Activity Transcript

Manal F. Abdelmalek, MD, MPH: Hello, I'm Dr Manal Abdelmalek, a professor of medicine in the vision of gastroenterology and hepatology at the Mayo Clinic. Joining me today are Dr Kathleen Corey, associate professor at the Harvard Medical School and director of the Massachusetts General Hospital Fatty Liver Disease Clinic, and Dr Stephen Harrison, who is medical director at Pinnacle Research. Thank you for both for joining us today and welcome. 

Kathleen Corey, MD, MPH: Thank you. Happy to be here. 

Stephen A. Harrison, MD: Thank you Manal, great to be here as well. 

Dr Abdelmalek: We've come a long way in the past few years with the emerging therapies in nonalcoholic steatohepatitis (NASH). In fact, the field has nearly exploded with a lot of very exciting and promising possibilities out there to see hopefully an FDA-approved compound and drug available for our providers in the upcoming few years. I hope that we can talk today about some really exciting recent data and have a chat around some of these new agents and how they can fit into the treatment paradigm once they're approved. There are certainly a few very exciting therapies, one emerging in late phase 2 clinical studies and several in phase 3 clinical studies. I hope we can have a really exciting dialogue around what our providers can see on the emerging horizon. So, Stephen, maybe you can kind of share with us some of your thoughts around efruxifermin. I know there's been some landmark data presented recently and it really is very enticing. 

Dr Harrison: Yeah, thanks Manal. I agree completely. Fibroblast growth factor 21 (FGF21) and is an endogenous metabolic hormone that has a lot to do with glucose and lipid homeostasis. So, targeting FGF21 makes sense in this metabolic liver disease called nonalcoholic fatty liver. But the problem has been, the half-life of FGF21 is short. So, pharmaceutical companies have really focused their efforts in modifying FGF21 to allow it to hang around longer. And so efruxifermin is one of those compounds in development. Now specifically, it's a bivalent Fc-FGF21 fusion protein that has balanced agonism towards 3 specific receptors: FGFR1, 2, and 3c. Now this Fc fusion scaffold and the point mutations allow for an extended half-life; the bivalent structure gives us greater affinity and stable binding. So, when we focus on the data that was presented at American Association for the Study of Liver Diseases (AASLD) that was so exciting, that centered around a study called HARMONY and that's a phase 2b randomized double-blind, placebo-controlled, multi-centered, dose ranging trial in adult patients with biopsy confirmed NASH and F2/3 fibrosis. 

And this built off of a prior 2a study called the BALANCE study, where efruxifermin showed significant reductions in liver fat content, markers of liver injury, and lipid and glucose metabolism, but histology was not included. So, in this particular phase 2b trial, as in any phase 2b trial in NASH, it's a paired-liver biopsy study--a biopsy to get in and a biopsy to get out. Now the unique thing about this particular trial is the primary endpoint was the proportion of patients who achieved at least a 1-stage improvement in fibrosis without worsening of NASH at week 24, despite the fact that this is actually a 96 week trial. So, patients are randomized to receive once weekly subQ doses of either 28 mg or 50 mg of drug or placebo for 96 weeks. But that liver biopsy primary endpoint is at week 24. 

Now, there were lots of secondary analyses done, all the ones you might expect with a phase 2, we're looking at magnetic resonance imaging (MRI) change, glycemic control, lipoprotein change, liver chemistry change, and that sort of thing. So, just quickly when we look at this particular phase 2b trial that was presented at AASLD and we focus on the demographics and baseline characteristics: generally balanced across groups of an advanced population of patients; I would say about 70% were diabetic; 66%, or two-thirds, were F3. Important to note that the biopsy reading methodology was relatively novel and consistent with kind of the new way that we're starting to read these. Meaning, in this particular case, 2 pathologists read every slide independently and then where they agreed, great. Where they didn't agree, they got together through a digital platform and assessed each of the criteria again to reach consensus. 

