What happens when seven people with diverse and divergent perspectives consider the implications of last week’s Digital ILC meeting? Professors Vlad Ratziu and Joern Schattenberg join the Surfers to reflect on many insights, some leading to clashing outlooks. From Peter Traber’s opening comments about the increasing convergence and energy around NASH to a closing discussion on how a finding on that liver disease is, in fact, the leading cause of mortality in NAFLD patients (a finding that, in the words of one Surfer, “stood things on their head,” ) this was a rollicking, passionate conversation with equal parts agreement, challenge, mutual respect and, of course, humor. Listen twice to get all the small points!
Roger Green: For everyone with an interest in NASH or, more broadly, fatty liver disease, surf’s up. Episode 24, Surfing the NASH Tsunami, starts now. Just to start, wasn’t Digital ILC fantastic? Kudos to EASL, who figured out how to put this together. A group of presenters and session chairs that figured out how to interact and keep everybody involved. On a smaller scale, our Surfers, who were attending sessions at four and five in the morning local time, depending on where in the US you lived, not you, Louise. Not you, Jorn, and then jumping on a two-hour recording session ten hours later, two days later, I’ve mostly recovered. I think we’ve got varying reports for the rest of the gang, Donna walking the dog in the rain, Stephen saying he needs another week. The rest of you we’ll see about as we go along. Okay. In addition to the five regular Surfers, we’re fortunate that Jorn Schattenberg was able to come back and join us again today. Jorn, great to have you. Thanks for being with us. Then just one more thing before we get started, I want to thank you, our listeners, for staying with us through this coverage, including today. Five of our six largest days since the cut-over are the days since last Thursday, when we recorded our first pre-session. We’ve had 400 listeners check in so far to listen to this podcast in twenty-one different countries. Thursday’s preview was our largest 24-hour audience until Friday. That was our largest 24-hour audience until Saturday. Y’all slacked on Sunday. But it’s been pretty good. We’ve grown over twenty people in the LinkedIn bulletin board, and we now have, actually, Vlad Ratziu, who’s joining us as well. Hi, Vlad. How are you?
Vlad Ratziu: Hello, everyone. Hi.
Roger Green: We now have Vlad with us as well, which is superb. So we’re not going to have to use any music, because I suspect this session may run a little bit long, and we’ll have enough to do anyway. We’ll be back on next week.
Roger Green: Onto the podcast. Let me start with this, just throwing it out to the group, different question than we usually have. What was the one thing you liked best about Digital ILC? Brave one, go first.
Donna Cryer: I love being able to sample so many different tracks, so many different types of presentations and areas of liver disease without running from hotel to hotel, jumping in cabs, Ubers, and the like. So being able to hear so much more of the science than I normally would was really exciting.
Peter Traber: I enjoyed being on my computer and being able to go and pull up papers that I might have on my computer, do searches about the presentation, and kind of learn across the whole medium while I was listening to presentations. So I found that to be a useful way to work.
Jörn Schattenberg: I found myself multi-channeling. I liked the digital channel setup, and I actually flipped back and forth. I think it was a little easier than changing meeting rooms. But on the other hand, as mentioned before, you really miss meeting people in between sessions. So I think both ways, but clearly in the future, I hope to meet in person again.
Louise Campbell: I think I shared both Donna and Jorn’s perspective on the conference, but the other thing I liked was being able to spend time with the posters, and some of the posters had presentations with them. That, I very rarely get to do when I go to the international conferences, because there’s just too many people usually around the poster. You try and skim-read quickly to try and get in the information so that you can move on to allow somebody else close. So I think that, I enjoyed really well this year.
Stephen Harrison: I would echo everything I’ve heard. So three major things I really liked about it, the ability to flip back and forth from one presentation to the next without having to run from one venue to another venue and being stopped along the way. Now, that’s pluses and minuses, because you have these mini network sessions that occur while you’re running from one place to the other. But for the purposes of just seeing a lot of content, it really allowed me to see more content. In fact, I would make the argument of maybe the past five years, whether it’s EASL or AASLD, I saw more content digitally than I did in person. Also, I’m up close and personal. I’m looking at the slides from a foot away, maybe two feet away, rather than, in some instances, being in the back of the room.
Stephen Harrison: The other thing I thought was intriguing was that having had to do these lectures, I was held to a ten-minute hard stop on my recording, which gave everybody five minutes for Q and A. It really opened up the opportunity to interact, whereas in a real live venue, many times, speakers go over their ten-minute allotment and there’s only time for one or two questions. I think there was a lot more interaction that happened because of the digital platform. Having said that, I’ve got some things I don’t like about it, but we’re not at that point yet.
Roger Green: Vlad, you in a position yet to talk about one thing you liked about the event. I know there were things you had issues with.
Vlad Ratziu: I don’t know about many things I liked about the event, other than not having to travel. I think it’s absolutely terrible. I totally missed learning from discussions with others. I totally missed the whole ambiance, the whole thing of people going to the microphone, asking questions, discussing with someone sitting next to you about the result that’s just being projected. I think it’s terrible. It’s really bad.
Vlad Ratziu: Of course, I understand you can do a PubMed search at the same time, but you can do that at AASLD as well. They have wifi. You have your computer on your lap. Honestly, I think we learned so much less, and it’s not only the meeting. It’s also when you meet people on the corridors, in between the meeting rooms, outside the convention center. There’s so much more opportunity to discuss the results, to share what other people say. Also, a lot of people are not interested in asking questions that are just by sending a text message. So you won’t find these people. For instance, I didn’t do it at all. So it’s a lot of opportunity lost, and it will be very sad if we have to move that permanently to this type of meeting. Very sad. I mean, it will lose a lot of interest. Let’s just publish the papers then.
Donna Cryer: May I add one thing to Vlad’s points, which I absolutely agree with? Because we had several people from the Global Liver Institute attending, we had set up a Slack channel just for discussions during the meeting. Sometimes several of us were attending the same session. Sometime we were in different sessions, sharing screenshots, comments, thoughts in real time. So it created an interesting feedback loop and discussion group. It wasn’t quite as good as whispering to the person next to you. But to the point of not attending a meeting alone and in isolation, it did solve a small portion of that.
