Ep. 4 WHEN YOU GET TO A FORK IN THE ROAD

Three possible scenarios for development of the NASH market.
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Roger Green presents three possible directions for the NASH market over the next 5-10 years and asks our panelists, including our guest, renowned nurse and patient advocate Louise Campbell, to suggest critical market-driving factors in our fourth episode, WHEN YOU GET TO A FORK IN THE ROAD…Three possible scenarios for the development of the NASH market.

 


 
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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 leaders, 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 (00:29): I’m Roger Green, and welcome to episode four of Surfing The NASH Tsunami. I want to thank those of you who’ve been with us for the first three sessions, particular shout out to the person who wrote in this week and said that he had binge listened to the first three episodes and found it relaxing and soothing. Needless to say, I never thought of my voice as being a particularly relaxing and soothing voice. So you gave me a good feeling. I appreciate that. And all of us, because we’re delighted since the person in question was a patient that you can get that reassurance listening to us, simply discuss what’s going on with the disease. That’s fantastic. As we get started, a couple of things are different and a lot of things are the same.

Roger Green (01:05): We are without Yasmeen today, she was unable to join us. Fortunately, we have an excellent guest sitting in with us. Louise Campbell. Louise is a patient advocate and a nurse activist based mostly in London, a couple of other places, she’ll talk about that. And among her other honors, was selected as the hepatology nurse of the year in 2018 by the British Journal of Nursing. As a patient advocate, Louise’s perspective is likely to be different than Yas’s as an investor or an analyst, but equally valuable in its own. And we’re really excited to have her with us. Good afternoon, Louise.

Louise Campbell (01:34): Good afternoon everybody. Nice to be invited and thank you very much.

Roger Green (01:39): We’re delighted to have you here. First of all, after episode two, [Nial 00:01:42] asked whether and when we intend to cover the NASH NAFLD versus NASH NAFL issue, that’s now scheduled two weeks hence, I’m delighted to announce that Dr. Quentin Anstee of New Castle university will be joining us to discuss the NASH NAFLD perspective on the issue. If you’re looking for a debate, I don’t think you’re going to get one. I think what we’re going to get is more of a conversation about the needs that drove that position and how to deal with it in an inappropriate global way. However, I think it’s going to be a really exciting session. That’s in two weeks.

Roger Green (02:12): Next week, Louise will be back and we’ll be talking about patient advocacy and supporting patients and how it’s similar and different in the US versus the UK. This week, we had a question, I do want to get to from Max in Canada. Max is in fact the binge listener in question who has a warm spot in my heart. And Max had two specific questions to Steven. I’m going to read them both Steve, and then you take them both together. Number one, does NASH always wind up paving the way for cirrhosis? And number two, can NASH be reversed ending in total recovery? Stephen, why don’t you start and then everybody else feel free to jump in.

Stephen Harrison (02:44): Thanks for asking that question. Maybe another way to ask the question would be how often does that occur? And that’s crazy. We don’t have a ton of data, but we do have a growing body of prospective data that shows that NASH can progress to cirrhosis in about a quarter of those cases. Another of the questions that often comes to mind when we think about epidemiology and natural history of the disease and NASH is who are those people that are likely to progress to cirrhosis that have NASH? And that’s another area of intense investigation. One of the things we do know, one of the contributory demographic factors that we do know is associated with progression of diseases. We know that if you have diabetes and you have NASH that your rate of progression of disease might actually be more than a non-diabetic, but certainly you have a higher probability over time becoming a cirrhotic patient.

Stephen Harrison (03:41): An additional data that’s come out is how quickly do people progress. And again, not a lot of data. The modeling that’s been done has shown that average rate of progression is approximately one stage every seven years. But again, based on the heterogeneity of this disease, that’s also highly variable and also influenced by the presence of diabetes. And there are likely genetic and epigenetic factors that are also linked to this. Some of the genetic factors that we’ve recently found to be associated with fatty liver and as well as the severity of disease, would be P&P and [inaudible 00:04:14] single nucleotide polymorphism, and then the HSD 17 beta 13, single nucleotide polymorphism, and then TM6SF2. There are others that are out there, but they haven’t been shown repeatedly in multiple different GY studies to be predictive of progression or associated with more advanced disease. And so I think the three big genetic single nucleotide polymorphisms are those that I mentioned.

Stephen Harrison (04:40): And then there’s epigenetic factors. These are also contributory and more often environmentally linked if you will. Maybe a simple way of looking at this is there’s a nurture and a nature phenomenon to progression of disease. If there’s a hundred million Americans with fatty liver, why do only 25 million have NASH? Why are the other 75 million protected? Free fatty acids are very, very toxic to the liver, as well as the components of cholesterol, the metabolites of cholesterol, which is diacylglycerols, ceramides and the like. So how is it that 75% of people with fatty liver are able to handle that free fatty acid load without developing a NASH phenotype? So that’s also a question, and not just a fibrosis progression to cirrhosis that occurs in about 25% of NASH. So maybe a long winded answer to the first question, as far as the second question goes, disease regression can occur naturally.

Stephen Harrison (05:38): We learned from the [Scenic River Rock 00:05:40] trial which was a trial that finished out a couple of years ago, where liver biopsies were done at baseline at year one and year two, there were two different dosing arms in a placebo group. And actually 25% of the cohort was placebo across all three liver biopsies, and were able to get really a mini natural history study if you will. From that trial we learned that about 20% of patients can regress their disease from year one to year two, and from year to year three, those that actually got better could get worse, and those that got worse can get better, and really nothing was done to temper that effect. There is a bit of a difference in fatty liver than there is say in hepatitis B or hepatitis C, where there seems to be a steady progression of disease over time.

