Ep. 11 Crystal ball tells us the most important story of the summer

CONSENSUS: the big story will be the regrowth of COVID-19 in the US and its implications
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The Surfers discuss different elements of the evolving COVID-19 story — what it feels like to live in an emerging “hotspot” city; new findings on the impact Fatty Liver Disease may have on disease severity; and the commercial implications of all this.


 
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Hi, this is Peter Traber, and you’re listening to Surfing the NASH Tsunami.

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 (00:36): For everyone with an interest in NASH or more broadly in fatty liver disease, Surf’s up because episode 11 of Surfing the NASH Tsunami starts now.

Roger Green (00:45): Okay. Last week we broke into double digits, this week is lucky 11. One of the things that’s happened is we’ve gotten formal confirmation that people listened to Surfing the NASH Tsunami more than 1,000 times in the last four weeks, and that’s more than double how many listened in the four weeks before that. So we want to thank you for coming, and listening, and staying, and hopefully telling your friends and colleagues about it and helping us to build momentum and a lot of listenership.

Roger Green (01:07): We’re not only lucky because this is week 11, but we’re lucky because Peter Traber is back after three weeks away. Hey Peter, glad you’re back with us.

Peter Traber (01:14): Thanks, Roger. Sorry to be away, and great to be back.

Roger Green (01:17): Super. And Louise Campbell is with us once again. If we’ve got time at the end, she will talk about the quokkas and the golf shirt that she’s wearing over video today. Hey Louise, how are you?

Louise Campbell (01:26): I’m fine, thank you.

Roger Green (01:28): Okay, excellent. Before we get started. One other thing I’d like to announce, we are looking into starting a segment of this program over the next couple of weeks called “Focus on Patients.” And what we’re hoping is that some of you who are patients or caregivers who are listening will write in with some specific questions you’ve got about your care, or about treatment, or anything else you really want.

Roger Green (01:47): And we will invite some of you to come on the show, ask your question in real time to us, and then to engage in dialogue with whatever Surfers happen to be around that day to get you the best answers we can. So if you have a question, particularly if you’re not shy and really if you want a career in audio, please make sure to send it in either to the webpage, click on the button, or send it directly to questions@surfingnash.com and we’ll get back to you on that. Thank you.

Roger Green (02:11): With that, let us start. This week is about professional highlights, everybody. One great thing that happened in your week professionally? Brave person go first.

Peter Traber (02:18): Yeah, I can go, Roger. As many of you may know, I spent about half my career in academia and about half my career in industry and I was reminded over the last few weeks the interaction between those two. I helped a fledgling NASH company put together and write its first abstract for the liver meetings and submit it.

Peter Traber (02:40): And it just reminded me and it was very rewarding about how academia, and academic meetings, and academic scientists interact with industry and just how important that interaction was. So that was a very rewarding professional activity.

Roger Green (02:56): Thanks Peter. That’s fantastic. Which one of you two folks would like to go next? Louise, Stephen?

Louise Campbell (03:00): I’ll go next. I suppose my professional highlight of the week is there’s a lot more interest now in adding FibroScan or liver assessment technology to some of the COVID clinical trials going on. And I think that will bring me on to why I’ll discuss what I’m bringing up later in the podcast this evening.

Roger Green (03:18): Well established. Okay, Stephen, you’re up.

Stephen Harrison (03:21): For me, welcome everybody to our show. Professionally for me, I don’t have any earth shattering news this week, just the daily grind of working through COVID. We’ll talk about that in a bit, but just keeping our research clinic open is a win for me professionally, given all that’s going on. So that’s how I’ll give my highlight for the week.

Roger Green (03:42): Okay. Thank you, Stephen. My professional highlight for the week involves watching somebody who I mentored in years past take a tremendous step forward in his career and dropping me a note saying, “Thank you.” The thank you was the less of it. The bigger part is that he will be making a rather fantastic contribution to marketing research and insight development in his new role. Didn’t want to be mentioned by name, but I am giving a shout out and I’m really proud. Thank you.

Roger Green (04:09): Okay. With that said, we would normally move on to our question of the week. This week’s question actually comes from a private investor who wanted to remain anonymous, but who listened in last week thinking that we would be talking a lot about advances in diagnostics technology, maybe liquid biopsies, maybe devices, maybe whatever. And in fact that wasn’t the conversation we turned out to have.

Roger Green (04:29): So the investor in question wanted to know whether that was because there are not meaningful advances or just because the conversation didn’t go that way. The answer I will give is, the conversation didn’t go that way. There are meaningful advances. Some of that may come up later in this conversation. More likely we will schedule a talk for some time in July where we can get Suneil back and maybe one or two other diagnostics people and make that conversation more explicitly about the issue of how the technology of diagnostics is changing.

Roger Green (04:55): That’s it for questions today, please be sure to send your questions in. And as I say, we are starting a process of inviting people to come on the air with us, ask your questions and engage in dialogue. So if you wanted to talk to Stephen, or Peter, or Louise, or even me about anything of interest we’ve covered on this podcast, send your question to the website or the questions at surfingnash.com and we’ll see where we go with that.

Roger Green (05:17): Now on to our main topic. Depending upon how you look at it, this drops on Thursday June 25th, which is either the first episode for us of the summer of 2020, or the last episode for us in the first half of 2020. Either way, it feels like a good time to look forward to the future. Unfortunately, as always, we have panelists who come from lots of different directions. Stephen thinking about testing and wide spread clinical trials, and also as a practitioner and someone who works with companies.