Roger Green: I think there were both pluses and minuses. The two things that caught me as pluses, number one was … Peter and I actually talked about this during session at one point. I think there were more questions. I’m not sure that’s a good thing or bad thing, but there are people who are shy about getting up and going to a microphone, or by the time you think of the question and you go to the microphone, you’ve moved on. As Stephen pointed out, there might not be time at the end. So it felt to me like there were more questions and questions coming faster. Then a small selfish thing, which is that I can’t take notes except on my computer, and the ability to take notes on the deck as it was going actually left me better organized when it was done.
Vlad Ratziu: Roger, there were more questions probably, but the questions weren’t necessarily better, and here’s why. When you have people like Stephen, like other guys that go the microphone, ask the question, formulate it in an elegant way, you get much more things that are expressed to us and conveyed through the question than just writing one line and a half. Some questions are too complex to write in two lines. So I think you do get possibly more questions, because there’s more time, as you said, but those questions aren’t necessarily the most interesting ones, because they have to be formulated in a short Twitter-type style.
Roger Green: There are things from that that might be worth bringing into this and things to learn that we can learn how to do better. We get to figure all that out as we go along, because at least the next couple of events will be digital. Hopefully people will learn as they go along. But I think EASL, for not really having a roadmap or rule book to work from, I think did an admirable job of anticipating what they could in going forward.
Roger Green: We had one question that came in during the bulletin board that I wanted to share and I wanted people to comment on. And then we’ll go to the epicenter itself. Okay. This is for Ian Rowe in the UK, and he wasn’t sure the clinical end points were the only way to put clinical trials together, and the comment was, “The evidence we have indicates that this will likely overestimate the true benefits of treatment to patients in terms of reduction of clinically meaningful end points, decompensation, HHC, and liver-related mortality as patients die from competing causes. The current treatment paradigm, in my view, envisions bespoke treatment with a specialty price tag. The magnitude of likely benefit to patients with F3 or less is likely to be modest and more akin to primary prevention strategy for heart disease, like a statin, where high-volume, low-cost drugs are king. If the trial designs don’t fit the problem or the final market, how will clinicians know how to use the drugs, and how will patients be able to understand what benefits they might get from treatment?”
Roger Green: I want to throw that out to you folks and see what thoughts you have on that.
Donna Cryer: I think that’s ignoring the value of time. Even stopping progression of fibrosis allows us time for a variety of interventions, whether that’s lifestyle or PO or what have you. I’m not just a liver patient. I’m also an IBD patient. Throughout the past three decades, I have been so grateful to be just one step behind the latest innovation, and now having been on every class of IBD drug and maybe needing the next, they bought me time. Time to the next innovation, time for some interventions that have sustained me. So I think the question has too narrow of focus and ignores the value of stopping progression and giving us time.
Roger Green: As a metastatic melanoma survivor, I definitely agree with that. When I got sick the first time, close to ten years ago now, my comment to my wife was that all we had to do was keep me alive long enough for the drugs to catch up, and, eventually, they would. Now, I was fortunate. I wound up doing okay even before the checkpoint inhibitors arrived, but I totally agree with you that if you’re in a severe situation, what you’re really rooting for is to stay one step behind science. Other thoughts?
Louise Campbell: I just had another thought, but it’s more in agreement with Donna’s point on time. The more we can get to early diagnosis or early location, the longer the time those individuals have, because there is a certain quality of self-care, self-wellness that they can instigate, those lifestyle changes with support. So the earlier that we locate disease, whether or not it’s cardiac, but through cardiovascular routes, Type 2 diabetes, a lot of these came up during the conference, but the more we go for early location, the longer the time becomes and the greater the effect that the patient can have or the person can have on their own health to even extend time longer, where we come up with new techniques, new treatments. So I suppose that supports a lot of what Donna was saying there. But I understand where he’s coming from on that.
Stephen Harrison: Yeah, I would agree with the comments made by Donna. We see people all the time where we’re just trying to extend … We’re trying to help them, but at the same time, by having them in a clinical trial, whether the drug is working or not working, we’re able to continue to dialogue with them routinely about lifestyle modification. We’re able to better assess where they stand with their liver disease, if they’re progressing, if they’re staying stable or they’re regressing. We have a better handle on where they are in their disease process. So I agree with the comments made.
Roger Green: With that, why don’t we dive in? I sent out just for the audience, I sent out a note to the Surfers offering everybody a chance to respond to one of four questions. I’ll read you the four questions, and then I think we’re going to start with Jorn, only because Jorn’s the only person maybe in the history of this podcast who never got to answer at the end of the episode what he found most interesting. No one got to answer on that episode, but the rest of us had done it before. So I think Jorn, we’ll start with you, if that’s okay.
Roger Green: Here are the four questions. Number one: what one thing did you believe heading into Digital ILC that you believe more strongly now? Two: conversely, what one thing did you believe heading into Digital ILC that you now question most strongly? Three: which of the presentations that you personally discussed on the podcast, do you feel will have the greatest long-term impact on how we diagnose and treat fatty liver disease, and why? Then four: from where you sit, what one unresolved issue might we actually answer in the next year or two that will have the greatest potential to improve real-world patient outcomes?
Jörn Schattenberg: All right. Great choices, Roger. Thank you for letting me go first, too. I think I’m going to start top up. What one thing you believed heading into Digital ILC do you believe more strongly now? I think, looking at all the great clinical trials, the presentations on substances and the prediction of outcome is something that will be in the main focus. We have to understand which patients do respond to drug, to actually subclassify and better define the inclusion into trials, moving ahead. I saw a lot of abstracts. I’m thinking of the resmetirom data that Rohit Loomba presented on the MRI-PDFF reduction and prediction of histological response. I’m seeing super responders emerge. If you reduce MRI-PDFF by 50%, you do better than you reduce it by 30%. It’s the linkage of those surrogates, which we know are important in the disease pathology, and now we can actually measure them more precisely.
