What Exactly Are We Trying To Achieve In Early-Stage Nash Therapy?

What Exactly Are We Trying To Achieve In Early-Stage NASH Therapy? Ep 25

The Surfers and guest Joern Schattenberg consider the implications of a Digital ILC presentation stating that the liver, not cardiovascular disease, is the leading cause of death for NAFLD patients.
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The Surfers considered the implication of a Digital ILC presentation by James Paik et al. titled “Causes of death in patients with non-alcoholic fatty liver disease (NAFLD): data from national vital statistics system (NVSS).” The presentation demonstrated that liver disease, not cardiovascular, is the leading cause of death for NAFLD patients, with broad implications for treating early-stage patients. Surfers asked: If NAFLD patients “feel bad” all the time, can patient-reported outcomes become a primary measure? Shouldn’t metabolic measures remain vitally important for patients most of whom are obese and exhibit concomitant Type 2 diabetes or cardiovascular disease? And which test(s) provide the greatest support for FibroScan in demonstrating positive predictive value? A tremendous amount of content and tips from Dr. Harrison and Prof. Schattenberg. You’ll want to listen more than once!


 
Roger Green: For everyone with an interest in NASH or more broadly fatty liver disease, surf’s up because episode 25 of Surfing the NASH Tsunami starts now. Because this is the end of Labor Day weekend in the US, we’re recording on Tuesday, not Monday, although you’re going to hear it at the same time you always do. However, Donna had a full day of commitments, so she’s not able to join us today.

Roger Green: And more importantly, Peter Traber who told us about his new job a month ago, has realized that the commitments associated with this new job did not align with him being a week-in, week-out surfer, and will not be a full timer on the podcast anymore. On behalf of all of us, I want to thank Peter for everything he’s done to help us get started, and his sage insight, and his amazingly encouraging note about what the meaning of Digital ILC was is on his valedictory episode that left Donna going, “Wow,” And I think the rest of us feeling a little bit better. Peter, don’t be a stranger.

Roger Green: With that said, we are tremendously fortunate to have Jorn Schattenberg back with us tonight, partly because Joern is generally a fantastic guest, and partly because this conversation follows up on last week’s, in which he also participated. Quickly, before we get started, I want to thank our listeners, old and new. Just to report, our listener base actually increased 50% since Digital ILC began. Day Two is our top episode ever, Day Three was our second best episode ever. Preview is our third, Day One was the fourth. Therefore I want to thank all of you for listening and telling your friends. I want to thank GLI, NASH-TAG, CLDF, everyone else who’s spreading the message.

Roger Green: And let us know before we start on music, before we find a more regular source of liver music that is not various Christmas songs and other things put to cirrhosis lyrics. I think what we’d rather do instead is keeping serenaded out by music from Jeff Ramsdale’s British Liver Trust concert, which I will make a contribution on behalf of HEP Dynamics at the end of every episode. So you’ll be hearing that for awhile. Everyone tells me they enjoy it. Enjoy it. Onto our podcast.

Roger Green: This week we’re going to go back to the old formula, and I would like to ask each of you to tell me about one good professional thing that’s happened for you in the past week. Brave one go first.

Jörn Schattenberg: This is Jorn. Thanks for having me again, Roger. And I have to think for a moment last week passed quickly. One thing I’m seeing is that despite increasing numbers of COVID, again here in Europe, and Spain has been hit pretty bad at this time, Madrid. I think I see continues back to normal with the usual measures of social distancing, wearing your mask in hospitals. It feels like my clinic is coming a little bit back more to normal than it used to those last weeks through COVID. So I think this is something from my side, very positive. And of course, for patients, I’m happy we can serve them again.

Stephen Harrison: I’ll go next. So, had to think about it for a moment, but I remember last week we came very close to finalizing our NASH-TAG agenda for January 2021, and it will be an in-person meeting. There will likely be some virtual component if you can’t make it, or don’t feel comfortable in making it, but it is going to be a jam packed session for two days. And again, remember the last meeting a lot of us went to in person was NASH-TAG 2020. And so there really hasn’t been an opportunity for open dialogue and exchange. And so that first section of NASH-TAG, where we show the data for studies that have been presented and then have a chance for open mic dialogue. We’ve expanded. So professionally, I think it’s going to be really an opportunity to do a deep dive with everybody back in the NASH space, as we begin to maybe improve from the pandemic that we currently are living in.

Roger Green: So Stephen, that’s really exciting. I know lots of people are looking forward to having that kind of opportunity. I will do the one political correct moment and say that, in fact, what you’re promising is a packed and socially appropriately distance opening session.

Stephen Harrison: Yes.

Roger Green: Right. The data will be packed and people will not be.

Stephen Harrison: True.

Roger Green: Superb. Very, very exciting.

Louise Campbell: I suppose last week, a sort of positive was that I’ve been very keen to develop our fiber scan within Australia and particularly Western Australia. And we are now registered in Australia. So we are coming. So that was nice to get our registration numbers so that we can now look and develop that out in Western Australia. So that was my positive for the week.

Roger Green: That’s excellent. I had a few positives through the week, but I’m going to stay with the podcast for the first time since we cut over three months ago, we were actually now hitting our audience target numbers as a result of ILC, but I think we’ll be able to maintain that and go forward from here. And we will start talking in a couple of weeks, maybe a month, about our AASLD coverage, which I’m very excited about as well. So I think that’s plenty for right now. We can get into our main subject. In terms of questions, Ian Rowe posted another excellent question, this time on the discussion group. I’m a big fan Ian Rowe questions. I’m not going to share this one immediately, but it is part of tonight’s key question, which is one dimension of what did we learn about the NASH/NAFLD treatment paradigm as a result of Digital ILC?