Roger Green (05:43): Peter is from a commercial C-suite point of view blended with a history and academia. Louise as a patient advocate, heavily involved in diagnostics through her work with the FibroScan, and me as a forecaster looking at markets in terms of how both disease, and treatments, and knowledge are likely to evolve to understand where we’re likely to go as an industry and as a society in treating fatty liver disease and NASH.

Roger Green (06:06): With all those perspectives in mind, what I’ve asked everybody to do in advance is to look forward to the summer and to the rest of 2020 with one simple question: what do you consider the most important story likely to emerge this summer in the overall context of NASH and fatty liver disease? With that in mind, knowing the question, Stephen I’d like you to answer first and maybe start by giving us a little bit of flavor for what’s been going on in San Antonio this week around COVID.

Stephen Harrison (06:31): This is an interesting time, unprecedented time, a time that I guess I thought we would be working through by now. So I sit down in San Antonio, Texas. We like most everybody else were ordered to stay at home sometime around the end of March, mid-March, end of March. And ultimately, that lasted for about eight weeks and the governor lifted the restrictions some time in mid-May and we were off and running again, and interesting things began to happen.

Stephen Harrison (07:01): So during the shutdown, we were struggling to continue to enroll clinical trials, and at our own particular institution, we decided to not perform new screens, but the screening that had already happened, we just pushed those people through as they were able to come in and randomize. So we kept the people in the trial that were in the trial already, and those people that were in screening, we continued to move them through screening where we were able to do that from a safety perspective.

Stephen Harrison (07:31): And then towards mid-May, we opened back up and things were getting back to normal or so we thought until last week and into this week. And what’s happened in San Antonio is people call it a second wave, other people call it just a resurgence of the first wave, whatever it is, it’s definitely a COVID tsunami. So we have the NASH tsunami, now we have the COVID tsunami superimposed on top of it.

Stephen Harrison (07:58): I’m looking at a graph right now, it shows Bexar County cases. And Bexar County is the County that San Antonio resides in. 812 new cases yesterday. We were hitting about somewhere between 40 and 50 new cases a day, basically from the end of March, all the way to the middle of May. And since then it’s steadily ramped up and then went parabolic this week. For the State of Texas, we hit over 4,000 cases in a day, and for that two-month period from mid-March to mid-May, it was somewhere around 1,000 cases a day.

Stephen Harrison (08:34): So Texas has increased significantly and I think the epicenter of that is San Antonio. So it’s interesting what, that’s happened, how that’s affected clinical trials. And I’ll use my own site as a microcosm and then we’ll expand out from there. A couple of things have happened here that have shed light on this issue, maybe that will allow me to provide some broader perspective.

Stephen Harrison (08:58): What this has led to is a situation where we have a couple of different issues. One, our patients historically have said, “Well, I’m a little skeptical about coming into the office. I’m concerned about myself and my family.” And so we did telehealth. We did telehealth in my clinical practice and we did telehealth even in our research practice. We were able to get patients’ IPs shipped directly to them.

Stephen Harrison (09:22): And then as we opened back up, patients were coming in, it was business as usual, except for maybe 20, 30% of the cases where patients still didn’t feel like coming in. Well, now that has become a big issue again where with the exponential rise and new diagnoses occurring in San Antonio, patients are fearful to get out, so they’re beginning to stay home. But that’s not the biggest challenge. The biggest challenge is our employees.

Stephen Harrison (09:55): We have about 70 employees and what happens is everybody now knows somebody that’s had or has COVID. And so if you come within what? Six feet and you’re there for more than 15 minutes, whether you wear a mask or you don’t wear a mask, you now are considered in close contact with the COVID positive patient, whether they’re symptomatic or they’re asymptomatic. And following the CDC guidelines, you either have to stay out for 14 days, that’s the time-based management strategy, or you have to do the test strategy, which means you have to have two negative RNA tests within, no sooner than 24 hours apart before you can come back to work.

Stephen Harrison (10:38): But you can’t mandate to your employees that they go get tested and on top of that, they have to pay for the testing. And because of the Relief Act the government enacted, if our employees want to stay home for 14 days, they can and we continue to pay for them to be at home. So imagine this playing out every day. Employees call in, “Hey, I think I was exposed to somebody,” or, “I think my kid was exposed to somebody, and then I was around my kid. So what do I do?”

Stephen Harrison (11:05): And then they begin to go down the process of quarantining or going to get tested. Or let’s say a patient comes in, they’re seen today. They go home and they find out that their best friend that they hung out with last night, they thought it was a close family contact and that they were safe to be around came down with COVID. Rightfully so they call us and they say, “Well, I had a close contact last night.”

Stephen Harrison (11:30): Well, five of my staff were within six feet of that patient today and so now they all have to go out. And it creates a situation where right now, at least 30% of our employees are at home quarantining and more and more are happening every day. So globally, I think we’re going to see this perpetuate. San Antonio just happens to be where it’s at right now, but we know Arizona, Florida, California are all experiencing resurgence of this.

Stephen Harrison (12:04): And a lot of our trial sites that were up and running and still are struggling to maintain at least a decent pace at finding patients and recruiting them are just struggling to keep the doors open because of not necessarily patients wanting to come in or not come in, but the staff not being able to come to work. So ultimately I’m not sure that clinical trial enrollment is going to get back on pace for quite some time.

