Q3 2022 Cymabay Therapeutics Inc Earnings Call
[music].
Good day, ladies and gentlemen, and welcome to see my base third quarter 2022 financial results and business update conference call. At this time, all participants are in 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 Sema Bay website at Www Dot Sema Bay Dot Com I would now like to turn the conference over to Mr. Paul Quinlan General Counsel of Sema Bay. Mr. Quinlan you May proceed.
Thank you operator, and good afternoon, everyone I hope that you've had a chance to review the press release, we issued announcing our third quarter 2022 financial results and business updates.
You can access that release on our website under the investors tab.
Joining me on the call today are Soochow Shah Chief Executive Officer.
Truck Mcwherter, Chief Scientific officer, and President of R&D.
Dennis Kim Chief Medical Officer Lewis Stuart.
<unk> commercial officer.
And Dan <unk> VP finance.
Following our prepared remarks, we will open the call for Q&A.
Before we begin I'd like to remind everyone that statements made during this conference call, including the Q&A session relating to <unk> expected future performance business prospects events or plans, including clinical plans regulatory approvals funding and repayment schedules anticipated timeline.
And data release dates cash runway and planning for commercialization are forward looking statements as defined under the private Securities Litigation Reform Act of 1095.
Although the company believes that the expectations reflected in such forward looking statements are based on reasonable assumptions actual outcomes and results are subject to risks and uncertainties and could differ materially from those forecast due to the impact of many factors.
The company assumes no obligation to update or supplement any forward looking statements, whether as a result of new information future events or otherwise, except as required by applicable law.
Participants are directed to the cautionary statements set forth in today's press release as well as the risk factors set forth in Sema days 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 has seen a day and any recording or rebroadcast is expressly prohibited without the written consent of <unk>.
At this time I'd like to turn the call over to Suzhou.
Thank you Paul.
Good afternoon, and thank you for joining us today.
Although our prepared remarks today will be brief.
We made significant progress during the third quarter towards our goal of bringing cell Adele par to patients with PBC.
We will cover our three key business updates and provide a summary of our third quarter financials before taking questions.
In the third quarter, we reported completing enrollment in response.
Our global Phase III registration study evaluating sell adult par in PBC patients, who have had an inadequate response to or are intolerant to first line treatment with MRSA Deoxycholic asset.
Today, Dennis will provide updates on our progress and plans for the sell down of our development program. The complete response and announce top line data in the third quarter of 2023.
In September we shared with investors our view of transforming the future expectation of treating patients with PBC.
Dr. Chris Cowardly, a prominent herpetologist discussed unmet needs in the management of PVC.
Our team then describe Philadelphia, <unk> clinical profile and its potential to provide a preferred option in second line treatment.
Including in key segments of the PBC patient population that are either under treated or not treated at all.
Lewis will provide a summary of his teams pre commercial work that we shared during this event in September .
Last week, we had the opportunity to share additional analyses and results from our prior clinical studies of sell at Alpha in PBC at the American Association of the study of liver diseases annual liver meeting in Washington D C.
This was the seventh liver meeting at which we've shared results for celadon par.
This important Congress provided us vital feedback on our program and allowed us the opportunity to meet with patient advocacy groups and thought leaders.
Dennis will return to share an overview of our presentation and activities held at this year's liver meeting.
To close out our call today, Dan will provide a short summary of quarterly financials.
Let me first turn the call over to our Chief Medical Officer, Dr. Dennis Kim.
Thanks, Joe.
Today I'll provide an update on the progress we have made as well as our plans going forward in our clinical development program across all of Bell part in PBC.
As we discussed during our last call we have fully enrolled our pivotal phase III PBC clinical study response.
With 193 patient volunteers and once again, we would like to extend our gratitude to our patients and clinical trial part partners and accomplishing this important milestone.
The response study is progressing as planned and continues to receive clear signals to proceed without any changes from the data safety monitoring board meetings.
That have taken place since the start of the study.
We continue to project being able to have top line data readout from the response study.
Q3 of next year and thereafter plan on submitting a high quality NDA to the FDA as quickly as possible.
In the Meanwhile, we are continuing to wrap up clinical pharmacology studies to fulfill the fda's requirement for a complete NDA.
We also continue to evaluate and follow up patients and assure our restarted long term safety study in which qualified patients who participated in one of our prior studies such as enhanced can rollover and receive open label, So they'll park daily.
We continue to gain important clinical experience through this study and will amassed valuable efficacy and safety data and a large number of PBC patients exposed to sell about par for months and years.
As of last month, we had more than 180, PBC patients and assure actively taking dailies have about par.
Our duration of exposures include more than 150 patients for at least one year and more than 65 patients for two years.
We believe that collecting this degree of long term safety and efficacy follow up is a significant differentiating feature of our program.
It is intended to substantiate sell about pars long term efficacy for biochemical response and pruritus. In addition to creating a large safety dataset.
The sell off our clinical program is expected to yield one of the most robust datasets for drug candidate in development for PBC.
We plan to have topline results from response in Q3 of next year, and then to compile and submit the NDA to the FDA as quickly as possible.
