Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Thank you for having me. Uh Here are my uh conflicts. So, a good place to start today's conversation is to note that the liver is a victim of the extrahepatic milieu. When we talk about ma sld, when we do a liver transplant, we put in an organ that is free of any fat. But when you follow individuals who have been transplanted for nash, over time, you see that fatty liver occurs almost universally and steatohepatitis follows. So what that tells us that it's not the liver but the surrounding milieu that is dr has an important role in the development of the disease and its progression. Furthermore, we now know that patients who have MA SLD and the nomenclature has changed, it used to be called NFLD. Now it is called MASL D or metabolic dysfunction, associated steatotic liver disease often have vascular disease, diastolic dysfunction, type two diabetes or chronic kidney disease as comorbidities that are commonly present. We used to think of these as risk factors for fatty liver disease. But what we have come to realize is these are competing threats to life and we need to think about patients more holistically. So, when we think about treating holistically. The root cause for all of these organ diseases is metabolically driven inflammation at the root of which is excess adiposity and the current pandemic of obesity. This of course has led to tremendous drug development for all of these different conditions. And the development of GLP one receptor agonist has been a landmark event in pharmaceutical development for metabolic disorders where from the first generation obesity medicines such as phentermine, et cetera, we have moved to the development of single uh agonists or GLP one. But from that, we have already moved on do oral agonists, dual agonists that target G LP and G IP or GLP and Glucagon triple agonists and then of course combination therapies. So there are already now uh critical criteria that have been established to determine whether an obesity drug is considered sort of a competitive agent within the current landscape. And these need to safely produce a 10% greater placebo, subtracted weight loss in clinical trials or to safely produce a greater than 15% weight loss in over half the patients as an adjunct to lifestyle. So it's really important as we think about treating this root cause that having a lot of therapeutic options enables the treatments to be tailored to the individual patients needs. So, what I'd like to cover for you today is in this framework, how do we think about G LP one based therapeutics and their impact on steatosis, steatohepatitis fibrosis progression to cirrhosis and stabilization of cirrhosis, which are all e concepts. As we think about the role of these in the treatment of M SLD. And MSH. First, let's start by asking the question if weight is the problem, does weight loss solve the problem? And what you see here are data from a highly cited study by via Gomez all where they did a lifestyle intervention and then they looked at the impact of weight loss uh on liver histology in patients with mesh. Now on the left, you look uh you, what is shown are those who had resolution of ST or hepatitis. And if you look at uh those who resolved their steatohepatitis, they had a greater weight loss. Similarly, those who on the right whose fibrosis improved, had a greater proportion, they had more weight loss. So from this arose the concept that if you have 5% weight loss, your steatosis gets better. If you have 7% weight loss, your steatohepatitis gets better. And if you have 10% weight loss, your fibrosis will get better. Now, let's kick the tires on this concept a little bit. Now, what I've CD for you here are those who did not resolve their steatohepatitis. And what you see here is that a large number of these patients actually had more than 5% steatosis, uh 5% weight loss. So having 5% weight loss does not necessarily guarantee that your steatohepatitis will resolve. Conversely if you draw the line at 10% weight loss and look at those whose fibrosis improved, you will notice that almost two thirds of those whose fibrosis improved had less than 10% weight loss. So the core paradigm itself somehow is wrong. What we can say is that of those who worsened with respect to their fibrosis, none of them had more than 10% weight loss. So having 10% weight loss may be protective against worsening, but does not necessarily mean that your fibrosis will actually regress because fibrosis can regress at lesser degrees of weight loss. So in summary of this, we can say weight loss does not guarantee national resolution and fibrosis improvement is not a simple function of weight loss alone. Now let us look at how GL PS could be used in the context of all of the patients with MS. So if you think about the distribution of people in our country who have steatohepatitis or fatty liver, the bulk of them are at the bottom and they have minimal fibrosis. Their risk of a liver outcome in the next few years is relatively low. Then you have people who have started scarring down their liver and you get progressive increase in the amount of scarring till at the top of the pyramid. You have those with cirrhosis. Now, historically, we have only targeted people who have started scarring down their fibrosis stage two and three disease. But what we know is at the bottom. Many of these patients, as I pointed out earlier already have obesity and type two diabetes, which are established indications for GLP one based therapy. So the question arises if you use GLP one based therapy in these people who have early stage disease for their obesity and diabetes, not necessarily directly targeting the liver. Will you be able to clean out the liver and will you prevent development of more advanced disease? And I think this is a relatively