Good day, ladies and gentlemen, and welcome to the Madrigal Pharmaceuticals MAESTRO- NAFLD- 1 Top Line Data Conference Call. At this time, all participants are in a listening mode. Following brief remarks from the company, we will conduct a question-and-answer session, and instructions will follow at that time. If anyone shall require operator assistance, please press star then zero key on your touch-tone telephone. As a reminder, this call may be recorded. I would now like to introduce your host for today's conference, Dr. Paul Friedman, Chairman and Chief Executive Officer of Madrigal. Dr. Friedman, you may begin. Thank you. Good morning, and thanks for joining our call. Next slide. This is 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. Next slide. The purpose of this call is to review top-line data from our phase III MAESTRO-NAFLD-1 study of resmetirom. As most of you have probably seen, we issued a press release this morning with the results we'll be referencing on the call. Before turning the call over to Becky Taub to summarize the data, I'd like to share some initial thoughts and provide background on our phase III program. The positive results we announced today represent an important step forward for Madrigal as we pursue our goal of making resmetirom the first approved treatment for patients with non-alcoholic steatohepatitis, NASH. The blinded placebo-controlled data from MAESTRO-NAFLD-1 reinforce our belief that resmetirom has the potential to be a transformative therapy for patients with NASH, for which there are currently no approved therapies. With its focus on safety and tolerability as a primary endpoint, MAESTRO-NAFLD-1 is the first positive phase III study of its kind in NASH, and also the first phase III study in NASH that doesn't rely on liver biopsy to identify patients and to measure treatment response. Biopsy is in fact rarely used to manage patients with NASH in clinical practice, so we often describe MAESTRO-NAFLD-1 as a real-world study. As a reminder, our second phase III study, MAESTRO-NASH, is evaluating resmetirom in more than 900 patients with biopsy-confirmed NASH with significant fibrosis. The primary and key secondary endpoints on biopsy are NASH resolution with at least a 2-point reduction in the NAS activity score, NAS, and no worsening of fibrosis at 52 weeks, a fibrosis improvement of one stage with no worsening of NASH, and we also have a key secondary endpoint of reduction of LDL cholesterol. MAESTRO- NASH will continue after 52 weeks as an outcomes trial with the goal of confirming clinical benefit. The MAESTRO studies together comprising well over 2,000 patients are designed to support accelerated approval of resmetirom for the treatment of patients with NASH with significant fibrosis. I'll turn the call over now to Becky to review the top-line MAESTRO- NAFLD results. Dr. Steven Harrison, Principal Investigator of the MAESTRO studies, is also with us today to share his perspective on the top-line data. Becky? Good morning. If we go to slide five, this shows you the basic study design of the MAESTRO-NAFLD. There are four parallel group randomized arms in the study, 80 double-blind, 80, 100 once a day, placebo, and there's an open-label arm, 100 mg that was randomized concurrently with the three double-blind arms, from which we've reported data. In total, 1,143 presumed NASH patients were enrolled entirely in the U.S. 972 randomized to double-blind arms, 171 open-label patients completed randomization of this arm July 1st, 2020. The double-blind randomized arm completed their enrollment in October of 2020. We have additional cohorts ongoing, including a well-compensated NASH cirrhosis open-label arm of more than 150 patients and some additional screen-fail patients from MAESTRO-NASH who had F2, F3 stage fibrosis on biopsy, but their NAS was not qualifying and was less than four. The inclusion and exclusion criteria were similar to the concurrent study MAESTRO-NASH, requiring at least three metabolic risk factors to be screened. The difference between the two studies is that, MAESTRO-NAFLD generally included an earlier fibrosis stage population at accepted sites not participating in MAESTRO-NASH, where FibroScans of greater than 5.5 kPa, which is thought to be the lower limit of fibrosis 1 stage, were allowed, at sites where both MAESTRO-NASH and MAESTRO-NAFLD were being enrolled, patients who had a kPa of 8.5 or greater had to screen for the serial liver biopsy study, MAESTRO-NASH. PDFF was also used as an inclusion criteria of greater than or equal to 8%. As you heard, this is considered a real life NASH study with non-invasive diagnosis and monitoring of patient response. Next slide. We've reported out, as I had mentioned, at AASLD, in November, the 171 patients in the open label non-cirrhotic arm, which was a 52-week study. Just to remind you, all of the patients were in the safety population. We had a 94% completion at 24 weeks, 89% completion at 52 weeks. This was consistent with a 52-week study in general, and similar to the completion rate of our phase II NASH study that's published in The Lancet. The AE discontinuation rate in that study was 1.2%. In the double-blind arm, a total of 972 patients were randomized. 