drive patients all the way to the 52 week treatment period. There is a 26 week assessment that John it's not a planned interim assessment in this study, but those markers in assessments are taken and we'll see that data along with 52 week.

So that we have.

Better sense on the progression of treatment effects from 12 to 26 to 52 weeks once the study concludes and the second quarter of next year.

Thank you team.

Hi, Thank you.

Our next question comes from Ali Marley with Cantor Fitzgerald. Please go ahead.

Hey, guys. Thanks for taking my question and congrats on the PBC enrollment just from P.S.C. on this interim analysis on that you're taking a ferry 10 patients in each reached 12 weeks I guess like what are you looking to see enough and.

I guess, what would you view is encouraging data given this is an early time plant and I guess outside of Oxxos, what endpoint and PFC are you most focused on whether it's a clever Stephan accident. I guess you know if you could just sort of talk about kind of the magnitude that you're hoping to see there and then I've a follow up thanks.

Yeah sure. Thanks for the question now and Al style kick it off and perhaps let Chuck add some things to the degree I Miss something really just to address the latter part of your question, we think about the potential benefit matched up with the unmet need and PSC of course. This is an indication for which there are no approved treatments for pay.

Patients today it is a in autoimmune call a static liver disease like PVC, although we recognize that that there are complexities, there's a greater degree of heterogeneity typically a greater degree of inflammation and fibrosis. So when we think about broadly assessment on various impacts us sell Adele par.

Yes, I think one we would like to continue to see and would expect to see the anti call a static activity that we've seen in PBC and even in the setting of Nash.

For PSC patients were also very focused on understanding whether or not the anti inflammatory effects that we also see in both PBC and Nash translate to specific benefits in patients with PSC. The primary endpoint on alkaline phosphatase that 24 weeks I think answer as part of that question with respect to.

The call it stays this that patients suffer from.

But as you know there are a host of key secondary measures that are in our study, including liver stiffness as you pointed out with fiber scan.

So very focused on understanding the impacts on liver stiffness over that 24 week period, we'll look at a host of additional wet biomarkers of inflammation as well as fibrosis, we're going to be doing some imaging in this study as well am RCP as well as MRC plus is actually incorporated in this study.

I think fundamentally what we're trying to get a better view on is the potential benefit again, specifically on inflammation and also on fibrosis in this setting up PSC and so to the degree that these secondary measures give us a better view on overall liver health and particularly on potential effects on fibrosis. Those we think could be quite.

Meaningful for for this population of patients with respect to the interim analysis as you've seen us due in the setting of PVC vast majority of the anti call a static benefit that we've observed a typically occurs within 12 to 16 weeks. So part of the interim is to give us some idea of the various doses.

We've incorporated into this study.

And the effects on alkaline phosphatase that that 12 week time point. It also gives us some interim analysis around general overall safety in the population as the steady progress there. So I think it can be quite informative for us the key in adding an interim analysis to a study in particular is to give us further insights on the on the key.

Conduct of the study beyond and we think this will give us an opportunity to have some view on the potential benefit of sell a doubt part in this population and how that may translate as patients stay on treatment to the conclusion of the 24 week treatment period.

Got it that's very helpful. And then just in terms of thinking about that timeframe for those that are on my I know you just started but no I guess, if there's any sort of you know.

Way, we should think about you know how long enrollment will take in order to get to the 10 patients per group and how we should think about kind of one nest interim might occur that'd be helpful. Thanks.

Yeah sure. This is part of the challenges we just get the study kicked off I think what we'd like to be able to do is provide.

More specific and more accurate guidance as the study progresses. So it's about 100 patients study as Weve identified so wouldn't be a typical for the study to really take till the end of 2020 to fully enroll but here again.

We'll provide more specific guidance, particularly around interim and final topline data as we get further into enrollment.

Got it thanks, so much.

Our next question comes from Steve seed House with Raymond James. Please go ahead.

Yes, Hi, this is some more vanik of on for Steve seat House.

We had a question about a couple of abstracts that is sold the.

That talked about proof of concept studies for Fenofibrates Embezzle Fibrates.

And in those cases patient started sort of in the 300 to 500 units per.

Leader LP range and went down to about 100 fairly quickly.

Sort of similar to what you saw in phase two study with.

So adult par.

And so I guess in the case it does a fibrate. It was actually part of a triple regimen with UGC and OCA and there was a quite quite a wide range of outcomes and there's also some inconsistent.