Jörn Schattenberg: I’m not convinced it’s going to be MRI-PDFF in the end, but it’s a technique that’s being run in all these trials, and I think we’ll end up with a composite score potentially combining artificial intelligence, a magnitude of imaging, and blood-based biomarkers. Now, I know that’s hard for the regulators, but we’ll have to better understand the complexity of the disease that’s pathophysiologically interacting at various levels. We’ll have to use some markers, combine them potentially with artificial intelligence to predict which patients will respond to outcome.
Jörn Schattenberg: I think after Digital ILC now, seeing data also from the post-hoc analysis of the obeticholic acid trials, Jerome Boursier presented data on NITs there to understand how the course of NITs is. They didn’t show the linkage to the histology data yet, outcomes, but I think that’s one way, moving forward that I do believe stronger, and we’re closer to defining patients that do respond to drug.
Vlad Ratziu: Just to add something to this, I think all these abstracts that attempted to show changes in NITs in these well-designed clinical trials, this is, of course, extremely important to see whether, in a trial setting, the NITs are tracking histological changes. But it’s very important also to understand that there are several levels of analysis here, and most of the time, what is presented is just
Vlad Ratziu: how did the marker change between beginning and end of treatment in the active arm versus placebo. And since you know that the active arm improves histology say, and then you show that the marker goes down in the active arm versus, it doesn’t change in placebo. You say, you go for victory, but that’s not a very good way of testing whether a marker is appropriate for that purpose. What is truly needed in addition to this analysis, would be to look whether a responder is defined histologically and non-responders differ in the kinetics of these noninvasive markers. In other words, does the noninvasive marker stay the same in non-responders, and is reduced in responders or not. And that regardless of the treatment arm, in particular, in the active arm, because that would be the only thing that would make it useful in clinical practice.
Vlad Ratziu: It doesn’t serve any purpose to know if the marker goes down, if you don’t know whether you can trust that to predict that the person was a responder. And this type of analysis wasn’t… It’s not yet presented for most of these abstracts. And it will be extremely important to know. And once you know that once you have shown that indeed there is a difference. The two curves diverge, the one in responders dives more than the one in non-responders, even that is not enough to make it a, truly to make it a tool to predict response. You would have to determine thresholds to measure how sensitive it is, how specific and all this methodology for diagnostic tests. And maybe you can make a test out of it. Maybe not.
Stephen Harrison: Yeah. And I’ll further that a bit. This is Stephen. So think of alpha fetoprotein for liver cancer. It’s not elevated in all people with liver cancer, but if it is, and you ablate the tumor, you resect the tumor, you treat the tumor, and alpha fetoprotein goes down. Not only is it a marker of a regression in disease, but as the marker comes back up, it’s a marker that disease has returned.
Stephen Harrison: And that’s another place we need to take these biomarkers. You put somebody on therapy, you follow their noninvasive test. You show that it goes down by the magnitude of effect size that we know is linked to histopathologic improvement, and then you stop the drug. And then you can use that marker as well, hopefully, to show that once it reaches a certain threshold, we need to re-institute therapy, or we need to change therapy, modify therapy, add therapy, or do something. So it’s a little bit of an extension taking that noninvasive test, not only to show that it’s linked to improvement, but also that it’s linked to recurrence down the road. I think that’s ultimately were we need to be with these NITs.
Jörn Schattenberg: Yeah. I have two additional thoughts after listening to those comments. And I think, both Stephen and Vlad, of course, are right on. I think we’ll see subgroups emerge a little bit, like Stephen mentioned, maybe the XY positive Nash subgroup that you can follow with a certain marker. And then, as Vlad said, a lot of those markers are diagnostic markers that we use to select and include patients into clinical trials. So I don’t think that FIB-4 is going to give us the prediction of response in the end of the day, we’ll need a prognostic or pharmacodynamic marker that is potentially unrelated to establishing the diagnosis. So it will be important to think in those different NIT categories.
Roger Green: Okay. Peter, I promised you’d go next. So why don’t you go ahead.
Peter Traber: Thank you, Roger. I’m going to take just a step back and look at where NAFLD is in the context of the liver meetings, from the perspective of looking at it over an entire professional career. In my view, I’m going to give you the bottom line up front and then tell you a little bit why I say that. So I believe that we’ve kind of reached an inflection point in NAFLD. We all know that there’s been a dramatic increase in the number of papers and so forth published over the last decade at international liver meetings. But what I see now in the field is kind of a broad consolidated approach to NAFLD and I think we’re really at an inflection point in the thinking and potential therapeutic approaches.
Peter Traber: So I started attending liver meetings in 1985, and when the ASLD was held in a single ballroom in Chicago. The focus at that time was on physiology biochemistry, and later in molecular and cellular biology of normal liver processes. And we had careful descriptions of disease. But very little therapeutics. Of course, all that changed with hepatitis C 1989, the hepatitis C virus was identified, in 1998 we had interferon and ribavirin approved and diagnostics continued to advance. And then in 2013, a long time after the discovery of the virus, we had direct acting antivirals that were approved. And now hepatitis C is in a global consolidation process with the focus on bringing therapy to everyone with the disease, and get closer and closer to a total cure. As we’ve seen that happen, we’ve seen the rise of NAFLD and the issues related to that.
Peter Traber: Now, let me just see, I looked up a few numbers. By 1990, there were thirty-nine articles with steatohepatitis in the title. Thirty-nine, that’s it. By 2000, there was 417. At that time, there were over 17,000 articles with hepatitis C in the title. By 2010, there were 3,800 steatohepatitis. And this year there are 11,000. And there’s still not even close to the 110,000 hepatitis C articles that are out there. So there’s been this big shift. Everybody recognizes it. So why do I say, I see this year, maybe last year as kind of an inflection point? What I’m seeing is a true consolidation of efforts around NAFLD. We’re seeing patient advocacy, like Donna’s group, we’re seeing medical and government groups getting together and thinking about disease awareness. We are seeing primary care doctors and hepatologists and tertiary care focused talking together and trying to increase disease awareness. I’m not saying there’s not a long way to go, but we’re seeing that really develop.