I'll now hand, the call over to our Chief Commercial Officer Lewis Stuart.
To share highlights from our Investor day held back in September .
Thank you Dennis during a recent PBC analyst day, I assured summary findings from Marcello Dalbar global market assessment, mostly focused on our U S based research, including recent insights on the PDC patient journey.
Findings reflect on the patient's emotions and active engagement from the onset of symptoms to diagnosis treatment and disease progression. As you know it is these insights from patients and their care partners that are foundational to the development of our Silverdale par launch plans.
We were so inspired by these patients their positive attitude optimism and motivation to improve their current liver health their desire to see improvements in their quality of life as well as how they leaned into their support systems.
This is a highly engaged patient population that constantly seeks new information.
Our active participants within the PBC community.
We learned that it may take up to two years for PBC patients to obtain a formal diagnosis with treatment initiated quickly followed by continuous management and monitoring their overall liver health.
Consistently heard patients share, how debilitating symptoms, where despite being on treatment.
Many patients expressed how itching and fatigue dominated their lives yet it is often neglect it are not adequately addressed by their health care provider.
In addition to these research efforts, we recently held a patient advocacy forum at the liver meeting attended by leaders of PBC advocacy groups from around the globe.
Their commentary and insights validated what we had learned in our market research during this forum and other liver meeting sessions pace.
Patients describe their itching.
Bugs crawling under their skin. Another verbatim heard was it's really limitless, it's like a life sentence of just being uncomfortable.
And thats scratching barely relieves their itch, sometimes leading to breaks and theyre scan and scarring. These.
These advocates shared their own research on how physicians perceptions of their pruritus are often underestimated versus patient reported severity. Most notable was the challenge to their providers to look beyond the numbers, referring to biochemical marker.
<unk>, so just a L P and bilirubin and focus on how their patients are feeling clearly there is an unmet need for more effective disease management, a PVC related pruritus.
As a reminder, approximately 60% of PBC patients experience pruritus, which has significant downstream effects on the patient's quality of life and ability to stay treatment compliance as one PBC patient advocate put it it's not just that I want to live longer.
But I also want to live well.
At the PBC Analyst day, I also share a summary of the patient segments, where sell it up or could experience rep to experience rapid adoption.
Which includes 14 to 16000 patients who are either incomplete responders to U D. C. A R have discontinued second line treatment of a better call it gas it.
Some of that benefit in addressing PTC related pruritus significantly expands its clinical utility to another 18 to 20000 patients. Moreover, seller that parse data set demonstrating normalization of key liver measures in both cirrhotic and non cirrhotic.
Support its reach to an even broader patient population with unmet need.
Clearly, we have a unique opportunity to elevate the goals for PBC treatment effectively addressing not only the patients overall liver health, but equally important the quality of their daily lives.
Sima Bay, we want to build a high touch commercial model that is designed to support patients and their caregivers as they navigate the health care ecosystem.
We believe our execution should focus on three pillars.
Medical education on seller, Dell parse unique product profile, optimizing patient access and services and last but not least active patient advocacy and engagement.
These themes will be IRA guidepost for supporting PBC patients providers and other key stakeholders.
I'll hand, the call back to Dennis to discuss our recent activities and presentations at the liver meeting in D. C last week Dennis.
Thank you Louis.
As usual mentioned last week, we had the opportunity to make two presentations of new analysis of clinical results for sell about par.
The first was a poster presented by Dr. Chris bullish the chief of the division of Gastroenterology, and Hepatology, yet UC Davis rips.
We're reporting on a post hoc pooled analysis of lipids from from this held up our open label Phase II and phase III enhance study using T V C.
This lipid EMEA is a common feature in PVC and so we are interested in understanding how lipids were affected by selling a part treatment in PBC patients.
Change isn't lipids were analyzed for 70 373 patients with PBC, receiving daily oral treatment with placebo five milligram or 10 milligrams upsell ballpark at one three and six months.
At baseline most patients had dyslipidemia for.
For example, average total cholesterol levels was elevated at 238 milligrams per deciliter with 77% of patients being above normal levels.
Similarly, the average LDL cholesterol level was high at 138 milligrams per deciliter with 54% of patients having levels above normal.
At month six the main change in total cholesterol from baseline and the placebo in the 'twenty three placebo patients was minus four milligrams per deciliter compared to minus 20 milligrams per deciliter for 70 patients taking <unk> 10 milligrams.
So a corresponding change in LDL cholesterol for placebo patients was an increase of <unk> five milligrams per deciliter, whereas the sell down of our 10 milligram patients value decreased by 18 milligrams per deciliter.
These changes changes were significant personnel ballpark 10 milligrams versus placebo.
Interestingly these effects were similar for patient groups on background lipid therapy to those without.
We expect to continue to collect additional data on lipids in our ongoing studies to support understanding what these changes could mean for patients.
A second clinical presentation was made by the <unk> research team describing an analysis of the sand metabolism of 160 patients completing three months of treatment and the enhance study.
This analysis found broad dose dependent changes changes in the unbiased survey of 1400 74 metabolites.
