Madrigal Pharmaceuticals, Inc. (MDGL) Earnings Call Transcript & Summary

Good afternoon and thank you for standing by. Welcome to Madrigal Pharmaceutical Conference Call, and webcast of the announcement of the FDA's approval of Rezdiffra. [Operator Instructions] As a reminder, today's conference is being recorded. I would now like to introduce Ms. Tina Ventura, Chief Investor Relations Officer. Please go ahead.

Thank you, Sherry. Good afternoon, everyone, and thank you for joining us to discuss the FDA approval of resmetirom, now known by the brand name Rezdiffra. It's the first ever medicine approved for the treatment of NASH, and is indicated for patients with moderate to advanced liver fibrosis consistent with F2, F3. Moderate to advanced fibrosis has the same meaning as significant fibrosis, the descriptor we've used prior to approval. We're also reviewing a slide presentation as part of our webcast today and will post it after the call. Please note, Slide 2, and we'll 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. On the call with me today from Madrigal is Bill Sibold, our Chief Executive Officer; Dr. Becky Taub, our Chief Medical Officer and President of R&D; and Mardi Dier, joined Madrigal as CFO at the end of February. We're also pleased to have Dr. Stephen Harrison join as well. Dr. Harrison is the principal investigator of our Phase III clinical program, and Medical Director for Pinnacle Clinical Research and Visiting Professor Hepatology at Oxford University. Bill will begin with a brief introduction. Dr. Harrison will provide an overview of NASH in the treatment landscape, followed by Dr. Taub, who will provide a review of Rezdiffra label and clinical data. Bill will then review our commercial strategy and launch plans and we'll end with Q&A. With that, I will now turn the call over to Bill.

Well, thank you, Tina. We're thrilled to announce FDA approval of Rezdiffra. The first medicine ever approved for NASH. It's an especially exciting day for NASH patients who until now had no other options. So before we move into today's presentation, let me briefly share with you the impact that NASH can have on a patient's life. This is Terri on Slide 4, a patient leader in the NASH community. Terri was told she had fatty liver, but not to worry about it. Unfortunately, her liver fibrosis was accumulating over time. She went in for gall bladder surgery and her health care team detected cirrhosis. From there, she developed a number of serious life-altering complications and would then diagnosed with liver cancer. She received the liver transplant and has faced multiple new health and life challenges post-transplant. Truly a heart-breaking story, but not uncommon for NASH patients with progressive fibrosis. And that's why the approval of Rezdiffra is so important. Patients now have an option to stop or reverse fibrosis before they progress to the types of outcomes that impacted Terri. So let's move to Slide 5 and the other important points I want you to take away from our call today. First, the approval of Rezdiffra marks an unprecedented milestone for the NASH community, the pharmaceutical industry and for Madrigal. Second, we've got a great label for Rezdiffra, and the product profile positions it to become the foundational therapy for NASH. And third, we have an experienced team in place to deliver a successful launch and maximize Rezdiffra's long-term potential. On Slide 6, you'll see the highlights of our label. We're very pleased. This is a label that clearly directs where to use Rezdiffra, F2, F3 patients who are most in need. First, we have a great indication statement exactly what we hoped for. It's for the treatment of NASH patients with moderate to advanced liver fibrosis consistent with stages F2 to F3 fibrosis, the patients we studied in our trials. Second, there is no biopsy requirement. Third, it's an oral once-daily pill, and we have simple weight-based dosing. And fourth, there are no contraindications, no box warning and no monitoring requirements beyond standard of care, very clean, very clear label. And as an oral once-daily liver-directed, well-tolerated medicine, Rezdiffra is positioned to become the foundational therapy for NASH with moderate to advanced liver fibrosis. Importantly, this label also sets the standard for NASH that any future treatments will have to meet. Let me turn the call over to Stephen to provide you a brief overview of NASH. Stephen?