Peter Traber: Noninvasive testing is being looked at kind of across the board. Experimental therapeutics, clinical trials of novel therapeutics. And then finally, we’re seeing a lot of genomic and personalized, targeted medicine being thought about and brought to bear. And what I am seeing from a historical perspective, some of the things that I saw with viral hepatitis C, where lots of different groups are coming together and focused on a disease with a large unmet medical need. This past weekend not, might not have been the exact inflection point. This year, last year, and going forward. I think we’re seeing an important shift in our focus on NAFLD and I believe frankly, that it bodes very well for accelerating and rapid progress in the area.
Peter Traber: So I thought I’d just give that bit of a historical perspective. Having seen this liver field grow over the years.
Roger Green: Donna, I see you nodding.
Donna Cryer: That was a wow. And a thank you. For putting that in context. That was really fantastic, Peter.
Roger Green: Thank you, Donna.
Roger Green: I think I have to agree. I mean, having spent the last thirty years, not living primarily in liver disease, but at different points of my career, working with clients who are in different diseases. You get these moments where things start to explode. And usually the proliferation is proof that investment and focus will lead to results on a different level.
Roger Green: I kind of had that feeling in NASH-TAG in January when people talked about how much bigger NASH-TAG was than it had been the year before. Not just bigger, but also more diverse in terms of who was there. And I certainly track that point when we talk about this Peter. I don’t have your thirty years of experience, but it feels like the right pattern, the stream is clearly getting wider and the water’s going faster.
Stephen Harrison: Peter, this is Stephen. Thank you for that historical walk through where we’ve been and where we’ve come with both Hep C and NASH. I would say to your inflection point, maybe just a comment and embedded in that is a question. It seems to me looking back on hepatitis C, that the real inflection came with the approval of a drug, because then, the marketing campaigns began the real outreach to patients and the real push into GI offices to use therapy and subsequently even to primary care.
Stephen Harrison: And my hope was, with fatty liver, that we would, we would hit that point this year. And unfortunately that did not happen. So I guess it’s a question in the sense of, do you think that the real next push will, will be when there’s an approved therapy? Because there will be a huge marketing campaign behind it. And the reason I asked that to you is because, one of the things that I still feel like is unresolved, the presentation GS 08, general session 08.
Stephen Harrison: It was from the UK and it was the primary care clinics basically showing us that we’re still doing a really poor job of identifying these people early. We’re doing a poor job of identifying them late, but certainly not picking them up early. And there’s just so much work that still needs to be done there. And I feel like through all the efforts that patient advocacy groups are making, like Donna and Wayne and then the work that Louise is doing and the efforts that we give giving lectures and talks, and all that. Ultimately is only going to get us so far. And we’re going to need to have the drug rep in the office, holding up the flashy monograph, showing these figures and showing therapy before we really reach critical mass in identifying even 30 or 40% of people with disease.
Peter Traber: Stephen, I think that’s a very good point and I, like many others, are disappointed that we don’t have an approval of the first drug in NASH this year. I think that the inflection of approval of interferon and ribavirin, wasn’t a very important step, although I never particularly liked treating my patients with interferon, but we all did. But I do think that the energy around the disease was maybe put into a bright light with the approval of the first drug and then industry got involved. But even before that, after the identification of the virus and widespread RNA testing and so forth, there was a crescendo of activity. And what I’m seeing in the field today from at least from my perspective, is an enthusiasm across various areas, which will yield important results that will end up with approval of a drug in the near term. But I do agree with you that, that will be a huge catalyst.
Donna Cryer: I also want to underscore Stephen’s point because I agree with the essential premise, but in addition to that, I’ve heard so many doctors, not only in this context in NASH, certainly, but in general, say, if there’s not something that I can do, I don’t want to diagnose. And so a lot of the barriers to screening and identification of patients and linkage to care, come from not having an approved therapy for NASH. And so that, cultural shift and that, understandable, physician wanting to have confidence that there is something concrete that they can do for their patients to be effective and successful while they’re doing their jobs is also a reason why the marker of having an approved drug is such an important catalyst.
Roger Green: Donna, I completely agree with that. I think, however, that one thing that’s changed that will actually make the work that people like you and Louise do even more important than it’s been in other disease areas…is if you go back to Stephen’s image of the sales rep with the glossy visual and the doctor’s office, fewer sales reps get into doctor’s offices when they do, there’s less time for the glossy visuals. So the traditional modes of education to take this story to primary care, aren’t going to work nearly as well as they have in the past. And what that’s going to rely on is the energy and momentum that comes from patients and allied professionals, pushing the story into the doctor’s office and putting the doctor in a place where they need to learn to stay up with where their patients are.
Roger Green: Now. I believe that that also will happen a lot more when there’s a drug, because the people will get help more than anyone else when there’s a drug are patients.
Louise Campbell: Can I put something into the mix? That’s coming from a different angle from what Peter was saying, and Stephen is. Do we think that… We’ve heard a lot of figures this week. Donna commented on 150 times more cost of a patient with fatty liver disease on the top of a patient with no fatty liver disease or a person with no fatty liver disease- percent increase.
Louise Campbell: Percentage increase. And 87.7 billion forecast between 2015 and 2025 is the additional cost of obesity on society and healthcare in Australia. The fact that this is an overwhelming problem financially, do we think that there is a chance that sort of insurers are going to take this on because they are hosing money on patients by not finding their quality of life, day’s work lost, and just generally they have more sick time. So whilst we look at the few that we get to see that come across our doorstep as physicians and nurses and healthcare, the majority staying outside, driving those costs up, and we all know that obesity is forecast to go 63% increased by 2030. So do we think there could be a push from the other side to try and help these people, rather than the medical side?
Donna Cryer: Payer conversations have become more difficult when the approval process got stalled. Two years ago, I remember having a conversation with a world renowned economist to help me think through how to paint the picture and tell the story of the urgency of identifying and treating patients with NAFLD and NASH in an instance where so few patients are currently in the system in current costs, or at least costs that are captured as liver costs, as NASH costs. And so for many payers right now, NASH shows up as a zero and any intervention or treatment is more than zero. So how do we make a case for economic savings? When right now there is very little spending that’s identified as for NAFLD and NASH. That’s the conundrum of, as we can capture more of those costs and appropriately categorize them as a NAFLD or NASH related, it will be easier to make that case to payers, whether they’re private or government, that there needs to be action. And so that is the sort of economist dilemma that I’ve been wrestling with for the past two years.