Stephen Harrison (12:35): There are still big studies that haven’t opened up. There are other studies that are just on the brink of beginning to open up this week, next week, and now all this is happening. So I don’t think we’re out of the window yet and I think that the impact of COVID on NASH clinical trial enrollment is going to continue to weigh heavily on companies that are wanting to get started, companies that are just about to get started and studies that have been ongoing.

Stephen Harrison (13:03): I think we’re going to continue to push out our enrollment timelines because we just can’t get the patients to come in, and if we can, we don’t have the staff to support them. It’s a struggle right now, the struggle is real.

Roger Green (13:15): Stephen, to start, I have two questions. First, before we came on the podcast, you mentioned two scenes that you’d seen recently, one a concert at a dock and the second public pool in town that were swamped with people who did not have masks. And one of our polls is recently as yesterday. Do you anticipate that there is a time at which either people will start to shut themselves down or the government will start to shut the town down again because of the rate at which the pandemic is running through San Antonio?

Stephen Harrison (13:46): To your point, just to elaborate on that a bit, this past weekend we were on a boat and pulled in to get some gas and there was a concert playing at the boat dock, great music. It was a band that was playing journey songs. It was a packed house. There was several hundred people there and there was no social distancing and nobody wore a mask. Lots of food, lots of barbecue, lots of beer and there was just no sense that there was this pandemic or that there was even a resurgence of cases.

Stephen Harrison (14:19): That was outside of San Antonio, but even more close to town and in town, I drove by a swimming pool yesterday in the evening on the way home from work that was packed with children, and moms, and dads. Again, no social distancing, no mask, just everybody seemingly business as usual, having fun like they would on any normal summer day. The virus doesn’t care about that, it’s going to spread.

Stephen Harrison (14:46): And I’ve already mentioned this parabolic uptick that we’ve seen in Texas. What I didn’t mention was the number of hospitalizations and the number of ventilated patients that we’ve seen a spike in. And it’s not going to be long before we overwhelm the healthcare system in San Antonio. And it’s a big healthcare system, huge healthcare system with hundreds and hundreds of beds, but the count I had yesterday was well over 100 ventilated patients now in the city and close to something like 500 hospital admissions for COVID throughout the city.

Stephen Harrison (15:19): If that rate continues, I don’t think that the health authorities and our elected public officials are going to have much choice, but to put another lockdown. Otherwise, we are going to overwhelm our health care system. This idea of flattening the curve has completely left the planet in Texas. We’re not flattening anything, it’s exploding. So I think we’ll know very quickly, Roger, probably by the end of this week.

Stephen Harrison (15:43): Either it’s going to just sweep through the whole town and you’re either going to have symptoms or you’re not, or we’re going to have to shut down the city and the State again to bring our healthcare system back into a manageable state. But right now it’s pushing the upper limit of what we can handle.

Roger Green (16:00): Okay. First of all, as a friend who knows of your military background and your general commitment to do the right thing, I know you’re going to find yourself on the frontlines, and good luck, and take care, and God speed and best wishes from all of us as you do whatever you have to do. Second, Peter, Louise, anyone have a question for Stephen on this before we go on?

Peter Traber (16:19): No, I don’t have a question, but I think it would be useful for Stephen to repeat what he said when we were talking amongst ourselves, and that is human beings’ response to crises and the whole issue of mask wearing. I thought it was very interesting, Stephen that you said, “People only have conviction about doing something for two or three months and then they stop doing it.”

Peter Traber (16:41): And that very well may be a human nature thing that we’re going to have to deal with as a society and as a world. Maybe even think of that in our plans as we plot forward what we’re going to do with this pandemic.

Stephen Harrison (16:56): It just hit me, I don’t know, yesterday, last week that I’ve talked for years about the smile curve for weight loss. And what I mean by that is, I’ll see a patient in clinic and I’ll talk to them about fatty liver and I’ll tell them that foundationally, they need to have a lifestyle change. They need to lose weight and exercise. They need to eat less and run more. They need to change their habits and take a broken piece and make a masterpiece. And it’s all in their hands and they’re fully capable of doing everything they need to do.

Stephen Harrison (17:27): And so they asked me more questions and we talk about low-processed carb diet. We talk about beginning to exercise, and that it’s painful, and that you’re going to get short of breath, and you’re going to get exhausted, you’re going to want to give up. And that they just need to persevere and they need to take it one day at a time. And they leave invigorated, and they leave motivated to do the right thing.

Stephen Harrison (17:50): And so I set them an appointment to come back and see me in one to two months because I don’t want them to get very far out without a followup. And they inevitably come back and they’re doing — not everybody, but the majority are making big stripes to try to get better and they’re very happy with the results they’re seeing. And maybe I see them back at 12 weeks and they’ve really continued to do well.

Stephen Harrison (18:11): Then I extend them out to another three months, which gets them to six months from the time I saw them at the very first visit, and between month three and month six, they basically gain all the weight back. That’s the smile curve I talk about. They start heavy and they nadir at 12 weeks, and they gained it all back after the next 12 weeks or six months, and this is repeated over and over again.

Stephen Harrison (18:34): We see that when we look at New Year’s resolutions and the number one new year’s resolution is I’m going to get in shape, and you see gym membership spike in January. You go to the gym and it’s packed in January, February, spawn off a little bit. By spring break, it’s almost back to where it was. And I think that’s just a function of human nature. We can get a focus on something and we can be really dialed in on doing whatever it is that our goal is focused, whatever we’re focused on, that goal, we’re really good at it for about 12 weeks.

