Perfect. Well, thanks everyone for joining us on the second day of the 43rd Annual Goldman Sachs Healthcare Conference. We're super pleased to have the management team from Madrigal with us. Paul Friedman, CEO, Alex Howarth, CFO, and Remy, CCO. A last-minute addition. With that, you know, maybe Paul, I'll turn it over to you if you'd like to make some opening remarks?
Well, I'd like to say that we have some very interesting data to be presented at EASL next week. Gonna be very busy there with four oral presentations and two posters, I guess, and we can go over them as we move through the Q&A. Our program is well along into phase III with resmetirom in a very late stage of the serial biopsy study that's needed to be able to use the data for a Subpart H NDA submission. We've guided to the fourth quarter for giving top-line data for that study, and we're hoping and trying to have it be early in the fourth quarter.
I'm afraid to pin myself down any more than that because we have to get the last biopsies before and get them read before we can collate the data. With that, I would say that that's where we are.
Perfect. Well, you alluded to the upcoming EASL meeting. Maybe just to start, maybe if you could recap the top-line data you have shared, and then what specifically should we be looking for next week?
Okay, we have a late breaker dealing with more granular and more data than we've currently presented from the non-invasive phase III study, MAESTRO-NAFLD-1. So far, we've reported on safety in groups and safety with respect to AEs related to therapy and dropouts related to therapy, which are very low, I mean, about as low as you're gonna find in the 2% range for all the arms. We've presented MRI-PDFF data on fat reduction over time, which is basically a recapitulation of what we saw in phase II.
We have presented data on the two scans, FibroScan and MRE, and demonstrated that there were statistically significantly more responders, that is patients who achieved at least a 2 kPa reduction in the FibroScan measurements and at least a 19% reduction in the MRE, which are highly significant changes. There were more responders in the resmetirom-treated arms than there were in the placebo. Now, that's important because that's the way the FDA will evaluate fibrosis. It'll be a responder analysis of treated versus placebo. It's encouraging because the degree of decrease in kPa and in percent on MRE are equivalent to about a one-stage improvement in fibrosis.
It gives you more confidence that when we do the biopsy studies, we'll see the same responder statistical significance. We've also pointed out that liver enzymes go down into the normal range for those that are elevated. We don't see any early blips in liver enzymes. In fact, if you look at the percentage of subjects who had at least a 3x increase above the limits of normal of ALT, for example, there's no trend. The 80 mg and 100 mg arms of resmetirom give about 1%-ish and if anything, the placebo group is higher. There doesn't seem to be any signal. We've now looked at probably 2,000 patients, and we've not seen a liver signal.
When you consider the fact that that's really the only organ that the drug gets into, if you rule out a liver issue, you pretty much have ruled out anything significant from a safety standpoint. That's the late breaker. We're under a significant embargo. EASL is fairly rigid about what they'll let you say. I would say we'll show more and more data on the scans. We'll get more granular on any safety events that are relevant. I think some of it will be recapitulation of what we've already shown.
Got it.
That's the late breaker. I could tell you the others if you would like to hear those or would like to ask me something else?
Yeah. Maybe just two follow-up questions on the late breaker. In terms of the threshold percentage of responders, that you've spoken about as being the more important metric as you look at fibrosis improvement, I guess, is there a clinically meaningful percentage that you're looking to look or to reach? Is the FDA requiring a certain percentage?
Well, I think you're gonna have to show statistical significance. There's some interrelated facts here that yield a p- value of 0.05 for the whole study. If we weren't doing the second study that I anticipate we'll get to, the p- value that you would have to get for fibrosis reduction and NASH resolution would almost certainly be 0.01 or lower. That you never really get a specific number from them, but it has to be highly statistically significant. In running the second outcome study, we're guaranteed to get 0.05 for the whole study. My own belief is you need to achieve statistical significance.
That's the endpoint that would not expend alpha for your p- value. I think that is clinically significant because it would be a reflection, almost certainly of the vast majority of other patients treated being stable or not quite reaching a one-stage improvement.
