Q1 2022 Madrigal Pharmaceuticals Inc Earnings Call

Okay.

Good day, ladies and gentlemen, and welcome to the magical Pharmaceuticals first quarter 2022 conference call.

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Operator: As a reminder, this call may be... I would now like to..., today's conference call. Chairman and Chief Executive Officer of Madrigal.

As a reminder, this call maybe recorded I would now.

I'd like to introduce your host for today's conference Dr. Paul Friedman, Chairman and Chief Executive Officer, Matt.

Operator: Dr. Friedman, you may begin. Thank you. Good morning, and thanks to all of you for joining us on the call. Here's the fine print dealing with our forward-looking statements. Please see today's press release and our SEC filings for forward-looking statements and risk factor considerations associated with these statements and our business. With me on today's call are our Becky Tau, President of R&D and Chief Medical Officer, Remy Sikija, Chief Commercial Officer, and Alex Haworth, Chief Financial Officer.

Freedman you may begin.

Thank you good morning, and thanks to all of you for joining us on the call.

Operator: We also have Dr. Stephen Harrison joining us to provide his perspective on the Maestro program updates we're announcing today. This morning, we issued a press release outlining a number of important clinical development program updates, including the acceptance of four resmeteram abstracts as oral presentations at ESL's International Liver Congress next month, additional positive data from the Phase III Meister of NAFLD-1 Safety Study, and a new outcomes trial that will evaluate resmeteram for the treatment of NASH patients with compensated cirrhosis. We also announced that Madrigal has secured a term loan facility, which puts us in a strong financial position for the road ahead.

He was the fine print dealing with our forward looking statements.

Please see today's press release, and our SEC filings for forward looking statement and risk factor considerations associated with these statements and our business.

With me on today's call.

Our Becky Taub, President Navarre, Indy and Chief Medical Officer.

As a teacher.

Chief commercial officer, and Alex or Howard <unk>, Chief Financial Officer, We also have Dr. Stephen Harrison joining us to provide his perspective on the Maestro program updates we're announcing today.

This morning, we issued a press release outlining a number of important clinical development program updates, including.

Including the acceptance of four resume ROM abstracts as oral presentations at <unk> International liver Congress next month.

Additional positive data from the phase III Maestro Napoles, one safety study and a new outcomes trial that will evaluate resume to Rob for the treatment of Nash patients with compensated cirrhosis. We also announced that magical secured a total term loan facility, which puts us in a strong financial position for the road ahead.

The decision to expand our clinical development program and raise additional capital.

Dr. Friedman: The decision to expand our clinical development program and raise additional capital reflects our conviction in the potential of resmeteron to be a transformational therapy for patients with NASH. The emerging data from Maestro Nafl-1 safety study, including the results we're announcing today, continue to support that conviction, and we look forward to sharing additional data in our late-breaker presentation at EAST. Now Becky is going to review the design of the new Meister Nash Outcome Study in more detail in a few minutes, but I'd like to say a few words about the medical and commercial rationales for the study. And I think, fairly obviously, patients with compensated cirrhosis are at significantly elevated risk of progression to negative clinical outcomes. And there is a high unmet need for an approved therapy to treat these patients.

Reflects our conviction in the potential of rest of matter on to be a transformational therapy for patients with Nash the.

The emerging data for Maestro in Apple one safety study, including the results. We're announcing today continue to support that conviction and we look forward to sharing additional data in our late breaker presentation at Aesop.

Now back is going to review the design of the new Maestro Nash outcome study in more detail in a few minutes, but I'd like to say a few words about the medical and commercial rationales for the study.

First.

And I think fairly obviously patients with compensated cirrhosis or had significantly elevated risk of progression could negative clinical outcomes and there is a high unmet need for an approved therapy to treat these patients.

Dr. Friedman: Second, resmeteron has been well-tolerated in this population, and early efficacy results are quite encouraging. Third, we believe this study can be conducted in a timely manner. And since in this more advanced population, events will accrue faster, it can provide an alternative path to an early full approval in non-serotic NASH than our ongoing clinical outcome studies in Meister NASH. And finally, by substantially expanding the NASH market opportunity to include patients with compensated cirrhosis, the therapeutic and commercial value of resmedarone for Madrigal and potential business development partners should be strengthened.

Second resume ROM has been one part and well tolerated in this population and early efficacy results are quite encouraging.

Third we believe this study can be conducted in timely manner and.

And since in this more advanced population events will accrue faster.

Can provide an alternative path to an early full approval.

In non cirrhotic Nash than our ongoing clinical outcome studies in mice turn Nash and.

And finally by substantially expanding the Nash market opportunity to include patients with compensated cirrhosis, the therapeutic and commercial value of resume around for madrigal and potential business development partners should be strengthened.

As we have gained increasing confidence that we will achieve both Nash resolution and the fibrosis improvement endpoints in the Maestro Nash biopsy study.

Dr. Friedman: As we've gained increasing confidence that we'll achieve both NASH resolution and the fibrosis improvement endpoints in the Meissner NASH biopsy study, we are moving one point of fibrosis reduction up the hierarchy to a primary endpoint along with NASH resolution.

We are moving one point fibrosis reduction up the hierarchy.

To a primary endpoint along with Nash resolution.

Dr. Friedman: The dual primary endpoints now for Meister NASH are NASH resolution without worsening of fibrosis or fibrosis improvement without worsening of NASH. And while we fully expect to achieve both endpoints, achieving either endpoint is compatible with a subpart HNDA submission according to FDA's draft guidance. Importantly, our planned MISR-NASH outcome study and the move to a dual primary endpoint in the biopsy study do not alter our timeline assumptions for readout of the biopsy study in Q4 or subpart H NDA submission for non-serotic NASH next year.

The dual primary endpoints now for Maestro Nash or Nash resolution without worsening of fibrosis for fibrosis improvement without worsening of Nash and while we fully expect to achieve both endpoints, making either endpoint is compatible with a subpart H N D H submission.

Cording to F D a draft guidance.

Importantly, our planned Maestro Nash outcomes study and the move to a dual primary end point in the biopsy study do not alter our timeline assumptions for readout of the biopsy study in Q4.

Or subpart H NDA submission in non cirrhotic Nash next year.

The term loan financing we announced today.

Dr. Friedman: The term loan financing we announced today will help fund the expansion of the Resmederon Clinical Development Program and reinforces Madrigal's solid financial position. As of March 31, Madrigal had cash, cash equivalents, and marketable securities of $220 million.

Will help fund the expansion of the rest of it are on clinical development program and reinforces Madrigal solid financial position as of March 31, <unk> had cash cash equivalents in marketable securities up $220 million and additional $50 million was drawn at closing of the new loan agreement.

Dr. Friedman: An additional $50 million will be drawn at closing of the new loan agreement. Alex will share additional details shortly. As we noted in our press release, Maestro Nafld-1 double-blind data was submitted as a late-breaking abstract to ESL and accepted as an oral presentation at the International Liberal Congress next month. So while we'd like to share the full data set with you, we're not going to be able to provide you with any additional data beyond today's update because the data are now under embargo.

Alex will share additional details shortly.

As we noted in our press release Maestro Nafud, one double blind data were submitted as a late breaking abstract that you saw and accepted as an oral presentation at the international liver Congress next month, so while we'd like to share. The full data set with you we're not going to be able to provide you with any additional data beyond today's update.

Because the data are now under embargo.

Dr. Friedman: Our team is looking forward to ESL, the first major in-person hepatology conference since 2011. I'd like to thank our R&D team for the work they've done in generating multiple accepted abstracts for the meeting, including the Meister and Appleton-1 late break. We'll be conducting an investor event after the new data are presented at ESOL, so please reach out to us if you plan to be in London for the meeting. Now I'll call, turn the call over to Becky. Good morning. So, on slide seven.

Our team is looking forward to equal the first major in person Herpetology conference since 2011, I'd like to thank our R&D team for the work they've done in generating multiple accepted abstracts for the meeting, including the Maestro now pulled one late breaker.

We will be conducting an investor event. After the new data are presented a diesel. So please reach out to us if you plan to be in London for the meeting and now call turn the call over to Becky.

Good morning.

So on slide seven.

Becky Tau: Here's the summary of the data that we presented on the January 31st webcast when we announced the top-line data from Meister and Nafl. Resveratrol was safe and well-tolerated at the top dose of 100, as well as 80 milligrams in Meister and Nafl. T-secondary endpoints were achieved in Meister and Nafl at both 80 and 100 milligram dose groups, including PDFF, LDL, cholesterol, APOB, and triglyceride reductions, which are consistent with the parallel randomized 100 milligram open-label arm that was from the same study that was presented at AASLD earlier in November 2021.

Oh.

Here's the summary of the data that we presented at January 31st Web quite cash when we announce the topline data from our milestone now Paul as a matter of ROM, a safe and well tolerated at the top dose of 100 as well as 80 milligrams and my style Hall key secondary endpoints were achieved.

In iPhone and Apple at both 100 milligram dose groups, including a PDF have LDL cholesterol April b and try Glyceride reduction switch.

Are consistent with the parallel randomized 100 milligram open label arm that had been.

From this same study that had been presented at Aes L D.

Earlier in November 2021.