novel concept because historically, we have only targeted those with more advanced disease. So GLP ones of course, have many, many metabolic effects. And we know that semaglutide, which is sort of the most widely used GLP one currently uh produces up to 14% weight loss. And these are the original studies from 2018 where patients got 0.4 mg daily, but currently you can use up to two point it's it's a weekly injection now with up to 2.4 mg. Now moving beyond semaglutide, what we see here are recent data from uh with retro which is a triple agonist where at the end of 48 weeks, eight and 12 mg of retrod could produce almost 24 25% weight loss. So this is pretty remarkable. This is we're talking about bariatric level weight loss within a year. And in these patients between 86 and 93% basically had less than 5% MRI PDF f so their fat content was nearly uh was basically returned to normal uh within these populations. So this tells us that if people who have very early stage disease are treated with these GLP ones for their obesity or diabetes, it will ameliorate whatever liver disease they have. We do need some long term data now to show that this translates into less progression into advanced disease. The second thing we have learned is that when you actually regress the weight loss and the liver fat content, when you follow them out, where you see the line beginning to level off is around 20% weight loss. And so it takes about 20% weight loss to completely defect the liver, not just to improve the steatosis to get your MRI PDF F under 5%. This other issue that has we have learned is that by week 24 whereas the liver fat is almost entirely mobilized and there is little further reduction between week 24 and 48 visceral adipose tissue as shown on the right, continues to decrease even up to week 48. And we don't have data past that, but it's possible that you could have even further reduction, but you can have up to a almost 50% reduction in visceral adipose tissue volume within a year. With these very active weight loss drugs that can actually reduce up to 24 25% of your body weight within that time frame. Next look, let's look at the more traditional patient population. These are people with MS who have high activity and stage two or three fibrosis. And ask the question, can these GLP ones through weight loss, regress activity and fibrosis? So first, let's ask the question about MS resolution. So what you see here are data with sema on the left, you see data for weight loss and you can see progressive weight loss in the and you can see a decrease in body weight. The absolute body weight is shown over here. This translates into the generally about a 12 to 14% weight loss at the higher doses. Now, when you look on the right, what you see is that up to 59% of patients actually had resolution of steatohepatitis. So it shows that when you have this type of weight loss, when you look at 0.4 mg on the left, you are getting about 14% weight loss on the right, about 60% of the people can resolve their steatohepatitis compared to only 17.2% of placebo patients. And you can see the weight loss for placebo on the left is relatively flat. Now moving on to more potent drugs like tiatide, you see the weight loss on the left and then this is the phase two trial in our NASH patients. So the weight loss here is a little bit lower than what's been reported in a general obese population. But that could be because some of these patients are diabetic. It's also possible that patients with mash are more persistant to weight loss, but it was 15.6% at the higher dose for what it's worth. And you can see that this is linked to, again, about 73% resolution of hepatitis. So again, it shows that with 14 15% you know, between 13 and 15% weight loss, you're getting somewhere between uh 60 to 70 uh 72% resolution of steroid hepatitis. Again, making the point more weight loss is better. Now, with this study, when they actually broke down the population by uh essentially the amount of weight loss. So if you are less than 5% 5 to 1010 to 15, et cetera, as shown on the X axis, what you look at when you look at the percent of responders, you can see that when you get to 20% which is the number I showed you earlier, you're now hitting n 90% plus people with uh uh resolution of steatohepatitis. Now, it's interesting that the numbers for uh percent is a little bit lower for those who had more than 30% weight loss, but the numbers are very small. So the percent change gets magnified. So I won't pay too much attention to it. The bottom line is with 20% weight loss. You really start seeing a N resolution in very high numbers. And of course, if you look at the bariatric population, once again, as you follow this, these are data from the brave study. And what you see here is that when you have 20 to 25% weight loss, you are again seeing 75% and higher degree of uh mass resolution. Now, there are components of steatohepatitis. When you look at GLP ones, here are the data for ballooning. And what you see over here is that with for about 14% weight loss, you're getting about 74% resolution improvement in hepatocellular ballooning compared to 38% in placebo where the weight uh where the uh where the weight change was relatively flat as you can see on the left. Similarly, when you look at inflammation, you can s see again that the data are actually uh more mixed. And um whereas with ballooning, you clearly saw that at the high dose of semaglutide, there was greater uh improvement in ballooning changes in inflammation were more mixed and not easily clarified. So when you put these all together and look at the NFLD activity score. Once again, you can see with weight loss, the more weight loss you get decrease in a deep markers of uh histological activity as well. Now when you look at adding glucagon agonism, now remember