Stephen Harrison (19:08): Then life gets in the way, things happen. And it’s usually one little event that triggers whatever you’re doing, going to the gym. Then there’s an excuse, you can’t go because you have a meeting you can’t miss, or your kid has an appointment you have to take them to or whatever it is. Then the next day, it’s easier to come up with an excuse, and then the next day. I think for us, just thinking about this from a COVID perspective, at least in Texas, we’re at that 12 week point.

Stephen Harrison (19:37): 12 weeks of social confinement, social distancing, staying at home, and then the order is lifted, and it was like, you let the air out of the balloon. People just said, “It’s time to get back to normal.” We’re not living in a vacuum, everybody reads the news, listens to the news. Everybody knows the virus in San Antonio is really ramping up, but yet even yesterday, everybody’s at the pool.

Stephen Harrison (20:02): I went to the grocery store, I walked around. There’s $1,000 fine in our city now if you’re not wearing a mask inside a building, half the store didn’t have a mask. This was last night. I’m just amazed. I think we’re learning a little bit about human nature here as well, Peter, just to follow up on that conversation we had earlier.

Louise Campbell (20:21): I did have a question when I was listening to what sounds like a rapidly developing nightmare for you down there, Stephen was that… And what did surprise me was, I think you mentioned that people have to pay for the test. Now, maybe I’m very used to the NHS, but how is it logical, if that’s correct that you can try and control a pandemic when people actually have to pay for the test to find whether they’re infected? Because surely that’s an obstruction to people finding it and being able to deal with the pandemic.

Stephen Harrison (20:54): I’m not sure that everybody has to pay. It depends on where you go and what tests you’re asking for. It’s a little bit different everywhere you go. You can go to emergency room, you go to urgent care clinic. You can go to these lab testing facilities that have popped up around town. It depends on where you go. But at the end of the day, I don’t think paying for it is the rate-limiting step. I think some people just don’t want to go get tested.

Stephen Harrison (21:22): It’s probably along the same lines as a vaccine. Even when we have a vaccine, there’ll be people that won’t want to get a vaccine for a myriad of reasons. For me as an employer, I can’t mandate that they go get it. At the end of the day, then they have to fall back on a 14, on a longer period of being out, and that’s what affects me. If you can go get tested twice and are negative and you can return to work.

Stephen Harrison (21:48): You still socially distance, you still wear your mask, you still sanitize, but you’re able to come to work and do your job. Whereas if you choose not to test, now I’ve lost your skillset for 14 days. That’s one of our challenges.

Roger Green (22:04): All right. Well, one thing I’m hearing is this is terribly sad, and I live in the Northeast where we don’t live in New York, but we’ve been following a lot more the lines that New York has followed and it’s tough, but you come out the other end of it having really done it rigorously for three, four months, and you hope you’re in a better place. Again, nobody knows.

Roger Green (22:25): One thing I hear you saying is that every prediction anyone has about how fast clinical trials will proceed going forward has got to incorporate a lot more variability because you’re not the only person having this problem. And as it spreads throughout the entire Sunbelt, and on to California, and presumably to other States that have not been quite so hard hit, and maybe even some of those that have.

Roger Green (22:46): That we’ll be seeing whether you call it the continuation of the first wave or second wave, whatever wave you want to call it, that there’s a lot more to play out here. And a lot more loss of access to care, and loss of access to talent, and inefficiency in the clinical trial system.

Roger Green (23:00): Louise, I know that you wanted to, as you mentioned before, talk about a different issue also related to COVID. Please go ahead.

Louise Campbell (23:07): Hopefully, I think the issue that I’m bringing might involvement with both some of what Stephen has been putting forward and also what Peter’s just been mentioning. It’s about a study that’s been released and we’ve discussed various occasions how we think NASH and NAFLD will come out of the COVID period in the ranges of broad NASH, broad NAFLD. Previously, another, it’s a pre-release, it’s not yet been peer reviewed, but it is obviously under going that and it was released by the initial UK Biobank observations.

Louise Campbell (23:43): And it was done with perspective, which obviously do dynamic fat fraction than LiverMultiScan. It’s also the first study that I’ve seen so far or set of evidence whereby liver scans were available on patients because it was a big biobank of over half a million patients, and I think 42,146 of these patients had had the scans. So they were able to then cross reference them with the patients who then by the 28th of May had developed COVID.

Louise Campbell (24:15): Now, we only tested in the UK patients that were admitted to hospital for COVID during that period, so it’s limitating on that. But of the patients that tested positive, what came out of the evidence is that patients who have 10% fat within the liver and obviously dynamic fat fraction is used in all of the studies that we’re doing currently for NASH and NAFLD with biopsy and is arguably one of the most accurate measures of that.

Louise Campbell (24:45): So for only 10% or more or less doubled the rate of developing severe COVID and being admitted to hospital. And I think it was an independent predictor. And what was also quite interesting out of that data set was BMI itself if they have normal liver fat, and we know lots of people with a high BMI could have normal liver fat, but in those patients, there was no increased risk of developing admitted COVID.

Louise Campbell (25:13): And I think that’s supported by Kusher, et al., last month where they did an analysis of several studies in China and the more severe the COVID illness, the higher the percentage of patients with fatty liver disease was present. And whilst there will need to be an awful lot more evidence in supporting these figures, but if we now have very accurate evidence in this level of scanning, that even 10% of liver fat significantly increases your risk of developing COVID to require admission, then it would concern me that we’re starting to look at FDA delay and medications that can help.