Thank you, Bill. It's a pleasure to be a part of this historic announcement today. I feel like it's Christmas in March. As a treater of NASH for the last 25 years, it's an incredibly exciting day to see the first medicine approved for NASH. We've had patients waiting and waiting for something that could impact underlying fibrosis in the setting of NASH. And this truly represents a milestone achievement that frankly I and many others have been working on since the turn of the century. Moving to Slide 8. As you heard from Terri's story, NASH is a chronic and progressive liver disease where the buildup of fat in the liver cells cause significant damage over time, including inflammation and scarring or fibrosis. We characterize the progression of fibrosis in 4 different stages. You can see in the two right-hand columns. F1 or mild, F2 and F3 moderate to advanced fibrosis, which is where Rezdiffra is indicated, and F4 or cirrhosis. Moderate to advanced fibrosis patients are on the cusp of cirrhosis, where we see a significantly higher risk of liver cancer, liver failure, reduced quality of life and death. And now we have Rezdiffra that after 1 year, either reverses fibrosis or prevents progression of fibrosis in more than 80% of F2 and F3 patients. So how do we, as treating physicians identify, diagnose and treat F2 and F3 patients? Well, patients typically present at their primary care provider with multiple metabolic risk factors such as obesity, diabetes and elevated lipids as well as elevated liver chemistry test. If the provider suspects they have NASH, they're referred to a specialist. Typically, a hepatologist like me or a gastroenterologist. Once at the specialist office, we rule out other liver diseases. This is really important. We look for other liver diseases, concomitant liver diseases and then assess for the severity of the disease with our noninvasive tests that we have in hand. The majority of NASH specialists have access to these noninvasive tests, and these include imaging tests like FibroScan or a proprietary blood test like ELF. Multiple medical societies, including AASLD, the European Association for the Study of Liver Disease or EASL and ACE have published guidelines or guidance documents endorsing their use. So it's fairly easy, and it's fairly well defined. A biopsy for diagnosis is rarely used in the real world. It's not standard of care, and I was pleased to see that the FDA didn't include it as a requirement in the Rezdiffra label. After diagnosis, the next step is treatment. Until today, there was no approved options to reverse NASH or fibrosis. While patients are treated with standard of care diet, exercise and weight loss recommendations and medications for their obesity and medications for other co-morbid conditions such as diabetes and cardiovascular disease, these interventions are not liver-directed and have not delivered a fibrosis benefit. Today's approval of Rezdiffra now changes the paradigm. For the first time, we have a treatment that works directly in the liver, halt NASH and reverse fibrosis. So Bill described the high burden Terri experience. And on Slide 10, you can see the facts. F2 and F3 patients have a 10 to 17x higher risk of liver-related mortality compared to a patient without fibrosis and is estimated that 1 in 5 patients with F3 fibrosis will progress to cirrhosis within a 2-year time period. In fact, NASH is the leading cause of liver transplantation in the U.S. for women and expected to soon be the leading cause for men, pretty terrible outcomes for our patients. So our goal as a NASH specialist is to halt or reverse fibrosis in stages F2 and F3 before a patient progresses to cirrhosis. Rezdiffra for the first time, affords us that option. I'll now turn the call over to Becky to discuss the Rezdiffra label and the clinical data that supports approval.

