Everyone, thank you for joining us on the second day of our 44th Annual Goldman Sachs conference. We're really pleased to have the team from Madrigal with us, Paul Friedman, CEO; Becky Taub, President of R&D and CMO; Remy Sukhija, Chief Commercial Officer, and Alex Howarth, CFO. With that, thank you guys for joining us this morning.
Thank you.
Paul and Becky, maybe I'll start with you. You guys have been in the NASH space for so many years, leaders in this space. Maybe from a high level, what has the last year meant to you, to the space, the progress that's been made not only by yourselves but by your competitors? Then maybe describe to us what it means to be here on the cusp of having the first approved therapy in NASH.
Becky, you want to?
Yeah, I'll talk about it. Thanks, first of all. What I think one of the things to think about is that, you know, NASH drugs now, it's almost, it's been almost 10 years since we actually saw some data from serial liver biopsy, NASH trials, starting with obeticholic acid in the FLINT trial. Almost it was 2014, I think, when that data came out that showed that potential for a drug to modify, be disease modifying in NASH, on both endpoints of fibrosis and NASH, or the inflammatory state of the liver. Subsequently, there were a number of programs targeting fibrosis, or targeting NASH, or targeting both, including some Phase II programs that were unsuccessful.
I think the early promise was then followed by some discouragement, to your point. Many drugs in phase II also failed to show good efficacy on liver biopsy endpoints. Our, our phase II trials had a lot of focus on a primary endpoint, which was liver fat lowering after 12 weeks, and followed by liver biopsy data at 36 weeks. We were able to show this relationship between what occurred by 12 weeks, which was a very highly significant liver fat reduction, and then reduction of NASH and resolution of NASH at 36 weeks. However, in phase II, resmetirom did not achieve a fibrosis endpoint, which we attributed to small study size, and actually the fibrosis stage of the patients.
That has been a lot of the issue in the phase II trials, that the studies have not been large enough to really see the full effect of the drug, and that phase III studies are very difficult. In the last year, I think we've seen some successful phase II's that have had last two years, some successful phase II that have achieved either NASH resolution or, and/or fibrosis benefit from semaglutide, from lanifibranor, from a couple of the FGF21 programs, and of course, Madrigal with our phase III data announcement in December, that in a 1,000-patient serial liver biopsy at 52 weeks, phase III study in NASH patients, that both endpoints of NASH resolution and fibrosis reduction were achieved.
We're in process of submitting our NDA for approval, for accelerated approval, for the treatment of patients with NASH and liver fibrosis to the FDA now. That's where we are.
Yeah, I have little to add to that. I think the field, there's an uptick in excitement because, and people have learned more about how not to fail in their clinical trials, and the compounds seem more on target for targets that matter. I think it's an exciting time for a disease state that is in great need of something to treat these people.
You'll have data next week at EASL. Maybe help frame for us what we should be specifically focused on that we haven't seen in the top-line data release.
Yeah. The EASL data will be a much more complete analysis of the liver biopsy results and the other results from the study. Just to first mention, you know, this is a phase III study. It's an analysis based on intention to treat, every patient who did not have a liver biopsy at the week 52 time point is considered a non-responder. Given that the study was conducted during COVID and that it's also hard to get liver biopsy, serial liver biopsies, this dilutes the treatment effect in a phase III study. However, the endpoints were very highly statistically significant. One of the things we'll show at EASL is really what the true response is in patients for either NASH resolution or fibrosis reduction or both.
will be convincing that resmetirom responders is a very high % relative to placebo of patients who are treated with the drug and continue on the treatment. Both doses we dosed showed similar effects on the endpoints. The 100 milligram, the higher dose, was slightly better and will be showing subgroups and the consistency of the data in various groups of patients, males, females, F2, F3, those sorts of data, other liver biopsy endpoints. We'll also show the types of imaging and biomarker endpoints that may be useful for following patients in real world. We do not expect, with an approved drug of NASH, that patients will be diagnosed based on liver biopsy.
There will be other types of tests that are used to demonstrate that they have NASH with significant liver fibrosis. It will be very important to show data that how resmetirom modifies some of these measures as a correlate for a treatment response.
Perfect. Maybe I'll ask you as a follow-up there. On the back of this data, there was a lot of debate around your endpoint and NASH versus NAS, and whether or not you were in true alignment with the FDA. Maybe just to level set here, where did this debate stem from? How confident are you that the FDA is in agreement with you on your selected endpoint?
