Madrigal Pharmaceuticals, Inc.

Good morning, and thank you for standing by. Welcome to Magical Pharmaceuticals' second quarter 2026 earnings conference calls. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will have to press star 11 on your telephone. You will then hear an automated message advising that your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference call is being recorded. I would now like to introduce Ms. Tina Ventura, Chief Investor Relations Officer. Please go ahead.

Good morning, everyone, and thank you for joining us to discuss Madrigal's second quarter 2026 results. 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, Dave Soergel, Chief Medical Officer, and Mardi Dier, Chief Financial Officer. They will provide prepared remarks followed by Q&A. Please note on slide two, 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. With that, I will now turn the call over to Bill on slide three.

Thanks, Tina, and thank you all for joining. Before we review our second quarter results, let me remind you why we're so excited about MASH and why we believe Magical is uniquely positioned to lead this market. The market fundamentals are exceptional. MASH is a high unmet need disease with the potential for decades of growth given today's low diagnosis and treatment rates and a rapidly expanding patient population. We are at the forefront of one of the most attractive growth opportunities in the industry. We also have what we believe is the foundational therapy. Resdifra is the first approved medicine for MASH, a liver-directed, once-daily oral medication with demonstrated efficacy across each MASH subgroup and an outstanding real-world profile. Add to that our commercial execution, our experienced team, and our industry-leading pipeline. We believe Magical is exceptionally well-positioned to lead in MASH today and define where this market goes over the long term. Slide 4 summarizes how we're executing on our two strategic growth priorities, maximizing the value of ResDifera and advancing our pipeline. ResDifera continues to exceed expectations as we steadily add patients quarter over quarter. Over the last 12 months, ResDifera has generated nearly $1.3 billion in net sales, reinforcing its mega blockbuster potential. We're also strengthening the long-term value of the franchise. A key pillar of that strategy has been to build a robust patent estate. Last year, we secured our pivotal 2045 F2F3 patent. This month, we build on that foundation with three additional patents, two that reinforce our protection in F2F3 and one supporting our potential F4C indication. As we've done successfully to date, we'll continue pursuing IP that protects the future of RISDFRA. And because we believe Red Differ is the foundational therapy in what will become a large specialty market, we're investing behind it. In less than a year, we've built what we believe is the industry-leading MASH pipeline, adding more than 10 programs. We now have four clinical stage assets following the initiation of the Phase I study of our oral GLP-1 last month. Each of our programs is designed to build on ResDifera's foundation and extend our leadership in MASH for years to come. We've accomplished a tremendous amount in a short period of time, but we're just getting started. Our team continues to execute on these priorities to strengthen the leadership position we've established. Let's move to our Q2 results, where I'll provide an update on ResDifera. Dave will discuss our pipeline, and Mardi will close with a review of our financials. Turning to slide six and net sales, we are continuing to see strong demand for ResDifera. Second quarter 2026 net sales were $364 million, representing year-over-year growth of 71%. This performance continues to reinforce that ResDifera is tracking in line with, and in many cases exceeding, the best-in-class specialty launches we compare ourselves to. Our strong performance is a result of successful launch execution. It's driving our near-term results and building the foundation for the long-term growth. We have effectively wired the system to build a broad and durable prescriber base. And importantly, prescribers continue to tell us that ResDiffer is performing even better in the real world, and that experience is translating into action. Today, our target specialists are prescribing risdifera more often, which is driving greater deaths across our prescriber base. That growing depth combined with broad first-line commercial access, risdifera's differentiated profile, and strong patient adherence continues to drive patient growth. That's why we've steadily added patients ending the second quarter with more than 49,000 active patients on risdifera, more than double a year ago. Importantly, Momentum remains strong as we progress through the third quarter, where we surpassed the 50,000 patient milestone earlier this month, a significant accomplishment in any launch. One of the things we're most excited about is how quickly this market is developing, as shown on slide 8. From year-end 2023 to year-end 2025, the U.S. addressable market has grown nearly 50%. from 315,000 diagnosed F2, F3 patients at our target specialists to 460,000. That's remarkable growth in just two years, and it's being driven by exactly what you'd expect in a new therapeutic category. Greater disease awareness, increasing diagnosis, more patients being referred to specialists, a growing urgency to treat, and increased investment by multiple companies. We have continued to see strong market growth again this year and expect the MASH market to expand at a double-digit pace for the foreseeable future. In fact, we see parallels between MASH and other large chronic disease markets like rheumatoid arthritis, IBD, and psoriasis, as shown on slide 9. Each started with one or two therapies and evolved into markets supporting more than a dozen products and more than $20 billion in annual sales. We believe that MASH will follow the same path and that Rizdifera has a stronger profile than the first products that launched in any of those categories. And today, we're only about 10% penetrated in a market with a roughly 10% diagnosis rate. Think about that. 10% of 10%, that's 1% of the total potential market. Yet even from that starting point, as shown on slide 11, ResDiffra is already generating north of a billion dollars in trailing 12-month net sales. That's why we're so excited about the future. We are still at the beginning of what we believe will become one of the largest specialty markets in the industry, where we have a first-to-market medicine with a best-in-disease profile. Everything I've discussed so far speaks to the strength and opportunity of ResDifera in F2-F3 MASH, but there is another significant unmet need ahead of us in well-compensated MASH cirrhosis, or F4C, as noted on slide 12. It's an untapped market with no approved therapies and a much higher urgency to treat. With approximately 245,000 patients under specialist care in the U.S., we believe F4C could double ResDifera's opportunity. We have an event-driven outcome trial underway in F4C that, if positive, is expected to support expansion into this indication and support full approval across F2 to F4C. And we see the market evolving beyond these initial stages as noted on slide 13. Like other complex chronic diseases, treatment will evolve to include multiple mechanisms, combination regimens, and increasingly personalized approaches. That's why we've strategically invested in building the industry-leading MASH pipeline. ResDifera gives us a foundation no one else has, allowing us to thoughtfully add complementary mechanisms that can provide even more efficacy, broaden patient reach, and define the next generation of MASH therapies. And one of the reasons we believe ResDifera is foundational is what we've heard consistently from prescribers over the last two years of launch. They not only value its liver-directed efficacy, well-tolerated profile, and once-daily dosing, but appreciate that ResDifera works across each patient subgroup in clinical practice. That breadth and consistency across patient subgroups is exactly what you want in a foundational medicine, and it's unique to ResDifera. Dayton will talk more about this in his section and share key data demonstrating where it differs broad efficacy. So with that, I'll turn it over to Dave.