969 patients were in the safety population. 943 patients in the mITT population for evaluation of key secondary and other endpoints. Study remains blinded at the individual patient level. Treatment groups are unblinded in top-line data, except in cases where group unblinding could result in individual patient unblinding. That was pre-specified as any determination that had less than 25 patients in total for that determination. The site data have all been collected, and their final checks are ongoing prior to individual patient unblinding. The objectives of MAESTRO-NAFLD. The primary safety objective was to evaluate the safety and tolerability of once daily oral administration of 80 or 100 mg resmetirom versus matching placebo, as measured by the incidence of adverse events in a timeframe of 52 weeks. It actually includes the one-month follow-up, 56 weeks. The key secondary endpoints were hierarchically controlled statistically, and they included a percent change from baseline in LDL cholesterol, percent change from baseline in ApoB at week 24. Percent change in hepatic fat fraction on MRI-PDFF at week 15. Percent change from baseline triglycerides, baseline ≥150 mg/dL at week 24. And change from baseline in FibroScan CAP and VCTE at week 52. Next slide. This provides additional detail on the study visits and endpoints. Visits were conducted every four weeks, 52 weeks on IP, with a follow-up visit at week 56. Laboratory and imaging assessments were conducted as noted here. The study was monitored every three months, along with MAESTRO-NASH by an unblinded data monitoring committee. There are adjudication committees, cardiovascular and hepatic committees that are blinded to evaluate any potential events. Patients completing MAESTRO-NAFLD-1 can enroll in a 52-week active treatment extension study, MAESTRO-NAFLD-OLE. Next slide. This slide summarizes the impact of COVID on the MAESTRO-NAFLD-1 clinical trial. MAESTRO-NAFLD-1 was conducted from December 2019 to November 2021 during the height of the COVID pandemic. Enrollment into the trial was robust and exceeded the original target of a total of 700 patients. Original intention was that 700 would include the open label and double-blind arm. As you've seen, the enrollment is 1,143, excluding the cirrhosis population, which adds another more than 150 patients. Maximum study withdrawals were patient-determined and occurred at the height of COVID infections in the November 2020 to February 2021 time period. Enrollment itself had been completed in October 2020. As you see from this table, withdrawals were not different according to randomized treatment in the double-blind arms. AE-related withdrawals were uncommon. 21 total AE-related withdrawals occurred in the 56-week study period. As I mentioned, since that number was less than 25, it has not been broken down according to treatment, but is similar to the AE-related withdrawal in the parallel 100 mg open-label arm where the withdrawal was 1.2%. The average COVID-related dose or visit interruption, which was a COVID missed visit or COVID-related missed blister pack delivery, was two visits per patient. If there was a total of 12 visits in the study, two visits on average were missed per patient related to COVID. The MAESTRO-NASH serial liver biopsy study has not been significantly impacted by COVID-related issues or patient withdrawals. The patient determined withdrawal is on the order of 5%-6% for the 52-week time period in MAESTRO-NASH, which is consistent with our pre-COVID expectations. Next slide. The baseline characteristics of the double-blind population are shown here, and this essentially demonstrates a patient population with a similar age to most NASH studies of 56, some female predominance, and consistent with the metabolic risk factors of NASH patients. BMI of 35, type II diabetes about 50%. Hypertension, about three-quarters of the patients. High ASCVD risk score and the baseline lipids are shown here. The baseline FibroScan liver stiffness is about 7.3, and it's significantly lower than MAESTRO-NASH because, as mentioned, this was a generally earlier patient population. The CAP is consistent with steatosis and as is the MRI-PDFF, which is on average about 18%. The next slide shows a review of the primary endpoint, which is safety in the study, including the safety population. Patients with at least one TEAE are shown to be in the 80s in all three treatment groups. At least one serious TEAE is not different, nor is the TEAE count of greater than or equal to Grade 3 severity. Severity was 8%-9% in all of the groups. As mentioned, a discontinuation from study was a total of 21 patients, which is 2.2% for the study. The Grade 1 and Grade 2 AEs were balanced across the arms of the study. AEs over 10% are consistent with what we've observed in our phase II study and also in the open-label 100-mg arm of this study, where there was diarrhea or loose stool at the beginning of treatment that generally resolved and did not lead to study discontinuation. An increase in nausea. If you do the calculation, the 80 mg dose