MDGL

Good morning, and thank you for standing by. Welcome to Madrigal Pharmaceuticals' first quarter 2026 earnings conference call. At this time, all participants are in 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.

Thanks, Brila. Good morning, everyone, and thank you for joining us to discuss Madrigal's first quarter 2026 earnings. We issued a press release this morning and posted a slide deck to accompany this webcast on the investor relations section of our website. On the call with me today is Bill Sibold, Chief Executive Officer, David Soergel, Chief Medical Officer, and Mardi C. Dier, Chief Financial Officer. They will provide prepared remarks, followed by Q&A. Please note on slide 2, we will 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. I will now turn the call over to Bill on slide 3.

Thanks, Tina. Good morning, and thanks for joining us. 2026 is off to a terrific start. We've made impressive progress towards our strategic growth priorities to maximize the value of Rezdiffra and build our pipeline. Rezdiffra has achieved blockbuster status, generating more than $1.1 billion in net sales in the last 12 months. That's a billion-dollar run rate in a market that's still in its infancy. Penetration is low, the diagnosis rate is low, unmet need is high, and the market is expanding at a double-digit pace. When you put those fundamentals together, the future growth opportunity is quite remarkable. Competition has helped grow the market, but not at the expense of Rezdiffra. Beyond F2, F3 MASH, we're advancing our F4-C outcomes trial, where an indication expansion could double the opportunity for Rezdiffra.

Because we believe this is one of the most compelling opportunities in the industry, we've moved quickly to build the leading pipeline in MASH. We added to it yesterday with a new siRNA asset that targets a mutation in the PNPLA3 gene, a genetically validated driver of disease in a meaningful subset of patients. When you step back, it is hard to find another opportunity with this combination of market fundamentals and product strength. We have a first-in-disease approval, a foundational therapy, a rapidly expanding market, and we are building an industry-leading pipeline. We believe Madrigal is exceptionally well-positioned to win here and continue to shape the future of MASH. I'll begin with an update on the Rezdiffra launch, hand it to Dave to discuss our pipeline and R&D strategy, and Marty will wrap up with a review of our financials.

Turning to slide 5 and net sales, 1st quarter 2026 net sales were $311 million, representing year-over-year growth of 127%. This performance continues to reinforce that Rezdiffra is tracking in line with, and in many cases exceeding, the best-in-class specialty launches we compare ourselves to. Over the last two years, we have wired the system to drive Rezdiffra's growth.

We built a large and growing prescriber base, secured first-line access with commercial payers, and established Rezdiffra as the foundational therapy in MASH. Combined with Rezdiffra's differentiated profile and strong patient adherence, our execution has enabled us to steadily add patients quarter-over-quarter, as shown on slide 6. We ended the first quarter with more than 42,250 active patients on Rezdiffra.

On a year-over-year basis, patients on therapy increased by two and a half times compared to the first quarter of 2025. That is a significant achievement by any standard, but especially in a market that didn't exist before Rezdiffra's approval. This momentum reflects strong execution by the team, the clear unmet need in MASH, and continued demand from both prescribers and patients.

Importantly, we are seeing that momentum carried into the second quarter. Slide 7 shows how quickly the MASH market is expanding. Since launch, we've seen the U.S. addressable market grow nearly 50% from 315,000 patients at the end of 2023 to 460,000 patients at the end of 2025. These are diagnosed F2, F3 patients seen by our target specialists.

Rezdiffra's approval, together with increased industry investment, has helped transform the market by driving greater awareness, referrals, diagnosis, specialist involvement, and more patients seeking care. Yet this market is still in its earliest stages. The diagnosis rate is just over 10%, and Rezdiffra penetration remains just under 10% of the 460,000 addressable patients.

The MASH market has expanded rapidly, and the opportunity ahead is substantial. That gives us a clear path to peak sales, and we believe no company is better positioned than Madrigal to capitalize on it. Being first in a large and growing market is only part of the story. We have established this leadership position because Rezdiffra is delivering what the MASH market wants, and that is what slide 8 highlights. After two years on the market, three things are clear. First, profile matters.

Rezdiffra is the only approved liver-directed therapy in MASH. It has broad proven efficacy across all patient subtypes and is an oral, once-daily, well-tolerated medicine with no titration requirements. In a chronic disease, this profile is a key reason why we continue to see strong persistence and increasing depth of prescribing. Second, real-world performance matters. Clinical trials get a drug approved, but real-world experience determines a product's success.

With tens of thousands of patients treated, we've received overwhelming feedback from the community that Rezdiffra's efficacy continues to exceed expectations in the real world. This includes improvements across liver stiffness, liver fat, liver enzymes, LDL cholesterol, and Lp(a). This is the kind of real-world experience that builds confidence with prescribers and helps establish a true standard of care. Third, we have built not only a leading product, but a leading MASH company.

We have the right team, the right model, and the right start in a market we developed from the ground up. We have executed one of the best launches in the industry, where our differentiated specialty model has set a high bar for anyone launching in this space. We have learned, refined, and improved our approach along the way. We were first to market and now have a pipeline with more than 10 programs designed to extend our leadership over time. Our leadership is also reflected in our presence at key hepatology, gastroenterology, and Endocrinology-focused medical meetings this month, where more than 40 Rezdiffra abstracts being presented.