Thanks, Bill. As Bill just mentioned, for a therapy to be truly foundational, it should work effectively across patient subgroups. This is especially true in a heterogeneous disease like MASH. The forest plot on slide 14 with data from our Phase III Maestro-NASH clinical trial demonstrates exactly that. Patients on risdifera consistently demonstrated improvements across key subgroups, including fibrosis stage, diabetes status, BMI, and genetic background, risk factors that may expedite disease progression. This is another way in which we are differentiating ourselves from the competition and why healthcare providers overwhelmingly prescribe risdifera when a patient is diagnosed with F2 or F3 mesh. But we're not standing still. Leadership means continuing to advance the science and generating evidence that supports risdifera's clinical benefit well beyond approval. It's an ongoing effort to better understand risdifera, answer important clinical questions, and continue to raise the bar for what's possible in MASH. At Eazl this year, we presented more MASH abstracts than any other company. I'll highlight three presentations that reinforce our belief that risdifera is the foundational therapy in MASH. First is our F4C analysis on slide 15 using the Anticipate NASH risk model. Anticipate NASH is a validated model developed specifically for patients with MASH cirrhosis. It estimates the patient's likelihood of developing clinically significant portal hypertension, or CSPH, and future liver-related events. The MASH field is rapidly evolving, and this model has become an increasingly accepted tool for assessing risk in patients with compensated MASH cirrhosis. This is an emerging area of science, and we are an early adopter of this new tool. That's an important part of how we approach leadership at Madrigal. We're not simply following the evolution of the field, but we're helping pioneer new ways to understand treatment response and disease progression. We applied the Anticipate NASH model to the 122-patient, two-year open-label cohort from our Phase III Nystro and FLD1 trials. The proportion of patients classified as higher risk for CSPH declined from 75% at baseline to 55% at two years of resveratrol treatment. Why is this important? The development of portal hypertension is the key pathophysiological inflection point in compensated cirrhosis. Once patients progress to CSPH, their risk of decompensation and other serious liver-related events increases by approximately five-fold. These findings further strengthen our confidence that resmediram has the potential to delay disease progression and improve long-term outcomes in patients with F4C MASH. The second data set extends our understanding of risdifera beyond the liver. Patients with F2F3 MASH don't just have liver disease, they also carry substantial cardiometabolic risk. In fact, cardiovascular disease remains the leading cause of death in this population, and MASH itself is an independent driver of cardiovascular risk. Our secondary analysis from Meister Nash and Meister Naphyl D1 showed significant reductions in the ApoB, including LpA and LDL, regardless of baseline statin use. Taken together, these data suggest risdifera may positively impact both liver disease and cardiovascular risk. Slide 17 highlights risdifera's performance in the real world. Clinical trials establish efficacy. Real-world experience builds prescriber confidence. After treating tens of thousands of patients, prescribers continue to tell us Restifera is performing even better than they expected. The data at Eazl support those observations. In one large gastroenterology practice, over a mean follow-up period of approximately nine months, nearly half the patients achieved at least a 25% reduction in liver stiffness, a key measure of treatment response. Real-world evidence like this complements what we've already seen in our clinical trials and reinforces ResDifera's best in disease profile. To deepen our understanding of ResDifera's full clinical potential, we're broadening our evidence generation efforts across real-world studies, investigator-initiated research, and company-sponsored trials. We will continue to pursue the questions that matter most to physicians and patients and work to generate new data that can further inform how MASH is diagnosed, treated, and managed. Putting it all together on slide 19, we've translated our leadership into action. In just one year, we built the industry's leading MASH pipeline with more than 10 programs, including four clinical stage assets, all anchored by ResDifera. This momentum will continue into 2027 when we expect to initiate three Phase II trials. The first, we'll evaluate MGL-2086, our oral GLP-1, in combination with resmeteron. Our goal is to potentiate resmeteron's antifibrotic effect. We began dosing MGL-2086 in a Phase I single ascending dose study in June. Results from this first in-human study will inform the Phase II trials. We also plan to initiate a Phase II study of our DGAT2 inhibitor, Avergastat, in combination with Rizmediram, and we'll engage with regulatory authorities on the design of a Phase II trial combining Rizmediram with MGL0795, our siRNA-targeted PNPLA3, and licensed from Arrowhead in May. We're also progressing one of the six preclinical siRNA assets that we unlicensed from RiboCure. We recently nominated the first candidate to move into IND-enabling studies. All of this is advancing alongside our two ongoing Phase III res differe trials. First, our F4C Maestro outcome study, which is an event-driven trial that we expect to read out in 2027. And second, the F2F3 Maestro NASH study, which is primarily histology-driven with data expected in 2028. We've made significant progress in a very short period of time. With RISDF as the foundation and long-term patent production providing the runway to invest and innovate, we have an opportunity to define the future of MASH care and meaningfully improve the lives of patients. With that, I'll hand it over to Mardi.