Roger Green: So at the end of last week’s session, Stephen headed into a discussion. One of the questions we had thrown out was, what was the most important paper in the entire meeting or the one that’s likely to have the greatest effect for the long term of the entire meeting? And Stephen, you highlighted a paper from Zobair Younossi’s group analyzing this registry and reporting on causes of death for people with NAFLD. You want to just walk us through why you thought that paper was so important? Take a couple of minutes to do that, please.

Stephen Harrison: Yeah, sure. So, it was just for years we have given lectures and debated the outcomes of fatty liver patients. And rightfully so based on data, have said that the number one killer of a NASH patient is cardiovascular disease followed by extra hepatic malignancy, and in third place at about eight to nine percent is liver related mortality. And that was actually born out in more than one study. And now we get to Digital ILC 2020, and in a very robust set of data that was put through a scientifically rigorous set of criteria, it turns out that liver related mortality, even when adjusting for confounding variables, is the number one killer of a NASH patient or a fatty liver patient. Now that’s provocative because it turns this whole paradigm on its head and puts liver disease at the number one spot, not the number three spot.

Stephen Harrison: It also highlights what we as liver doctors have been seeing in our clinical practice, and that is more people progressing to cirrhosis. And there’s data to show that when we look at the number one reasons for liver transplant, the top reasons for liver transplant, NAFLD is the one that’s steadily increasing. So it’s not surprising what we’re seeing in clinic, what we’re seeing in the transplant center, is now actually being born out with prospective data or retrospective data, but done in a very rigorous set of analysis.

Stephen Harrison: So what does this mean? Well, I think it really causes us to want to look at where we are with our drug development, but also maybe looking at this from a slightly different perspective. And we know that from our fibrosis data, that fibrosis portends a worse prognosis. You’ve heard me say that before. And really for liver related mortality, that hazard ratio begins to rocket up at F2 disease. You could begin to make the argument two different ways. One would be, well, should we then focus all our efforts on F2 or greater, maybe F3 or greater, and leave behind the milder forms of NASH and NAFLD? Or should we look more broadly? If liver related mortality is number one, what about quality of life?

Stephen Harrison: And it’s interesting. Quality of life issues for NASH have really been put on the back burner. And I think for a long time, because we really have looked at fatty liver as being an asymptomatic disease, but more and more data is coming out to the contrary. In fact, Zobair Younassi, the same senior author on the paper that was presented that we’re discussing, has also led the way on PROs and health related quality of life as it pertains to NASH for some time now.

Stephen Harrison: And I’m reminded of a recent paper published in Clinical Gastroenterology and Hepatology 2020 in the July issue, on the real world burden of nonalcoholic steatohepatitis. And in that study, there was a cross sectional analysis of data collected July through November 2017 from the growth from knowledge disease Atlas, real world evidence program, which was reported by physicians in the United States, France and Germany. A total of 1200 patients were analyzed and ultimately the take home point here is that 48% of patients who completed the survey reported various symptoms associated to their NASH. And these symptomatic patients reported significantly lower health related quality of life than patients without symptoms. The conclusion in that paper was in the analysis of data from three countries; NASH is associated with regular use of medical resources and patients with symptoms of NASH have reduced quality of life.

Stephen Harrison: And let’s take it one step further. This has been further analyzed by recent abstracts presented by Zobair’s group at DDW 2020, where specific quality of life issues were highlighted. And I don’t recall all of them off hand, but they were quite unique and specific to our patients. And I think it highlights the fact that, while we focused our treatment on reducing fibrosis, because that is what leads to liver related death, the FDA approves drugs based on how it affects a patient’s function, how they survive, but also how they feel. So when we think about the FDA and the regulatory authorities approving drugs, it’s based on how a patient feels, functions, or survives. And so I want to highlight ‘feels’, because that’s what PROs do. They assess how patients feel. And clearly we’re gaining knowledge that NASH is associated with worse feelings.

Stephen Harrison: So circling back to your original question. I think, for me, as a hepatologist focused on the front lines of NASH drug development, it encourages me to continue to push the fight to find effective therapies to reduce fibrosis, and prevent progression to cirrhosis and decompensation, liver cancer, and ultimately death, but it also reminds me that that’s not the only thing we’re trying to make better. We also want to make patients feel better, and that doesn’t necessarily mean targeting just the advanced fibrotic patients.

Jörn Schattenberg: Very important points. Roger, if I may, I have some thoughts that I’d like to add on to Stephen’s comment here, which I think was excellent. The paper he’s been discussing, first author James Pike, I think it’s extraordinary for some reasons. It’s a new source of data we’re actually seeing here, and you have to let the data speak. So I think it’s very important you look at the absolute numbers. And I think on the test certificate basis, those numbers are real. Now there can be discussions on how many patients are actually included here: Are some overlooked? How many relative to how many patients with liver disease should that number that’s been reported in the paper be? But in the end, the number with the patients with a death certificate give you a clear number that are dying related to NAFLD. So that’s one thing.

