Ep. 14 Respect for the liver

NASH is not merely a byproduct of obesity.

Browse Our NASH and COVID-19 Coverage

The role the liver plays in non-liver comorbidities is complex and important. Join the Surfers as they give the liver the respect it’s due. “The ways liver affects outcomes is a very, very complex topic which, for the sake of argument, is sometimes simplified down to obesity…but like our perspective on NASH demonstrates, there’s a lot going on.” – Suneil Hosmane

Drug developers, investors, researchers, and corporate executives wrestle weekly to understand what is happening in commercial development of NASH medications. Join hepatology researcher and key opinion leader, Stephen Harrison, C-Suite veteran, Peter Traber, and forecasting and pricing guru, Roger Green, as they discuss the issues affecting the evolving NASH market from their own unique perspectives on this week’s edition of Surfing the NASH Tsunami.

Roger Green (00:00:00): For everyone with an interest in NASH, or more broadly fatty liver disease, surfs up. Episode 14 of Surfing the NASH Tsunami starts now. Over the last couple of weeks I’ve made a fuss about us being preteens and teenagers, but we’re now officially old. We’re on episode 14. The age at which my kids told me they knew more relative to me than they did at any other point in their lives. This is an unusual week for us. The entire lead surfing crew is here this week. Peter say, hi, welcome back.

Peter Traber (00:00:39): Yeah, hi, Roger. It’s great to be here.

Roger Green (00:00:41): Good to have you back with us.

Peter Traber (00:00:42): Thank you.

Roger Green (00:00:42): Okay, Suneil, say hi.

Suneil Hosmane (00:00:44): Hello, everyone. Nice to be back.

Roger Green (00:00:46): Louise?

Louise Campbell (00:00:48): Hi, everyone.

Roger Green (00:00:49): Stephen, who needs no introduction.

Stephen (00:00:52): Hola.

Roger Green (00:00:53): Gracias, amigo. All right, we’re all here, and that’s exciting. We’ve got lots of interesting things to talk about, and we’ve had some interesting news over the past week. So first, if you’ve been to the webpage, or you’ve seen any of the promo, we started an advanced notice section.

Roger Green (00:01:11): Depending upon which podcaster you follow, you may be getting our webcast as late as six to eight hours after it drops, sometimes even later. If we have your email address, we will send you a letter as soon as it drops, and a link to the actual Surfing NASH page, so that you can get to it as quickly as possible. People have said they lost a day. We’ve occasionally gotten a letter saying, “Gee, it’s not up on my server yet, what are you guys saying this week?” This would make that problem go away.

Roger Green (00:01:38): We’re also starting to get ideas about patient segments, and I expect we’ll be feeding you more information about patient-focused programming within the next week or two. If you have thoughts about patient-focused programming or questions in general, questions can go to questions@surfingNASH.com. And with that said, let’s get on to our podcast. This week, we’re going to talk about professional highlights. Brave one, go first.

Peter Traber (00:02:07): Yeah, hi. This is Peter. This isn’t necessarily a highlight, but it’s an observation that I’ve made over the last week. I have two clients that are submitting INDs, or have submitted INDs for COVID-19-specific trials, and I have a number of clients that are submitting, or have submitted INDs unrelated to COVID-19, and what I’m seeing is the FDA and the EMA getting pretty much inundated with COVID-19-related INDs, and they’re going through and they’re working very hard on them, and all the other business that the agencies do is getting pushed back and postponed. So they’re doing their best to keep up, but we’re definitely seeing an effect in the industry of the very large number of COVID-19 projects that are going forward.

Roger Green (00:03:19): Thanks, Peter. That’s an interesting thing for everybody who’s in planning or in trial development to note, so thanks for sharing that.

Stephen (00:03:30): This is Stephen. So professionally, I would say that despite the COVID resurgence in states like Florida and Texas, Arizona and California, which is predominantly where a lot of our Summit network sites reside, we have continued to push through enrolling NASH clinical trials, and the statistics we just looked at this week show 50% of all clinical trials enrollment are coming through the Summit network.

Stephen (00:04:08): So that’s a nice milestone for us, and kudos to the sites that are taking part in that, for pushing though despite the challenges that we see with COVID. They’re real, and we are dealing with them, and doing so while maintaining excellent data integrity, and ensuring the safety of our staff and patients at the same time. It takes a lot of work, but kudos to the team for making that happen.

Roger Green (00:04:42): Okay, that’s great. Louise, go ahead.

Louise Campbell (00:04:44): I think a positive for us was that we volunteered to scan some people who were put into isolation who were taken off. They were rough sleepers, and they were taken into isolation, and offered support, and they’ve engaged with services, and we’re going to provide scanning facilities so that these people can all be scanned before they move on into different aspects of care, having engaged very heavily now with support services, getting clean, getting dry, and I think that’s been an encouragement out of what has been a disaster, or could’ve been a disaster for them. But there’s been a very positive take up on that.

Suneil Hosmane (00:05:32): So I just wanted to say that as COVID has been taking hold, and has been modulating throughout society, I’ve originally just kept in touch with the high level epidemiology type aspects, but as of the last week or two with new data coming out, I’m really digging into understanding how this disease is impacting various other organ systems, how it’s influenced by comorbidity.

Suneil Hosmane (00:06:02): So I think there’s a lot of good science coming. We still have a lot to learn but I think that’s been kind of a revelation, at least in terms of the way that I’ve been thinking about the field.

Roger Green (00:06:14): So is there any one particular insight that you’ve gleaned that you want to share that’s either overarching, or really powerful in general?

Suneil Hosmane (00:06:22): I think certainly there is a tight story between COVID and the liver, and I think we’re still unpacking all the details of what that is, but certainly with ACE2 receptors being present on cholangiocytes, and just how people have been tested showing positivity in the upper respiratory tract in early stages of disease, and then towards the end of disease still having positive viral loads, but they’re not in the chest anymore, they’re actually in the GI system. They’re detected through fecal matter.