GLP S have no uh receptors in the liver. So all their work is outside of the liver and we already established that the extrahepatic milieu is extremely important. Now, we add a little bit of liver targeting by a molecule that also targets the Glucagon receptor. And this is the silver data. And you're seeing even though they have somewhat less weight loss that they're actually having 83% resolution of steatohepatitis. And up to 63% of patients who had both a baseline and end of study biopsy. They are getting improvement in fibrosis, which of course, then allows us to move on to the question of fibrosis. So how much weight loss do you need? Really? Because we sort of debunked the 10% number ear earlier. So these are data from the brave study, which is a bariatric study comparing lifestyle to room wide to sleeve gastrectomy. And you can see about 50% had a stage one of this population, about 50% actually had only stage one fibrosis. But clearly the proportion of people who had fibrosis improvement was higher than placebo. But these were early stage fibrosis. And we're really now talking about people who have what we call clinically significant fibrosis. This is fibrosis stage two and three, which are associated with increased liver outcomes. Stage 0 to 1, it has a very modest effect or minimal effect on outcomes. So, you know, you could argue that that's probably not the critical population we're talking about. So when we talk about this population, we know that with retro for example, which produce that 24% weight loss that I showed you that fibrogenic drive as measured by PRO C three is decreased. So we think this will translate in the long term into less fibrosis. When future studies are needed to show that. Now, coming back to semaglutide again, what you see here is that with 14% uh weight loss, you are getting 63% of patients who are actually uh showing improvement. Uh This is data for steatosis and uh uh you know, no surprise over here. But when you look at fibrosis over here uh with fibrosis regression, uh what you see over here is that uh uh while there is a trend, uh it, you're just beginning to get a signal now for fibrosis improvement compared to placebo. When you look at the 5 mg 10 mg and 15 mg in this study, those who actually had uh started with stage three disease actually had more pronounced fibrosis improvement than those who had stage two disease. So that may be another thing to keep in mind. So when you again break this weight loss in the ter appetite study from uh uh uh into different categories of weight loss, what you see is that when you get to 20% and higher, that's when you start seeing fibrosis improvement in the 70% plus range. And even again, small numbers, uh uh there's some noise over here, but uh basically at 20% weight loss. It looks like you are beginning to pull away from placebo. Now, remember that over here in the less than 5% weight loss, uh, you really have only 49 patients and, uh, uh, those who had more than 30% weight loss, they were only nine patients. So, so, you know, the, I won't get too hung up on the percent numbers, but generally looking at the trend line where with greater weight loss, you actually have, you know, greater fibrosis improvement. Now, this brings us back to the issue of what do we do beyond GLP one, can you really push the envelope further? And what you see here are the GLP one combined with Glucagon and the molecule we are talking about is voet, there's another molecule called cotadutide, there's pide, these are just the GLP Glucagon coagonist the GLP one through insulin and food intake, you know, are expected to improve steatosis and glucose dependent insulin secretion. Uh I impact gastric emptying and food intake and thereby lead to a metabolic benefit. Whereas the Glucagon allows us to increase energy expenditure, increase lipolysis and and enhance fatty acid oxidation promote glycogenolysis and uh but it also increases gluconeogenesis and it also increases lipolysis. So the gluconeogenesis could offset the glycemic benefits of GLP. One if the molecules are heavy on the glucagon agonism. So it's very important that these molecules have to be balanced in terms of their affinity for GLP one versus Glucagon. And so is one of those molecules uh which are somewhat optimized, which are heavy on the GLP one with a little bit of Gluco coagonist. And here are the data and for fibrosis, where you see the data for paired biopsies. Again, if you look at the entire study population of our stage two, these are data that were published in the New England Journal earlier this uh year. And you can see when you include the whole study population, clearly significant improvement in fibrosis uh compared to placebo. And if you look at just the F two F threes, we are seeing approximately about uh 60% 56 to 60% improvement in uh fibrosis. Therefore, with uh 4.8 the numbers were again a little bit lower. Uh but it's in that range, but clearly these are, these are while they intermediate range was not significantly different from placebo. Uh there are two other doses and overall the those on SVO had significantly better fibrosis improvement compared to placebo. So, II think really to shift the needle on fibrosis within a relatively short period of time about one year or so, in addition to weight loss, you probably need to have some direct liver targeting. Cause remember if you're with the GLPs that do not have a receptor on the liver, whatever is happening outside of the liver has to improve the delivery of lipotoxic lipids and cytokines to the liver, which should improve the steatohepatitis and injury, which when it cools off will reduce the fibrogenic drive all of this takes time. So we the conversation would not be complete if we did not also consider that there are other drugs that are currently approved for uh mesh