Dane, thank you for standing by. Welcome to Madrigal Pharmaceuticals' Rezdiffra Two-Year Compensated MASH cirrhosis Data at EASL 2025 Conference Call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. As a reminder, today's conference call is being recorded. I would now like to introduce Ms. Tina Ventura, Chief Investor Relations Officer. Please go ahead.
Thank you, Livia. Good morning, everyone, and thank you for joining us for our webcast on compensated MASH cirrhosis, or F4C. Our goal today is to provide a deeper understanding of this high-risk stage of MASH and share the latest open-label Rezdiffra data presented at the EASL Congress this past Saturday. A slide deck accompanies this webcast and is available on the Investor Relations section of our website. Please note on slide two, we'll be making certain forward-looking statements today. We refer you to our SEC filings for a discussion of the risks that may cause actual results to differ from the forward-looking statements. Joining me today, as noted on slide three, are Bill Sibold, Madrigal's Chief Executive Officer; Dr. Michael Charlton, our Head of Clinical Development, Hepatologist, and former Director of Hepatology at the Mayo Clinic; and
Dr. Naim Alkhouri, Chief Academic Officer at Summit Clinical Research and Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio. With that, I will turn the call over to Bill on slide four.
Thanks, Tina. Good morning, everyone. We have three objectives for today's webcast. First, to provide a clear understanding of compensated MASH cirrhosis, or F4C, and the clinical reality for these patients. As Michael will explain, these are very sick patients who still have liver function but are on the verge of serious consequences. Clinically significant portal hypertension is the tipping point. Once it develops, patients are at risk for the most serious outcomes of cirrhosis. Second, Dr. Alkhouri will present new findings that he just shared at EASL from our two-year trial in F4C patients, which is part of our MAESTRO-NAFLD-1 trial. While this is an open-label study without a placebo arm, we're very encouraged by Rezdiffra's broad and consistent effect across the totality of the data.
Third, these data reinforce our confidence in our pivotal phase III MAESTRO NASH Outcomes trial, which is evaluating Rezdiffra's ability to reduce liver-related events in F4C patients. This is an event-driven trial where we expect results in 2027. If positive, this could support both label expansion into F4C and full approval for Rezdiffra. Let me set the stage with slide five. At Madrigal, our purpose is simple. We're here to lead the fight against MASH. It drives everything we do, from clinical development to community engagement. MASH is a serious liver disease and one of the leading causes of liver-related death. It's the top cause of liver transplants in women in the United States and the second most common in men. Rezdiffra became the first and only FDA-approved treatment for MASH last year for patients with moderate to advanced fibrosis, consistent with F2 and F3.
In phase III, it halted or improved liver stiffness in 91% of patients. It's once daily, well-tolerated, and easy to take, and the real-world feedback has been overwhelmingly positive from both physicians and patients. This continued into EASL last week, where I spoke with many prescribers and heard the same response. Rezdiffra's strong efficacy and attractive real-world profile are driving meaningful adoption. As we shared on our Q1 call and on slide seven, the launch continues to perform exceptionally well, with steady physician uptake and over 17,000 patients treated at the end of the first quarter of 2025. The momentum driving our U.S. Rezdiffra launch in F2, F3 MASH is one piece of our broader leadership strategy. As shown on slide eight and the focus of today's call, we're also working to expand into F4C, which could effectively double Rezdiffra's market opportunity.
We're also preparing for global expansion with a mid-year regulatory decision expected in Europe. Finally, we're building for the future, actively evaluating new assets across multiple mechanisms to strengthen our pipeline beyond Rezdiffra. Now, let's turn to slide nine and why we believe Rezdiffra has strong potential in F4C. First, F4C is a serious progressive liver disease with no FDA-approved treatments. It leads to life-threatening complications. The urgency to treat is clear, and the unmet need is significant. Second, Rezdiffra's liver-directed mechanism of action, targeting fat, inflammation, and fibrosis, makes it highly relevant in this population. Dr. Alkhouri will go into more detail, but Rezdiffra selectively activates THR-beta to increase hepatic fat metabolism and with direct and indirect impact on liver fibrosis through stellate cells. A study in Nature has previously identified THR-beta as a master regulator of liver metabolism.