The percentage of measured metabolites with significant changes below the point P. M P value of less than zero five levels were six 6% on placebo.
21% on solid op at five milligrams and 39% on sell up our 10 milligrams.
So that part was found to increase serum markers of mitochondrial and practice all mall fatty acid beta oxidation indicated by increase in kind of team in April kind of teens and decreases in diatribe oxalates and significant reductions.
Reduced serum levels of inflammatory lipid mediators, including long chain fatty acids motto, and ISO glycerol <unk> surmise in single Islands.
Measured in our target PBC population. These results provide clinical evidence of <unk> impact on mitochondrial function as well as reductions in the serum of NN.
Known inflammatory mediators.
These insights have the potential to suggest future approaches to elucidate the underlying reasons for effects of sub par on cholestasis liver injury and inflammation.
I'd like to now turn the call over to Dan metals VP of finance.
For a review of our financials in the second quarter.
Yes.
Thank you Dennis.
There's others on the team have highlighted during the third quarter, we directed our resources towards executing the patient treatment phase of the fully enrolled response study and continuing enrollment of the first study.
We also work to closeout and summarize the results of certain required clinical pharmacology studies and we continue to advance other required clinical and regulatory activities necessary to complete our late stage development of cell Adele part in PVC.
Finally, we made progress in manufacturing development as well as in medical Affairs, and commercial where we continued to plan and prepare for a potential future launch of cell Adele part in PBC.
Turning to a brief review of our third quarter financial position and operating results, our cash cash equivalents and investments totaled $153 4 million as of September 32022.
We believe this cash on hand is sufficient to fund our current operating plan through 2023.
Our net loss for the quarters ended September 32022, and 2021 was $24 $5 million and $22 $7 million or 28, and 33 cents per share respectively.
Net loss was higher in the quarter ended September 32022, compared to the corresponding period in 2021, largely due to an increase in interest expense accretion related to the Abbvie worth development financing agreement.
This increase was partially offset by a decline in research and development expenses, which moderated following the completion of the enrollment phase of the response trial in July 2022.
Net loss for the nine months ended September 32022, and 2021 was $79 4 million and $63 5 million or <unk> 90, and 92 per share respectively.
Net loss was higher in the nine months ended September 32022, compared to the corresponding period in 2021, largely due to an increase in interest expense and to a lesser extent an increase in research and development and other operating expenses associated with the ongoing late stage development of cell Adele part in PBC.
Moving forward, we expect our operating expenses to increase in the future as we continue to execute on our clinical development manufacturing and commercial readiness plans for PBC.
I now hand, the call back to <unk>.
Thank you Dan.
It's been another exciting quarter for us here at team a day as our teams focus on the day to day execution of our clinical programs manufacturing campaigns and regulatory and commercial preparations.
We have been fortunate to add experienced talent across functions and are well positioned for transformational catalysts expected over the next 12 months.
In his expanded role as Chief Scientific Officer, and now President of research and development Dr. Chuck Mcwherter will lead our development function, where his depth of experience and knowledge in PVC and the leverage across the organization.
I have tremendous confidence in our entire leadership team and then all of those in the company, whose daily contributions are vital to our success in delivering improved treatment alternatives for people with PBC.
As we turned the calendar into 2023 in the coming weeks.
We will be focused on a broad range of priorities centered around key objectives, culminating in releasing top line data from response.
In the third quarter of 2023.
And filing for regulatory submissions as quickly as possible thereafter.
We look forward to providing you with updates at future meetings and calls.
We're now happy to take questions.
Sure.
Thank you we will now begin the question and answer session to join the question queue. You May Press Star then one on your telephone keypad, you'll hear a tone acknowledging your request if youre using a speakerphone. Please pick up your handset before pressing any keys to withdraw your question. Please press Star then two we will pause for a.
A moment of callers join the queue.
Yeah.
Our first question comes from Yasmin Rahimi of Piper Sandler. Please go ahead.
Hi, Thank you for taking my question. This is Lauren on for yes, just a couple of questions. The first one where do you guys stand currently in terms of the patents without without part and parcel of lifecycle management.
And then with that what are the post marketing requirements are based on your FDA interaction.
Yeah sure. Thank you for that question. So we actually have issued composition of matter patents on Philadelphia are one that goes to 2025 and another on the lysine salt form which is the only form and does element that goes to 2026. Neither of those terms actually includes the potential for five year.
Patent term extension for time in development. We're also a broad range of method of use patents that cover or sell it out bar in PBC as well as in other liver disorders specific to PVC. Once again those method of use patents go to 2035.
Our plan ultimately is to continue to develop.
That protect obviously sell at <unk> as we think about our path forward you asked a little bit about lifecycle management and that's certainly part of that process and we will speak more about that in the months and years ahead.
As part of lifecycle management. We also believe there are some significant opportunities for us to continue as Louis talked about exploring Philadelphia for broader patient population. Once again, we've done a fair bit of this work internally as well as with consultation from thought leaders and patient advocacy groups.
Highlighting those unmet needs that continue to exist.