Thanks, Stephen. I'd like to echo the comments you and Bill have made. This is an incredibly exciting day for Madrigal and for NASH patients now, that now have a treatment for their disease. I also want to thank the members of our team, the Phase II and Phase III trial investigators and thousands of patients in our trials that helped us move the [ NASH trial ] forward and reached this tremendous milestone. On Slide 12, you see that our approval is built on one of the most comprehensive clinical development programs in NASH. This includes 52-week data from the 1,200-patient MAESTRO-NAFLD Safety Study and the ongoing 54-month 1,750 patient MAESTRO-NASH Study in patients with moderate to advanced fibrosis that supports this accelerated approval, and eventually, with the outcomes portion of the trial will support full approval. We also have our MAESTRO-NASH outcome study that's enrolling patients with well-compensated NASH cirrhosis that will support full approval for cirrhotic and noncirrhotic NASH. So it's a well-designed program that has set the bar exceptionally high. On February 8, our Phase III trial results were published in the New England Journal of Medicine. This landmark publication of detailed efficacy and safety data provide clinicians with a wealth of valuable information about Rezdiffra as they consider it for their patients. On Slide 13, you can see the breadth of Rezdiffra's response. 50% of patients showed either NASH resolution or fibrosis improvement. More than 70% of patients achieved at least a 30% reduction in the noninvasive MRI-PDFF test results correlating to response at both endpoints. This is one of several measures we've shown that demonstrate noninvasive tests predict treatment response and more than 80% of patients achieved either fibrosis improvement or no progression of fibrosis on biopsy. And that really is the most important goal for NASH patients, reversing or stopping fibrosis. Let's move to Slide 14 and our indication statement. Really a best case scenario for us. Rezdiffra is indicated for patients with moderate to advanced liver fibrosis consistent with F2, F3 not later-stage patients with cirrhosis. Rezdiffra has no biopsy requirement, no contraindications, no box warning and no additional monitoring requirements beyond standard of care. In the limitations of use section, again, it's very clear Rezdiffra shouldn't be used in patients with decompensated cirrhosis. On Slide 16 is the dosing information, very simple weight-based dosing with 80-milligram and 100-milligram recommended and a 60-milligram option for some patients on a moderate CYP2C8 inhibitor. On Slide 17, you'll note that there are no contraindications. We have no box warning. And warnings and precautions, there is a reference to hepatotoxicity which is based on a single patient from our safety trial who did not have NASH. The label reinforces standard of care monitoring of patients. Gallbladder related AEs are also referenced. There is a higher incidence of gallbladder events in NASH patients, and the overall incidence was low for acute gallbladder events, less than 1% with Rezdiffra. Moving on to efficacy. On Slide 18 is a snapshot of the efficacy included in the Rezdiffra label. The results are shown by the 2 individual pathologists that read the liver biopsies as FDA believes this is an easier way for providers to understand and interpret the results. The FDA also only included F2, F3 patients in their analysis and use slightly different endpoint definitions than Madrigal and their prespecified and New England Journal publication. You can see that Rezdiffra demonstrated an improvement compared to placebo for each pathologists at both endpoints. The label also notes that the [ analysis ] incorporating both pathologists independent readings, Rezdiffra achieved statistical significance on both endpoints for both doses. On Slide 19, we show the statistical endpoint calculations based on the label defined 888 patient F2, F3 population and FDA's analysis and the predefined 966 F1B, F2, F3 population in Madrigal's primary analysis. As mentioned there were small differences in end points using the label and the agreed prespecified endpoints used by Madrigal. The results are entirely consistent and reproducible and responses are reserved that are highly statistically significant in each population with either endpoint for fibrosis improvement or NASH resolution and at both doses. You've also seen this consistency across multiple subgroup analyses as noted in the label and in our 80-page supplement to our manuscript in the New England Journal of Medicine. And Slide 20 covers adverse events, nothing new here. The most frequent adverse events were GI-related occurred at the beginning of the study and were generally transient and reduce over time. I will now turn it back to Bill.