Third, we are pioneering clinical development in compensated MASH cirrhosis. Today, we'll discuss our two-year open-label data from the MAESTRO-NAFLD-1 trial. We're also advancing our pivotal phase III MAESTRO NASH Outcomes trial in F4C patients. Importantly, this trial is aligned with FDA guidance for F4C trials. Finally, we expect to have outcomes data years ahead of any competitor and a first-mover advantage in F4C. By then, prescribers will have significant real-world experience with Rezdiffra in F2, F3. That familiarity, combined with a strong clinical profile and positive outcomes data, may position Rezdiffra to be the first treatment approved for F4C, and we believe the leading therapy from F2 to F4C, period. I'll now turn the call over to Dr. Michael Charlton on slide 10, who will provide a more detailed overview of F4C and its associated adverse liver-related events. Michael?
Thank you, Bill. Before joining Madrigal last October, I spent over 30 years treating patients with MASH as a hepatologist. I've seen firsthand how devastating this disease becomes once it progresses to cirrhosis. That's why I'm so energized to be part of the team aiming to bring the first approved treatment to patients with compensated MASH cirrhosis or F4C. As we work toward that goal, it's critical to understand how this disease progresses and how Rezdiffra's ability to reduce liver stiffness and the risk of clinically significant portal hypertension may translate into a successful outcome in our phase III trial. Let's start on slide 11 with the basics. MASH is a chronic and progressive liver disease characterized by the accumulation of fat in liver cells.
Over time, this triggers inflammation and leads to scarring or fibrosis, which can progress through four stages, as shown from left to right on this slide. F4 is cirrhosis, the point at which scar tissue has replaced much of the liver's healthy architecture. CSPH, or clinically significant portal hypertension, is a hallmark consequence of cirrhosis and a major inflection point in disease progression. As shown in slide 12, it's driven by increasing liver stiffness, which restricts blood flow through the portal vein, the vessel that carries blood from the gastrointestinal tract and the spleen to the liver. As pressure builds, blood backs up into the spleen, causing it to enlarge and sequester platelets, leading to lower platelet counts. This is the moment when the liver begins to lose its ability to compensate and when the risk of serious complications rises sharply.
When a patient starts to decompensate, they face serious events like ascites or buildup of fluid in the abdomen, variceal bleeding from ruptured veins into the gastrointestinal tract, and hepatic encephalopathy, when toxins normally cleared by the liver reach the brain, causing confusion, coma, or worse. The risk of death rises sharply, reaching nearly 60% within a year at the late stages of decompensation. At that point, patients have run out of time. It's well established that CSPH is the tipping point, after which patients face a significantly higher risk of serious liver-related events. In clinical practice, hepatologists use the Baveno criteria to assess CSPH risk. It's a widely accepted, non-invasive approach that combines two key markers: liver stiffness measured by VCTE and platelet count. On slide 13, you see how these markers are used to stratify risk, moving from left to right.
CSPH is excluded when liver stiffness is under 20 kPa and the platelet count is above 150,000. CSPH is possible in patients with liver stiffness between 15-20 kPa and platelets between 110,000-150,000. CSPH is identified when liver stiffness is 25 kPa or higher, regardless of the platelet count. As Naim will show, we use this model to assess patients in our open-label trial, and 65% of patients on Rezdiffra with clinically significant portal hypertension at baseline moved into a lower CSPH risk category. That result was statistically significant, and as a hepatologist, I can tell you this type of shift is clinically meaningful for our patients. As clinicians, our goal is simple: to keep patients from progressing to those devastating complications. We know that reducing the risk of CSPH directly lowers the chance of liver-related events.