Yeah. Our endpoints were approved in 2018. You know, more than five years, we've not changed our endpoints. The endpoints are the same as we had in our phase II study. They are reasonably likely to predict clinical benefit. I think that's kind of a silly... There is no such thing as worsening of NASH, that you have to say what you're actually measuring, and NAS is the measure of NASH, so we use worsening of NAS. I can tell you that resmetirom lowers every component of NASH, so it wouldn't matter what the endpoint is. When fibrosis is reduced, NASH is also reduced by any parameter, so it doesn't matter, is the point.
Is there a scenario where you would come out and present that data set.
No, because it's not valid to show any of that. I mean, I've seen that perhaps other drugs, why that might have been a concern of FDA with other drugs, is that they can cause some liver damage. Even if it looked like fibrosis went down, there might have been a concern by FDA that some other aspects of the liver looked worse. This was not a concern with resmetirom. We, you know, have no concern about our endpoint.
It just doesn't happen.
Doesn't happen.
In phase II, not a single patient-
There wasn't a single instance of a component increasing.
In fibrosis improving.
Yes.
Got it. You touched upon this slightly, but you're in the throes of preparing for this NDA submission. Maybe just an update on where you stand there and if you are still on track for the first half of this year.
Yes, we're still on track, and, you know, it's a lot to put together. A lot of times we don't speak with, at meetings or with investors about the totality of the program, but we have almost, 20 clinical trials.
Okay.
including a very large number of phase I trials and, obviously, a large, non-clinical package and drug manufacturing package, and all of that has to go into the NDA.
How important is?
It's a big commitment.
How important is Breakthrough Therapy designation?
Hmm?
How important is Breakthrough Therapy designation for resmetirom?
The Breakthrough Therapy designation, we had Fast Track, which gives you most of what's needed for the type of NDA review process that you would want, and we got Breakthrough status based on our phase III data, which we sent to the agency. The fact that we got it on the, with the phase III data, we believe is very helpful for us when we request a priority review, which is, you request at the time of your NDA submission, which would then be a more rapid, the target would be a six-month review as opposed to a longer review cycle. That's the utility of it.
Perfect. Last month, we saw an AdCom for your competitor, Intercept. Anything to take away from that or potential read-through that you see to Madrigal and to resmetirom?
I think that, first of all, that AdCom was very helpful to us for a couple of reasons. Certainly provided us with the perspective that the FDA has around approval of NASH drugs, their adherence to the endpoint, the fact that they actually do not like liver biopsy as a methodology, which was stated in their briefing book. Also their commitment to risk-benefit and demonstrating risk-benefit in the patients, or benefit over risk in the patients who are treated in an approved drug. We also were able to see the advisory committee, which we weren't quite sure who was on the advisory committee. That was a good exposure for us. It helps us for writing our NDA.
Also, it doesn't mean that we will have an advisory committee necessarily. The issue, of course, is that the study, MAESTRO-NASH, the 52-week liver biopsy endpoint, is the first primary endpoint of the study. It's a 54-month study. It's ongoing, it's blinded, and the long-term outcome at 54 months is to prove clinical benefit in non-cirrhotic NASH. We also have a parallel outcome study in cirrhotic NASH. The issue with the AdCom type of platform is that there tends to be unblinding of individual patients in AdComs, and there was plenty of that in the Intercept AdCom. I know that FDA will be very sensitive about that, so we'll see whether we get an AdCom or not.
One of the interesting points that came up is the idea that hitting only the fibrosis endpoint doesn't really give you the information on whether or not you have impact on the underlying disease. You're in a position where you've achieved both endpoints. Do you feel like you are maybe in a better position, I think, to be able to make an argument for resmetirom as a therapeutic for NASH?
Yeah, hitting both endpoints, basically provides you a story. You can tell a story. You know, the drug reduces NASH, reduces the inflammation in the liver, and the fibrosis, which is a product of the inflammatory state of the liver, is also reduced. It's sort of almost like a sequential effect that many pathologists, certainly, and NASH experts have always felt was very important to reduce NASH in order to reduce liver fibrosis. This is how we're looking at our data. The fibrosis reduction and, you know, potential lack of worsening of fibrosis, which is ultimately the issue, this is what we're concerned about in NASH patients, is that they're going to transition to cirrhosis, that is plausible when the drug is reducing the inflammatory state of the liver. Yeah, I think it helps to hit both endpoints.