Suneil Hosmane (00:06:57): So I think that, it’s moving through the body. There’s definitely something going on with the liver. Liver fat and other features seem to have a prognostic threshold or potential, so I think that just as an overarching, liver and COVID is not nonsense.

Roger Green (00:07:18): Okay. And you’re about five minutes ahead of where I would’ve wanted you to be in the podcast to be perfect, but that’s great, and will set up nicely every place we’re going. My personal best, actually, is about the podcast, we are constantly amazed to learn how many of you are listening that we don’t know, haven’t met, don’t touch, but somehow you’re out there.

Roger Green (00:07:42): My favorite this week was a tweet that Louise actually picked up third or fourth hand from a hepatologist somewhere in the UK who saw the initial announcement from STAT Plus on intercept, and immediately tweeted out to his friends, “Can’t wait to hear what the HEP Dynamics people have to say about this.”

Roger Green (00:08:00): My second favorite was the podcast I got on LinkedIn, the tweet I got at four in the morning when we dropped that episode a little bit late, saying, “I’ve been waiting to hear what you have to say. When’s your podcast coming out?” So if we’re providing that kind of service for you folks, that’s really exciting. We always like to hear good news. We like to hear that people are paying attention, so feel free to write us and share as best you can.

Roger Green (00:08:22): My favorite comment from last week actually came from a friend of mine, who I didn’t know was listening. Dr. Mick Kolassa, really a legendary guy, one of the leading pharmaceutical economists in the industry, one of the best tarpin fishers in the world, and a guy who, in his 20s, and then again in his 60s has been a chart-busting blues recording artist. Fascinating guy, good friend. Michissippi Mick,” as the blues people know him, asked, and I quote, “How far do these diagnostics take us down a path to where we can tailor therapies to specific patient needs, and then make the process economically sound?”

Stephen (00:09:13): Yeah, I think that’s a great question, using non-invasive tests to tailor therapies to specific needs. We’re just in the infancy of beginning to understand the pathogenesis of this disease, and there’s still a lot more, to use Suneil’s term, unpack, than what we’ve already done.

Stephen (00:09:38): There’s lots of different biomarkers in development. There’s wet, or blood-based biomarkers that reflect inflammatory changes, that reflect metabolic changes, that reflect fibrotic changes, and trying to figure out which ones are unregulated or downregulated in an individual patient is one thing, but to try to figure out what that is in a whole population is another thing.

Stephen (00:10:06): And then reflecting on the context of use that we discussed last time, meaning is it a diagnostic, is it a measure of therapeutic efficacy, or is it a predictor of long term outcome. I think really where I would angle on the question is how do we begin to use these non-invasive tests to predict long-term outcome in different populations of patients?

Stephen (00:10:33): And that is definitely something I think we have the capability to do, but we just aren’t refined enough with our current noninvasive tests to do that. I think it’s a great question, and you keep playing the blues, and we’ll keep looking for the answers.

Roger Green (00:10:54): I’m sure he will do that because he’s really good at it, and has a lot of fun with it.

Peter Traber (00:11:08): The commercial folks in the room in thinking about NASH therapies are always going to be thinking about which non-invasive tests both diagnose the patients appropriately for the particular drug, and one that correlates with significant changes.

Peter Traber (00:11:39): So I think that the large efforts that are underway to look at non-invasive markers, and in particular those positive clinical trials that also utilize non-invasive markers are going to be really critical to the commercialization of these drugs. So we talked a lot a couple of weeks ago about the big endpoints, based on liver biopsy, or outcomes, but from a commercial standpoint, the critical issue for getting drugs into clinical practice is going to be what non-invasive test we use to diagnose and to follow patients.

Roger Green (00:12:39): Thanks, Peter. Suneil or Louise, anything to add?

Suneil Hosmane (00:12:44): I can just provide something that’s pretty much in line with what’s been discussed. I mean, I was at a Payor Ad Board centered around a non-invasive technology a few years back, and I was sitting next to someone who actually was a former Hopkins alumnus as well, so we have that going, and we had a side conversation, and really the same thing that Peter just said came up again.

Suneil Hosmane (00:13:11): They were saying, ideally, we would want to have something that was used to identify patients, and then at the same time is modulated with, as they get better or get worse, therefore not only can I use it to identify, but I can use it down the road to monitor, and presumably have stopping conditions and things of that nature.

Suneil Hosmane (00:13:32): So I think it’s the totality of that story that’s going to be really important, and we’re all seeking it. It takes data, and it takes time, but I think we have some promising things already in hand, and looking to generate more data.

Louise Campbell (00:13:51): The more we can move to non-invasive technology, and secure the quality of data that we want, the more that that advances patients who get access to treatments, to trials, and I think I discussed last week around about multiscan with Perspectum and FibroScan that you need a funnel-type system to bring people down.

Louise Campbell (00:14:16): So you need your non-invasive markers that are wet markers along with non-invasive scanning equipment. And hopefully one day we’ll get to a position whereby we actually do not need to stick a needle in anybody’s liver if we can avoid it, the more that this technology goes. And I think the more we can make it handheld, the more broad the areas that we can put these into, because there’re some very difficult areas in the world with some very high prevalence rates.

Roger Green (00:14:46): Agreeing firmly with all that, and I’m actually going to run around to the other part of the conversation last week which was about AI. The more I read, and the more I see, the more excited I get about the prospect for AI to simplify and streamline the entire process, because if you can get precise and consistent readings, even with biopsies that we’re doing right now, it enables us to do a much better job.

Roger Green (00:15:09): If we have a better independent variable, like I said last week, we do a much better job at predicting, which means that can figure out how these individual tests slot in the different patient situations and needs, and can move the whole process efficiently to getting folks to the right diagnosis a lot faster.