We also know lowering liver stiffness is one of the strongest predictors of improved outcomes. That is well established in the literature, including a 2024 JAMA publication. There is broad consensus on this point at EASL this past week as well. That is what makes Rezdiffra data so compelling: its ability to reduce liver stiffness and, in turn, lower CSPH risk and improve a broad array of other key markers of liver health. Slide 15 shows the design of our MAESTRO NASH Outcomes. This is a large phase III double-blind, placebo-controlled, event-driven trial evaluating progression to liver decompensation, where we enrolled 845 patients with compensated MASH cirrhosis. The patients enrolled in MAESTRO NASH Outcomes are similar to the open-label cohort presented at EASL. We designed the outcomes trial in alignment with FDA guidance, which recommends that clinical trials in F4C patients use outcomes as the primary endpoint.
The primary outcome is time to first adjudicated events, which includes a number of events we discussed today, such as ascites, hepatic encephalopathy, and variceal bleeding. Many of these outcomes are directly linked to CSPH, which is why we believe Rezdiffra's impact on liver stiffness and risk of CSPH could translate to clinical benefit. With that, let's move into the open-label data in Naim's presentation. Naim?
Thank you very much, Michael, for this excellent overview of MASH cirrhosis and clinically significant portal hypertension. Over the next few minutes, I will share with you my presentation at EASL. Treatment with resmetirom for up to two years led to improvement in liver stiffness, fibrosis biomarkers, fibrosis scores, and portal hypertension in 122 patients with compensated MASH cirrhosis. As a background, as you heard from Bill, resmetirom is an oral, once daily, liver-directed thyroid hormone receptor beta agonist. This was approved by the FDA in March of 2024 to treat patients with MASH and F2, F3 fibrosis. However, we have no approved therapies for patients with compensated cirrhosis due to MASH. As you heard from Michael, cirrhosis is highly associated with clinical outcomes, including decompensation, liver failure, the need for liver transplant, and overall mortality.
Now, in terms of the mechanism of action of Rezdiffra or resmetirom, we know that in patients with MASH, there is accumulation of lipids within the hepatocytes, and there is lipotoxicity leading to oxidative stress and damage to the mitochondria. This leads to the activation of the inflammation cascade and the activation of the hepatic stellate cells, and that leads to the progression of liver fibrosis. On slide 19, we show how resmetirom works. By restoring the thyroid hormone receptor beta signaling within the liver with resmetirom, we actually lead to a process called mitophagy, which is getting rid of the inefficient mitochondria that cannot utilize fatty acids. We induce a process called mitogenesis. We produce new efficient mitochondria that can utilize fatty acids in a process we call beta oxidation of fatty acids.
That leads to decreasing the amount of lipids within the hepatocytes and improving lipotoxicity. That can lead to decreased inflammation in the liver and reduction of liver fibrosis in direct and indirect mechanisms. We have data showing poor long-term outcomes and liver-related events in patients that have low THR-beta expression in the liver. Moving on to the design of the current trial. This was the open-label 52-week cirrhosis arm of the MAESTRO-NAFLD-1 trial, followed by an extension trial for another 52 weeks. To be included, we needed these patients to have three metabolic risk factors and have compensated MASH cirrhosis. Cirrhosis was defined either on liver biopsy or a combination of non-invasive tests such as vibration-controlled transient elastography, magnetic resonance elastography, or the enhanced liver fibrosis test. We allowed the platelet count to be as low as 70,000 in this trial.
It is important to note that the lower the platelet count, the more likely these patients will have clinically significant portal hypertension, and there is an association between platelet count and long-term outcomes. The first part was the open-label 52-week cirrhosis arm. Patients were treated with resmetirom 80 milligrams for 52 weeks, open-label. There was a variable gap between 1-12 months where the patients were not on treatment. We did the open-label extension for another 52 weeks with the same dose of resmetirom 80 milligrams daily. The primary endpoint was safety and tolerability of resmetirom in cirrhotic patients, but we had several secondary endpoints to explore efficacy, including changes in VCTE, MR elastography, MRI-PDFF, and several biomarkers. On slide 21, we showed the trial flow chart.
