Ep. 2 FIVE $IMPLE PIECES

What investors want to know about NASH development during the pandemic.
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Five questions for NASH investors about the impact of COVID-19 on NASH clinical and commercial development and our panelists provide answers in our second episode, FIVE $IMPLE PIECES: What investors want to know about NASH development during the pandemic.

 


 

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, Star Equity analyst, Yasmeen Rahimi, 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 (00:31): This is Roger Green, and welcome to the second installment of Surfing the NASH Tsunami. For those of you who were with us last week, thanks for joining. We’ve gotten excellent feedback on the conversation and a couple of spectacular questions, one actually from a patient which is really exciting to me. And as we committed, we are going to start with a short round of introductions, then we’re going to answer the questions that we’ve gotten in this week. And then I think you’re in for a really great session.

Roger Green (00:54): Yasmeen Rahimi has identified five questions that she frequently gets from investors trying to sort out the NASH market, and Peter, Stephen and I, are going to take turns arm-wrestling to see who gets the best answer. And Yas has the right as the referee and questionnaire to interject with follow up questions whenever you want. For those of you who don’t know us, this is a group of at least three people who can talk about anything at a drop of a hat speaking quickly, and one who does the speaking a little more slowly. Credit to Peter’s pacing. So I think this should be fantastic.

Roger Green (01:23): This week’s question, over the last month and a half, what is the single biggest change that the pandemic has caused in your professional life? Yasmeen.

Yasmeen Rahimi (01:31): Thanks, Roger. I would say that probably one of the biggest challenges has been as a [inaudible 00:01:37] analyst, as we continue to work and be up to speed on many of the different companies we cover, including a large portion of NASH companies, a lot of investors are really, in my view, preoccupied on understanding the movement on COVID-19 and when the markets will return. So it’s been very challenging to get the attention from investors, and I think that’s probably one of the things that I haven’t experienced. We’re noticing that many of the top ones in-house are spending tremendous amount of resources and time to really figure out the question that all of us have, is when will COVID-19 be over with.

Yasmeen Rahimi (02:16): And I think that is the part that I think trying as [inaudible 00:02:20] analyst, finding creative ways to battle that, and our way has been to launch a daily COVID-19 note to be up to speed on it. But I would say that’s been probably the biggest modification. And obviously, typically, many of the in-person meetings and road shows and all those things have come to a stop. So we definitely, I think like everyone else, has to figure out innovative ways to capture and drive value and information in these challenging times.

Roger Green (02:50): Thanks, Yas, that’s a great answer. And I’m going to take a second and give a shameless plug to a friend of mine. If you don’t get the Roth newsletters and you’re not reading Yasmeen’s series on COVID, you’re really missing. It’s well thought out, it’s really well-researched, not surprisingly, given that it’s Yas, but I’m learning a ton every day, and it’s one of my guideposts on how do I think the world is changing as we go through all this.

Yasmeen Rahimi (03:09): Thanks, Roger. And I promise I didn’t pay him to say that.

Roger Green (03:12): How can a listener arrange to get that report?

Yasmeen Rahimi (03:15): Usually they can send me an email at yrahimi@roth.com, and we can make that available and add them to our distribution.

Roger Green (03:22): Thanks, Yas. Stephen, you come next, what’s the biggest change in your professional life in the last month and a half because of the pandemic?

Stephen Harrison (03:28): You know, the biggest change for me, is I was supposed to be at EASL, the European Association for the Study of Liver Disease. Still supposed to be there today on the 21st of April. And I’m a people person, I have to see people, I have to shake their hand, I have to look them in the eye. And it’s been hard doing these conference calls and Zoom meetings, go to meetings, Google meet, it’s been challenging.

Stephen Harrison (03:51): One of the things that we were going to debate at EASL was the terminology of non-alcoholic fatty liver disease versus a recent publication interestingly that was authored by all Europeans, or at least it didn’t have any North American thought leaders on it, that felt like we should rename NAFLD to MAFLD, which is metabolic associated fatty liver disease. So this past week, my colleagues in the US and I have spent the week writing an editorial, if you will, saying maybe we’re jumping the gun on that and we need to spend a little bit more time and dialogue in thinking about it. I would say, that’s probably been on my mind the most this past week.

Roger Green (04:29): Okay. NAFLD MAFLD thing may wind up being a subject of a future episode, but the observation I made to Stephen about this is you learn a lot about national cultures by learning how they describe their national soccer team. So the English call the English team The Three Lions because that’s what’s on their crest, and the French Les Bleus, and the Italians Azzurri, both of which are blue in their respective languages, which is the color. The Germans call theirs the National mannschaft, which is basically the national machine, and the Americans call theirs the USMNT, the US Men’s National Team, but that’s because we like acronyms better than we like words.

Roger Green (05:02): And when Stephen explained to me the challenge was shifting from NASH to MASH, a lot of it was about getting people comfortable with the acronyms we have. And Americans don’t give up their acronyms easily. Did I get that right, Stephen?

Stephen Harrison (05:12): Absolutely. There’s many other things that we can talk about in a future podcast, but metabolic associated fatty liver disease brings in so many other things besides what we’re really talking about here, which is fatty liver associated with obesity and diabetes predominantly. Metabolic associated fatty liver disease encompasses all the lipo dystrophies, even alcohol is considered in there to some degree. So, you just need to be careful about it and be methodical about it, just like we did with primary biliary cholangitis. We debated it, we talked about it, we came to the right renaming, and that was appropriate to do. And I think it’ll be appropriate to do that for NAFLD. Instead of saying what it’s not, let’s describe what it really is. There may be subsets of it, it’s not just one umbrella term.