In underserved populations are patients that are not really treated with adequate treatments. Today. So we think there are certainly some lifecycle management opportunities that we will continue to commit to in order to ultimately achieve the objectives, we have a putting philadelphia or in the hands of as many PBC patients that we believe may benefit.
Some of this we've talked about in terms of those patients that could benefit from full normalization of biochemical markers of disease progression and inflammation as well as relieving a greater array of the clinical symptoms that patients experience every day in order to improve quality of life.
In terms of the last part of your question around post marketing I think all.
Here know that in the setting of PBC.
We expect that the accelerated approval pathway is in fact in the best interest of patients and certainly will remain available to sell adult bar as it has been for other agents in PBC that would of course put us in a position I've really committing to better understanding the long term outcome benefit.
I'll bet treatment life cell Adele par should should we be successful at gaining registration and being on the market.
Thank you for those answers and just a follow up from what you lost that what is the company doing in terms of commercial preparedness, tiring salesforce et cetera, getting those activities at or where do you guys stand right now.
Sure. Louis do you want I can take that overview on that.
Absolutely. So I think certainly our focus as we looked at 2023 will be more focused on pre commercial activities, where it will be getting a R. M. S sales in the field to begin engaging Kols will also of course began to think about how our engagement with payers as part of that pre commercial strategy.
<unk> the Salesforce will come a bit later, we would typically time the salesforce. After we've of course file the NDA, but I think our field exposure with Kols will be an important priority in 2023.
Thanks, so much for taking the questions.
Our next question comes from Stephen seat House of Raymond James. Please go ahead.
Okay.
Hey, great. Good afternoon. Thank you I just wanted to ask about the.
Lipid analysis data presented at <unk> and specifically.
So even something as simple as statin.
There is there could be contra indications with active liver disease that there could be liver function test elevations trades overnight.
So I'm curious in these patients with PBC that have dyslipidemia or elevated cholesterol is theres. Some hesitancy among herpetologist to sort of use just commonly prescribed dyslipidemia medicines and as this.
A place where Philadelphia or you could sort of carve out.
Yeah.
Niche that addresses some some prevailing hesitancy.
Okay.
Yes, Steve This is Chuck Mcwherter I'll take that question.
It's a good observation there has been in the past quite a bit of that and see around.
Using statin, particularly for for muscle effects, but also for transaminase elevations.
Over time that hesitancy has.
Abated somewhat so for example in our studies with hundreds of patients have been screened.
We find a roughly 20% to 25% of patients.
We're using statin so although they are often not controlled.
For their LDL cholesterol and total cholesterol levels.
So I'm not sure that I would view it as a replacement for stack it may be.
As an additional feature of the drug that should be considered.
And our population these are typically middle age patients.
We have a number of risk factors cardiovascular risk factors.
About 30% of them are overweight or obese.
Many of them are taking anti hypertensive medicines.
As I mentioned about 20% to 25%.
Our our lipid lowering therapy, so I think.
From our perspective, it's a drug that addresses.
These activities B B C.
Improved symptoms, but also may have a benefit on lip or lipids for.
Cardiovascular risk for patients for AG and that can only be a benefit.
But as we mentioned in our remarks will continue to collect this data in.
In response and assure to build out the story.
And I apologize if I missed this but in response to that by the way, but in response do you have a sense of.
The proportion on these lipid lowering medicines in proportion with these risk factors is basically similar to the pooled analysis you did it.
And the completed studies.
Yeah, well at the end of the study is still still blinded and ongoing so we haven't dealt to those kind of.
Baseline characteristics quite yet.
Surprised to find that her any differences you know given that.
We've screened over 1000 patients in our program today as our PBC program.
So we have a very significant PBC patient experience.
But time will tell we'll report that out when we've done the analysis.
Thanks, so much.
Our next question comes from Christian <unk> of Cantor Fitzgerald. Please go ahead.
Hi, Good afternoon. Thanks for taking my question and congrats Jim Chuck on your promotion.
So there are some presentations on real world analyses from other therapies in PBC at the liver meeting wondering if you have any takeaways from the presentation that further underscore where a therapy like so adult buyer could best and whether this is from your own interpretation.
Based off some of the extensive feedback it sounds like you had with numerous engagements at the conference.
Yeah. Thank you. Thank you for that question Kristen we follow very closely the announcement you referred to in some of the presentation.
And publications on outcome studies in PBC, our own dialogue in fact with the F D. A N post marketing obligations.
It is included extensive discussion of external controlled studies and and these discussions we've had with regulators really have taken place over the last several years in fact, we.
We had had input also from many leading experts recently around this topic and based on this we believe that we understand both the opportunities as well as the challenges.
External control approaches.
And ultimately we remain engaged on the topic.
Nevertheless, we see that sell Adele par has breakthrough designations and the clinical profile, thus far on markers of progression.
Disease and onto your writers and if confirmed in response, we believe we will fulfill many of the unmet need for improved treatments for PVC across disease stages. So as I mentioned before we still believe the accelerated pathways available foreseeing a date specific to your question, though around real world data and real world evidence.
We continue in fact to investigate and we will continue into the future to investigate real world data from the use of Sabadell par one of the things I think that gives us. Some advantage here is as Chuck had mentioned the extent of the overall pace overall patient population and.