Becky Tau: The safety and efficacy of the study are in line with the expectations from the phase two liver biopsy study and the randomized parallel open-label 100 milligram arm of Meister and Nafl, and positive results from this trial support our conviction that resveratrol has the potential to be the first medication approved for the treatment of NASH patients with liver fibrosis. Next slide

The safety and efficacy of the study are in line with the expectations from the phase two liver biopsy study and the randomized parallel open label 100 milligram arm of Maestro naphtha.

Positive results from this trial support our conviction that <unk> has the potential to be the first medication approved for the treatment of Nash patients with liver fibrosis next slide now there will be multiple presentations.

Becky Tau: Now, there will be multiple presentations of Madrigal's program data at ESOL's International Liver Congress, including a late-breaking presentation, primary data analyses of Meister Nafl, a 52-week double-blind placebo-controlled phase 3 clinical trial of rismetarone in patients with Nafl. We will also be presenting three other oral abstracts, the impact of rismetarone-mediated reductions in liver volume This refers to a technique using artificial intelligence to read fibrosis on liver biopsy slides.

Ah <unk> program data at <unk> International liver Congress, including a late breaking presentation primary data analysis of Maestro Naphthol, a 52 week double blind placebo controlled phase III clinical trial for <unk> in patients with Nash.

We will also.

And three other oral abstracts.

The impact of risk, Matt around mediated reductions in liver volume in steatosis compared with placebo on the quantification of fibrosis using second harmonic generation in a serial liver biopsy. This refers to.

Tech technique using artificial intelligence to.

Read fibrosis on the liver biopsy slides.

We will present, an abstract utility a fib four thresholds to identify patients with at risk F. Two or three Nash based on screening data from a 2000 patient liver biopsy.

Becky Tau: We will present an abstract utility of fib-4 thresholds to identify patients with at-risk F2F3 NASH based on screening data from a 2,000 patient liver biopsy cohort of our phase three clinical trial maestro NASH. And a fourth presentation, biomarkers, imaging, and safety in a well-compensated NASH serotic cohort treated with resmetarom, a thyroid hormone receptor beta agonist for 52 weeks.

Cohort of our phase III clinical trial my strike Nash.

And Ah.

Fourth presentation.

Biomarkers imaging and safety and are well compensated Nash cirrhotic cohort treated with Chris Matt around a thyroid hormone receptor beta agonist for 52 weeks.

Becky Tau: And we also have two posters, one looking at the association of FYP4 with healthcare costs and a second using a different AI methodology to review our slides and confirm the Significant Treatment-Induced Changes in Histologic Features of NASH from our Phase 2 study. There's an additional satellite symposium which will discuss identifying, managing, and treating patients with NASH in more detail. So, on the next slide, slide nine, additional data from the Meister-Nafl trial. As Dr. Friedman mentioned, detailed results of this trial are under ARGO until the late-breaking presentation at ESOL.

And we also have two posters.

One looking at the association of Fib, four with health care costs and a second.

Using a different AI.

Methodology to review our slides confirm.

The significant tree induce changes in histologic features.

Nash from our phase two study.

There's an additional satellite symposium, which will discuss.

Identifying managing and treating patients with Nash and significant fiber.

Doses.

So on the next slide slide nine.

Additional data from the <unk> trial is S.

Dr. Friedman mentioned detailed results of this trial.

Under Argo until the late breaking presentation that he saw.

Becky Tau: However, we will focus on some of the important results here, similar to what was reported for the 100-milligram open-layer arm in November of 2021. Patients in the parallel arms, 80-milligram and 100-milligram treated with resmetarom, achieved reductions from baseline in ALT that were P equals 0.002 and less than 0.001. 0.0001 relative to placebo. Transient ALT increases that were greater than three times the upper limit of normal occurred in 0.61% in the rismetarom 80 milligram group, 0.31% in the 100 milligram group, and 1.6% of patients in the placebo group, indicating that if anything, there was a lower increase in patients treated with resmetarab, and this was across the entire 52 weeks of the study.

However, we will.

I'll focus on some of the important results here are similar to what was recorded for the 100 milligram open label arm and November of 2021 patients in the parallel arms 80, milligram and 100 milligram treated with west matter ROM.

Achieved reductions from baseline and a L P.

P equals <unk> <unk> or two in lesson.

Oh, one relative to placebo.

Transient L T increases that were greater than three times, the upper limit of normal.

<unk> and <unk>, six 1% and the risks in that around 80 milligram group.

31% and 100 milligram group and one 6% of patients in the placebo group.

Indicating.

That if anything if there was a lower.

Increase in patients in treated with ferrous matter op.

And this was across the entire 52 weeks of the study.

Becky Tau: Treatment, Emergent, Adverse Events of Greater than or equal to grade 3, greater than or equal to grade 3, occurred in 7.6% of patients in the res moderum, 89% in the 100 million group, and 9.1% in the placebo group. This was data that we also presented in January. Withdrawals due to adverse events were very low in the study, 2.4 percent in the 80 milligram group, 2.8 percent in the 100 milligram group, and 1.3 percent in the placebo group.

Treatment emergent adverse events greater than grade three greater than or equal to grade three incur occurred in seven 6% of patients and the risk around 89% and 109.

Nine 1% in the placebo group.

This was data that we also presented in January withdrawals due to adverse events were.

Very low in this study are two 4% in the 80 milligram group two 8% in the 100 milligram group and one 3% in the placebo group.

The Gi related adverse events that we had shown at the end of January were increased in the drug arms relative to placebo.

Becky Tau: The GI-related adverse events that we had shown at the end of January were increased in the drug arms relative to placebo. However, further analysis has shown that these increases in GI adverse events, diarrhea, and nausea, did not occur after the first few weeks of therapy. Next slide, if I can.

Further analysis has shown that they.

These increases in Gi adverse events diarrhea and nausea.

Did not occur after the first few weeks of therapy.

Next slide slide 10.

Becky Tau: Endpoints related to a FibroScan were evaluated in this study. Patients had a screening or pre-screening FibroScan that then allowed them to be screened for the study based on their CAP and KPA values. And then they had a second FibroScan at week 52. The FibroSan CAP score, which is reflective of hepatic fat, was statistically significantly reduced, P less than 0.0001 in the resumator arms as compared with placebo. Fibroscan liver stiffness reductions were presented for the 100 milligram open label arm in November of 2021 and showed a marked reduction from baseline, and these reductions were similar in the 100 milligram open label and double blind arm.

Endpoints related to a fiber scan were evaluated in this study.

Patients had a screening or prescreening fiber scan.

That would then allow them to screened for the study.

Just on the.

The cap and Tpa values.

And then they had a second fiber scan.

At week 52.

The 5% cap score, which is reflective of hepatic fat or statistically significantly reduced P less than <unk>, one in the estimate around arms as compared with placebo.

Fiber scan liver stiffness reductions were presented.

For the 100 milligram open label arm in November of 2021 and showed a.

<unk> reduction from baseline in these reductions were similar and the 100 milligram open label and double blind arms.

Becky Tau: Responder analyses of the FibroScan VCTE reduction, or KPA reduction, and percent reduction from baseline comparing resmetarom 100-milligram open label and the two double-blind arms with placebo showed a significant increase in responders in the treatment arm, around 44 percent, averaged across the resmetarom arms compared with placebo, and this was statistically significant. There appeared to be some dose relationship between the 180-milligram doses in this study, um, if we examine mean reduction in FibroScan. A-A-A-A, range with Lisa Sohn.

Responder analysis of the fiber scan.

V Cte reduction or kpa reduction and percent reduction from baseline comparing.

RASM at around 100 milligram open label and the two double blind armed with placebo showed a significant increase in responders in the treatment arm around 44% average across the risk matter AUM arms compared with placebo on this list assist pretty significant there appear to be some dose.

Relationship.

Between the 180 milligram dose.

Doses.

And in this study.

If we examine the mean reduction in fiber scan.

Liver stiffness.

Becky Tau: And right now, thank you all. Thank you very much, in the resmedarone double-blind arms. These were numerically greater than placebo, but not statistically significant in this study. I will also note at this point that the threshold for an eligible fiber scan was 7.2 kPa, which is consistent with approximately F1 to F2 fibrosis stage compared to liver biopsy historically in the literature. And this was a fraction of the patients in the Meissner-Nafl study, which was in general an earlier population than Meissner-Nafl. MRE responders, as measured by KPA reduction, were also significantly greater in resmetarom-treated groups compared with placebo and showed a similar level of responders in all resumator of dose arms.

And the rest met around double blind arms, these or numerically greater than placebo, but not statistically significant in this study.

I will note also at this point that.

The threshold for a an eligible fiber scan.

It was 7.2, Kpa, which is consistent with approximately F. One F to fibrosis stage or compare to liver biopsy historically in the literature.

And this was a fraction of the patients in the MISO snaffle.

Study, which in general earlier population in my straight Nash.

Maury.

Responders as measured by Kpa reduction were also significantly greater in <unk> treated groups compared with placebo and showed a similar.

Level of responders and all rest of matter of dose arm. So that would be a 100 milligram open label 100 milligram double blind and 80 milligram.

Becky Tau: So that would be 100 milligrams open label, 100 milligrams double blind, and 80 milligrams double blind arms showed a similar reduction in MRE, and this was in patients who had at least 2.9 kPa at baseline. The intrinsic variability of Fibroscan, 35 to 40 percent, which has been confirmed many times in the literature, limits its use as a sole measure to diagnose or follow NASH patients, but it is an excellent office-based enrichment test and was an excellent enrichment test in both of our maestro studies in enabling us to rule out patients without significant fibrosis and identify potential NASH fibrosis. We will be presenting additional data on FibroScan and other eligibility criteria to diagnose NASH in one of our oral abstracts at ESOL. However, only a few of the highlights are shown here.