Thank you, Dave. Turning to slide 20 and a summary of our financial results, we delivered another strong quarter with second quarter 2026 net sales of $364.3 million, representing 71% growth year over year. Demand for ResDifera remains strong. We once again steadily added patients, more than doubling patients on ResDifera compared to a year ago. We also continue to effectively manage growth to net and continue to expect our growth to net discounts to be in the mid to high 30s for this year. Taken together, these fundamentals support our expectation for continued steady patient ads and robust net sales growth. Moving to operating expenses, which included a total of $35.4 million of non-cash stock-based compensation expense in the quarter compared to $25.2 million in the prior year period. Cost of sales for the second quarter of 2026 was $40 million compared to $9.1 million for the prior year period. Cost of sales was primarily driven by an increase in royalties payable to Roche and a write-down of certain work-in-process inventory. R&D expenses for the second quarter of 2026 were $91.2 million compared to $54.1 million for the prior year period. The increase was primarily due to a one-time upfront business development expense of $25 million related to the in-licensing of MGL 0795, a clinical stage siRNA program from Arrowhead. SJNA expenses for the second quarter of 2026 were $289.4 million compared to $196.9 million for the prior year period. The increase was primarily due to continued investment in commercial activities for RISDFRA, 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 a full year 2026 SG&A expenses to increase compared to 2025 with the annualization of the end of Salesforce as we continue to support the launch of ResDifera and build the foundation for long-term growth. Net loss for the second quarter of 2026 was $57.9 million compared to $42.3 million for the prior year period. Net loss for the second quarter was inclusive of a one-time upfront business development expense of $25 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 second quarter of 2026 with $838.9 million in cash, cash equivalents, restricted cash, and marketable securities, compared to $988.6 million at year-end 2025. With a strong cash position, we continue to be well-resourced to support the ongoing launch of RISDFRA, the advancement of multiple pipeline programs, and continued business development. So, to conclude on slide 21, We believe Magical is exceptionally well-positioned for continued value creation. With nearly $1.3 billion in trailing 12-month net sales, Rizdifer is on its way to mega blockbuster status. And as Bill said, the third quarter is off to a great start. We've more than doubled the number of patients on therapy over the past year, while the addressable NASH market itself has expanded by nearly 50% in just two years. and we believe it's still in the early stages of what will be decades of growth. We're building on those different foundations with the industry-leading pipeline of more than 10 programs. We look forward to multiple future data readouts, including our Phase III F4C trial. We're investing from a position of strength with an R&D strategy designed to extend our leadership and create long-term value. Taken together, we believe Magical is exceptionally well positioned not only for continued growth in 2026, but for sustained value creation for many years to come. I'll now turn the call back over to Tina to begin the Q&A session. Thanks, Mardi.

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

Thank you very much.

At this time, we will conduct the question and answer session.

As a reminder, to ask a question, you need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Prekar Agwal of Cantor Fitzgerald. Your line is open.

Hi, congrats on the quarter, and thank you so much for taking my questions. I had two. Firstly, I wanted to ask about the 3Q trends. What are you seeing in expectations for net patient ads for remainder of the year? Just wanted to get a little bit of better color on what segments are going to drive further growth here, and how do you feel about where the consensus is sitting for 3Q and for year 2026? And second question, You started targeting endocrinologists last year. Any initial thoughts on what you are seeing on the uptake among endocrinologists? Could that be a meaningful growth segment, or is it more niche right now? Thank you.

Thanks for the question, Prakash. It's Bill. Maybe just a comment on where we are. year-to-date here. We had really, I think, an exceptional quarter in Q2 that was driven by exceptional execution, exceptional market dynamics, and I think that is really the best indicator of where we're headed for the future. The fundamentals of the business are terrific. We have great access. 2026 is going to be another great year. As you know, we exceeded Q2 expectations. Q3 is off to a great start. We have said and we continue to steadily add patients with over 49,000 patients at the end of Q2, more than doubling year-over-year patient numbers. And we did announce this 50,000 milestone, which that is a really remarkable number in any launch. I don't care whether you're in a specialty launch, non-specialty launch, 50,000 represents great progress. And that's something that we got across in July. So we continue, now looking forward to Q3 and beyond, to steadily add patients. We've been steadily adding. We're going to continue to steadily add patients through third quarter and through the rest of the year. So I think we're set up really well for 26, but Mardi, do you want to talk maybe a little bit about some of the specifics?