This includes a poster presented at DDW this week, where nearly 70% of Rezdiffra prescribers surveyed said Rezdiffra has improved their patients' quality of life, and nearly 70% expect to increase their Rezdiffra use over the next 6 months. Later this month at EASL in Barcelona, we will present additional data that reinforce the breadth of Rezdiffra's effect.

That includes a secondary analysis from our MAESTRO-NASH and MAESTRO-NAFLD-1 trials showing that Rezdiffra reduced Lp(a) and LDL-C in patients with MASH, supporting its potential to reduce cardiovascular risk independent of baseline statin use, along with two real-world data sets that demonstrate Rezdiffra's benefit in everyday clinical practice. We believe evidence generation is a strategic advantage for Madrigal. The more we can show prescribers and payers about Rezdiffra's performance across clinically relevant endpoints, the more it's solidified as the foundational therapy.

Everything we've discussed so far speaks to the strength of Rezdiffra in F2 F3 MASH, but there is another significant opportunity ahead of us in well-compensated MASH cirrhosis, or F4-C, as noted on slide 10. It's an untapped market with no approved therapies and a much higher urgency to treat. We believe F4-C could double Rezdiffra's opportunity with approximately 245,000 patients under specialist care in the U.S. We have an event-driven outcomes trial underway in F4-C that, if positive, is expected to support expansion into this indication as well as support full approval across F2 to F4-C. Before I turn it over to Dave to talk about our pipeline, let me reiterate how rare an opportunity Madrigal has.

We were first to launch, we rapidly achieved blockbuster status, and we are still at the very beginning of the development of this market. It's hard to find a comparable opportunity in the industry where the fundamentals are this attractive. From that position of strength, we are now investing in the next wave of innovation to extend our leadership and define the future of MASH. With that, I'll turn it over to Dave.

Thanks a lot, Bill. Our objective at R&D is straightforward: deliver the industry-leading pipeline in MASH to make better therapies for patients with Rezdiffra as the foundation. As shown on slide 11, we're doing that through targeted business development and smart clinical execution, leveraging the expertise of an R&D team that pioneered modern MASH drug development.

Our strategy has four goals. First, deliver outcomes data and full approval for Rezdiffra from F2 through F4-C. Second, advance complementary mechanisms for combination with Rezdiffra to deliver the best efficacy across the MASH spectrum. Third, remain modality agnostic with development of the best combination re-regimens as our strategic aim. The recent addition of siRNA assets to our pipeline underscores that approach.

Fourth, leverage our experience to design smarter, more informative clinical trials and use capital efficiently, taking more shots on goal and advancing only programs that serve patients' needs more effectively. The first pillar of this strategy is delivering outcomes data in F4-C on slide 12. Our confidence in the MAESTRO-NASH OUTCOMES trial is informed by the 2-year open label experience in 122 F4-C patients from our MAESTRO-NAFLD-1 trial.

Those data are best understood in the context of how MASH progresses to cirrhosis. The critical inflection point in this process is the development of clinically significant portal hypertension, or CSPH. It marks the transition from well-compensated disease towards decompensation when the most serious complications begin to occur. The literature is clear that patients with CSPH have meaningfully higher rates of liver-related events, and reducing CSPH risk lowers those event rates.

That's why the two-year data are so important. 65% of patients with CSPH at baseline shifted into lower risk categories by year 2. We also saw favorable movement in other biomarkers, including liver stiffness and fibrosis-related measures. Taken together, these results support Rezdiffra's potential in F4-C and reinforce confidence in our event-driven outcomes trial.

The second pillar of our R&D strategy is advancing combination therapies anchored by Rezdiffra, which we know works broadly across patient subtypes. Slide 13 highlights our newest addition, ARO-PNPLA3, a clinical-stage siRNA that we recently in-licensed from Arrowhead. We're especially excited about this asset for a couple of reasons. One, PNPLA3 is a well-understood and known target for MASH based on extensive epidemiological and genome-wide association studies. Two, this is a clinical-stage asset that has completed phase I studies.

3, we know Rezdiffra works well across all patient subtypes, including PNPLA3. A combo including Rezdiffra and this asset has the potential for improved efficacy in a subset of patients that are especially vulnerable due to their genetics. The PNPLA3 mutation is particularly prevalent among Hispanic patients. Compared to those with wild-type PNPLA3, MASLD patients homozygous for the I148M mutation of PNPLA3 have a twofold higher risk of liver-related events.

Approximately 30% of F2 F3 MASH patients are homozygous carriers of the PNPLA3 mutation, making it a meaningful target for our development efforts. This asset has completed phase I studies and demonstrated two important things. First, it's selectively effective in the genetically defined population of PNPLA3 homozygotes. Second, after a single dose, it reduced liver fat by up to 46% at 12 weeks at the highest dose.

We know from MAESTRO-NASH that the greater reductions in MRI-PDFF are associated with better fibrosis reductions with Rezdiffra. The goal here is straightforward: combine a foundational therapy, Rezdiffra, that works broadly with a targeted agent that may move more patients into a high response category and potentially improve anti-fibrotic efficacy with a genetically tailored approach. Stepping back on slide 14, our pipeline now includes more than 10 programs. Rezdiffra continues in 2 phase III outcomes-based trials. First, our F4-C study, which is an event-driven trial that we expect to read out in 2027. Second, the F2 F3 study, which is primarily histology-driven with data expected in 2028. These trials would make Rezdiffra the first fully approved drug with outcomes data, well ahead of other competitors.