Vlad Ratziu: If I, if I can jump in now-
Roger Green: Please.
Vlad Ratziu: This is, a fantastic discussion. And all of you made very important points. But just two things regarding the explosion of information and studies on NASH, it makes no doubt that a lot of this has to do with therapy and the ultimate pickup in society has to do with the availability of drugs.
Vlad Ratziu: And therefore all these things that happened this year, we’re at great risk that this might put a halt on the whole process. So we have to be extremely careful about, that the situation is very fragile. And it is fragile, also because we have specific challenges in NASH that we might not have had in HCV. One of them is that you can’t cure NASH as you cure HCV. So the curative aspect of a treatment adds enormous value and people are ready to pay a lot because they know that there’s cure and the cure is definitive. Now, another thing is that not only there is no cure, but a lot of these diseases are sort of preventable too. And when you have a preventable aspect to management, it’s a whole new equation to write and to solve if you want to stress the importance of drugs, in particular.
Vlad Ratziu: You know outside this circle of specialists, when you go out there at large in the medical community, people said, “We already have treatments of NASH. Is exercise more, eat less, eat better, be less sedentary. And that’s the best exercise for NASH.” And it’s true that as a preventative measure, it works really well. The problem, of course, being once you get the disease in individuals that have comorbidities, it doesn’t work well at all. But it’s very hard to fight against that. So that’s another thing that you didn’t have truly with HCV and HIV. Another thing is that while, we as hepatologists and maybe some infectious disease specialists, saw most patients with HCV. We as hepatologists, do not see most patients with NASH; they’re actually scattered across different specialties. So it is very hard really to get a sense of the whole work that needs to be done. The whole reservoir of population, the severity of the disease. We don’t see a lot of the cases including those that are severe.
Vlad Ratziu: So all this makes it a very different scenario from the viral hepatitis of course. But the strongest catalyst is of course, whether you have drugs that change the natural history of the disease. And if you don’t have these drugs, I’m very afraid that the situation we’re in can go backwards. And people might lose a lot of interest for the reasons I said: no corrective treatment, preventative strategies that are effective. The second comment is about cost. So here again, very difficult to find out what part is proper to NASH and what part is proper to comorbidity’s, when you say obesity increases tremendously health cost. Yes, it does. But that we know for a long time, we know that obesity, diabetes, heart disease that comes with it, increases the cost. The problem is how much is the liver perceived adding to those costs? And here hit another problem, which is that fortunately, most of the costs for liver in fact, are at the cirrhotic stage. You don’t spend so much money at zero, F1, F2, F3, other than monitoring and monitoring practices are not that expensive. So we have to figure out a way to understand better the costs, direct or indirect, knowing that they’re not uniformly distributed through all the early stages of disease. It’s a very complex situation and it’s still a very fragile conundrum. But we’re going the right direction, but we have to be aware of those shortcomings.
Jörn Schattenberg: I’m thinking incentively about what Vlad said. A lot of things I am echoing. And I agree with his statements. It’s always that I’m disturbed when I speak to colleagues that tell me, your patients should exercise more and eat less. Because it feels to me as a hepatologist, that’s not the reality that I’m faced with in my patients. And I know that, if I just tell this, my patient, let him go, he’ll have a variceal bleed or progress or whatever. So I think the few patients we’re seeing as hepatologist who are at risk, we really need something for them to offer beyond the good advice and structured prevention. So while I think Vlad is right, I’m always frustrated a little bit with the reality that I see in clinic.
Donna Cryer: I remember an early conversation. I remember an early conversation with Wayne Eskridge, who we all know as a cirrhosis patient from NASH who has been successful in controlling his disease through diet and exercise intervention. But, early in his advocacy, I emphasized to him, “For some people, all the olive oil in the world is not going to cure this, is not going to make them better, is not going to be successful. And so it’s not “an either or,” it’s an “and”. And I think as he’s evolved in his advocacy, he has come to recognize that.
Vlad Ratziu: Donna, I wanted to ask you, based on what Jörn said. In my practice, in my experience, it’s very surprising paradoxical in my patients. If you tell them, just go out there, eat better, exercise. They’re not happy. They’re unsatisfied with the answer. They say, “I don’t eat much. I only eat salads. I’m running two times or three times a week.” So in my experience… But here’s the question I’m asking you, is it the same from your point of, from the people you’ve dealt with? Patients want medicines and they sort of trust you more if you give them medicine than if you just give them some sort of vague dietary and lifestyle measures. And it is paradoxical. But this is what happens. Maybe there’s a bias in the type of patients I have. But do you all have this experience?
Donna Cryer: I think Vlad that you’re unfortunately, absolutely correct. I remember a conversation I had with a 30 year old Marine actually, who was mad. He was visibly upset. And he said to me like, “Are you serious? All there is, is diet and exercise?” And I was like, “Well, it’s not only. And when done at a certain level, it can be helpful.” But yes, people are not only resistant to the idea, partially because they hear diet and exercise message from everywhere all the time anyways. But there is an expectation that medicine will have more for them. Is that a reasonable expectation to have? Not all the time, but I think you’re absolutely right. That is the context.
Donna Cryer: I think of it and I talked to patients throughout my own journey, certainly as someone who has benefited a lot from medications and surgeries and therapies of various types. But it’s my obligation I feel as a patient, to give the science, give the medicine the best opportunity to work. So if I can do everything I can on my side, in terms of diet or exercise or what have you, I think that’s sort of my part of the partnership, my part of the equation to add to the medicines that are available. So that’s how I approach it in talking with people. But you’re right. The expectation is there. And in fact, yes, the credibility and trust is there, if there is something very concrete, a medicine and a surgery or something that people can have. Otherwise, why are they going to you?