Yes, absolutely. And hi, Prakhar, and good morning, everyone. As Bill said, we're off to a great start in third quarter, and we're going to expect to steadily add patients, as he just discussed. And with respect to third quarter and fourth quarter, what we'd like to say is that, yes, we're comfortable with a consensus quarterly growth rate for the rest of the year. So that means from going the growth rate, the consensus growth rate from second quarter to third quarter, and then again, the consensus growth rate from third quarter to fourth quarter. So taking together, just as we said, robust sales growth for 2026.

And Prakara, just to talk about kind of the segments where it's coming from, you know, this continues to be driven by HEPs and GIs for the most part. That's just where the prescriptions happen, where we would expect that they're going to continue. You also asked about endocrinology. Endocrinology was a fourth quarter 2025 focus of ours. So, you know, we're still really early into that. And you have to remember, endocrinologists, just I'll make two real quick points about them. Number one, They've been using GLP-1s for over a decade, and they still are seeing lots of mash and want to talk about Red Diffra. You know, check that box. Number two, they just got started really in the fourth quarter of last year, so they're in kind of that first year of launch. And HEPs and GIs, they have to take their own time to wire the system, know how they're going to access their NITs, what's the pathway they have for their practice. So lots of potential in endocrinology and time, but you have to just know where they are. They're kind of nine months into the launch, really, at this point. But certainly very promising. Thanks.

Great. Thanks, Prakhar. Corey, next question, please.

Thank you very much. Our next question comes from the line of Ellie Murley of Barclays. Your line is open.

Hey, thanks for taking the question and congrats on the strong performance. Just in terms of patient growth, it seemed to accelerate versus the first quarter. I guess, what are the drivers of this and your expectations for patient growth from here? And then just in terms of F4C, I guess, How is the event rate tracking in that study and any clarity on when in 2027 you might expect to release the data? I recognize you might not comment, but figured I would try. Thanks.

Thanks, Allie. Thanks for the question. On the patient growth, now I just want to make sure, just a little bit, the way we report patient numbers is the number of patients that are on Red Zip or on the last day of the quarter. and that is the net of patients that are coming in the top of the funnel and patients that are going out at the bottom of the funnel, right? I mean, you know, as you get a bigger and bigger denominator, you have more and more patients exposed to, you know, potentially dropping off. Now, the great news this year is that we continue to steadily add patients, as I've said, and we don't see that slowing down at all. But remember, you really have to do work a lot harder on the top of the funnel as you have a bigger denominator that patients can fall out of. We're seeing persistency like a well-tolerated oral. A well-tolerated oral at the one-year mark is in that 60% to 70% range. No changes there. Products have been performing exceptionally well. When we talk to the community, we hear stories of persistence which are even higher than that. So we have Thank you for joining us. and to keep patients on and then we get to that net number. And we think that we have a really good approach and that's why we continue to say what we expect to steadily add. Maybe, Dave, I'll turn to you on F4C. Yeah, sure.

Hi, Ali. Yeah, a quick update. So, I mean, clearly, Maestro Outcomes is an important trial for the field given the unmet medical need and the fact that this is going to be the first outcomes trial in F4C to read out with outcomes, which is, you know, a big thing for the field. So the good news is we're seeing events accrue in the trial. However, as we've said in the past, you know, this isn't, you know, like, for example, a cardiovascular outcome study where you have a large number of target events. So in this case, precision is very difficult. And when we can be more precise, we'll provide you an update at that point. But right now we're tracking to 2027, as we've said.

Great. Thanks, Ellie. Corey, next question, please.

Thank you very much. Our next question comes from the line of Thomas Smith. Thomas, your line is open.

Hey, guys. Good morning. Congrats on the nice quarter here, and thanks for taking our questions. I was wondering if you could clarify and maybe expand on the comments regarding gross to net and inventory dynamics in the quarter and how you see those evolving through the balance of 26. And then could you also clarify the contribution of Europe to the worldwide revenues and patient numbers. We saw there was an early access program that launched in France during the quarter. Anecdotally, from some KOLs, it sounded like there's been some nice early uptake there. But can you just comment on that program and how you think about Europe contribution for the year? Thanks so much. Great, Tom. Thanks. Mardi, do you want to talk about gross to net?

Yeah, absolutely. So gross to net, as we said last quarter, our gross to net projected for 2026 is in the mid to high 30s. and we are right in that zone for 2Q and that's what we expect for the rest of the year. And that's really balanced with a, you know, mostly with a high demand quarter with respect to inventory just as we have with every quarter, no big changes there. So overall, everything's going well for the rest of the year in 2026 as we've discussed what we believe the growth rate is for the rest of the year.

Thanks for the question, Tom. Look, contribution of Europe is negligible in the quarter, and we would expect that to be for the year. Now, let me just talk a little bit just with XUS in general. You know, we've launched in Germany, and as you say, we have the early access program in France, and we received approval in the UK. A couple observations. This is not a U.S. disease. It's a global disease. There's a high unmet need. Interest is really high from prescribers and from patients. Reimbursement is a challenge. You have to remember we're in an MFN context here where there's still uncertainty about where that all lands. And I think we're going to be in a period in the next 12, 18 months where things are still settling down. So systems... have not, when I say systems, other countries have not yet adopted what the ask is of the administration and MFM, which is paying U.S. prices. So that's something that we're at the table. We're talking with all of the governments there about this. I'm really hopeful for a long-term solution. But as I said, in this time where it's just kind of really dynamic and a lot of uncertainty as to where and so forth. That's why we say it's going to be negligible. But remember, we've only launched in Germany. That's where we've done our bills. We've been extremely disciplined about the buildings then there. So more to come in the following quarters. But as I said, there certainly is a high unmet need. It's just we've got to solve the reimbursement piece. And this isn't a Magribol specific issue. This is an industry issue overall.