You can see that in the open-label cirrhosis arm in the MAESTRO-NAFLD-1 trial, we included 180 cirrhotic patients, and 89% of them were able to complete 52 weeks of treatment. We had the gap again between one to 12 months. We enrolled 122 patients in the open-label extension trial. Again, resmetirom was well tolerated, and 93% of these patients were able to complete an additional 52 weeks of treatment. These 122 patients represent the analysis population and the results that you will see in the next slides. On slide 22, we showed the baseline characteristics, and we divided patients into those with baseline MRI-PDFF more than 5% fat. This is typically what we call a classic MASH cirrhosis. They still have steatosis in the liver.
Those that have baseline MRI-PDFF less than 5%, and this is what, historically speaking, we called cryptogenic cirrhosis. These patients tend to have more advanced and aggressive disease. As you can see here, in terms of VCTE, patients with less than 5% liver fat had higher liver stiffness. They also had higher liver stiffness on MR elastography, lower liver fat on MRI-PDFF by definition. These patients also had larger spleens, so the spleen volume was higher in patients with less than 5% fat on MRI-PDFF. They also had lower platelet count and higher FIB-4 index, all indicative of potentially a more advanced population. We will go to the next slide, slide 23. This is where we showed sustained reduction in liver stiffness after two years of treatment with Rezdiffra.
First, we showed that the mean change from baseline in VCTE at year one was a reduction by 6.4 kPa, and this was significantly better than the baseline. This was sustained through year two with a reduction of 6.7 kPa. Importantly, after two years on resmetirom, more than 50% of patients achieved a sustained more than 25% reduction in liver stiffness by VCTE. This threshold has been established in the literature as a predictor of the development of less major adverse liver outcomes. This is very clinically relevant for us as hepatologists. We then looked at the percentage of patients that converted from F4 cirrhosis to potentially F3. This is basically a regression of cirrhosis to advanced fibrosis. This was defined by having VCTE after the two years less than 15 kPa, and a reduction by 25% from baseline.
This was achieved at year two in 35% of patients. About one-third of patients potentially had a reversal of their cirrhosis. On slide 24, we looked at clinically significant portal hypertension categories. We initially used the traditional Baveno criteria that Michael shared with you. Definite CSPH was defined as having VCTE more than 25 kPa at baseline. Probable CSPH was defined as having VCTE between 20-25 kPa and platelet count less than 150,000, or VCTE between 15-20 kPa and platelets less than 110,000 based on the Baveno criteria. No CSPH was basically not meeting the above criteria. To address some of the limitations of transient elastography in patients with MASH cirrhosis that typically have higher BMIs, we also used the modified Baveno criteria.
In addition to having VCTE more than 25 kPa to identify CSPH, we required that you needed one more criteria. The criteria were either platelet count less than 150,000, or MR elastography more than 5 kPa, or ELF score more than 11.3. When you look at the traditional Baveno criteria, at baseline, 35% met the definition for clinically significant portal hypertension. By year two, only 15% of these patients had clinically significant portal hypertension. Also, at baseline, 51% of patients had no CSPH. By year two, this percentage increased to 70%. You can see a similar pattern was noted with the modified Baveno criteria, giving us more confidence in the results. On the next slide, slide 25, we actually divided patients into their baseline CSPH category.
We started with patients with no CSPH at baseline, and we showed that by year two, 88% continued to have no evidence of CSPH. When we looked at patients with probable CSPH at baseline, by year two, 57% had no evidence of CSPH. Most importantly, when we looked at the patients with CSPH at baseline, only 35% continued to have CSPH by year two, and 65% transitioned from definite CSPH to lower risk categories. We looked at reduction in liver fat on slide 26 on MRI-PDFF and CAP from the FibroScan. We looked here in patients that had baseline fat more than 5% on PDFF, and we showed significant reduction on PDFF by 37% and on the CAP score by 43%.