Louise Campbell (25:52): The article and the research itself even go so far as looking at making rapid changes and bringing in medication like [Resimidron 00:26:01] and NGM282 because they show… We discussed them recently, which is coming in to Peter’s point. We showed recently that they have very rapid effects on liver fat. And one of them, I think is Resimidron’s by 12 weeks, you can tell who’s going to make a very good progress.

Louise Campbell (26:19): I think what we’re now starting to see is this growing body of evidence where people are looking for fatty liver because not a lot of people that I scan with 10% body fat, even on FibroScan, which is not as accurate as MultiScan have elevated LFTs. And I think by looking at these research where they have liver scans already and cross referencing them with the patients who then go on to COVID may well provide us with that evidence.

Louise Campbell (26:50): But if it is at all true and the strength of evidence have been ready, seems to be quite good is that this offers us an opportunity because people on that borderline between 10, 20%, looking at Stephen’s own work early in the ‘2000s, that 3%, 5% body loss can make such a difference. And if you have a reason like COVID to just alter your body composition, and sometimes we can alter body composition and liver fat without necessarily losing weight.

Louise Campbell (27:22): We can change fructose. You use the fructose syrups in the U.S., it’s a big problem. I think 61 grams per 2.5 or 2.6 grams that we use equivalent in the UK. So I think we’ve seen Remdesivir, we’ve seen lots of other medications get fast tracked because of COVID-19. We are now getting more and more evidence showing that fatty liver disease could be a bigger predictor of severity and yet it would be nice to see whether or not we can obtain more of that evidence more rapidly by going back to these big cohort research institutes.

Louise Campbell (28:02): They’ve already got scans ready for these NAFLD and NASH studies. They may not have made into those NAFLD and NASH studies, but they had high fat content cross-referencing with those who have then gone on to get COVID and looking at severity and outcome. Maybe one way that we can support this evidence because we can get a treatment, whether it’s weight loss, whether it’s exercise, going back to Stephen earlier, walk more, run more, eat slightly less or change something that reduces liver fat.

Louise Campbell (28:33): If it actually can make a benefit COVID-19 survival rates and protecting healthcare with a rise in ITU admissions, as Stephen’s alluded to, then I think it deserves merit because we’ve discussed multiple times during these podcasts that it is, I suppose, the elephant in the room. We talk about cardiovascular disease, we talk about hypertension and we talk about Type 2 diabetes.

Louise Campbell (28:58): Although looking at the diabetes cohort, Type 1 diabetes seem to be marginally more affected than type two, but fatty liver is in the background of most of those diseases. And I think it is now interesting that people are able to go back to some of these cohorts. I think we also have to remember that the liver does metabolize every single drug that we’re using to treat COVID-19.

Louise Campbell (29:20): So if we have an increased risk that is 10% of liver fat, that’s actually quite small in the comparison of what we, and what I would probably normally be seeing by the time they get to hospital, by the time they get to a scanning, and we need to be looking to make those changes now rather than wait. And in fact, it’s probably a better outcome than Remdesivir.

Louise Campbell (29:41): So mine is not as long, but I think from a patient perspective, we have opportunities to look at something that we can utilize to prevent severity. Until we have a vaccine to prevent the virus, preventing severity admission, and particularly ITU admission in these patients is key. And it’s identifying that 10% fat cutoff that doubles the rate of chances of people having COVID-19 being admitted and having severe COVID. That’s fairly interesting evidence that’s coming out.

Roger Green (30:13): That was fantastic. You shared this with me yesterday and I took a look at the article and then went back and took a look at the pre-publication. One of the things that struck me is that while as you pointed out, obesity was not an independent predictor of COVID severity. Obesity plus 10% fat was I think a two-and-a-half-fold predictor, better predictor than that fat level, per se.

Roger Green (30:34): I mention that because I suspect that the way most of us, and I’m not a clinician, but I’m going to guess this is true for a lot of clinicians as well, think about this as first, they look at obesity and then they’ll look at liver fat. And if you went in that order, since there’s some correlation between obesity and liver fat level, you would probably decide that obesity was the key point because you would do the test and most of those patients would show up and you wouldn’t think independently of liver fat because we don’t think of that at the 10% level.

Roger Green (31:01): So I think some of our own processing biases in terms of how we look at characteristics in patients may make this result more important if proven out on peer review because it would help us look at things differently and maybe get more people treated better, faster. Just a random thought. Peter, Stephen comments on Louise’s rendition, the paper itself, or the point I just made?

Peter Traber (31:23): I think that Louise makes a brilliant point here, and it also shows an ancillary benefit of this very large program that was put together in the UK to look at LiverMultiScan over a population base. So this is a benefit that came out of a large study that wasn’t designed for the purpose of looking at COVID obviously, but has come up with this very important finding. And I think Louise’s analysis is spot on and her idea that we can do something about COVID susceptibility even before we have treatments or a vaccine is a very good one.

Stephen Harrison (32:03): Yeah, I’d agree. It sheds light on another epidemic. It’s not a virus, it’s a metabolic disease that affects the liver. And ultimately lipotoxic fat leads to dysregulation within the liver, immune cell dysregulation, mitochondrial stress. In the setting of mitochondrial stress, ultimately, that leads to an inability to process energy effectively.

Stephen Harrison (32:33): And then when you stress the liver with an infection such as COVID, binding to ACE cells, we know they’re ACE cells in the liver, hepatocytes that whether there’s a direct effect or an indirect effect of the virus on the liver, you already are dealing with a stressed out liver, and now you just sit systematically and systemically made it worse with the virus. So it makes sense that that would happen.