Stephen Harrison (06:25): This one is more like a two steps forward, one step back phenomenon. And it may explain in part why the placebo group, and a lot of our drug development trials in NASH seems to be higher than in other studies. But having said that, we do know both from bariatric surgery data, significant weight loss studies, that you can literally reverse this disease. Now, what is often confusing to the population is once you get scar tissue in your liver, can that be reversed? And I think the answer is unequivocably yes, up until a certain point. I personally believe that once you develop cirrhosis with complications of what we call portal hypertension, meaning develop hepatic encephalopathy, develop fluid in your belly that we term ascites, you develop significant varices, these dilated veins in the esophagus and stomach that the physiology becomes different. And it really becomes challenging to reverse that. But up until that point, I firmly believe that fibrosis is reversible. So I’ll stop there and maybe open it up to my colleagues to see if they have anything they’d like to add.

Louise Campbell (07:34): Absolutely second everything that you’ve said there, the only thing that I could add to that is that having done an awful lots of patients, say hepatitis C, with decompensated cirrhosis as part of one of our advanced programs at the NHS, and very early, we have seen a number of patients with that background, reverse and come out support for hypertension as their liver softens up. And I just wondered whether or not you could suggest there could be a similarity if you removed and treated with weight loss and programs, at that stage would you expect to see an improvement in the liver condition in decompensated cirrhosis for example?

Stephen Harrison (08:12): I followed a couple of patients clinically for about 15 years, that underwent either significant lifestyle modification, where they lost by themselves 100+ pounds. Some of these people actually had cirrhosis with portal hypertensive complications. And while yes, I’ve seen the ascites go away, I’ve seen the encephalopathy improve to some degree. I even rebiopsied one of these people, and they remained cirrhotic and their platelet count remained very, very low. That’s one of the things that I have noticed particularly with NASH, is that I can’t get the platelet counts back up. Once they go down, they tend to stay down.

Stephen Harrison (08:50): But I don’t think we have really studied enough of these people Louise, to really answer your question. I totally agree. I can take an autoimmune hepatitis cirrhotic, a hep C cirrhotic, a hep B cirrhotic. I can cure them or suppress them, and I see reversal of cirrhosis. We know that has been shown in those liver diseases. I just don’t think we’ve got good enough therapies yet to know what kind of reversal of disease we can get. And is it only going to be clinical improvement or will there be concomitant histopathologic regression of scar to the point where we say there is no longer evidence of nodular formation, we’re back to bridging or something like that.

Louise Campbell (09:31): Thank you.

Roger Green (09:32): Okay. That’s great. Let’s jump into the opening round of introductions and just check-ins with everybody and then we can go into today’s main topic. Let me start with Louise. Louise let me invite you to give a brief introduction to who you are and what you’ve done in liver disease. And then the other question that goes along with that is the most encouraging thing that you’ve seen in your professional life in the past week. Although you may talk about one in your personal life.

Louise Campbell (09:52): I’m a nurse from the NHS. So 35 years, and I left the NHS in September having established a FibroScan delivery company, which was the first in the UK, called Tawazun Health, and Tawazun for those who don’t know it means balance, equilibrium, and harmony in the Urdu and Arabic languages. And of course the liver is all about balance and health. I’ve worked extensively in the NHS. I was also fortunate to be asked to co-chair the Inaugural Nursing and Associates Forum at [Easel 00:10:23] in 2012, with [NIDASA 00:10:24]. I hold a master’s degree in advanced practice and I’ve worked in liver disease for over 30 years. The predominant reason I left the NHS was actually to allow patients or individuals, because we could all get patients, create [inaudible 00:10:37] to diagnostics to give them the opportunity to find fatty liver disease and liver disease generally a lot earlier, to potentially prevent developing type two diabetes, heart disease, and those increased risks.

Louise Campbell (10:49): And as we discussed and have discussed, people can reduce and reverse methods in earliest stages and therefore reduce the risk of comorbidities that are driving noncommunicable disease. So that’s why I’m here and advocating for patients and the greater access to medications, trials and diagnostics to find a disease a lot earlier than we do currently. I suppose my personal is that after 10 weeks of locked down, I absolutely managed to do a social distancing meet up with my parents, and my mother unfortunately is one of the 1.7 million people in the UK that is isolated, with my dad. So that was nice to see them looking so well and not touch anything or go anywhere near, but seeing them physically, which was great. And I suppose from my professional life, I suppose being asked to be part of your group, which has been extremely interesting and enlightening to listen to over the past three weeks.

Roger Green (11:47): Thanks Louise. That’s great. Peter, why don’t you go next?

Peter Traber (11:49): Most encouraging thing in my professional life is for the past two years I’ve doing consulting for large pharma and small biotech in the area of liver disease and drug development. And what I have seen over the last week is an increasing need for the type of consulting advice that I provide. So there’s no shortage of work, there’s no shortage of companies to work with. And I think that that’s very, very encouraging because as many of you would know, our consulting services are typically one of the first things to go away when economic times are hard and so forth, but this encourages me because it means there’s a demand for planning for the future. And people thinking about clinical trials, thinking about drug development. So I found that very encouraging and something that I’m experiencing real time at this point.

Roger Green (12:44): Okay. That’s great. Stephen.

Stephen Harrison (12:45): Professionally for me this week, exciting times in Texas, we have opened back to screening. So we are… I wouldn’t say full speed ahead with screening. We are dipping our toe back in the water. Hopefully this will be a sign of things to come throughout the country as we begin to get back to some level of normalcy, even though we have to all double mask and keep our distance and that sort of thing. We are still at clinic tomorrow. It’s still going to be telehealth clinic, 15 minutes per patient over the phone. It’s hard to do new consultations by the way as a hepatologist over the phone, but it’s something that we’re trying to work through. But good news, we opened back to screening, and so hopefully that’ll continue.