Now when we look at the results, just jumping to a brief conversation about that. Primary endpoint: fibrosis improvement. At least 1 stage for no worsening of NASH; we see 20% for placebo, which is about normal for a fibrosis response for placebo. The 2 doses: 39% for the low dose; 41%, high dose--both statistically significant, meeting the primary endpoint over placebo with a treatment effect delta of 19% to 21%. It gets better from there however, Manal. When we look at NASH resolution with no worsening of fibrosis at week 24: 15% for placebo; again, kind of what we would expect for a placebo response rate there. Drug group: 47%, low dose; 76%, high dose; with a treatment effect delta of 61% for the high dose. Super exciting news there. And then when we look at the combined, more rigid endpoint of both fibrosis improvement and NASH resolution: 5% for placebo; we know that placebo response is going to plummet when you try to put both of those endpoints together. But in the drug group: 29%, low dose; 41%, high dose; treatment effect delta 36%. So, from a histopathologic perspective, this is...well, there's nothing that's shown this sort of result. So, great news there. And then of course when we look at the extra hepatic benefits, which I think are critical for drugs now in 2022-2023. There were very nice effects on triglycerides around 25% to 30% for the 2 doses of drug. The high-density lipoprotein (HDL) also has increased significantly, marginal improvement in low-density lipoprotein (LDL) and some improvement in non-HDL cholesterol. On glycemic control, about a half a point drop in diabetics with NASH in this study, all comers about a 0.3 to 0.4 drop on hemoglobin A1C; C-peptide also dropped. And in the high-dose group we're seeing body weight reductions of about 2.6%. From a safety and tolerability perspective, I think we can say that it's generally well tolerated and it's certainly safe. 

The treatment-emergent adverse events were balanced across the groups, with more frequent diarrhea and nausea in the high-dose arms--or in both arms compared to placebo, but accentuated a little bit in the high-dose arm. But these were generally grade 1 and grade 2, mild to moderate. So, in general, I would say the tolerability was what you would expect with an injectable. Remember with any injectable in the field of NASH, whether it's a glucagon-like peptide-1 (GLP-1); a GLP-1/glucagon, or a GLP/gastric inhibitory polypeptide (GIP), or the FGF19s or the 21s, the gastrointestinal (GI) tolerability tends to be what we're focused on or what we see the most of. And I would say true to form, that's what we're seeing here, but in general, well tolerated. So, let me stop there and see what you guys think. 

Dr Abdelmalek: I think that treatment response delta over placebo certainly is a wow factor! Very exciting and will be very exciting to see this program transition into its phase 3 trial program. How do you think this compares to what we're currently seeing with other injectables now that are in phase 3, such as semaglutide, Stephen? 

Dr Harrison: Yeah, I think when we look at the semaglutide data, that also is a phase 2 trial design that we have data on. Remember, semaglutide is already FDA-approved for obesity and type 2 diabetes. Now they're seeking a NASH indication and they're currently in phase 3. They got there because of their phase 2 trial, which was a very large study for phase 2, about 80 patients randomized in each group. There were 3 different doses vs placebo-- treatment a little bit longer here--72 weeks in duration. But when we look at their primary endpoint, which is different, it was resolution of NASH with no worsening of fibrosis in the high-dose group, 59%; placebo 17%. So again, it's hard to compare apples to apples here; it's more of apples to oranges because these weren't head-to-head comparisons and different pathologists, different treatment durations. But you look at the placebo group, 15% for efruxifermin, 17% for semaglutide, so roughly the same there: high-dose, 59% was semaglutide, and 76% for efruxifermin. 