Thanks, Becky. Let's move to our commercial strategy then. As we've discussed, this is a specialty launch where we're focusing on the 315,000 patients in the U.S. diagnosed with moderate to advanced fibrosis, consistent with F2, F3 that are being seen by the 14,000 physician specialists we are calling on. And is a sizable population that has a tremendous unmet need. Slide 23 shows where Rezdiffra fits in the NASH treatment paradigm. On the left, you see no or mild fibrosis patients who are treated for their cardiometabolic risk. As you move to the middle, this is the population of patients with moderate to advanced fibrosis consistent with F2, F3 where Rezdiffra is approved and where a liver-directed therapy is needed to reach the treatment goal of reversing or halting the progression of fibrosis. As Becky noted, our data shows that 80% of F2, F3 patients saw their fibrosis halted or reversed with Rezdiffra. On the right are patients with cirrhosis or F4 patients. We have an ongoing outcomes event-driven trial in patients with cirrhosis that we expect to read out in the '26-'27 time frame. Through our market research, we know physicians, patients and payers are excited and ready for a NASH treatment like Rezdiffra. Physicians have expressed a high urgency to treat, patients said they would proactively seek a medicine like Rezdiffra and payers viewed the need to treat F2 and F3 patients as high to very high. Based on feedback from our meetings with payers leading up to launch and supported by our label, we don't expect the biopsy requirement as part of their utilization management requirements. So we just established that we have a well-defined patient population in need of a liver-directed therapy with stakeholders who are ready and waiting for Rezdiffra. Now it's about wiring the system over the next 12 months to develop the market the right way to ensure successful treatment experiences for patients and physicians and a blockbuster launch. Our approach centers on partnering with the community. This includes educating physicians on NASH and Rezdiffra and helping physician offices establish certain processes for the first time. Our teams know what they need to accomplish, which includes ensuring that Rezdiffra has been added to physician office EMR systems, helping offices align on what noninvasive tests will be required for diagnosing patients, processing a Rezdiffra prescription through a specialty pharmacy and fulfilling that prescription with assistance from our patient support team. Leading up to approval. Our market access team has been engaging with national and regional payers to educate them on NASH and its downstream costs. Now that we have approval, they will begin to discuss and understand each payer's planned requirements for covering Rezdiffra. We expect payers to require a prior authorization and establish noninvasive test requirements for diagnosis as part of their reimbursement process. From our market research, we know that our target physicians have access to noninvasive tests and are skilled at using them to diagnose and stage NASH patients. As coverage is established, we will help physician offices understand each payer's requirements and align the process in their offices for use of NITs. We would anticipate treatment guidelines to be updated with Rezdiffra, which will help to reinforce for both physicians and payers how and when to use Rezdiffra. We expect commercial coverage to steadily ramp up over the course of the year to achieve approximately 80% of lives covered by year-end. We expect the minority of plans will reimburse immediately with a temporary policy until they review and confirm final coverage through a P&T committee process. Other plans may institute an NDC block until a coverage decision for Rezdiffra is made. For those plans, patients will be able to access Rezdiffra through a medical exception process. While that takes additional work and time for the physician's office, it is the standard approach for newly approved specialty medicines. We expect full Medicare coverage in place beginning in early 2025 based on the annual review process for new medications. We expect the mix of our business to be 50% to 55% commercial, 35% to 40% Medicare and 10% Medicaid. And as is typical with the new product launch, gross to net will be noisy until the reimbursement pathway stabilizes. As physician offices work through the prior authorization and medical exception processes and commercial plans continue to establish coverage we expect the average time to fill a prescription to improve from about 60 days at launch to about 30 days or less by 6 months post launch. And while we anticipate high demand for Rezdiffra based on our research, we expect physicians to prescribe Rezdiffra as their patients come in for regularly scheduled visits, which take place once or twice a year on average. So over the next 12 months, we are taking the important first steps required to build a blockbuster and establish ourselves as the leading NASH company. On Slide 26, you can see we've built an expert team across sales, medical affairs, market access and patient support to execute on a successful specialty launch. Our commercial and medical leaders each have more than 25 years of industry experience and have launched dozens of blockbuster medicines. So we're ready to go with the right people and the right experience to make this launch a success. On Slide 27, we're announcing the price, which will be an annual WACC price of $47,400. This is a high-value medicine for a disease that has a significant burden on patients in the health care system. Our comprehensive clinical development program, combined with the robust evidence package supports the value Rezdiffra brings to patients as the first and only approved therapy in NASH. This was also supported by a favorable third-party assessment by ICER. We want to ensure there is equitable access and affordability for all eligible patients as the launch progresses. We are committed to helping all appropriate patients who may benefit from Rezdiffra, access the medication through our Madrigal Patient Support Program. As you can see on Slide 28, this program is designed to help patients navigate insurance and affordability challenges and provide copay support for eligible patients. Madrigal has also established a patient assistance program to help patients with no insurance to access Rezdiffra. So today is an incredibly exciting day. I'm just finishing my 6-month market magical, and it's rewarding to look back on how much we've accomplished in such time. And I know for Becky and Stephen, who have been working on this goal for years, it means so much more. It's remarkable that Madrigal has achieved today in NASH, what this industry has been working on for years, even decades. And we not only achieved approval but also a label that clearly defines the appropriate patients for Rezdiffra, and that's what's most important that patients will be able to finally have a treatment for their disease. Our team is ready to go, and we look forward to a successful launch transforming the treatment of NASH for patients and establishing our company as the leader in NASH for years to come. I'll turn the call back over to Tina.

