Hi, good morning everyone, and thank you for joining us. My name is Edward Nash, one of the Senior Biotech Analysts here at Canaccord Genuity. I'm pleased to have with us today the management team from Madrigal Pharmaceuticals. This is a name that I currently cover with a buy rating. Joining us, we have Dave Soergel, Executive Vice President and Chief Medical Officer, Carole Huntsman, Executive Vice President and Chief Commercial Officer, and Tina Ventura, who is the Head of Investor Relations. Thank you all for joining us today. I really appreciate you taking the time. We've seen a number of major announcements that Madrigal has had between the first quarter and second quarter of this year. Could you maybe provide a quick update on some of those important things that you guys hit over that time period?
Then maybe talk about the Rezdiffra launch experience that you've seen to date.
Absolutely. It's been a really busy and exciting past few months. We've accomplished a lot, and each has been the deliberate execution of our strategy. First, we have a new U.S. patent that extends out to February 2045 that we're really excited about and building long-term. We also have received CHMP opinion in June, and we're expecting an EC decision later this month. We'll be launching in Germany in the near term. We also shared compelling 2-year F4c data from our OLE study at EASL, and that data gives us great confidence in the outcome study that we'll read out in 2027 in F4c. We in-licensed an GLP-1 most recently to combine with Rezdiffra. Really, really exciting news and milestones. What really underlies and is critical to our success is the execution of the U.S. launch.
We had earnings last week, and we announced $213 million in sales, so annualizing now over $800 million. We reached a major milestone in that 80% of our top targets have begun to prescribe Rezdiffra, and 60% of our total targets, so 14,000, have now prescribed Rezdiffra. Breadth and depth are really critical to the long-term success of a product. We also announced more than 23,000 patients on therapy, and that's super exciting. We have steadily added patients and will continue to do so throughout 2025. That's at the end of the second quarter, and we're really, really excited about how the launch is going and really excited about what's going forward, especially as you think about what we look at, which is we look at the best specialty launches over the last 10 years, and we're tracking aligned to those launches and all of the KPIs that we follow.
Very exciting news that we shared last week.
On the metrics you just went through, that shows that there's obviously, it's been a very successful launch to date. Maybe could you give us a little bit of color on what have been some of the feedback from key opinion leaders in treating patients? You guys have the unique advantage of being the first approved drug in the MASH space. That would be great to kind of hear what the docs are saying on a qualitative basis.
Absolutely. You know, a lot of times when a new medicine is introduced, their profile looks the best that it's ever going to look. It diminishes after entering the real world. We see really just the opposite with Rezdiffra. We are hearing very positive feedback from providers on all of the metrics that matter to patients: liver stiffness, liver fat, liver enzymes, LDL, triglycerides, really, really looking very positive in their experience. Recently, I was at a dinner in New York with about 25 hepatologists, and they were sharing their experiences and talking about how Rezdiffra has really outperformed their expectations. Our label includes a composite endpoint, a biopsy-driven endpoint, and people don't do that in the real world. They really follow patients with non-invasive tests. What they're seeing is that at a year, patients are improving one or two fibrosis stages at a year and really exceeding expectations.
That was really the consensus in the whole room of hepatologists that were there. That consistency of effect is really what our feedback is. When you think about consistency, it's also consistency of effect across patient subtypes. For instance, patients with type 2 diabetes, these patients are at more risk of progression and often have more difficulty losing weight. About 60% of patients with MASH actually have type 2 diabetes. This is a very important subtype. Rezdiffra is consistently effective regardless of whether you have type 2 diabetes or not, but also regardless of your fibrosis stage, of your BMI, or even your genetic makeup, very consistent efficacy results, which gives prescribers a lot of confidence in prescribing and knowing that the patients will actually respond. It's also very easy to prescribe and to take. It has a very easy, it's a once-daily well-tolerated pill. That kind of simplicity matters.
It matters to prescribers. It also matters to patients. We're really positioned well moving forward.
Often it's the case you have to adjust as things happen on the fly. As much as you plan, especially if something is major and important as a new drug launch, how has the commercial strategy at all changed from what you initially had planned and have enacted in any way? Is there anything that you've learned on the fly and really had to adjust for?
