Madrigal Pharmaceuticals, Inc. (MDGL) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to the Madrigal Pharmaceuticals MAESTRO-NAFLD-1 Top Line data Conference Call. [Operator Instructions] 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 a 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. Next slide. The purpose of this call is to review top line data from our Phase III MAESTRO-NAFLD-1 study of resmetirom. And 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 nonalcoholic steatohepatitis, NASH. The blinded placebo-controlled data for 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 NASH 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. Stephen Harrison, principal investigator of the MAESTRO studies is also with us today to share his perspective on the top line data. Becky?

SP-2 Good morning. So if we go to Slide 5, this shows you the basic study design of the MAESTRO-NAFLD. There are 4 [ ROL ] group randomized arms in the study. There is [indiscernible] 80-, 100-milligram once a day, placebo. And there's an open-label arm, 100 milligrams, that was randomized concurrently with the 3 double-blind arms from which we've reported data. In total, 1143 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 1, 2020. The double-blind randomized arm [ completed ] their enrollment in October of 2020. 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 it was less than 4. The inclusion-exclusion criteria were similar to the concurrent study, MAESTRO-NASH, requiring at least 3 metabolic risk factors to be screened. The difference between the 2 studies is that MAESTRO-NAFLD generally included an earlier fibrosis-stage population at accepted sites not participating in MAESTRO-NASH, where FibroScans 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%. And as you heard, this was -- this is considered a real-life NASH study with noninvasive diagnosis and monitoring of patient response. Next slide. So 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 Lancet. The [ AE ] discontinued study -- discontinuation rate in that study was 1.2%. In the double-blind arms, 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 and that was prespecified 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 milligrams resmetirom versus matching placebo as measured by the incidence of adverse events in a time frame of 52 weeks, it actually includes the 1-month follow-up 56 weeks. The key secondary end objectives were hierarchically controlled statistically, and they included a 1% 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 16, percent change from baseline in triglycerides, baseline greater than or equal to 150 milligrams per deciliter at week 24 and change from baseline in FibroScan CAP and VCTE at week 52. Next slide. So this provides additional detail on the study visits and endpoints. Visits were conducted every 4 weeks, 52 weeks on IP with a visit, a follow-up visit at [indiscernible]. Laboratory and imaging assessments were conducted as noted here. And the study was monitored every 3 months, along with MAESTRO-NASH by an unblinded data monitoring committee, and there were there were -- there are adjudication committees for cardiovascular and hepatic committees that are blinded to evaluate any potential events. Patients completing MAESTRO-NAFLD can enroll in a 52-week active treatment and extension study, MAESTRO-NAFLD-OLE. Next slide. This slide summarizes the impact of COVID on the MAESTRO-NAFLD clinical trial. MAESTRO-NAFLD 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, that 700 would include the open-label and double-blind arms. And 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. And enrollment itself had been completed in October of 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, to 21 total related withdrawals occurred in the 56-week study period. And as I mentioned, since that number was less than 25, it has not been broken down according to treatment, but it's similar to the AE-related withdrawal in the parallel 100-milligram open-label arm where the withdrawal was 1.2%. As the average COVID-related dose or visit interruption, which was a COVID missed visit, or COVID-related missed blister pack delivery, was 2 visits per patient. So if there was a total of 12 visits in the study, 2 visit 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 determine withdrawal is on order of 5% to 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 2 diabetes, about 50%. Hypertension, about 3/4 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 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 1 TEAE are shown to be in the 80s in all 3 treatment groups, at least 1 serious TEAE is not different nor is the TEAE count of greater than or equal to Grade 3 Severity. Severity was 8% to 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 and AEs over 10% are consistent with what we've observed in our Phase II study and also in the open-label 100-milligram arm of this study, where there was a diarrhea or loose stool at the beginning of treatment that resolved -- generally resolved and did not lead to study discontinuation. And then an increase in nausea. If you do the calculation, the 80-milligram dose was less than 10% over placebo for diarrhea and 4% for nausea. And the 100-milligram 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 end points were achieved in this study including LDL cholesterol, lowering where the results from all of the randomized arms are shown here. So the range of placebo was minus 1.7% and then 21% in the open-label 100-milligram arm, about 13% in the 80-milligram arm and about 14.4% in the double line 100-milligram arm. ApoB, as we've seen previously, is somewhat higher than LDL-cholesterol lowering with this mechanism. And 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 milligrams with P less than 0.0001, and these results are very consistent with what's been predicted from the Phase II and also from what we reported for the 100-milligram open-label arm at both week 16 and also shown for week 52 as well in the study. And what we've indicated here is that resmetirom has an impact to reduce liver volume of greater than 20%. And so the actual PDFF that needs to be corrected for liver volume. And so that increases the amount of PDFF reduction up to 60% and 61% in the open-label arm where liver volumes have been measured. And finally, just a comment that lipid reductions were numerically greater in the 100-milligram open-label treatment arm compared to the 100-milligram double-blind arm. Patients in the open-label active treatment arm were less impacted by COVID-related dose interruptions, then double-blind patients, in part because they completed the randomization 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-PDFF. The next slide comments on the overall safety database that has -- that is being accumulated in the number of patients who have already been dosed. Based on patients dosed with at least 100 or 80 milligrams for dose -- per day and completed an ongoing study, so it's not around the dosed number of subjects in relevant studies that we believe is consistent with ICH guidance for safety database for long-term treatment therapies indicated is at least 1,500 patients dosed for specified lengths at the top approved dose. We've conducted a total of 12 Phase I studies. And I will only comment that as we have previously, that there was no incidence of diarrhea seen in the multiple that attending -- multiple ascending dose study up to 200 milligrams. And the incidence has been low or nonexistent in other Phase I studies. We completed 2 Phase II studies and have 3 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 at the top dose of 100 milligrams as well as 80 milligrams in MAESTRO-NAFLD. Key secondary endpoints were achieved in MAESTRO-NAFLD at both dose groups as well as in 100-milligram 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-milligram 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.