Uh-huh double blind arms showed a similar reduction in MRE and this was in patients who had at least at $2 nine.

At baseline.

The intrinsic variability of fiber scan, 35% to 40%.

In the what just been confirmed many times in the literature.

<unk>.

Limited chooses a sole measure to diagnose or follow Nash patients, but it is an excellent office space enrichment cash and was an excellent enrichment tests in both of our Maestro studies.

In.

Enabling us to rule out patients without significant fibrosis and identify potential Nash fibrosis patients, we will be presenting additional data on <unk>.

Fiber scan and other eligibility criteria to diagnose Nash and one of our oral abstracts that ESAU.

However.

You have the highlights are shown here the screening fiber scan.

Becky Tau: The screening FibroScan of greater than 8.5 kPa in Meister NASH predicted significant fibrosis on biopsy in approximately 50%, and a high percentage of positive FibroScans did not have significant liver fibrosis. The MRE of 2.9, which was not used as a pre-screening test, but we have data from the study, predicts significant fibrosis on screening biopsy in about 80% of the Mae The intrinsic variability of the MRE is approximately 19%, so it is lower than the fibrosis.

And then eight five kpa in Maestro Nash predicted significant fibrosis on biopsy.

And approximately 15%.

And.

A high percentage of positive fiber scans.

<unk> did not have significant liver fibrosis.

The MRI <unk> of $2 nine.

Which was not used as a pre screening tests, but we have data from the study.

Predicts significant fibrosis on screen.

Screening biopsy and about 80% of the nice Maestro Nash population.

Intrinsic variability of the MRE is approximately 19% so lower than the fiber scan.

Becky Tau: And we believe that additional biomarkers, and there is a huge amount of work going on this in the field, including composites or more specific imaging tests like MRE and MRI PDFF with the Fibroscan may increase the accuracy in diagnosing and monitoring patients with NAS in the Meisler-Nash Outcome Study that we are planning to start over the next few months, to give you some brief comments on the study design. It is a randomized, double-blind, placebo-controlled study in approximately 70 patients with early NASH cirrhosis to allow for non-invasive monitoring of progressive two-liver decompensation events. Just to make this clear, these are patients who have never decompensated, so they have early NASH cirrhosis.

<unk>.

We believed at additional Biomarkers and there are huge amount of work going on this in the field, including composites or more specific imaging tests like MRE in MRI PDF with our with the fiber scan may increase the accuracy of diagnosis and monitoring patients with Nash.

In the MISO Nash outcome study.

We are play.

Planning to stop.

Start over the next few months just to give you some brief.

Hi.

Our comments on the study design is a randomized double blind placebo controlled study in approximately 70 patients with early Nash cirrhosis.

To allow for noninvasive monitoring of progression.

Two liver decompensation events just to make this clear these are patient.

Who had never D compensated so they have early Nash.

Nash cirrhosis.

They are very simple this is a similar population to an ongoing.

Becky Tau: They're a very similar population to an ongoing open-label arm of more than 180 patients with well-compensated NASH cirrhosis from our Maestro-NAPL study. The FDA has publicly stated that an outcome study in NASH cirrhosis patients can support full approval of non-cirrhotic NASH, and Madrigal met with FDA to confirm the strategy and study design. Maestro NASH outcomes is designed to assess the rate of disease progression in early NASH cirrhosis patients and enhance the statistical power of maestro trials to assess clinical benefit.

Open label arm of more than 180 patients with well compensated Nash cirrhosis.

Our maestro a Nash Napoli study.

The FDA has publicly stated.

Is that an outcome study in Nash cirrhosis patients can support full approval not cirrhotic Nash and <unk> met with FDA to confirm the strategy setting design Maestro Nash outcomes is designed to assess the rate of disease progression and early Nash cirrhosis patients and enhance the statistical power of Maestro.

Trials to assess clinical benefit.

Becky Tau: The decompensation events that will be assessed include development of ascites, bleeding varices, hepatic encephalopathy, and increased smell greater than or equal to 15 and are expected to occur at a rate that is higher than in maestro NASH. This is because the maestro NASH patients who are past week 52 and are assessed out to month 54 are non-cirrhotic, and these are in the best NASH outcomes; these are early NASH cirrhotic patients, and so the rate of decompensation will be higher in this population. Importantly, liver biopsy is not an end point.

Decompensation event set but it will be.

SaaS to include developed.

Development of Ascites, bleeding, varices, hepatic encephalopathy, and increase now greater than or equal to 15.

And are expected to occur at a rate that is higher than in.

Mr. Nash this is because.

The Maestro Nash patients too.

Our past week 52.

And our assessed out two months before our non cirrhotic.

And these are in Maestro Nash outcome piecer.

These are early Nash cirrhotic patients and so the rate of compensation will be higher in this population importantly, liver biopsies not an endpoint.

In my soon Nash out outcomes.

Becky Tau: In maestro NASH outcomes, the outcome portion of the trial of maestro NASH, the liver biopsy study, there is a third liver biopsy occurs at month 54. So here in maestro NASH outcomes, the invasiveness and variability of liver biopsy are avoided. Several biomarkers and imaging techniques will also be employed to assess correlates with disease progression.

The outcome portion of the trial of Maestro to ash the liver biopsy study there is a.

Third liver biopsy occurs at about 54.

Here at Magic Maestro Nash outcomes, Invasiveness and the variability of liver biopsies avoided seven.

Several biomarker imaging techniques will also be employed to assess correlates with disease progression.

We will be presenting additional data on the open label study of more than 180 patients well compensated Nash cirrhosis.

Becky Tau: We will be presenting additional data on the open-label study of more than 180 patients with well-compensated NASH cirrhosis at ESL, and these data support the potential of resmetarom in this patient population. We have reported data from patients with NASH cirrhosis at international meetings and demonstrated that resmetarom reduces liver fat, liver enzymes, liver volume, fibrosis markers, and atherogenic lipids in this population. But, before...

At Aesop and.

These data support the potential of <unk> in this patient population, we have reported data from the <unk>.

Patients with Nash cirrhosis at.

International meetings.

And demonstrated the risk matter AUM reduces.

Liver fat liver enzymes liver volume fibrosis markers atherogenic slippage in this population.

So before.

Dr. Friedman: I'm asking Remy to give us a commercial update. I'd like to ask Dr. Harrison to share his perspective on the planned Meister and Ash Outcomes Study. Thanks, Paul.

Asking remy to give us the commercial update I'd like to ask Dr Harrison or his.

Perspectives.

From the planned my store Nash outcome study.

Thanks, Paul.

Dr. Stephen Harrison: So first of all, I think this is incredibly important. I think it shows progression in the development of resmedarone to kind of address all the aspects of what the FDA is looking for. So I think this is the final piece, the Maestro-Nash Outcomes Trial in a well-compensated group of over 700 cirrhotic patients. And I think the unique thing about this study that I find incredibly important and encouraging is the fact that we're able to use noninvasive techniques to enroll the patient population.

First of all I think this is incredibly important.

<unk> progression in the development of resin that around two.

To kind of address all the different aspects of of what the FDA is looking for.

So I think this is the final piece the <unk> Nash outcomes trial and are well compensated group of over 700 cirrhotic patients.

So I think the unique thing about this study that I find incredibly important and encouraging is the fact that we're able to use noninvasive techniques to enrolled the patient population.

Dr. Stephen Harrison: And so here, for the first time in a very large study, we're able to move away from liver biopsy. And so I think that provides an additional positive point relative to the study. So the outcomes are well validated. They're known, development of ascites, bleeding varices, hepatic encephalopathy, and increase in the MELD score greater than or equal to 15.

So here for the first time in a very large study, we're able to move away from liver biopsy and so I think that provides an additional.

Positive point relative to the to the study.

The outcomes are well validated they're known.

Feldman of ascites bleeding varices product can suck velocity increase in the meld score.

Greater than or equal to 15, so I think this.

Dr. Stephen Harrison: So I think this sets everything up very nicely to augment the Maestro-NASH program and also extend benefits potentially to cirrhotic patients as well. So I think it's exactly what we needed. Thanks very much, Stephen. I'll turn the call now over to Remy to provide a commercial update. Thank you, Paul. Good morning, everyone.

This sets a REIT everything up very nicely to augment the Maestro Nash program and also extend benefit potentially into cirrhotic patients as well so.

Just I think it's.

I think I think it's exactly what we needed.

Okay. Thanks, very much Steven appreciate that.

I'll turn the call now over to Remy to provide a commercial update.

Thank you Paul.

Remy Sikija: NASH is a truly exciting commercial opportunity, and I feel both fortunate and privileged to lead our team's commercial planning efforts for a potential first to market launch in the category. As a reminder, we view this as a specialty product launch focused on the NASH specialists, who we define as a subset of hepatologists, gastroenterologists, and endocrinologists who already manage a substantial number of patients that are living with NASH with fibrosis. To create the NASH therapeutic market, we are engaging with all key stakeholders.

Good morning, everyone Nash is a truly exciting commercial opportunity and I feel both fortunate and privileged to lead our teams commercial planning efforts for a potential first to market launch in the category.

As a reminder.

We view this as a specialty product launch focused on the Nash specialists, who we define as a subset of Herpetologist Gastroenterologists and endocrinologists, who already manage a substantial number of patients that are living with Nash with fibrosis.