Stephen Harrison: Yeah. Just one quick point. To maybe just to tag onto what Donna said. There’s actually legitimate data that’s been generated on this. Where patients are surveyed about their experience with their physician, their clinician, their appointment, and whether or not they walked out of that office feeling like they were heard and that they had a good experience. And if I remember correctly, if they walked out of there with a prescription in their hand, that they ranked that visit significantly higher than if somebody just told them a couple of things to do on the side. And it’s amazing to me. I mean, I even thought about writing down on a prescription pad, exercise and the right diet. Thinking that might actually help them reinforce that needs to be done, but it’s well-stated.
Peter Traber: Well, I just wanted to say Roger, that my only wish would be that I could make a comment that would lead to such a brilliant discussion every week. Because I think around the table, everybody has made excellent points. And I would agree with all of them. The only thing I would say is that that one opportunity is to expand what we think about physicians and nurses and allied health care professionals delivering. Because I agree with you that the patient would would like much more to walk out with a prescription for a once daily pill. But I guarantee you having been a person that recently lost twenty pounds, that if you help that patient lose twenty pounds, when they come back they’re going to be much happier with you then when you gave them a pill. Now, if you don’t give them the help and support to accomplish that, I think they’re going to be very disappointed. But once they do lose that weight, they’re going to be very happy with their physician and their healthcare services in general. We may need to think about this in a different way.
Roger Green: So two thoughts real quickly. Number one, we’ve now moved from the Old Testament to the New Testament, which is we have learned from teaching a man to fish versus give a man a fish.
Roger Green: Yeah, there you go.
Roger Green: So we’re staying biblical, we’ve just moved to the other side of the birth of Christ. But the second point, which I think is more important is we treat this like this is a liver issue, but it isn’t really, only. Think about the sources of antibiotic resistance and how much of that has to do with people with common colds and viral infections, going to primary care doctors and expecting that if they don’t get a prescription, the doctor isn’t listening to what they’re saying. Which goes precisely back to Stephen’s comment.
Roger Green: So we deal with this really all over the society. And then you get to the issue of how many people taking statins, at least in the States, I can’t speak for the rest of the world, but I assume it’s not terribly different. To some degree their cholesterol goes down, but if their cholesterol drops enough, they use that as a rationale for eating more cheeseburgers, just to pick one noted example. So this whole interplay of what people use medication to do and what they expect from medication and what they expect from doctors, is a complicated subject. And it doesn’t always work to the best benefit of health care.
Louise Campbell: I think that’s correct. But I also think picking up on what Donna and everybody’s been saying is, different people will respond to different approaches. And I think by teasing out the ones who have obesity as a complicated disease process, and there was quite a few presentations at the digital conference on obesity and its targets and how difficult it is to treat. But if I look back at patients that we treated with interferon and ribavirin. Particularly our genotype for heavy Egyptian, Arabic population. If you could get them to lose weight and they engaged in this really well, it improved their outcome of going on interferon. So we would use it, right patient, right time, right drug. But we would maximize their chances of cure within all of the data that we had. It was bringing their weight down, really getting the opportunity and they would go on and statistically do and get their procure.
Louise Campbell: And I think the harder you work for the longer period to get the engagement, actually the better the rewards can be. And there are patients that respond or people who respond very well to that. And I think getting those patients engaged and then working on the others side, who do need medication and do need different approaches, bariatric surgery, or more psychological counseling into their habits. Because no one size fits all. It may not be the liver disease we’re treating, it’s the contributors to the liver disease, which are far more complicated than probably the liver disease itself.
Roger Green: We could let this one go for another couple of hours, but Stephen, you have one, you want to contribute?
Stephen Harrison: Yeah. So this has been a tremendous conversation. I do think it’s probably worth throwing out a couple other thoughts from the digital ILC. So we talked about an unresolved issue. Which is disease awareness, which is an ongoing battle. And I don’t think we won that battle yet, as was illustrated by several abstracts presented here. For me, I was really intrigued. I want to go to question three, which of the presentations you discussed in the podcast do you feel will have the greatest longterm impact on how we diagnose and treat fatty liver disease?
Stephen Harrison: I’m going to twist that a little bit to say, I didn’t give this discussion on this abstract. But it was one that was discussed. And that was the Zobair Younossi one. Vlad, I don’t know if you presented that one or not. I think somehow we commented on it, showing that liver disease actually was the number one killer of a NAFLD patient. Which totally flipped the whole paradigm on its head, where we’ve been preaching cardiovascular disease is the number one risk factor. And it was pretty compelling evidence. Now granted, it was older data, but it’s some of the better data that we have out there to take a look at. So maybe I’ll throw that out there to the group to get comments. Are we going to flip the script now and put liver related death as the number one cause? Or, are we going to still say cardiovascular disease is number one? With the caveat that there’s one study presented in abstract form that says otherwise.
Vlad Ratziu: Stephen, just a short comment. Actually it wasn’t all data. It was 2018, if I remember well.
Stephen Harrison: It was more recent data for sure. I got that one confused with the one abstract that showed that GLP use was only in 2% of patients. Whereas we know now, reality is in diabetics, about 20% or more of our patients are on GLP-1s. So that one I think was a little outdated.
Vlad Ratziu: So my point here would be the following. We are liver doctors. So yes, people die of a lot of things. But we need to concentrate on the cause of liver death and prevent that. Trying to have us, in our hands, a drug that will reduce all types of cause mortality. It makes no sense. There are cardiologists that know how to treat coronary heart disease for now tens of years. There are diabetologists that know how to treat diabetes and its complications. Our job is not to worry so much about whether we’re using cardiovascular complications, with NASH targeted drug. Our job is to reduce liver related outcomes and increase liver related survival with our NASH drug. And let the others do the rest because they know how to do it. They already have plenty of drugs to do that. They have guidelines, they have management strategies.