Thanks, Bill. Given this call is already into the evening, we're going to try and keep the Q&A efficient. So Sherry, if you can open the call for questions.

[Operator Instructions] Our first question will come from the line of Yasmeen Rahimi with Piper Sandler.

Congrats for an incredible achievement really on behalf of all of us, just really excited to see this. One simple question. Given the current pricing, could you comment on what have been some of the preliminary commentary from payers in regards to which NITs they prefer? And I'll jump back in the queue. And thank you again for bringing these exciting news to us today.

Great. Yes, first of all, thank you for the comments. It's really a thrilling day here. Look, I think the price that we've chosen actually really is a nice balance for value and access. We've been talking with payers now for over a year. And a lot of that's been education on the disease to the extent that we could talk about any of the product attributes and outcomes, we did that as well. So we've had very productive conversations, and we have really starting from a great clinical package that's been put together through the development program, very strong health economics work that has been completed. So therefore, as you saw, as we mentioned in the presentation, there was a nicer range, which we think fairly supported the value that the product brings to the system. So we've had these conversations, and we're expecting that, first of all, it's not going to be a surprise for payers and that we'll be able to secure access for patients. Now I don't want to kid you that you have a product approved and you have easy conversations. No, look, we're expecting we'll have some really good conversations with payers over time. But we're convinced that this is going to be the right balance to ensure that there's going to be access for patients as well. And as I said earlier, affordability is a key here, and we're taking that very seriously to provide equitable access for patients regardless of their insurance type or background.

Great. Thanks Yas. next question please.

And that will come from the line of Liisa Bayko from Evercore ISI.

And I'm going to stand in line with everyone else and pop the champagne bottle, congratulations on this great achievement. I have a question for Dr. Harrison and that there's these things called GLP-1s out there. You may have heard of them. How are you thinking about incorporating sort of all these different modalities that are available now weight loss drugs and resmetirom into your treatment practice for patients with NASH? And then also just the mention of some of the statins, how much of a, I guess, a headwind might that be having to do some dose adjustments for the statin class?

Liisa, thank you for the question. Before I pass it over to Stephen. Just as we talk about any other products in the space, I think the one big difference of any other product in development is we're approved today. We're the first NASH product approved. And we've considered that we have years of head start before anyone else. And I think that first-mover advantage is something which is absolutely critical. Sometimes it's not recognized as much, but all the data supports that first to market enjoys a significant position in that market for years and years and years. So Stephen, do you want to maybe provide some color on that as it was asked to you.