We also looked at changes in liver stiffness based on MRE, and here we divided patients into those with baseline PDFF less or more than 5%. We showed reduction in MRE liver stiffness in both populations, regardless of the baseline MRI PDFF. We looked at MRE response, and this was defined as improving your MRE by more than 19% relative improvement from baseline. We showed that regardless of the amount of liver fat at baseline on PDFF, there was improvement in MRE, and a significant percentage of patients achieved that MRE response. We also looked at liver enzymes, ALT and gamma GT, and we showed significant reduction in ALT at year one, and this was sustained at year two in patients that had ALT more than 30 at baseline, regardless of the baseline PDFF liver fat.
A similar story was noted with gamma GT, with significant reduction at year one that was sustained through year two. On slide 28, we looked at fibrosis and liver injury biomarkers at year two. First, we started with PRO-C3, which is a fibrosis biomarker, and we showed a significant reduction at year one, and this was maintained at year two. Then we looked at cytokeratin 18, which is a biomarker of hepatocyte apoptosis. We know that hepatocyte apoptosis is a major driver of the disease, and it can induce hepatic stellate cells to produce fibrosis. By year two, we showed a significant reduction by 321 units from baseline in CK18. Finally, we looked at changes in adiponectin, which is an adipokine that reflects metabolic health and can also affect liver fibrosis.
We showed that there was a significant increase in adiponectin by year one, and there was a further increase up to 42% from baseline at year two of treatment with resmetirom. On slide 29, we looked at reduction in atherogenic lipids, and similar to the MAESTRO NASH trials, where we showed significant reduction in lipids here in a cirrhotic population, regardless of the baseline liver fat on MRI-PDFF, there was significant reduction in atherogenic lipids, specifically reduction in LDL cholesterol between 19%-21%, reduction in ApoB, lipoprotein(a), and triglycerides. Finally, in terms of efficacy results, we looked at MRI-based liver and spleen volume assessments. It is important to note that in the trial, liver volumes were increased in patients with compensated MASH cirrhosis by approximately 40% to what you would expect for liver volumes.
There was a significant reduction in liver volume by 20%-25% with resmetirom treatment at year two, and this was independent of baseline MRI-PDFF liver fat. We also used MRI to measure spleen volume. We showed an inverse correlation between platelet count and spleen volume, and these are both surrogates of portal hypertension. Also, importantly, we showed that the mean spleen volume was reduced by resmetirom treatment at year one and two in patients with baseline platelet count more than 100,000. There was also significant correlation between spleen volume and changes in platelets and also changes in transient elastography. On slide 31, we shared the safety summary data after two years of open-label treatment with resmetirom 80 milligrams in patients with compensated MASH cirrhosis.
In terms of the common adverse events, they were similar to what we saw in the non-cirrhotic populations, with diarrhea and nausea being the most common adverse events. They're noted in 38% and 31%, respectively. The study was conducted during the COVID-19 pandemic, so we had several cases of COVID-19. Importantly, when we looked at serious adverse events, we had 27. None of them were attributed to resmetirom based on the investigators' assessment. The discontinuation rate, even in this more advanced cirrhotic population, was very low at 2.5% related to gastrointestinal adverse events. We had two deaths in this study. One was related to COVID-19, and the other one was due to metastatic cancer, so not related to the study drug.
Also, importantly, six out of the 122 patients experienced decompensating events through two years of treatment, and five out of these six patients had either elevated baseline MELD score indicating more advanced disease and/or baseline platelet count less than 100,000, also indicating more advanced disease. To summarize on slide 32, resmetirom was tolerated over two years in patients with well-compensated cirrhosis. Safety data looked very promising. This was really the primary endpoint of this trial to show safety, and we were able to demonstrate that. More than 50% of patients achieved a sustained more than 25% reduction in liver stiffness, and this is the threshold that has been established in the literature to predict less progression to major adverse liver outcomes. We know that lower VCTEs are associated with less decompensation.