Moving down the pipeline for ervogastat or DGAT2 inhibitor, the drug-drug interaction study with resmetirom remains on track to begin in the fourth quarter of this year, and we expect to initiate a phase II combination study in 2027 following regulatory discussions. For MGL-2086, our oral GLP-1, the phase I single ascending dose study remains on track to initiate later this quarter. For ARO-PNPLA3, our next step will be to engage with regulatory authorities on a phase II combination trial. Our six siRNA targets are progressing at various stages of preclinical development. Our approach is consistent. We're building around a foundational therapy and prioritizing mechanisms that we believe are complementary, mechanistically sound, and capable of improving outcomes either broadly across the population or in important patient subgroups.

Our goal is to ensure Madrigal is engaging with the community and driving the science, so we're delivering meaningful advances for patients. With Rezdiffra's long-term patent protection, we have the runway to invest, innovate, and define the future of MASH care. With that, I'll hand it over to Mardi.

Thank you, Dave. Turning to slide 15 and a summary of our financials. First quarter 2026 net sales totaled $311.3 million, up 127% year-over-year. We're off to a strong start in 2026. As we discussed on the last call, our results reflect a typical Q1 effect due to benefit plan changes and insurance reverifications, plus a step-up in gross-to-net related to our commercial contracting efforts for first-line access. The team did an excellent job managing all the moving parts in the quarter, where we were able to steadily add patients and our gross-net came in better than we anticipated. We now expect our gross-to-net discount to be in the mid to high thirties for the rest of 2026.

Looking ahead, the fundamentals of the business are strong, and as Bill discussed, Q2 is off to a great start. For the rest of 2026, we expect to steadily add patients and generate robust net sales growth. Moving to operating expenses, which include a total of $34 million of non-cash stock-based compensation expense in the quarter. Cost of sales for the first quarter of 2026 was $26.8 million compared to $4.5 million in the prior year period. Cost of sales at this point primarily reflects royalties owed to Roche. R&D expenses for the first quarter of 2026 were $108.7 million compared to $44.2 million in the prior year period. The increase was primarily due to one-time upfront business development expenses of $54.3 million.

As a reminder, the $25 million upfront payments and related expenses for ARO-PNPLA3 will be recorded in the second quarter. SG&A expenses for the first quarter of 2026 were $268.5 million compared to $167.9 million in the prior year period. The increase was primarily due to continued investment in commercial activities for Rezdiffra, including headcount for the Endocrinology field force expansion that occurred in the fourth quarter of 2025, as well as marketing efforts, including our DTC campaign. Looking ahead, we expect full year 2026 R&D expenses to be roughly the same as 2025, which is inclusive of the one-time upfront payments we've announced for strategic business development investments in both periods.

We expect full year 2026 SG&A expenses to increase compared to 2025, with the annualization of the Endo sales force as we continue to support the launch of Rezdiffra and build the foundation for expected long-term growth. This includes some choppiness with higher Q2 SG&A expenses in 2026 due to timing of certain marketing expenses, including DTC, then studies for the rest of the year. Net loss for the first quarter of 2026 was $94.4 million compared to $73.2 million for the prior year period. Net loss for the first quarter was inclusive of one-time upfront business development expenses of $54.3 million. While our focus remains on supporting our top-line growth and building our pipeline, we are also preparing for profitability.

Turning to our balance sheet, we ended the first quarter of 2026 with $817.9 million in cash equivalents, restricted cash and marketable securities, compared to $988.6 million at the end of 2025. The balance reflects several quarter specific uses of cash, including one-time upfront business development payments and timing of API purchases to support future Rezdiffra manufacturing. With a strong cash position, we continue to be well-resourced to support the ongoing launch of Rezdiffra and the advancement of multiple pipeline programs and continued business development. To close, slide 16 captures what we've discussed this morning. Rezdiffra continues to deliver incredible commercial performance with a trailing 12-month net sales now exceeding $1.1 billion, and demand remains strong, with patient growth more than doubling since Q1 2025.

We are leading in a market that is still in the early stages of development that has already expanded nearly 50% in the last 2 years. This reinforces both the scale and the opportunity and the runway that remains ahead of us. We also see significant upside beyond F2, F3 with F4-C representing an important next phase of growth in an indication where there are currently no approved therapies. Importantly, we're not standing still. We're investing in our pipeline of more than 10 programs designed to build on Rezdiffra's foundation and extend our leadership across the full spectrum of MASH. Taken together, this is a company built for sustainable value creation. We believe Madrigal is exceptionally well-positioned in 2026 and beyond. I'll now turn the call back over to Tina and open the Q&A session.

Thanks, Mardi. Let's move into the Q&A portion of the call. Brilla, please go ahead and provide instructions for the Q&A session.

Thank you. We will now open the lines for questions. To open your line, please press star followed by the number one on your telephone keypad to be added to the queue on the call. Our first question comes from the line of Prakhar Agrawal with Cantor Fitzgerald. Please go ahead.