Yes, absolutely, Bill. Thank you. So look there's a bit of a paradigm shift that happened today, right? So heretofore, we would be seeing clinic, like I saw clinic yesterday, a whole handful of fatty liver patients. And the only thing I had was things that were off label, right? So we were targeting comorbidities in managing those. And we have used GLP-based therapies to help us in that regard. Now with this paradigm shift, as Bill said, we have an FDA-approved therapy that's liver directed and targeted at those people with moderate to advanced fibrosis, the group of people that are at greatest risk of developing a liver-related complication. Now we have a tool in our tool chest to target those particular patients. It doesn't mean we quit using GLPs, but I think we now begin to look at the stage of disease of these patients and what their greatest risk of having a negative outcome is. So if the greatest risk is cardiovascular and that would be patients with mild to no fibrosis then it makes sense to target a non liver-directed therapy in those milder patients because they're at greatest risk of dying of a comorbid illness unrelated to their liver disease. However, as you progress now into F2, where we talked about a 10 to 17x increased risk of developing a liver-related complication. Now I think the new idea is let's focus on liver-directed therapy where we actually have something that can be beneficial to the fibrosis that is portending a worse prognosis. And we know the GLP-1-based therapies to date have not shown a benefit in that regard. So hopefully, that clarifies. And then your question about statins is another good one. And I think it's important to step back and look at the totality of the data, the robust amount of data that we have accumulated over the course of the past several years in many of the Phase III trials that have been done. And what we know is that the interaction between resmetirom and statins is mild. About 50% of NASH patients were on statins in our trials, and there was no excess adverse events and no statin-related toxicities observed in these trials. The recommended statin doses in the label are consistent with statin doses that are commonly used in NASH patients and clinical practice and were used in our clinical trials, not restricted dosing. So we've carefully looked at the safety relative to the statin dosing. And these are statin doses that NASH patients are usually on based on clinical practice, and there are no restrictions. So if you look at the label, where you're able to use rosuvastatin and simvastatin up to 20 milligrams pravastatin and atorvastatin up to 40 milligram, then that's clinically what we're using. So I don't really see this as an issue. And so for that, let me pause and turn it back to Bill.

Thanks, Stephen. Thanks, Liisa. We'll take the next question, please.

And that question will come from the line of Ritu Baral with TD Cowen.

I wanted to add my congratulations and Dr. Harrison, it must be exciting to be able to finally offer something to your patients after long last. I wanted to address this question to you, actually, Dr. Harrison, about the NITs and the current understanding of the field of your average hepatologists on the NIT values that correspond to the F2, F3 for the language on the label and what your understanding of NIT technology availability is in hepatology offices or gastroenterology offices. And then basically a question on how the payers view this in your opinion?

Thank you for the question, Ritu. Stephen, if you could take that, please?

Yes, absolutely. This is really I think an important question, something that we've thought a lot about, something that we are certainly focused on. As we are celebrating the fact that liver biopsies aren't going to be required because I think that is a huge win for us in this field. And that makes sense because it's not standard of care in our clinical practice anyway. And I think that's an important point to make here. Because we are already doing NITs to find these patients and as somebody that helped prepare the AGA guidance document and a reviewer of the AASLD guidance document. What I can tell you is that we're all aligned, whether you're in Europe with EASL, you're an endocrinologist and you help wright the ACE guidance or you're a gastroenterologist with AGA or a liver doctor with AASLD, we're all aligned in how we want to tackle this. And really, we wanted to build muscle memory with our easy -- with something easy that could be used in clinical practice, and that's FIB-4. Now while that's not the absolute best test out there, we do know that it does provide us very helpful information, particularly at the 2 extremes of the test. So less than 1.3, we can safely say these people are not at greatest risk of disease progression, greater than 2.67 those are people that really should be seen by a GI or Hep. The values in between are what we call indeterminate, and that drives a second noninvasive test, so we call sequential testing. And right now, those guidance documents are all aligned that, that will either be a FibroScan or ELF. And there, if you look at those tests, the cutoffs are 8 to 12 or greater than 12 or less than 8. So I think at 8 to 12, we want to send those people to the GI docs, in the Heps and let them work those guys up for moderate to advanced fibrosis or even potentially cirrhosis. ELF scores less than 7.7, we're not going to worry so much about them. 9.8 or greater, they definitely should be seen by GI-Hep, and in between, again, that's a patient that needs probably some further workup, maybe MRI or other NITs that we have at our disposal. The take-home message is, while not every GI clinic in this country has every tool, every GI clinic and Hep office in this country has access to some tools to help navigate what these patients to stage these patients appropriately and to get them on therapy. We don't have to be precise. It's another great thing about the label moderate to advanced, that gives us room on a lot of these NITs to find the right patients, but importantly, exclude those that don't need therapy right now and also importantly, exclude those with cirrhosis for which the label is not indicated.