We're also able to show a reduction in clinically significant portal hypertension risk score based on the traditional Baveno criteria and also modified Baveno criteria that included other non-invasive tests. As Michael shared earlier, clinically significant portal hypertension predicts progression to decompensation. We also demonstrated very clearly that multiple biomarkers and imaging tests showed evidence of improvement. This includes liver enzymes, ALT and gamma GT, fibrosis biomarkers like PRO-C3, liver stiffness improvement on MR elastography, and we also showed improvement in atherogenic lipids. These results support the potential clinical benefit of resmetirom in MASH cirrhosis that is being evaluated in the fully enrolled ongoing MAESTRO NASH Outcomes trial. I want to thank you for your attention, and I will turn it back over to Bill to conclude this presentation.
T hank you, Dr. Alkhouri.
Before we move to Q&A, let me close by summarizing the key takeaways from today's call. F4C is a high-risk, high-end met need population, and we believe Rezdiffra is uniquely positioned to help. These patients are at a critical tipping point in their disease progression, and there are currently no approved treatment options. Rezdiffra's liver-directed mechanism of action targets the key drivers of fibrosis and could have a unique role in F4C. We're encouraged by the two-year data from our open-label F4C cohort. Rezdiffra showed consistent improvements across multiple liver health markers alongside a well-tolerated safety profile. These data reinforce our confidence in the drug's potential to benefit patients at this advanced stage. MAESTRO NASH Outcomes is designed to assess Rezdiffra's impact in F4C. The trial is aligned with FDA guidance, event-driven, and evaluating hard clinical outcomes like decompensation, transplant, and mortality.
We expect data in 2027. If successful, we believe Rezdiffra will be the first approved treatment for F4C, cementing its role as the foundational therapy from F2 to F4C. We expect to have outcomes data ahead of any competitor, and by then, prescribers will have years of real-world experience with the medicine. We're proud of the leadership position we built in MASH, and we're committed to delivering for patients across the full spectrum of the disease. I'll now turn the call back over to Tina for Q&A.
Thanks, Bill. Livia, let's open the call for questions.
Thank you. We will now open the lines for your questions. To open your line, please press star 11, and you will be added to the queue on the call. Now, our first question coming from the line of John Wallivant from Citizen GMP Security. Your line is now open .
Hey, congrats on the day, and thanks so much for taking the question. Maybe for Dr. Alkhouri or Dr. Charlton, wondering how you think about, given the population enrolled, the number of decompensation events, and then also what you saw with the risk of portal hypertension in those patients as well, if there was an association there predicting what eventually happened.
John, thank you very much for the question. Dr. Alkhouri , let me turn that over to you.
Yeah, very important question. I think it's important to understand the baseline characteristics of the patient population that you enroll in the trial. We typically expect to see more events in patients that have higher liver stiffness at baseline, those with lower platelet count at baseline. And within the compensated population, there's also a difference between Child-Pugh A and Child-Pugh A5 and Child-Pugh A6.
When we looked at this patient population in this open-label cirrhosis study, you can see that the baseline platelet count was relatively low. There was an increase in liver stiffness, and you would expect in a population like this, in my experience, to have an annual event rate between 5%-10%. If you think about it, we had 122 patients that were treated for two years, and we ended up with six decompensating events. In this study, the annual event rate was around 2%-3% per year. In my mind, this is very encouraging. It speaks to the potential effects of Rezdiffra in this patient population. I think the nuances, looking again at what was the lowest platelet count that was allowed in the study, what were the baseline characteristics, these all play an important role in determining the annual event rate.
Again, I think what we saw in this trial is, at least in my opinion, less than what you would expect in a cirrhotic population with these baseline characteristics.
Have you guys looked at if they saw a shift in their risk of portal hypertension as well ahead of the events?