Hi, congrats on the quarter, and thank you for so much for taking my questions. Maybe just on Rezdiffra, what are you seeing on the Q2 trends so far and the expectations for patient adds for rest of the year? As a follow-up, now that Wegovy has been on the market for MASH for a few quarters, what are you seeing on the impact to Rezdiffra in the market, if any? Thank you.

Thanks for the question, Prakhar. Look, as we take a look at the Q2 trends, I mean, First of all, they're great, so I'll get to that in a second. Context, over 42,250 patients on drug as we exit Q1, 2.5 times growth over last year at this time. Really impressive. In the context of we are at the very beginning of a market. We fully expect this is gonna be a mega blockbuster. $1.1 billion in the last four quarters. We're in a really great space. If to put in perspective, how are things going in the second quarter, we're off to a strong start. We're carrying that momentum. We're steadily adding patients. Maybe it's best to put it in the context of Wegovy that you mentioned as well.

You know, Wegovy's had now 3 quarters of launch that we've been out there. It's being used, but certainly not to the detriment of Rezdiffra. We continue to steadily add patients through it. You know, you have to think Wegovy and GLP-1s are really becoming a background therapy. In fact, most of the doctors that we talk to say they're already on a GLP-1 when they come into the office. They're coming into the office on a GLP-1, and they have F2, F3 MASH. You know, our profile looks really, really strong there. It's out there. We're seeing them, but we're not seeing any real difference. Maybe as a final proof point, last quarter, I talked about us having our best NBRx week in the last quarter.

As we exit, April, it's been our best NBRx month since launch. You know, we're really excited about the rest of the year. We'll be steadily adding patients, just as we've said from the beginning. Thanks, Prakhar.

Thanks, Prakhar. Next question, please.

The next question comes from the line of Ashwani Verma with UBS. Please go ahead.

Hi, congrats on the quarter and thanks for taking our question. Maybe just, can you talk about the breadth of prescribing right now and how do you think that would evolve? Is it fair to assume that bulk of the prescribing right now is coming from gastroenterologist and when do you start to get traction from hepatology, which is kind of like a smaller patient audience and then endos, when does that become a big source? Then on the 1Q new patient add dynamics. It seems like roughly 6,000 new patients that you added, which is lower than some of the recent quarters. We saw this dynamic in the first quarter of last year as well when you had 5,000 and then kind of doubled from there.

Is it primarily the new year insurance deductible reset that's driving that? How does the rest of the year shake out on a new patient add dynamic? Thanks.

Great. Great. Thanks, Ash. Let me start there. The Q1 adds, again, it falls into our steadily adding patients. It is a Q1 effect. That's really it. When you think about the Q1 effect, the Q1 effect applies to virtually 100% of your patients on therapy. Remember, what we are presenting is the number of patients that are on drug on the last day of the quarter, right? You have patients that are coming in the top and then the patients that are on drug. That's the Q1 effect that you have since everyone's exposed to it. As I said in the last question, we expect to steadily add patients throughout the rest of the year.

Q2 is off to a strong start. Maybe discussion then about breadth of prescriber. You know, we have over 10,000 prescribers now, which is plenty of breadth for us, though we continue to add new prescribers every day. When you think about just the numbers of physicians, gastroenterologists outnumber hepatologists 10 to 1. You're gonna see the majority of prescriptions that are flowing through them. Hepatologists, you know, they were out of the gates a little faster. They treated the disease longer, probably a little bit better prepared. In fact, we know they were better prepared. You know, we had to wire the system practice by practice with the others. Endocrinology, they're just coming on board.

It was really fourth quarter that we started our efforts there and, you know, you have to think about endocrinologists as being where gastroenterologists were about 2.5 years ago, right? It's something that they've been seeing some MASH, but they haven't really thought about it. Now they're starting to more actively look and, you know, we're wiring the system for each of those endocrinologists as well. We see them as in the future being a really productive specialty for us. You know, as I said, they see all these patients with background GLP-1s, yet they're still seeing F2, F3 MASH. We think that in the future, that becomes a valuable specialty for us as well. Thanks.

Great. Next question, please.

The next question comes from the line of Kripa Devarakonda with Truist Securities. Please go ahead.

Hey, guys. Thank you so much for taking my question. I had a question about patient mix. I think, you know, that GLPs are likely gonna be backbone therapy, but you had also previously talked about how 25% of Rezdiffra patients are on a combo. Can you talk about how that has evolved over the last few quarters? Also, you know, some of the KOL checks, not all, but that we've done say that they prefer Rezdiffra for F2. Would be helpful to understand the F2, F3 split that you are seeing in the real world. Thank you.

Yeah, thanks for the question. You're right, we still continue to see, you know, 25+% of patients that are on Rezdiffra also on a GLP-1 and over 50% have been previously exposed. You know, we expect that trend to continue. We expect that most patients that are gonna come in in the future will have had experience with a GLP-1. You know, those dynamics seem to be in place. Now, your second question was-

Was F2, F3 split?

F2, F3 split. It's about 50-50 still. You know, I know some people have thought, well, wouldn't prescribers want to clear the F3s first? I think it has to do with you have a patient sitting in front of you that's 1 to 2 steps away from cirrhosis. Are you going to wait to treat an F2, not knowing how fast they're going to progress to F3 or to cirrhosis? No, you're not going to wait. You're going to make the call on that patient, what you think their risk factors are and initiate therapy. We still see, and that's been pretty consistent since the start of launch, about a 50-50 split between F2, F3.