<unk>, both efficacy and safety database that we continue to collect in a shore.
Which will grow as patients from response continue to roll into that study over time that will give us our own.
Really I think closely evaluated datasets that we can continue to compare to real world evidence real world data that exist of course, as well and so I think it's really important given some of the challenges to long term outcome studies in a setting like PVC.
For many patients are relatively slowly progressing disease.
So our commitment remains to continue that work that others have had traded as well around exploring some of these extensive control datasets.
In comparison to potential real world data, we can collect for sell in to help our again through assure and through our clinical experience.
Thank you.
Our next question comes from Patrick Toso of lifestyle capital. Please go ahead.
Hi, Thanks for taking the question.
Earlier this year, we saw transaction for ex U S rights to Butte acrylic acid could you just remind us of your plans in regards to commercialization ex U S.
Are there any unique perspective towards marketing in the U S versus abroad, whether it would be kind of a different treatment paradigm patient access et cetera.
<unk>.
Yeah, Great Great question, Patrick I'll start it out and perhaps Louis or others can provide any additional color that I may Miss you know first of all in terms of our strategy I think as we continue to articulate our goal is to get Philadelphia or in the hands of patients globally that we think can benefit certain.
Really the response clinical phase III registration study is one that is a global study.
We believe based on our dialog. It's a study that would allow us to have an opportunity to register Philadelphia or in the U S as well as the U K and Europe .
When we think about other geographies, where additional clinical work would be required for example, Japan and China those are settings in which we our goal is to try to partner as soon as possible. So some of that work in fact, Ken can continue in parallel with our ongoing clinical activities.
As it pertains I think to geographies such as the U K and Europe , just as examples again, given we believe our studies would allow us to registered in those geographies. We certainly have the wherewithal to complete our development program in parallel to having discussions with third parties that that yeah, we may determine.
Might give us both the economics and the ability to really get filadelfo into a broader set of patients.
More quickly and more efficiently. So I think I would simply tell you Stephen that we're open to that dialog is continued for geographies, particularly outside the U S. Our strategy fundamentally is to execute on a plan that allows us to launch a sell it out far at least in the U S on our own and potentially other geographies, but at least in the in the <unk>.
U S alone it is of course.
The majority of the overall commercial opportunity just based on various dynamics, including some of those that you alluded to.
Those opportunities are.
Other treatment alternatives for patients in the treatment paradigm fundamentally as well as other dynamics of course, including pricing.
There are some off label treatment in PBC that are used in even in guidelines outside the U S. Do you have some impact in terms of how other treatment alternatives could be used and how citadel park of deals, but I think even as we think about global settings outside the U S. We're incredibly encouraged.
By the datasets, we've generated to date and if response data that confirms the profile of Philadelphia that we've seen thus far we think even in those geographies that include more off label use for example of trunk like these at five right. There are some very unique characteristics that Philadelphia profile both on efficacy.
Biochemical markers of disease progression and clinical symptom burden as well as an overall safety.
They'll make it a potential compelling alternatives in those various geographies. So we're excited about those you talked a bit about the ex U S rights being purchased for a vertical like acid.
Philadelphia now as we've also talked about on these calls remains the only fully unencumbered late stage program in the setting of PBC today, and so to the degree that we think there could be alternatives to bring in a significant amounts of non dilutive capital and also again importantly have partners with experience.
On the ground that can accelerate that work outside the U S. We continue to have that dialogue and are excited about those potential opportunities.
Super helpful. Thanks Hugo.
Thank you Patrick.
Our next question comes from Ed Arce of H C Wainwright and co. Please go ahead.
Hi, <unk>.
Thanks for taking my questions and let me add my congrats to check a few questions for me firstly.
Just on timing assuming positive data from from response and given.
Given your breakthrough therapy designation would you be applying for priority review.
One.
And two on for sure I just wanted to confirm.
The purpose of this study beyond meeting the minimum number of patients for the the NDA safety database.
And then thirdly.
Quick question on the poster presentation last week on the lipid profile.
<unk> mentioned that.
The treatment effects were similar.
Whether or not patients were on.
<unk> lipid lowering therapy, and so I'm just wondering.
Perhaps Chuck could explain how this fits with the known mechanism of Pea part Delta for Citadel Park. Thanks, So much.
Yeah, absolutely thanks for the questions and I'll tick through one and two and then and then ask Chuck to chime in and number three.
Given as you mentioned, we have breakthrough therapy designation in the U S and Brian access in Europe , certainly again as it pertains to the U S. We will in fact.
Seek to have priority review.
Just to answer to your first question with respect to assure their there of course is the purpose that you described to ensure that we have an adequate.
<unk> database at the time of NDA filing and filings outside the U S. In fact as well.
We certainly as we've mentioned believes that that we will have in fact.
A significant number of patients for overall safety and and even longer term safety out to one in two years and beyond from a shore as well as obviously leading in from our prior clinical experience, perhaps perhaps in fact, the most robust safety dataset at.
At the time of a regulatory filing.
There are many other benefits obviously from a sure we continue to chip collect.