So, I think we give the edge to the FGF21 class here, but still a very, very positive result for the GLP-1. On secondary endpoint for fibrosis improvement, the different doses bounced around a bit. It was 49% for the low dose, 32% for mid-dose, and 43% for high dose. The problem is we had a huge bump in placebo response to 33%, arguably one of the highest placebo response rates published to date for fibrosis. And when we look back at the efruxifermin data, it was 20% in that placebo response rate. So, a little bit unfair to semaglutide here, but it did not hit statistical significance for fibrosis. So again, I think comparing head-to-head is a bit challenging. I would say, still good results for semaglutide. When you look at prevention of progression of fibrosis, semaglutide did very well there and I think it's more a reflection of that placebo response rate being high that they didn't hit statistical significance. But all in all, again, as I mentioned before, industry-leading histopathology with efruxifermin, but still very good results on the NASH resolution front with semaglutide. 

Dr Abdelmalek: So, I guess it's fair to say that we're going to be seeing some exciting data on the injectable landscape, both with FGF21 and GLP-1 receptor agonists and time will tell us to the outcome of the ongoing long-term phase 3 trial with semaglutide? 

Dr Harrison: Yeah, absolutely. I completely agree. And we have to keep in mind also that the FGF21 class, there's many drugs coming up behind efruxifermin that look very promising. And there's also the combination of the GLP/GIPs, the GLP/glucagons as well, that we need to keep an eye on for those results coming up. 

Dr Abdelmalek: Yeah. So, Kathleen, maybe you can tell us a little bit about some of the landscape with oral therapies. We have the FDA also looking at obeticholic acid (OCA) currently and possible reason to be excited about the Farnesoid-X receptor (FXR) class. 

Dr Corey: Yeah, absolutely. I think even with all these newer compounds coming out and newer mechanisms of action, I do think there's still a reason to be excited about the FXR agonist, including obeticholic acid. And just as a reminder, the REGENERATE Study was published in 2019. That was the interim results in a phase 3 study of patients with NASH and F2 or F3 fibrosis. Two doses of obeticholic acid daily or placebo, with the primary endpoints being either fibrosis improvement with no worsening of NASH or, as we saw before, NASH resolution with no worsening of fibrosis. Now interestingly in that study, the NASH resolution endpoint was not met, but the higher dose of obeticholic acid--25 mg--did meet the primary endpoint, with fibrosis improvement in 23% compared to a relatively low dose--speaking to what Stephen was suggesting--a placebo response rate of 12%. 

Now, interesting data, but there's some new data that was presented at the liver meeting just recently looking at different ways of looking at the biopsy results. So, before it was a single pathologist who was reading these biopsies and looking at the outcome and so we saw the 23% vs the 11%. In the new analysis, while there wasn't a dramatic change in the number of responders with fibrosis improvement, about 22.4%, the percent of responders in the placebo group and the obeticholic acid 10 mg group, did go down. And this was by using 2 pathologists who had to be in agreement. And if they weren't, they had a third pathologist as a tiebreaker. 

So, we did see less of a placebo response rate and a more significant than response rate when compared to the obeticholic acid 25 mg. And while we didn't see a dramatic difference, I think it really speaks to the importance now going forward of using more than just 1 pathologist reading these slides. And either, as Stephen discussed, using 2 pathologists who have to agree on the outcomes, or 2 with a third pathologist as a tiebreaker. 

I wonder what you all think going forward if you think that we should be using the 3-pathologist method or whether the 2 pathologist having to have agreement is sufficient?  I, personally, like the 3 pathologists having the tiebreaker, but it does bring a whole third opinion into the mix. 

Dr Harrison: Yeah, I think you bring up a good point. Look, at the end of the day, what we know is we want to minimize the noise of this. The variability, we want to try to minimize, particularly as it pertains to placebo response rates. And I think we've seen a couple of times now--from the efruxifermin data and now from this data, the re-look at the obeticholic acid data--that having at least 2 pathologists look at them independently and where they agree, great. Where they don't, they have to gain some sort of consensus. I think is absolutely kind of the way we're headed. 