You know, we hired a very, very experienced team at Madrigal, and we've taken a long-term view. This is really just the start of treating MASH in this category. It's going to be a very, very significant category over time. We've really planned for the long term. For a first-in-disease launch, there's been a lot of work to do in terms of education, in terms of really ensuring that providers not only understand the disease but also have access to non-invasive tests, and they also understand the product. We've had a lot of wiring the system to do, so to speak. We have field teams that are working with providers, educating not only on the disease but also on Rezdiffra. We've begun to educate patients as well, and we've initiated DTC to really activate patients to go into their provider and ask for Rezdiffra.
In the second year of launch, we're really continuing to execute the plan. We talked a little bit about breadth and depth and how important that is to your long-term success. Now that 80% of our top targets are prescribing and 60% of our full 14,000 target universe are prescribing, we're focusing a little bit more on depth. That very positive experience with the product, the very positive real-world profile, is leading to further focus on depth. We certainly watch what's happening very quickly, very closely, and we listen to what's happening in the field from the community, from providers and advocacy organizations, patients about what's happening in MASH. We're constantly looking to course-correct, minor course-corrections, tweaks to our strategy. For the most part, we're really executing our launch plan, and we're very confident that we'll continue to see additional success and growth in the quarters and years to come.
One of the things you mentioned at the top is the new patent that you guys have had issued. Maybe you could talk a little bit to the importance of that patent and your confidence that it's something that's very defendable.
Absolutely. You know, this patent, which was just listed last week, is a game changer for our company. It's a game changer in two ways. One, it really gives us the benefit of time and flexibility to be very thoughtful and deliberate about how we build our future pipeline. Two, it gives us another decade of protected sales, which really is, of course, a big value driver for the company. The protection takes us out to February 4th, 2045, and it will be listed in the FDA Orange Book. It covers claims directed to commercial dosing of the product. There's a clear and compelling finding that our internal clinical teams found related to dosing of the product. Basically, they found that different doses of Rezdiffra that were provided to different subgroups of cohorts of patients comprising different body weights really optimizes the efficacy and the safety of the product.
Our teams had this finding and shared it with the FDA, and now it's part of our label. It's really important to note that there was nothing in the public domain, either from the study design or the publication of the study results itself, MAESTRO-NASH, prior to filing the patent. We feel really confident about the patent. It's also supported by precedent U.S. case law, and we're so confident in the patent that we're actually, you know, this has become our new base case in terms of planning moving forward. The bottom line is that any potential generic competitor would take on our label, and then by definition, they would be infringing on our patent. We feel really, really confident about this moving forward.
Thank you for that. One of the other key milestones you mentioned from the top is the F4 compensated cirrhotic patient population. This is another real driver for the company. Could you talk a little bit, Dave, just about the data that was presented at EASL in your outcomes trial, and then how you see Rezdiffra kind of competing with the FGF21s?
Sure. Maybe I'll comment on the data first, and I'll ask Carole to talk a little bit about the implications on the opportunity for Rezdiffra on the market. The data we presented at EASL a few months ago were from a 122-patient cohort of individuals with compensated cirrhosis, so F4c, as you said. These are folks on the far end of the spectrum of MASH and are really kind of at that tipping point towards decompensated cirrhosis. That's where morbidity and mortality really escalate in this population. Historically, one of the biggest issues in this population has been nothing has worked, and there's been nothing that's really, you know, been effective to reverse their disease. It was particularly exciting to see these data where we showed that Rezdiffra actually did have a beneficial impact in these patients. Let me come to the last question you asked about FGF21s first.
After we presented these data, one of the leading experts in the field came up and said, basically, these data look like an FGF21. The only difference, and it's a crucial difference, is that Rezdiffra is a single-day oral pill that's well-tolerated. FGF21s are injectables, obviously. Secondly, they come along with certain side effects, especially bone mineral density, which in a cirrhotic patient population are particularly challenging to manage. These are folks who are already frail and fragile. Reducing bone mineral density in that population might be an even bigger issue. We think the profile of Rezdiffra for F4c as a chronic therapy is much more compelling. Let's talk about the data. What we showed in this 122-patient cohort is that over a 2-year period, we're able to reduce liver stiffness. Liver stiffness is a measure of fibrosis, a pretty well-validated measure of fibrosis.