Outcomes in terms of Pruritis and so how do you see this results in comparison to Philadelphia and would you consider in the future, perhaps running a head to head study. Thank you.

Okay Great question.

I think it's a little premature for us comment specifically about what type of future clinical studies that we might we might contemplate but I do think that we you know as anyone would in our position.

Continued to.

Make ourselves aware and to look and understand how other agents in the space or are you is particularly in Europe . As you know Piza Fibrate has has.

Off label use so it's used quite consistently we saw the paper from Christophe corporate show and the New England Journal.

That was I think in 2017 web with some some nice effects on biochemical normalization and then we saw last year correctly. It was easy earlier this year it easily.

Frederic Nevins had had an investigator study looking at.

At Triple therapy, and then here and this particular case, we have a professor corporate show once again coming forward with the study where he's looking at triple therapy I think.

The signals are interesting I think in the case, where a better cholic acid you see where you have in some instances in complete responses. It makes sense that people are really validates our position people is really have a lot that offer in terms. This anti call a static and anti inflammatory off.

Our next.

End of working the other way and as well as to potentially help to ameliorate some of the chain issues that have been are well known in part of the label for a better cholic acid kind of working the other way around I think piza fibrate tend to add Adam good to it which was also part of this study showed that there was there.

Some additional benefit.

Con when added on top I think the challenge for these studies as they're small the study that you mentioned is not just in PBC. It's also in PSC, they're not.

They're not studies that are would be conducted in a typical double blind randomized controlled controlled fashion. So it's a little hard for us to draw conclusions, but we do agree that theres, some interest herein and ability to combine mechanisms where patients are unable to get get to treatment goals for ourselves we.

We remain convinced that sell Adele par really looks.

Quite favorable in terms of the profile, we've seen through through phase two we seek to confirm that enhance but if you can imagine us future state were approved on the market I think that.

Well, we'll certainly look towards comparing ourselves to others as well as in the future we'd be open to contemplating looking that at combination therapies as well, but right now front and center for us is as getting enhance across the across the finish line.

Okay. Thank you for the detailed answer here and I guess there are other question is on Nash. So your Nash read out those into Q2 0, and it's going to be a busy time, because obviously, there's there's also a couple of competitive updates at least two.

Starting with.

There's potential for some good try to update and also elephant burn or around April of next year. So on one hand super nor would be a more direct read through but some of low tide could also be those results look good could potentially be negative for the Nash space. Because there is also reached.

And updates using oral semaglutide not just subcu. So I guess what are your thoughts on those competitive updates.

Coming up in 2020, thank you.

Well thanks for the question well first of all you know I think Nash is a very complex.

Seized with.

Several different contributors to its etiology and and treatment and I think everyone is pretty pretty well grounded in the fact that thats, probably going to take more than one therapy that not all patients are going to respond to just a single magic bullet, we do agree oral semaglutide and the GLP ones looked like they have some some beneficial effect size.

Parameters that should translate into Nash.

Benefit, particularly weight loss I think as is one feature also the ability to help with glucose control and a population that has.

A large co morbidity with diabetes. So it's our view is that it's inevitable, but that that would be a need for multiple therapies.

Last year, we had made some presentations, where we've examined combinations of cell adult par with in this case, we use liraglutide, but I think mechanistically conceptually it showed that both agents.

Worked well together there were additive effects on weight loss on hepatic leprosy control on inflammation and particular solid Valspar really added an additional component of it of anti fibrotic activity at least in this mouse model that wasn't present with the GLP one analog Sun as you may know in the lean study that was this.

Similar profile less was seen in the mice.

So I think Thats said, that's a that's an inevitable world that sponsors that work in Nash live and Theres a lot of data Readouts Theres a lot of emerging therapies, there's a lot of interest and there's a theres a lot of need as well.

With respect to Ela fiber, nor I think that we understand folks are are naturally comparing and contrasting sell adele par, which is a potent and selective delta to Ela fibrin, our which has a mixed alpha delta, but there are some key differences.

In terms of the potency effects on the selectivity we point out.

We havent, we haven't conducted any head to head study. So of course, it's a challenge to be able to interpret but from what we've seen for example affects on Transaminases at 12 weeks and that Nash, we think sell Adele par looks favorable few look in PBC.

Call a static disease again effects on trans M&A. This for cell Adele part in the Delta mechanism.