Great. Thanks, Tom. Corey, next question, please.

Thank you very much. Our next question comes from the line of Ritu Baral of TD Cohen. Your line is open.

Good morning, guys. Thanks for taking the question. I wanted to drill down a little further on outcomes, F4C timing, and sort of the drivers there for the data. Can you guys confirm that per your Design Publication that you're still aiming for that 92 event threshold? Or is there a possibility that you might want to boost powering based on what you're seeing? And based on further, just based on our conversations with KOLs, they indicate to us that like events in F4 tend to be almost more asymptotic in the sense that they accumulate much, much more rapidly and barely at all in the first part of the trial versus more sort of linear cardiac outcome study event accumulation. Can you comment on what the natural history tells you on that event accumulation curve and how that contributes to how you're approaching giving us additional clarity and narrowing of data timing guidance? Thanks.

Great. Thanks, Rita. I'll pass that over to Dave.

Yeah. Thanks, Rita. How are you doing today? You know, I think the first thing to comment on is we haven't actually confirmed the target number of events. So what we've said generally is there's a publication by Harrison that's a few years old that was sort of, you know, evaluating an earlier version of the protocol, and we've heard other numbers out there. What we've said in general is that, you know, most of these numbers are in the ballpark, but we haven't confirmed the actual number. I think to your point about accumulation of events, look, I mean, We're pioneering in this space. As we've said many times before, this is really the first well-controlled F4C outcomes trial with a therapeutic agent. We've heard the same thing from KOLs, that the possibility is that events accelerate over time as patients age through the F4C pathophysiology and the development of, for example. I think the good news is, like I said, we're seeing events accrue. They're in line with our projected completion date in 2027. So, you know, when we can be more precise, we'll provide more precision. But I think what you're highlighting is one of the questions that's out there, right? So it's how does the placebo sort of evolve over time within a controlled trial?

Great, thanks. Thanks, Ritu.

Thank you very much.

Oh, yeah, go ahead. Corey, next question.

Thank you very much. Our next question comes from the line of Andy Chen of Wolf Research. Your line is open.

Hey, thank you for taking the question. So we noticed that you provided a timeline guidance on the oral GLP-1 and the DGAI-2. Just curious, can you maybe tell us a bit more about the Arrowhead asset? When is Phase 2 going to begin?

And then with the oral GLP-1, the SAD has initiated, is it reasonable to maybe predict that maybe we're going to get data next year? Thank you. Great. Thanks, Andy. Dave? Yeah. So, well, first of all, thanks for the question, Andy, on the pipeline. I love it. You know, it's one of the main reasons why I came to Mattergold, sort of the opportunity to build a pipeline in a space where there's so much potential and so much need. and what I love about our pipeline is that we have a diversity of mechanisms and yet all of the mechanisms we know a lot about already, right? So there's a lot of data on GLP-1, there's a lot of data on DGAT, there's a lot of data on PNPLA-3. So specifically with respect to the programs, all of these programs have been chosen because there's a strong scientific rationale for complementarity with thyroid hormone receptor beta agonism, with res metron. So specifically for the Oral GLP-1, as you recall, we're developing the Oral GLP-1 ultimately in combination with resmediram to dial in a little bit of weight loss to potentiate resmediram's efficacy. So as you pointed out, we started our SAD last month and we'll be running the SAD and the MAD sort of through this year is our plan. And then the data from that trial will then inform the phase two study, which after we talk to health authorities would start in 2027. So timing, with respect to timing, we haven't given a specific date to expect phase one, but that study will sort of proceed through this year. Similar story with DGAT. We've talked about running a pretty straightforward drug-drug interaction study later this year with Resmediram and Avergastat. Again, we know a lot about Avergastat because Pfizer took the compound through phase two. So we know it provides a lot of PDFF reduction in patients with MASH. And that PDSF reduction could also potentiate res metaroms efficacy. So once we finish that drug-drug interaction study, again, go to health authorities, talk about our Phase II plan, and estimate to start that in 2027. Same story with PMPLA-3. So that siRNA program that we licensed from Arrowhead We start with some very good phase one data where we have a good understanding of dose range with the molecule as a monotherapy. Again, we'd have to go to health authorities, talk about the combination program, and again, estimating a start in 2027. We'll provide more of an update on the specific plans in phase two as we get closer to the initiation. But right now, just based on where the programs are and their life cycle, we'd expect them to start Start Phase 2 in 27.

Yeah, and you know, just maybe just a point on the pipeline. We've brought in these assets to be used in combination with ResDiff. As Dave pointed out in the presentation, as I said, ResDiff is a foundational therapy. You see it working across various groups within MASH consistently. So our objective is to find even more efficacy either in a subgroup or in the total MASH population. And you think about that in comparison to the rest of the industry or those that are participating in MASH. They have single assets that they're hoping, you know, still to read out maybe positive data and maybe get approved and then be able to launch. They're going to be doing that and we're going to be already moving forward with our combo strategy, which is going to raise the bar for the entire field. but there's only going to be one company that has risk different. I think that's a point that sometimes just doesn't get quite picked up or understood. We are starting from kind of that foundational therapy which is the building block for MASH. Thanks for the question.