Whether you bring a third one in to do the adjudication or you just have the 2 adjudicate. I don't know if we know which one is better--if one is better than the other--but I think just having an additional set of eyeballs and having them bounce the ideas off of each other about why they wanted to call it a certain thing, a certain stage, or a certain grade, I think is important. What I think is going to be interesting is where artificial intelligence (AI) digital pathology (path) comes into play here as a companion; look, it's almost like an open-book test. If you have the AI digital path sitting right next to you and you're looking at the digital slide, you're saying, "this is a computer read, and this is what I'm seeing." And I think it just adds another layer of validity to what they're going to call. 

Dr Corey: Absolutely. I really see a big role for that. And maybe that will be the third pathologist, is the AI readings helping to adjudicate. 

Dr Abdelmalek: And certainly, the strength of some of the other surrogate markers that are predicting disease outcomes that are non-biopsy-based are going to play a role in how regulators deliberate the outcomes of these trials. So, fortunately, we have a good armamentarium of tools that might aid and help our pathologists leverage their interpretation of slides or potentially even in the future, replace the biopsy altogether. So, time will tell how that unfolds. 

Dr Harrison: Manal, can I just add one more comment? I think one of the important things about the obeticholic acid data that were presented at the liver meeting was the additional safety data. Because now we're looking at, if I'm remembering right, 8000 patient-years' worth of data. So, over 1000 patients treated for at least 4 years now with OCA. And what I was encouraged by was it looked like the LDL spike returned to baseline--even if you weren't put on a statin--it kind of returned back to normal. We didn't see any increased cardiovascular (CV) outcomes in the patient's on drug. Yes, there were some issues with gallstone formation and maybe cholecystectomy, but I didn't see a lot of liver injury popping up as far as certainly Hy's law. There was some elevated liver chemistry test without evidence of liver synthetic dysfunction and I think we still need to work through some of that. But all in all, I think encouraging to see that, again, even at the high dose, there were a lot of patients showing stability across safety. Another thing I didn't mention is pruritus. It's still there. We still have some dropouts from that, but I think one of the important things with the dropouts from pruritus is there was a built-in protocol where they had to drop out if they reached a certain level of itch. So, I'm anxious to see if the new drug application--they say they're going to submit it by the end of the year--if this gets a favorable look from the FDA this time around. 

Dr Abdelmalek: I would agree with you, Stephen. I think the safety data that was presented at AASLD was very encouraging. It certainly is the largest, most robust data set we have with the longest follow up. And we have to keep in mind that patients with nonalcoholic fatty liver disease (NAFLD) and obesity have a background risk of cholecystitis and cholelithiasis. So how that compares when data is unblinded would be interesting. But so far it certainly has demonstrated the test of time for safety and it'll be interesting to see how the FDA and regulators plan on that. Let's make a little shift here. Another very exciting compound, resmetirom, in the treatment of NASH that's led us into both phase 2 and phase 3, now, clinical trials. 

Dr Harrison: What I want to talk about next is the MAESTRO-NASH phase 3 trial. And here, this is the trial that was put together to achieve subpart H approval--or conditional approval--for the drug. And I want to dive into that right now. So, this is the study design of that trial; again, it's called MAESTRO-NASH. It's a randomized, double-blind, placebo-controlled trial. You see the study schema on the right; 2 different doses of drug--80 mg or 100 mg--vs placebo with equal randomization of 1 to 1 to 1.  

Now you had to have a biopsy to get in, and you had to have a biopsy at week 52 and that was the primary endpoint. So, if you look down in the red, the primary endpoint was a dual primary endpoint; resolution of NASH with at least a 2-point reduction in the NAFLD activity score with no worsening of fibrosis; or, reduction in fibrosis stage by 1 point with no worsening of the NAFLD activity score (NAS); or, reduction in fibrosis stage with no worsening in NAS on week 52 biopsy.  