Yes. Thanks, Paul, and thanks, Becky, for that wonderful presentation. So I mean, to me, just looking at where we are in the field of NASH, I think this is a great story. Paul, 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 noninvasive 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, really important. This is a patient population that is generally asymptomatic. They'll need to take this medication for a prolonged period of time. And as a clinician and somebody that sees patients with NASH, I can tell you that there are patients who want a therapy that's not going to cause a lot of issues for them. It's something that they can take over the long haul and have a benefit from. So the primary endpoint of the study was safety and tolerability. And I think this very large study shows that resmetirom, even at the higher doses of 80 and 100 milligrams, is well tolerated and certainly safe. So I think that's a great new story. And then when we look at the secondary end points of key noninvasive assessments, I just -- what stands out to me is the positive impact of the PDFF and where that stacks up in the field, I think it's important to reflect on that as well. So when we looked at the post-hoc analysis of the Phase IIb 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 ] published in Clinical Gastroenterology and Hepatology highlighted again that hitting relative reductions of this magnitude was linked to NASH resolution. So 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. And there's a significant -- there is significant data out there relative to the thyroid hormone receptor beta drug when we look specifically at PDFF. And so 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. So 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. So maybe I'll stop there, Paul, and just say again, very pleased with the results that we are reporting today.

Okay. Thanks very much, Stephen, for those remarks. I'm going to ask the operator to open the call for Q&A with a caveat that our responses will be based on the top line data as additional analyses are ongoing, and we do want to preserve some of the findings for presentation at upcoming scientific congresses. Operator, please open the conference call for Q&A.

[Operator Instructions] Our first question comes from Andrea Tan with Goldman Sachs.

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 are -- have not been analyzed and now 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 time frame from today without specifying the exact date.

Got it. And then just with the totality of the data you have now, does this change your outlook for MAESTRO-NASH in anyway? And then 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 milligrams, will successfully achieve the endpoints. Clearly, this study shows that. And it also increases confidence in the higher dose group of 100 milligrams, where we had really limited data until -- first, the open-label arm of MAESTRO-NAFLD and now this blinded 100-milligram dose arm.