Stephen Harrison (33:03): I guess, I’m unclear if what we’re detecting on imaging is just a result of a large population that has a metabolic disarrangement. We know that diabetics, 70% of them have fatty liver, 90% of metabolic syndrome patients have fatty liver. I don’t know the data well enough to know if this was put through a multi-variant logistic model and it identified 10% liver fat to be independently predictive when you stratify for diabetes. Louise, do you know if that was done?

Louise Campbell (33:39): What they did was a univariate logistic regression. So they compared the dynamic fat fraction of more than 10% cT1 of greater and equal to 825 millimeter second over the age of 65, BMI of greater than 30, male sex, nonwhite ethnicity, diabetes, and hypertension. And I think they didn’t have any liver function tests, which I find unusual for the bio study, but what they looked at was a whole host of self-reported diabetes and that’s…

Louise Campbell (34:13): Most of them we knew were certainly higher risks. What they didn’t expect to find was the 10% fat fraction within the liver. And that differentiation between the obese and non-obese because 37.2% of patients who were obese but had normal liver fat actually had no increased risk of COVID severity. So about 32% the other way who were obese, who had liver fat have severe risk or had an increased risk of developing quite severe COVID.

Stephen Harrison (34:48): Do you have a comment on the 825 milliseconds for cT1? That’s a number that has been tossed around as being consistent with the diagnosis of NASH. Did that stand out? Was there a difference in NASH as well, or was it just the liver fat that made the difference?

Louise Campbell (35:08): Off the top of my head without reading it, I don’t think from recollection it seemed to cause too much of a problem. The biggest thing was the 10% liver fat, but in fact it wasn’t. It was 0.4% of the entire population that they looked at, which I think was 42,000. So the cT1 of less than 8.25 millimeters/second was just under 0.2 of the population, whereas the cT1 of greater than 8.25 was just under 0.4%.

Louise Campbell (35:39): So there was a marked difference in the rise of that and that correlated with the rising liver fat of greater than 10%. So to answer your question, yes, there was a difference.

Stephen Harrison (35:48): That’s certainly something that draws your attention towards fatty liver and managing it for sure. We talked about Resimidron, we talked about NGM282, or it’s commonly known now as aldafermin, but also sheds light on the Keros FGF21 press release data showing 85% of those patients having a 30% relative reduction in liver fat.

Stephen Harrison (36:12): So we are really getting to the point where we have effective therapies at de-fatting the liver and the positive impact that can have. Not just on a viral infection like COVID potentially, but also on global health, I think is yet to be seen. But I can’t imagine there being something negative about de-fatting the liver. I’m anxious to see how this looks in the long term, what this does to long term patient outcomes.

Louise Campbell (36:42): I agree with you and I think that was one of the reasons that I brought this article for discussion this evening and the fact that based on their data, they do go on to recommend that we look at trying to use these medications and get some plan in place. But also on their figures, just on their study on the Biobank, it would be 11% of the UK population would be at risk of developing severe COVID.

Louise Campbell (37:07): Now, those are 11% of the population we’ve discussed ad infinitum and the fact that these patients or these people do not know they’re at risk. And I think any preventative strategy for health screening to find and locate these people may well be one thing that can come out of the longer, or certainly more data because how long can we wait?

Roger Green (37:29): Louise, thank you for that. I’m struck that the three of you have brought some meaningfully different issues to the fore. I’m also struck by what I think is an underlying similarity between what Stephen and Louise are talking about in a very different sense. The first problem with what’s Stephen talked about, as I mentioned at the time, well, there’s a tremendous human cost.

Roger Green (37:49): But if you think about this, not in terms of the human cost, but in terms of the dynamic implications on development of medications, markets, then we’re adding a tremendous amount of uncertainty in the market because we don’t know now how far it will push back development times on trials.

Roger Green (38:06): We don’t know how many people are going to get sick, we don’t know how long this will last at the crisis level, but it’s not unreasonable to assume based on New York where Andrew Cuomo almost stopped doing his daily briefings on Monday after 111 straight days, that a city like San Antonio is on its way into the chasm. It might be three to four months before you come out of it, which is scary as heck, but not necessarily an unrealistic prediction.

Roger Green (38:32): And the real point is nobody knows. We know it’s not good, we don’t know how bad it is. That in and of itself leads to tremendous uncertainty. If large parts of the country have to shut down again or really shut down this time because they’ll be in crisis as compared to merely trying to flatten the curve a little bit, then you run the risk of all kinds of bad things. One notably being a second stock market crash, for which I don’t think the market would recover as quickly as it did the first time.

Roger Green (38:56): And there was potential to take a bunch of equity and bunch of funding out of drug trials, except in things that are recognized as crisis. So we will keep pushing forward on vaccine because that’s a politically tenable target that might hit by the end of the year, save that thought for a minute.

Roger Green (39:13): The kinds of things we’re talking about now, investigating the role of fatty liver, which may in many ways be a more practical way to get a better, faster outcome. Less likely to be considered or less likely to be considered as promptly because there will not be the kind of public pressure behind it. So I think there’s a risk around that.

Roger Green (39:28): Stephen mentioned San Antonio, it’s striking to me the degree to which wearing a mask has for better or for worse become a political symbol of who you sympathize with. And it doesn’t make one side right and the other side wrong, everybody’s got arguments on this stuff, but the truth is that parts of the country that are now experiencing increases are the same parts of it that politically might have more people who believe that not wearing a mask is a statement of freedom. Which means that the way that New York was able to crack down, it may be harder to do that in some of the places we’re looking at now or not, but it certainly won’t be easier.