Thanks, Corey. Next question, please.

Thank you very much. Our next question comes from the line of Yasmeen Rahimi of Piper Sandler. Your line is open.

Good morning, team. Congrats on a great quarter and all the color. Maybe we'd love to get color as you guys have been, and I'm sure you're tracking sort of event rates in the real world in the F2, F3 population, which is the indication, but maybe to the extent that you're seeing, you know, if there is any off-label use in F4s, any observations that being made there, whether it's you know, consistent with the mice to OLE data, which you reminded us of earlier today. Just would love to get sort of real world experience. And I know it's limited and it's probably, you know, occurring at a less extent, but appreciate any color around that. And thank you. It seems like probably we could quantify, you know, like your confidence that the data is in 2027 and the likelihood that it could get pushed out into 2028. That could also be really helpful. Sorry for the very long-winded question.

Yes, thanks for the question. I mean, maybe just a comment on kind of the real world, what we're seeing in F2, F3. You know, you never know what's going to happen in the real world, right? You have your clinical studies. They read out that they're well-controlled. Everything is controlled for patients. Stay on drug and you do the readout and you create a bar chart and everyone starts comparing against the bar chart. Then you get to the real world and that's really what counts. How does the product perform? And what we're hearing overwhelmingly from patients and prescribers is that RedDipra is performing exceptionally well. I don't hear stories of RedDipra not working. And I speak, as you know, to hundreds of physicians, hundreds of prescribers, and I have not heard anyone say, Bill, it isn't working. What I hear is that this is working better than I even thought it would. It is effective, well-tolerated, safe, easy to use, supported by a great patient support program that we have here. So, you know, we really take care of patients, take care of prescribers. So, early feedback, and we're seeing it also in real-world evidence that's being reported, product is performing really, really well. And, you know, that's exciting. You never know that. So, you know, as you think about, as I said, you can compare products on a bar chart, but what really counts is when you move into the real world. And, you know, you didn't ask a question about SEMA. But, you know, SEMLA, I think, is on kind of the opposite side of that. Well-controlled clinical trial looks good in a clinical trial. In the real world, though, you have to stay on a drug, get to a high enough dose, and be on it long enough for it to actually work. And I think that's a really, really great example, and I think that as we look into the future, Profiles really matter, and we've got a great profile. I like to call it a holy grail profile. Having been in the industry 35 years, you know, this is what the industry has always wanted to have, a once-a-day pill that works, right? So maybe that's the place, just to give you some context on what we're hearing in the real world. Now, regarding off-label use, look, we've been crystal clear from day one. Do not use resdifera. and F4C patients until we have the trial complete and we know that it works. And I think that is just the responsible thing to do. And also, look, it makes sense. What you don't want to do is have a product used in an area where there could be any kind of adverse event that then carries back to your already indicated population. So, you know, I think there is some use. We can't quantify it, and there isn't a lot of data to suggest what the experience has been with people. So maybe, Dave, can I turn it over to you?

Yeah, just a quick add. I mean, you made a comment about the open label experience, and so we didn't talk about it this time around, but we have in the past where, you know, the event rate in that 122-patient cohort over a two-year period is quite low. It's a 2% to 3% annualized rate. So even though it's an open-label population, it's a well-controlled and well-characterized population with F4C that looks very much like the Meister Outcomes Phase III population. So that low event rate is some of the basis for our confidence that ResMed-ROM could be effective in F4 as well. I think with respect to timing, as we said, when we have more precision, on the estimate. We'll provide you with an update. At this point, we're still projecting into 2027.

Great. Okay, thanks, Karen. Our next question, please.

Thank you very much. Our next question comes from the line of Akash Tiwari of Jefferies. Your line is open.

Hey, this is Manoj on for Akash. I just want on the FOC outcomes tribe. So given the mean baseline platelet count in open level was around 125K, somewhat higher than the baseline of 150K in the FOC trial, do you view the event rates observed in the OLE as the realistic guide for what we should expect in the FOC? And also, are the blinded event rates in the outcomes trial is tracking in line with what we would expect from the OLE data? Just an estimate on that point. Dave, do you want to?

Yeah, sure. Yeah, I think with reference to the platelet count, I mean, you know, there's going to be some variability, as you know, in the measure of platelets. So, you know, in general, we enriched both populations by having a very low exclusion criterion for platelet count. So, you know, greater than 70,000 in the study. And the distribution, as we've talked about, of patients with CSPH is pretty similar when you look at the open label Thank you. So I think the fact that we've sort of pushed the population towards the higher CSPH risk is one of the reasons why we're seeing events and maybe other programs at other sponsor companies are maybe not seeing as robust accrual of events. We think we've enriched this trial in a particularly effective way, both in terms of CSPH and using other markers like MRE. So I think that's the key point. Your second question was? Yeah, so as we've said, I mean, the events are tracking in a way that would estimate a delivery of the data in 2027. And when we're able to provide more precision on that estimate, we'll give you an update. But right now, 2027. Great.

Thanks, Inej. Next question, please.

Thank you very much. Our next question comes from the line of Ash Verma of UBS. Your line is open, Ash.