In addition to safety data efficacy data that we will have the opportunity to continue to mine as we think about.
No patient populations and use as we think more about the potential to address.
Things like longer term effects on liver stiffness.
But you know the various parameters that may give us greater insights into the potential longer term benefit.
And even potential outcome benefit I talked a little bit about the potential for sure also to give us just extensive real world data.
Post potential approval on marketing if we're successful in and that I think is another key benefit from from the assure steady overall, just a very rich experience in what is obviously a rare.
Rare disease. So so I think there are in fact many benefits.
Even beyond just having a minimum number of patients for safety.
And then finally I'll, let Chuck talk a little bit more about that.
Around the significance of the lipid data in patients that either had been on prior statin lipid lowering treatments versus those that did not.
Yeah. Thank you for the question Ed and thank you for your.
Uh Huh comments.
So the mechanisms are really quite distinct.
Those patents.
Inhibits synthesis of cholesterol true inhibition of <unk>.
<unk> reductase.
We had previously studied sell it at par in Hyperlipidemia.
Just draw your attention there's two papers.
Was published in the journal of clinical Endocrinology and metabolism.
In 2011 and another in atherosclerosis.
In 2012, where the mechanism was shown to be quite distinct.
From a statin it really inhibits synthesis.
Reduction of library protein particles LDL, So April 100.
Was it inhibited secretion to VLDL.
Which is the precursor of LDL.
Also inhibited that was shown in those studies.
And in particular in addition in patients with PBC.
We showed that cholesterol itself dietary absorption.
Was it inhibited by sell it apart.
As well as cholesterol synthesis in the mechanism.
Different and doesn't involve H H.
<unk>.
Kuwait dark days.
So I think it's a unique and complementary.
Mechanism.
For solid El Pas reflect.
In clinical studies two different populations.
And that probably explains some of the observations that we had.
Where we saw decreases both with and without the tariffs.
Great that's helpful.
<unk>.
One follow up if I may just wondering about the.
Manufacturing and supply chain function.
The activities that you mentioned are continue to.
Progress wondering if there's anything there that could pose a potential gating factor to the NDA submission.
Yeah. Thanks, Thanks for highlighting that and you know, we pay particular attention to ensuring.
Quality in the work that we do with respect to manufacturing and a real focus on ultimate supply chain.
We've done some of the validation work on drug substance that work will continue on drug product, we don't see anything as of now frankly.
In terms of anything that would be gating to the timelines that we expect should we be successful in response and successful in being able to register or quickly thereafter.
Thanks, so much.
Okay.
Our next question comes from Mike Mom Danny of B Riley. Please go ahead.
Good afternoon, and thanks for taking our questions and then you add Michael that's too Chuck and expand the goal. So just a few follow ups for me.
Could you talk to the person data response patients taken biopsy in it and would you look to disclose baseline characteristics and pool.
You know prior to a third quarter data disclosure at some point next year what.
Should we be expecting that.
Yes.
Yeah. So I'll start off we have not disclosed any specifics around the base line characteristics, including the percentage of those that have agreed to and volunteered to have baseline biopsies, we certainly.
Feel confident that we have a subset of patients that have agreed to baseline biopsy that we again hope to.
A 52 week biopsy year round in order for us to gain additional insights and meet the regulators' requirements. So we don't see that fundamentally today as any sort of risk based on those that agreed in baseline we've not traditionally <unk> disclosed overall baseline characteristics until we release top line data.
That would that would be our plan here is well I think in order for our investors and others to gain some confidence given how much clinical experience we have in PVC, both in our phase II as well as our phase III clinical programs and as Chuck had mentioned you know we've had over 1000 patients screened in our.
Clinical trials to date I think if you go back to the baselines in the populations in phase two and phase III, what we're enrolling in response.
As largely an identical patient population to what are we involved in enhanced based on inclusion and exclusion criteria and so I think there should be some some comfort around those characteristics looking looking similar to what we had before and then we will release those details at the time, we shared top line.
Data.
Got it. Thank you and could you also talk to the status of the hepatic impairment study and also.
Sure.
If the outcome you know whatever until you're able to glean there would.
Would you be able to compare that against.
It just makes dollar his daughter goes controls as you know some of those are not letting you moved through it by the Globe Company I mean, you are there.
And also do some of those analysis around the extent of the historical control and so I'm. Just curious if you are long term studies can do as you know a similar kind of analysis real world evidence based.
Sure.
Yeah sure. Good question. So we continue to execute on the hepatic impairment study in PBC patients I think as you know study.
Study, that's important for us to understand the exposure as well as a safety and efficacy in patients that are cirrhotic, both compensated cirrhotic as well as those with some decompensation a very difficult study to enroll given how few patients.
Among the broader PBC populations are in those categories, but something that we continue to be committed to and in order to ensure that we've got a good sense of.
Philadelphia is again efficacy as well as.
<unk> safety and exposure in that patient population that that work continues.
And we don't see it again as being gating to our other activities as we think about our overall timelines with respect to assure absolutely you know look I think one of the benefits I described earlier in the Q&A session around.
Collecting AR.