Vlad Ratziu: So you have to be modest here. And regardless of what the other causes of death are, the only concern is do you, by treating the liver with one particular drug, do we increase the risk of death from other organs. That would be bad. But if it’s neutral, if it doesn’t change it, while still reducing the risk of liver-related death. That is all we need. We can discuss about more. But I think in a nutshell that would be my opinion
Donna Cryer: Vlad, I understand that from a hepatologist ,point of view. And certainly agree in terms of designing drug development and regulatory process. But as a patient, if I’m dead, I’m dead. I’m less concerned about why I’m dead. And I’ve had this conversation with other patients as we go back and forth. And I’ve had this conversation also, when I was on the ABIM Gastroenterology specialty board. And sort of watching the various factions and facets of gastroenterology, focus narrowly sometimes on just their part of the digestive tract or just their part of the patient. And it gets very frustrating, tiresome and in some cases dangerous when doctors are so organ-focused, that they lose sight that the patient has all those organs, all those parts. And things work together. And so while you’re right in one aspect of it, it sends up red flags and alarms for me as a patient who has gone through a very fragmented healthcare system. And sometimes has fallen through the cracks into a hospitalization. And I’m just lucky to be alive. And so I just have a concern with too narrow focus sometimes.
Vlad Ratziu: I understand that. However, if you are a patient that has NASH and coronary artery disease,
Vlad Ratziu: are you going to come to me to fix both problems, or are you going to come to me for the liver problem and to a cardiologist for the heart problem? If I were a patient, that’s what I would do.
Donna Cryer: I just need you to both have the same understanding of the problem and be on the same page about what you’re doing for me and with me, because too often that’s not the case.
Roger Green: Vlad, two thoughts, and at Stephen. First of all, if you take Zobair’s paper and you take the paper that Dr. Chalasani presented on Thursday, that suggested that a lot of the growth of liver stiffness occurred in F3, you really make it hard to build a case for using a lot of the medications that are out there right now to treat patients prior to F3, because if liver disease is what we’re trying to deal with and liver disease is what happens after liver stiffness sets in, then the question becomes, why are we worried about F2? I don’t buy that argument for a second, but the economics of ‘when do you treat’ and ‘who do you treat’ starts to change. And what do you treat for starts to change.
Vlad Ratziu: Then why do you want to eradicate HCV then? Why just not treat cirrhotics with HCV?
Roger Green: I think that’s where that issue was. I don’t happen to agree with it. I’m talking about it from a policy perspective. If the economics aren’t in treating earlier, and if the severe events or what happened in F3, if people are going to die from liver, then you say that the cardiologist doesn’t worry about your liver back in F2. The cardiologist figures, you can take care of that later. A lot of the things that we’re developing right now become, I think, a little bit harder to promote and get paid for. I don’t think it’s right, I just think it’s what might happen.
Donna Cryer: In HCV, you’re preventing infection and a spread of infection to other people. If you’re curing it at any time, you’re preventing all sorts of complications and things like that. It’s both an individual and a public health solution.
Vlad Ratziu: There are non-hepatic complications of fatty liver disease. We’re very far from demonstrating that if you treat fatty liver disease, you’ll have less diabetes, or less coronary heart disease, or less pre-atherosclerotic lesions, but it might be the case. That is one thing. The other thing is that in the end, it’s not a matter of when you treat, it’s a matter of how much it costs and what are the side effects. If you have a drug that treats NASH that is very inexpensive with no side effects, then it’s okay to treat F0, F1s, because that’s where you will have most of the impact in terms of public health, not including just the most advanced ones. That’s when you really stop the development of the disease. But if the drugs are very expensive, it’s a different story.
Roger Green: Going back to Stephen’s comment about Zobair’s paper, and Stephen help me, or anyone else, would that paper support Vlad’s statement that you want inexpensive drugs in F0 and F1?
Jörn Schattenberg: I don’t think we know yet. We cannot give you that answer. I think from a pathophysiology perspective, I’ll always say it could make sense to decrease that NASH, and I don’t know whether that patient with F1 today could be a fast progressor and hit my clinic again with a pre-cirrhotic liver a couple of years down. We need those biomarkers I mentioned in the beginning to predict a little bit of the course, which isn’t even in all patients. You mentioned to not treat F0.
Jörn Schattenberg: There are certain risk factors and we understand the patient population, but it’s very difficult to predict the individual course at the patient level. Donna mentioned that patients don’t want to get lost. I think that’s one thing.
Jörn Schattenberg: The other thing is that we still have to understand the disease, I just saw a lady again today, she came with F3 to my clinic and she told me. “Well, my liver function tests went up. The first thing my primary did was stop my atorvastatin.” We add on the cardiovascular disease here just by having that liver disease. I think that’s a bad thing.
Louise Campbell: Can I just comment on, I think Jorn was right at the very beginning, he was asking and saying that we’re closer to being able to identify patients who respond to treatments, but also the prediction of outcomes.
Louise Campbell: If we take Vlad’s comment and look at treating F1 and F2, if we can predict with F1 and F2 with NAFLD, who is going to be the people who cost and go on to develop type two diabetes instead of the cardiovascular disease or the hypercholesterolemia or the hypertension, and we can tease out those populations who go on to have different problems, then we can directly treat each of those populations.
Louise Campbell: But I think, going on to Donna’s point, that we’re not siloed in healthcare. I think the GP, Dr. Pryke, she was very keen on the fact that GPs won’t help in multi-morbidity management.
Louise Campbell: There’s a lot more multi-morbidity management going into health care now, with our partners with endocrinology, cardiology, rheumatology, and obesity. Because I think there is now an understanding beyond the research populations, that we are actually reliant on each other to provide better healthcare, detection, management, and treatment to the patient. If we work individually, that is never going to be, in my mind, the best way to treat somebody. I think we do have to coordinate, but I do understand that we have to be very specific sometimes on a research question, but we’re moving this beyond research into populations that are vastly in need over the next ten, twenty, thirty years.
Roger Green: I agree, lest my statement be under misunderstood, I’m in complete agreement with that. I think that it’s important for us to focus on liver as part of the broader whole. The risk I see is that you can take a couple of these study outcomes and a definition of what we’re supposed to focus on and box ourselves, and a lot of patients, into a corner I just don’t think we want to be in.
Donna Cryer: I think this has been an excellent conversation. I think one of the best episodes yet, and we need to be mindful of everyone’s glucose management, I think.