with fibrosis. And I'm talking about ResMed, which is an approved drug therapy. The GLP based therapies, these are all in clinical trials. These have not yet been approved for uh use specifically for MS. Uh their approvals are for diabetes and for obesity. Similarly, pioglitazone and Vitamin E also have been used uh with varying degrees of success and these are unapproved users and represent off label uses of these molecules. But resol which is a thyroxine beta receptor agonist is conditionally approved for the treatment of mesh with fibrosis. And so this is an important sort of uh element and I for this population is the only approved drug out there and should be considered frontline therapies. Now, the essence trial which is the phase three trial with semaglutide, we expect it to read out by the end of the year. And then of course, we are eagerly anticipating those results to see whether there is an improvement in fibrosis uh with semaglutide in that setting. But regardless when you think about competing threats to patient's life, the benefits of GLP one therapy on obesity, diabetes, cardiovascular outcomes, mace chronic kidney disease and renal outcomes. These are all well established at this point. And so it is quite likely that regardless of what their final role in mass treatment ends up being that this will be part of background therapy for their underlying obesity and metabolic syndrome. Now, lastly, what about cirrhosis? So these are data from the semaglutide trial and you can see again a small amount of weight loss and while uh there was some more patients who had mass resolution, it was not statistically significant and there was uh no signal for anything happening with fibrosis. So this was a negative study. So it seems that the degree of weight loss induced by semaglutide is not sufficient within the time course of this particular trial to shift the needle on fibrosis. And we know fibrosis is critically important for clinical outcomes. So what about bariatrics in this setting, which has always been sort of a historical reference standard? So we know with bariatric surgery, these are data from France that up to 90% of patients will have mass resolution particularly with substantial uh improvement in BMI. However, if you look on the right, where you look at the fibrosis stages, what you see is the proportion of people with cirrhosis really remains unchanged all the way up to five years and about half the patients with F three or bridging fibrosis actually show improvement uh by five years and most of that improve, do you get a little bit of improvement by year one? And then additional improvement between year one and year five. But even at the five years, half, about half the patients with uh or uh somewhere between a third of be between a third and half the patients who had uh F three will continue to have F three even five years out. Now, having said that there is a, this is, these are data that were presented at EASL earlier this year. And I believe this manuscript is under review and essentially looks at patients who had MS and compensated cirrhosis. And what you see here is that compared to non surgical controls, those who, those who had metabolic surgery actually had a reduction in major adverse liver outcomes. There was less progression from compensated to decompensated cirrhosis. The percent change of body weight over here on the average by the time things leveled off by 3 to 6 months was in that 20% range or plus again. And of course, the this was also associated with improvement in hemoglobin A1C. So once again, that 20% number pops up even in the context of compensated cirrhosis. Uh a caveat here of course, is that particularly in the cirrhotic population, when you lose weight, a certain proportion of your weight loss is n uh lean body mass and uh a certain proportion is adipose tissue. So about 20 to 30% is non adipose tissue, lean body mass. And if you induce sarco worsen the sarcopenia in these patients, you theoretically, you can dip them into decompensation. But what you see in this study is actually a remarkable decrease in clinical outcomes and stabilization. So maybe this will be a non-issue in the long term. But I think this needs more careful follow up and much more work needs to be done to be able to uh uh provide the kind of data we need to be comfortable with weight loss of 20% or higher in those with compensated cirrhosis to be sure that we are doing this safely and that it indeed does translate into less clinical outcomes. One problem has been and why the semaglutide trial may not have been positive is that it did not achieve the kind of weight loss needed to actually stabilize the disease. So here are the data of uh hepatic decompensation events from this study. And what you see over here is that a reduction in encephalopathy in the non surgical controls, 24 out of 100 and six had a encephalopathy episode for there were a total of 27 encephalopathy episodes and there were only three in the metabolic surgery group. Similarly, when you look at ascites, uh there were only three compared to 21 in the non surgical controls. That's where the biggest set of differences were. And then of course, if you look at all cause mortality, you have six out of 62 in metabolic surgery and 26 that's about 10% right. So, and then you have about 26 out of 100 and six, that is almost 20 something percent, uh 24 25%. So it does appear that if you can get this weight down, even in this compensated cirrhotics, uh there is a potential opportunity to stabilize the disease. What we don't know is if you already have clinically significant portal hypertension and you're on the verge of decompensation, how far can you do this safely? I think. So this is still, I think is in the realm of research, not ready for full time routine use. But these are really, really