To create the Nash therapeutic market, we are engaging with all key stakeholders. So far in 2022, we have gained a deep understanding of market dynamics with the health care provider payer and patient lenses based on extensive market research and advice from <unk>.

Remy Sikija: So far in 2022, we have gained a deep understanding of market dynamics with the healthcare provider, payer, and patient lenses based on extensive market research and advice from thought leaders. And we have advanced health economics and outcomes research that will inform future value assessments of res mirum and health disease education sessions with U.S. partners that together cover roughly 80 percent of all branded prescriptions in the U.S. You can see examples of our market development activities on this slide.

Peters.

And we have advanced health economics, and outcomes research that will inform future value assessments of resumes.

And held disease education sessions with U S pairs that together cover roughly 80% of all branded prescriptions in the U S.

You can see examples of our market development activities on slide.

Remy Sikija: For the remainder of the year, we will have a particular focus on education initiatives at U.S. medical congresses like DDW, ACE, AGA, and, of course, AASLD. Our first major digital disease education campaign for the health care provider audience, NASH Reimagined, will be launching in the U.S. in the coming weeks. We remain heavily focused on partnering discussions.

For remainder of the year, we will have a particular focus on education initiatives at U S. Medical Congresses like Didi W. H, a G E and of course Aaas L D.

Our first major digital disease education campaign for the health care provider audience Nash re imagine we'll be launching in the U S in the coming weeks.

We remain heavily focused on partnering discussions as we have stated previously our plan is to establish an ex U S. Commercial partnership following phase III Maestro Nash data readout.

Remy Sikija: As we have stated previously, our plan is to establish an ex-U.S. commercial partnership following phase three Maestro-Nash data readout, and we have already begun discussions with multiple potential partners. Overall, I'm pleased with the progress we have made so far in 2022 and the momentum we have established with our commercial strategy and execution. With that, I will turn it over to Alex for a financial update. Thanks Remy and good morning everyone. Based on our cash position and term loan facility announced today, Madrigal is on solid financial footing for the road ahead.

And we have already begun discussions with multiple potential partners.

Overall I'm pleased with the progress we've made so far in 2022.

And the momentum we have established with our commercial strategy and execution.

With that I will turn it over to Alex for a financial update.

Thanks, Rodney and good morning, everyone.

Remy Sikija: As of March 31, 2022, Madrigal had cash, cash equivalents, and marketable securities of $220 million compared to $270.3 million at December 31, 2021. Operating expenses were $57.6 million for the three-month period ended March 31, 2022, which comprised research and development expenses of $47.9 million and G&A expenses of $9.7 million. The operating cash burn for the period was $49 million.

Based on our cash position and term loan facility announced today medical is on solid financial footing for the road ahead.

As of March 31, 2022 medical had cash cash equivalents and multiple securities of $220 million.

Compared to 202 hundred $17 3 million at December 31, 2021.

Operating expenses were $57 6 million for the three months period ended March 31, 2022, which comprised research and development expenses of $47 9 million and G&A expenses of $9 7 million.

The operating cash burn for the period was $49 9 million.

Please refer to this morning's press release and 10-Q filing if you would like additional details on Q1 financial results.

Alex Haworth: Please refer to this morning's press release and 10-Q filing if you would like additional details on Q1 financial results. I'll now turn to the Term Loan Facility. Madrigal has secured a $250 million term loan facility with Hercules Capital Inc. Committed Capital strengthens Madrigal's balance sheet, providing an additional source of funding to support strategic priorities, including the new Maestro Nash Outcome Study. Under the terms of the credit facility, $50 million was drawn at closing.

I'll now turn to the term loan facility.

Madrigal has secured a $250 million term loan facility with Hercules Capital Inc.

The committed capital strengthens medicals balance sheet, providing an additional source of funding to support strategic priorities, including the new Maestro Nash outcome study.

Under the terms of the credit facility $50 million was drawn at closing.

Madrigal may also draw an additional $125 million in two separate tranches upon achievement of risk metro on clinical and regulatory milestones.

An additional 75 million may be drawn by magical to support operational activities subject to the approval of Hercules capital.

With our existing cash access to the term loan our existing ATM facility and other potential financing sources, we are well positioned to execute on our strategic objectives are as much wrong.

Alex Haworth: Madrigal may also draw an additional $125 million in two separate tranches upon achievement of a resmetarom clinical and regulatory milestone. Additionally, an additional $75 million may be drawn by Madrigal to support operational activities subject to the approval of Hercules Capital. With our existing cash, access to the term loan, our existing ATM facility, and other potential financing sources, we are well positioned to execute on our strategic objectives for Resmetteron. With that, I'll now turn the call back to Paul. Thanks, Alex.

With that I'll now turn the call back to Paul.

Dr. Friedman: So we've delivered quite a bit of news today. I'm sure you have questions you would like addressed. We're going to open the call momentarily for Q&A. But I just wanted to let you know that the company has a hard stop at 9 o'clock, so we have 30 minutes.

Thanks, Alex So we've delivered quite a bit of news today I am sure you have questions you would like address.

We're going to open the call momentarily for Q&A I just wanted to let you know that the company has a hard stop at nine.

Clock. So we have 30 minutes, we will answer as many questions as we can in that time operator, please open the call for Q&A.

Dr. Friedman: We'll answer as many questions as we can in that time. Operator, please open the call for Q&A. Thank you. To ask a question, you will need to press star 1 on your telephone.

Thank you to ask a question you will need to press star one on your telephone.

Operator: To withdraw your question, press the pound. Please stand by while we call the Q&A. Our first question comes from Ritu Baral on Cowen. Your line is open. Good morning, guys.

Draw your question press the pound key.

Please stand by what we call the Q&A roster.

Our first question comes from Ritu <unk> with Cowen Your line is open.

Good morning, guys. Thanks for taking the question I'll keep it brief.

Ritu Baral: Thanks for taking the question. I'll keep it brief. So is it fair to say that now that you've incorporated fibrosis, you've got a hierarchical non-gating analysis as the prior Nash company did? And since this isn't an interim, is the assumption that you guys have full alpha, 0.05 of alpha to spend on that primary endpoint? This is Becky.

So is it is it fair to say that now that you've incorporated fibrosis that you Scott.

Hierarchical.

Analysis.

As prior Nash company.

<unk>.

Since this is from.

Is the assumption that you guys have.

We'll also point out five of alpha spend on that primary endpoint.

So this is mackie. Thank you. Thank you ritu.

Becky Tau: Thank you. Thank you, Ritu. I think that, you know, your comments showed an excellent understanding of what we said. We are in the process of finalizing the statistical analysis plan, and so the details of, you know, the alpha and the hierarchy, et cetera, we won't, we aren't discussing. The idea is that this is similar to really every other NASH study, where there are dual endpoints, both fibrosis and NASH resolution, dual So we're not requiring achievement of both of NASH resolution and fibrosis, although we believe that both endpoints will be achieved. And what drove inclusion?

I think that.

Your comment.

Show extra.

Excellent understanding of World said.

We are.

And in the process of the Finalization of the statistical analysis plan.

And so the details of the alpha in the hierarchy and et cetera.

We won't we arent discussing but.

The idea is that this is similar to really every other Nash study.

Where there are dual endpoints.

Fibrosis and Nash resolution.

Dual primary endpoints, so that achievement if either of those two end points.

It can lead to a successful study.

So we're not requiring achievement of both of Nash resolution and fibrosis, Although we believe that both endpoints will be achieved.

And what drove inclusion FTE payer and character of the data the MRE.

Becky Tau: Was it FDA input, payer input, or the data, the MRE data that you generated? We've actually had this plan for quite some time, and it was a matter of consolidating the entire Maestro development plan and finalizing it at this point in time. As we mentioned on the call, the FDA providing the opportunity for the maestro NASH outcomes in the early NASH cirrhosis population helped support the statistical power for determining clinical benefit.

You generated.

We've actually.

Had this plan for quite some time and it was a matter of consol.

Consolidating the entire.

Maestro development plan.

And finalizing that.

At this point in time.

The.

As we mentioned.

Paul.

FCA, providing the opportunity for.

For the maestro cash outcomes and the early Nash cirrhosis population help support.

The statistical power for determining clinical benefit and so I think that also helped us in terms of.

Becky Tau: And so I think that also helped us in terms of our statistical plan for maestro NASH week 52 bio. Great, thanks for using the call. Our next question comes from Thomas Smith, SVV Securities. Your line is open.

Our statistical plan for my Stern Nash a week 52 biopsy.

Great. Thanks for taking the questions.

Our next question comes from Thomas Smith <unk> Securities. Your line is open.

Okay.

Thomas Smith: Hey guys, good morning. Thanks for taking the questions. I guess first on the Meister and Affold detailed data that we're expecting at EASL. I understand you're under embargo and kind of limited in what you can say in terms of the additional data sets, but maybe you could help set the stage for what other data sets we can expect to see from this presentation at the meeting. I think, you know, it is a primary presentation of the data from Meister-Nafl and will include, you know, the primary endpoint and the key secondary endpoints, and as well as additional safety and more exploratory endpoints of the study.

Hey, guys. Good morning, Thanks for taking the question.

I guess first on.

The maestro natural detailed data that we're expecting it easily understand you.