Roger Green (13:29): Excellent. So I’m laughing about your comment about telehealth as a hepatologist. I had an appointment scheduled for Thursday with my dermatologist, because I had skin cancer in the past. And I got a call from the office asking if I wanted to take the appointment as telehealth, I casually explained what the appointment was for and asked if they had a way to do this via telehealth and the receptionist started laughing. That’s right. There’s some medicine you just can’t do that way. That’s fair.

Stephen Harrison (13:52): Yeah, there’s only so much you can do when you ask your patient, “Feel your right upper quadrant. Do you have abdominal pain? Can you feel an extra edge there beyond the rib? And do you have ascites?” At some point they can tell you if their legs are swollen and you can look at them and see if they’re jaundiced. That’s the one good thing about being a doctor? First thing that we’re taught is to determine sick versus not sick. And often that’s as simple as looking at the patient. Beyond that, the nuances of establishing a venous hum or a S3 on a heartbeat or something like that, we’re going to be unable to do through telehealth. It’s still limited.

Roger Green (14:30): But as you point out, getting in the right direction, my professional for the week is really simple as listeners to this podcast will learn over the next couple of few months, one of my soap box issues and liver diseases about diagnostics, and what would we want to know and how would we want to do diagnostics in a more ideal world, or even if we were a different disease that had different kinds of histories and patterns. I’ve had a bunch of conversations about diagnostics with different people this week that suggests to me progress is being made. So I’ve found myself in more conversations with different classes of stakeholders about diagnostics and how to improve diagnostics in the past week that I want to say I had in the preceeding month and a half. So I think that’s a good thing because I think that’s an area that will need work and conversation as time goes by. With that, as we noted last week, this is my week to set up the conversation and certain panel members suggested that I might or might not be up to the pressure. So let’s see what happens.

Roger Green (15:21): I would like today’s exercise to build on comments we’ve heard from all our panels previous to this week. Peter’s concept that hope is not a strategy. Stephen’s comment last week, that the relationship between NASH and COVID-19 could wind up being anything from, I would describe it as coincidentally, they’re both happening at the same time, but they’re not related, to causal which is clearly liver health drives response to COVID-19. And then the general question that’s arisen as to whether COVID-19, will the government agencies, payers, and profession to think differently about the goals of treating patients with liver disease. Where that could lead us is the size of the market and the nature of the agents that are a value can vary dramatically, depending upon one of three foreseeable big picture scenarios that might emerge over the next five to 10 years. I’m going to call those narrow NASH, broad NASH, and broad fatty liver.

Roger Green (16:18): In narrow NASH, the emerging correlation between COVID-19 and NAFLD proves to be a correlation but not causal. There’s nothing about NAFLD that causes COVID to be more serious or more often mortal. In fact it might be the other way around or it might be a thing. And it turns out that treating the liver itself does not provide dramatic benefit in metabolic syndrome, compared to treating the other elements that we’ve been treating for a longer time, diabetes, cholesterol, hypertension, et cetera. At that point, the economic value of NASH drugs rests largely on their ability to prevent cirrhosis and liver cancer, with subsequent cost of transplant and a long, slow, expensive less six months or 12 months of life, with much hospitalization in many events. That would be narrow NASH. Broader NASH, COVID-19 and NAFLD correlation turns out to be non-causal as I described, but NASH developers prove significant independent value in treating metabolic syndrome patients beyond what we’re doing with therapies that we already have for other manifestations.

Roger Green (17:19): So due to smart development combination therapies and the research I just described, robust real world evidence in health economics, outcomes studies, combined with smart pricing decisions, to create a NASH franchise that transitions from merely preventing cirrhosis to having an impact on total cardiovascular or metabolic health, in anybody even with early stage NASH, that’s broader NASH. Broad fatty liver is what I just described for broader NASH. Plus it turns out that NAFLD is a predictor, maybe even a robust predictor, of how sick people who experience COVID will get and how many of them will die. That may also turn out to be true in other aggressive viruses. It’s reasonable to believe that COVID-19 is not the only novel pandemic quality virus we’ll see in the next 20 years.

Roger Green (18:03): And as a result, treating NASH provides independent benefit in all these diseases and a market develops to treat the NAFLD patients, particularly those have other risk factors involved. So that they don’t react so severely to viral infections at the same time that we’re also focusing on metabolic health and early stage NASH, and cirrhosis and liver cancer and late stage NASH. Those are the three scenarios. And I’d like to ask each of the panelists, speaking from the perspective of your stakeholders. So Peter the C suite, Stephen the clinical research [inaudible 00:18:37] community, Louise patient advocacy, three questions. The first one’s an easier one I think. Take a hundred points of likelihood, and divide them between the three scenarios. So how many points would you put on narrow NASH being the outcome? How many points would you put on broader NASH being the outcome, and how many points would you put on broad fatty liver disease being the outcome?

Peter Traber (18:56): I’ll go ahead and start, Roger.

Roger Green (18:59): Thanks Peter.

Peter Traber (18:59): Thinking about putting from the constituency that I’m trying to represent on this podcast, which is really the company leadership boards, stockholders, investors, C suite of drug development. I want to point out that these tend to be conservative views. I would probably in terms of that ranking, out of 100 points, I would probably say the first scenario is about 40 points, the second scenario is 50 points and the final scenario where COVID-19 and liver health are intricately related and causal is only about 10%, thinking about the future. So the reason I ranked things in that way from looking at it through the eyes of the constituency I’m representing, is that this is a highly regulated area with regulatory agencies being very important. If they tend to move deliberately is one way to describe it.