We showed that if you look at patients with CSPH at baseline, there was a shift into no CSPH or probable CSPH in 65%. This is very important. Only 35% of patients continued to have CSPH by year two. I think this speaks to the fact that these patients should expect to see less decompensating events when you transition them into lower CSPH risk categories.
Great. Thanks, Naim. Livia, next question, please.
Thank you. Now, next question coming from the line of Andy Chen with Wolfe Research. Your line is open .
Hi. Thank you for taking the question. Another question for Dr. Alkhouri. Assuming this is approved, to what extent will physicians proactively incorporate portal hypertension data into their therapy selection process? Is this something where Madrigal would basically have to raise awareness later? Can you maybe quantify what % of your peers are unaidedly excited about the portal hypertension data here? Is there a difference between hepatologists and GIs? Thank you.
Thanks, Andy. A lot of questions there. Dr. Alkhouri, why do not you take those?
Yeah, thank you, Bill. No, I mean, I think as a hepatologist, every time I see a cirrhotic patient, the first question I am asking is, do they have clinically significant portal hypertension or not? This is what is recommended by all the society guidelines from AASLD to EASL because that has great implications for these patients.
When you identify clinically significant portal hypertension based on the Baveno criteria, the recommendation now is that you get them started on a non-selective beta-blocker or carvedilol. This has also great implications on deciding who needs upper endoscopy. Sometimes we end up doing what we call band ligation for patients with large varices. I do not think this is a new concept. I think this is an established concept. Any competent hepatologist or gastroenterologist should be asking if their compensated cirrhotic patients have CSPH, yes or no. I think, again, maybe between community gastroenterologists, there would be some need for education, but I think among hepatologists and expert gastroenterologists, this is a standard of care.
Great. Thanks. Thanks so much. Next question, please, Livia.
Our next question comes from the line of Rita Barrow with Tina Kyle and your line is open .
Rita, are you on mute, maybe?
I am. Sorry about that. First question is for Dr. Alkhouri. Dr. Alkhouri, would you expect an additional cohort of patients to see benefit after year three of treatment, or is there a cohort that's sort of beyond the point of help and regression? And then a quick question for Bill. On one of the earlier slides, Bill, you mentioned that you thought that the F4C population could double risk as far as opportunity. Could you clarify the parameters that it could drive that? Thanks.
Yeah. Thank you, Rita. Maybe I'll start and then hand it over to Dr. Alkhouri. Yeah.
Look, as we look at the population of F4C patients, we see it as smaller than the F2, F3 population, but we would expect that the urgency to treat and penetration would be higher so that actual number of patients could approximate an opportunity equivalent to the F2, F3. That is the math behind it, Rita. As we get closer, we are going to provide a little bit more EPI to show exactly how we see the number of patients of F4C and the whole market, okay? Dr. Alkhouri, the first question?
Yeah. I mean, I think it is important to keep in mind that what we are trying to do here and the most important outcome we are trying to achieve is to prevent decompensation and need for liver transplantation.
I think the FDA guidance is very clear that to get full approval in cirrhotic populations, you need to show reduction in outcomes. I feel like when we are taking patients from the verge of decompensating when they have clinically significant portal hypertension, when they have very high liver stiffness, and we show improvement, even if they stabilize after year two, I think this is a very desirable outcome for us as clinicians. Do I expect to see further improvement at year three? Potentially. I mean, we saw actually further improvement between year one and year two in almost all the biomarkers that we looked at.
I think the key point I want to drive here is that even if we stabilize these patients, so I take someone from CSPH to no CSPH, if they stay in that category, we are doing a very good thing for these patients. The same is true for VCTE. If we can drop it by 5-6 kPa units, or if we can drop it to less than 15 kPa, even if they stay there at year three and year four, we've taken that patient from the edge to a much safer place, and they will have less likelihood of developing outcomes. At the end of the day, this is what we care about as clinicians. This is what patients care about, and this is what the FDA cares about.