Broad set of longitudinal data in that study and four as we mentioned now north of 180 patients.
Is that are in assure you just gives us that opportunity to compare to some of the external controls. We've in fact worked very closely with.
With groups that have collected these datasets that continue to collect these datasets I think it's one of those alternatives.
Among other alternatives from with respect to regulatory options that we believe could be available to us and we.
They have to be committed to regulatory requirements to demonstrate outcomes based on outcome studies, but certainly in parallel to that having the opportunity to understand the datasets out of assure them and how they compared to external control will also be important for us to generate in parallel and I think again.
It gives us an advantage given how many patients are in a short today and how many leads we continue to expect to come into that study.
Uh huh.
Got it. Thank you so as you lindon on the phase III PBC study that we're running slightly ahead of you are you looking to bring that he has the information from the <unk> study designs are identical and it would be helpful. If you can confirm that inside of that.
Semi designs out of actually identical between them.
The big programs.
Yeah, sure and just to be clear are you referring to the phase III study for LSA burn or you know a couple of things I'll first mentioned about response you know response is really as we describe it.
A study that we designed based on our experience and enhance our prior phase III what had intended to be prior phase III Global registration study.
What we learned from our prior phase II experience and enhance really.
The driver around the design for response and in many cases I describe it as a rinse and repeat if you will of the enhance study. So what we've done in response is design a study with the <unk>.
Really the same patient population, we studied and enhance the same optimal 10 milligram dose of Philadelphia as well as the same primary and two key secondary endpoints that we evaluated in enhance so to the degree that the phase III study for <unk> Super nor is it similar to response I think it's similar.
To even what we had done an enhanced when you look at the overall endpoints and the patient population that we're studying of course, we are in our experience also leverage the work that had been done with a vertical like acid in their phase III study.
Thats published so I think if you look across these various studies the phase III poise, a vertical like acid study, both our enhanced and response study as well as the phase III for alethia.
We're gonna see largely met.
Many similarities if if you will when you think about those study designs. So.
I think certainly we always learn from new datasets that are released and as you pointed out at least based on what those sponsors have indicated for those studies.
Data may come.
Shortly before our expected phase III topline data. So we'll of course learn things, but obviously responses really set forth based on the experience we've had to date in PVC, including in our prior enhance study.
Got it thanks for taking our questions.
Yes. Thank you.
Our next question comes from Jay Olson of Oppenheimer. Please go ahead.
Oh, Hey, congrats on the progress and thank you for taking the questions can you share any physician feedback on the posters presented at Ada U S. L D, especially with regards to how lipid benefits could differentiate Philadelphia from OCA in patients with PBC and I had one follow up if I could.
Yeah.
Yes, sure maybe I'll ask Dennis do you want to share some of what you learned from many of the.
Thought leader discussions, we had and it certainly I can I can add some additional color.
Sure.
Yeah, I think you know it.
As Chuck mentioned before the lipid lowering effects are solid that part is yet another differentiating feature of the drug.
And <unk>.
Because many patients with PBC have this dyslipidemia.
When they're diagnosed.
As a as it already has been discussed there's consternation about whether to treat and if to treat with what medication since there are.
Liver toxicity effects that one has to keep in mind. So in a in a position of a herpetologist who's now looking at a newly diagnosed patient or a patient who is being referred to that herpetologist, who may already be on UDC, a and have dyslipidemia.
We think it's an easy choice for settled up hard to be the next line of therapy, not only because of the the efficacy that we've demonstrated with celadon par, but also the the plethora of benefits that you can gain from that choice is the second therapy, not only with risk.
Spec to pruritus.
But also with improvement of lymphedema.
As opposed to perhaps another second line therapy that we already know can can worsen pruritus as well as cholesterol levels.
The contrast is fairly striking and I think it's so easy one to detect and thats, what the physicians are telling us.
Great. That's super helpful. Thank you for that and just to follow up on earlier question about the real world evidence for <unk> treatment of PBC patients that was presented at a S. L D.
Reduction in relative risk of death.
Liver transplant and <unk>.
Pat a key compensation, which I think intercept said would be submitted to support full FDA approval of OCA for PBC.
Do you expect that outcomes data to impact your strategy to pursue full approval citadel parts for PBC.
Yeah Jay.
I'll start off and say this I think certainly as we see intercept strategy and particularly regulators respond.
Their strategy I think there certainly could be an impact that will pay very close attention to.
We think in fact that the impact could be favorable depending on how they choose to.
To determine medical agassiz effects in those real world evidence studies that had been conducted at least to date. We would also say this however that we fundamentally believe.
That committing to demonstrating outcomes is very important for the population of PBC patients as well as obviously for regulators who are acting on behalf of patients and at least to date conducting and collecting real world data and real world evidence in parallel to that.
We think is likely to be the path forward. There. There are certainly we know opportunities and benefits from collecting this real world evidence, but there are of course, some challenges as they relate to things like biases.
<unk> data sets.
Thank God missing follow ups I think theres. Some some challenges that continue to be worked out.
We know that regulators recognize in rare disease settings that these are things that must be evaluated and we certainly are committing ourselves and evaluating both of these pads ultimately in parallel.