was less than 10% over placebo for diarrhea and 4% for nausea. The 100 mg dose was about 17% excess for diarrhea and 10% excess for nausea. No other AEs were over 10%. Next slide. The hierarchically controlled key secondary endpoints were achieved in this study, including LDL cholesterol lowering, where the results from all of the randomized arms are shown here. The range of placebo was minus 1.7% and then 21% in the open label 100 mg arm, about 13% in the 80 mg arm and about 14.4% in the double-blind 100 mg arm. ApoB, as we've seen previously, is somewhat higher than LDL cholesterol lowering with this mechanism. I'll jump down to triglycerides and just mention that the triglyceride lowering was very robust in all of the MAESTRO treatment arms. The MRI-PDFF at week 16 was the key secondary endpoint, and that was achieved at both 80 and 100 mg, with a P < 0.0001. These results are very consistent with what's been predicted from the phase II and also from what we reported for the 100 mg open label arm, at both week 16 and also shown for week 52, as well in this study. What we've indicated here is that resmetirom has an impact to reduce liver volume of greater than 20%. The actual PDFF needs to be corrected for liver volume, and so that increases the amount of PDFF reduction to 60% and 61% in the open label arm where liver volumes have been measured. Finally, just a comment that lipid reductions were numerically greater in the 100 mg open label treatment arm compared to the 100 mg double-blind arm. Patients in the open label active treatment arm were less impacted by COVID-related dose interruptions than double-blind patients, in part because they completed their randomization certainly slightly earlier, and also because the missed visits due to blister pack production did not impact the open label treatment arm because those patients received study drug in bottles. PDFF reductions were robust in all arms, even though some double-blind patients had COVID-related treatment interruptions prior to the week 16 or week 52 MRI- PDFFs. The next slide comments on the overall safety database that is being accumulated in the number of patients who've already been dosed, based on patients dosed with at least 100 or 80 mg per day and completed in ongoing studies. Resmetirom has dosed the number of subjects in relevant studies that we believe is consistent with ICH guidance for safety database for long-term treatment therapies, indicated as at least 1,500 patients dosed for specified lengths at the top approved dose. We've conducted a total of 12 phase I studies. I will only comment that, as we have previously, that there was no incidence of diarrhea seen in the multiple ascending dose study up to 200 mg. The incidence has been low or nonexistent in other phase I studies. We've completed two phase II studies and have three phase III studies, as mentioned, MAESTRO-NASH, MAESTRO-NAFLD, and then MAESTRO-NAFLD-OLE, which is a 52-week extension study of MAESTRO-NAFLD. In conclusion, next slide, resmetirom was safe and well-tolerated. The top dose of 100 mg as well as 80 mg in MAESTRO-NAFLD. Key secondary endpoints were achieved in MAESTRO-NAFLD at both dose, in both dose groups, as well as in the 100 mg open label arm. Safety and efficacy are in line with expectations from the phase II liver biopsy study and the randomized parallel open label 100 mg arm of MAESTRO-NAFLD. Positive results from this trial support our belief that resmetirom has the potential to be the first medication approved for the treatment of patients with NASH and liver fibrosis. Okay, before taking your questions, we'd like to have Dr. Harrison share his perspective on the top-line data. Yeah. Thanks, Paul, and thanks, Becky, for that wonderful presentation. I mean, to me, just looking at where we are in the field of NASH, I think this is a great story. You know, all the commentary that you made, Paul, at the beginning, I think is spot on. This is the first phase III non-liver biopsy-based trial using non-invasive tests to enroll our patients and then follow them over time. We're dealing with a once-a-day oral medication, and when we look at the landscape, we know that safety and tolerability are really important. This is a patient population that is generally asymptomatic. They'll need to take this medication for a prolonged period of time. As a clinician and somebody that sees patients with NASH, you know, I can tell you that our patients want a therapy that's not going to, that's not gonna cause a lot of issues for them. It's something that they can take over the long haul and have a benefit from. The primary endpoint of this study was safety and tolerability. I think this very large study shows that resmetirom, even at the higher doses of 80 and 100 mg is well tolerated and certainly safe. I think that's a great news story. Then when we look at the secondary endpoints of key non-invasive assessments, I just... You know, what stands out to me is the positive impact of the PDFF, you know, and where that stacks up in the field. I think it's important to, you know, to reflect on that as well. When we looked at the post-hoc analysis of the