Jörn Schattenberg: And the liver related cause comes up as the top, number one cause. And if I think back to some of the regulatory trials now, the REGENERATE Study or also the STELLAR trials, and we reported some data from the STELLAR trials on MACE in ILC. So STELLAR enrolled a little bit over 1600 patients, and actually there was only eighteen major cardiovascular events recorded in that short study period. And I think, this comes back to the discussion around subgroups. So which patients are we seeing as hepatologists? It’s going to be the ones that we preselected for trials with advanced fibrosis, potentially rapid progression that we think we’ll run into liver problems, already have based on their compensated cirrhosis. And these, we enroll into trials. In the trial period, these patients don’t particularly frequently develop cardiovascular events, and that’s one thing that shows me we’re able to look at liver outcomes and select patients with liver problems that should be treated for the liver disease to decrease fibrosis burden, as Stephen mentioned.

Jörn Schattenberg: The REGENERATE trial, also a big trial, I think there was below two percent of the participants actually developed in that study period, which is just the interim analysis up until this point, but there was a low cardiovascular event rate. So I think that’s important, and I agree that as a hepatologist, we’ll have to focus on the liver in treating and modifying risk and disease factors. And the quality of life aspect, that’s also a very important one. And in a European led study, we’re able to show that quality of life actually correlates to some of the histopathological aspects of NASH. And Zobair Younossi did a lot of work related to the degree of fibrosis. That’s a correlation. We are even able to see some impact of steatohepatitis, the degree of inflammation, which by itself has to be taken carefully with regards to which pathologists scores this and so on and so off.

Jörn Schattenberg: There’s clear data that quality of life is influenced by the liver disease severity. So in the end, what does that mean? I think the liver phenotype is driving our patients to liver end points and decreased quality of life, and we as the hepatological community will need drugs and enroll our patients to prevent these end points. And I think that’s the way forward.

Roger Green: The paradigm before the conference might have looked like: “we treat in early stages to address cardiovascular issues and we treat in later stages to address hepatic issues as well as other issues.” Maybe I’m oversimplifying, but the way I heard your comments was that we take out the phrase “cardiovascular issues” and replace it with the phrase “quality of life issues.” And That would be the major shift in the paradigm the way I’m listening to the two of you. A: Louise, are you hearing something different? Then, B: Stephen and Jörn, is that what you’re expressing?

Louise Campbell: I’m not hearing anything different. And I think the data that the paper referred to was relatively recent, it was 2017 to 2018. And I think to be able to turn, in today’s age, that amount of data around to extrapolate, as Steven said, a very well-designed and robust set of work on it was quite startling, I suppose. But cross reference that with the report out of The Lancet, the NCD Countdown 2030: pathways to achieving sustainable development goal target 3.4. Now that target is reducing mortality by NCDs by a third by 2030. Now, I’ve gone through that today and what is startling in that in comparison to this, yes, that data looked at an original data set from 2015 is what we’re comparing it to, but what has absolutely blown out of control through 176 nations throughout the world is liver cancer.

Louise Campbell: Now, they put down the primary for NCDs as obviously cardiovascular risk, type two diabetes, respiratory disease and cancer. But if you look at where the mortality is arising and the rate of liver cancer increase in all of these nations, it’s actually very interesting to put these two sets of papers together, to look at where in the world we’re increasing our mortality rate. Now, if we’ve got such a rise in liver cancer globally, it does not surprise me now to see liver cancer and mortality from liver disease being the fundamental killer of liver patients, which is sad. But the other thing is that is a disease that is an end stage liver outcome, which is a shame that the first time it appears and that people start to recognize that, as we talk about here, is that when it gets to cancer people start to recognize it.

Louise Campbell: So I’m not hearing anything different, but I do think looking at the broader aspect and bringing in where the other figures seem to correlate, or the trend correlates, there are some improvements and you could say they’re cooking the books slightly because the figures of people with all of these condition increases, but we just get slightly better at stopping them dying. So that mortality rate is coming down in some areas, but not in liver cancer.

Jörn Schattenberg: The cancer issue is obviously an important one too. And a different set of data you could look at, and Steven mentioned that briefly, is the liver transplant data sets. I think that’s a very robust data set and we have a lot of information and they actually go through hepatologist or transplant hepatologist hands in order to distinguish an alcoholic from nonalcoholic fatty liver disease. I think on the transplant list we still see more HCC from alcoholic at this point, in particular in males. Clearly decrease on the HCV patients. But for females, luckily the HCC isn’t as high, but still the numbers of transportation are increasing.

Jörn Schattenberg: So with the HCC, I think even in the pre-cirrhotic space, we have a clear dominant male aspect here and globally that’s something that’s increasingly important too.

Stephen Harrison: Let me add to that just some statistics. Hepatocellular carcinoma accounts for the majority of primary liver cancer and as of 2018 liver cancers were the fourth most common cause of cancer related death. This data comes really from a New England journal paper published in 2019 by Villanueva as the first author. World Health Organization estimates more than one million patients will die from liver cancer in 2030. In the US the rates of death from liver cancer increased by 43% between 2000 and 2016. And with a survival rate of 18% over five years, liver cancer is the second most lethal tumor after pancreatic cancer.

Stephen Harrison: And to the point that Jörn and Louise made, this rapid rise in liver cancer is not unique to the US. It’s seen or around the world and it doesn’t necessarily follow, at least related to fatty liver, a cirrhosis paradigm. There’s been increasing rates of liver cancer outside of a cirrhotic paradigm. And most of that data is generated in Asia, but it’s beginning to become more and more common to see that around the world. So it’s a real issue, the liver cancer piece to this, for sure, Louise, thanks for bringing that up.