Now, to get into the trial you had to have at least 3 metabolic risk factors, or what we call metabolic syndrome; a FibroScan that was consistent with F2-3; a controlled attenuation parameter (CAP) that was ≥ 280 dB/m. The reason we did that is we wanted to minimize screen fail on magnetic resonance imaging proton density fat fraction (MRI-PDFF), which was set at 8% liver fat content.  

And parenthetically, when you set that cap at 280 dB/m , you get a screen fail rate of around 17% to 20% when you set your MRI-PDFF at 8%. So, just something to think about for future trials.  You also had to have a NAS of 4 or more, with fibrosis stage 1A, and this was limited to about 3% of the population; or stage 1B, which is more representative of stage 2, quite frankly, and a total F1 population of up to 15%. The F3s had to be at least 50% of the trial and the rest were F2s.  

It's important to note 2 other important factors. There was a key secondary endpoint on LDL cholesterol lowering, not at 52 weeks but at 24 weeks. And there was a composite liver-related outcome slated to be studied over a 54-month time point, to reach a certain number of adjudicated events. And those events were evidence of cirrhosis on biopsy; Model for End-Stage Liver Disease (MELD) ≥ 15; hepatic decompensation; liver transplant; or all-cause mortality.  

Now, moving quickly through the baseline characteristics, what you can see is this is very well distributed and very representative of an advanced NASH population. And one way you know that is when you look at female gender. Whenever there is a predominance of females in a clinical trial for NASH, there tends to be more advanced disease. This was also supported by our FibroScan vibration-controlled transient elastography (VCTE) at baseline between 13 kPa and 14 kPa, and you see our baseline NAS ≥ 5, where 80% to 90% of the patients in these cohorts had lots of disease activity and more than 60% of the cohort was F3 across the different groups.  

So, looking at the primary endpoint, the first one being NASH resolution by intent-to-treat (ITT) at week 52 using the primary statistical model that was laid out in the statistical analysis plan. You see a dose-response relationship highly significant for both doses relative to placebo, with the high dose achieving about a 20% treatment effect delta.  

Now, it's important to note that this is ITT analysis. That means any person getting a single dose of drug were counted in the analysis, regardless of whether they had an end-of-treatment liver biopsy or not. That means if they did not have an end of treatment biopsy, they were counted as a null responder.  

That's just important to note because when you see these phase 3 trials read out by ITT, you sometimes think, "Well, the treatment effect was not that great." Well, remember you're throwing out quite a number of patients that didn't have an end-of-treatment biopsy. And historically in large clinical trials with paired liver biopsies, you can expect about a 20% dropout rate.  

Now, when we look at fibrosis and improvement of at least 1 stage or more. Again, similar dose response relationship treatment effect delta of around 12% for the high dose. So, both endpoints were hit in this particular phase 3 trial; very, very encouraging.  

Now, it was also looked at through a different lens methodologically, this was done a priori at the beginning of the trial. This is not a post-hoc look; this is just another way of looking at the data histopathologically and this is the consensus assessment approach.  

Again, very, very similar results for NASH resolution, you see 28% vs 8%. Treatment effect delta again is 20%. And fibrosis, 26% vs 12%. Treatment effect delta 14%. So, whether you looked at it in the primary statistical model or in the consensus model: highly significant for both endpoints, treatment effect delta is about the same.  

Key secondary endpoint I mentioned at the top here in reference to this particular trial was LDL cholesterol lowering at week 24, again by ITT. And you see a dose-response relationship again relative to placebo with about a 16% reduction or a 17% treatment effect delta on LDL lowering with a high dose.  

Now, as far as safety, it's important to note that resmetirom is safe and while tolerated. This was previously shown in the very large NAFLD-1 trial. This is again confirmed here.  

You see serious adverse events equivalent across the board from the 2 dosing groups to placebo. Study discontinuations for adverse events slightly numerically percentage-wise higher with resmetirom 100 mg. And you see that this is mainly due to 2 GI-related adverse events, that are diarrhea and nausea. The nausea tends to be more in females and more early on within the first 12 weeks; the diarrhea tends to be more of a loose stool that occurs more commonly in the first 12 weeks and then tends to mitigate a bit over time.  