Stephen Harrison (05:55): I think for lots of reasons, we’d like to keep it but it is now, just mainly because of patient awareness, disease awareness, investor awareness, NAFLD and NASH have kind of become terms that people are familiar with. To change it I think would require some careful thought.

Roger Green (06:12): Okay, that’s great, Stephen. Peter, what is the one biggest change you’ve experienced in the last six weeks or so because the pandemic?

Peter Traber (06:19): My business for the past two years is consulting for both large and small companies in biotech on Nash and liver disease. And probably the biggest change that I’ve seen is, of course, there’s no travel, not less travel, but no travel. I was supposed to be at EASL as Stephen mentioned. And therefore the number of meetings that are on various platforms like WebEx or Zoom or whatever have dramatically increased. One would think that that was a good thing that you don’t have to travel as much, but in fact, the Zoom meetings take up so much more time over the course of the day, because where you might have had a short conversation, it turns into an hour Zoom meeting.

Peter Traber (07:06): one of the things I’m finding is it’s challenging to find time to do other work. To read, to think about various strategic issues. So that’s one major issue that I’ve identified. The other thing is, now, a topic on everybody’s list, in addition to all the other issues in a development program, is how does COVID-19 impact this development program? And so, therefore, we have double the number of discussions because we’ve got to have a discussion about the development program, and then we have to have a discussion about how COVID-19 impacts it. So, I have found that the balance of my work and interaction with companies has changed fairly dramatically.

Roger Green (07:49): Okay, that’s great. For me, I think the biggest difference has been similar to what Peter said, which is, there are more phone meetings and they tend to go longer. What happens is, what could have been five minute hallway conversation becomes a 30 minute meeting. And then there’s this phenomenon I described as and while we’re on the subject, which is as long as we’ve got 22 minutes left on this call, let’s use them. So in our firm, we’ve started giving people bonus points for something called giving time back. We literally get to the end of the immediate subject, say okay, can we give 18 minutes back right now. That’s helped somewhat.

Roger Green (08:19): The second thing is that because people are a little fearful and panicky of what they’re in the middle of losing, we not only get a lot more questions about COVID, but we get questions out of left field about kind of what’s the worst thing that could happen to us right now? What happens when Godzilla comes back? Just crazy stuff that doesn’t necessarily appear to align, but people get worried and they develop their panic lists and away we go. So, thanks, everybody for that opening.

Roger Green (08:44): I want to tell you one of the most exciting things to me is that the first question this podcast ever received was from a patient who found it on his own. And the patient’s name is Charles. Charles is overweight and has gotten a personal trainer to help them manage their weight better. The personal trainer recommended a fast weight loss program. The question is Charles had heard that a fast weight loss program was not good for liver function or liver health, and he wanted to know if in fact he should be following his trainer on this or not. And why? We only have two clinicians on the phone. One of you guys want to jump in?

Stephen Harrison (09:17): Yeah, I’ll take it. This is Stephen. That’s an excellent question. It’s one our patients ask us all the time. There was some press out in the distant past actually around some of the biliary diversion procedures that were done for weight loss. And the rapid weight loss that was associated with [inaudible 00:09:41] actually lead to worsening of NASH.

Stephen Harrison (09:46): The current surgeries that we do, whether it’s [inaudible 00:09:49] gastric bypass [inaudible 00:09:52], balloons, things of that sort, can still be associated with pretty significant weight loss over a short period of time, and haven’t translated into worsening of underlying liver disease. Simply aggressive dieting and exercise done at home without the benefit of surgery has led to profound and significant improvements in liver disease, but without the detriment of their liver getting worse.

Stephen Harrison (10:26): So, I think it’s perfectly fine and reasonable to do it as long as you’re doing it naturally. You’re cutting back processed carbs, and that would be the cakes, candies, pastas, tortillas, bread, rice, potatoes, potato chips, and sucrose containing beverages like Mountain Dew, Pepsi, Dr. Pepper, things of that nature. And then augmenting that with weightlifting and with aerobic exercise. And quite frankly, we see this often. Patients will lose 10, 15 pounds right off the bat in a week or 10 days, and then it’ll begin to taper a little bit after that. That weight loss is perfectly reasonable.

Stephen Harrison (11:07): The only thing that we worry about or that I worry about as a gastroenterologist is the development of gall stones, which are stones that are generally cholesterol based and they’re found in the gallbladder and can potentially lead to obstruction of the bile duct or the plumbing in the liver. And we see that associated with rapid or significant weight loss. So, that’s the only thing I would caution you to be worried about in that setting. But otherwise, I think it’s fine. Just to caveat to that, we see bariatric surgeons often put people on a carb free diet for two weeks to shrink the liver from the fat so that they can mobilize the liver out of the way to do their surgery. And they’ll often lose quite a bit of weight in that two week period of time. Long-winded answer to your question, but it’s perfectly fine.

Roger Green (12:03): Thanks, Stephen. Anyone else have anything to add before I go on to the second question?

Peter Traber (12:06): I would just say that I agree with everything that Stephen said. It was an excellent and complete answer. And I think that the risk of not losing weight is higher than the risk of losing weight too rapidly in most situations. Even the ketogenic diet, where you end up being ketotic are beneficial to the liver in terms of mobilizing fat, reducing insulin resistance and so forth, which Stephen mentioned related to cutting out carbohydrates.