Roger Green (00:15:24): I suspect in some ways that AI will be transitional, that if we’re able to do more with non-invasive testing and less with biopsy, that the biopsy portion of AI will matter less. But the ability to use machine learning to keep getting smarter about the differences between patients and patient types, and what we need to have test each, I think that’s not going to go away, and I think that’s really a fascinating adjunct to having better tests is the ability to have a license, or make better use of them.

Peter Traber (00:15:53): Yeah, let me make one more just brief comment on this area. A lot of times when people come and ask you about non-invasive testing, they’re expecting some brand new, miraculous thing to come dropping out of the sky, and make a big difference. I think we probably already have the testing that is going to make the kind of difference that we’re looking for in clinical diagnosis and monitoring patients.

Peter Traber (00:16:22): It really is going to take creative and clever ways of looking at the data and analyzing it, and putting together algorithms, and I think you’re exactly right that AI is going to be a huge help in that. Yes, there are some things that are on the horizon that are new, and novel, that may be helpful, but I think we probably already have it, and have to focus on much of what we are already doing.

Roger Green (00:16:48): Okay. Thank you, Peter. You’ve now gone full circle to where we started the first discussion with Professor Rinella on Diagnosing Diagnostics One several weeks ago. So I think it’s great point to step off since we’re right back at the beginning of the carousel ride.

Roger Green (00:17:06): On to today’s topic. Over the past couple of weeks, we’ve gotten a bunch of responses to some of what Brian Harvey talked about during episode 12, some positive, some negative. But one of the assertions that’s got some attention was the statement he made that he felt that NASH might represent a failure of primary care medicine.

Roger Green (00:17:29): I’m not sure I understand his point exactly, but I think what he was referring to was the idea that if we did a better job at treating obesity and diabetes, NASH would never come to the fore, because if you treat obesity well enough, you can get people to lose enough weight, and if you couple that with diabetes, the metabolic issues become a lot less severe.

Roger Green (00:17:46): Okay. Someone who sent a note choosing to remain anonymous because that person’s job deals with regulators in the US, and didn’t want to be identified by name wrote, and I quote, “Maybe so, but it’s equally likely that identifying and determining how to treat NASH demonstrates success in peeling back the layers of easy to measure metabolic metrics to appreciate the structures that drive underlying disease.”

Roger Green (00:18:12): So Peter and I were talking about all this on the phone last Friday, and we kind of came to the conclusion using one metaphor, that liver is a little bit like the Rodney Dangerfield of the body. The organ that gets no respect when it deserves it. We decided it would be interesting to do an episode that we loosely called Respect for the Liver that would talk about different ways that we don’t appreciate enough the role of the liver in the disease processes that you need to diagnose and treat.

Roger Green (00:18:48): Mindful of that, Stephen, I recall, describes frequently and publicly as being like the canary in the coal mine, which I’ve always taken to mean that liver disease, depending on where you’re looking, has three different outcomes, and sometimes it applies to issues of viral response, sometimes cardiovascular, sometimes end-stage liver disease. So Stephen, do me a favor. Amplify a little bit on the canary in the coal mine comment.

Stephen (00:19:21): Well, the canary in the coalmine mentality, as it relates to fatty liver, is, I think, a very apropos statement, and it’s one that I use with my patients almost every week. I guess if you don’t know the canary in the coal mine, were that comes from, it’s probably worthy of a brief introduction to that so you don’t have to go look it up.

Stephen (00:19:49): But basically my understanding of the canary in the coal mine originated in the setting of mining towns back in the day, when mining shafts weren’t ventilated well, and there was an opportunity, or a probability that one would pickax, or somehow uncover a gas pocket that had carbon monoxide, or some other noxious gas, and it would not have a smell, and the next thing you know, these miners all dying.

Stephen (00:20:32): And so back in the day, they decided to take down a little bird with them in a cage, thus the canary, and they would just prop the bird up in the cage on the side of where they’re working, and ultimately, every now and then check on the bird, and if the bird was good, they felt like they were good. The bird was dead, they needed to get out.

Stephen (00:20:52): So it was as sensor of something bad happening. I think it’s very apropos because the liver is essentially that same organ-type thing for the body, such that for patients with fatty liver that have dysregulated metabolism, the way that the body handles excess energy is it converts it to fat, and it stores it very readily in skeletal muscle and in the liver, and to some extent, even in cardiac tissue.

Stephen (00:21:30): And the pancreas as well, and maybe other organs that I’m not quoting right now. But since I’m a gastroenterologist, I used most of those. The cardiology piece is just something that’s in the literature. But ultimately, identifying a patient having fatty liver, assuming that it’s not due to alcohol, or it’s not due to medications, or it’s not due some other lipodystrophy event, that you can link to dysregulated energy metabolism.

Stephen (00:22:05): So the first thing that improves, believe it or not, when you begin to eat right, exercise, undergo lifestyle change is the liver begins to clear itself of the excess fat. So it both is a predictor of what’s likely to happen, we know that fatty liver predicts the onset of diabetes by about two fold, and then it also is a good marker of improving your overall health.

Stephen (00:22:41): We also know that fat and NASH are drivers of fibrosis, and you might ask well why is fibrosis always standing out as a predictor of a bad outcome? It’s because NASH, it’s a colinear variant. It’s sitting there in the same space as fibrosis, so it’s always going to get drowned out when you do a multivariate analysis, but it doesn’t mean that NASH doesn’t have a role to play here.

Stephen (00:23:13): So that’s where I get the canary in the coal mine mentality, ultimately, there’s more to fatty liver than just liver outcomes. We’ve talked about this before, it’s well known in the literature. Number one and number two killer of a fatty liver patient is not decompensated liver disease, it’s number one, cardiovascular outcome, and number two, all-cause malignancy that’s not hepatic related.