Roger Green: So educate me, remembering again that my last natural science class was high school biology, the paper that captured me most, I’m wondering how in your minds it plays into all this, and that was the paper that Naga Chalasani presented called “Present Progression of Liver Stiffness and Development of Cirrhosis and Histologically Characterizee Patients with Nonalcoholic Fatty Liver Disease”. Where basically to recall they went into the NASH CRN Database 2 study. Starting at 2014, they were doing transient elastography on patients wherever they could, if they had biopsy proven NAFLD. They tried to correlate time with stiffness in each stage of disease and what they found was a highly significant increase in liver stiffness during F3 and no significant change at any other stage. And to the degree that anything even looked like it was close to a significant change, that was at F0 where they had a P value of 0.08.

Roger Green: So if the lion’s share of the significant increase in liver stiffness takes place during F3, what does that tell us about what to do before F3? What does it tell us what to do during and after? If we’re living in a world where we’re focusing more on quality of life early and liver cancer and cirrhosis liver disease later.

Louise Campbell: I’ll jump in on this one slightly and following up just from what Stephen said earlier about the quality of life of these patients. I think on the Younossi article that he went on to talk about cost and cost burden of NASH, he estimated that 226 billion would be spent on advanced NASH population and it was going to be highly costly.

Louise Campbell: But if we look earlier in the timelines, if you look at the Allen study from I think it was last year or maybe the year before, when they just looked at NAFLD, the amount of time these patients present to primary care physicians not feeling well, the amount of time they lose from work, their quality of life is effected well earlier than we’re looking and locating it. So purely the cost of NAFLD, I think it was $7,800 for the new diagnosis of NAFLD and annual longterm costs of $3,789. Now, that was put in comparison to $2,298 dollars for a patient without NAFLD.

Louise Campbell: So I do think Stephen’s very correct on quality of life. And I think we brought up the issue when the FDA turned down OCA for its early approval, as to the quality of life issues and why patients weren’t considered in that. So I think it does come down to quality of life, but it comes down to health care. These patients present and present and present before we actually detect NAFLD and NASH. And I think utilizing elastography or any other mechanism where we can try and locate these disease earlier, is actually going to help be cost effective. The earlier we find it, the earlier we can look at an option, and a lot of lifestyle options and changes are cheap and cost effective.

Louise Campbell: But there was also some very good papers. There was one from Newcastle that look at how patients are motivated, and bringing back to a discussion that Stephen and I had a while back with Donna, the more regular they’re seen by healthcare, the more they keep on track with changes. So I think there’s a whole host of paradigms that we can discuss and look at just on cost-effectivity of patients and the ability to control quality of life.

Jörn Schattenberg: This is really an impressive cohort. A lot of patients enrolled, over a thousand patients with liver histology, and out of the NASH CRN saw the highest quality you can get. But of course it’s an academic referral cohort. And I think we discussed this a couple of times, it’s important to look at the data that’s available for the analysis. The data clearly shows, Roger, your way. I think if you look at the data, it’s the F3 patient that advances, and it makes sense pathophysiologically to focus on that F3 patient. They’re most advanced and they’re going to reach an end point sooner than a patient in earlier stages. So if you’re working on a drug development program and you want to show a benefit in your drug in a decent timeframe, you take that patient population and you support it by data shown in this trial, in this study, that F3 patients advance.

Jörn Schattenberg: Now, the downside of this is that this is not a population based study. This is not all patients with NAFLD. This is a selected cohort. And we don’t know it’s the same in other populations. So while the data is there and it’s the correct interpretation at this stage, I think it’s always important to look at where is that data generated.

Stephen Harrison: I think Jörn did a great job of setting the stage for the trial, just to add a couple comments about the tool used to assess fibrosis, was FibroScan. And look, we know F3s progress, they progress faster than F2s, than F1s, to cirrhosis. We know that. We also know that fibrosis content is not linear. Patients with F3 have significantly more collagen than an F2, and so it just makes sense. So in a way, the data that was presented is not inconsistent with what we already know. So I want to talk to what the data didn’t show. And that is the data didn’t show a lot of F4 progression to decompensation, it didn’t show that F2s progressed. Although, if you look at the curves that were presented, the F4s almost have like a smile curve, if I remember right, and the F2s have a trajectory that’s moving up and then it kind of really begins to ramp up towards the end, but it didn’t reach statistical significance. And I just am cautious about looking at that data and understanding that the limitations of the tool that’s being used, and that is FibroScan is best utilized for it’s negative predictive value, not its positive predictive value. And that’s not a knock on FibroScan. I use it every day in my clinic. It’s literally a sixth vital sign. However, what we do know is that combining a wet biomarker with FibroScan gives us a better AUROC for predicting advanced disease and I can’t help but imagine that combining FibroScan with another noninvasive test would give us a higher yield on understanding how rapidly an F2 progresses and an F4 progresses. It wasn’t clearly demonstrated in this particular trial, so I take it for what it is. The F3s progress, I got it, that’s validation of that. But I don’t think we should walk away thinking that F2s aren’t progressing and that F4s aren’t progressing based on this one assessment tool.

Roger Green: That’s fair. I think the way I read the results, understanding all that was a little different, which is that if there is in fact a steep change at one point in the curve then it might simply change how you think about exactly what you’re treating for before and after, and exactly is really the key phrase there, right? Because if somebody arrives at F4 you would obviously want to reverse fibrosis if at all possible, because even if it were not progressing as fast at that point, or in all patients, that’s just not a good way to live and not a good functional level for the liver. And then you go back to your quality of life questions.

Roger Green: So is there something that changes in how we think about the drugs we want to use to treat and what we’re looking to see them accomplish in phase three than earlier? And the answer might be “No.” Because as you say, we’re talking about a negative predictive value, but it lead me to wonder if in fact the paradigm changes when you get to that point in disease in terms of exactly what you’re trying to do.