We're able to reverse their disease and show a beneficial effect on stiffness. In addition, beyond VCTE liver stiffness measurements, we showed improvements in MR Elastography, which is another measure of liver fibrosis, and other biomarkers that are consistent with protecting the liver, like reduction in liver enzymes, for example, and other effects on lipids like Carole mentioned earlier. These are all very compelling findings, I think, from this open-label experience. Importantly, the cohort that we enrolled in and presented in this study is very similar to the cohort of patients that we've enrolled in the phase III outcomes trial that we're currently prosecuting, called MAESTRO Outcomes. That gives us even more confidence that the MAESTRO Outcomes study could be positive. That study, of course, we expect in 2027. On balance, I think very exciting data in this very difficult-to-treat patient population.
We're years ahead of the competition in this space and in this indication with a really compelling profile.
Just to add on to that, Dave, I mean, very exciting that we're going to be first to market in F4c. There's a huge unmet patient need there. When we look at the population in the marketplace, it's about 245,000 patients with F4c, so a smaller patient population than what we target in F2, F3, which is 315,000. However, because they're much sicker, we would anticipate a deeper penetration and a more rapid uptake in this group. Essentially, this doubles our opportunity. The F4c indication doubles our opportunity in MASH. Since there's so much positive experience with Rezdiffra based on the positive profile that we have, we really see providers being quite comfortable by the time these study results are released in prescribing in F2 through F4c, period, to really cement our leadership in MASH going forward.
Obviously, you don't market it this way, but I assume you see much off-label usage already in the F4 patient population because there's nothing there that doctors are saying, we're going to go ahead and put it there because we've seen it through other studies where you've had patients who had F4 that the drug is effective in that patient group.
You know, certainly, there is some off-label use. We don't track that too extensively. What we're seeing right now is about a 50/50 split between F2 and F3. We're actually really dissuading the F4c patients from going on until we get the study results. You're right, as the data is released and we get closer to that date, there's certainly, you know, because of the great unmet need, a temptation to go there.
Sure. You recently announced the acquisition of an oral GLP-1 that you're looking to combine with Rezdiffra. Could you maybe discuss a little bit how you decided on this particular mechanism? Is oral delivery the most important attribute of the drug, or are there other attributes that you saw that you think would be very amenable to using in combination with Rezdiffra?
Combining a GLP-1 with Rezdiffra, I think, just makes a ton of sense from a clinical standpoint and from a scientific standpoint. If you think about GLP-1 reduces the excess intake of calories, which is going to reduce liver steatosis. We've seen that from the ESSENCE study and from other phase II experiences with GLP-1s. We know that the reduction of external caloric intake is going to improve liver steatosis. Combine that with Rezdiffra, which works in the liver to improve the efficiency of burning liver fat. Those two combined mechanisms will reduce liver fat more effectively together. That reduction of liver fat then reduces the stimulus for inflammation and fibrosis and scarring, which leads to MASH and progression of disease. We think combining the two mechanisms makes a lot of sense.
With respect to our data, the other piece of information we had as we were looking at potential opportunities is from the MAESTRO-NASH study. We know that Rezdiffra works better if you get a little bit of weight loss. If you get, for example, greater than or equal to 5% weight loss, there's an improvement in the histologic outcome of patients treated with Rezdiffra. We saw that in the MAESTRO-NASH study, and we presented that at scientific conferences. The important thing to realize is that weight loss was actually not from GLP-1 administration. It just happened during the trial and actually probably because Rezdiffra has a little bit of a weight loss effect itself. We saw a bit of a shift in weight loss in the study. The way we look at GLP-1 component of a combination therapy is a way to enhance Rezdiffra's efficacy.
We don't need to achieve annual weight loss of 20% to be successful. We just need to get patients above that 5% threshold to show better efficacy with Rezdiffra. It's a different hurdle. The differentiation of the oral GLP-1 in our hands is its combination with Rezdiffra. We've been scouring the earth for business development opportunities for quite a while. This particular opportunity was the one that sort of rose to the top the quickest, and we were able to execute. The molecule was licensed from CSPC Pharmaceuticals, which is a major producer of pharmaceuticals in China, just an impressive organization. I had the opportunity to go visit there a couple of weeks ago. This molecule is based on the Orforglipron structure. It is de-risked from a chemical standpoint, and the preclinical pharmacology looks very similar to what you see with Orforglipron in preclinical species, both rodents and cynos.