Got it. Just on the safety events that you will be disclosing with these additional ones, I guess maybe what are the nature of the safety events that we should be, you know, expecting a little bit more detail on that would be important here?
We'll go through liver, thyroid, in particular cardiac. Honestly, it's really hard to answer that question because there hasn't been anything. There really hasn't been anything. I've dealt with a lot of development programs over the years, and this is the safest drug that I've been part of the development team. There just isn't anything except for a mild stool loosening or an episode of diarrhea in the beginning of therapy and some mild nausea. We're talking about 10% of people. It goes away after the first week or two. The only interesting aspect of that, other than the fact that it exists, is the fact that you don't see it in people without NASH.
It suggests it has something to do with maybe clearing fat or because all fats may not be blown off by CO2.
Okay. Maybe switching to the open label cohort data that you'll have in cirrhotic patients. We've seen a first look at that. We're expecting an update. Anything you can share there in terms of maybe, you know, your surprise, perhaps in terms of the resmetirom's activity in this population? And what additional data can we expect next week?
We have an oral which is entitled Biomarkers, Scanning Results and Safety in this well-compensated cirrhotic group, about 180 patients, many of whom have gone for more than a year. It is. You have to understand that it's a spectrum. A well-compensated cirrhotic is just a little bit more advanced than an F3. Therefore it's. They tend to have less fat in the liver at that point in time, but you still clear fat, you still reduce the liver volume substantially. Drug is very well tolerated in that population. The other things that will be presented, I don't really feel comfortable, you know, trashing the embargo, but there are some other interesting parameters that will be described.
Awesome. Well, we look forward to that next week. Maybe switching over to MAESTRO- NASH. Obviously, this has been I think a huge focus for us as well as investors heading into the fourth quarter. Just would love to hear maybe how you're thinking about this data read and help frame for us what we should look for? What your expectations are? And how confident you are heading into that?
With respect to NASH resolution, I'm very, very confident there for the following reasons. In phase II, with half the patients being on an active but not adequate dose of 60 mg, and now we're at 80 mg and 100 mg. The placebo rate of NASH resolution using our more stringent definition was, I think, 6%, and it was 27% in the treated arm. It's highly significant. The study wasn't powered for that. It was powered for MRI -PDFF 12-week results. We saw it. In addition, in the patients who achieved at least a 30% reduction in fat as measured by MRI -PDFF, something like just under 40% of patients resolved their NASH.
At 80 and 100 milligrams, the doses that we're using in phase three, almost all the patients get rid of at least 30% of their fat. When you look at NAS, NASH activity scores, the NAS across disease severity from F0 to F3, number doesn't change very much. It's not like you have a higher hill to climb to be able to resolve the NASH 'cause the components of the scores for inflammation, steatosis, and ballooning are not very different. I mean, it's a slightly higher total that you find in the F3s than you find in F0 or F1s. If you put all that together, we have 10x bigger study, higher dose, longer time period. We ought to make that endpoint.
You know, I'm not gonna put a percent on it, but I'd be, I wouldn't say shocked, I'd be very, very surprised if we don't make that endpoint. With respect to fibrosis, we had a trend in phase II, again, with quite a few of the patients on 60 mg. If you looked at patients who resolved their NASH, something like, I think 60% of those patients had at least a one-stage improvement, and fully half of them resolved their fibrosis. Again, by precedent, what we saw in phase II is highly encouraging to make the fibrosis endpoint. We're going longer, we're using higher doses. The other interesting aspect of this is we analyzed. This is another one of the oral presentations.
We analyzed the biopsy specimens by artificial intelligence, HistoIndex, technology. Interestingly, the most pronounced effect were in the F3s, where fully half of those patients had a one-stage improvement in fibrosis, and no F3 that was a placebo did. I think that's pretty encouraging. When you consider that over half of the patients now in phase three are F3s.
Mm-hmm.
It gives us, I think, a good deal of confidence we'll make that endpoint as well.
Got it. Just remind us on the decision to, I guess, make it a dual endpoint here, and that change and what prompted that?