Great. Thanks, Kripa. Next question, please.

The next question comes from the line of Ritu Baral with TD Cowen. Please go ahead.

Hi, guys. Thanks for taking the question. I have a more sort of high-level question on diagnostic growth as you see it, Bill, through the rest of the year and next year. Do you think that it could be worthwhile to spend more on disease awareness now that competitive diagnostic awareness programs may be slowing with the, you know, the maturity of the GLP-1 launches in MASH? You know, how you think about maybe stepping up SG&A to support top line growth versus clinical development versus your approach to profitability. If you have, there's some client questions coming in on how you think about estimates for the full year, which still sit at 1.48, I think. This change in gross to net. Thanks.

Okay, let me start off with on the diagnostic growth question, Ritu. Thanks for the question. Look, I think the proof is in the market sizing that we've seen. In just two years, the market grew almost 50%, from 315,000 addressable patients to 460,000 addressable patients. We think that and remember, diagnosis went from 1.5 to 1.9 million. What you're seeing there is that there are more patients that are being diagnosed, and most importantly, they're getting into the specialist offices that we're calling on so that there's a potential for them to get a Rezdiffra prescription. I think our efforts and, you know, this is where, you know, we believe Novo's helped as well by creating more awareness of the disease.

I think that we've already seen the proof point that by having a product, by having more than one company, the market's growing. Specifically on diagnostics, you know, what we're also seeing is more and more interest by practices, purchasing NITs and being able to do point of care diagnosis. That's another good trend that we expect to continue over time. I think that will also facilitate staging of patients and then the ability to treat, and then most importantly, to see how the patients are doing over time. Maybe what I'll do now is turn it over to Mardi to answer the rest of the questions.

Yeah. Thanks, Ritu. I think you had a number of questions embedded in there. I'll pick through them, starting with SG&A. Yeah, clearly we wanna support this, what we think is gonna be a mega blockbuster brand, through the efforts of our sales force and our commercial efforts, including marketing campaign and DTC. We talked about that. We talked about SG&A for the rest of the year. You're gonna see an increase in Q2, then steadies for the rest of the year. Absolutely, we wanna be in front of the growth and support the brand as best we can. That leads to a question about gross to net for the year as well. How did that look?

Gross to net, as we said, we believe we have some favorability going into the rest of the year. We now have better clarity after we got through Q2. Remember, this is a new brand, so we get clarity every quarter. This was, you know, a Q1 quarter that we look at what the various components are. I would say the team did an excellent job managing gross to net for the quarter and set us up for the rest of the year. We believe we'll be in the mid to high thirties for the rest of the year, and I would say for Q1, we're even a little bit more favorable to that, but we're in good shape on the gross to net side.

That leads us to now SG&A and gross net, what we think for the full year. The full year, we are good with the consensus that you mentioned for the full year. That sounds good, and we're also looking good for Q2 with the same analogy. We seem to be right on track and feel good about the rest of the year. The last point that you brought up was about profitability. You know, as we look at it, profitability, we believe is inevitable. We're gonna be a profitable company, and that's why we're preparing for profitability now. If we look at 2026 specifically, we're not gonna be profitable in 2026. You know, specifically in Q2 with the PNPLA3 acquisition, you know, we will not be profitable in Q2 either.

Could there be other quarters where we tip into profitability? Perhaps, but it's really gonna depend on our one-time spend. Beyond 2026, and without specifics, you know, profitability is inevitable, and we're planning for that.

Great. Thanks, Mardi. Next question, please.

The next question comes from the line of Yasmeen Rahimi with Piper Sandler. Please go ahead.

Congrats, team, to a strong quarter and also really great news on hearing gross to net to go down with one of our favorite questions. Let me transition to MAESTRO-NASH-OUTCOMES. I mean, we're almost halfway through the year. Would love to understand at what point do you really get visibility on how the events are tracking and fine-tuning guidance and sort of also helping understand expectations. I know you take blinded looks at the event rates. You've been consistent saying they're tracking. Would love to kinda get sort of color on how you're thinking about what we could learn more around MAESTRO-NASH-OUTCOMES in the upcoming between now and sort of year-end to kind of prep us for a very important pipeline expansion opportunity.

Great. Yas, thank you very much for the question. You know, it represents a huge opportunity for us. This is a really high-end met and even need. Dave, could I pass it over to you to answer the specific questions, please?

Yeah, sure. Yeah. Thanks, Yas. Yeah, I mean, obviously, a critical, a critical study for us. As we've said, we're seeing events track in range of our expectations, and we continue to project the trial to deliver in 2027. You know, with these, you know, smaller-sized trials, precision is sometimes difficult, and we wanna give you know, a good estimate of when to expect that. When we have that precision, we'll provide you an update. Right now, we're still saying 27, events are tracking, and we're excited to see the results.

Great. Thanks, Yas. Next question, please.

The next question comes from Eliana Merle with Barclays. Please go ahead.

Hey, guys. Good morning. Thanks for taking the question. Bill, you alluded to this with patients coming in already on GLP-1, but can you elaborate on what you're seeing in terms of combination use with GLP-1 specifically, maybe the latest in terms of the proportion of Ryzdegib for patients also on GLP-1? What does payer coverage for combination look like since Wegovy got the formal label for MASH? Thanks.