Thanks, Dr. Alkhouri. Livia, next question, please.
Our next question coming from the line of Tom Smith with Leerink Partners, your line is open.
Hi, this is Nat Charoensook. I'm for Tom Smith. Congrats on the data. We have a couple of questions for Dr. Alkhouri. The first one, are you surprised to see more reduction in liver stiffness as measured by MRE in the cryptogenic population? Do you have any rationale for such observation? Also, do you observe any common features among responders, specifically those that show improvement in portal hypertension risk category versus non-responders? I have a follow-up.
Great. Thanks for the question, Dr. Alkhouri.
Yeah. No, that's a very important question. I think what we showed at baseline, that patients with what we used to call cryptogenic cirrhosis or lower liver fat on MRI-PDFF, they tended to have higher MR elastography at baseline.
They had more room to improve in response to treatment. That is why potentially we saw that they had higher response on MR elastography. When we looked at the MRE response, more than 19%, I think we saw a good percentage in both populations achieving that threshold, which is very encouraging. I also want to highlight that MR elastography is more difficult to move in the context of clinical trials compared to transient elastography. The fact that we are able to show a significant percentage achieving that MRE response is very encouraging. Have we analyzed the data into responders and non-responders? I think I also got asked that question at ESO. Very relevant question. We need to agree on what we define as responder, but this is very feasible, and we will be looking at that.
Thanks, Dr. Al-Khari. Livia, it looks like we have time for one more question, please.
Our next question coming from the line of Andrea Newkirk with Goldman Sachs. Your line is open.
Good morning. Thanks for hosting this event. Also, two questions for Dr. Naim Alkhouri. Just curious if you'd be willing to put these results in the context of what ACCARO showed with the FRXA phermin this past weekend and how you view the mechanism of THR-beta versus others like FGF21s for treating this patient population. Then secondly, if you could speculate what would have been the clinical effect had there not been a break between the open label and the extension portion of the trials. Thanks so much.
Great. Thank you, Andrea. Dr. Naim Alkhouri?
I was encouraged to see the ACCARO data presented at EASL, and it's good for our patients to have multiple options.
It is important to understand the nuances and the differences between the two patient populations. I do believe that we included a more advanced patient population in our resmetirom trial because we allowed lower platelet count. Again, there is a strong association between platelet count, the presence of clinically significant portal hypertension, and also the development of outcomes. I think we looked at the placebo response rate in the ACCARO trial in terms of VCTE. I just wanted to highlight that there was a lot of variability there. If you look at 72 weeks in terms of liver stiffness, there is absolutely no reduction in the placebo arm. This is important to understand. I presented data at EASL with Belapectin. This is the medication by Galectin. We had a placebo arm that included 88 patients, and we looked at their liver stiffness.
The reduction in the placebo arm was 0.7 kPa. We also have data from other clinical trials showing that typically in the placebo arm, you do not expect to see significant reduction in liver stiffness. I think, again, at the end of the day, we had a more advanced population. I do believe that the reduction we saw in liver stiffness and transition in CSPH category are very clinically meaningful. I am also encouraged to see the ACCARO data. It is known in the field that if you do a study and you require a liver biopsy, typically you need higher platelet counts for inclusion, and typically you end up with a less advanced patient population. What was the second part of the question? I'm sorry.
The second part was just if you could speculate on what you think the clinical effect would have been had there not been a break between the open label, the first 52 weeks, and then the second 52 weeks, could we have seen maybe even greater improvement there? Thanks so much.
Yeah. I mean, I think it would have been nice to have continued the treatment for consecutive two years. There were logistical issues related to the COVID-19 pandemic. I do not want to speculate on this. I think we continue to treat these patients, and we will have more data in the future. It is really hard to tell because the gap was between one-12 months. I prefer not to speculate.
Good. Thanks, Dr. Alkhouri. And thank you, Livia. Thank you all for your time and interest today. This now concludes our call.
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