interesting data that tell us that yes, we need to continue to try to push the envelope on the weight loss to find and clearly define the region of safety where you can get the weight down without causing a problem and actually help the patient by stabilizing their liver disease. It is encouraging to see that uh phase one hepatic impairment trial with. So which is a, a GLP 1 g uh Glucagon coagonist. Uh And this study had to be done because there was direct liver targeting with Glucagon. Uh in child pa and B, we are actually seeing improvement in liver stiffness. There was no evidence of uh disease worsening in this population. And this is a, the uh these are data from a hepatic impairment study for this population. No, the benefit of this weight loss on the liver disease probably is going to be more heterogeneous. We would love to be able to say one size fits all. You just do this and forget about it. But the reality is there are some people who improve and as you saw some people who did not improve, why is that? I think this has to do with the heterogeneity of the disease. We previously shown that even in the same animal moi animal model studies, once you start a high fat diet in the initial phase, you get a lot of metabolic genes that turn on, then you get inflammatory and fibrotic genes. And as you get further out the metabolic genes, even though you're continuing the high fat diet, the metabolic gene expression levels tend to return to baseline where you have continued oncogenic and fibrogenic signaling. So, it depends on where you catch the person molecularly in the course of their disease. And then it depends on the degree of improvement in their systemic metabolic state that determines how much glucose and fatty acids are delivered to the liver, other lipotoxic lipids, whether they are being decreased uh in terms of delivery to the liver such as ceramides. What happens to adiponectin and other adipokines, which are actually good actors and insulin sensitizers will these activate AP kinase, for example, and to what degree are inflammatory fibrogenic cytokines decreased. How are the changes in the microbiome relevant? Over here, there have been a number of studies on changes in microbiome after bariatric surgery, there's still a relative paucity of data with G LP one. So I think these all need to be resolved. As we think about how we use GL PS across the entire spectrum of MA SLD and try to identify at different points in the course of the disease based on the severity of the underlying liver disease, uh the uh ability to resolve the steatohepatitis and improve the fibrosis with the ultimate goal of improving clinical outcomes. So I think what I've shown you is that to completely defect the liver unit 20% or more fat. Uh weight loss, similarly, for steatohepatitis resolution, uh 20% seems to be the number. Certainly with fibrosis here, the data are not quite as clean. Uh It seems that 20% or higher will be the number that we may need. We need more data for it to see how much weight loss will translate into less progression to cirrhosis. So, if you cool off the steatohepatitis today in five years, will you have less progression to cirrhosis? There's some epidemiological data and uh that suggests that may be the case. And then certainly for those who have developed cirrhosis, uh that uh really you need more than a little bit of weight loss if your goal is to stabilize the cirrhosis and reduce the likelihood of uh liver decompensation events. There's also data that weight loss uh actually may improve uh portal hypertension uh from Barcelona and uh that may be yet another mechanism by which the reduction in body weight actually stabilizes uh the cirrhotic state. So what I'll try to finish up here with is that, you know, where we have come to is a long ways from where we started even five or seven years ago where we would just say lifestyle is just diet and exercise. We understand the importance of sleep. We understand the importance of mental health and these are really applicable for everybody in the context of when we think about their overall metabolic health, we need comorbidity care for all. I mean, because there's no point fixing the liver if they're gonna die of something else within the same timeframe. So all of that has to be done. And of course, GL PS play a very important role in that with respect to the liver disease for people with low risk where the main cause of death is cardiometabolic and cancers. I think treatment of underlying obesity type two diabetes for which there are clear cut indications will help reduce those cardiac risks may potentially also reduce cancer risks. And so should be considered for those who are in the middle where you start now scarring down the liver and you have increased liver related risks. You have a number of options and ResMed, of course is the only approved drug therapy. Whereas GLP one and Vitamin E pioglitazone, et cetera are currently not approved therapies and would be off label treatments in this population. And then of course, for those who have advanced fibrosis. In addition to the usual things we do such as HCC surveillance vaccinations, use of carvedilol if they are features of clinically significant for hypertension monitoring, for mild monitoring, for sarcopenia, et cetera. And then uh following these patients for and management of decompensation, uh significant weight loss, I think can be accomplished in these patients. But we need to define how far you can take this because there are a lot of people with compensated cirrhosis, some who look more like bridging fibrosis, but there are others who are on the verge of decompensation. So I think we need more work in that space. So with that, I will stop and thank you for giving me the opportunity to talk to you about GLP BA one based therapeutics for MS LD.