Peter Traber (12:33): The only thing in addition to gallstones that I would caution people is that people can also get kidney stones because they tend to get dehydrated on some of these diets. So hydration is really quite important, and because kidney stones can go up as you change your diet, increase your amount of oxalates that you might eat nuts and that type of thing. So, keep yourself well hydrated, and I think that the benefit of losing the weight will far outweigh any problem with losing it too fast.

Roger Green (13:05): Thanks, Peter, that’s great. So, speaking as a guy who’s lost a decent amount of weight twice in his life, I agree with all that. And Charles, another benefit of hydration is if you drink a lot of water, your stomach is actually fuller, you find yourself wanting to eat less, and you’re also better empowered to do more exercise. I drink a lot of water anyway, but I go to like two gallons a day, roughly, if I’m ever trying to lose weight. Hopefully I’ll never do that again because I take better care of myself now. That’s great.

Roger Green (13:32): Second question comes from Bob Lieberman at Contello Consulting. Bob’s comment was, in crises, things never happened exactly as expected. Usually, at least one really good thing comes out of a crisis, and then there’s one unintended consequence that winds up having serious long term implications. When you think about what the pandemic has done to clinical trial, what would you say is the one good thing and what is the unintended consequences that might turn out to be a big negative long term?

Stephen Harrison (14:00): This is Stephen, I’ll take first shot at that. Unintended negative consequence, if I could say that, is we’ve seen a delay in enrollment in these trials, and a delay in the initiation of trials. And the problem will hit us in Q4 of this year when you have trials that have kind of been paused, not completely put on, in some cases, completely put on hold, and others paused that are revving back up. And then you have additional trials starting, it’s going to compound the competition for enrollment in Q4 and Q1 at 2021. But I would say a positive that’s come out of this is really zeroing in on what we’re doing and why we’re really doing it.

Stephen Harrison (14:46): I think Yasmeen may allude to this in some of our questions, so I’ll save some of my gunpowder for that. But the end of the day, the patients I saw this morning, they’re coming in in their mask, I’m wearing a mask. We’re checking their temperature, we’re asking them for symptoms, we’re keeping our social distance, except when I have to put a stethoscope on their chest or back or feel their abdomen. And you ask these patients, why are they coming in? It’s a very easy answer for the patients. It’s like, hey, look, I know I have a problem. I have a liver disease. And I know my liver is critically important to my survival and well being. If I don’t have a healthy liver, I don’t exist. And COVID, while it’s scary, and while it’s out there, it’s not a reality for me. The reality is my liver disease, and I need to make sure that I’m treating it, that I’m caring for it. And they’re very appreciative of us persevering and continuing to provide that level of care that they have come [inaudible 00:15:53]

Peter Traber (15:58): Roger, I would say that, just to expand a little bit on what Stephen has already said, we have done a lot of things in clinical trials over the years that have become established kind of procedures, that a lot of people don’t question. I think this time of COVID-19, is having us question all kinds of things. Do we need to do that particular safety lab? Do we need to draw blood that many times? We’re supposed to always think about those, but I think it’s put a much sharper focus on thinking through what’s necessary as part of a clinical trial, and how we can do it most efficiently. And I think sometimes, it takes a jolt like this for people to start thinking creatively that way. So I think that’s a good thing that will come out of this for clinical trials now and in the future.

Yasmeen Rahimi (16:55): I think as we’re learning more week by week about COVID-19 and continuing to collect data, and more able to see the true comorbidities of patients who are at highest risk, I think we’re going to realize that majority of these patients are NASH patients. I think as we continue to fight against COVID-19, we’re starting to learn, I think the public will learn more about NASH. One of the criticisms for a long time has been that NASH is an asymptomatic disease and many of the public world does not understand NASH. And I think that as we’re uncovering COVID-19 and realizing that NASH is a high comorbidity, increased risk of mortality, that I think we’re starting to probably go into next upcoming months as people are thinking COVID is going to come back almost every year, that we’re learning, indirectly, maybe not the best way to learn about NASH, everyone in the world, but I think this could actually capture a broader awareness among the communities about this silent disease. So this is something that we have heard, and I think we’ll monitor that as you go week over week.

Roger Green (18:06): One of the challenges that we’ve seen particularly with payers is they tend to take the perspective that goes, if I’m going to improve NASH drugs, it’s going to be based on what they do for NASH. Don’t talk to me about other metabolics. Every other metabolic parameter that a NASH drug can touch, something else does better. So if I want to lower lipids, I got a better way to do it. If I want to lower HbA1c, I got a better way to do it. Tell me what you do for NASH? The more we understand all the different ways that a poorly functioning liver is implicated in a broadening array of metabolic issues, including the idea that some of the NASH drugs are being looked at for what impact they have in COVID-19. I think that will help reduce the barriers, that people will look at NASH more broadly in the context of holistic health as compared to a single disease. If we get payers to do that, it will get the right drugs approved for the right reason, so I think that’s a better thing.

Roger Green (18:56): The only thing that would concern me, I made the comment last week, that if trials space out, second, third, fourth entrance with a motive action, may have a tougher time finding their legs and getting to market. Since usually, it’s the third or fourth drug in in a category that winds up being the best general drug over time, I would hate to see that innovation process for incremental improvements slowed down, because people are worried about the time lag to get the results. I’m not sure that’s going to happen, and Yas, that may play into your questions, but those would be mine. And with that, let’s transition to today’s main topic, which is Yasmeen asking five questions that you hear a lot from investors. And Yas will ask a question and then we’ll have a free for all.