Dr Abdelmalek: Another exciting compound. So more to come with resmetirom, certainly. Kathleen, I know we've seen some data with a peroxisome proliferator-activated receptor (PPAR) lanifibranor, exciting phase 2 data and a drug that's currently also in phase 3 clinical trials. 

Dr Corey: Yeah, absolutely. I think the lanifibranor is an interesting investigational compound. It's a pan-PPAR agonist, as opposed to things like pioglitazone and lanifibranor, and therefore hitting all 3--alpha, gamma, and delta--receptors. And we saw that in a study that was published in the New England Journal of Medicine in 2021, that those patients who received 2 doses of lanifibranor met the primary outcome compared to those on placebo, fairly significantly. They were using the steatosis, activity, and fibrosis (SAF) score, which is different than what we see a lot in NAFLD activity score, but even in primary reduction in SAF score improvement of fibrosis improvement in NASH resolution, we definitely saw exciting results with lanifibranor. And what they presented recently at the liver meeting really showed some other exciting ancillary data that lanifibranor had positive effects on markers of cardiometabolic health. Specifically, they saw an increase in adiponectin as well as beneficial effects in markers of lipid and glucose metabolism and an insulin resistance. 

There is some weight gain associated with lanifibranor, like in many of the PPAR agonists, but interestingly, that was a weight gain that was associated with improved insulin sensitivity. So, seemed to be if you have to have a weight gain, then a metabolically healthy weight gain, if we think about it in that way. And then further, really looking at biomarkers was something that they focused on at the liver meetings and just recently validating the FAST score. So, the FibroScan-aspartate aminotransferase (AST) score as a promising noninvasive test for active NASH with fibrosis. And also, they identified a signature interestingly, that could predict with a sensitivity of 70% and a specificity of 95% NASH resolution and fibrosis improvement. So, they looked at baseline adiponectin, baseline ferritin, and relative changes in MMP-9 and transferrin at the end of treatment, and they could predict who would have NASH resolution with fibrosis improvement. So, 2 ways that we're really trying to push past the need for liver biopsy that were validated in studies with lanifibranor. 

Dr Abdelmalek: That's exciting. We've now talked about literally 5 different classes of compounds from an FGF21 to a GLP-1 receptor agonist, an FXR, a beta thyroid hormone receptor agonist, and a pan-PPAR. Thinking about the landscape here, which is very exciting, how are we going to put all this together? What is the treatment landscape you think going to look like for providers using such therapies in the future? 

Dr Corey: Well, I totally agree. It's a really, really exciting time and hopefully as the next year or 2 progresses, we'll have more options. I know you said it years ago, Manal, when you really said, "we need to be thinking about combination therapy," and I think you were definitely ahead of your time there when I think we're still looking at the combination and we'll need to be looking at combination therapies for this treatment and we'll hopefully have more in our armamentarium to be doing that. 

Dr Harrison: And I think combination of therapies are eventually going to be where we head. In the short term, I think we're on the verge of having 1 or potentially 2 FDA-approvable drugs to treat this disease, which is--I mean, in my lifetime as a physician--that has not existed for sure, and I've spent the better part of 20 years trying to find one. So, I'm super excited to think that we are really on the cusp of leaving a big fat dent on this planet, in the name of fatty liver. What is it going to look like? Well, I mean, if obeticholic acid gets approved and resmetirom gets approved, I think there will be relatively rapid uptake. It depends on what the payers are willing to allow use in and what we're going to use to diagnose. But my guess is we'll probably start much like we did with hepatitis C, with the more advanced patients and then potentially gradually work our way backward. 