Stephen (00:23:44): So this would be colon cancer, breast cancer, lung cancer, pancreatic cancer. And this is pretty obvious. The presence of metabolic syndrome in Type 2 Diabetes and obesity appear to select patients with NAFLD who are increased risk for both NASH and cardiovascular complications.

Stephen (00:24:02): It’s hard to tease out the differences, and it’s not uncommon to see these patients having increased incidences of renal insufficiency, which is known to further accelerate atherogenesis in cardiovascular disease. But I think it’s worth noting that people always say, “Well, maybe there’s an association with fatty liver and heart attacks.” But it’s not just heart attacks.

Stephen (00:24:28): There’s hypertensive heart disease, left ventricular diastolic dysfunction that leads to heart failure, and so in diastolic dysfunction, you make a stiff right ventricle, you overload that with fluid, and you have heart failure as well. So there’s a lot to the story when we begin to talk about the liver being central to overall health, and a predictor of outcome. So yeah, I think canary in the coalmine is a very apropos statement to define what the liver does and is.

Roger Green (00:25:28): Okay. Thank you, Stephen. That was, I think, a really good, succinct explanation of all the ways in which the liver chirps, if you will. Comments from anybody, in terms of how this canary in the coal mine phenomenon affects you and the work that you do, or in the things you’ve observed about the liver?

Suneil Hosmane (00:25:49): From the perspective of developing diagnostics, which is my day job, certainly that underlying pathophysiology, which is not necessarily in your face and super apparent, I think that’s both the challenge, but that’s also the reward when you can discover something, because it’s really not something that’s very easy to delineate.

Suneil Hosmane (00:26:27): I think the biology of the liver is actually very sophisticated. Yes, it’s a mega-metabolic warehouse, and there are so many things that it contributes to the body, but with that said, being able to tease apart some of these very specific pathways that may be modulated with NASH is very, very challenging.

Suneil Hosmane (00:26:50): And when you find that, and when you find those processes and you find those biomarkers, or you find that elevated stiffness, it really tells you something about the processes going on in the liver, and the kind of more global heath of that individual.

Suneil Hosmane (00:27:15): We’re seeing some things that we can talk about later on, like with regards to COVID that sort of exacerbate this, or provide some context for this, but it’s not something that you just immediately see or recognize, but when you do find it, it has significant meaning that should, at least, help put that person into a broader context.

Louise Campbell (00:27:40): I think, Stephen came from exactly where I come from. By the end of it, it was like scan everybody, or find everybody, and then we can locate those other diseases. When I think back to the episode that we did for the global NASH event, I looked up the term of advocacy, and it’s all about pleading, and pitching in for your patient portfolio, or your condition.

Louise Campbell (00:28:13): I think, I mean it’s sad that I describe much of liver-related NALFD/NASH, and all of the comorbid conditions that this is now associated with, plus when you add in Hepatitis B and Hepatitis C, which between them take up 1/12 of the global population with Hep C being the largest viral killer, I think if you also then add 240 million dependent drinkers that are estimated, the fact that we are having a conversation, or still pleading for liver disease to be taken seriously, and looked at by each of these specialties, the time for pleading is coming to an end, I think.

Louise Campbell (00:28:57): You actually have to recognize that this organ is a really significant part of your patient’s pathway, and if we ignore it, then we’re not doing our patients great service, because we’re avoiding one of the big parts of where that patient has traveled through their journey, and we’re missing it.

Louise Campbell (00:29:19): Now, is that protectionism for your own disease? I don’t know. But I remember distinctly sitting in a boardroom discussing how we could add things like liver testing to different specialties, to be greeted with a cardiologist saying, “Well, if you cure cardiac disease, where’s my job gone?”

Louise Campbell (00:29:41): And I think that’s not about the patient. So this self protectionism for our diseases, and silo thinking when you have an organ that really is a major contributor to a lot, and even dementia nowadays, metabolic dementia or Alzheimer’s, there’s growing links for that. I think we do have to take a step back and say we’ve got to be collegiate. We’ve got to work together. We’ve got to really wake up and smell the coffee, and get the liver round the table as one of the first diagnostics. Let’s rule it out, then we can move on to something else.

Peter Traber (00:30:22): The liver is a glorious organ. I decided in 1983 that I would pursue gastroenterology and hepatology as a subspecialty, and I did that because of the central nature of the liver to so many metabolic, synthetic, and detoxifying functions in the body. By making the liver central to the pathophysiology of metabolic disease as we’re talking about, it’s really a beautiful concept.

Peter Traber (00:31:04): I’m a drug developer, a scientist, a physician, but in every meeting I sit in with industry, there’s a quiet person over in the corner who is a commercial person. They often don’t say very much, but they do after the meeting, and when you don’t get calls back from companies, it’s often because the commercial person spoke up.

Peter Traber (00:31:37): In the context of commercial drug development, although we have a lot of positive things going for us.

Peter Traber (00:32:01): There’s going to be some commercial focus in our drug development and comorbidities that we’re going to have to focus on in order to really understand how NASH drugs, not lifestyle changes, but NASH drugs are going to affect this area.

Peter Traber (00:32:30): So for instance, and I’ll have more to say about this later, but the commercial person is sitting there thinking about full approval perspective. They’re also sitting there thinking about comorbidities, and how do you treat those? Weight change or what effects the drugs Might have on that, weight change, insulin resistance, lipids.

Peter Traber (00:32:53): They’re thinking about trial design. What are payers going to want as part of the trial design and run-in for clinical trials to try to determine what the real effect of your drug is, versus any effect from diet, exercise, and other things. So I think that the liver is central, and because it’s central, it’s challenging to tease out the real effect from a commercial standpoint.

Peter Traber (00:33:30): What I’m saying doesn’t negate anything that Stephen, Suneil, and Louise have talked about, because I violently agree with everything they’ve said, but I think it does have implications for the clinical development of commercially viable drugs.