Yasmeen Rahimi (19:38): Thanks, Roger. We have constructed just five questions that we want to discuss that I think we’re getting concurrently from numerous investors. So, as you can imagine in these challenging times, investors who have made financial commitments at NASH companies or are looking for investment opportunities in companies who are developing NASH therapies, are fixated to really figure out five basic questions. One of the first questions that we frequently get is the following. What is the patient perspective towards being part of a clinical study?

Yasmeen Rahimi (20:11): So given that maybe these patients are diabetic, overweight, cardiovascular and understand that they’re at the highest risk, are they fearing to be part of that study or are they more inclined to be part of it? And the fear comes if patients are scared to be of a clinical study, it would potentially result in reduced enrollment rate, and therefore, also dropouts as patient who are currently in a steady, maybe fear that maybe it’s not a good idea to be coming in for their visit. That’s the first question, so I’ll pose it to Stephen first to maybe start on it.

Stephen Harrison (20:47): I hinted on that a little bit in my previous comments, just in part based on my experience today in clinic, where I saw three people that needed [inaudible 00:20:56] follow up appointments. Again, these patients are smart people. They understand why they’re in a study, they understand why they need to help their liver get better. And so, having that in their hip pocket, they’re more concerned about dealing with what’s in front of them and what’s possible. And what’s possible is they could have an underlying respiratory infection called COVID-19, but it certainly hasn’t impacted them yet. But what has impacted them is their underlying NASH. They want to get that treated.

Stephen Harrison (21:31): They also understand by reading the news and visiting the CDC website, which many of them do, that they have risk factors, as you alluded to before, which puts them at greater risk for a negative outcome if they were to get infected. And so, while they’re not infected, they want to do everything they can to manage those comorbidities to include overweight, obesity, diabetes and underlying liver disease.

Stephen Harrison (21:53): Where I would say that we have the biggest pushback is not necessarily a patient worried about his or her own well being in the setting of COVID-19, but who they live with and who they care for. And many of our patients are in their mid 50s to low 60s and they’re now the primary caregiver for their parents, which are in their 80s. And so they’re concerned more about going out in the community, getting infection and bringing that back and giving it to a loved one. So what we’ve seen is about a third of our patients are asking to hold off on screening, or is there some other way which we can get drug to them and do the safety checks without them having to leave the safety of their home, to protect those around them that they love.

Stephen Harrison (22:45): That’s kind of where we are at least today. I would say that there’s light at the end of the tunnel. We are hearing at least in many southern states, in the state of Texas, an idea that openings are coming soon. In fact, many of our clinics can start seeing patients in Texas on Wednesday, and elective surgeries can begin to be had as well. So, I think what that’ll mean is opening up of liver biopsies and MRI centers where they have currently been shut down in some of these areas. And even for us in clinical practice, we’ll begin to see people start to come back in slowly but surely, still wearing masks, still socially distancing. But we’re beginning to see that turn just a little bit now.

Yasmeen Rahimi (23:30): Thank you, Stephen. very insightful.

Roger Green (23:32): I said two questions. Let me ask the first one first. So Stephen, one of the things you talked about last week was the importance of investigator passion and keeping patients engaged. Is this one of the cases where investigator passion is particularly helpful or is this really patient generated? You can only see what you’re working on, but is this patient generated emotion and commitment or does investigator passion play a role in this kind of issue?

Stephen Harrison (23:56): I think that’s very insightful, Roger. I think it’s probably both. I was talking to one of our summit sites outside of Sarasota, Florida last week, and one of the practices that they’ve seen change prior to COVID and now post-COVID or in the middle of COVID is they’ve kind of spread their patients out a little bit so that they can sanitize in between and they can maintain that social distancing. But they’ve also become a little bit more instructive and educational about NASH to the patients. In fact, the PI there, a guy named Guy Neff, Dr. Neff, who is a transplant hepatologist by training as well is now sitting down with the patient after they have a liver scan. He finds the patients like the terminology liver scan better than fibro scan.

Stephen Harrison (24:49): And so, he goes over that liver scan with them in the clinic and actually spends 20 to 30 minutes with these patients just explaining their liver disease, the epidemiology to natural history, the non-invasive testing strategy, when liver biopsies are necessary. And the current treatment algorithm which is foundational in diet and exercise. And he goes into the fact that there’s no FDA approved treatment for the disease, and that’s where we are with clinical trials with many exciting late phase drugs and development.

Stephen Harrison (25:19): And after that amount of time spent with the patient, for which he is very passionate, they often move right into screening for a clinical trial. So, to your point, a lot of it is taking a deep breath, explaining what fatty liver disease is to patients. Again, I hate to use the fact that patients I saw this morning, but one of our guys was a retired Navy individual, Hispanic guy, he’s overweight. His wife was with him today, and he had a liver biopsy, and it came back with NASH and stage three fibrosis. And I’m looking at a fiber scan that has a cap score 385 and a kPa of 27. And he goes, “Explain that to me.” And so, I explained it to him. I said the cap over 280 is fatty liver. So certainly he had fatty liver. I explained to him that the kPa was 27, Kilo Pascals. Anything above eight and a half, we get a little concerned about liver stiffness. I related that to his liver biopsy that showed stage three.