I think sorry, Rita you'd asked a question about the just reimbursement and so forth right now?

Yes.

That's part of what our teams are going to be doing is helping to understand on a kind of per payer basis, what's expected, et cetera. What we're hearing right now is that a lot of the NITs they're already available, widely available. Virtually all of the targeted prescribers have access to NITs, and FibroScan in particular. And we think that that's not going to be a barrier. But again, we have to understand on a payer-by-payer basis, what's going to be expected and each of the physician and practices will have to then secure that test. Now the other thing I'll say is what we believe is over the next 1, 3 and 5 years, there's going to be evolution of NITs. I think that it's still an evolving field. I don't think that there's any single winner at the moment and pure standard of care. And I think over time, as we understand how best to sequence, combine and any new NITs that may be available, I think you're going to see as this market develops and grows that will have just a lot more precision and perhaps even alignment around how best the sequence is. So maybe we'll go to the next one.

Yes. Thanks, Bill. Next question please.

And our next question will come from the line of Andrea Tan with Goldman Sachs.

Congratulations on the approval here. Dr. Harrison, maybe another question for you, if you could speak to the proportion of your F2, F3 patients that you plan on putting on Rezdiffra upon its availability, and then more specifically, if you envision there being a bolus of patients coming online, just given they have been waiting for a novel therapy here? Or do you think it truly will be slower as you wait for patients to come through from their normal visits?

Thanks, Andrea, for the question. Just before I turn it over to Stephen, as we commented in some of the opening remarks, what we're hearing across the physician network or physician landscape, if you will, that people are tending to be planning to see patients as they come in for their regular visits, which is once or twice a year. I think we've heard some examples where there are some practices that are a little bit better organized, anticipating approval and trying to get patients lined up. But for the most part, it is as they come in. But Stephen, I'll pass over to you for your experience.

Yes. And I agree with that, Bill. I mean, I think we heard at NASH-TAG by Michael Charleston, only 2% of the population has been diagnosed right now. We're going after those that have been diagnosed and that are routinely being seen in our clinic. Like I said, I saw clinic yesterday, a number of those patients actually came forward to ask about resmetirom and when it would be available. It's certainly something that I'm going to use. I've been waiting for, gosh, since Becky and I started talking about this 8 years ago to where we are today. I've seen so many patients benefit from this drug in the trials. I'm anxious to get it into patients in the real world. And I think instead of looking at this as F2, F3, I really want to begin to change the paradigm to think about this from a moderate to advanced fibrosis perspective because our NITs aren't granular enough to pigeon hole a patient directly into an F2 phenotype or an F3, it's going to put us into a range, and we're going to exclude the cirrhotic. We had very good test to help us do that. and we're going to focus on those, eliminating those that don't really have fibrosis that is putting them in a worrisome category. And then I'm absolutely going to use liver-directed therapy and those people that I feel are at greatest risk of disease progression, which is what's in our guidance document. Those patients that are deemed by that guidance to push them into a high-risk category. So focus would be, first on anybody with the FibroScan KPA above 8 and an L score that's also elevated in the setting of an indeterminate or high FIB-4. Now I don't routinely use FIB-4 in my practice, but I use FibroScan. I use other clinical data to help me find the right patient -- the right patients that would fit that category. The other thing is we focus on those that have demographics that put them in the higher risk category as well. So it's kind of -- it's a very structured way that we approach this and GI and Heps do this well. And they also have guidance to help them with that, too. So, so yes, just to summarize, I'm excited about it. I'm excited about a first liver-directed therapy and absolutely going to be using it.