Okay. We've been talking about doing that for a year. We could have done it earlier, but we chose to do it as we are doing two other things that make it appear completely logical to do it. One is our SAP is nearly completed, and we were able to incorporate the significance of that change in endpoints to the final SAP. The other is, as I said earlier, with adding the second outcome study in the well-compensated cirrhotics. We gain a lot of alpha in the study, and even bringing it up to a primary, that primary still has more alpha.
Mm-hmm.
Than we would have had we only done one study. All other people who have been in phase III have gone with the dual endpoint. It's pretty logical to do it. It's just that we were a little late in the game to make a change.
Got it. From your experience and your conversations, and Remy obviously would welcome your thoughts here, is one endpoint more important than the other in terms of clinical and commercial uptake?
Clinically, and I'm fighting against almost like Don Quixote on this one. To me, by far, the most important thing is to shut down the hepatitis. Because the fibrosis is a secondary phenomenon because of the ongoing inflammation. Yes, it's important to not have people get so much scar in their liver that they either die or they get transplanted, but the NASH resolution endpoint requires that there's no worsening of fibrosis. If the amount of scar tissue you had in your liver was an F3, your liver function tests are quite normal. You could live your whole life that way if you never got rid of the scar. For me, I think that's more important clinically.
There are a lot of people that disagree with me. I just think they're wrong. Remy should comment on what he's learned, I think.
Sure. Andrea, similarly to what Paul has stated, the community doctors, hepatologists, GIs, endos are actually treating NASH patients today. Their understanding of the disease process is much greater now than what it was five years ago. They're not so laser-focused on fibrosis improvement. They wanna modify the disease, they wanna stop the disease. When it comes to either of the two surrogate endpoints, either one is fine for them. What they need the most is, at this point, a drug that's FDA approved because they have been identifying patients over the last, you know, four or five years, as the ICD-10 code for NASH has existed.
We estimate there's about 1 million patients that have been identified in the U.S., and right now, these physicians that are taking care of these patients have nothing for them. Whatever target endpoint, this is all based on market research with treaters, is fine with them. FDA approval is what matters. They want to stop the disease, they want to modify the disease. Payers' view is similar, which is, you know, listen, you know, this is a high unmet need disease. We're talking NASH F2, F3. They feel the need to cover drugs for it. At the end of the day, the population that is covered is based on the label and the indication.
I believe we're going to hit both endpoints later this year when we reveal MAESTRO-NASH, but I, as a commercial lead, will be happy with us hitting either, taking this drug to the market.
Perfect. Maybe let's turn to the new outcome study that you've recently announced. The ability to use this study to support full approval in the non-cirrhotic population, even though this second outcome study will look at well-compensated cirrhotic patients. Just walk us through, I guess, maybe how the FDA has, you know, provided guidance on this front and your thinking behind this?
It's about a year ago, the FDA made a presentation where they offered an alternative to continuing the biopsy study until you had enough cirrhosis events, essentially, to call it a win. I think they recognized that there were a couple of problems with that, and we're continuing that study because they've asked us to do that. You have a situation where a company makes one of the endpoints, so they're able to put Subpart H in, the drug gets approved on an accelerated basis. These outcome studies run for 54 months.
You have to ask yourself, would a physician who's treating a NASH patient and knows that the parameters he's following in that patient isn't seeing improvement? Or the patient knows he isn't seeing improvement. You're asking those patients to be controls for a long period of time. You're gonna have control dropouts. You may have enough at the end that you can do the analysis. I'm not saying you can't, but I think that's one of the challenges of that study. What they did is they said, "Look, if you do a study where you show benefit, clinical benefit in cirrhotics, so no biopsy, it's clinical endpoint, so hepatic encephalopathy, variceal bleeding, ascites, and a MELD score greater than 15.
Any of those would qualify as an event. You can get full approval for NASH without fibrosis without cirrhosis. They've offered that. They made presentations. It's pretty obvious. I think people shy away from it because cirrhosis scares people. These patients are a little farther along than the F3s, and they can be benefited by something that would work. That's one of the things that I think you'll get a flavor for when we make that presentation. It's a quicker study. It's a study that will be very easy to enroll. We were oversubscribed for the open label arm that we ran. It's gonna be a 700-patient study.