Stephen Harrison (26:17): He stopped me and said, “Doc, you say stage three like I should know what that is. Tell me what stage three is.” And by the time I got through the explanation, he was like, “Well, you have to fix my liver. I don’t want to progress to stage four. I have underlying diabetes and other things.” And I think when we just step back and we take the time to explain, it took me about 30 minutes to go through all that with him, but he was very appreciative of that, he had a better understanding of his current situation. And quite frankly, the need to push on with investigational therapy that might not only help him, but to his point, he goes, maybe it could have helped my brother who didn’t do well with this liver disease, had found out about mine earlier and participated in a study sooner.

Roger Green (27:02): Let’s go on to Yas’ second question.

Yasmeen Rahimi (27:06): So the second question that we get is directed to Stephen and Peter. Can you share with us exact examples of how creative drug developers and sites have gotten to continue to keep patients on drug and monitor for safety and collect data for the integrity of the trial, beyond the use of telehealth and blood collections at home? So, can you share with us some stories that gives us sort of a glimpse on the level of innovation that comes from the sponsors as well as the site?

Peter Traber (27:39): Yeah, I can make a comment on that, Yas. I think it’s a very important point. Now, remote interaction with patients and site collection of blood at their location are two very important things. But as a corollary to those things, that helps you keep the connection with the patient. But I think we forget about the fact that the patient likes to feel connected to the larger study as well. And even if you can communicate directly with the individual patient, they lose that connection to the site and the receptionist and the nursing staff and the place where they go.

Peter Traber (28:22): I’ve had discussions with people, how do we keep patients being involved in and understanding the larger clinical trial that they’re part of because people are interested in their individual health, but they’re also interested in being part of a larger effort to learn about a disease and look for treatments and cures. So, how do you do that? I think that there are ways to link up the sites to have communications from PIs across the study for Chief Medical Officer officers to speak with all the sites, to include some patients in that. I haven’t come up with a perfect formula, but I think that people need to think about that, the connection of the subjects in the trial to the larger study.

Peter Traber (29:18): Some sites do a better job of that even in non-COVID times when we’re not social distancing than others. Patients feel more committed to a clinical trial if they really understand the bigger context and that they’re in this with people across the world at many sites, and what the results of their participation could really mean, not just to them individually, but to the overall understanding of the disease.

Roger Green (29:48): Thanks, Peter. Stephen, go ahead.

Stephen Harrison (29:50): I would agree with that concept in the way that Peter outlined it pragmatically kind of being the principal investigator for a lot of these trials as well as principal investigator for my own site. Patients love to hear from us. I’ve never, even when I was an intern back in 1995, and I would call patients late at night, on the weekend, six o’clock in the morning, they never said, doctor, why are you calling me now. They were thrilled, not always thrilled at six in the morning, but they were receptive to the call.

Stephen Harrison (30:23): And now, in the middle of this COVID pandemic, they really like to hear from us. They like knowing that we’re invested in their health, that we’re concerned about them. And so, just to reiterate what Peter said, they want to hear from us, they want to hear that they’re part of a bigger picture. Some of the things just to drill down on what Yasmeen asked us to mention relative to some of these creative ways that sponsors are working with us to get follow ups done, to get safety tests done, to get drug to patients, to get follow up lab work, follow up primary and key secondary endpoint analysis done, is a couple things.

Stephen Harrison (31:01): Number one, where available and where willing. Some of our PIs are actually going to the patients’ house directly. We know that is happening in Arizona. Others are choosing to do the telehealth, that’s what I do in San Antonio. And we ship IP or ship drug directly to the patient’s house where necessary, and we send phlebotomist to the homes as Yasmeen’s mentioned. The other thing that we can do, which I’ve done in San Antonio, is we can delay collection of a liver biopsy, we can delay collection of an MRI, by keeping an extending patient on IP, even though the study ended at 52 weeks, we keep them going to 56 weeks or whatever, and just continue to provide them IP until such time that we can get the liver biopsy or the MRI.

Stephen Harrison (31:52): Really, it’s all about the safety of the patient. So our primary concern is do we want to continue to give drug if we can’t monitor the patient effectively and efficiently and feel good about it? So, we do everything we can, whether it’s picking the phone up, whether it’s doing face time or getting them to come by the clinic for a visit. That’s what we’re trying to do. And we’ve been very successful at that. I think a lot of worry has been given to the integrity of trials, to the safety of patients, and I can tell you that’s not something to worry about. Patients as a general rule know that they need to have these tests done. They know that endpoints of MRI and liver biopsy are critical. We’ve been talking to them since day one about the importance of getting these follow up tests done. And they’re very proactive usually in the larger sense of the word in helping us get those endpoints achieved.

Stephen Harrison (32:49): I think part of these questions are driven because their concerns as Yasmeen mentioned. And I would say that data collection for integrity of a trial, it turns out that it hasn’t been that big of a concern at least in the studies that I’m involved with.

Roger Green (33:02): Stephen, I come out of a marketing background where what we tell clients all the time is there is no such thing as The Patient, or The Doctor, they’re segments. Is there a segment of the study population of patients that has the reaction that everybody is afraid of? And if so, 5%, 10%, 20%, could you give a guess on what range that is?