Great. Thanks, Ellie. We're still seeing around 25% of patients that are concomitantly on GLP-1 with Rezdiffra. You know, we think that's gonna increase. That's our belief is that it's just inevitable. I mean, there's just, you know, really so many patients that are on a GLP-1. Regarding access, we have great access, I have to say. I mean, Since day 1 of launch, we have had, I would call it even exceptional access. As we moved into 2026 with the contracting that we did, we maintained that great access. You know, I think it's like everything else, it's a subtlety.

You can use a GLP-1 in combination with Rezdiffra if the GLP-1's prescribed for one of the other indications that a GLP-1 is indicated in. What we haven't seen and don't have good data on is just if there's any that have a double MASH prescription. We don't think payers would allow that, but they're certainly allowing a GLP-1 to be used for another indication, and then Rezdiffra being used for MASH. I think, you know, from what we're hearing more and more from prescribers is that having the combination makes sense in a lot of ways, and certainly we believe that based upon us going out and getting an oral GLP-1 last year. We think that it is a combination that could make sense.

If you recall, if we saw greater than 5% weight loss in patients that were not on a GLP-1 in our MAESTRO-NASH trial, that it led to a improved effect on fibrosis for Rezdiffra. We're gonna pharmacologically induce that, so to speak, with the GLP-1. That's the hope and that's the study that as Dave said or we said previously, we have that phase I study of our oral GLP-1 kicking off in the next weeks.

Great. Thanks, Ellie. Next question, please.

The next question comes from Thomas Smith with Leerink Partners. Please go ahead.

Hey, guys. Good morning. Congrats on the quarter, and thanks for taking our questions. Your pipeline's extended substantially here over the last 12 months, multiple siRNA programs, the oral GLP, the DGAT2 inhibitor. Sounds like a lot of optionality, but can you just provide some updated thoughts on the clinical strategy and positioning across these doublet or triplet combos, and maybe the criteria you're gonna use to advance these programs beyond proof of concept? And then can you also comment on your appetite for additional deals in BD following this string of recent deals? Thanks so much.

Thanks, Tom. Let me just provide maybe some context about how we're thinking about our pipeline, Dave, if you could jump into the specifics. It goes back to this opportunity that we have. We're at the very beginning of the treatment of a disease that's had no therapies and is a incredibly high unmet need, number 1 cause of liver transplants for women in America, number 2 for men. We have the foundational therapy, we expect that this market is really set up for decades of growth. We're at the front end with a foundational therapy that is really effective, we're seeing that in the real world. Feedback has just been, you know, impressive from what we're hearing from prescribers that are using the product and from patients as well.

When you've got this opportunity with a product that's already a blockbuster to think about long-term leadership, you take that opportunity based on the success of Rezdiffra and the future dynamics of the market and the fact that so many people have decided to step out of the market. Pfizer steps out, J&J steps out, BMS steps out, et cetera, et cetera, based on failure with some of them. I mean Pfizer actually just, they couldn't bring it forward, so, you know, it was better in our hands. What we've done is we've gone out and looked for mechanisms of action that we think make sense in combination with Rezdiffra. Those mechanisms may not have been strong enough, good enough to compete as a monotherapy.

If we can put them together with Rezdiffra and get even more efficacy across the whole population or a subpopulation, that is a step to long-term leadership, either as a fixed-dose combination if it's an oral or as a regimen where you've got a once-a-day pill and then every 3-to-6-month siRNA, just like the deal that we did with Arrowhead Pharmaceuticals, which we think is fantastic. We've also been able to do this in an incredibly capital-efficient manner. For under $300 million, we have assembled a leading pipeline. You just don't see that. I haven't seen that in any other therapeutic area. We, because of our leadership position, I think, have been able to access opportunities that others, it probably wouldn't make sense for.

That's how we're thinking about it, and yes, we've done, you know, a really good amount of BD in the last 10 months now, I guess it is. What's our appetite going forward? Look, we're still constantly looking at everything out there that is potential in MASH. Where we see an opportunity that could make sense with a mechanism that we like and we don't have, we would look at that opportunity and bring it in. Again, think about how we've done it already, which is extremely efficiently, and we will keep that discipline going forward. Maybe with that, I'll just pass it over to Dave to comment on any specifics.

That's, that's, I mean, great summary, Bill. I mean, I think the, you know, one way to think about it, as Bill was highlighting, is we have the foundational therapy, right? We have Rezdiffra to look for combination partners with to improve efficacy and improve outcomes for patients. That's the idea. Our approach has been, we look for validated targets with complementary biology, and we're modality agnostic. That's how we built the pipeline. We have small molecules, we have siRNAs. Anything that could potentially work more effectively with Rezdiffra, that's great. You know, it's important to start off with, you know, Rezdiffra also sets a high bar, right? Rezdiffra works very well across all subpopulations, as we've seen from MAESTRO-NASH.

You know, our bar for bringing products forward, when we, when we conduct phase II studies is that they have to be meaningfully, you know, they have to deliver a potential meaningful benefit to patients at the, at the end of phase II. Our, our decisions will all be data-driven, and we've talked about a couple of different examples, where we talk about, for example, PNPLA3, where there's a very specific patient population that we're targeting. Patients who are homozygous for I148M PNPLA3 mutations, again, highly prevalent mutation, highly burdensome in terms of clinical outcome. We believe that with Rezdiffra as the foundation, adding PNPLA3 may provide an even greater benefit for those patients. As Bill was just highlighting for GLP-1, it's a different strategy, right?