Look to us to be something Thats, a feature that you'd like to have an aggregate lease.

And of course people react how they react in terms of halla fiber nor seats out if it's positive I'm sure I would I would say thats good for us if it's if it's not that I would just draw people to the clinical data and Fortunately, we will be it will be arriving at the end point around the same type.

Okay, great. Thank you very much.

Our next question comes from Joel Beatty with Citi. Please go ahead.

Hi, guys. This is Sean Egan, calling in for Joel Thanks for the update on for taking my question can you remind us what the clinical development pathway currently stands and PSC have discussions with the FDA established what type of endpoints could support or an official pathway or.

Components of your phase two data they are kind of hoping to get shaped that's question I have a follow up as well.

Yes sure. So thanks for the question, Sean we're having dialogue with the agency, particularly as part of really a consortium.

Where folks here at seem a day along with other sponsors regulatory agencies patient advocacy groups and thought leader as all participate in some discussions at the PSC Forum.

Much of that dialogue in the setting a PSC is focused around study design and endpoints in particular, given once again there is nothing approved for patients with PSC today.

I think the dialogue largely is focused around a recognition that in addition to benefits around call. It stay says.

There is there's a need for demonstrating an overall benefit on liver health and so.

Today, what we do now is that Gilliat is launching into a phase three study in which biopsy is required at this stage I will point out that biopsy is not typical for PSC patients similar to PVC, but nevertheless, there phase three study includes a biopsy assessment now in particular there.

Good on fibrosis, and biopsy is an endpoint around.

Not seeing progression of fibrosis as a poised as opposed to seeing improvement as you as you need to do in the setting of Nash. So I think that forms at least the agencies current view, but but as I mentioned, there's a significant amount of dialogue and recognition that biopsy is not normal for patients and and the.

10, Shelton developed surrogate endpoints in PSC is an active discussion that were involved with here internally as well.

Great I appreciate it maybe I'll just follow up on on your answer or any of the non diagnostics and Nash.

Any potential read through MPSV in that regard.

Yeah, I think when we when we think through some of the markers that that can be potentially correlated to overall lever house, yes, I think if you look at liver stiffness with fiber scan.

You look at some of the wet biomarkers of fibrosis bit al for proceeds three.

There's a there's some.

Data, that's that's been collected and other studies Sina, particularly the since using that study that gilliat conducted their locks locsin Ace inhibitor has generated as a fairly significant amount of data that's helping point towards some of these noninvasive markers as potential surrogate endpoints and that those those are the types of things.

Things that are in active discussion at the PSC Forum, which again involves the regulatory agency.

And the only thing I would other value added maybe in a bit of contrast, certainly matrix biology, there's some shared characteristics. Some shared cell types or is deposition of matrix in some of the activation pathways potentially could be the same and then you have of course, there's a there's a natural as part of the wound healing the scoring process.

Turnover, so those things hi, commonly from afar are all kind of treated well, they're the same right, but anatomically.

Station at least in the early stages of fibrosis.

PSC is a perry billiard fibrosis, it can evolve extra hepatic ducks as well as intrahepatic Ducks and it has a very particular type of.

No.

Pathology, you referred to as an opinion scan and that's really different than lobby LER inflammation and fibrosis. So.

Some things are the same some things are different and so why we might hope that the biochemical measures are.

Shared and so maybe they will be.

Something that predicts read through the outcome I think I would just say that it's a little bit.

It's a natural thing to do we will do it but I think time will tell as the whole field learns earns more about how these noninvasive tools are going to be used.

Yeah that makes sense I appreciate the color and one more if I could pricing in PBC I. Appreciate there a number of kind of moving lever is right now or you can you talk about any kind of market research you have to on and how your thoughts are kind of evolving there.

Sure. So I think as you correctly pointed out there are a whole host of moving pieces and we have in fact initiated some of the work here for us as we continue to progress so adult far through the clinic and so you mentioned that our prior call Jana Dorling joined us as Chief commercial officer, So theres a concerted effort on.

Turning now here internally inclusive of some folks we have in the field and medical affairs and gathering the kind of information and data that we need to better understand the overall patient population. The overall opportunity, yes, I'll highlight this for up from our perspective on the strength of the phase two data that we've generated today.

He has asked going into phase three and now nearing the completion of full enrollment and enhance our positioning for cell Adele par really is focused on rare and orphan disease. So when we think about the overall pharmacoeconomic benefit our mindset is thinking about sell Adele part in the context of rare and orphan disease.