One other point from the AdCom was to, something you mentioned on the use of non-invasive tests or the use of biopsies to identify these patients. Doctors we've spoken to are pretty mixed on biopsies versus non-invasive tests, but the guidelines seem to be shifting, and you've been heavily involved in that. Maybe just speak to where you see the field evolving. What will it take for maybe the FDA to get behind the-
This is a very complicated issue, and it does sort of then get into the sort of medical affairs and the commercial aspects of patient diagnosis. The availability of diagnostic testing to confirm the diagnosis of NASH, which is in some ways a diagnosis of exclusion. There are several causes of liver disease, and we want to make sure, first of all, that they don't have hepatitis from viral causes, or it's not an alcohol-related liver disease or some other form of liver disease. That is part of your diagnostic in our clinical trial protocols and also in real world. I think there's a lot of capability to do that.
You're left with, well, you know, a patient has a positive FibroScan test, or they have a positive ultrasound, or they have some other blood tests that suggest that they have... and they have the metabolic constellation, which was very important in our trial. You've got a few pieces there, but in the real world, the availability of fancy testing is probably less, and we believe that we have to allow physicians to have multiple options to confirm the diagnosis. That's kind of what the guidelines are saying right now, that you get to a level of suspicion that this is probably NASH, and there are several sort of confirmatory types of approaches that can be taken.
The FDA in the past has always recognized that that is what's going to happen in the real world, that you can't require certain tests because they may not be uniformly available.
To add to that, there are 1.3 million patients in the United States that have been ICD-coded as NASH. Of that 1.3 million, I'm not saying all of them actually have NASH, probably a significant portion of them do. Only about 2% have had liver biopsies to make the diagnosis. It's just not done. There isn't the capacity in the country to do it without the, not, without providing a disservice for the patient population.
Remy, maybe I'll bring you in then on this very point and the work that you've been doing across different stakeholders here. What are you hearing from your research? Is this backing up this broad acceptance and this willingness to move to non-invasive testing?
Yes, absolutely. I mean, I'll, you know, give a little flavor. Let's talk about patients. Who wants a harpoon into their liver? No one. Physicians, as Becky has mentioned, as you know, Paul has mentioned, the treaters, so we're talking hepatologists, gastroenterologists, endocrinologists. I mean, they are quite comfortable with non-invasive approaches. Guidances, as you have mentioned, are very much focused on non-invasive approaches. Payers, that's also a very important question to ask. I mean, we've done a ton of market research with U.S. payers. Their answer is clear. They are going to follow the guidances. They're going to follow what was done in the clinical trial, to understand which non-invasive thought leaders, what are they saying. They only bring biopsy into the mix if a company were to, for example, price a NASH drug at an orphan disease level pricing.
Nobody's really going to do that. listen, I mean, you know, I think Becky and the clinical trials will have quite a bit of role in defining the future of NASH treatment. Our clinical trials have such a treasure trove of non-invasive data. It's going to be very, very important for them.
On that point of pricing, you guys received a positive ICER draft evidence report, that suggested there is quite a range that you could price resmetirom based off of its clinical profile. What is the latest thinking on where resmetirom might fit?
Listen, it's a good question, the one that we're not prepared to answer right now, because number one, we don't have label in hand. You would expect that. Also, I mean, you know, we're meeting with the top executives of payers to understand some of their pressures, their thinking. This has to work for, you know, all people involved in delivering this drug to patients. ICER report gives us a lot of flexibility. I think, you know, people have not been close to it. A couple of points to keep in mind, ICER analysis for resmetirom profile indicates their assessment that the drug could be cost-saving for the U.S. system at $20,000, cost effective at $30,000-$50,000. Again, too early to signal anything specific on pricing, but that's a lot of flexibility to work with. That's a good place to be, you know, eight months or so from PDUFA.
You've spoken in the past about your own independent work here, that has suggested around that $18,000-$19,000 annual price. Just curious if that is still consistent with the work as it's been evolving.
Yeah, I mean, I think what we have said in the past is before the ICER report came out is, you know, payers were thinking about, for example, Wegovy, which is, you know, a treatment for obesity, but also being studied for NASH. I mean, that's in their mind as some sort of pricing, you know, dynamic in NASH, but nothing more specific than that. ICER has, you know, given us a better way of thinking about pricing.