phase II-B trial, we identified that a change in PDFF of 41.5% gave us the best sensitivity and specificity for resolution of NASH. In fact, if you just looked at what we call responders, which is those with a 30% relative reduction in liver fat, that was linked with a significant odds ratio to NASH resolution that increased as you went to 40% overall resolution or improvement in PDFF and 50% relative improvement in PDFF. Subsequent to that, paper by Rohit Loomba and Stein et al., published in Clinical Gastroenterology and Hepatology, highlighted again that hitting relative reductions of this magnitude was linked to NASH resolution. I think the key take-home point from PDFF change with this particular mechanism is that we have to look at each of these changes in PDFF relative to the mechanism of action. There's significant data out there relative to the thyroid hormone receptor beta drug when we look specifically at PDFF. I think the data we're seeing today, despite all the issues with COVID and dose interruptions, is that we still saw a robust reduction in liver fat content. The LDL changes that we see, again, are consistent with the phase II data, consistent with the open label arm that we've already shown, and again, I think are encouraging for our patients with NASH that often have the comorbidity of hyperlipidemia. Maybe I'll stop there, Paul, and just say again, very pleased with the results that we are reporting today. Okay. Thanks very much, Steven, for those remarks. I'm gonna ask the operator to open the call for Q&A with the caveat that our responses will be based on the top-line data as additional analyses are ongoing, and we do wanna preserve some of the findings for presentation at upcoming scientific congresses. Operator, please open the conference call for Q&A. Thank you. Ladies and gentlemen, if you have a question at this time, please press the star and then the one key on your touchtone telephone. One moment for our questions. Our first question comes from Andrea Tan with Goldman Sachs. Your line is open. Hi, everyone. Thanks for taking the question and congratulations on the data. Two questions for me. I recognize that the data collection is still continuing, but just curious if you could share anything on what you saw with the FibroScan measurements or other fibrosis biomarkers and when we might see that data? Those data have not been analyzed and, you know, analyses are being conducted, will be conducted over the next few weeks. We do expect to have additional data to share, but within a reasonable timeframe from today, without specifying the exact date. Got it. Just with the totality of the data you have now, does this change your outlook for MAESTRO-NASH in any way? Can you just confirm that this is still on track for top-line release in the third quarter of this year? MAESTRO-NASH is still on track for the third quarter. As we had indicated in making a decision on the dosing and strategy for MAESTRO-NASH, we believe that both doses, 80 and 100 mg, will successfully achieve the endpoints. Clearly, this study shows that, and it also increases confidence in the higher dose group of 100 mg, where we had really limited data until the open label arm of MAESTRO-NAFLD-1 and now this blinded 100 mg dose arm. Great. Thanks again. Congratulations. Our next question comes from Akash Tewari with Jefferies. Your line is open. Hey, thanks so much. So look, on the diarrhea signal, there, what was the percent of patients who were experiencing diarrhea at week 12 versus week 52? Does the diarrhea seem to be transient as we've seen historically? And did you introduce anything in your protocol to help patients manage this side effect? We also noticed on MRI-PDFF relative change for placebo, it was 6% at week 16, but it was +8% at week 52, which is a notable worsening over time. How surprising was that signal internally, and what are your kind of expectations for the phase III NASH study on MRI-PDFF relative change at week 52? Thank you. First of all, this is diarrhea is mild, typically single or a few loose stools at the beginning of therapy. In phase II, we showed that there was no increase in diarrhea, except at the initiation of therapy. This study we expect to be consistent with that open label arm we have analyzed, which is consistent with that. This study has not yet been analyzed. You know, we're confident that it will see the same thing, that this is a self-limited mild increase that appears to be specific to this patient population as it has not been observed in healthy volunteers at a 100 mg dose or other doses used in phase I studies. In terms of the PDFF, it's very analogous to what we saw in phase II. First of all, let me just say that I think if you look at the placebo data in the study, this shows you that this is a well-controlled study. The placebos had well-managed lipids. They didn't have an increase as we sometimes see in, you know, LDL or triglycerides during the study. The reduction in PDFF in placebo. The slide has a typo. It should say - 8%. Minus 6% and minus 8% is also similar to what we saw in the phase II study where, you know, the placebos had a similar PDFF reduction. There's nothing in this study that's inconsistent with what we've seen previously in the placebo. There's a clear differentiation between resmetirom and the placebo throughout the duration of this study at both 16 weeks and 52 weeks. Great. Thanks for clarifying that. Appreciate it. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Good morning, team, and congratulations to the data. I have two questions for you. The first question is, team, could you maybe comment on a little bit more whether on the safety side, did you see any abnormalities or deviations in the PGR axes, any bone biomarker differences such as the DEXA, any patients exhibiting liver enzyme elevations? I have a second question. Okay. What we can comment on is that we did serial DEXAs at week 36 in phase II. There was no change with resmetirom treatment. We've stated that we analyzed serial DEXAs in the 100 mg open label arm, that we did not see change in DEXA in that population. Clearly, we have not analyzed the DEXA data yet in this study. But we do not anticipate based on our previous data and the way resmetirom works, you know, that it's a TR beta agonist, very selective in the liver that there will be no bone findings at all in any non-clinical studies, that we anticipate this will continue to be demonstrated in this study. The liver enzymes we've also shown from the parallel open-label non-cirrhotic arm and the fact that the liver enzymes, which are elevated at baseline, go into the normal range during the course of weeks. We have not analyzed the liver enzymes yet. This also was seen in phase II. There's nothing to suggest that these arms will be any different, and we expect to see the same trajectory of liver enzymes in this study. What about the thyroid axis, too? Oh, thyroid axis. Yes. The thyroid axis has been thoroughly evaluated with this drug and there are no changes. We published in phase II no changes in TSH, no changes in the active thyroid hormone free T3. There's a very small shift around 11%, not clinically meaningful, decrease in free T4, which is a liver effect that results in converting the prohormone free T4 into the active hormone in the liver. But other than that, there are no thyroid hormone relevant changes, no symptoms related to either hypo or hyperthyroidism. Essentially this has been shown many times. It was shown also in the open-label non-cirrhotic arm of the study and we expect it to be exactly the same in this study. Thank you, Becky. Yeah, go ahead. Sorry for interrupting you, Becky. Thank you so much for the color. If I may ask a question to Dr. Harrison, who is also on the line is, Dr. Harrison, in the past you presented really great analyses of MRI-PDFF predicting NASH resolution and fibrosis. I would love to hear your thoughts now after seeing the MAESTRO-NAFLD data where, you know, we see a relative fat reduction of 48% and more than 50% of patients achieving greater than 50% fat reduction. I think the fundamental question that comes from a lot of our clients are how do we take that and extrapolate what the responses could be for NASH evolution and fibrosis? If you could provide us some color around that central question, that could be helpful. Congrats again, team. Yeah. Thanks, Yas. Appreciate the question. I think that's, you know, that's kind of the fundamental question around this particular non-invasive test, and it's something that we elaborated on a bit at NASH-TAG as well. You know, I think it's becoming clear that MRI-PDFF can be used as a marker in specific mechanisms of action relative to NASH. We see a lot of data now being generated with MRI-PDFF and we have a lot of data relative to the thyroid hormone receptor beta agonist, particularly when we went back and mined the post hoc data from the phase II. In addition to that, we have data from FXRs and a nice review written by Stein and Loomba published in CGH in 2020. Again, just highlighting a couple points from that paper. Again, that's a pooled analysis of data. From there, if you look at MRI-PDFF responders as defined by a 30% relative reduction in liver fat, 41% had NASH resolution. When we look at the odds ratio for NASH resolution achieving that 30% relative reduction in liver fat, it was 5.45. Now, that's NASH resolution. We still don't have that same analysis with fibrosis. It's a more challenging endpoint to hit just by looking at MRI-PDFF. I think the data's still out relative to what amount of fibrosis we can expect to see on liver biopsy relative to MRI-PDFF improvement. Once you get above PDFF reductions of 50% or so, there is data with resmetirom that we are seeing fibrosis improvement. But just caution that data there is a little, it's small. Most of our data is around improvement in the NAFLD Activity Score of at least two or more points and NASH resolution. I just, you know, highlight the fact that that is encouraging to see consistent data not only in the phase II- B trial where we treated patients for nine months, predominantly with lower doses. When we looked at the open label arm, we saw robust reductions over 52 weeks, consistent again in this double blind arm. The totality of the data