As PVC fundamentally as.

And Thats effectively how we continue to progress in our understanding of what we think is a very significant opportunity for solid LR.

Frankly, even independent of how some of these moving pieces may play out from some of the market. If you will today there continues to be a very significant need for patients to have improved efficacy. There are still a significant number of patients that are effectively incomplete responders as Chuck was mentioning and of course.

Clinical symptoms of the disease are not yet ameliorated with any treatments that are available today for patients have a significant challenges patients have with pure write us with fatigue, and we think all of these things offer real opportunity for cell Adele part to be positioned in this fashion.

Thanks, so much appreciated.

Once again, if he would like to ask your question. Please press star one on your telephone keypad.

Next question comes from my Yank Montani with B. Riley. Please go ahead.

Thanks for taking my question and congrats on the progress, especially the embrace study enrollment.

Quickly on PSC. Most of my question. This follow ups BSC in the context of the give the on premise trial that you mentioned Suzhou.

I see did the 400 patient goal that they have is a pretty aggressive goal to have for within a given.

Given that a 96 week endpoint, they're looking at so fibrosis I'm. Just curious is just as you start dealer study are you experiencing.

Like diagnosis for these patients improving now that that treatment options.

Investigators have out there to until then trials.

Yeah, I think I. Thanks for the question Mayank look I think a couple of important things for me to point out.

The strength of the data to date in PBC is something that's generated a significant amount of enthusiasm for investigating sell Adele par in this setting of PSC. So that is clearly to our advantage again going beyond the anti call a static effects, we've seen to date and PBC patients, but but really the antisense.

Commentary benefits were seeing as well across other populations have generated a significant amount of enthusiasm not to mention again.

The effects, we see on clinical symptoms in those settings. So we have that as a wind at our back if you will.

What we've decided to do clearly here is a very robust dose ranging in PSC as we typically have done in all of our proof of concepts studies being PBC or in this setting of Nash. So thats important one we thought about this this specific study design. We also recognize that it was important for us to collect a host of secondary measures.

That would give us some greater insight into the potential to advance seller to help our into phase three as the dialogue at the agency continues to progress away from biopsy that clear difference between our phase two study in Gilead has phase three study other than the patient size. As you mentioned is their study require.

As biopsy.

And I think if you talk to those in the field.

Clearly see that that is.

Fairly significant hurdle in terms of enrollment in this setting of PSC. So we have an advantage I believe in terms of being able to get this study up and running and enrolled as quickly as possible. So that we have an opportunity to better understand.

The potential benefit settled out par band that provide.

Great and on Nash.

Are there any markers of insulin sensitivity that have been looked at in this incremental PD analysis.

Yeah, no they certainly will be but.

Typically the types of things that we would look at our fasting plasma glucose and fasting insulin so but there were no.

Yes of course, Hey, when see will also be available to us, but theres not been any specific.

Procedure measures like clamps or anything like that that were part with that were part of this study.

Okay, Great and then lastly on DTC and Susan just thinking about the 2020 spend.

Any incremental trial you would expect obviously you have seen very promising data on the.

Compensated cirrhosis patients there was a discussion on combinations anything from an R&D standpoint for granted Wendy and also obviously now that.

Enhances progressing ahead of plan.

Hey to designation.

Launch could be potentially bush, Doug. We're also seeing anything on any color on that would be great.

Yeah, Let me maybe start with the latter question.

Well again, we couldn't be more excited about having hit these key achievements with enhance earlier than originally projected we continue to be on pace to have data in early 2021, and as you correctly pointed out in particular with a breakthrough therapy designation of course, we have an opportunity to have a rolling and da submit.

And the opportunity to submit various parts of the NDA, even ahead of the clinical piece.

So at the our focus clearly my guess is to progress as quickly as possible.

But it is a little bit premature for me to talk specifically about changes to overall filing deadlines and eventually ultimately the approval process and launch.

But it is without question our number one focus here here in internally.

No I think.

Remind me what the first part of your question was just lifecycle planning for sorry beyond enhance for us and identified for let's say strategy.

Yes, no. It's another good question I think as Chuck mentioned Theres, a fair bit of dialogue, we're having here internally thinking about beyond enhance around the overall positioning for cell Adele par. These these.

Considerations include.