You're under embargo and kind of limited in what you can say in terms of the additional datasets, but maybe if you could help set the stage for what other data sets. We can expect to see from this presentation at the meeting.

I think.

It is a primary presentation of the data.

From.

From Maestro Naphthol and will include.

<unk>.

The primary endpoint and the key secondary endpoints and as well as.

Additional safety and.

More exploratory endpoints of this study.

<unk>.

Thomas Smith: Beyond that, you know, I don't want to get into more detail, but I think that it will provide a lot of information about the clinical trial, much of which we've already presented. So, in terms of safety, we have said that, you know, in terms of the safety, the only AE that was, you know, disproportionate in the maestro rismetarom arms were early diarrhea and nausea, the GI-related AEDs that were self-limited and did not lead to study discontinuation. Okay, great. Well, we'll look forward to more color there.

Beyond that.

I don't want to get into more detail, but I think that.

It will provide a lot of.

Information about the clinical trial much of which we've already presented.

So in fact, we have said that.

In terms of the safety.

That the only AE that was.

Thank you.

Disproportionate.

In maestro.

Risk matter ROM arms.

No.

The early.

Diarrhea.

And nausea Gi related Aes that were self limited and did not lead to study discontinuation.

Becky Tau: And then just one on the new Maestro Nash outcome study. Can you talk a little bit more about the level of regulatory engagement here as you were putting together plans for this study? And then can you comment at all on the potential timelines, the data, and the estimated cost for this additional study? I can comment on some of that.

Okay great.

Look forward to more color there and then just one on the.

The new Maestro Nash outcome study can you talk a little bit more about the level of regulatory engagement here as you were putting together plans for this study and then can you comment at all on the potential timelines to data and the estimated cost for this additional study.

I can comment on some of this.

Becky Tau: So the FDA, really last year, publicly commented on what they called a parallel path for full approval in non-serotic NASH, where they showed a study designed in non-serotic NASH that's very similar to the liver biopsy portion of myosin NASH, you know, with a baseline biopsy and then a follow-up liver biopsy after, you know, a year to a year and a half. And that would And then they showed a parallel study, an outcome study for clinical benefit in an early NASH cirrhosis cohort and commented that those two studies would support, you know, positive outcomes from those two studies would support a full approval for non-serotic NASH and that it would also have the additional benefit of also a potential for approval in serotic, in early serotic NASH.

So.

The FDA really it was last year.

Publicly commented on what they called a parallel path.

Total and non cirrhotic Nash.

Where they showed a study design in non cirrhotic Nash, it's very similar to the liver biopsy portion.

Maestro Nash.

With a baseline.

Biopsy and then a follow up liver biopsy after.

A year or two a year and a half.

And that that would be a completed study and then they showed a parallel study.

Outcome study for clinical benefit and a early on Nash cirrhosis cohort.

And commented that those two studies would support.

Positive outcome from those two studies.

Good support.

A full approval for non cirrhotic Nash and that it would have the additional benefit of also.

Potential for approval in.

Cirrhotic.

In early Cirrhotic Nash.

Becky Tau: And so we followed up with them with an inquiry and solicited advice and then had a direct meeting to discuss the strategy and the potential protocol for it that we plan to initiate in the next few months. And, you know, the cost of the study is consistent with what you would expect for a 700-patient study that would go on for two to three years. It has non-invasive imaging and biomarkers, but otherwise is a fairly simple design, and so it is not as expensive as some other studies like the early portion of the Meister-Nash study. And, you know, it does impact the numbers of patients that need to be enrolled in the Meister-Nash study for the long-term 54-month readout.

And so we followed up with them with.

An inquiry.

And then.

Solicited advice, and then had a direct meeting to discuss the.

The strategy and the potential protocol on that.

We.

Planned to initiate in the next few months.

And the cost of the study.

Yes.

Okay.

Is <unk>.

Consistent with what you would expect for 700 patient study that would go on for two to two to three years at <unk>.

Has noninvasive.

Imaging and Biomarkers, but otherwise apparently simple design.

And so really not as expensive as.

Some other some other studies like the early portion of the Maestro Nash study.

And.

It does.

Impact.

The numbers of patients that need to be enrolled in the Maestro Nash study.

For the long term 54 month readout. So the total costs we haven't.

Becky Tau: So the total cost we haven't absolutely calculated, but we think there are some cost offsets from the study for the total program to acknowledge today. Again, just to reinforce what Becky is saying, the details of the study are less onerous in terms of the biopsy work, etc. So overall, the costs are more modest compared to the early portion of the MISRO-NASH study, but we won't go into specifics, obviously, of the details, the totality of the study costs. That's just not something we will do.

Absolutely calculated but.

We think there's some cost offsets.

From this study for the total program.

Okay.

Yes, I mean, just and again just to reinforce what he is saying.

Details of the study.

Less onerous in terms of the biopsy work et cetera. So overall costs were modest compared to the early portion of the Maestro Nash study, but we won't go into specifics obviously of the details of.

The totality of the study costs us just not something we will do but just just so Tom it's just too.

Emphasize one thing.

We.

Becky Tau: We had said we would enroll up to 2,000 people in the NASH 54-week biopsy study, and we won't go that far. I think Becky alluded to that, but we don't have to recruit as many patients there now that we have this second study to start in a couple of months. And this study should end well before... the current outcome study that's ongoing in Meister National. Okay, understood. And just one last question on the Meister and Nash outcomes.

We had said we would enroll up to 2000 people in the Nash 54.

Week biopsy study.

And we won't go that far I think Becky alluded to that but we don't have to recruit as many patients. There now that we have this second study.

To start in a couple of months.

In this study should okay, and this study should end well before.

The.

Current outcome study, that's ongoing and moisture in Nash.

Okay understood and just one last question on <unk>.

<unk> outcomes.

Are you planning to take forward.

Becky Tau: Are you planning to take forward one dose arm, the 100 milligram dose, or two dose arms into this study? The dosing of this patient population is something that is under consideration in the final details of the protocol. But I will note that in the ongoing NASH cirrhosis cohort, the well-compensated NASH cirrhosis cohort where we enrolled more than 180 patients, the starting dose is 80 milligrams in that population, and there are patients who then receive 100 milligrams. So this design, as I said, is under discussion, but we have precedent from our ongoing NASH cirrhosis open-label cohort. Okay, I got it. Thanks for taking the questions, guys. I appreciate it.

One dose arm 100 milligram dose or two dose arms into the study.

The dosing.

All of this this patient population.

Is it is something that it's under consideration.

The final details of the protocol, but I will note.

That in.

The ongoing Nash cirrhosis cohort.

Well compensated Nash cirrhosis cohort.

We enrolled.

More than 180 patients.

The starting dose is 80 milligrams in that population and there are patients who then receive 100 milligrams. So.

This design as I said is under discussion, but we have a precedent from our 100 are ongoing Nash cirrhosis.

Open label cohort.

Okay got it thanks for taking the questions guys I appreciate it.

Our next question comes from Jonathan <unk> with JMP Securities. Your line is open.

Operator: Our next question comes... Hey, good morning. Thanks for taking the question. I was hoping you could just remind us of your reading methodology for biopsies in the phase two study and how you're doing it in Mastro-Nash, please. So, we haven't, We haven't discussed the entire detail of the biopsy review. And as you know, there have been a lot of recent theories about, you know, practices for biopsy review, none of which are, by the way, validated.

Hey, good morning, Thanks for taking the question.

Was hoping you could just remind us of.

Youre reading methodology for biopsies and the phase III study and how youre doing it in a master batch. Please.

So we.

Haven't.

Discussed the entire detail of.

The biopsy review.

And as you know there's been a lot of recent.

Theories about.

Practices for biopsy review, none of which.

By the way validated.

We are using.

Operator: We are using two central readers, the same two central readers that read our Phase 2 biopsy and had consistent results between the two readers. And we believe we have a good methodology to gain agreement on the final outcome of the study based on these two central readers. So that's the bottom line.

Two central readers the same two central readers that red or are phase II biopsy and had consistent results between the two readers.

And we believe we have a good methodology.

Two.

Okay.

Gain agreement on the final outcome.

Of the study based on.

These two central leasing two central leader. So that's the bottom line just to again mention how this has played out in the past.

Becky Tau: Just to again mention how this has played out in the past, the same two central readers read our phase two study. There was a primary central reader, and then there was a second reader who read the entire phase two study. We showed their results in an oral presentation a couple of years ago at ESOL. Dr. Rohit Lumba presented their data, and we showed an excellent correlation between the determination of NASH resolution between the two readers who were both blinded, and they were blinded to each other's scoring.

The same two central readers read our phase two there was a primary central reader and then there was a second reader.

Who read the entire phase II study.

We.

We showed their results at an oral presentation, a couple of years ago.

At at <unk> Doctor Rohit remember presented their data and we showed in.

An excellent correlation between.

The determination of Nash resolution between two readers, who were both blinded and they were blinded to each other scoring.

And.

Becky Tau: And subsequently, and every component of NASH, fibrosis reduction, inflammation, and steatosis was greater in patients with a PDFF response, which was one of the highlights of our phase two. Subsequently, we had this approach validated, and it will be another one of our presentations at ESOL from PATH-AI, where they also read the full phase two biopsy study using artificial intelligence and got the same result as the So we believe, between that precedent and what we're doing now, that we have a very good plan to get a convincing read of the liver biopsy study in Meister and Adler. That's helpful. Thanks, Becky.

Subsequently.