Roger Green (00:33:48): Thanks, Peter. I want to come at this from a different angle because I’m a forecaster with something of a statistics background. So Stephen mentioned the covariance of steatosis and fibrosis, and the fibrosis will always win out. First of all, when you apply statistics inappropriately, like trying to focus on too narrow an area, you miss the ability to capture the richness of multidimensional relationships, which is exactly what Stephen’s talking about.

Roger Green (00:35:13): Number two, a lot of times when two numbers covary, one might be a slightly better fit to a specific problem than the other one is, but the second one might do a better job of explaining the underlying phenomenon. So if we’ve got things that are highly correlated, the rule that we teach in marketing statistics is use the one that makes the better sense in the overall context, which might not be the one that has the higher value for that particular exercise.

Roger Green (00:35:45): I think that’s what you’re talking about here. If you look at this specific problem, fibrosis might matter more. If you take a look at the broader context steatosis might have greater value. Peter, I think that goes back to your point, as well, which is it’s hard enough to think in terms of complex univariate stats, let alone multidimensional things. We talk about it being so hard to play chess in three dimensions, let alone two.

Roger Green (00:36:14): If you try to define things as being on one dimension or other, something like fat will not do a great job at doing that because it will have a role to play in so many different dimensions. So every time you look for a clean solution to a problem, it’s like saying, “Okay, how do I solve this dimension?” That’s not going to be the first thing that pops up.

Roger Green (00:36:35): But the holistic value of fat as the second player in can take you in lots of different directions, and solve lots of things at once. It makes it extremely enticing, it makes it tough to describe commercially, but I think that’s the challenge that we face. Peter, am I tracking you right?

Peter Traber (00:37:00): Yes, the case for the liver being a central metabolic organ in the pathophysiology of multiple things IS increasingly challenging to show from a clinical trial standpoint.

Roger Green (00:37:30): That completely follows. So with that as a general background, I’d like to dive into one specific set of issues. Okay. Part of what I believe Brian was positing was that obesity matters more than liver does, and that if you dealt with obesity you wouldn’t have to worry about NASH.

Roger Green (00:37:53): Certainly the two are correlated. If you lose body weight, you can have an effect on steatosis at 3%. But there is work in both COVID and cardiovascular disease that suggests the simple idea that obesity matters more might not capture the dynamic as well. So Stephen, do me a favor. Take a minute and talk about how that applies in cardiovascular disease, maybe in the context of diabetes as a set for comorbidity or otherwise, and then we’ll go on and talk about the liver and a couple of other issues.

Stephen (00:38:30): As I mentioned earlier, it’s hard to tease out cause and effect, and what comes first, the chicken or the egg, and all that. But if you posit that the main cause of mortality in patients with non-cirrhotic NAFLD/NASH is heart disease. There’s some interesting statistics that are coming out. The incidence of heart disease in fatty liver has been shown to correlate with a degree of fibrosis in the liver up to cirrhosis Child’s A with five points.

Stephen (00:39:09): So Child-Turcotte-Pugh score A is either five points or six points, and then B is seven points, and then so on. But you can actually tease out Child’s A5 from A6, and we know that the incidence of heart disease in fatty liver has been documented to correlate all the way up to A5, and then the liver related mortality increases in fatty liver only when patients progress to A5 to A6 and beyond.

Stephen (00:39:45): And again, just going back to what’s been shown in the literature, we know heart disease, or at least ischemia and atherosclerosis. What we classically call coronary artery disease, or cerebral vascular accident CVAs, peripheral vascular disease are associated with fatty liver. But there’s also relationships to left ventricular muscle remodeling, which leads to diastolic dysfunction, and what we call H-PEF, or Hef-pef, which is heart failure with preserved ejection fraction, what we call HFPEF, H-F-P-E-F.

Stephen (00:40:36): We also know already, as I mentioned a degree of diastolic dysfunction, and impairment of exercise tolerance is directly linked to fibrosis stage in pre-cirrhotic NAFLD. We know NAFLD Linked to arrhythmias, QTC prolongation, AFIB, even ventricular arrhythmias and sudden cardiac death. And also to normal calcium deposition in the coronary arteries, as well as carotids and other large arteries, even valvular issues like mitral annular calcification, aortic sclerosis, and stenosis.

Stephen (00:41:12): This notion that you just manage the obesity, or manage the diabetes, and you’ll take care of heart disease, I think, is maybe a little myopic. There’s more to the story than that for sure, and I think we’re just beginning, again to use Suneil’s term, unpack all this pathogenesis. It’s not in a vacuum. You would think that if it was just all about weight loss that bariatric surgery patients, they lose 100 pounds that they’re going to live to be 300 years old, and that just doesn’t happen.

Stephen (00:41:54): They still die of CV outcomes and other issues. They may have controlled their diabetes, and lost weight, and their blood pressure’s under better control, and maybe they lost fat, maybe even NASH, but we’re beginning to understand that in a lot of ways, maybe weight loss doesn’t have such a dramatic impact on fibrosis as we once thought it did.

Stephen (00:42:22): And I’ve tried to get at the bariatric surgery literature a bit here to understand it. The problem is that most people with advanced liver disease, either they’re not studied in the setting of bariatric surgery, or they’re not included in bariatric surgery trials. There’s very little data on cirrhotics that undergo bariatric surgery, and what happens to them relative to their underlying liver disease. So it’s a complex issue.

Suneil Hosmane (00:43:05): I completely agree. I think it’s a very, very complex topic which, for the sake of argument, is sometimes simplified down to say, obesity, but just like how we’re talking about NASH, and our perspective on NASH is there’s a lot going on there.

Suneil Hosmane (00:43:39): I mean, obesity, if you really want to go backwards, technically everyone in the NFL is obese. If you were to use simply a BMI scale, that would be true, which we know is not true. They’re some of the most healthiest people on earth.