Stephen Harrison: No, I don’t think it does. I think it helps me in selecting the tool I’m going to use to measure it.

Jörn Schattenberg: I agree. I don’t see a paradigm change here. I think I can echo what Stephen said, I think. F3 patients are progressive. We focus on F3 patients because we have to do studies in a reasonable timeframe at this point and it just takes a lot longer as an old paper dissecting the progression of one stage of fibrosis in NASH and NAFLD, that’s a couple of years. I tell my patients, this is not a disease that’s sprinting, it’s a long distance run. And there’s a couple of time points where you can change some things. Once you get to F3 I think you need something in addition and that’s when the FibroScan here picks up the worsening of the disease.

Jörn Schattenberg: Listening to you, Stephen, I was interested, what would be your favorite wet biomarker to combine it with FibroScan to detect that? Maybe increase the sensitivity a little bit. You got an idea on that?

Stephen Harrison: Well, I don’t have all the answers here for sure. Quite simply, I use AST and FibroScan and there’s FAST out there. FAST obviously is a combination of AST cap and KPA. For the purposes of enriching for clinical trials, mainly targeting NASH with an NAS of four, with F2 or greater fibrosis. I really just use an AST above 20 and a FibroScan KPA above eight and a half. And that is not perfect, but it really begins to hone in on a patient that has some degree of fibrosis and likely some degree of inflammation. And how do we know that? Well, in the phase three trials REGENERATE and RESOLVE-IT our screen fail rate on liver biopsy was 60%.

Stephen Harrison: With application of that simple two-test rule, AST greater than 50, KPA above 8.5, our liver biopsy screen fail rate, at least within our network, is down to around 30 to 35%. Almost cut it in half by adding that. In fact, a more recent cut of the data shows if you were to add metabolic risk factors in there such as obesity or diabetes and AST greater than 20 and KPA above 8.5, you can actually get the liver biopsy screen fail rate down to almost below 30%. And I think we’re going to be stuck there until we can figure out a better way of analyzing our imperfect gold standard.

Louise Campbell: Stephen and Jorn, there was a lot said at the conference, obviously, on different sort of combinations of white markers, so FIB-4, ELF. If you were to be using those, which ones would you prefer to couple with FibroScan?

Stephen Harrison: So there’s a lot we’re learning about various markers as it relates to fibrosis. My problem with FIB-4 is the cut points depend on the age of the patient. They also depend probably on the region of the world you’re in, and maybe ethnicity. I’ve seen people use cut points of one for FIB-4. Rohit Loomba uses that. Others, 1.3, if you’re older, it’s 2.0. And really what drives FIB-4 is AST and ALT. So to me, I’m not sure I’m getting a lot more by combining FIB-4 with FibroScan as if I were just combining AST with FibroScan.

Stephen Harrison: We saw a lot of that at EASL on FIB-4. It’s attractive to people because there’s an online calculator and it uses very simple clinical data that most people get in their practice. They can throw it into this online calculator and it gives them a low cut point, which is a highly sensitive cut point, a high cut point, which is highly specific, but yet there’s this indeterminate range that’s about 30% of the population. And that’s where then people say, ‘Well, then do the FibroScan to narrow down that indeterminate range and improve the accuracy of the overall test.”

Stephen Harrison: I think at the end of the day, we’re beating an imperfect test to death and I think we need to look beyond FIB-4. If we’re going to improve our accuracy, maybe that’s with PRO-C3 or a variant of it that. So PRO-C3 is a marker of fiber genesis being developed by Nordic Biosciences, but there’s also what’s called 3CM, which is a marker of fibrosis degradation. Some studies that we’re doing, some sponsors like NGM for instance, have looked at the PRO-C3:3CM ratio as more of a holistic marker of what’s happening to fibrosis.

Stephen Harrison: More recently, NGM presented a poster at the Digital ILC looking at PRO-C3X, which is a marker of cross-linked collagen. And they compared NASH patients to PSC patients and showed that NASH patients had less cross-linking than PSC patients suggesting that it might be easier to reverse fibrosis in a NASH patient than a PSC patient. That might actually prove to be an interesting biomarker.

Stephen Harrison: ELF is interesting in the sense that there’s data that Gilliad has generated showing that greater than 9.8 predicts the development of cirrhosis. Greater than 11.3 gives you a five fold increase risk of developing decompensation and a drop of half a point is predictive of a change in histology. So that’s attractive, needs to be validated. And once it’s validated, I think it can become an attractive biomarker. Maybe combining it with FibroScan would be the way to go.

Stephen Harrison: The problem with the biomarkers I just mentioned is that they’re proprietary, it takes about two weeks to get a turnaround. And so you do the FibroScan, you order the blood tests and you’re sitting there waiting. And So for a quick ready reference in your clinic, if you had the AST and the FibroScan, maybe that’s all you need. I’d like to see a head to head comparison of that versus ELF and FibroScan or Pro-C3 and FibroScan or even I think we have data on FIB-4 and FibroScan relative to AST. I can’t remember which one is better if there is one that’s better. So I don’t know if that helps with your question, but that’s my thought.

Jörn Schattenberg: I think the FIB-4 is like the old version of your phone, and you want to have the new one. I think those markers have been around for some time and they’re very useful and they’ve been studied over and over again. It’s just something that if you think about the pathophysiology and Stephen mentioned a couple of very interesting markers that are directly related to fibrogenesis or potentially also fibrolysis. So the turnover in the liver tissue, which is physiological to a certain extent.