Peter Traber (20:01): And we only recently have acceptance of a one-stage reduction in fibrosis in pre-cirrhotic NASH with no change in NAFLD activity to be an endpoint that’s approvable. And there’s a lot of data that links the degree of fibrosis with morbidity and mortality in the disease. That has been a struggle to obtain that regulatory guidance. And I think each step of the paradigm that you’ve described, which is really a fascinating hypothetical structure, is going to take a lot of effort and clinical trials and so forth before you get to those regulatory requirements. And so I think that companies are going to be conservative in that regard. So for instance, we’ve got now one phase retrial with a better cholic acid that has met the primary endpoint for phase three. Clearly there is a lot to be desired and a lot of room for improvement over the cholic acid results.

Peter Traber (21:04): We’re now waiting for elafibranor results to see whether we can actually reverse NASH in a phase three clinical trial. That will be a second important step. And each step of the way, whether it’s reducing fatty liver and its association with cardiovascular disease or overall outcomes is going to be a lot of efforts. So I think that the first one we’ve got relatively well established, the second area we have data coming out and it’s looking interesting to combine the cardiovascular risk factors together. The third point about a healthy liver in support of fighting serious viral infections is going to take some time to structure the studies that can weigh in on the regulatory infrastructure.

Roger Green (21:55): Okay. Thanks Peter. I guess Louise you are next.

Louise Campbell (21:58): I think obviously I’m going to try and look at the patient’s perspective from this. And I think it is one of those things that we’re going to have to answer very quickly in some respects, we’re not as conservative. If I had to look at the three scenarios from a now perspective, which is probably very battling COVID-19, it’s startling how much liver involvement is in all of the comorbid conditions that cause severity. I think both the American association for liver and the European association for liver, we’re very early in their timeline when they produced guidance detailing that people with NAFLD and NASH were at high risk of severe COVID 19. And I think that could be what we’re seeing, but I’m also surprised that whilst we mentioned all comorbid conditions, we actually don’t mention liver at all, except predominantly what is COVID-19 doing to the liver enzymes.

Louise Campbell (22:53): If we look at patients with NAFLD, most of them are not diagnosed. You stated earlier, Stephen did, that you’ve got 100 million people with suspected NAFLD in the US. We have 14 million suspected in the UK, but there’s very little screening going on for diagnosis. And I think we have patients or people and individuals, mothers, fathers, cousins, brothers, and sisters, who are at risk of NAFLD, who may have prediabetes and comorbid conditions that they haven’t yet found. So if I was to look at these scenarios now and so where we need to be feeling safe and where we can make a difference from a patient’s perspective.

Louise Campbell (23:33): We all want to know what we can do now. And I think I would probably ask, probably on 50 on the broad fatty liver opportunity, and at the moment there’s quite a lot of synergy going on with some of these time comorbid conditions, obesity and [ascnesity 00:23:49] involvements. I would go for 30 on broad NASH opportunity and probably 10 on the narrow NASH opportunity, because whilst we don’t have a vaccine, we do need to try and answer some of these questions quite quickly with retrospective data, using ultrasound as diagnostic because liver function tests are not going to be the best way in a septic condition of any description to help us look at that.

Roger Green (24:16): Thanks, Louise. That’s a great answer. Stephen.

Stephen Harrison (24:18): So just from my wheelhouse and where I see this, I put 20 points on narrow NASH, 70 on broader NASH and 10 as Peter did on broad fatty liver. What I’ve noticed with this pandemic is that everybody is aware that there’s a pandemic, unless you’re living in some remote island. 187 countries have been impacted by this disease. And I can say that COVID-19 did in a matter of one quarter, what NASH has never been able to do. And that is disease awareness happened just like that with COVID-19. My question is rhetorical in a sense, but what would it take for something similar to happen in the NASH community, with fatty liver community? And I think we never would want NASH to go the way of COVID-19. We don’t want to see the morbidity and the mortality to NAASH that we’ve seen with this pandemic.

Stephen Harrison (25:23): But it brings about a point, and that point is there is a cross link. There is a Venn diagram, if you will, between COVID-19 and fatty liver. We’ve seen that in publication after publication and more data is forthcoming, where we see that people that get into trouble with COVID-19 tend to be those that have the exact same co-morbidities as a NASH patient. So we have the number one liver disease on the planet, which is fatty liver. And we have a pandemic. And I think can we use this opportunity or is there a way in which disease awareness maybe spawned through the pandemic, showing that there’s a link with co-morbidities to NASH, and elevated liver enzymes in the setting of NASH to drive disease awareness? I think where that happens that will be key. But ultimately I put most of my points in the middle category, broader NASH, because I do believe that the number one killer of a fatty liver patient is not liver disease. It’s heart disease.

Stephen Harrison (26:27): Now what’s less clear is a NASH patient at higher risk of NASH, than a NAFLD patient or somebody that has fat, but not the components that would give them NASH. I think that’s less clear. But I do think, that has been shown in multiple studies, that there is a link between CV outcomes and fatty liver. Now here’s the kicker, in 20 years cardiologists have never been able to improve on primary prevention of a myocardial infarction. The rate of myocardial infarction to my knowledge as a dumb hepatologist, is exactly the same as it was 20 years ago.

Stephen Harrison (27:03): Now where we’ve gotten better is secondary prevention, by giving medications that lower LDL cholesterol and managing comorbidities, aspirin a day, things like that we’ve impacted. But why haven’t we changed the primary prevention in this disease? In my opinion, I think because so many people have fatty liver and so much systemic inflammatory response is generated from the inflamed liver, that I suspect it’s contributing to unstable plaque in the coronary arteries. And if we’re able to mitigate that inflammatory response generated by the liver, then we will have impacts beyond the liver, on comorbidities such as CV outcomes. And those trials by the way are just now beginning to get underway.