That's to produce, you know, modest but important weight loss for patients that can drive Rezdiffra's antifibrotic effect. What we're looking for in early clinical development in these sort of initial combination studies are, you know, primarily will be, you know, biomarkers like changes in MRI-PDFF, but also other biomarkers of fibrosis and other blood-based and imaging biomarkers to help us make decisions about what to move forward into phase III. That phase III transition, you know, has to be, you know, underpinned by data that leads us to believe that these products are gonna be meaningful additions to the therapeutic armamentarium. In every case, we believe that these programs all have that potential.

Right. Just maybe to put a finer point on it as well, if they show a benefit, move them forward fast. If they don't, kill them fast. That is a little bit of a again, another difference with Madrigal. We're not beholden to a single pipeline asset performing for the, you know, for the company to actually be something, we can be ruthless in our prosecution of these trials, and we will. If it works, great. If it doesn't, I mean, great, we move on because we're already starting with the product that we have, which is Rezdiffra, which is the enabler of this strategy. Thanks for the question.

Excellent. Yeah, good question, Tom. Next question, please, operator.

The next question comes from Akash Tewari with Jefferies. Please go ahead.

Hey, this is Manoj on for Akash. Just one on from our end. Maestro outcome baseline poster show around 150k mean platelet count in the population. While this seems lower than around 180k seen in the SYMMETRY phase II, it still seems to be higher than the F4-C, the early data you were showing, like, which was, I think, around 120k. In the early data you saw around 2%-3% of annualized event, given this outcome, that baseline population platelet count is above that early data. Do you expect to see some difference in the event rate there based on this platelet count difference, I mean, platelet count difference?

Great. Thanks for the question. Dave, I'm gonna pass that over to you.

You got it. You know, you're highlighting a really important point, which is in these F4C trials, you have to ensure that you enroll the right patient population within the F4C population. F4C is not a, you know, monolithic disease, right? Patients who've just transitioned, for example, from F3 to F4, you know, it might take them a while to progress to decompensation, whereas patients who have CSPH, clinically significant portal hypertension, are right on the cusp of having a decompensation event, and those are the patients that are more likely to drive events in the near term. As you're highlighting, one way that you measure clinically significant portal hypertension is including platelet counts along with liver stiffness measurements, using the Baveno criteria.

As we've talked about before, both in our open label extension study and in MAESTRO-NASH OUTCOMES, we've allowed patients with low platelet counts, so, greater than or equal to 70,000 k, to enroll in the study. There are patients with quite low platelet counts, and that's not uniform across all phase III F4-C protocols. We believe that our outcomes trial is enriched exactly the right way. Using a variety of criteria to enrich the population to make sure that we see the outcomes as we are, and yet have an opportunity to bring these patients back from the brink of being on the cusp of decompensation and bring them into a less urgent stage of their disease.

You know, I think, on that basis, if you look across the open label extension period open label extension study and MAESTRO outcomes, the populations are broadly comparable. There are gonna be some differences just because the sample sizes are very different. The inclusion criteria are very similar, and we are seeing, you know, rates of CSPH in both studies that give us confidence. I think I'll leave it there.

Great. Appreciate it. Thanks, Dave. Operator, next question please.

The next question comes from Mike DiFiore with Evercore ISI. Please go ahead.

Hi, guys. Thanks so much for taking my questions, and congrats on all the progress. Two for me. First on PNPLA3, that was previously partnered and later returned to Arrowhead. Without asking you to speak for J&J, could you walk us through what Madrigal saw in the asset that made it attractive today, and what diligence gave you confidence in the program? Then I have a follow-up.

Great. You know, look, maybe just a general statement, I started with that, then I'll pass it to David. You know, a lot of companies, big pharma, have opted out of MASH, right? They either had failures or they thought they have a single asset, maybe it's not enough, which is a little bit different than us. David, you know, I'll pass it over to you to ask the specific question about why we're so excited about this asset.

Yeah, look, I think, I mean, you touched on it before, Bill. I mean, I think, you know, starting with the fact that we have Rezdiffra, you know, we think in our hands adding a PNPLA3 targeted agent could deliver even better efficacy to the patients who are homozygous. Again, coming back to the strategy, validated targets, complementary biology to Rezdiffra and being modality agnostic. Why did this asset sort of fit into this? Well, clearly, it's a validated genetic target. PNPLA3 is a validated genetic target, clearly linked to more rapid and progression of disease of MASH and an emergence of liver related events in patients who are homozygous versus those who are wild type.

you know, I think second, it's a proven modality. siRNA, you know, as we've seen, you know, with other products getting to the market, siRNA products getting to the market, it's a safe modality that you can deliver once every 3 to 6, even up to 12 months. A highly attractive modality with great tolerability. Last, there are clinical data, right? we had, you know, we had phase I data in patients where we could see reductions of liver fat, so we had a proof of concept in phase I. as we've seen, you know, with the MAESTRO-NASH data with Rezdiffra, if you can reduce more liver fat, we can see more efficacy with resmetirom.