What does that look like? Well, if we only have resmetirom and obeticholic acid--or one or the other--then I think that's what we use. If you gave me all 5 of these drugs, Manal, and said, "they're all going to make it across the finish line, tell me in your crystal ball how these are going to be used?" I think we have to remember that NAFLD/NASH is generally speaking relatively asymptomatic. Yes, I know there are patient-reported outcomes (PROs) that are out there that leak, patients have more fatigue, whatever. But generally speaking, when I see patients, and I think you guys see the same, they say they feel generally fine, maybe intermittent right upper quadrant pain or whatnot. So, we're going to need therapies that can be well tolerated. We don't get, generally speaking, well tolerated therapies with the injectables. Yes, if we titrate, start low and go slow, we can minimize side effects or mitigate them to some degree. 

But I still think these injectables are more potent generally speaking. We saw that with efruxifermin and even with semaglutide and aldafermin, if we go all the way back to the FGF19, so I think they're going to be used for induction therapy. Let's get them on this drug, hit them hard, treat them for relatively finite period of time. What is that? Maybe 24 weeks, maybe a year; transition them to something oral that's better for the long term. Nobody thinks we're going to treat these people for 6 months and be done with it. The other option potentially is cyclical therapy. If we really want to use an injectable, treat them for 6 months, a year, go off the drug, come back a little bit later, and treat them, I don't think that's really the way we want to do this. Ideally, we want to get them on something and maintain them in remission, if we can use that word. 

But I think that's the way I would go with the more advanced patients. For the milder patients, once we get to that part of the treatment paradigm, I think we just start with something oral and go there. Now the other thing to think about in all this is the extra hepatic manifestations of their disease. Is it a brittle diabetic? Is it a patient with super-high triglycerides? I mean, there's all kinds of patients in different perturbations of this that we need to think about, and in those situations, maybe we need to use something that's a little bit more potent on apolipoprotein B (ApoB) or LDL or glycemic control and maybe less potent on histopathology if that's not the main driver of what we think is going to impact their life. [If it's more a diabetic situation or a cardiovascular disease situation and they just happen to have a little liver disease too, then maybe that changes what we do. But I'd love to hear your take on this as well. 

Dr Abdelmalek: You know what, my take has been a little different. While I appreciate there is a little bit more complexity to using an injectable and some of the side effects, I also see that the foundation of treatment is going to be an antimetabolic therapy, whether it's an oral or an injectable. And that additional therapies would be tailored into that potentially in combination if we're dealing with somebody who has significant metabolic drivers. But on top of that, it has hepatic fibrosis or a really bad NASH phenotype histologically such that those therapies that have or hit both the dual surrogate endpoint or even just a more fibrotic endpoint could be added into blunting the metabolic upstream drivers, which may not hit those later stage injury pathways and use them dually together. Now, certainly I think for all patients, irrespective of agent, any drug that stands alone with a favorable cardio metabolic profile or can be combined with another drug that further attenuates the antimetabolic response, such as semaglutide with a PPAR, you get a little weight gain, but then you get weight loss in your net neutral with weight, for example. But you have a really defined effect on insulin resistance, metabolism, and potentially even NASH and fibrosis or combining an antimetabolic resmetirom with an FXR agonist or semaglutide with an FXR agonist. I think we're going to tailor these drugs to the phenotype of patients as we understand that better. But I'm excited to see that we have various options because as you and I and everyone knows, the challenges around these clinical trials are the various phenotypes of patients that have gone into it, and hopefully we'll be able to tease out predictors of treatment response for any drug within these classes for that unique patient. So, exciting times and more to come on this front. But Kathleen and Stephen, I thank you both for a great discussion and a great overview of our most promising drugs on the horizon of NASH therapeutics. 

Dr Harrison: Yeah, thank you for having us. It's an exciting time to be in this field and seeing what is right around the corner for our patients. So, thank you for having me. 

Dr Abdelmalek: And thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. Thank you. 

This transcript has not been copyedited.