Roger Green (27:48): Okay. Thank you, Stephen. My answer that I would have given in the first place, you folks have just done a really good job of explaining why I’m about to give this answer. So I’ll explain a little bit first, please note on the issue of NAFLD and COVID, that if you come from a medical perspective or a clinical perspective, you tend to rate that very low right now. If you come from a patient perspective as Louise did you rate it quite high. A lot of that, by the way, is linked to Stephen’s question about what would it take for NASH to get the awareness that COVID did, behavioral economics predicts that nothing is going to get more attention than something that has a really high risk factor associated with it, that comes on you fast and you have no idea how to control, say a pandemic. Whereas a disease that creates toxicity over a longer period of time, that folks have lived with is just not going to have the same drama.

Roger Green (28:39): So I think the answer to the question, the third point about fatty liver and pandemic, will have much to do with the intensity of the second wave of this pandemic. And whether we see another one for a year or two. If it turns out that the first pandemic of COVID is a one off event in the world, things will never go back to exactly what they were, but focus on finding a more wholistic understanding of serious viral disease and particularly pandemic level viral disease will matter less. If there’s a second wave in the fall, or another pandemic in the next couple of years that number will go way up.

Roger Green (29:13): Me, I happen to think based on everything I read. Second wave in the fall will be reasonably significant. And as a result, I probably put the broad NAFLD number somewhere between 35 and 40, because I think we’ll find something there. If we get desperate enough to do anything and the drugs we’re approving right now, with limited trial, a certain level of desperation has indicated this is a solution people will look for. I think the odds on narrow NASH being the end market are negligible because I agree with Stephen. I believe that the studies emerge over time will demonstrate real power behind the implications in cardiovascular syndromes. So I probably wind up going 10, 50, 40, somewhere in the middle between all of you. But I think that’s how it turns out. Let me just ask real quickly before we go on to the next question. Without any explanation, what would your individual assessment be in the odds of those three scenarios? And Peter I’ll start with you again, just the numbers this time.

Peter Traber (30:04): My individual assessment would be 30, 60 10.

Roger Green (30:11): Okay. Louise.

Louise Campbell (30:12): I think if I had to say my personal view and looking more in the future, I looked at from a current perspective and the need, I would probably go 30, 60, 10 again.

Roger Green (30:24): Okay. Stephen.

Stephen Harrison (30:26): Well, given that I’m from Texas and I think that my views are exactly the views that should be applied by everybody. I’m keeping them what I had before, which was 20, 70, 10.

Roger Green (30:40): Okay. And as I say the problem with my view is that it’s not purely scientific. It’s predictive on how desperate we are to stop the pandemic. But if you simply asked me to choose numbers because I thought they were right, I’d probably wind up somewhere around where you guys are, or maybe a third upfront. So it winds up being 33, 57, 10, but that’s just because it’s one in three, one in 10, and then whatever’s left. So 33, 57, 10. It’s interesting we wind up in the same place ourselves and somewhat different places when we think about our stakeholders. I think that’s fascinating, maybe a subject even for another day, but not this one.

Peter Traber (31:14): I have a general scientific feeling, clinical and scientific feeling. That the ability of the liver as a central metabolic organ, to respond to insults, including overwhelming viral infections such as COVID-19 is very important. So that’s number one. And I agree with Louise on that. The second thing is that the fact that the liver is so important in so many diseases that liver disease and particular NAFLD and NASH are intertwined with all other comorbidities, maybe with the exclusion of pulmonary fibrosis. But even there there might be some interaction, but cardiovascular disease, diabetes, obesity, et cetera. So teasing out the effect of the liver versus other comorbidities is a challenge. Now I’m 100% percent behind the idea that this association that has already been shown between NAFLD, NAASH and the COVID-19 infection, can be instrumental in dramatically increasing the visibility of fatty liver disease and a reason for individual liver health and promoting liver health.

Peter Traber (32:45): The issue I think for drug development is are we going to have enough data and enough understanding of how to evaluate that in clinical trials to support a drug to be used in a hundred million people in the United States for NAFLD, and that’s where I think some of the likelihoods starts to unravel a bit. But that’s not maybe as important as having the general public recognize that healthy lifestyle and weight loss and exercise is important for your liver health and the healthier your liver is, the less likely you’re going to be to have severe COVID-19 disease. So I just wanted from my perspective to link all those things together a little bit.

Roger Green (33:34): Okay. Thanks, Peter. I think I agree with you that probably the largest single challenge on all of this is going to be there will be no way to do a prospective study on pandemic intensity virus and say response to any kind of drug, really liver drugs certainly because the ethical consequences of getting somebody to take placebo will not be allowable. By the time we get to standard of care, the numbers will be a little decent standard of care that the need will be a little greater. We’ll see how all that plays out. Let me ask each of the group, I’ll reverse order this time, start with Stephen. What do you see is two or three things that will happen over the next five years, any different clinical trials, MNA activities, retrospective studies, stock market issues, political events in any part of the world, that will serve as the key forks in the road in terms of whether we wind up going… whether the medical treatment and the market goes narrow NASH, broader NASH, broad fatty liver.

Stephen Harrison (34:28): This one is a little bit tougher for me I think to pontificate on, just because of the unknown. It seems like we’ve been doing drug development in NASH for a while now, but we’re still so early in our understanding of the pathogenesis, even the natural history of this disease and certainly therapeutic efficacy. You think about the first drug coming to market, and by intent to treat you’re looking at about a 14% Delta in fibrosis improvement of drug over placebo, and that drug is very likely to be approved. So the bar is pretty low on where we’re going. But I think there will be some seminal forks in the road if you will that allow us to converge on a way that we can identify and treat these people. And I think one of those is focused on the liver itself.