Suneil Hosmane (00:43:59): But even from an obesity standpoint, when you talk about fat, you’re talking about two major things going on, and not all fat’s the same. Not just in terms of quality, and also storage. If you take excess caloric as an input, and then you say, “Well, where can I put?” Well, it can either go, for example, I’m keeping it very, very general, subcutaneous fat. It’s trying to store it away, it’s trying to store it away in a relatively safe place.

Suneil Hosmane (00:44:29): Of course, the effect of doing that is you start to look big, as you should, because that’s what the body is trying to do. It’s trying to store things and put things away. But the other place where it could go is it can go directly into your organs, in the form of ectopic fat.

Suneil Hosmane (00:44:49): That’s far more pathogenic in nature. It can lead to insulin resistance, and this obviously drives many processes, including Type 2 Diabetes. So just in that sense, right, it’s not really the same, and so the second case is far more severe, and maybe in those individuals, rapid weight loss confers some type of health benefit and improvement to organ function, including the liver, and things of that nature.

Suneil Hosmane (00:45:24): But at the same time, you can’t generalize that to the entire population. And to the comment around cirrhosis, which is another fascinating area which I think we’re still learning more and more, we know that fat is not necessarily as important. I’m not saying it’s not important, but the disease evolves, and so when you start to think about people who are late stage, or even well-compensated cirrhotic, the liver fat begins to disappear, yet the disease is still moving forward.

Suneil Hosmane (00:46:03): Clearly, it was necessary to initiate the disease and take it to a certain place, but after that, the disease itself may take a life of its own, and it can be very much inflammatory and fibrotic in nature, and more so than metabolic. So even in the natural history of disease, I think you start to see these multi-dimension, multi-parameter elements evolve in their weights, which I think is fascinating.

Roger Green (00:46:29): Okay. Thanks.

Peter Traber (00:46:33): Yeah, I’ll make just a couple comments in two different areas. First of all, I’m not going to repeat the nice descriptions we’ve heard about pathophysiology, and heart disease, and so forth. I just wanted to mention that that pathophysiology is a combination of both changes in lipids and inflammation, and I think we haven’t given full focus on the relationship between the intestine and the liver. As many of you know, the omentum and the mesentery in the intestinal track contains a lot of fat, and it’s inflammatory type fat that can build up there, and cause additional problems with the liver.

Peter Traber (00:47:22): I think that’s something that may be involved in both NASH as well as cardiovascular disease. But beyond pathophysiology, I just want to make a comment about what we do to try to move clinical development forward in NASH, and I believe that there are three points I want to make. One, on comorbidities, two on trial design, and then three on a full approval perspective.

Peter Traber (00:47:56): From the standpoint of comorbidities, I think NASH drugs should have no effect on comorbidities from the standpoint of adverse effect. Or, it could have improvement and a benefit in the magnitude of the effect on comorbidities, and I think that would be the best. But adverse effects on those comorbidities are going to be viewed by commercial folks as very questionable, and so I think that’s a really critical thing.

Peter Traber (00:48:29): So for instance, if a drug works well, but it causes weight gain, depending on what the weight gain is from, whether it’s fat, or whether it’s fluid, that’s going to be a problem whereas weight loss is going to be a benefit. Insulin resistance, lipids. If your LDLC goes up, it’s going to be questioned. If it goes down, it’s going to be a positive. So I think that clinical development needs to focus on these comorbid areas very clearly.

Peter Traber (00:49:05): Secondly, trial design. I think that commercial organizations and payers are going to look at the design of trials and say well what did you do in the run in to the trial to ensure that you’re seeing the effect on your drug? And I do think, hearkening back to what Brian Harvey mentioned is that we do need to council on diet and exercise, optimize dyslipidemia therapy. Optimize diabetes therapy and hypertension therapy, because unless we do that, there’s always going to be a question about what the effect of the drug is, versus the other issues.

Peter Traber (00:49:51): And then finally the full approval perspective. I know that this is going to be controversial for some time, but trust me, commercial folks are going to be thinking about how can you get a full approval for this drug? And if you only talk about surrogates, it’s going to be a challenge to get engagement from commercial folks.

Peter Traber (00:50:20): So I think that all the things that we’ve talked about over the last four, five weeks kind of mean that we have to have at least a practical approach right now for the development of NASH drugs, which take all that into account. If we design our trials that way, we can tease out some of these subsets as well as pathophysiological effects.

Roger Green (00:50:52): Peter, I want to see if I understand you correctly. In the moment, if we have to go all the way to endpoints, that will cost a lot more money, a lot more time. A lot of the development is coming from small companies. When you talk about a practical approach, how does that factor in the reality of where drugs are getting developed in this market?

Peter Traber (00:51:26): Well, that’s a good point, Roger. I think that when I talk about a full approval, I’m really talking about pre-cirrhotic NASH, and the progression to cirrhosis, which is still a histological endpoint, but it’s an agreed clinical endpoint by the agencies at this point. That is an endpoint that can be reached in a reasonable amount of time with a reasonable number of patients, if you have a drug that acts in a robust way.

Peter Traber (00:52:02): I think that that’s going to be a challenging endpoint for something that has a 20% one stage reduction in fibrosis in the group. But as we’ve talked about before, 40, 50% one stage reduction, you could conceive of getting to that decrease in progression to cirrhosis pretty quickly. And Roger, I’m not saying that we shouldn’t continue to pursue the surrogate endpoints, because I’m 100% in agreement with Stephen that that is something we should never take off the table, and we could keep pushing. What I’m talking about is the commercial perspective right now is going to be focused on that, and that’s something that we have to keep in mind when we think about drug development.

Roger Green (00:52:56): I see where you’re coming. I think we’re going to keep circling back to that issue over, and over, and over again. It was raised once, and kind of pops up again, and I think we’re going to come back towards that in a bunch of different contexts. And yes, I do understand what you’re saying. I think it does make sense.