I guess maybe part of the pricing considerations rely on the patient population that you think will be addressable by resmetirom. Maybe walk us through the characteristic of the patient that you think will come on to resmetirom upon approval.
Again, it's very much in line with what Becky said. These physicians, we're not, we're not talking PCP here. We're talking specialists, hepatologists, gastroenterologists, a subset of endocrinologists, ones that truly have learned about this disease and their practices are very much in line with the guidances. They look at the constellation of comorbidities, metabolic comorbidities, and then, as Becky said, assuring there's not another reason for why they're seeing the abnormalities in the liver.
There's a proof of certain level of fibrosis progression. I mean, you know, in market research, a physician, you know, what they're telling us, the trigger to treat a patient with resmetirom, with the profile it has emerging, could be a kPa of 8, alpha of around 7-8. This is very much in line with AFLD and AGA guidance. They're very much looking forward to a, you know, a liver-directed treatment. Fortunately, we have one coming soon, hopefully.
I guess maybe in the context of those criteria that you've just listed, how do you think about maybe this idea that only lean NASH patients should be treated with resmetirom, or maybe those are the patients that would be most ideal because they're not on a background with one, they're not diabetic, they're not morbidly obese? Does that jive with any of the things that you've been hearing?
only which patient?
Lean NASH.
Lean NASH.
Oh, I've never heard that. Never.
Okay.
In fact, our study, if anything, we focused on cardiovascular risk factors, that included the five features of metabolic syndrome, of which one of them is obesity. Essentially, every patient in our study was obese. One of the reasons that patients have lean NASH is if in the case of alcohol excess, because ASH, which is alcoholic steatohepatitis, and NASH, nonalcoholic steatohepatitis.
I mean, one, we really wanted to make sure they had the metabolic form of fatty liver disease. Obese, diabetic or insulin resistant, I think it was 70%, diabetic or 60%, 70%. Hypertension, 70% or 80% in our study, dyslipidemia, at least 70%. This is the classic NASH population, and it's certainly not lean NASH. I think, lean NASH is a heterogeneous population, and there may be some features it of very high insulin resistance in patients that otherwise don't look obese, but they have that profile, and there are certain genetic factors that can contribute to that. It's not a disease that we've studied with resmetirom. Yeah.
Andrea, I would just add, you know, when we, when I talk about physicians saying the trigger to treat with resmetirom or liver-directed therapy could be a kPa of 8, assuming all those other things that we've mentioned are there, is on the background of GLP‑1 therapy on a big subset of patients. There is a perception that GLP-1s for NASH are not sufficient. Liver-directed treatment is needed when the patient gets to a significant fibrosis level.
maybe.
I mean, I think the GLP‑1 story is a little bit confused in people's minds. I mean, people are, who are diabetic, and including in our study, our MAESTRO-NASH study, about 12% or 14% of patients in each arm of the study were on diabetic, chronic diabetes level of GLPs. It's known that these GLPs at those doses don't treat NASH, and in fact, they have the same level of liver fat, they're just as obese, and they have just as much NASH as patients who are not on GLPs. We showed with MAESTRO-NAFLD, actually, our earlier study, using non-invasive tests, that there's no actual beneficial contribution of patients who are on GLP to responses of using non-invasive technology. It doesn't really do much.
If we also showed that if patients acutely lose weight, and slightly more patients lose weight on resmetirom than placebo, but lose at least some weight, 5% or more, so not a huge amount, that it does help, is beneficial to resmetirom's effects, and to the patients in general, but especially, it's beneficial to resmetirom's effects. We do believe that diet and exercise is a component of the therapy, and I'm absolutely sure that if you started a GLP and a resmetirom at the same time, you'd get a really, you know, good benefit, on NASH. Patients chronically treated with these diabetes levels, it's not a factor.
Perfect. Then remind us here, you spoke about MAESTRO-NAFLD, and it has a cohort looking at F4 patients. How does that opportunity really, I guess, maybe magnify where resmetirom could be used? Especially as you think about the MAESTRO-NASH outcomes, that is a population that you could achieve here.
I think this is one of the most important aspects of our program, that it's critical when you're going to have an indication in non-cirrhotic NASH, as we will with resmetirom, that we show that the drug's safe in cirrhotic NASH. That was the goal of that study, where we had something like 200 patients with NASH cirrhosis, and some of them are out almost three years now, so we've extended their dosing beyond that. What the key feature is that they're taking the same doses of resmetirom as our non-cirrhotic. They're taking 80, primarily, but some are also taking 100 milligrams, and the drug is safe and well tolerated in NASH cirrhosis.