Stephen Harrison (35:27): One way to look at it is let’s look at the liver itself and begin to see what we’re doing to improve that. Another one would begin to look at outcome measures, and outcome measures I’m speaking of here are outside of the liver sphere, and particularly that CV outcomes. So cardiovascular disease outcomes. And a third category that’s marching in parallel with this is the development of our disease state awareness and a noninvasive testing strategy that allows us to do three different things. Very uncharacteristic of me, I have three different categories, and then some sub categories under there. So just bear with me as I work through this. So in the liver world, first of all I think once we have a drug that really impacts [inaudible 00:36:12] and NASH resolution, I think that’ll become the benchmark drug. That’ll become the 800 pound gorilla, the backbone therapy for this disease.

Stephen Harrison (36:22): Now ideally we want that to be oral, we want it to be well tolerated. We want it to be once a day, like taking a vitamin. Something that doesn’t have any side effects, people just take it. And it does miraculous things to both inflammation, part of cellular injury, fat and fibrosis. We’re not there yet. We have some early drugs in earlier development that look like they may be impactful in this arena, but I think once you get an FDA approved treatment that hits both endpoints at the same time, that’ll be a watershed moment in this disease and for the entire field. Moving away from that and now focusing on extra hepatic manifestations or improvements in this disease I think is cardiovascular outcomes. Once we have something that gives us a signal that we’re changing the paradigm of how these people die, most commonly over time would be impactful.

Stephen Harrison (37:17): Now we’ve never mentioned the second leading cause of death in fatty liver patients, which is non hepatic malignancy. And there’s significant links in the literature to breast cancer, colon cancer, pancreatic cancer, and I’m missing several cancers. But ultimately these are all inextricably linked to insulin resistance and obesity. And I think that ultimately we’ll see improvements there. But the third area that is critical is this noninvasive testing, because we’re never going to get where we want to be if we have to do liver biopsies. There’s just not enough people to do liver biopsies, the complication rate is not where we would like it to be, even though it’s low, but maybe the biggest thing is it’s scary. It’s scary to have a harpoon shoved into your liver. And that’s why we try not to show the patients the needle when we do their liver biopsies, because it’s scary. But let’s focus on noninvasive testing, there are three different context of use where we really need to develop something.

Stephen Harrison (38:17): One is the diagnosis, the diagnosis of NASH versus fatty liver. I need to know as we talked about at the top of the broadcast, I need to know who is going to develop the more severe form of fatty liver and progress to cirrhosis and develop a decompensating event. So that’s one. Number two is markers of therapeutic efficacy. I need a noninvasive test to tell me if I put them on drug Y, that it’s working and how long I should treat them before I stop the drug, if at all. Number three, I need a marker that tells me longterm patient outcome benefit.

Stephen Harrison (38:51): And I think once we have a tool or multiple tools that can answer those three contexts of use, we’ll be moving into that next fork in the road. So collectively just to review, a drug that moves fat and fibrosis, so steatohepatitis and fibrosis will become a backbone drug. I think a drug that modulates CV outcomes and I think noninvasive tests that address the three different contexts of use. Wherever those come down the road and whatever order they come in, each of those will be a fork in the road that gets us further to our overall goal of success in eradicating this disease.

Roger Green (39:33): Thank you Stephen, that’s a great answer. Louise. Why don’t you go next?

Louise Campbell (39:36): Thank you Stephen, I felt that that was a great summary and it is a complicated area. I’d like to see this more as an opportunity. And I think the opportunity is there to make this more of a broad fatty liver opportunity, by a disease awareness that allows people who are currently undiagnosed and unscreened to be located. Now I think that means that we can be aggressive across the timeline, we can look at medications that can help people maximize their own input into their lifestyle alterations and monitor with noninvasive devices like FibroScan and some of the blood parameters. And I think it’s an opportunity to be able to help with healthcare costs, because if we can utilize this to help reduce people’s risk of NAFLD, we can help reduce the risk of the cost to cardiovascular symptomology and mortality. The cost acquired for type two diabetes, vascular surgeries when limbs are lost.

Louise Campbell (40:41): And it’s an early opportunity now to change the trajectory of metabolic disorders in patients that can make a vast difference to their own health, but only if they know that they have these risks. Currently the majority of people as we know are undiagnosed. And when we all talk about patients in our practices and who we see, it is only the 1% that has gone to a physician who’ve made it through the pathway of healthcare, to get to healthcare and specialists, who then get the opportunity to participate in these clinical trials. And I think I’d also like to see this as an opportunity by awareness of metabolic syndromes and diseases. They’re all co-related to improve the amount of people who want to participate in clinical studies to find mechanisms to improve liver health, beyond their own ability with lifestyle modifications, weight loss, a bit of exercise particularly in children and teenagers. Because I think we’re going to see cardiovascular in the mortality age groups drop, as childhood obesity and fatty liver in children increases.

Louise Campbell (42:03): So I think there’s multiple forks in the road. For me I think they’re all about the opportunities that we can gain out of the period that we’re in now. So yes, I’d ultimately like to see the patients and people take the power back with medications and with the healthcare professions to try and reduce the co-morbidities, there’s liver cancers associated with diabetes. And we know in a lot of these guidelines, patients with type two diabetes it is recommended that they are screened for liver cancer and liver fibrosis because of their increased risk. But we don’t see it happen too often. Hypertension is recommended that patients undergo assessments for fatty liver disease. But again, I know lots of people I see, I have seen for years, who have been told by their GP and primary practice, years ago on an ultrasound that they had fatty liver, but it wasn’t seen as important.