Jörn Schattenberg: And then if you have a disease kicking in, you change that ratio of fibrosis buildup and fibrosis degradation. The more we understand of those collagen markers, potentially also non-collagen markers, matrix markers that are in the liver, if you tease out for a certain disease that balance that’s altered through the disease process, I think we’ll get much closer in refining those to noninvasive diagnostic markers. Or potentially, and I think that’s what I like about them, they change and they predict on how things will be, because if you have more fibrosis build up, the patient will have more fibrosis down the road. So these could be very well suited to study pharmacodynamic aspects or do something prognostic here.

Louise Campbell: I agree with both sets of comments and I think getting it more accurate and I think we’ve got done about next week where we go beyond biopsy. And I think if I look at what happens, and I think you probably see them in your clinics when you look at FibroScan, you get the ones who are not fasted and it will have a normal scan. You’ll get the ones who are non fasted, get an abnormal scan. We bring them back and they’ve dropped back in to the normal range. And then you’ve got your non-fasted abnormal that stays abnormal when you bring them back. And I’m struck by the fact that the first one that’s normal has no pathway, it goes back to the GP, or if it’s got steatosis, it gets some treatment.

Louise Campbell: The abnormal abnormal stays within pathways because we’re very keen to keep them for obvious reasons. But the ones who are non-fasted abnormal, fasted normal, what do we do with those? What is it showing us? Is it showing us that our liver is slightly stiffer because we’ve obviously eaten, we’ve now increased our blood flow and is our liver creating a bit more vascular resistance? Because we know that FibroScan traditionally isn’t good at detecting F1 and F2, but maybe it’s able to tell us a bit more the more we study it and the more we do it in the real clinic world about early changes. Do either of you see those in your clinic?

Stephen Harrison: We do, we do see them in the clinic for sure. If a patient tells me that they’ve eaten and they’re non-fasted, I believe them. If they tell me that they did fast, I don’t always believe that. I’ve seen that pan out too many times with fasting insulin levels, quote unquote, “fasting” insulin levels that are super high. You only get there because you just had a McDonald’s Whopper. So I tend to just look at the reading and usually if it’s a new patient, I look at the cap and that’s going to tell me if they have fatty liver regardless of whether they ate or they didn’t eat, as long as the IQR is less than 40 I tend to believe the cap.

Stephen Harrison: And then on the stiffness measurement, if it’s low, if it’s less than six, whether they ate or they didn’t eat, I’m believing it. And I’m going to move forward with my counseling as appropriate. You have fatty liver, but no real fibrosis. So lose weight, exercise, eat less, run more, and I’ll get a little more specific with that and I’ll have them come back and see me in six months. For those people that have a high cap, meaning above 280 and a high KPA above 8.5, I’m going to tell them the same thing, regardless of whether they ate or they didn’t eat. And that is, I am concerned about your liver. You have fatty liver, you may or may not have fibrosis I need to worry about.

Stephen Harrison: We need to do a little bit more workup. I get my full biochemical and serological panel. I make sure that there’s no other coexisting liver disease. And then I talk to them about their options. Lifestyle modification number one, further workup to more clarify that fibrosis content that’s in the liver, that might be an MR elastography, it might be a multi parametric MRI, or it might be a liver biopsy. It really just kind of depends on the case. If the diabetic that I’m talking to is obese, that’s post-menopausal female, that’s Hispanic, I’m probably going to be a little bit more aggressive in my discussion with the patient.

Stephen Harrison: If it’s a thin under 40 African American or Caucasian male with no diabetes, I might have a different conversation there. I weigh the risk. I have this pyramid that I use to illustrate high risk NASH patients, and at the tip of the pyramid would be KPA above 8.5, AST above 40 ideally, that puts them in the high risk category in my estimation. And then of course, the high FIB-4, the high NAFLD fibrosis, post-menopausal female, diabetic, and BMI above 30. That’s my high risk group.

Stephen Harrison: And so I have a lower threshold to push forward with an abnormal FibroScan in that group of patients then I would, say, my low risk group that just has maybe a high KPA, but everything else speaks to low risk. And that’s a patient I might chalk up to a slightly false positive. Maybe they ate and that’s the reason, but they’re a little bit lower on my threshold to push forward, certainly to liver biopsy.

Jörn Schattenberg: So that’s clearly a very patient-orientated approach Stephen is describing. I think I handle it the same way. My ethnicity here is a little less diverse in the background, but I think the age is an important factor and you mentioned that. And I kind of take a U shaped approach to that or the other way. You tend to not biopsy young patients for purely NAFLD because you know age isn’t a risk factor. And then once they reach a certain age, you think, well, they’ve come that far, what are we really going to do with that? And how urgently do I need to establish the fibrosis stage? So I think it’s the in between, the middle aged population, that still has twenty years to go that you’re particularly worried about because they hit end stage faster. I think that adds into my risk permits and the discussion here.

Roger Green: This has been a fantastic discussion and covered a lot of really good territory. My next question, Louise, you and Donna both last week talked about the importance or the idea that a large part of therapy was simply to buy time for patients until more better came along. How does any of what we’re talking about today or what we talked about last week change the definition of what we’re buying time for or who we need to buy time for?

Louise Campbell: Is it buying time or is it actually trying to associate all of the diseases where there’s a commonality? I think if I look at the MCD from the Lancet that came out this week and I compare it to the study we were talking about at the beginning about liver-related mortality being the biggest cause of death in patients with NAFLD and NASH, I think I’m struck with the fact that we don’t identify a disease that is attributable by facts and figures and all of the research that’s coming out either digital or in the conferences before.