Great. Thanks, Stephen. Next question, please.

Our next question will come from the line of Akash Tewari with Jefferies.

This is Amy on for Akash. Congrats on the approval. So you've previously alluded to gross to net discounts for Rezdiffra not being that high out of the gate. Just wanted to revisit this comment and how you expect GTN to evolve over time?

No. Thank you for the question, and thank you for the congratulations. I mean we are not planning on contracting for Rezdiffra at this point. We think that it has tremendous value, and we are really excited to have conversations with the payers in the coming days and weeks that we have started already over the past year. So I think one of the comments I made about gross to net in the opening remarks is that when you're in the first rest of the year of launch, first year of launch, because you have patients that are going to be perhaps on patient assistance program or a bridge program that you have some choppy gross-to-net until reimbursement stabilized and then you can have a -- it's much more consistent and easier to read through.

Great. Thanks, Amy. Next question, please.

The next question will come from the line of Ellie Merle with UBS.

Congratulations. In terms of payers, I guess, from your conversations so far, do you expect any plans to acquire any step through such as diet and exercise or GLP-1. And how are you thinking about what hurdles there might be for payers? And then just lastly, what is your expectation for when ASLD will issue treatment guidelines?

Okay, Ellie. Thank you. A lot of questions in there. Let me see if I can get to them all, and remember them all. First of all, I think from a payer perspective, the first question was what payers and?

Step through?

Yes, yes. Look, I think we have to step back and make sure we understand. This is a high burden disease. And these patients are 1 to 2 steps away from becoming cirrhotic. And that is a very, very difficult place for somebody to be from a health perspective. And from a cost perspective, we know that it's a significant increase in the cost 4x the cost for the payer for the system to absorb. We think that these patients have stepped through just about anything that they possibly could at this point. And now they finally have a product that is approved for the indication that they have been waiting for. So while there may be some requirements, we'll see. The label says clearly that it's with diet and exercise that you use resmetirom, we would expect most patients would be already doing that. So we don't expect that there's going to be significant hurdles, especially since, there's no other product that has ever been studied that has Phase III data that is hit on both endpoints. And most importantly, that's approved. So look, I think these discussions are ahead of us with the payers. But we feel pretty confident that given what all of these patients have gone through already and what potentially lies ahead for them, that Rezdiffra is going to be something that payers look to work with us on.

Thanks, Ellie. Operator, I think we're up to the 6:00 mark. We've got time for one more question, please.

And that question will come from the line of Thomas Smith with Leerink Partners.

Let me add my congrats on the approval. Maybe just a follow-up on the last question around treatment guidelines. Just wondering if you could talk about your expectations around how quickly these could be updated to reflect the Rezdiffra approval? And then from an access perspective, just talk a little bit about how important the guideline updates are to securing the more favorable access and achieving that 80% of commercial lives covered threshold?

Thanks for the question. And we would expect medical society guidelines to be updated with Rezdiffra in the near future. I mean, look, these things they sometimes are on a regular calendar basis. But I think what we've heard certainly is that there's a lot of interest in Rezdiffra. And so we would expect in the relatively near term to have the guidelines updated. Now it is helpful for coverage, absolutely when talking with the payers to be able to point to guidelines. But it's not going to be a requisite for the guideline to be there before decisions are made. We think that we can start tomorrow having real substantive discussions with the payers to start to secure access to this very important medicine for patients.

Great. Thanks. Thanks, Bill. And operator, I think we'll end the call today. Thank you all for your time and your interest, and a replay of this call and webcast will be available in approximately 2 hours. So thank you for joining us.

Thank you all for participating. This concludes today's program. You may now disconnect.