Stephen Harrison (33:24): It’s low. Certainly, I wouldn’t say more than 10%. Every single patient I’ve talked to has said, Dr. Harrison, thank you for calling me, I’m definitely interested in continuing in the study. I just am concerned about getting out of the house right now and how can we make this happen, how can we continue? Or if it’s a new screen, would it be okay if we waited a couple weeks till things cleared up a bit and then I’ll come in? I don’t think I’ve had a single call where they’ve just said, I don’t want anything more to do with this, I’m done. They generally are not that way. But I can’t say that to everybody so maybe 5% of people, small minority, maybe.

Roger Green (34:02): So Peter, does that 5% to 10% number sound right to you as well?

Peter Traber (34:05): Yes, I agree with that. Although there are very likely regional differences that you have to take into account. Different regions of the country, different approaches to medicine and so forth I think makes a difference.

Stephen Harrison (34:20): Let me second that because obviously I’m not in a center that’s considered a hotspot. If I were in Detroit or New York, New Jersey, Boston, Louisiana down in New Orleans, maybe it would be a different situation, but at least not where I’m at in San Antonio.

Roger Green (34:36): And you might actually be losing patients too, which would add to that number not due to will but sadly due to disease. Yasmeen, third question?

Yasmeen Rahimi (34:43): The next question is, can you share with us what is the percentage of high enrolling sites that are currently located in the epicenter? And how will their protocol change from the sites that are less impacted by COVID-19? And then if you could just geographically tell us as of right now, which sites are more impacted, and specifically as we think about the East Coast, New York, New Jersey, Boston, like these sites, are these the highest enroller sites? I think that’s something that investors would be really interested in hearing your thoughts on.

Stephen Harrison (35:17): Yasmeen, are you directing all these questions at me?

Yasmeen Rahimi (35:21): Well, not all of them, but this one would be I think directly more applicable to you since you oversee many of the sites and have a very good understanding. But Peter would be more than happy to add on comments as well.

Stephen Harrison (35:33): I like Peter’s comments. He always is much more thoughtful than I am in mine. The Summit Clinical Research Network that I run has about 60 centers throughout the country. In the northeast, we don’t have any sites. We have one in Ohio. But the vast majority of them are located in the south. And these are all high enrolling private GI endocrine liver primary care centers. So they haven’t really been impacted from one of these hotspots, if you will. The impact has come more from governors putting shelter in place orders, California, for instance, Texas, Florida. And in those states, it’s up to the local authorities as to whether research is an essential service.

Stephen Harrison (36:21): And most have tended to think that it is an essential service. However, a large percentage of the Summit sites I would say probably 40 of the 60 have determined that screening new patients is not essential given that this is a disease that marches over years, not days. And so, delaying a couple weeks to a month or two to screen them is probably the prudent thing to do. However, if they’re in screening or they’re currently on drug, we’re doing everything we can to push those people through into randomization, or if they’re on drug, keep them on drug and do the appropriate safety checks.

Stephen Harrison (36:59): So, I would say, to my knowledge across the board, there aren’t high enrolling sites. And there may be 1z, 2z exceptions to that rule. In Europe, it’s a different story. In Europe, pretty much everything is shut down. And so, if you are a large phase two or phase three with x US sites, potentially there’s more of an impact for those study.

Yasmeen Rahimi (37:23): Thanks, Stephen.

Peter Traber (37:25): I don’t have a lot to add to that, except I’m aware of a situation, which is not a NASH study per se but many studies have similar aspects. And what I found in some hotspots, let’s take New York City, which is the example I’m thinking of, some of the larger institutions are very challenged, meaning hospitals and health systems have been very challenged and shut things down. And what we’ve found is that the PIs can be very creative in those situations. So the PIs have actually taken it upon themselves to find other sites where they can see the patients that are enrolled in the trial. And so, the motivated PIs can often find even in hotspots, places where they can see the patients or get them their drug or whatever it may be.

Peter Traber (38:18): So, I think that even in hotspots, keeping in close touch with your PIs and encouraging them to be creative about continuing to keep patients on IP is a very important aspect of it.

Roger Green (38:32): Thanks, Peter. Let’s go on to question four. Okay?

Yasmeen Rahimi (38:35): Sounds good. This question is for all three of you. Can you share how regulators and sponsors are going to handle missing data, for example, I know Stephen you mentioned even if a biopsy is missed let’s say it week 52, which could be done at a later time points ending with [inaudible 00:38:52]. So what is the exact path towards maintaining integrity of trials? What is the roadmap? Have sponsors already initiated those discussions with the FDA? And how can we visualize that?

Peter Traber (39:03): This is, I would say, a very important question because it’s not just when the trial gets completed, it’s the quality of the data that you eventually have to interpret. And the FDA is quite burdened right now in terms of the work that they need to accomplish. But they’re very helpful if you speak to them and stay in contact with them. So I think it’s really important to communicate with the FDA to think about how statistical analysis plans might be changed, and to do that with consultation with the FDA and prior to making any drastic decisions about what you might do with the interpretation of the clinical trial or timings or patient populations, how you will treat them and so forth. Because if you communicate with the FDA and send revised addendums to your statistical analysis plans ahead of time, it’s going to go much better with you in discussing those data with the FDA in the future, FDA or EMA, I would say the same thing.