And every component of Nash fibrosis reduction.

<unk>.

Inflammation and Steatosis.

Greater than patients with a PD F. F response, which was one of the highlights of our phase II.

Subsequently we add.

This approach validated and it will be.

One of our presentations at <unk>.

From the path AI, where they also.

Read the full phase II biopsy study using artificial intelligence and got the same resolved as the two.

Patent biopsy reader, so we believe between.

That precedent and.

And what we're doing now that we have a very good plan to get a.

A convincing read of the liver biopsy study in Maestro Nash.

That's helpful. Thanks, and one more if I may you discussed the expansion in the cirrhotic population can you give us.

Remy Sikija: And one more, if I may, you discussed the expansion of the cirrhotic population. Can you give us some thoughts about how you're thinking about that commercial opportunity versus the earlier stage NASH that was the, you know, earlier primary target? Rami, do you want to handle that one?

Some thoughts about how you're thinking about that commercial opportunity versus the earlier stage Nash that was the earlier primary target.

Rami do you want to handle that one sure thing Paul So when you think about commercial opportunity. There's probably three things generally speaking you got to think about one the addressable patient population to unmet need three whats your competitive set looks like so when you look at Nash with compensated cirrhosis the prevalence.

Remy Sikija: Sure thing, Paul. So, you know, when you think about commercial opportunity, there are probably three things, generally speaking, you got to think about. One, the addressable patient population. Two, the unmet need. Three, you know, what your competitiveness looks like. So, when you look at NASH with complicated cirrhosis, the prevalence of the disease, if you look at the ST publication that we all seem to look at, is around two million people in the U.S. today. Probably rising to 3.5 by the end of this decade.

Remy Sikija: Now, we got to balance that by saying, hey, listen, you know, most of these patients are not identified right now because there's really nothing to do with them. But as NASH drugs enter the market, that diagnosis rate should go up. So, overall, the addressable patient population could be quite large. For unmet need, we've talked to both payers and NASH specialists. I mean, these patients are on the cusp of very bad things. I mean, to point out the obvious, you know, liver transplant, death, hospitalization. So, there is a high unmet need.

Of the disease. If you look at SD publication that we all seem to look at is around 2 million is the prevalence 2 million people in the U S. Today, probably rising at three five by the end of this decade now we've got a balance that by saying Hey, listen you know most of these patients are not identified right now because there's really nothing to do with them, but as Nash drugs and to the <unk>.

Get that.

Diagnosis rates should go up so overall, the addressable patient population could be quite large unmet need we've talked about with payors.

And the Nash specialists I mean these patients are on the cusp of a very bad thing to point out the obvious you know liver transplant death hospitalization. So there is a high unmet need.

Remy Sikija: If you look at the pipeline, it's pretty sparse, especially compared to NASH with fibrosis. So, when you put it all together, I mean, we're quite bullish about the commercial potential for resmidiram, assuming it gains an indication for NASH with compensated cirrhosis.

Look at the pipeline, it's pretty sparse, especially compared to Nash with fibrosis. So when you put it all together I mean, we're quite bullish about the commercial potential for us mid around assuming again that indication for Nash with compensated cirrhosis.

Perfect. Thanks, again for taking the questions sure.

Remy Sikija: Thanks again for taking the questions. Sure. Our next question comes from Yasmeen. Handler, your line is open. Good morning, team.

Our next question comes from yesterday to meet with Piper Sandler Your line is open.

Operator: I have a few questions for you. Maybe the first place to start off is, are you seeing some improvements in event rates in your open-label cirrhosis cohort that motivated you to want to run these parallel design studies? If you could just kindly comment on that. And then I have a second question.

Good morning team a few questions for you and maybe the first place to start off at our U C.

Some improvements and event rates in your open label.

Cohort that motivated you to wanting to run that parallel design studies you can kindly comment on that and then I have a second question.

Becky Tau: So we'll... You know, I don't think we mentioned event rates in our ongoing Open Label Active Nascerosis cohort because there is no placebo control group in that study, but we will say that the patient population has done very well and the safety has been excellent, and, you know, but I think it's always important if you're going to talk about event rates to have a relevant control group in the study. So, the only thing I would add to that is that you over the time that we've treated the population. Statistically, you would have expected to see...

So.

No.

I don't think we mentioned event rates and our ongoing open label active Nash cirrhosis cohort.

Because there is no placebo control group.

And that study.

We will say that the.

Patient population has done very well and safety has been excellent.

And.

But I think it's always important if youre going to talk about event rates to have a relevant control group.

In this study.

So.

I would add to that is.

You all over the time that we've treated the population.

Statistically you would've.

You would have expected to see.

Becky Tau: Some hepatic decompensation events, which, I mean, in other words, what he's saying is that the rate is extremely low to non-existent in the study so far. But, again, you know..., I will defer to having a placebo-controlled study to measure the event rate. I don't know, Dr. Harrison, if you want to comment at all on this topic. Yeah, I mean, I think you hit on all the right points, Yasmeen. We just, we don't have a placebo control, but what we can say is that, you know, the event rate is incredibly low, but that's not necessarily inconsistent with the disease state. I mean, these events take time to accumulate. So I just, you know, I don't think that's necessarily the reason for pushing this trial.

Some hepatic decompensation events.

Which I mean in other words, what he's saying is that that rate is extremely low to nonexistent.

In the study so far.

Yes.

But again.

Hello.

I will defer to having a placebo controlled study to measure the event rate I don't know Doctor Harrison if you want to comment at all on this on this topic.

Yeah.

Yes, I mean, I think you hit on all the right points, Yes, I mean, we're just we don't have a placebo control, but what we can say is at the event rate is incredibly low, but that's not necessarily inconsistent with the disease state.

These events take time to accumulate so just you know.

I don't think that's necessarily the reason for pushing into this trial I think its more to align with the FDA around the parallel trial design. So that we don't have to wait forever for the Nash <unk> Nash trial to read an outcome we can.

Dr. Stephen Harrison: I think it's more aligned with the FDA around the parallel trial design so that we don't have to wait forever for the Maestro-NASH trial to read an outcome. We can move forward with a non-invasive assessment of these well-compensated serotics to try to get to an endpoint quicker. And so I think that's the reason for doing it. Thank you, team, for the detailed answer.

Can move forward with a noninvasive assessment of these well competency well compensated cirrhotic to try to get to an endpoint quicker and so I think that's the reason for doing it.

Dr. Stephen Harrison: And then, um, you know, I acknowledge that the FibroScan and MRE measurements were in the Maestro Nafl studies of earlier patient populations and maybe didn't reach that sick for based on all the reasons you outlined, but are you able to comment on whether those two non-invasive biomarkers tend to show really remarkable differences, at least in the cirrhosis cohort? I think investors might struggle with why, you know, what evidence do we have for all the data that's going to be presented on its anti-fibrotic activity given that those two measures, unfortunately, did not hit STATSIC. And I would appreciate any color you can give us.

Thank you team for the detailed answer.

And then.

I acknowledge that the fiber scan and MRI measurements, where in that Mike.

Shouldnt Apple studies earlier patient population and maybe didn't reach stat Sig.

Based on all the reasons you outlined but are you able to comment on whether those two noninvasive biomarkers tend to.

Yeah.

So really remarkable differences at least in their cirrhosis cohort I.

I think investors might struggle with why.

What evidence do we have for all the data that's going to be presented on its anti fibrotic activity.

Given that those two measures Unfortunately did not hit stat Sig.

And I appreciate any color you can give us thank you for taking the questions.

Becky Tau: And thank you for taking the questions. Well, I mean, I don't mind starting there, Becky, if you kind of like... I mean, so, first of all, I mean, what you've mentioned is that they're in a responder analysis. I think that there is statistical significance, there is a difference. And remember that there is a significant coefficient of variance in fibroscan from one point to point two in the same patient over time.

Yes.

Well I mean, I don't mind, starting their Becky if you like.

So so first of all I mean, what was mentioned is that they are in a responder analysis I think there is statistical significance. There is a difference and remember that there is significant coefficient of variance in fiber scan from one point to point to in the same pace.

<unk> over time.

Becky Tau: So to be able to have a responder analysis where we're actually showing a significant difference is significant, even in this milder disease state population of myosteroid NAFLD1. As far as looking at other biomarkers, I think, you know, MRE is more specific. It picks up more accurately the amount of collagen that's in the liver. And if you look at those scans that were abnormal, defined as greater than 2.9, there was a nice reduction in MRE listography. So I think.

So to be able to have a responder analysis, where we're actually showing significant difference I think is significant even in this milder disease state population of Maestro Napa one as far as looking at other Biomarkers I think MRE is more specific it picks.

So more accurately the amount of college and that's in the liver and if you look at those scans that were abnormal defined as like greater than 2.9, there was a nice reduction in MRI and in more or less geography, So I think.

Dr. Stephen Harrison: I don't know if, from an investor perspective, I'm not sure what you would take from that. But as a clinician, I understand that that's very, very positive data. So, you know, I'll just stop there.

I don't know if from an investor perspective, I'm not sure what you would take from that as a clinician I.

That's very very positive data.

So yes.

I will just stop there, but but.

Dr. Stephen Harrison: But, you know, I think it's looking very good. One of the things that I would add is in the evaluation of an improvement in fibrosis in the phase 3 NASH biopsy study, the way that's done is through a responder analysis. Ergo, we have statistical significance for responder analysis, even in this earlier population. Yeah, I just also think that, you know, one of the things that my staff was setting up was trying to understand the value of these biomarkers and how best to analyze them.