Our next question comes from Akash Tewari with Jefferies.

So look, on the diarrhea signal, what was the percent of patients who're 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 the side effect? And then we also noticed on MRI-PDFF relative change for placebo. It was 6% at week 16, but it was plus 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?

So first of all, this is -- diarrhea is mild. Typically, single or a few loose stools at the beginning of therapy. This study is not -- 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, [indiscernible] we have analyzed is consistent with that. But this study has not yet been analyzed, but we're confident that we'll 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 100-milligram 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, where -- 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. So the placebos had well-managed lipids. They didn't have an increase as we sometimes see in LDL or triglycerides during the study. The reduction in PDFF in placebo, and it should have said -- the slide has a type of split, should say minus 8%. So minus 6% and minus 8% is also similar to what we saw in the Phase II study, where the placebos had a similar PDFF reduction. So there's nothing in this study that's inconsistent with what we've seen previously in the placebo. So there's a clear differentiation between resmetirom and the placebo throughout the duration of this study at both 16 weeks and at 52 weeks.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congratulations to the data. I have 2 questions for you. The first question is, team, could you maybe comment on a little bit more, whether, on the safety side, do you see any abnormalities or deviations in the [ PTR ] axis, any bone biomarker preferences such as the DEXA? Any patients exhibiting liver enzyme elevations? And then I have a second question.

Okay. So 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 stated that we analyzed serial DEXAs in the 100-milligram open-label arm that we did not see a 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, that it's a TR-beta agonist, very selective in the liver that will be -- and no bone findings at all in any nonclinical studies that we anticipate this will continue to be demonstrated in this study. The liver enzymes, we've also shown from parallel, open-label, non-cirrhotic arm and the fact that the liver enzymes, which are elevated to baseline go into the normal range during the course of [indiscernible]. We have not analyzed liver enzymes yet. And 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.

You have the thyroid axis [indiscernible]...

Thyroid axis, Yes. The thyroid axis has been thoroughly evaluated with this drug, and there are no changes. So we've published in Phase 2, no changes in TSH. No changes in the active thyroid hormone, T3. There's a shift, very small, around 11%, not clinically meaningful decrease in free T4, which is a liver effect that results in converting the pro forma of free t4 into active hormone and the liver. But other than that, there are no thyroid hormone relevant changes, no symptoms related to either hypo or hypothyroidism. And so essentially, this has been shown many, 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 [indiscernible]...

Thank you...

Yes, go ahead.

Sorry for interrupting you, Becky. And 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 analysis of MRI-PDFF predicting NASH evolution and fibrosis. I would love to hear your thoughts now after seeing the MAESTRO-NAFLD data where 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. And congrats again.

Yes. Thanks, Yas. I appreciate the question. And I think that's kind of the fundamental question around this particular noninvasive test. And it's something that we elaborated on a bit at NASH-TAG as well. So I think it's becoming clear that MRI-PDFF can be used as a marker in specific mechanisms of action relative to NASH. And what we see a lot of -- we see a lot of data now being generated with MRI-PDFF. And it's -- and we have a lot of data relative to the thyroid hormone receptor beta agonist, particularly when we went back in mind the post-hoc data from the Phase II. But 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 of points from that paper. And again, that's a pooled analysis of data. And 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 of the fat is 5.45%. Now that's NASH resolution. We still don't have that same -- we don't have that same analysis with fibrosis. And so it's a more challenging endpoint to hit just by looking at MRI-PDFF. So I think the data is 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, the data there is a little -- it's small. Most of our data is around improvement in the NAFLD activity score of at least 2 or more points and NASH resolution. And I'd just highlight the fact that it is encouraging to see consistent data not only in the Phase IIb trial where we treated patients for 9 months, predominantly with lower doses. And then when we looked at the open-label -- the open-label arm, we saw robust reductions over 52 weeks, consistent again in this double-blind arm. So 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. So for me, looking forward, I'm very encouraged by this reduction. Again, just to summarize, we have more data on NASH resolution and fibrosis improvement. But nonetheless, the data is quite encouraging.