Roger Green (40:09): And that means that things might last longer, particularly because in New York city, at least it’s such a large metropolitan area with a throw-weight that if you really pound it, you could hit tens of millions of people at once. Here, the metropolitan areas are smaller, so the messaging of getting people with two States apart or Texas, several hundred miles apart, it just might be tougher to get everybody to do the same thing at once, particularly if we’re not consistent in the message that we’re sending.

Roger Green (40:36): So for all those reasons, the thing I think we need to look at over the next three months is going to be, as COVID grows and spikes in different places, in different parts of the country, A, how well will we respond to it as a society? Will we show the will necessary to shut it back down, particularly given Stephen’s smile rule, which I think is fundamentally correct? B, how will markets respond to that? Will there be money and equity left to do the things that we need to do to move this forward?

Roger Green (41:04): C, will we rush to the obvious solution vaccine, fast drugs and away from things that might have more value in the long term (fatty liver). Then D, how will all the messaging play out? If the FDA approved a vaccine in the second half of October to treat COVID, some people will think it was fantastic event. Some people on the left will think that it was Trump pushing the FDA.

Roger Green (41:27): Some people on the right are anti-vaxxers by nature would say the vaccines are tyranny, and it’s not clear even then that we would get the kind of unified public health push behind the vaccine that you’d like to see, no matter how good or bad the vaccine is. I think frankly, at that point, the quality of the vaccine is going to matter less than the ability to manage the political debate and all the noise in the background.

Roger Green (41:46): I have some real concerns if COVID comes back up that we as a society will have the will to act as strongly, as uniformly, or as aggressively as we should. And I believe the things to watch there are going to be can cities shut down again, how the markets react and can we knock down the noise on both sides of the political system in the pace of everything else that’s going on?

Roger Green (42:09): None of that has anything to do with the science of medicine, but I think all of it has to do with the practice of how medicine is going to be applied here. Questions, comments, thoughts?

Stephen Harrison (42:18): I think for sure the comments you made are definitely in play and will be important parameters to consider moving forward. Texas is a very conservative State, very proud state. The people are very independent and outspoken. They have for 200 years been that way, if not longer. The science of this is relatively clear, the virus, we know generally how it spreads and we know that if you don’t socially distance, and wear a mask, and sanitize, and wash your hands, that probability of getting infected is going to go up significantly.

Stephen Harrison (43:00): So this is where the will meets science. At some point, we know who’s going to win. And it’s just a matter of letting it either play out or somebody is going to take the bull by the horns and shut it back down. But I think at the end of the day, your comments are well-taken.

Peter Traber (43:17): Roger, I think you bring up an important and broad point and that is that beating something like this requires a broad and deep commitment from many areas in our society, including the regulatory agencies, investigators, industry, the political systems. Every single person and organization in the country has to be aligned in order to beat something like this. And that means everybody being aligned on social distancing, and wearing masks, and having faith in an eventual vaccine and the vast majority of people using it.

Peter Traber (44:04): I think the concern I have is that the foundation of our society now is not prepared for something like that. Therefore, I think that there’s a high likelihood that even if each component in our society does the right thing, it may fail to have the highest and greatest effect because of that disjointed societal view.

Peter Traber (44:31): I’ll just comment on one area, the anti-vaccine people are An anathema to civilization. I couldn’t understand them regardless of how long I listen to their arguments and yet they purportedly are a powerful force in the circles that they run in. How do you overcome something like that to attack a pandemic?

Peter Traber (44:58): I have a positive view of all the different steps that the appropriate people are taking, but a pessimistic view as to whether each component of society can come together to fight the pandemic effectively.

Roger Green (45:15): At the risk of being redundant, I agree with what you said. I found it particularly fascinating that anti-vaxx is one of these issues that cuts across left and right. You find anti-vaxxers on both sides of the political spectrum with very-

Peter Traber (45:29): That’s because they’re all nuts.

Roger Green (45:31): Yeah. Look, I think that’s right, 20% of America is nuts, period, end of sentence. And you can be nuts on the left and you can be nuts on the right, but at a point in time where I think our politics have become pretty polarized. So people tend to think of things in terms of left, right, Trump, anti-Trump, whatever. Here, the anti-vaxxers cut across all that, and that to me makes them especially dangerous at this moment.

Peter Traber (45:53): That’s very true.

Louise Campbell (45:55): I’ve just got a comment having listened to you all and having taken on board what you were saying, and it drew me to something I’ve read a while back, delivering universal health coverage for 2030. It was done in 2018 where lots of governments got together and it’s entitled, Health: A Political Choice. And I was struck by the speech that Angela Merkel gave, and it’s ironic because Germany have just locked down another County with a big spike in their R-rate with an arbiter.

Louise Campbell (46:24): She was very strong on SGD, the Sustained Development Goal number three, which was to ensure that healthy lives and promote wellbeing for all at all ages. And she was key when she said, “Strengthening national health care system is after all in the vested interest and incidentally also in the economic interest of every country because health is a key prerequisite for national economic development.”

Louise Campbell (46:49): And I think staying well, keeping the workforce well allows that development, but I’m just going to finish on what she started with, having listened to the discussion this evening. And it was a quote from Sebastian Kneipp, and it goes that, “Those who do not find time every day for health must sacrifice a lot of time one day for illness.” It probably brings us back to where Stephen started with people not necessarily social distancing and taking the regard, and the economic consequences may be quite concerning of that, which is where you finished for me.