The estimate is based on very conservative event rate percent that it would take two to three years to complete the study. We're gonna start it this summer. It should enroll pretty rapidly, and it should end well before the other study that we're running. The beauty of it is not only can you get full approval sooner, but you're gonna get an expanded label. There are quite a few of those patients, which again, Remy could comment on what he's learned about that population.
Sure. Andrea, from a commercial perspective, NASH with compensated cirrhotic, I think IQVIA's publication estimates around 2 million today in the U.S., growing to probably 3 milion-3.5 million by the end of this decade. These patients, again, based on market research and treaters and also payers, extremely high uptake. NASH with fibrosis indication, resmetirom, should be quite attractive, commercially speaking. Getting this indication makes the asset significantly more attractive, and the rationale being unmet need. I mean, when you look at the pipeline, so emerging competition is much smaller for this patient population, NASH with compensated cirrhotics. Imagine a world in 2026, 2027, you know, in three, four, five years, resmetirom with an indication for F2, F3, and F4c in the minds of treaters and payers gives us an edge.
The, you know, bringing the full sort of treatment for that patient population makes the asset even more competitive. You know, for all the good reasons, let's hope that we are successful with this trial, and there's a lot of patients waiting for it.
Got it. Any questions from the audience? Well, Remy, maybe I'll continue with you here on in terms of the outreach that you've done to physicians, how you're thinking about the initial population of patients. We've talked in the past about patients who are currently on Vitamin E, and they may be or I guess maybe they represent a potential pool of the patients that could come onto therapy initially? Just curious, you know, maybe the learnings that you've had over the last couple of years and if it's evolved in any way?
Sure. You know, much as we are doing on the R&D side, we're very much data-driven. Everything we think about in commercial planning, it's based on significant market research. In the U.S., we've probably done primary market research with over 1,000 physicians that are treating patients, you know, payers that are covering 80% of the branded Rx in the U.S.. It's all data-driven what I'm going to tell you next. Based on these insights and also discussions with thought leaders because they're highly involved with us, you know, with physicians, you know, we have been holding symposia at congresses like NASH-TAG, DDW, CLDF to get disease education out. Additionally, we're launching our NASH Explored, a digital campaign to educate the market, you know, as I said this month, so in June.
With patients, we've been heavily involved with patient advocates, with payers. I talked about market research, but also we've done significant education around NASH with payers. These are all the sort of right things anybody in our shoes should be doing. Once we have MAESTRO-NASH data in hand, we will pivot to more patient education around the disease, patient activation appropriately at the right time. And then also, you know, with MAESTRO-NASH data in hand, our discussions with payers can pivot more towards cost effectiveness and budget impact modeling closer to the launch. We're lockstep with where we should be, and there's a clear way forward for us.
Got it. I guess any initial thoughts you can share on how you are thinking about pricing this to ensure patient access?
Yeah. I mean, the obvious answer is it's way too soon, right? Price is decided literally at the last moment based on the FDA-approved label. That is, you know, what is the right thing to do here. I can share that based on market research and one-on-one discussions with strategic payers, they're expecting NASH drugs to be in specialty drug corridors. And then, you know, they're aware of OCA sort of review by ICER, in NASH, placing it at about $15,000-$20,000 based on which quality measure do you wanna look at. I think we'll have a lot of flexibility with resmetirom with the emerging profile, but the decision will be taken closer to launch. We wanna make sure patient affordability is there. We have the right programs, but we feel that we're in a good place with that.
Got it. Then what are, I guess, maybe the updated thoughts and on the potential of using resmetirom in combination with other drugs? I think there's obviously been. You guys have seen good data in your own trials, but there has been this interest in potentially combining them with GLP-1s or other types of drugs.