Not all that surprised that some of the data that came out of the work with the vertical like asset on real world data and real World evidence I think it certainly <unk>.
Parallels or confirms if you will some of the datasets that had been generated for example by the global PBC study group that are originally looked at alpine phosphatase reductions in bilirubin normalization as surrogate endpoints.
What might lead to improved outcomes and so it.
Again, I think there's a lot of strong rationale around our opportunity to continue following both of these potential paths.
That's helpful. Thanks for taking the questions and congrats to Chuck.
Our next question comes from Tom Smith of S. V. B Securities. Please go ahead.
Hi, everyone. This is Mike on for Tom Thanks for taking my question and again you know they can.
Congrats to Chuck.
There's been some recent commentary from competitors highlighting the importance of changes in bilirubin as the most predict development leading to longer term and improved outcomes for PBC patients.
But if there's something like al <unk> and just curious if you tend to think of one being more important than the other between bilirubin and now fast this as they relate to longer term outcomes in PBC.
Maybe I can try to answer that for you.
So it really depends upon disease stage. So if you look at both alkaline phosphatase.
And bilirubin in their predictions for outcomes.
In early stage disease alkaline phosphatase shows up as.
Cholesteric Parker that projects you know the most the most comprehensive.
Difference in risk profile.
Ruben itself, it's true becomes an important predictor.
But it shows up generally when patients become duct a payment that is they've lost her bile ducts.
And then in the later stage you should get a very sharp price.
And increases in bilirubin, so in that sense.
Thank you could say both are correct both have some role.
Predicting risk and in different time courses or different aspects of the natural history.
There is another feature of bilirubin, that's emerged as a very interesting aspect predictor and that is <unk>.
Patients, who have bilirubin, which are in the normal range, but.
But in the upper end of the normal pace that is between six and one times upper limit of normal.
Those patients are at still at elevated risk production for crushing excuse me.
And it's believed that if you can bring patients down into the lower etch a lot.
Say below 0.6 with a normal how fast could you can essentially.
Stop progression of disease all together.
And so that's another aspect that we continue to monitor.
Philadelphia.
As others are looking at patients.
Strata.
Still higher risk between 0.6.
And one times upper limit of normal to see if we can decrease that.
And in fact in our two year data that was presented.
At the liver meeting too.
In 2021 we showed that about half of the patients.
Who had a bilirubin at baseline between <unk>, six and one times upper limit of normal.
Were put into the lower strata by two years.
So we think that's a different twist to make the question you asked.
Got it I really appreciate the color thanks for taking my questions.
Our next question comes from Sean Kim of Jones trading. Please go ahead.
Yeah, Hi, Thank you for taking my questions first a quick question, what's the split the powering.
Response trial.
And my second question is based on the pilots you all saw they'll par.
Or would you expect the response could dip in between month six seven months of 12 or was it more or less stabilized drink at a time period. Thank you.
Yeah, Sean. Thank you for the question I think when you look at overall powertrain.
Particularly I would guide folks towards the enhanced three months dataset.
That's available on our website.
In terms of presentations at medical meetings as well as in our corporate deck and you can see there with as few as 55 patients around 55 patients in placebo and around the same and the 10 milligram dose group.
We hit the primary composite response rate at three months with a P value of less than 0.0001. So.
I think when you look at 193 patients enrolled in response to the one that would help our 10 milligrams versus placebo. We are highly highly overpowered on the primary outcome measure the target, which had been 180 patients was really on powering with at least 80% power.
Sure.
H, but both the primary and then the key secondary on now composite tastes normalization.
Ah well over well over 90% powered.
Based on the total number of patients that we brought into the study and the expected treatment effects.
In terms of what we would expect between month six and month 12 here I would guide you towards looking at the percent reductions in alkaline phosphatase and our phase two experience north of a 100 patients out to a year.
And north of 50 patients out to two years of treatment.
Link between months six months 12, you really see a very consistent and leveling a percent reduction in alkaline phosphatase.
And so we would expect that to really be somewhat consistent between months six months 12. There there may be some increase I think typically you see a relatively small increases over time I think what was particularly interesting and some of that data as we continued to see an increase between year, one and year two for those patients that had been on track.
And then out to two years.
So encouraged by those data sets that we have again for patients out to about six months.
As well as 12 months and even out to two years.
Great. Thank you.
Yeah.
This concludes the question and answer session I would like to turn the conference back over to Shuja al for any closing remarks.
Thank you operator, and thank you all once again for joining us today.
The highlight of our time at <unk> last week in D. C included a meeting we had with patient advocacy groups supporting people with PBC from around the world.
Having the opportunity to speak to them and importantly to learn from them has always been a vital part of our process here has seen a day.
It's exciting for us to provide them with many of the updates we have shared with you all today and to continue partnering with them to make sure. We are focused over the coming year on executing with patients in mind.
We're a company with a singular focus but with many upcoming transformational catalysts ahead that we are excited to share with you throughout the coming year.
Thank you.
This concludes today's conference call you may disconnect. Your lines. Thank you for participating and have a pleasant day.
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