Stephen Harrison (40:12): I think Peter did a great job of framing the left and right boundaries of that question. And just to fill in a little bit of the parts in the middle, boots on ground, we’re just trying to get the data, and we’re trying to do it in a safe and effective way. And at the end of the day, when all this is done, we’ll sit down and hopefully the sponsors will sit down and look at this data very pragmatically. And through consultation, as Peter mentioned, with the biostatisticians and the FDA, we’ll come up with a way to analyze the data. For an MRI-PDFF, as long as it’s within four weeks, and they’re on study drug, it’s very unlikely to change, at least at the 12 to 16 week time point, even with our most aggressive therapies like what we’ve seen with some of the companies, where we see dramatic changes in PDFF at week six, maybe 12, those changes begin to plateau out a bit after that time point.

Stephen Harrison (41:05): So, the concern would be as you take a patient off IP and they go more than two weeks, three weeks, and then you try to get the MRI, at that point, I think you might be in a bit of a problem. And the same thing with liver biopsy, where we can, we want to keep people on IP until they get those endpoint analysis done. And then at the end of the day, if we sit down and we have a group of people that had their endpoints taken outside of the window, by the way, these are typically all these violations, these protocol deviations, are run by the local or central IRBs so that they’re aware of this as well. And the FDA and EMA also.

Stephen Harrison (41:44): So I think at the end of the day, we’ll sit down and look and see what we’ve got, and then how best to analyze that data.

Roger Green (41:50): That’s great, both of you. I guess the question I have is, if you start with 5% to 10% of patients falling off because of general fear and attitude issues, and then you put a significant number of your patients in hotspots, is there any risk that you lose enough patients that it becomes a threat to power calculation? Simple question, yes or no? Is there any risk that would happen, start there.

Stephen Harrison (42:13): I would say sure, there’s a risk it’ll happen Roger, but you’re talking about the smaller trials, the big phase threes, those that are going for Subpart H approval, or even the larger phase 2Bs. Generally speaking, your power calculations are built around 20% dropout rate. Their power “weather the storm” so to speak, it’s the smaller phase 2As that are just proof of concept where there’s a razor thin margin for dropouts or collecting data that is not really considered valuable in the primary analysis. So I would say it’s not zero, but it’s really a bigger deal for the smaller early phase trials in the later stage.

Peter Traber (42:54): Just a follow up on that. When you’re dealing with a phase three trial, registration trial, it can be a little more challenging to make changes. And most of those are overpowered really for primary endpoints. For phase two clinical trials, I think it’s important to think through what COVID-19 may do to your trial, to communicate that to the FDA, because they are going to be receptive to understanding that COVID-19 may affect your dropout rate or other things related to the trial out of window assessments and so forth, and then give rationales as to why you want to change something.

Peter Traber (43:34): Stephen gave an example of an MRI-PDFF that might be a month out a window. That seems reasonable to me, but backup everything that you make suggestions with data because the FDA is going to be data driven, they’re going to be somewhat flexible in thinking about protocol deviations, but then they want to have that data backed up. And if you do that up front, it’s going to be much better later.

Peter Traber (44:00): The other thing I would add is that companies that have phase two programs should think about if there is an increased dropout, and if there is a challenge with tests that are out of window. Think about what additional secondary endpoints you could add to your analysis to bolster whatever effect you might see in your primaries. That’s an area where I think people should focus on.

Peter Traber (44:26): Now, if you miss your primary endpoint because of something that happened as relates to COVID-19 drop out or whatever because the study is not powered well enough anymore, it’s not necessarily going to help the investment community be more enthusiastic. But if you have secondary endpoints that support your drugs effectiveness, it will be important for the potential of progressing that asset into a phase three.

Peter Traber (44:55): And we always need to remember that we would like all of our endpoints to be positive in a phase two. But from the FDA’s standpoint, the purpose of phase two is determine whether it makes sense to go into a phase three regulatory trial. So I think giving some thought about secondary endpoints that can help bolster the clinical trial is something people ought to think about.

Roger Green (45:19): Thanks, Peter. Yasmeen, fifth and the last question.

Yasmeen Rahimi (45:23): The last question is, do you think if the FDA and EMA are likely to view NASH therapies differently in the COVID era? And then Roger, you want to comment also a little bit more on what the payer perspective is in regards to NASH pricing in this time?

Peter Traber (45:37): A lot is going to come out on epidemiology and comorbid effects or patients who get COVID-19. And I think that that will change perspectives on what’s important, what comorbid features are important. And of course, our patients with NASH have metabolic syndrome, they have outright diabetes, hyperlipidemia, hypertension, comorbid heart disease etc. And I think that as that epidemiology and those factors are sorted out, that focus on NASH might be much more important in a situation where you have increased susceptibility to a SARS type of event such as COVID-19.

Peter Traber (46:19): So, I do think that the perspective of the disease could change. Similar to when it was established that the presence of NASH is a cofactor or a risk factor for cardiovascular disease, that really gave kind of NASH a bump in perspective. And I think that its association with morbidity and mortality with COVID-19 could do the same thing.

Roger Green (46:48): Okay, thanks, Peter. Stephen, of what we’ve discussed this week, what is the one thing you would like people listening to this conversation to take away with them?

Stephen Harrison (46:57): I think the most important thing for is to realize that the patients are persevering. The patients are still making efforts to come to clinic where they can or continue to provide the safety checks that are necessary to keep going. And they’re getting after these endpoint analysis that were raised as a concern. Just reassurance that patients are in this for the long haul. They’re in it to get better. And they understand that their liver disease is a real problem. even in the setting of a pandemic.