I think it's looking very good.

Yes.

One of the things that I would add is in in the evaluation of an improvement in fibrosis in the phase III Nash biopsy study.

The way that's done as a responder analysis.

Ergo, we have statistical significance for a responder analysis, even in this earlier population.

Yeah, and I, just also think that.

One of the things that we.

MISO example was setting up what's trying to understand the value of these biomarkers and how best to analyze.

Dr. Stephen Harrison: And to Paul's comment, you know, when Dresmetterum is approved as therapy, the clinicians are not going to be looking at the average response on Fibroscan or MRE; they're going to be looking at an individual patient, and so it may well be that a responder analysis for these tests is a more important way and a better way to do the analysis.

And to Karl's comment.

Win win.

Yes, Matt around.

<unk> is approved.

Therapy.

The clinicians are not going to be looking at the average response.

On fiber scan or MRI, <unk> theyre going to be looking at an individual patient.

And so it may well be.

A responder analysis for these task is a.

More important way in a better way to do the analysis.

Sure.

Got it thank you team for the detailed answers.

Becky Tau: Thank you, team, for the detailed answers. Our next question comes from Andrea Tan with Goldman Sachs. Your line is open.

Okay.

Our next question comes from Andrea <unk> with Goldman Sachs. Your line is open.

Andrea Tan: Hey everyone, thanks for taking the question. Remy, maybe just one for you. We'd love to hear you speak more on the market dynamics that you've been learning from this additional work, anything new or different than what you were previously thinking. Thanks. Yeah, Andrea, is your question relative to just NASH overall or the NASH serotic population specifically?

Everyone. Thanks for taking the question maybe just one for you I would.

I would love to hear you speak more on the market dynamics that you've been learning from this this additional work anything new or different than what you were previously thinking thanks again.

Yes, Andrea as your question relative to just Nash overall or Nash cirrhotic population specifically.

Our Nash overall, yes.

Remy Sikija: Yeah, so Andrea, I think, you know, key things that we can talk about that we probably haven't in the past is, you know, considering Nash is a nascent, you know, therapeutic area, you know, the question is, are patients actually being identified? So we've done that sort of work, looking at patient claims data, insurance claims data, and quite surprisingly, we found that about a million people may have already been identified and coded with ICD-10 code for, you know, Nash, and that's, you know, pretty exciting for therapies coming to market because, you know, they would, one can expect a pool of patients that physicians can, you know, actively determine if the drug that's approved is right for them.

Yes, so Andrea I think.

Key things that we can talk about that we probably haven't in the past is.

Considering that Nash is a nascent.

Therapeutic area.

The question is are patients actually being identified so we've done that sort of work looking at patient claims data insurance claims data and it's quite surprisingly we found that about a million people may have already been identified and coded with ICD 10 code for Nash and that's pretty exciting.

Writing for therapies coming to market because they.

One can expect a pool of patients that physicians can add.

Actively determine if the drug that's approved is right for them. So it doesn't take away our responsibility to continue to educate the market, but it's a good finding that we've had.

Remy Sikija: So it doesn't take away our responsibility to continue to educate the market, but it's a good finding that we've had, you know, as of late. And Remy, let me, this is Dr. Harrison, let me just add to that.

As of late.

And Rami let me. This is Dr. Harrison, let me just add to that so just to provide a little bit more color on the progression.

Dr. Stephen Harrison: So just to provide a little bit more color on the progression of the prevalence of more significant NASH, NASH with F2 or greater fibrosis. I published two papers, two prevalence papers, one in Gastroenterology in 2011 and one in J-hepatology in 2021. So over that decade of difference, we've seen a rise in moderate to severe fibrosis from 1.9 to 6% in a cohort of patients. So we're beginning to see in real life what's happened in the modeling of disease progression and prevalence over time.

The prevalence of more significant Nash Nash with F two or greater fibrosis.

Published two papers too prevalent papers, one in gastro in 2011, and one in J herpetology in 2021, so over that decade of difference we've seen a rise in moderate to severe fibrosis.

From like one 9% to 6% and a cohort of patients so.

We're beginning to see in real life play out what's happened in the modeling of disease progression and prevalence over time and so on top of diagnosing bore and beginning to spread.

Dr. Stephen Harrison: And so on top of diagnosing more and beginning to spread the disease awareness news, we're seeing an increase in the prevalence of more diseases as well. So all in all, Andrea, I think this market is ready for NASH therapies. We're excited to be the lead horse at this point.

The disease awareness news, we're seeing.

We're seeing an increase in the prevalence of more disease as well.

So all in all Andrea I think this market is ready for Nash therapies, we're excited to be the lead horse at this point.

Current timelines hit resume around could be on the market two or three years ahead of any other products. So when you think about it all I mean.

Remy Sikija: You know, if current timelines hold out, Resimitaron could be on the market two, three years ahead of any other product. So when you think about it all, I mean, you know, again, we have to look at my extra NASH data. We expect it to be positive. If Resimitaron is the first drug to the market, it couldn't be the backbone of NASH treatment considering it has two to three years of lead time. So it's an exciting place to be.

Again, we have to look at <unk> data, we expect it to be positive if resume <unk> is the first drug to the market. It could be the backbone of Nash treatment are considering it has two to three years lead so it's exciting place to be.

Remy Sikija: Perfect. Let me just follow up on what you were just saying. How are you guys thinking about potential combination therapies at this point? [inaudible] Maybe, you know, Dr. Harrison or Becky would want to elaborate on this. You know, at this point, we are excited about the program, the way it's shaping up, the data that is shaping up, and we see significant commercial potential for resmitirum as monotherapy. So no worries there.

Perfect.

One follow up to what you were just saying how are you guys thinking about potential combination therapies at this point.

Maybe Dr. Harrison, our Becky will want to elaborate on this at this point.

We are excited about the program the way, it's shaping up the data that is shaping up.

The significant commercial potential for resume Durham as monotherapy, so no worries there, but I think as we look at some of the emerging data. We find there is mineral actually has.

Providing additional efficacy orrick it works even better in patients that are on background type two diabetes.

Becky Tau: But I think as we look at some of the emerging data, we find that resmitirum actually has, you know, provides additional efficacy, or it works even better in patients that are on background type 2 diabetes therapy. So in a way, that data is already pointing to a beneficial effect of resmitirum on top of type 2 diabetes patients', sorry,therapies. But maybe Dr. Harrison or, you know, Becky, you want to elaborate further on that when it comes to the combo question.

Therapy. So in a way that data is are you pointing to beneficial effect of <unk> on top of type two diabetes patients I'm, sorry therapies, but maybe Dr. Harrison or back you want to elaborate further on that when it comes to the combo question Yeah.

Becky Tau: Yeah, I would just simply say that, you know, we're doing combos. I mean, these patients, NASH patients, are on many, many drugs. You know, more than half of them are diabetic, as Remy alluded to, and a significant fraction are taking drugs such as SGLT2 inhibitors or GLPs that cause some degree of weight loss.

Yes, I would just simply say that.

We are.

Have are doing combos I mean, these are patients Nash patients.

There are many many drugs.

More than half of them are diabetic as Randy alluded to and.

A significant fraction are taking.

Drugs, such as <unk>, two inhibitors or <unk> that cause some degree of weight loss. So they are on a stable background therapy that allows us to look at.

Becky Tau: So they're on stable background therapy that allows us to look at whether resmetarum has an enhanced effect in combination with those drugs. So those are some of the things that we will be – we've talked about a little bit in the past with our open-label study, but we'll also be talking about it from the Mystronaphyl data set. Steven, do you want to add any comments to that?

Whether it's a matter of them has an enhanced effect.

In combination with those drugs. So those are some of the things that we will be.

We've talked about a little bit in the past with our open label.

Study.

But we'll also be talking about it from the milestone Apple dataset.

Stephen did you want to add any comments to that.

Dr. Stephen Harrison: Well, just to say that we understand that one size doesn't necessarily fit all, and ultimately, you know, we want to reach as many patients as we can with this disease. And where we're able to combine therapies, we think there is a role, in my opinion, for a THR beta like Madrigals or Esmeterome to be a backbone drug. But it doesn't mean we can't continue to look at synergistic benefits.

Well just to say that look we understand that that one size doesn't necessarily fit all and ultimately we want to get at as many patients as we can with this disease and where we're able to combine therapies. We think there is a role.

In my opinion for a THR beta like madrigals or as a matter of them to be a backbone drug.

But it doesn't mean, we can't continue to look at synergistic benefit and to me the ideal Nash drug is one that's oral it's well tolerated it's safe it can be given for the long haul.

Dr. Stephen Harrison: And to me, the ideal NASH drug is one that's oral, it's well-tolerated, it's safe, it can be given for the long haul, and not only does it have a histopathologic benefit on NASH resolution and fibrosis improvement, but you also get after the extrahepatic manifestations of the disease, the atherogenic lipids, the glycemic control, the lipotoxic fat And so where we're able to leverage the benefit of Resmedarum, targeting the majority of what I just mentioned, and augment that a little bit, as Becky mentioned, with potentially diabetic therapy that we've already shown synergistic effects with relative to some of the outcomes we're looking for.

And not only does it have his to pathologic benefit on Nash resolution and fibrosis improvement, but you also get after the extra hepatic manifestations of disease. The atherogenic lipids, the glycemic control the LIFO toxic that and all those are critically important so.