Yeah. I'll give you a commercial answer to this on how I'm thinking about that emerging competition. Maybe Paul wants to, you know, mention since the clinical side, some, you know, aspects of our trials and the like, and the role of GLP-1. From commercial lens, Andrea, you know, I had that question, which is if physicians are using diabetes drugs right now, does that mean that they're satisfied? Is that gonna be a dampening of the demand for resmetirom? We went back and looked at our demand study data, and actually, physicians that are using drugs off-label, including diabetes drugs, actually showed a higher affinity, higher demand for resmetirom profile, indicating the market is not satisfied with off-label treatments at this point.
I would say, you know, NASH is a lifelong sort of disease, as we state the obvious here. I mean, you need a treatment that is safe, that's oral. You know, we have that with resmetirom. Resmetirom shown effect on fibrosis, effect on NASH resolution. You know, the emerging profile is very attractive, commercially speaking. When you think about current timelines, resmetirom may be on the market two to three years before any other asset. In the commercial world, that's a lifetime to establish your drug as the backbone. Paul, would you like to comment on trials?
I mean, we do have a significant number of people in the phase IIIs, both the non-invasive and the formal biopsy study, who come in on stable doses of SGLT2s or GLP-1s. I mean, what that tells you first off is that people on diabetic doses of those agents still have NASH, or they wouldn't have qualified for the study. It's not like you're wiping NASH out with these diabetic doses. Even the diabetic doses, people don't tolerate them terribly well, and something like 40% of patients have discontinued by one year. These higher doses that are being used, I don't know how well tolerated they're going to be. The positive side of it is they combine very well with resmetirom.
They're very well tolerated, and you get additive benefits, say, for example, in fat removal from the liver as measured by MRI-PDFF. It's a fairly logical combination because a lot of these patients have diabetes, and I'm sure that's going to happen. With respect to other compounds earlier in development, our way of looking at that is we're a phase III asset. We're almost to the finish line. About the last thing we would wanna do is to get some safety signal. We'd like to see those programs put through their paces a bit more so that we can understand more about the efficacy and the side effect profiles.
Got it. Alex, maybe I'll turn one over to you. Just in terms of how, maybe how you're thinking about the ex-U.S. strategy here. You've obviously talked in the past about looking for a partner. Where do things stand right now with that?
Yeah. Just to confirm, our intention is to, as you say, sort of find an ex-U.S. partner with the intention and preference that is a single partner rather than doing multiple regional deals. That will logically most likely be with a large multinational big pharma company who has the expertise to launch and execute simultaneously across multiple geographies. As we've previously disclosed, we are in ongoing discussions right now. As you would expect for a late phase III asset with the potential for a near-term launch in a you know very significant market with high medical need, the interest is very high. As I say, discussions are ongoing, but our intention is to. That's not a fire alarm, is it?
Hopefully it's not just.
Keep going. No one's running for the doors yet.
Just start first.
Yeah, exactly. Our intention, though, to be clear, is to actually conclude that transaction after we have the MAESTRO-NASH data, so we're not doing anything ahead of that.
Got it. Perfect. Where do you see Madrigal evolving as a company? I guess you have resmetirom, U.S. launch, finding partner ex-U.S. What kind of is the, you know, the next step post that?
Well, I mean, we've been pretty laser-focused on this program. We've looked at a number of in-licensing possibilities, all of which are in this space. If we were to expand the pipeline, that would be the type of asset we'd be looking for. If in fact we do end up launching the drug ourselves in the United States with a partner, we would look for a few assets in the NASH space. We have a few molecules of our own that we've made that have different properties from resmetirom that could be used for thyroid diseases, so that'd be a little bit outside of the NASH space.
On the other side of the coin is if in fact we don't launch and we're acquired, then we wouldn't obviously be a good time spent doing this. We've just have decided if things come in to us, incoming assets, we look very carefully at them. When we peel the onion back, we haven't found anything yet, but we haven't ourselves gone out and made a big sweep of what could be available. I think that's going to have to wait until after we get the NDA.
Perfect. Well, with that, thank you to the Madrigal team and for everyone for joining us this morning.
Thank you.
Thank you.