Potential head to head or switch studies, they are not yet baked into our guidance with respect to the operating plan in the burn so.

The carryover in terms of cash taking us into 2021 are really outlined by the activities that we've currently specifically.

In committed to and that's largely.

Just a focus our risk of ours internally to get to the finish line in PBC, but also to make sure that we have proper thought around those additional studies that would best physician sell Adele par so that sense that will be an ongoing ups area as an update for us to provide you as well.

Great. Thanks for taking my questions.

Next question comes from Ed Arce with H.C. Wainwright. Please go ahead.

Hi, Thanks for taking my questions.

Most at this point I've been asked did have a couple of more.

Just more granular.

First on enhance.

Congratulations by the way on.

The enrollment.

So target is to 40.

Which you've reached and you're going to continue through the end of the month.

I'm just wondering is.

Is there if you could remind us what the powering assumption is for the study and since Youre.

Slightly ahead of.

Casual or is this just a question of.

Having the time too.

Strengthen the the powering a bit more with extra patients.

Thanks for the question Ed No I think in terms of the execution of the study as you know you have a host of patients in the screening window, even as you read your target enrollment.

And you want to make sure that you stop screening at a specific time, after which you're going to at least get tier 240 not under it.

Ed So did the idea around the fact that were there are still some patients that were in the screening window at the time, we stop screening is what will ultimately contribute to slightly over 240 patients into the study overall so screening has been stopped as soon as we knew we would hit the 240 and it's not atypical to still have paid.

Since then or in that screening window that ultimately qualify and that you would add on to put into the study thats.

Typically a comfort level that somewhere around 5% to 10% beyond your target. So thats, what we imagine will likely happen with those final patients in that are still in the screening that we're still on the screening window when when we stop the study right.

Right Okay.

Understood. Thanks for the clarification.

And then maybe just one.

Follow up on a Youre PBC study this is.

Been asked a couple times in various.

Different ways, but I wanted to get back to.

You know the regulatory pathway here.

Honestly this is still something over to be as you mentioned the PSC Forum.

And you had mentioned.

Two particular areas.

Of interest.

Sure benefit Cola stages, as well as overall labor health and function and I'm wondering how discussions are evolving in terms of.

Which are.

Like we.

Markers, where a LP might fit into that.

And any sort of commentary there would be helpful.

Yeah, well, maybe this is Chuck high add how're you doing that maybe I'll just I'll try to render reiterate some of the high points that I think that.

So Joe mentioned first of all I think the agency is really.

Dividing PBC into two sub populations at similar to what they've done and other liver diseases in particular Nash, both one being non cirrhotic and the other being cirrhotic. They view the the severity of the disease and the risk for the patients and the features of the disease that need to.

He addressed as being kind of different in those two categories.

Our first study is in non cirrhotic PSC and there I think you have potentially a different set of.

Measures are markers that disease progression, one could one could think about.

We're limited in the sense that ours are study is only going to be 24 weeks, but just in general for non cirrhotic.

See you can imagine the features of Cola space as the ones that we've already mentioned people think about.

Foster a number of others GGP I think is one that's particularly interesting trance M&A cases bilirubin, it's obviously something that you monitor as well and then a variety of the noninvasive markers. Then I think that you have issue of liver stiffness. So this is a disease with.

Progressive fiber inflammatory processes.

Beginning in the in that and the variability or a spaces and then potentially spreading this the disease worsened and so some measure of being able to use that as.

Say some way too.

[noise] assess clinically sickness suspected cirrhosis could be another measure I think the agency for non cirrhotic, maybe open to thinking about.

Progression to cirrhosis as being one one kind of of endpoint.

At least that some of it some of the discussions so anything that could could reflect on that.

In terms of measures of progression to that would be something that could be part of a consideration and a longer larger larger study in that and that population.

Okay, great. Thanks for the comments I appreciate it.

Thank you at thank you I would now like to turn the floor over to Sue Hall for closing remarks.

Thank you operator.

I'd like to close by once again thinking those that make our work possible. We're grateful for their commitment of our patients their families caregivers and their staff and all of those we partner with to accomplish our goal is advancing care for patients with serious liver diseases.

As active as of the year as it's been thus far in 2019, we expect an even busier year ahead, we look forward to seeing many of you in Boston later this week at the liver meeting and thank you once again for joining us today.

This concludes today's conference you may disconnect your lines at this time and thank you for your participation.

Good bye.