Where we're able to leverage the benefit of Reds veteran targeting the majority of what I, just mentioned and augment that a little bit as Becky mentioned with potentially diabetic therapy that or we've already shown synergistic effects with relative to some of the outcomes. We're looking for I think that's important it doesn't mean that there aren't other combination.

Dr. Stephen Harrison: I think that's important. It doesn't mean that there aren't other combinations that might work well together, but just taking it one step at a time, first figure out how effective your drug is. How effective is resmedarum? People know that from the data that we're generating in MN1, MN2, and MN outcomes, as well as the open-label extension of the MN1 trial. Huge amounts of data are being generated to really get at what the foundational answer is.

That might work well together, but just taking it one step at a time first figure out how effective your drug is how effective is red <unk> will know that from the data that we're generating and maestro Napoli, one <unk> Nash and Maestro Nash outcomes as well as open label extension of the <unk> Napoli one trial huge amounts of data.

Regenerated to really get at what is the foundational answer what can resume their room do by itself and then begin to look at iterative steps to improve.

Remy Sikija: What can Resmedarum do by itself? And then begin to look at iterative steps to improve. Thank you. Our last question is from Lisa Bayko, with Evercore ISI, Yourland. [inaudible] Hi, thanks for taking my question. You know, Charles, before, I've looked at co-primer endpoints very similar to what you're looking at. Why the change now?

Thanks, everyone.

Thank you our last question from Lisa <unk> with Evercore ISI. Your line is open.

Hi, Thanks for taking my question.

Yes.

Charles before I've looked at co primary end points very similar to what you are looking at why the change now is there anything in the.

Becky Tau: Is there anything in the...that you've observed in the Meister-NAFLD1 study that makes you more or less confident around NASH resolution and fibrosis? And then do you expect these, I guess you're gonna have alignment between FDA and EMA and any power changes, how does it affect powering and whatnot that you have kind of now two shots on goal in a way? Yeah, so I think, you know, one of the kind of confusing words is the word co-primary versus dual-primary. A co-primary means you have to make both primary endpoints. This is not what this is.

That you've observed in the naphtha the MISO Snaffled one study that makes you more or less confident around you know.

Nash resolution and fibrosis.

And then do you expect these I guess youre going to have alignment between FDA and EMA in any power changes.

How does it affect powering or whatnot.

Now two shots on goal in a way.

Yeah. So so I think one of the.

Kind of a little confusing is the word co primary versus dual primary.

Our coal co primary means you'll have to make both primary endpoints. This is not what this is.

Becky Tau: Obviously, we are going to evaluate the percentage of patients that achieve both fibrosis reduction and NASH resolution, but that's not the endpoint. So this is dual primary, and if either endpoint is achieved, either primary endpoint is achieved, then there's an opportunity to submit for approval. We made a decision to include this endpoint, you know, quite a while ago when we believe, based on our data, and from the phase two data, and from the continuing data that we've seen, that Resmedaram is lowering fibrosis biomarkers.

Obviously, we are going to evaluate.

The percentage of patients that achieve both.

Gross reduction in Nash resolution, but that's not the end point. So this is dual primaries and if either endpoint.

Is it Chi EBIT parenting endpoint is achieved then there is the opportunity to submit.

Net for approval.

We.

<unk> made a decision on include excluding this endpoint.

Quite quite a while ago when we.

We believe based on our data and from the phase from the phase II data and from the continuing data.

That we've seen.

That resume ROM.

Is lowering fibrosis, biomarkers, knowing biomarkers and fibrosis on biopsy.

Becky Tau: As we know, it's just biomarkers and fibrosis on biopsy. And, you know, we've discussed many times that the phase two study was not, you know, powered. There weren't a sufficient number of patients to observe the fibrosis endpoint.

And we've discussed many times that the phase two.

Study was not.

Power that we're in a sufficient number of patients too.

To observe the fibrosis endpoint there was an increase in fibrosis responders.

Becky Tau: There was an increase in fibrosis responders, particularly, actually, on both AI technologies. And so we believe that the fibrosis endpoint will be achieved in phase three, and this gives us an opportunity to evaluate both endpoints. So, Lisa, what I would just add is, while we're not going to get into details of our SAP, we have gained statistical power by virtue of committing to the second outcome study, which, which, which makes The Alpha situation for having a second primary pretty much a wash. So it's entirely logical to move fibrosis up into a primary endpoint slot based on the power that we've gained by virtue of doing the second study Okay. And then there's just a commercial question for Remy.

Particularly on actually on both.

<unk> technologies and so.

So we believe that the fibrosis endpoint will be achieved.

In.

The phase III and this gives us an opportunity.

To have to evaluate both both endpoints so Lisa what I would just add is while we're not going to get into details of our.

S P.

We have gained statistical power by virtue of committing to the second outcome study.

Which which.

Which makes.

The.

The alpha situation for having a second primary.

Pretty much awash.

So it's entirely logical to move fibrosis up into a primary endpoint slot.

Just on the power that we've gained by virtue of doing the second study.

Okay.

Just a commercial question for <unk>.

Rami.

I think investors have been asking a lot about sort of the.

Remy Sikija: I think, you know, investors have been asking a lot about sort of the kind of fusion of the obesity market with the NASH market and kind of the rising use of GLP-1s and interest there. And can you maybe talk about how these markets may kind of overlap or what the increased use of GLP-1 and any influence of that on the opportunity for Riz Mataram and NASH. Yeah, I think you know, the answer is similar to the sort of question and the answer we gave around combo therapies. So, you know, with the current sort of treatment paradigm for type 2 diabetes and obesity, when we talk to the clinicians, there's a very high unmet need.

Fusion of the obesity market with the Nash market and kind of the rising use of guilty ones and interests there and can you maybe talk about.

These.

These markets may kind of overlap or what the increase use of G. L. P. One in any influence of that on the opportunities for at risk matter Rodman Nash. Thanks.

Yes, I mean, I think the answer is similar to the sort of question and the answer we gave around combo therapies.

So you know what.

With the current sort of treatment paradigm for type two diabetes and obesity when we talk to the treaters, there's very high unmet need so.

Remy Sikija: I mean, it's one of those things; physicians are actively waiting for NASH-specific drugs, drugs that work in the liver, that are approved by the FDA. So are patients going to be on background therapy for type 2 diabetes and obesity by the time the resumator arm launches? The answer is yes.

I mean, it's one of those things physicians are actively waiting for Nash specific drugs drugs that work in the liver that are approved by the FDA. So are patients going to be on background therapy.

Or type two diabetes and obesity by the time resume launches the answer is yes.

But the attractiveness the commercial potential.

Remy Sikija: But you know, the attractiveness, the commercial potential is not diminished by any of that. And also remember, I mean, NASH, as far as unmet need and patients are concerned. The size of the population, I mean, it's going to support multiple drugs. And we really have to think about, you know, different solutions for different patients. But being a leader, being the first to market in a high unmet need market across the continuum of NASH, it seems like, as far as our phase 3 trials are concerned, it's a good place to be.

Is not.

Diminished by any of that and also remember I mean Nash as far as unmet need in patients the size of the population I mean, it's going to support multiple drugs and we really got to think about different solutions for different patients, but being a lead horse being the first to market.

In a high unmet need market across the continuum of Nash.

As far as our.

Phase II trials its a good place to be.

Remy Sikija: So, what I would add to that is we have a significant number of patients who are on stable doses of SGLT2s and GLP1s in the Meister and Nash study, which means that on biopsy after being on the drug for six months or more, they still have NASH. So we have to see ultimately what those drugs show in their own phase three studies. But that doesn't, in any way, go against what Remy just said about the commercial opportunity in any event.

No.

What I would add to that is we have a significant number of patients who were on stable doses of <unk> twos and GOP ones in the Maestro Nash study.

Which means that on biopsy after being on the drug for six months or more.

They still had Nash.

We have this will have to see ultimately what those drugs show in their own phase III studies.

But that doesn't in any way.

Go against what room, he just said about the commercial opportunity in any event.

Excellent. Thank you so much.

Remy Sikija: Excellent. Thank you so much. Thank you. I would now like to turn the call back over to Dr. Okay, thanks. I want to first thank Dr. Harrison for spending some time with us today. This is a pivotal time for Madrigal.

Yes.

Thank you I would now like to turn the call back over to Dr. <unk> for closing remarks.

Okay. Thanks, I want to first thank Dr. Harrison for spending some time with us today.

Dr. Friedman: I'm pleased with the progress that we've made. Our clinical development program continues to advance with multiple data presentations at ESOL, followed by top-line results for the biopsy study in the fourth quarter. The new outcomes trial we announced today further strengthens the program, we think both clinically and commercially, and we're in a strong financial position for the road ahead. So I want to thank all of you for tuning in today, and we look forward to seeing many of you in London for the ESOL meeting. This concludes. Thank you for participating. You may now disconnect. transcript Emily Beynon

This is a pivotal time for madrigal.

Pleased with the progress that we've made.

Our clinical development program continues to advance with the multiple data presentations of diesel followed by topline results for the biopsy study in the fourth quarter.

The new outcomes trial, we announced today further strengthens the program, we think both clinically and commercially.

And we're in a strong financial position for the road ahead. So I want to thank all of you for tuning in today and we look forward to seeing many of you in London for the East will meeting.

This concludes.

So thank you for participating you may now disconnect.

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