speaks to the fact that we are seeing significant reductions in liver fat content and historically, and when looking at other mechanisms where we have correlated improvement in histopathology with PDFF, we're hitting that mark that I spoke about. For me, looking forward, I'm very encouraged by this reduction. Again, just to summarize, we have more data on NASH resolution than fibrosis improvement, but nonetheless the data is quite encouraging. Yeah. I just would add to that because I think that with our data, and I totally agree with what Steven said, that it's hypothesis generating. With our mechanism, the 30% reduction did correlate with more patients achieving the 1-point fibrosis reduction. So it actually correlated with improvement in every component, not only steatosis, but ballooning inflammation and also fibrosis reduction. A high percentage of patients who achieve NASH resolution in our phase II study also did achieve fibrosis reduction. Clearly, you know, we're projecting that and hoping that that also is validated by data from our phase III studies. Thank you. Our next question comes from Liisa Bayko with Evercore ISI. Your line is open. Hi. Congratulations on the data, and just a couple additional questions. Can you comment at all on discontinuations by cohort or, if you can't, give us any numerical, can you just comment on any sort of high level differences between the arms? In terms of? Discontinuations by cohort. Oh, okay. We showed a slide, which was slide eight. You can see that the discontinuations in the study were not different between the cohorts in this study. If we compare it to the parallel arm, the open label non-cirrhotic arm, the discontinuation rate at the 100 mg dose was significantly lower in the open label arm. It was a 89% completion rate and 94% completion at week 24. Okay, great. Thank you. Just could you. I know you said that you'll do one more public disclosure at some point before you present at a medical conference. Could you give us a sense of what we can expect in terms of what you might release at that public disclosure, just so we kind of can anticipate what's coming? What medical conference are you targeting? Would this be EASL? Thanks. The next major medical conference is EASL, which has been delayed to June. We mentioned in our discussion that we have additional safety readouts and imaging readouts, some biomarker readouts from the study. We have not at this point made a decision of what exact readouts we are going to share. We do plan to do that, as we mentioned in the press release. Okay, thank you. Thank you. Our next question comes from Ritu Baral with Cowen. Your line is open. Good morning, guys. Thanks for taking the question. Becky, what was the most common AE related to discontinuation in this study? And how are you looking at the nausea and diarrhea rates compared to the totality of the clinical data generated? They do seem like a little bit of an outlier, especially compared to the open label. You know, are there any changes in formulation required for blister packs or anything that- No. You might kind of look at? Rates are comparable to the open label. It's the same pills. Just in one case, in the open label, the pills are in a bottle. And in the other case, it's a blister pack, which the patients are actually taking multiple pills because of blinding and et cetera each day, three pills each day to blind for placebo and other changes. They're exactly the same pill. The AE rate is in line. And clearly, you know, these are mild AEs. The discontinuation rate of you know 1.2% in the open label arm is very similar to a discontinuation rate of 2.2% in all three arms of the blinded study combined. We do believe it's consistent. Got it. And even in the.. Also with- Oh, go ahead, sorry. I was just gonna say it's also consistent with the level that we saw in phase II, so it's been consistent across the studies. Got it. Even in the press release you mentioned, you know, the event was related to, sorry, increased stool frequency at the beginning of therapy. When you define beginning of therapy, just as we sort of look at our models, is that a 12-week timeframe where these events tend to occur? Is it like a- No. 2- to 4-week timeframe? It's right away. No, it's within. Okay. the first week or two. They taper off within First dosage. Yeah. Got it. I know you had answered other AE endpoints. Could you just address if you've been able to look at heart rate at all? You said the decks weren't analyzed, but have you or the DMC been able to look at heart rate and have a takeaway there? We've looked at heart rate in, you know, thousands of patients. I mean, this is, you know, thyroid hormone-mediated changes in heart rate can be seen in phase I. So there is no change in heart rate with this drug. That said, yes, of course, there is monitoring of heart rate at every visit. There are EKGs, you know, during the study. There have been, you know, special studies, as well, the standard studies that one does to evaluate any changes on EKG that are box checking exercises. Nothing special with this particular drug. So there's no suggestion at all anywhere that the