Yes. I just would add to that, because I think that with our data, and I totally agree with what Stephen said that its hypothesis generating. But with our mechanism, the 30% reduction did correlate with more patients achieving the 1.5 fibrosis reduction. So it actually correlated with improvement in every component, not only steatosis, but ballooning, inflammation and also fibrosis reduction. And a high percentage of patients who achieved NASH resolution in our Phase II study also did achieve fibrosis reduction. And so clearly, we're projecting that and hoping that, that also is validated by data from our Phase III studies.

Our next question comes from Liisa Bayko with Evercore ISI.

Congratulations on the data. Just a couple of additional questions. Can you comment at all on discontinuation 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?

Discontinuation by cohort.

Okay. So we showed a slide, which was Slide 8. And you can see that the discontinuations in the study are not different between the cohorts in this study. And if we compare it to the parallel arm, the open-label non-cirrhotic arm, the discontinuation rate at the 100-milligram dose was significantly lower in the open-label arm. So it was 89% completion rate. And 94% completion at week 24.

Okay. Great. And then just could you -- I know you said that you'll do one more public disclosure at some point before you present it 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 anticipate what's coming and then what medical conference are you targeting? Would this be EASL?

So 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 readout, some biomarker readouts from this study. We have not, at this point, made a decision of what exact readouts we're going to share, but there is -- we do plan to do that, as we mentioned in the press release.

Our next question comes from Ritu Baral with Cowen.

Becky, what was the most common AE related to discontinuation in this study? And how are you looking at the nausea and diarrhea rate compared to the totality of the clinical data generated? It seem like a little bit of an outlier, especially compared to the open label. Are there any changes in formulation required for blister packs or anything that you might kind of look at?

No. So the 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 -- 3 pills each day, to blind for placebo and other changes. So they're exactly the same pill. The AE rate is in line. And clearly, these are mild AEs and the discontinuation rate of 1.2% in the open-label arm is very similar to a discontinuation rate of 2-point -- 2% in all 3 arms of the blinded study combined. So we do believe it's consistent.

Got it. And even in the...

I was just going to say it's also consistent with the level that we saw in Phase II. So it's been consistent across the studies.

Got it. And even in the press release, you mentioned the event was related to -- sorry, increased to a frequency, at the beginning of therapy. When you designed beginning of therapy just as we sort of look at our models, is that a 12-week time frame, where these events tend to occur? Is it like a 4-week time frame...

No, it's right away. No, it's within the first week or 2.

And then they keep...

Yes.

Got it. And then I know you had answered other AE endpoints. But could you just address if you've been able to look at heart rate at all? You said the [ DEXA is ] analyzed but have the -- have you or the DSMB been able to look at heart rate and have a takeaway there?

We've looked at heart rate in thousands of patients. I mean this is -- 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. Their EKGs during the study, there have been special studies as well, the standard studies that one does to evaluate any changes on EKG. There 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 I guess we should leave it at that.

Got it. And quick last question for Dr. Harrison. Dr. Harrison, you mentioned -- 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.

Yes, that's a good question. I mean I think at the end of the day, what we've learned is that 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 mechanism is ALT reduction. And as a clinical hepatologist, I can tell you, I use ALT reduction and normalization to monitor every liver disease that I treat. So just at top level, if I were looking at a combined NIT assessment, I would look at PDFF and ALT. That's -- that's specifically for histopathology though. And I think it's important to remember, and I showed this in a lot of my slides, when we're treating NASH patients, if 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.

Our next question comes from Jon Wolleben, JMP Securities.

Congrats on the data. Just wanted to clarify a point from earlier, Becky, did you say that the placebo PDFF rejection was an 8% decrease at week 52? And I was also hoping you could comment on any weight loss in the study between the arms?

Yes. Yes. So I apologize for the typo. Yes, it should be minus 8%. So 8% reduction or minus 8% and minus 6% at week 16. We have not yet analyzed the weight loss data in the study. But obviously, that's one of the things we will be looking at in both the drug treatment and placebo arm.