Louise Campbell: Where it accounts for nearly 70% of those patients with hypertension or over 60% of those with type two diabetes. If we’re going to separate an NCD like hypertension or diabetes or cardiovascular disease, and we’re looking at risk prevention, then the earlier we locate the common part of those diseases that we can target multilaterally through all of the other diseases they’re connected to, we can come up with more effective strategies. So it’s not just buying time for those patients with liver disease. And Donna was right when she was saying to Vlad who was very much of “I’m a liver doctor, I want to only treat liver”. She was right. Dead’s dead. It doesn’t matter which doctor or which disease profile we have. The liver doesn’t just think singularly.

Louise Campbell: So I think we have to go beyond that. Personally, I think we have to not only buy time to get better treatments and better scenarios for NAFLD, but by locating liver disease in any of its formats early, we buy time for those people who can be prevented from developing type two diabetes or cardiovascular disease. There was a paper that got presented at the Global NASH Symposium in February and I think it was redone again recently in a publication where they looked at mice models and they had a mouse on its normal diet, a mouse on a high fat diet and a mouse type on a fast food diet. And they were lipidemic mice and they’ve got a mouse model out.

Louise Campbell: But within twenty-four weeks, these mice had arteriosclerosis and cardiovascular disease on the fast food diet. And I think if we avoid looking for the common disease in all of these NCDs, then we are missing, we can’t see the wood for the trees. Anywhere where you’ve got a disease process that takes up more than 50% of the cohort of patients, it has to be front and central. So that’s the time I’m talking about. Donna may have a different idea of that and she’ll be here next week, but it’s not just time for NAFLD and NASH, it’s time for every other condition where the liver has any input. And the more we find out about liver disease, the more we’re finding how many disease processes it’s actually involved in. So maybe ruling it out before we continue may be a better strategy than waiting to rule it in at a late stage.

Jörn Schattenberg: I think that’s a set of important points, Louise. To me, the reason, again, I think I mentioned that before, the reason we’re studying pre cirrhotic and cirrhotic liver

Jörn Schattenberg: is because if you run a trial, you have to reach an endpoint that has been agreed on with the regulators in a reasonable time. The ongoing registries we’re seeing in Europe and in the US that enroll all patients of all fibrosis stages and continue these patients looking forward, will be able to answer some of the questions which end points are reached by which patients in what timeframe beyond those clinical trials that cannot normally afford to enroll in F0, F1 and then wait for a liver endpoint to establish. And I think that’s the important thing. As a hepatologist, I know where I feel this is important for my patient, but in the clinical trial landscape, we’re just bound to those end points arising within a reasonable time. So, that’s my take on why the focus is so much on that, of course.

Roger Green: Apropos of what Stephen was saying earlier about quality of life. Does that mean that a quality of life endpoint might be a benefit if somebody decided they needed to go do, or chose to go do trials in earlier stage patients?

Jörn Schattenberg: I think Stephen should comment on that again, but from a theoretical standpoint, you could get a drug approved based on improvement on quality of life. You have to show your tool applies, or is in concordance with FDA requirements. I think there’s one drug that has been traditionally approved for quality of life endpoint, not in hepatology. I think it’s an important point. You want to show a quality of life changing as I understand the disease depending on your mechanism of action and side effects, obviously, but improving NASH should have an impact on quality of life in your patients.

Stephen Harrison: It’s interesting as we learn more about NASH and we learned that patients feel bad in a lot of ways. I think one of the mandates that the agency has laid down is they approve drugs based on how a patient improves relative to how they feel. And as Jörn mentioned, I think the precedent is already out there for that in a different disease state, but there is a very prescriptive way to develop, and validate the PRO tool that’s being used. And I think very rigid and strict set of guidelines that have to be met. So it’s not just as easy as taking something like maybe the CLD queue and just testing it on a couple of hundred people showing that there’s a difference. And now you get the drug approved. I think it’s more complicated than that, but to your point, Roger, it seems to me that there is a door open to develop a drug for milder, and I say, “milder” NASH patients.

Stephen Harrison: I’m describing NASH patients that have all the histopathologic features of NASH, but have less fibrosis content than or NASH with F2 or F3 fibrosis or even greater. So, I think as we learn just how impacted or NASH patients are relative to how they feel that we will have a better dialogue with the agency around developing drugs that target the PROs for patients with NASH. I just don’t think that’s really been a discussion point with the agency. It’s all been focused around NASH resolution and fibrosis improvement because that’s what has been linked to progressive liver disease. So, now shifting gears and talking about how a patient feels rather than how they survive, I think is a worthy discussion. And one that we’re really initiating here on the podcast. I mean, this hasn’t been really a point of discussion at any major meeting I’ve been a part of other than really just the education of the fact that patients with NASH feel bad, but taking it to the next level has not really been a discussion point. Jörn, have you heard of that at any one of the meetings you’ve been a part of?

Jörn Schattenberg: No, I can’t say that. If this comes up in the secondaries, maybe last bullet points and by the way, we’ll throw in a quality of life measure and everybody goes, “Yeah, that’s a good idea.” It’s fascinating. It can be a little dangerous, as you said, because to me, there are believers and nonbelievers in this quality of life thing. As a physician, I’m a believer because I know that what the patient reports and they sit in front of you and they have unspecific complaints that you have to channel through a tool in order to analyze them well and standardize. So that’s one of the challenges you need a good tool, but I think they’re pretty good tools that have been defined and that are being redeveloped and they need to be validated in a way that you can go and talk to the regulators with that tool. And then I think this can be one path moving forward, and it could be something like a conditional approval. You still might have to show endpoints on top of that, but I’m thinking of a Subpart H conditional approval endpoint here, quality of life. Yeah.