drug changes heart rate and, you know, I guess we should leave it at that. Leave it at that. Got it. Quick last question for Dr. Harrison. Dr. Harrison, you discussed the PDFF levels specific for this mechanism that are indicative of potential primary endpoint changes. If you had to pick a second, either biomarker analysis or endpoint to put together with PDFF that would give you an even better idea, what would you pick for this, for the THR mechanism? Yeah, that's a good question. I mean, I think at the end of the day, what we've learned is that, you know, additive NITs are very helpful in understanding what's happening histopathologically with this disease. The one variable that tends to stand out over and over again that's agnostic to mechanism is ALT reduction. As a clinical hepatologist, I can tell you, I use ALT reduction and normalization to monitor every liver disease that I treat. You know, just at top level, if I were looking at a combined NIT assessment, I would look at PDFF and ALT. Super. Thanks so much. That's specifically for histopathology, though, and I think it's important to remember, and I show this in a lot of my slides, when we're treating NASH patients, there's more to it than just the liver. We also want to address their comorbidities, and I think it's also important to look at what's happening relative to those assessments as well. Thank you. Our next question comes from Jon Wolleben, JMP Securities. Your line is open. Hey, good morning. Congrats on the data. Just wanted to clarify a point from earlier. Becky, did you say that the placebo PDFF reduction was an 8% decrease at week 52? Was also hoping you'd comment on any weight loss in the study between the arms. Yeah. Apologize for the typo. Yes, it should be minus 8%. 8% reduction or minus 8%, and minus 6% at week 16. We have not yet analyzed the weight loss data in the study. Obviously that's one of the things we will be looking at in both the drug treatment and placebo arm. Got it. Just one maybe mechanistically, it seems like we're seeing the most bang for our buck historically, at least in terms of liver fat in the first three-four months, but then you're seeing some improvements over time in other markers like ALT in previous datasets. What else is going on at the level of the liver when patients enter resmetirom for extended periods of time? Do you have any insights there based on what we've seen? Well, we have hypotheses as to what is going on over time. You know, resmetirom is involved in important pathways in the liver. Certainly, reduction of lipotoxic inflammatory fat occurs rapidly by several different pathways, predominantly fatty acid oxidation in mitochondria. But it also is very important for overall liver health and we know that NASH patients have a disruption in their thyroid beta axis, thyroid beta receptor function in the liver, specifically in the liver, and that they have a deficient thyroid hormone receptor beta activity. What is known is that the thyroid hormone in the liver, in hepatocytes is important for mitochondrial biogenesis and mitochondrial health, which are abnormal in NASH patients. We believe that over time, the liver function in many ways is actually benefited by this mechanism. That's very helpful. Congrats again on the data. Our next question comes from Ed Arce with H.C. Wainwright. Your line is open. Great. Thanks for taking my questions. Let me add my congrats on this data set. A couple questions for me. I wanted to ask you about, to better explain the significance of the liver volume corrected PDFF, you showed minus 60% at week 16 and minus 61% at week 52. Just again, the significance of that and how to interpret this relative to other drugs in the space, especially those that may not reduce liver volume. Just as a side note, will we get this data for the randomized double blind arms at some point? I have a follow-up. Okay. Thank you. The purpose of showing this here was simply to say that, you know, First of all, NASH patients have very large livers to start with. You know, if the average liver size in an adult is around 1400 CCs, the NASH livers are over 2000 CCs. They're very elevated, both non-cirrhotic and cirrhotic NASH. We investigated the effect of resmetirom on liver volume and found that it resulted in about 20% reduction in liver volume at the doses used here in this 100 mg open label arm. The point of this particular slide was simply to say that if you have a smaller liver, whatever fat is in the liver will appear more concentrated, which will give you a higher PDFF signal, and that's why the correction is shown. The mechanism behind the liver volume reduction and why we're getting greater liver volume reduction with resmetirom than simple weight loss where PDFF goes down. Placebo or other mechanisms that reduce weight may reduce PDFF, but they don't reduce liver volume as much. There's a component of this that is greater with resmetirom. In terms of the mechanism, that is something that we're investigating further, whether our work on PDFF is done by Mustafa Bashir at Duke University, and they have automated the measurement of liver volume, and whether or not