Got it. And 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 3 to 4 months, but then you're seeing some improvements over time in other markers like ALT and previous data sets. What else is going on at the level of the liver when patients is on resmetirom for an extended period 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. 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 mitochondrial. But it also is very important for overall liver health and we know that NASH patients have a disruption in their thyroid beta access -- thyroid beta receptor function in the liver. Specifically, in the liver. And that they have a deficient thyroid hormone receptor beta activity. So what is known is that the thyroid hormone in the liver and hepatocytes is important for mitochondrial biogenesis and mitochondrial health, which are abnormal in NASH patients. So we believe that over time, the liver function and the liver -- the function in many ways is actually benefited by this mechanism.

Congrats again on the data.

Our next question comes from Ed Arce with H.C. Wainwright.

Great. And let me add my congrats on this data set. A couple of questions for me. Firstly, I wanted to ask you about the -- 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. And then just as a side note, will we get this data for the randomized double-blind arms at some point? And then I have a follow-up.

Okay. Thank you. So the purpose of showing this here is simply to say that when a drug such as -- first of all, NASH patients have very large livers. Sorry -- And if the average liver size is in adult is around 1,400 CCs, NASH livers are over 2,000 CC. So they're very elevated, both non-cirrhotic and cirrhotic NASH. So 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-milligram open-label arm. And the point of this particular slide was simply to say that if you have a smaller liver, whatever fat is in the liver is -- 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 more greater liver volume reduction with resmetirom than simple weight loss where PDFF goes down. So placebo or other mechanisms that reduce weight, may reduce PDFF, but they don't reduce liver volume as much. So there's a component of this that is greater with resmetirom and in terms of the mechanism, that is something that we are 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 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. And can we expect to get this data set for the 2 double-blind arms in the future?

Yes. So that I'm saying that we have not measured it. The double-blind arms, it's a large, large, large number of patients. So that's a lot of data. And we haven't made a decision as to whether we are going to measure liver volume and this entire data set.

Okay. Understood. And then 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 end points that are of greatest interest and understanding in terms of the study. So those are what we're focused on. And also any kind of safety data that we -- that would be key in the study. We believe we've -- we're not seeing any safety that's inconsistent with prior studies. But for example, we've been asked about the serial DEXA scan, that would be one thing. I also want to 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, but those are data that as well that you can expect down the road.

Great. Thanks, Becky, and congrats again on the data.

Our last question, Ellie Merle with UBS.

Congrats on the data. Maybe just a last one for Dr. Harrison. Just in terms of maybe longer-term thinking about your prescribing, I guess, how important is the histology endpoint on fibrosis at a 52-week endpoint. You're thinking about the NASH Phase III readout later this year. Just in my kind of the discussion around some of these secondary biomarkers as well as the increasing importance of noninvasive tests relative to sort of biopsy. I guess, how are you thinking about how you're prescribing 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?

Yes. So I think -- and I'm going to let Stephen also comment on this. But there's a growing body of evidence, for example, an elevated MRE is predictive of worse or increased MRE over a certain level predictive of a worse outcome and there's some data with FibroScan along those lines as well. A bunch of the fibrosis biomarkers such as health and potentially PRO-C3 may have some predictive benefit as well. And so of course, in our Phase III study in addition to liver biopsy and in this study as well, we'll have these kinds of biomarkers to correlate with response? And, Stephen, do you want to just comment more on that?

Yes, I think it's a great question. As a clinician, we worry about progression to cirrhosis and decompensation. And 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, but one thing we don't talk a ton about, and I think it's important to notice, 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, we're measuring lots of noninvasive tests. More and more, we're learning how these tests correlate to outcomes. We see significant data sets coming out, making MRE to outcomes. So same thing for ALT, 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. And there's a collinearity that exists between NASH and fibrosis. And I think it's clear to show that -- it's clearly been shown in multiple different data sets, including all the way back to Elafibranor with Genfit, where you improve the NAFLD activity score, we see improvement in fibrosis. And so 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. And so at the end of the day, we're going to have that data available, and I'm very hopeful that we'll be able to hit on all of those endpoints.

So this is Paul. Thanks very much for those remarks, Stephen 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. And 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.