Louise Campbell (00:53:34): I think the point that I’ve tried to make, and I think a lot of requires more and more evidence, but I think I was very early in the timeline saying that these comorbid conditions are staring us in the face, and are the early sort of evidence that came out was all about diabetes risk, cardiovascular risk, hypertension.

Louise Campbell (00:53:59): But actually the elephant in the room was most of these conditions have something else in relation, and that was the liver fat, and the high liver fat. I think more and more studies have started to now be looking at that. More and more time has been taken to look at MR`I scans on some of the patients that were done. At that time, you didn’t get the opportunities to do some of the tests that we would have liked to have been done, and I think retrospectively we can go back and collect some of that data.

Louise Campbell (00:54:36): But I think one of the key ones that, obviously we’re aware, hasn’t been peer reviewed yet was the UK Biobank and Perspectum study which came out of Oxford University, and I think coming to what Stephen, Peter, and Suneil have been taking about is that that wasn’t so much that the obese population had the highest risk, because 37.2% of obese patients, where they had normal liver fat were seen to be at no higher risk of COVID.

Louise Campbell (00:55:09): I think we do need to look at where we’re storing fat, and obesity, there’s multiple reasons for being overweight. A lot of this could be down to advertising techniques, most countries don’t have a national strategy for liver, let alone a national strategy for fatty liver, and a lot of that is down to lobbying by alcohol and food manufacturers.

Louise Campbell (00:55:50): Also, it’s not within a government’s interests in a lot of areas, because a lot of tax comes off these areas. So where they’re harboring and promoting in one respect, we’re dealing with the downstream consts, and the biggest downstream cost, we could now find out, could be in our country 300 billion to a disease that we’ve developed and created with over 25% of our population being obese, but not 25% of our population have NAFLD.

Louise Campbell (00:56:25): I think looking earlier downstream, and interesting listening to the conversation the guys were having is that we’re talking about some all conditions after the horse has bolted, because they’ve been developed. By going further to the underlying cause in all of these, which is NAFLD and NASH, if you can detect the point that somebody’s liver becomes fatty, and the definition for the UK Biobank study was just 10% was counted as severe fatty liver. I think if we can find the time that that liver becomes more fatty, then we’ve probably got the timeline start for cardiovascular disease, for Type 2 Diabetes. There was a very interesting study done out of Sweden last year, in December, just before COVID came down, and it as done on the amount of fat in the liver predicts mortality and the development of Type 2 Diabetes in NAFL patients.

Louise Campbell (00:57:42): And what they’ve done, it’s one of the first studies I’ve ever seen, they took 106 patients with no diabetes at baseline, followed them at 13 years, and 23, and biopsied at all three time points. In the patients where the fat was measured, where it went up they developed Type 2 Diabetes.

Louise Campbell (00:58:07): However, where it came down, they did not develop Type 2 Diabetes. So they themselves asked the question whether or not Type 2 Diabetes could be avoided, as you suggested earlier, if we actually prevent the liver fat starting in the first place. So this becomes not so much primary care and failures with primary care, this becomes health education in schools. This becomes monitoring of health in schools.

Louise Campbell (00:58:34): They’ll get a test, they get their jabs in this country at certain ages. Childhood diabetes and obesity is escalating. 10% of all 10 year olds who are morbidly obese have cardiac symptoms. So this becomes where are we going to monitor this? Can we put it into a timeline for schools, and find it?

Roger Green (00:58:58): Okay, Stephen you were going to come back to something Peter had commented on?

Stephen (00:59:07): Just some, I guess, pragmatic observations about looking at progression to a hard endpoint, it’s easy to do that, right, to say that. I mean progression to cirrhosis is clearly an endpoint that is associated with a negative hepatic outcome. But we also know that if you delay progression to cirrhosis that that is also applicable in a lot of ways.

Stephen (01:00:05): Just kind of working through as a thought experiment what Peter was saying, if you analyze your data through an interim analysis, and you showed maybe through artificial intelligence using fully quantitative assessment of collagen that you had less progression of disease, but you didn’t reach a clear number that said we had 300 patients progress to cirrhosis in the placebo group, and we had 100 in the drug group, so therefor we reached a pre-specified endpoint, and we should get approval.

Stephen (01:00:58): If you showed that you were marching towards that with some very validated markers then I think that would be one way to get accelerated approval, even though you didn’t hit the number, because I think it takes time, right. The alternative is you have to enroll a large number of patients, like a huge number of patients, more than what we typically enroll in a phase 3 NASH trial, and they need to be F3s, not F2s.

Stephen (01:01:35): Or we need to figure out what the rapid fibrosis progressors are and only enroll those guys because ultimately, that’s going to get us to a progression to cirrhosis endpoint quicker. I think the way the paradigm currently is, if we enroll F2s and F3s, the F2s are going to have a Much harder time even in the placebo group getting to cirrhosis in any time period less than 10 years.

Stephen (01:02:03): If you look at Rohit’s work, it’s about one stage every seven years to progression. So if we’re going from an F2 to an F4, that’s 14 years on average, so. I think that would kill drug development if we had to do that, but I think that getting something short of that by showing that we’ve reduced the rate of fibrosis progression, an AI is going to look at this from a percentage basis right, rate of halting progression of disease would be interesting to consider. But at the end of the day, I’m still a believer in accelerated approval, I just think maybe we need to make it easier for the endpoint to be defined.

Stephen (01:02:56): And I think we wouldn’t be having this discussion really if there weren’t issues with the way the pathologists are interpreting the data. If we had a clear agreement across the board with high kappa statistics, we wouldn’t be having this discussion, really. I think it would be a moot point. Making a surrogate endpoint easier to define, clearly having it linked to an outcome, I still think we can use accelerated approval to get these drugs to market, particularly some of the new drugs coming that have a potential major impact on CV outcomes as well.