we'll do liver volumes in this, you know, 1,000-patient study or simply rely on the data we have is, we obviously haven't done it yet. But it is something that can be done in an automated way. Great. Can we expect to get this data set for the two double blind arms in the future? Yeah. That I'm saying that we have not measured it. The double-blind arms, it's a large number of patients, so that's a lot of data. Right. We haven't made a decision as to whether we're measuring liver volume in this entire data set. Okay. Understood. Just wanted to ask you about the additional data sets. I know you haven't made any decisions yet of how much or what and when, but clearly looking for the imaging data, both FibroScan and MRE, and that would be something we could expect in the relative near term, correct? I think it's fair to say that we will focus on those endpoints that are of greatest interest and understanding in terms of the study. Those are what we're focused on and also any kind of safety data that would be key in the study. We believe we've you know, we're not seeing any safety that's inconsistent with prior studies. For example, we've been asked about the serial DEXA scan. That would be one thing. I also wanna comment that we had a positive patient-reported outcome from our phase II study that's published, where patients responding to resmetirom showed an improvement in quality of life. Those are analyses that we will be conducting. Those are more likely to take longer. Those are data that as well that you can expect down the road. Great. Thanks, Becky, and congrats again on the data. Thank you. Our last question, Eliana Merle with UBS. Your line is open. Hey, guys. Thanks for squeezing me in, and congrats on the data. Maybe just a last one for Dr. Harrison. Just in terms of maybe, you know, longer term thinking about your prescribing, I guess, how important is, you know, the histology endpoint on fibrosis at the 52-week endpoint thinking about the NASH phase III readout later this year, just in light of the discussion around some of these, you know, secondary biomarkers as well as, you know, the increasing importance of non-invasive tests relative to sort of biopsy. I guess, how are you thinking about how your prescribing, you know, patterns might be influenced by the biopsy data relative to, say, some of these endpoints, like you mentioned, say, ALT in terms of being predictive of fibrosis? Thanks. Yeah. I think I'm gonna let Steven also comment on this, but there's a growing body of evidence that, for example, you know, an elevated MRE is predictive of worse or increased MRE over a certain level is predictive of a worse outcome. There's some data with FibroScan along those lines as well. A bunch of the fibrosis biomarkers such as ELF and potentially PRO-C3 may have some predictive benefit as well. Of course, we in our phase III study, in addition to liver biopsy, you know, and in this study as well, we'll have these kinds of biomarkers to correlate with response. Steven, do you wanna just comment more on that? Yeah, I think it's a great question. You know, as a clinician, we worry about progression to cirrhosis and decompensation. You know, what we don't talk a lot about is halting progression of disease, which I think is just as important as regression if I can prevent a patient from progressing from one stage to the next. Yes, we'd like to have regression of disease and cure, for sure. One thing we don't talk a ton about, and I think it's important to note, is if I can arrest disease in a certain spot and you're asymptomatic and I can keep you there, I think that's also a very positive thing. As Becky alluded to, you know, we're measuring lots of non-invasive tests. More and more, we're learning how these tests correlate to outcomes. We see significant data sets coming out linking MRE to outcomes. Same thing for ELF, as Becky mentioned. We now have it with FIB-4. We have it for FibroScan as well, the combination of FIB-4 and FibroScan. I think it's also important to realize that you don't get fibrosis without liver cell damage and inflammation. There's a collinearity that exists between NASH and fibrosis. I think it's clearly been shown in multiple different data sets, including all the way back to elafibranor with GenFit, that where you improve the NAFLD Activity Score, we see improvement in fibrosis. I think at the end of the day, it's all important. You need to improve the comorbidities of these patients. You need to improve the histopathology, not only fibrosis, but also underlying NASH. At the end of the day, you know, we're gonna have that data available, and I'm very hopeful that we'll be able to hit on all of those endpoints. This is Paul. Thanks very much for those remarks, Steven, and for joining us. I'd like to thank all of you for joining us today. As I mentioned in my opening comments, these positive top-line data reinforce our belief that resmetirom has the potential to be a transformative therapy for patients with NASH, and we look forward to speaking with you again soon. With that, I'd ask the operator to end the call. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.