Great. Yeah, thanks for taking our question. Yeah, I got two on F4 also. So just maybe, can you talk about, like, what type of relative risk reduction on the composite would position risdifera as a drug that can have broad adoption based on the feedback that you're getting from physicians? Is it realistic, 50%? type outcome or can we get even a broader adoption with a lower risk reduction? That's first. And then secondly, a lot of discussion on just the event rates here. Maybe just like if you can help us understand on the placebo events in this study, like why would this be any different in this study versus the prior 5% to 10% annualized event rate that you've seen? And I believe your stat plans assume to analyze 10%, but if it's more like a 5%, is it still 2027 readout? Thank you. All right, Dave.

Yeah, well, I mean, I think, look, first of all, what's a clinically relevant reduction and hazard in F4C? The reality is, I think anything that's statistically significant and yields an approval would be clinically relevant. I mean, this is a disease where there is no treatment, and these patients are really on the cusp of end-stage liver disease and either death or a transplant. So I think, you know, I think one of the really important things is getting a medicine to these patients, and any risk reduction is going to be a big change in the field for patients. With respect to the placebo rate, I mean, we've sort of guided to the 5% to 10% range based on the natural history. As you pointed out, in the earlier Harrison paper, which again was done, sort of drafted using an earlier version of the protocol, The estimate of the placebo rate was about 10%. The 10% placebo rate, as you know, determines sort of the duration of the trial. It doesn't really affect trial powering. So, you know, the hazard reduction is the key thing that determines trial powering. And those two things together, the placebo rate and the drug effect, determine the blinded event rate. So, as we've said, the blinded event rate is tracking in line with delivery in 27. and when we have more data, we'll provide you more precision on that estimate.

Thanks. Thanks, Ash. Corey, next question, please.

Thank you very much. Our next question comes from the line of Michael DeFiore of Evercore ISI. Michael, your line is open.

Thank you. Thanks so much for taking my question, guys. Two for me. The first regarding different patient growth and underlying demand. Can you separate 2Q patient growth into new starts versus reactivations following first quarter insurance disruptions versus discontinuations? And my second question is, you know, you've already reached over 10,000 prescribers that have indicated that the commercial focus is increasingly shifting towards prescription depth. My question is, what percent of 2Q new prescriptions came from existing prescribers? versus first-time riders, and how is that mix changing? Thank you.

Hey, thanks, Mike, for the question. Maybe let me start a little with that. You mentioned the 10,000 prescribers. That is another really, really significant milestone to cross in a launch. I mean, my experience, you exceed 10,000, and you've really got your base of prescribers that can drive your future into, in this case, a mega blockbuster. And that's something which hasn't stood still. We haven't reported on that number in a while, but it continues to grow. We have new prescribers all the time. When you think about that mix, you're always going to have more of your scripts on a monthly basis coming from the existing pool of prescribers. Think about it. If you add 10 prescribers on the 10,000, disproportionately, there's so many. That's not the right number, adding 10. We're adding more than that, I can assure you. It's always going to be weighted towards... The current prescribers, and that's why depth becomes much more important than breadth once you cross that 10,000 threshold. And we're continuing to see across all of the prescribers just increased depth of prescriptions. And why is that? Well, because they're having good results. Why is that? Because they're diagnosing more patients. and they're learning the product. They're wiring their system. They're setting up their pathways. They're making sure they have access to or have their own NITs. So that is what takes time in a launch and that's why products typically don't go from zero to 100. It takes kind of years to get to full penetration because people just get more comfortable and work down through their deck of patients, if you will. And we're seeing exactly that and we're tracking exactly like we do. had hoped and liked what we had thought we would. Now, so how does that translate now back to your question about monthly ads? Oh, you had said the mix. We haven't reported out on the mix of prescribers and so forth. If you think about HEPs and GIs are the predominant riders. GIs outnumber HEPs just in the market in the country by about 10 to 1. So that's where the volume is going to be because they just have more patients and more prescribers, okay? Now, what about patient ads? That net number that we show, we don't break it out into what's coming in the top of the funnel, what's going out the bottom of the funnel, and net. And as you can see, that steadily adding, when you look back over the quarters, that's kind of our definition of steadily adding. And most importantly, we expect to continue to do so going forward. Now, we're going to do everything we can to accelerate adding to the top and decelerate leaving from the bottom. That's what we do. That's what continues to make it a great launch. So that's what I'll leave it now, Mike, and we'll update in the future. But we are in really, really great shape on kind of all key metrics. And really the one at the end of the day that counts is patients. And that's the one that I think that is this 50,000 milestone. That is a big number. I just and that's why we kind of pulled that one ahead. We didn't want to wait another quarter and say, and we knew everyone would be doing, well, what day of the month was it that it happened? Let me assure you that 50,000 is consistent with a steadily adding patients. It's a big number that the world should know about. Thanks.

Thanks, Corey. Thank you. Next question.

Thank you very much. Our next question comes from the line of Jay Olson of Oppenheimer. Jay, your line is open.

Hey guys, congrats on all the progress and thank you for providing this update. Since you have a number of new patents and multiple levers available to drive res difference sales growth, including potential combinations, how are you thinking about the peak sales magnitude and timeline to achieve peak sales? And what's your vision of how the mass market dynamics may evolve in the next 10 years in terms of patient segmentation, and which genotypes or phenotypes do you suspect might be appropriate to target for a more personalized approach to treating MASH with precision medicine? Thank you.