Peter Traber (01:03:36): To a certain extent, Stephen, I’m playing devil’s advocate here. I am completely invested in what you just said, and the desirability of having an interim endpoint that’s going to give you confidence about whether you can hit the hard endpoint of progression to cirrhosis, and I think that that may be doable, I think the real question is whether the FDA or the EMA is going to approve a drug based on that kind of interim endpoint.

Peter Traber (01:04:14): But you will agree, I think, with me that if a drug has 50% of the patients respond with at least a one stage reduction in fibrosis, and 25% respond with a two stage reduction in fibrosis in F3 and advanced F2 patients that that drug has a much better chance of hitting the endpoint of progression to cirrhosis than some of the drugs that we’ve seen so far.

Peter Traber (01:04:54): And I think that’s kind of what people are going to be looking at, a drug that has enough robust activity to be able to hit that endpoint of decreased progression to cirrhosis. So I’m just playing a little bit devil’s advocate about what our expectations might have to be to get a drug approved.

Roger Green (01:05:21): One of the nice things about drama series is that they always have cliffhangers at the end, so that there’s always something to come back to the next episode. Let’s leave this topic in that category, and I also want to revisit the three-way relationship between Type 2 Diabetes, cardiovascular disease, and fatty liver when we come back to this, which I’m sure we will next week or the week after.

Roger Green (01:05:52): For now, I want to remind the audience we’re looking for guidance on exactly how to shape patient segmenting, and any other questions you’ve got on this, please email questions@surfingNASH.com or go to the webpage. I think this has been a great discussion. It’s been everything I hoped it would be, maybe a little bit more actually, and let’s just go back around one more time. Something you heard today that surprised you.

Peter Traber (01:06:26): I think what surprises me, or at least an observation from our discussion today, is we’re talking on two ends of a spectrum. One, a very important public health pole of what we do with fatty liver and early disease, and society, how we identify the disease and so forth, and on the other hand, how we develop a drug for more advanced disease with fibrosis.

Peter Traber (01:07:08): Those two poles are challenging to bring together, and I think that’s one of the things that we’re struggling with in trying to do, and I think it’s a struggle we should continue to explore, because that’s where some unique thinking might come forward.

Stephen (01:07:35): So just to follow on what Peter was saying, I don’t think that developing a drug for fatty liver has to just be about a liver endpoint, and maybe this is just not necessarily something that surprised me, but it’s something that gained a little more clarity from the conversation, and getting at drugs that can modulate the liver, but also impact CV outcome, for instance, is something that I think warrants a discussion, warrants a clear line of understanding and guidance by the regulatory authorities on how this can be done.

Stephen (01:08:31): I think it can be done relatively easily, and they’re drugs that are mainly going to go after the liver-related endpoint of trying to reverse the scar tissue and the fibrosis, either through hitting the drivers of fibrosis or hitting fibrosis directly. Or, they’re going to go after some of these extra hepatic endpoints at the same time. Maybe they’re not the greatest drug for fibrosis improvement, but they’re working on some of the drivers of NASH that actually may have more of an impact on CV outcomes. I think to your point, I think that’s worthy of a discussion on a different podcast.

Louise Campbell (01:09:20): I think my surprise today was how we all agreed that in the future we would really like non-invasive technologies at all to be the cornerstone of where we’re heading, because it’s advantageous to everybody, but once we’re there, and once we’ve got accurate ways to pick up the liver.

Suneil Hosmane (01:09:45): So for me, usually not a direction I go in, but I guess the one thing I’m surprised is that while we all agree that AI-based systems are going to have the potential to be very transformative, and we may be there from a technology standpoint, we haven’t discussed yet the other side of it, which is the business model side of that endeavor, because clearly data’s paramount. Data has a significant value, and a challenge in healthcare, in general, has been sharing of that data. So how do we realize it in practice, because I think there’s some nuances there that may get in the way of that coming into fruition sooner than later.

Roger Green (01:10:41): It might be fun at some point to get a couple of people who can comment specifically on ai to come on and talk about what could we do with better data techniques, ai and maybe some of the other, and machine learning and some things that go along with that, because I think what surprised me today was more realization than anything else, which is that if you work out from the liver, you go in a lot of different directions. That in a logical world, the way the market would go is that we would find ourselves to accelerated approval, get a couple of drugs on the market, and then start to see what actually happens.

Roger Green (01:11:13): Because if we posit complex pathways using second and third level data that don’t have the clearest relationships, and we’ve got to do all that before we have therapies, I have a hard time figuring out how we’re ever going to solve the problem, therefore how we’re ever going to proof the case. So either we’re going to solve it by getting drugs in some kind of accelerated approval setting, or by having such good machine learning and ai that we can start a model out at a level of complexity that I can’t see my way to yet, but my surprise is to think that that might be an answer, really.

Roger Green (01:11:48): Okay. I think we’re good for today. I want to thank all the surfers for coming on. I want to remind you to send us questions and comments about what we’re doing. I want to thank engineer podcaster Frank Sacco for making us sound good. Social media master Eric Rounds. Ellyn Charap has come on board as an editor and content manager, and an extra special thanks to you, our subscribers, and our listeners, some of whom we know, and a lot of whom we find out about every week who’ve made this an honest to goodness fast-growing place where people look for information about fatty liver disease.

Roger Green (01:12:23): We will be back on July 23rd, Thursday, with episode 15. We’re working on a couple things that might be real juicy at the time. If not, maybe we’ll just pick up this conversation where we left it and keep going through these kinds of issues, because I think they’re fascinating, and at least the panelists agree as well. Love to hear from the listeners. Until then stay safe, surf on, thanks everybody, see you next week.

Roger Green (01:14:35): I totally get that. Thanks guys, talk to you in a day or two.

Suneil Hosmane (01:14:38): Right. See you.

Roger Green (01:14:38): Bye.

Suneil Hosmane (01:14:39): Bye.


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