Louise Campbell (43:02): And I think we’re driving now opportunities for clinical trials whereby this is probably one of the most important conditions. But we just don’t see and hear liver mentioned enough by any healthcare providers. It’s the poor relation. And I think we need to say the word more often. And we need to understand that everything we eat and drink goes through the liver. Every medication that we’re using to treat coronavirus and everything to these patients gets metabolized in the liver. So there is a potential knock on effect to the more patients that we can get and locate the more opportunities we have, to do all three of these scenarios, because we’re going to find them at different stages on the pathway. So all three, if you narrow broad fatty liver, are really important as to where we’re going to locate this population, at 23% of the global population are estimated to have NAFLD. So it’s a big ask.

Roger Green (44:06): Thanks for an excellent answer and a really different perspective. Peter, what do you think are the two or three major inflection points?

Peter Traber (44:11): I’m struck with the fact that listening to both Louise and Stephen’s answers that I’m not often violently in agreement with everything they said. They come from different perspective but I think that everything they said was quite right. I would think about the milestones that are going to change things as one inexpensive readily available point of care test for significant fatty liver disease. I think that’s really a very critical thing. And once we start identifying more people and can get broadly out there, I think that that that’ll move things forward. I think that a drug that has sufficient efficacy, that in both fibrosis and NASH and fat, as Stephen said, is also very important. And we are very far away from that.

Peter Traber (45:06): Remember that something like a statin decreases cholesterol in everybody. You may not get optimal control with just a statin but it decreases cholesterol in everybody. What we’re seeing right now is as Stephen said in fibrosis, the drug that is being reviewed for approval has a 14% marginal efficacy over placebo, while that drug is never going to get close to broad use and preventative use. So a huge milestone and inflection point will be when there is a sufficient percentage activity in both fat and fibrosis to start thinking about those more preventative or earlier therapies. And I think that we are headed towards things like cardiovascular and cancer outcomes and the same goes for COVID-19. I think that we will have increasing data to show that COVID-19 outcome is related to liver disease. And the more data that we generate there is going to push forward specter of liver disease in community. So I think there are a number of different inflection points that are going to affect this disease and market.

Roger Green (46:28): Okay. That’s great Peter and a really nice summation and third point. Forecasters have to answer questions about inflection points all the time. So I think I’m probably a little… I have clearer sense of where this goes. I believe the first key inflection point is going to be this fall and it will have a lot to do with the level of a second wave of the COVID-19 pandemic. If there is, as I said earlier, if there’s a robust second wave and a lot of people are affected and there’s high mortality, that will drive response that focuses a lot more on COVID and pushes to a broader fatty liver issue. If that’s relatively muted then I think you’re less likely to see that more focus on typical liver and metabolic issues, number one. Number two is Stephen pointed out the need for noninvasive tests, noninvasive tests are pivotal.

Roger Green (47:18): And the more informative those tests are, not just on what is your level today, but our ability to understand the path of disease over time, the better we’ll become at devising solutions that can include both drugs and also behavioral interventions and other kinds of things. And the third one as Peter pointed out, we need a medication that affects both processing of fat and fibrosis, at the same time in significant portion of the people. My guess would be over 50% in both, is the point at which we cross a line and we say, “Okay, we have drugs that do a good job at treating this therapy and can be trusted.” So I would say those are the three. Third question, what is the one thing that you think your stakeholders are undervaluing when they look at this issue downstream? And what do you think they’re overvaluing?

Louise Campbell (48:01): I think if I have to say what some people hike or undervalue is the fact that they’ve suffered from that for so many years that they lose the confidence that they can make a significant difference to their own disease, very small changes. And when you talk about diagnostics, yes I use FibroScan but I use FibroScan a brief interventional therapy. And I think patients really engage with it. And I think very few patients engage with a biochemical formula that we use in clinics. But they do engage with seeing it and watching the technology. And I think they value that change that they can see, visualize regularly.

Louise Campbell (48:44): So I think they undervalue their own ability to make it a significant difference to liver health with minor changes. And I think what we may overvalue is looking for somebody else to provide us with the solution, the one pill that fits all, as Stephen described earlier. It would be lovely to think about that but it may not happen right in the near future. And we can make a difference and patients and individuals can make a difference to their own liver health, cardio-metabolic health, and everything, with really small changes to lifestyle. And it’s achievable if supported in the right way. And I think that’s key. They’ve got to be supported throughout this.

Stephen Harrison (49:26): Okay. Well, I actually would agree with Louise on the undervalue. I think we say eat less, run more, very tongue and cheek ways when we talk about lifestyle modification. And I don’t think that we really reinforce enough to a patient the benefits of what they can achieve with 10% weight loss, 7% weight loss, 5% weight loss, heck any weight loss. There’s an old paper published from the [Ann Heins 00:50:00] database looking at people with fatty liver. 50% of them are couch potatoes. Literally they don’t get off the couch. Their idea of exercise is reaching for the clicker, and going to the refrigerator, and their eyes moving when they read a book or something. Literally the idea of even getting out and walking around the block is daunting to them. So I think just having a conversation about just hashtag real talk, what are you doing every day?

Stephen Harrison (50:32): And it’s something I tell my kids every day. It’s not one time that my son runs five miles and comes back in and says, “Dad, look what I did.” It’s can you do that every day? Can you be consistent with it? It’s one thing I learned in the military. When I wake up at four o’clock every morning, and go do pushups, sit ups, and run and get yelled at by the drill sergeant, after about a month of that, it becomes just what I do. And four years after being retired, I still do it. And it’s just part of my DNA now. And so it’s not part of the DNA of these patients. And so I know I’m going over my minute, but I’m on my soap box, and Louise gave me that opportunity by mentioning what she said. And I totally agree with it.