Roger Green: Yes we do. All right, then with that, why don’t we just go to a final question? I think we all agree this has been a fantastic conversation. Donna, let me start with you and then everybody else. What do you think is the one best or biggest thing that comes out of it for you, the conversation we had?
Donna Cryer: Well, it certainly reinforces how we have set up the Global Liver Institute’s NASH Council with internal medicine, endocrinology, and cardiology at the table with hepatology from the beginning, because it’s going to take all of us to solve this problem.
Louise Campbell: I can go next. For me, it’s being aware to remember that we move research from bench to bedside and research enables us to, hopefully, treat people better and get better outcomes, rather than being varying. We can be very narrow in a research question sometime, and it may not be the best care that they get because they’re answering the question of the trial, but interpreting it and put it into the real world is actually the skill of where we’re trying to take this research to.
Roger Green: Stephen, if you’re still here, go next. Are you still here?
Stephen Harrison: I’m going to be a little provocative. I love the fact that the Atlas Trial was presented and that there was a solid effort made at combination therapy. Maybe this isn’t very popular with people, but it’s going to be said by me anyway. That is, we need to have more combinations. We need to have more combination therapy.
Stephen Harrison: We all talk, Jorn, and Vlad, and myself, and Peter and others, talk about combination therapy and that’s where we’re going to wind up. I firmly believe that.
Stephen Harrison: Here’s what I want to see. I want to see drugs that are moving the needle in NASH as monotherapy begin to come together in combination therapy. That’s not taking drugs that have shown minimal effects as monotherapy and try to hit a home run by combining them with another minimally effective drug. Let’s take drugs that are really moving the needle and combine them where it makes sense, looking at novel mechanisms of action that actually augment and harmonize and synergize with other drugs. We had that first shot over the bow in this trial, now let’s magnify and really begin to enhance what we’ve seen here moving forward.
Vlad Ratziu: This last comment, very interesting. But we still don’t know what the best combination is. I used to think like Stephen, which is if you want to do a combination, take the best players and put them together, the most efficient or the ones that are complementary, one does one thing that the other can’t do. However, one of the most successful combinations, Stephen, in hepatology, was between a drug that was moderately effective, Interferon, and a drug that has almost no antiviral activity, which was Ribavirin, and yet the combination did much better than anything else before. Bottom line, you never really know until you test them, what is the best combination? Of course, we want to try drugs that are effective to put them together, but sometimes we have surprises.
Vlad Ratziu: As a general final comment, I think, from what you, because you asked us a general comment on what was discussed, this was really a very nice discussion. I think it’s a discussion that needs to be again presented. We need to go over these things again in the future, because you see how many specific things are there about NASH relationship, the natural course of disease, very particular, the fact that it’s a chronic disease, you can’t cure it, the fact that it depends so much, it’s so intricate, with other comorbidities that are competing risk of mortality. Do you treat early? Do you treat late? All this depends on all these things. I think it’s very nice to exchange ideas around that. We’re still far from having a consensual view on all these aspects, including what the job of the hepatologist should be in this multi disease process.
Roger Green: Jorn. By the way, Stephen, you don’t have to accept the nomination or decline it, we’ll just let that hang out there.
Vlad Ratziu: I want to be his Vice President, be supported by Big Pharma.
Roger Green: You would be eminently qualified, Vlad.
Donna Cryer: I’m happy to chair the board.
Roger Green: Jorn, go ahead.
Jörn Schattenberg: Very interesting. I think the reassurance that Peter expresses into some of the lead PIs on this talk too, is clearly, I think, as hepatologists, we know, I raise the question, which patients would we treat? Which markers are the right ones? I think we know the disease is real and the patients hit the end stage. We have a pretty good picture of which ones to select for clinical trials. I think that’s why we’re seeing so many good clinical trials being performed.
Jörn Schattenberg: I really enjoyed in this discussion here, the patient perspective. I think Donna said something where the patient wants to have this flow all together. I think in the end we have to address politics and policymakers a little bit more.
Jörn Schattenberg: As a hepatologist, we know which way we want to go. I think we need support in having the NASH nurse or somebody that helps the patient pull these things together. Because that’s difficult from the physician’s perspective.
Roger Green: I think these are all excellent points. I think this has been a fantastic conversation. I’m watching the people who aren’t too hungry to speak smiling as we get to the end of this. My only thought would be this, that the reason the company has sponsored this is called HEP Dynamics, is because systems are dynamic in their nature. One of the things that dynamic systems yield is the law of unintended consequences.
Roger Green: When I ask questions, like some of the things I was asking today, the issue really is we have to understand how all the different stakeholders are likely to take the points that we make and how those things come together and where the energy is.
Roger Green: No one ever gets unintended consequences, right? That’s why they’re called unintended consequences. But the broader a vision we can take as we go forward, the better chance we have of getting it right, which circles me back to Donna’s point about if you could bring all different parties to the NASH council, you have a much better chance of getting to a conclusion that makes sense and that represents the complexity of what we’re dealing with.
Roger Green: With that, this has been amazing. Vlad, I’m glad you’re able to join. We didn’t expect you. I’m thrilled you are here. Jorn, thanks for coming on Surfers. You guys have been amazing. We will be back next week. Until then, special thanks to Mic Wilson, our engineer, and belated thanks to Tom McDonald who stepped in and did amazing real time editing for us while we were on ILC last week.
Roger Green: To Buzz Sprout, to Eric Rounds, who does our social media, to Politeia Le, who coordinates all the media, Ryan Segura does our editing, and mostly to you, our listeners who keep pushing us to get into more interesting topics in more fascinating ways.
Roger Green: We’ll be back next week. I don’t know what we’ll be talking about. I’m thinking seriously about Vlad’s idea about how often do we bring groups like this back together simply to think about big issues, because I think these are great and really valuable conversations. Until then, everybody stay healthy, surf on, and we’ll see you on the podcast next week. Bye bye now.
Donna Cryer: [crosstalk 01:17:41]. The compensation package might be nicely arranged, though.
Roger Green: That’s why I want the [crosstalk] piece of his action. Thank you everybody.