Again, the complementarity of these two mechanisms was particularly compelling as well. I think for all those reasons, you know, we bring in a clinical-stage asset, advance our pipeline, and have a potential offering for patients who really need a therapy.

Yeah. I mean, look, it was a 46% reduction in liver fat. I mean, that's a pretty impressive efficacy from our perspective and, you know, let's see what happens when you put it in combination. I think it's a really exciting question to ask. Look, it's been through phase I, right? You know, this is an acceleration of our siRNA efforts.

Great. Thanks, Mike. Operator, next question, please.

The next question comes from Andy Chen with Wolfe Research. Please go ahead.

Hey, this is Brandon for Andy. Thanks for taking the question. We're curious to know if you can rank order the different NASH combos that you have. Which one are you most excited about clinically? Thank you.

Thanks for the question. You know, I'll pass it over. Today my view is it's whichever one works the best is gonna be the one that we like the best or those that work the best. Dave, how are you thinking about it?

Right. Pick amongst our children. I mean, I, you know, I think there. We brought them in, we brought each of these assets in for the reasons that we've talked about, because they all have the potential to significantly move the needle on efficacy for a subpopulation or within the broader group. You know, the decision is about which to move forward into phase III programs and ultimately to registration depends on the combination data.

As, as we've outlined, you know, we have because we're focused in MASH and we have experience in this field, a lot of experience running clinical trials in MASH, we know the sites well, we know how to run the trials, we're gonna be able to be efficient, run these studies and deliver the data that helps us make that decision. As I said, the data have to be meaningfully different. For PNPLA3, like Bill said, 46% reduction in MRI-PDFF is great. Combined with Rezdiffra, if that's even more, we push more patients into that super responder category, amazing. We're gonna bring that program into phase III. That's true for all of these programs.

It's really proof, you know, proof will come from phase II, and we'll move the programs forward in a way that's gonna make sense to build a pipeline and to deliver value to patients.

Great. Thanks, Dave. Operator, next question, please.

The next question comes from John Wolkoff with Citizens. Please go ahead.

Hey, thanks for taking the question, and congrats on the progress. Bill, you made a comment about, I think, a path to peak sales, and I'm wondering if you could talk a little bit about what that path looks like in terms of timing, how long you get there, and, you know, how big you think Rezdiffra could be down the road.

Thanks, John. You noticed. Look, I think that in our belief this is gonna be a mega blockbuster. How do we get there? We continue to do what we're doing. We have the diagnosis rates increasing. We have more patients get on drug. We steadily add patients, and we build our path to peak sales. I think it's pretty straightforward. We just continue to do the hard work we're doing. There's plenty of patients. The market's growing. Penetration rate is low. Diagnosis rate at the moment is low. All of these things are increasing, so there's literally years and years and years ahead of this market expanding. You know, as I said earlier, as more companies come in, it actually helps us 'cause it drives market expansion.

You know, our initial focus was always on that 315,000, just who was sitting in those prescribers' offices at the moment. Fortunately, now we even have more potential with the advent of other companies coming in and driving diagnosis, et cetera. Keep doing what we're doing, you know, steadily add, and we'll find our path to peak.

Great. Thanks, John. Operator, we have time for one more question, please.

The next question comes from William Wood with B. Riley Securities. Please go ahead.

Hi. Thanks for taking our questions and congrats on a very nice quarter. Just thinking about in terms of your pipeline, as you said, you've got about 10 pipeline assets as is. You know, should we expect any more add-ons to your pipeline? You know, if so, what might you be looking for, whether it's more oral options, more siRNAs or maybe something that we're not really discussing here?

Then also in terms of just sort of, in terms of that go, no-go situation, I was curious if any projects that you've sort of brought on or been developing internally have sort of hit that threshold that you've already called and maybe speak to anything that, you know, that might have changed where you're looking in the future or if you're pretty content, with what you've got now and you're just looking to execute. Thank you.

William, thank you very much for the question. You know, look, we have assembled, I think, you know, the leading pipeline in MASH, and we've done it for less than $300 million. Again, you know, that, as I said, says a few things. It says a lot of people still aren't interested in MASH, which is great because we are, and we're in a better position to lead the innovation based on our ability to use Rezdiffra as a foundational backbone therapy. Yeah, we're still looking. Clearly, you know, we've taken quite a bit off the table for us to pursue, but it would be very mechanistic driven. Is there something that we think looks particularly interesting?

There's still, you know, I would say a couple of mechanisms out there which look interesting. The question becomes finding one and finding one that's transactable. You know, expect that there may be additional. Certainly we'd like to, you know, kinda round out the pipeline, if you will, with our, with the, you know, remaining some remaining mechanisms, but we're a big way through it now. Efforts are really focused towards now getting these in the clinic, generating data and being able to make decisions. That's how we're thinking about it.

It's really, you know, again, in less than a year's time to have come from a single asset company that has an incredibly promising future, you know, growing into a mega blockbuster to now because of that success be able to build that next stage of leadership, which we think is really long-term focused.

Great. Thanks, Bill. Thank you, Brilla, and thank you all for your time and interest today. This now concludes our call. A replay of this webcast will be available on our website in about two hours. Thanks for joining us.

Ladies and gentlemen, thank you for your participation in today's conference. You may now disconnect. Have a wonderful day.