Stephen Harrison (47:30): And the importance of what Peter said about consulting with the FDA, I think you need to make sure all the sponsors have an open line of communication with the regulatory authorities, as well as with their local institutional review boards or central institutional review boards to make sure that things aren’t done in a bubble, that they’re very transparent and patients will accommodate and do what is necessary to continue to drive things forward.

Roger Green (47:58): Thank you, Stephen. And thanks for all your comments today. We’ll see you next week.

Stephen Harrison (48:01): Thank you.

Roger Green (48:03): Yasmeen, I think the payer question is interesting, but I think it’s a bigger question. We’re worried right now about getting the economy back on track. I don’t think we’ve focused nearly enough on the health care costs. And the healthcare dislocation, there was an article today, I think in the New York Times, that suggested that half of all medical practices are laying off staff right now, and that hospitals are losing money hand over fist. And we have more uninsured patients than we did a couple years ago, and uninsured patients are somewhat more likely to be the patients with COVID and also maybe NASH.

Roger Green (48:37): So, I think there’s going to be a larger reckoning around payer economics and healthcare payer economics. Within that context, if the people who are paying take a more holistic long term view, for example, shifting towards if not single payer, a system where there’s more transparency or interchangeability between payment options, then I expect the effect should not be particularly dramatic, specifically if this links NASH more tightly to other diseases and chronic conditions.

Roger Green (49:05): If you’ve got a bunch of private payers trying to stay afloat without adequate support from the government, then there’s going to be a lot of tightening around the edges, and I’m not sure what that will mean for NASH, or frankly, a whole bunch of other diseases.

Roger Green (49:18): Yasmeen, thanks for all those questions. I think they were fantastic, and I think the answers that they stimulated were exceptional. I’m wondering, listening through the ear of the people who are asking you questions, how do you anticipate they’ll react to this kind of feedback and these kinds of insights?

Yasmeen Rahimi (49:34): I think the comments and the color that was provided by you, by Peter, as well as Stephen was very insuring in my view, as I listened to them, and I think as investors would be listening to them. And I think each answer is specifically starting off that patients are going to be still proactive on wanting to be part of a study and too, that sponsor as well as clinical sites are doing everything in their power to keep patients on drugs and making sure to sustain the integrity of the trial. And as Peter and Stephen alluded to, that sponsor should be communicating ahead of time with regulators about modifications from the protocol for data analysis, and that FDA is willing to work with them, and that there’s a path forward.

Yasmeen Rahimi (50:25): And then lastly, that I think probably the biggest positive news in my view was when we spoke about the distribution of trials across the US and where the high enrolling sites are, I think given that the epicenters are significantly New York, New Jersey, Massachusetts, more of the East Coast states, was informative that although there is a delay, but maybe have the majority of the larger bigger sites, and other geographies that maybe have not been as impacted. So I think overall, all the comments that was provided in my view were far more insuring and positive than maybe investors are at this moment perceiving them to be.

Roger Green (51:08): That’s an interesting point, Yasmeen, and I think a really good point on which to wrap up the body of the conversation. Peter, let me turn to you next. The one thing you took out of today that you think people need to understand going forward.

Peter Traber (51:21): One of the things that came out of this discussion is a bit paradoxical. And what I mean by that is in this time of social distancing, and being on Zoom calls from your basement and so forth, the thing that came across as most important or insuring that patients stay in studies and stay engaged, is interpersonal communications. And Stephen really set it nicely when he said, patients want to talk, they want to hear from their PI, they want to have that interaction. And even though it may be over the phone or over a video chat, it’s that personal interaction that is going to drive success of clinical trials in this time of social isolation. So, I think that is what came through to me the most, Roger.

Roger Green (52:11): Thanks, Peter. Yasmeen?

Yasmeen Rahimi (52:14): Yeah. I think for me the biggest takeaway besides what Peter alluded to is the continued commitment for patients probably to take their liver health more serious than ever before given in this COVID era. So I think that to me is very eyeopening and maybe a perspective that I did not spend too much time. It does make sense that if I was a patient with NASH, I was at risk COVID-19, as I don’t have control over contracting COVID despite social distancing and all those things, double benefit is to really do everything in my power to get a better, healthier liver. So I think that perspective was insightful Peter and Stephen provided, and that I may have overlooked.

Roger Green (53:05): So, I agree with you. In fact, that was one of the things I had overlooked as well is the level of patient commitment around this set of trials, even though it’s not screamingly in the news right now. What that says to me when I look at the future of drugs and development is that COVID is a speed bump but it certainly isn’t a wall in any meaningful sense. If your trial is as far along as 2b, you probably have enough patience in it so that your power to absorb any dropout rates that you’re likely to have given how things are playing out. Maybe you get some things delayed a little bit, but that would be it.

Roger Green (53:42): If you’re early in the process, you might be holding up on trials right now, many people are doing that. And that will give you time to rethink the question about power calculation and secondary measures, as Peter pointed out. So it feels to me that the net result of COVID on the clinical trials is that things will be delayed but they will not be derailed, and drugs will still be allowed pretty much to stand or fall on the innate quality of the molecules, which is I think the best outcome anybody could have asked for.

Roger Green (54:09): With that said, let me thank Stephen and Peter and Yasmeen for great comments and Yasmeen for fantastic questions. And for our friend Frank [Sasa 00:54:18] from Newport city for engineering today’s session. We will be back with you next week, where Peter will be taking us through the C-suite perspective on the events of the last couple of months. Everybody have a good week, stay safe and surf on.

Speaker 1 (54:31): 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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