We also saw some very nice pharmacodynamic effects of the drug that could translate into long-term benefit in NASH cirrhosis, and that's why we're doing a clinical outcome study in NASH cirrhotic patients, which would be a great indication to get because it is a very, very high unmet medical need population. For the current label that we're going to achieve, the cirrhotic NASH will not be, you know, part of it. However, just to comment that it's not always so straightforward based on these non-invasive tests, to distinguish cirrhotic and non-cirrhotic, or even on liver biopsy, because the liver can be very heterogeneous in that range. Having that safety is really important.
So-
Yeah.
I just would add to that. If the data that we have so far gives us a high degree of confidence that that MAESTRO-NASH outcome study with the F4s is going to be a positive study. If it is, and we get that indication, that doubles the market potential because you get high penetrance into that population. It's a pretty important study.
Look forward to it. Remy, one more question for you.
Sure.
Where do you stand in terms of commercial launch preparation, the team build out, and do you think you're adequately positioned to launch this in the U.S.?
Yeah. I mean, I'll give you a perspective on where we are internally, but also, you know, externally, what we're walking into, it's important to remember 3 things. One, Paul has mentioned, based on our patient analysis, patient claims analysis, there's about $1.3 million NASH ICD-10 coded patients today. There's about 100,000 being coded every year, and even without anybody doing anything to increase that or with a drug that's approved. Two, physicians are expressing high unmet need to treat NASH F2, F3, sort of, you know, severity disease with liver-directed treatment. Payers, number 3, are expressing high degree of comfort based on how they are thinking about NASH or openness to cover first approved drugs. Where we are? Listen, we've been at the job for about three years now. We've had MSLs engaging with thought leaders for over three years.
Strategy is set on the commercial side. Go-to-market plan is set. We're in execution mode now. Organization-wise, my leadership team is here. Our market access team gets fully onboarded and starts working with national accounts and regional accounts probably summer of this year, June, July. We've been educating payers for about two years now. Sales force, probably a couple of two, three months before PDUFA, is the expectation. We're doing all the right things we need to be doing to get ready for the U.S. launch. That is my job. We take it very seriously. Lastly, I would say is, you know, we've been educating payers, but also HCPs, for about a year and a half now through NASH Explored campaign, and we just launched our patient disease education campaign this month as well, Taking on Fatty Liver. That's where we are.
Alex, maybe I'll bring you in here. You guys have discussed in the past an ex-US partnership. Maybe update us on where that stands and then also within that context, where the filing in Europe also stands?
Yes. Excuse me. In terms of the partnership, as we sort of said publicly previously, our preference is for a single, typically large pharma partner that can obviously encompass all of the geographical regions outside of the U.S. versus doing separate regional deals across, you know, different areas of the globe. Those discussions are ongoing. Obviously, they're confidential, so we can't go into any details, but when we're ready to announce a deal, we'll announce a deal.
Just remind us on your cash runway and what that's expected to support?
Sure. We ended the Q1 with $330 million. That will take us through the potential priority review and approval of resmetirom in the US and into the early stages of launch. We will need to secure additional capital to get to profitability. We basically reregistered our ATM facility, which will bring in an additional potential to bring in an additional $200 million. We also have a credit facility with Hercules Capital for $165 million. 30 of that is actually already committed by Hercules and an additional 75 tranche, which is linked to approval. The balance is basically a discretionary tranche that, you know, we have to request, and then Hercules then has to bless, basically. that provides an additional $365 million.
Paul, maybe I'll end in the last minute here. Just any last thoughts on where we stand in the NASH field? What else needs to be done to further advance it as resmetirom comes to market?
Well, I don't think a single drug is going to be a panacea for everyone. One can conceive of fixed those combinations and of multiple mechanisms that, you know, that could cover a broader group of patients. I think it's a miscalculation to just look at the percentages of response in the current studies. I think, as Becky said, at EASL, we'll show that majority of patients do respond positively to resmetirom. We feel as though resmetirom is going to be the foundational therapy for treatment and other things might be added to it at a later date or used in the unusual situation where resmetirom is not working in a patient.
Perfect. Well, with that, thank you everyone for joining us. I got cut, but thank you.
Thank you.
Thank you to the Madrigal team.