Louise Campbell: What if your quality of life outcomes were improved days back at work, a better economic impact to the country? Those sorts of ones that when we get NAFLD for example, when patients improve and feel healthier, they’ve got more energy and they’re back to work. The concentration levels are higher. So the economic impact of improving quality of life in lower disease, maybe one of the targets and end points. It may also be a cost effective analysis as to whether or not treatment outweighs the need to the economic impact of being sick.

Jörn Schattenberg: I think you can use that to talk to the payers, but I’m not sure that’s going to change the needle with the regulators there. In Europe or in Germany, that calculation isn’t too useful. I think we have a different way of thinking and looking at the numbers. Some healthcare systems are more towards the QALYs and that’s not uniformly accepted, I think.

Roger Green: Certainly not in the states, QALYs don’t do well here, historically. I think that’s accurate. I guess the point behind my last question goes back to Stephen’s comments, right at the beginning of reviewing the paper for Dr. Younossi’s group, the rationale that has historically been used for early stage treatment was based to some degree on the concept of cardiovascular disease being a critical issue here. So, if it’s not, then you can prove that you have significant effect on NASH, but then you get to the, ‘so what’, and the ‘now what’ of it. I guess my question was, this is a unique place to look, but is it a place to look for ‘so what’ because if you can find the ‘so what’, then ‘now what; I think, becomes pretty straight forward, at least on a social level. That was the thought.

Stephen Harrison: Yeah. I would just add that this is a systemic disease. I say this all the time that fatty liver is really the canary in the coal mine to metabolic sensing. And if we can get the fat out of the liver through lifestyle modification, patients are going to feel better. They’re probably going to have less risk of developing diabetes, heart disease, and maybe even extra hepatic malignancy. Although some of that is yet to be determined. So in drug development for NASH, while a lot of focus is on de-fatting the liver, where we’re able to have additive benefits on lipids or insulin resistance. I think that is going to be key. That’s going to be key, because ultimately it’s not just about the liver, right? And Louise has made this point and Donna has made the point. We don’t have a magic bullet, but if we did, it would be one that de-fats the liver, works on fibrosis, improves lipids, loses weight, and improves insulin resistance, right?

Stephen Harrison: I mean, that would be really the holy grail of drug development for NASH. And I don’t see a single pill that’s going to get us there, but we do have unique potential combinations that may be able to hit on all of those. And so I think just circling back around again, to say, look, heart disease is still important. And even if the new data being generated, vaults liver disease to the number one spot, we know these patients are at least at risk for heart disease. And it is a significant issue. So where we’re able to target that as well. We absolutely should do it.

Roger Green: I think that’s a great place to stop. So, with that, let’s move to the last question. One thing you heard today that surprised you or struck you the most forcefully?

Jörn Schattenberg: For me, the discussion was great. And we evolved around the theme of cardiovascular events in these patients, I think as a hepatologist and… I do have a better understanding of the pathophysiology in end stage liver disease. So I feel, and I think that hitting liver end points is something I address and improve in my patients. And I feel even stronger about we need trials to examine these liver end points. It should not look for cardiovascular events in liver trials too much. We need some good support to establish a benefit here for our patients.

Louise Campbell: For me, I think it was the fact that we would like to move towards patient quality of life has an end point for the FDA. I suppose. Which would be nice, and I’m sure Donna would applaud that one.

Stephen Harrison: I’m not sure I have a surprise from this podcast. It maybe more just clarification of thought around where we need to be headed here. And certainly I think developing drugs that target the outcome of survival is important and critical and fundamental to what we do, but also broadening that out to how a patient feels I think would be important as well and we are developing the tools that will allow us to measure that. And I think the first thing we’re learning is that this isn’t an asymptomatic disease, that even patients with milder disease have issues. They just don’t necessarily have issues with survival today, but they may in the future, but certainly they have other concerns that they would like to have mitigated.

Roger Green: Excellent points. The reaction I had was twofold, first of all, we started with the paper from Dr. Younossi’s group, because when you throw everything up in the air, it takes a while to figure out how it’s going to land. But the second point, I think it was the last one that Stephen made, which is the liver is a complex organ. The ways liver affects life are complex. We need to think about a more complex view of what medications will do that will help us fully appreciate the benefit that we’re bringing our patients, when we treat. That’s not a surprise, it’s just kind of… It’s not even, shouldn’t be an ‘ah ha’, but for me, it was kind of when you throw it up in the air that we get to see how it lands. This would be an exciting path. With that, we’re done for today.

Roger Green: I want to thank our engineer, Mic Wilson, Buzzsprout, who makes it easy for us to get this podcast out to you guys. Social media master, Eric Rounds, Politeia Le, who coordinates all our media, Ryan Segura, our editor. Stephen, Jörn, Louise, all fantastic points, all great conversations. And then you our subscribers and listeners will help us as we continue to build this podcast. And if you’re one of the 50% who’ve joined us for the last three weeks, tell your friends because all the feedback we’re getting from people who just found us is “Gee, why didn’t I know you existed all along?” We will be back next Thursday. wWe’ll be talking about “Beyond the Biopsy,” GLI’s campaign. Until then enjoy Jeff Ramsdale’s music, have a wonderful week, stay safe, surf on, see you on the podcast. Bye, bye.

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