Roger Green (47:24): Louise, I think that’s the perfect ending note for what I can’t say has been an uplifting discussion exactly. I’m not sure listeners are going to leave this a lot happier than they started, but I think it’s an important and well-thought one on everybody’s parts. I want to thank all of you for fantastic comments.

Roger Green (47:40): I want to remind the audience that one of the things that we would like to do, if you’ve got questions is bring your question and we will bring some of you on the podcast to chat with us about it. So we’ve touched on a lot of issues today that might interest people, we would love to hear what you have to say, and what you think, and what you ask, and we’d like to make you part of us.

Roger Green (47:57): With that noted and given that we’ve been doing this for a while today, I want to go around to our last question. One thing you heard today that surprised you the most? Peter, I’ll start with you.

Peter Traber (48:07): I think the most surprising and pertinent issue I heard came from Louise and her analysis of the large survey looking at liver fat and COVID-19 severity. I think a very important finding, and brings us back to some of the early podcasts where we were talking about the potential relatively increased importance of NAFLD and NASH in a time of COVID. And I think that’s some really important data and she really put it forth quite effectively.

Roger Green (48:41): Spoiler alert, before we play tag to Louise, one of the things we will be doing in the next arc of episodes of subs here, say in the next two to three months is taking a look at exactly what the implications of NAFLD and NASH are for people with different medical conditions and situations. Obviously COVID would be one of them. Louise, Peter tagged you. What surprised you today?

Louise Campbell (49:01): Other than the fact that people might have to pay some money towards their COVID tests, but I’m a little bit reassured that it wasn’t everybody. I suppose it was this sudden spike again in San Antonio and what that means for healthcare, what it means for Stephen’s clinical trials or anybody’s clinical trials who’s trying to run these currently in such uncertain times. So that saddened me as both a healthcare professional and as a patient advocate, that it delays things, but I suppose that was the surprising thing for me this evening.

Roger Green (49:33): Stephen.

Stephen Harrison (49:35): Well, what I take away from this is the fact that, “You can run, but you can’t hide,” mentality. It’s just amazing how everything comes back to fatty liver. It’s ubiquitous in our society. And now we have the beginnings of data that begun to show that an underlying fatty liver leads to worse outcomes and things that have nothing to do with the liver. Then knowing that this pandemic is a serious issue, we still see people challenged to do the right thing relative to their own health and it’s just amazing to me.

Stephen Harrison (50:14): We can tell patients that they have a bad liver, that they have heart disease, that choices they make are going to have long-term implications on their health. And this gets back to the last comment, you’re going to have to say that again, Louise, that comment that you made, the quote that you made.

Louise Campbell (50:32): It was by Sebastian Kneipp, and I’m not too sure I can pronounce that correctly, but she started her speech with this. “Those who do not find time every day for health must sacrifice a lot of time one day for illness.”

Stephen Harrison (50:45): That should be our tagline. That’s an amazing quote to end this podcast. No doubt. Again, it’s not a surprise necessarily, but it’s really a nice synthesis of a lot that’s going on.

Roger Green (51:00): I’m not going to ask Louise to read the quote the third time, but we may actually put it at the end of my comment. I think the thing that surprised me and it shouldn’t because as I look at things is how many forces are swirling at once in a way that wouldn’t lead to good outcomes. The number of things, and the scale of the things, the trends that we would need to countervail to get the U.S. at least moving in a constructive direction right now is really pretty daunting.

Roger Green (51:28): And that has become clearer to me as we’ve gone minute to minute all the way through this session. So Louise, you want to read that quote one more time so that nobody loses it, please?

Louise Campbell (51:40): “Those who do not find time every day for health must sacrifice a lot of time one day for illness.”

Stephen Harrison (51:45): You got to send me that in an email.

Louise Campbell (51:47): I can send you the whole speech. It’s actually really… That’s why Germany did so well because they did a pandemic run through of their entire health system in 2018 just before she wrote this.

Roger Green (51:59): Louise, why don’t you send it to us and we’ll actually post it on the website?

Stephen Harrison (52:01): I want to frame that and put it in every patient room I have.

Roger Green (52:06): And I think you’re right, Steve. We will find ways to make better use of it. Listen, I want to thank all three of you for, I don’t know how long this is going to be when it gets to the air, but for those of you who don’t know, we’ve been kicking this issue around after close to an hour and 40 minutes and what’s usually an hour and 10 minute taping session. But we’ve been doing that because I think we’ve all been so overpowered by the scope of subjects and issues and where we find ourselves in the moment.

Roger Green (52:27): I want to thank the three of you for bringing great topics, and open minds, and willingness to discuss. And I want to thank Frank, who makes our sound good, although you’re going to have your work cut out this time, dude. And Eric Rounds and Ellyn Charap, our social media team, and the next special thanks to you folks who listen and who made us the fastest growing fatty liver podcast in the world.

Roger Green (52:46): Please, this episode, I implore your share with your friends, think about it, ask questions of each other, ask questions of ourselves. We have so much to do to confront how to make this work better for us and it’s such a pivotal time to do it. So thank you, everybody. Surf’s up, surf’s on. See you next week. Bye-bye.

Louise Campbell (53:03): “Those who do not find time every day for health must sacrifice a lot of time one day for illness.”

Speaker 2 (53:08): 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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