Stephen Harrison (51:13): So undervalue, we have to do a better job of communicating with our patients and driving the real value into these patients to make the change they need to make. And as far as what I think we overvalue, I’m just going to agree with her again. I think we overvalue the importance of better living through chemistry. And while that is great, we clearly need that. I don’t think we spend enough time on the fundamental foundations of what we need to do to improve these liver diseases. And I could keep going but I’m going to stop there. I hope I bought Peter enough time.

Peter Traber (51:51): You certainly provided me with an answer. I think that both Louise and Stephen very nicely raised the specter of lifestyle and weight loss and so forth. One of the things that I think we undervalue as a medical community and people interested in public health is the fact that there’s a very broad spectrum of behavioral and dietary things you can do to lose weight. And I think when we talk to our patients, we tend to do a very narrow nutritional focus that leaves out a lot of practical things, a lot of different dietary approaches that can help people. For the longest time, as a medical profession we told people, “A keto diet is just not good for you.” Well, we now know that a keto diet is okay for you and it can really kick start people into a weight loss. So I think we undervalue the broad range of things that can be used for lifestyle changes and dietary changes.

Roger Green (53:03): Okay. So I want to thank all three of you for sharing a perspective that I think is a lot more patient focused, which is a good thing and an important thing in looking at the issue of what we don’t think about enough or what struck us forcefully in today’s conversation. I want to come at the same question from a slightly different answer. I think what we overvalue is the role of the doctor in driving behavioral change. I think what we undervalue is the ability that some of these new apps and programs that are online have to affect that kind of change. My wife works for one of the behavior change companies, and I am constantly impressed at what she and her colleagues are capable of achieving. Not every patient that they deal with gets better, but people who make the commitment and stay with the commitment can have fantastic effects on their life in terms of weight loss, metabolic health, improved exercise, all the things that we strive for.

Roger Green (54:02): I believe that there’s advocates and nurse practitioners and physician assistants and people like Louise can also have that effect strongly. I believe that there’s enough complexity in how patients view doctors, and ways that the title doctor leads patients to feel intimidated, that to expect the physician to carry this weight on her or his shoulders, without the support of health professionals who I think are in a better position to do that, and the behavioral apps I think in that regard we’re likely to do less well. So I would see putting less emphasis on the physician per se, more on other health professionals and even more to the point on the behavioral apps, and that will get us where we want to go a lot faster. Last round of questions, the one thing you heard today that surprised you the most or enlightened you the most, take it either way.

Stephen Harrison (54:52): I liked your comment Louise, changing the trajectory of a patient outcome by bringing awareness to the patient, that small changes can equate to big changes down the road. And my analogy to that would be, again an army analogy in doing land navigation. If you give me an eight digit grid coordinate that’s 20 miles away, and you give me a compass and say go get it in the middle of the night with no lights. If I’m one degree off, well for the first 100 yards I can still be on target, I can readjust. But if I’m one degree off and don’t reset my [inaudible 00:55:30] after the first mile, I’ll never be able to regroup and get back on track. So it’s all about perspective and it’s all about small steps and readjusting and reevaluating and being persistent and being consistent with our messaging to our patients. And I think that was something that I’m going to reiterate in my clinic tomorrow. So thanks Louise for that input.

Roger Green (55:56): That’s great. Peter, next.

Peter Traber (55:58): I think the most surprising thing to me other than Louise around the table, we’re all focused on drug development, and yet the conversation in this regard really was most rich when we started talking about societal issues and lifestyle issues and diet and patient perspective. And I think that that really highlights where the fundamental solutions to fatty liver disease are going to lie in the near future, before we have really drugs that work in a very high percentage of people. And even then they’re going to have to be really safe and really cheap, and sometimes cheap doesn’t get into the equation. So I think that where we shifted in terms of our discussion around the patient perspective around public health and lifestyle issues, I think is very telling.

Roger Green (56:53): Peter thank you for that, Louise.

Louise Campbell (56:56): I think I echo what both Peter and Steven have said, and I think there’s room in the treatment of NASH and NAFLD for everybody. And I think it is going to take everybody to pull together to help reduce the mortality that we’re seeing and the rising mortality that we’re going to see in all of these. And I think from my perspective, there are quick wins for patients. Walk down the stairs then catch the lift, that’s way easier. It’s a quick calorie burn. You don’t need to get your heart rate up to 135, but you might just need to start walking. Let’s start with small steps. And I think it is making it achievable, and we can use the medications as we need them. I would just echo what Peter yourself and Stephen have said all the way through the podcast.

Roger Green (57:38): Louise, thanks for joining us today. Making really great contribution. For your first podcast, fantastic. What struck me, is that, going back to what Peter said, when you think in terms of drug development, you think in terms of years. So something that might look like it’s in the near future might be three, five, seven years away. Even without the issues of the pandemic. I don’t think we have three, five, seven years to wait on this. And the powerful idea of the patient perspective as Louise points out is you can get someone to start walking down the steps tomorrow, literally. That’s the place where we can make a difference now, and making a difference now is vitally important. And I think that’s the one thing we’ve all taken away from this. I want to thank our panelists for today.

Roger Green (58:17): I want to thank Louise for stepping in. Louise actually we’ll be back with us next week, because our topic is going to be taking a look at differences in patient treatment in the US versus the patient advocacy, really and support as well as treatment in the US versus the UK. And I want to thank our panelists for a really instructive session today. I want to thank Frank for being fantastic as always on the board. I want to thank Eric [Rams 00:58:41], our social media guru, who never makes it to these things, but has been exceptional in getting us awareness out in the world. And we’ll all be back with you next week on Surfing The Nash Tsunami. Thanks and have a good day.

Speaker 1 (58:53): You’ve been listening to Surfing The Nash Tsunami, send in your questions to surfingnash.com, and our panelists will spend the first five minutes of next week’s episode, answering your questions. Visit us online today. Surfingnash.com

 

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