We still have some work to do to get the IND work completed. Once that's complete, we expect to enter the clinic in a prototypical first time in human study, SAD and MAD, in the first half of 2026.
Does this have the potential to be co-formulated? Is that something you're going to be looking at?
Yeah, that's something that we're looking at. Based on our evaluation of the molecule, it's a crystalline structure. It looks like it should be combinable in a fixed dose combination, but it doesn't have to be. It could be a loose combination as well. We would consider that. We haven't done any studies yet combining the two products either in vitro in preclinical species or in humans. We'll have to test that during the development process.
Would this product, if approved, replace Rezdiffra in general, or would there still be a place for Rezdiffra as a standalone?
Yeah, I mean, I think that's a great question, and we'll have to see how the studies turn out. You know, I think if we see an improvement in the efficacy, as we think we'll see, then I think it will probably be used in place of Rezdiffra.
I think it depends on the profile. We'll see. It's a little early to make that definition right now.
The prevailing thought is that GLP-1s, if approved for MASH, would be required as a step edit before using other therapies. An advantage of the GLP-1s is that they're approved for multiple indications beyond MASH, so the comorbidities such as type 2 diabetes and obesity. Would the approval of Rezdiffra's GLP-1 combo potentially circumvent this potential step edit for payers in your minds?
I think, as Dave said, we're probably years out from actually having the combination product of Rezdiffra and the oral GLP-1. We have certainly been asked about step edits in advance of the launch of Semaglutide. I think what's important to remember is that GLPs are not new. They've actually been on the market for more than 10 years. While we're hearing, as we've discussed, very positive feedback about the profile of Rezdiffra, we also know that there are 10 million patients on GLPs in the U.S., and yet the incidence of MASH is increasing. Today, about 25% of the patients who are on Rezdiffra are also on a concomitant GLP, and about 50% of the patients are already exposed to a GLP.
When you think about step edits, it's really a bit too early to tell because we don't have an approved product yet, and we haven't seen the FDA-approved label. We really need those two pieces to continue our dialogue with payers. I mean, we're in discussion with payers now and partnering with them, but those two pieces are needed to really see where we land. I think what's important for us is that we have planned for all scenarios, and no matter what scenario there is, it doesn't change our position on the opportunity for Rezdiffra. When you think about what the GLPs are looking for, they are looking to drive millions of patients into the top of the funnel. Because of the challenges that they have with persistence, ultimately, those patients will all end up on Rezdiffra.
Also, if you think about the 315,000 patients that we're targeting right now, we're only 7% penetrated into those patients that are already diagnosed and sitting in our provider's offices right now. When you look at the math, you do the math with the patients that Novo will drive into the top of the funnel, and the discontinuation rates, that is multiples of our 315,000 that we're targeting today. We're planning for all scenarios where we see huge success for us in all scenarios because, again, we're really at the beginning of the market development in MASH. There will be room for multiple [MOAs ]there. We're quite confident going forward.
With the little time we have remaining, you guys are expecting EU approval this month for Rezdiffra and just wanted to see how the launch prep is going over in Europe.
Thank you for that. As we discussed, CHMP opinion in June, we're expecting EC decision by the end of this month and plan to launch in Germany. We will take a country-by-country approach as it relates to launch in Europe, but we have committed to the launch in Germany. We've made a lot of progress in the launch in Germany. We've hired the leadership. The field teams are in place. We're continuing to do the disease education. We've identified who the prescribers are for MASH. We're continuing, we're starting to wire the system there. Also, Rezdiffra is already noted as a first-line therapy in the EASL guidelines. We're very well positioned for progress moving forward there. Like the U.S., we took the approach of identifying patients who were already diagnosed with F2, F3 MASH and under the care of a liver specialist in Europe.
We estimate that number to be 370,000 patients across Europe who are diagnosed with F2, F3. We will take the learnings from our U.S. launch. Obviously, first in disease, it will take some time, but we have this real-world experience from the U.S. that will transfer to our outstanding teams in Europe as they continue to move forward with the launch. We will share more details as we decide where we go from Germany.
Fantastic. It has definitely been a very strong launch in the U.S. I look forward to bringing the EU on board there and then further expansion into the F4 indication. I really appreciate you taking the time to be here with us.
Excellent. Thank you so much.