Okay, thanks for the question. Let me start with kind of the market dynamics because I think this is something which is really so remarkable about MASH. I'll go back, first of all, to when we communicated what the approachable patient number in F2-F3 was at the end of 23. That was the 315,000. And we did that same analysis at the end of 25, and that was 460,000. So almost 50% growth in patients. Now, you would say, well, gee, how sustainable is that? Well, here's why it's really sustainable. Because it's about 10% diagnosed today. And we have about 10% penetration. So we're about 1% into the journey. Now, that is a setup where all the demographics, everything that we're looking at is driving towards MASH continuing to be a challenge, not just for the next, you know, 3, 5, 10 years, but decades. So that's the backdrop that we're against. We had almost 50% growth in two years. We expect double-digit growth for the foreseeable future. And you heard me say that Q3 is off to a strong start, but that we are expecting and seeing patient growth in the market in 2026, consistent with what we've communicated before. So that growth of the market is where the real opportunity lies. As great as Red Differ is, as I said, in my opinion, holy grail profile, we're looking for even more efficacy in either the whole population or segments of the population. And, you know, a real specific, you said, how do you, you know, kind of personalize medicine. This is where the PMTLA-3 deal that we did with Arrowhead, we're so excited about. You know, that is a very specific, identifiable patient population that could benefit from having not only a foundational therapy like ResDiffra, where we work really well in that if you look at our presentation, but if you add to that this targeted siRNA, could we get even more efficacy? So we look at, there's going to be these segments that open up in time, partially driven by the data, partially driven by just natural market evolution, So that's why we're not only optimistic about ResDiffra but a whole franchise and having a solution for patients that cover really the gamut of MASH. We haven't commented on peak and we're not but you have heard us say that we think that ResDiffra has mega blockbuster potential and that's even before we start to add these next generation products that we're working on which again I'll remind you as we have combo products others will be still fighting for their first product in a pathway that we probably already got a compliment.

Great. Thanks. Thanks, Jay. Corey, next question, please.

Thank you very much. Our next question comes from the line of Kripa Devarkonda of Truist Securities. Your line is open.

Hey, guys. Thank you so much for taking my question, and congratulations on the quarter. I wanted to ask about the competitive landscape. You know, as we get closer to a competitor phase three data in 4Q of this year, I was wondering if you can comment on how you view any potential impact on the trial were to be successful and MASH patients get another oral option. I think it also takes back to the prior questions regarding fragmentation because some of our KOL checks have suggested that this drug could target specific sub-segments or drugs in general could target different sub-segments. So would love to hear your comments on that. And also wanted to just ask about also the recent patents issued for resmatrim. You know, you already had a previously issued patent extending resmatrim to 2045. Can you just talk about the impact of the recently issued ones and how that strengthens the profile

Thank you very much for the question. There's a lot there. Maybe just starting with IP. Last July, actually, we secured our pivotal F2F3 patent, which is the weight threshold dosing, which gives us out to 2045. And the reason that patent was so important, it allows us to think about are pipelining portfolio a little differently. We have a lot of time with Red Difference, so we can place a bet on earlier stage programs or later stage programs. We don't have a short-term problem, so that's really good. The patents that we announced just, I guess, this month, was it? We secured two new F2F3 patents. And those cover important safety information in our label. So, you know, generics have to include that type of language in their label. So them trying to do a skinny label really makes it challenging for them. And these are both orange booklisted patents. So that's just, you know, further, further reinforcing the 2045 patent that we have. We now have a new F4C patent. I'm really excited about this because this, remember, 45 came out of the approved label. And we don't have a label yet in F4C, but we've already secured a use patent, which gets us into the 40s as well. And that's before a label where there's potentially other opportunities to generate IP. So I feel like we've said all along that IP is really important. and we've made it a focus and I think we've made really, really significant progress with our IP strategy. Now, I think you're probably referring to the Atlanta Fibonacci. That's what it was, right? And look, what we've always said and you've heard me say before, this is going to be a big market. It can support multiple products. And the new entrants we think help us if there are new entrants. You still have to have a successful product. You have to get it approved in all those minor details, build a big commercial organization and launch. But, you know, If you get to market one day eventually, it can really help to drive growth. And I think we've seen that with Lugobi. I think their being here has really helped us. You heard me say a little bit earlier, though, this isn't about comparing bar graphs anymore. It's really about the real world. We're over two years on the market, over 50,000 patients. We have high satisfaction by prescribers and patients. And it's just continuing to press. So against that backdrop, it's kind of hard to see where Lanofibrinor will fit. You know, it comes down to profiles, if you've heard me say it many times, and we've got a great profile. Lanofibrinor, 1,200 milligram pill, it's a PPAR associated with weight gain and edema. Now, this is at a time when the world is obsessed with weight loss. So, we don't see weight gain as a real benefit, particularly in MASH, and we did some market research with prescribers, and 80% a prescriber said they wouldn't use Lana Fribenor because of the weight gain. So if they get here, look, MASH is a big market. We've got lots of room for more product. That's why we're building our pipeline. We think it overall helps, but they've got a long way to go, and we wish them luck. I think that's where I'll leave it.

Great. Thanks. And actually, we're past the top of the hour, Corey, so I think we'll conclude today's call. And so thank you all for your time and interest. This now concludes our call. A replay of the webcast will be available on our website in approximately two hours. Thanks for joining us.

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