Dr. Rinella relays valuable takeaways from the EASL International Liver Congress including diet and weight loss approaches, biomarkers, and emerging therapeutics for Non-Alcoholic SteatoHepatitis.
Welcome back everyone. Um It is my absolute pleasure to introduce our next speaker who is mary Rinella, she's professor of medicine in the division of GI and Hepatology at the Northwestern University Feinberg School of Medicine and runs the Northwestern Nash program as well as the Sld Nash task Force. She was agreeable to present our nash talk and I have to give her extra kudos because she's giving us an update on the easel international liver congress that literally just ended today. So mary was able to put this data together in record time and she is a well known expert in Nash. We're looking very much forward to her presentation. Thank you so much. Doctor Rinella. Thank you Catherine and thank you paul for the invite. Um sort of right, this is hopefully going to be okay for you guys. This was as Catherine said just presented a lot of these papers were presented yesterday. Um So what I'm gonna try to do is I picked out some of the most some diagnostics but mostly therapeutic updates that might be of interest to you. Mhm. So Here are my disclosures uh none active but those are my prior disclosures in the past 12 months. Mm. So a matter of outline, we're going to talk a little bit about diet and weight loss approaches because there were some interesting updates on that, a little bit on biomarkers and then emerging therapeutics as I mentioned. So before we even start this, I think it's important just to reiterate that there's no FDA approved therapy for Nash. Um Final approval from the FDA will come when a therapeutic agent alters the way people feel function and survive. And as you can imagine in the context of Nash, it's a very long process to develop compensated liver disease and symptoms. And so what we're looking for is conditional approval. Which can be met only if one of these two histological end points are achieved. So either resolution of nash without worsening and fibrosis or reduction in fibrosis without worsening of nash. And that is because fibrosis is what's linked to hard outcomes in the disease. So uh to sort of put things in perspective on the bottom on the X axis, you can see numerous therapeutic interventions that have published histological data, but by far and away, the most effective way to get rid of nash is by losing weight. Even small amounts of weight loss are effective, but more, the more weight loss, the more impact you have. And the so far we'll talk a little bit about sema glue tied because it's been the most impactful with respect to national resolution. But again, because it causes people to lose weight so we really need to focus on is helping people lose weight. So this is a study out of Sweden presented by homer from Hannis Holmstrom's group and what they did is they took a they they compared standard standard dietary advice to which basically was individual consultation with a Hepatology gist, which, as you might know, may not be the most detailed information. They were given written instructions on how to choose a healthy lifestyle. General advice on how to exercise, but nothing really more specific than that. This is compared to a 52 diet. We're in two nonconsecutive days you take in less than 500 calories or if you're a female or 600 of your mail and in the alternate days, 2000 and 4000 calories, respectively. Um and then some more specific recommendations and they compared that to the low carb, high fat diet, which is pretty much sort of an Atkins diet. This was a 12 Week trial and let me go through some of the results. So, not surprisingly, there was a reduction in liver fat scene, but really compared to the standard of care, which is really not much specific advice. You see a nice reduction and it had a fat content, both the 52 diet in the low carb high fat diet. There were really no difference between those two interventions, but they were both better than the standard of care and with respect to relative reduction in liver fat fraction. Um, the number that you need to sort of remember is 30%. So what we found in most, I shouldn't say most many mechanisms of action. Uh, there's a histological improvement. Once you exceed that 30% relative reduction threshold. And you can see here Both of them handling that that with 50% that reduction over 12 weeks, which is pretty, pretty darn good. So um here you can see that it's really related to weight loss. So both the 52 diet and the low carb high fat diet achieved a nice weight loss 7.7 and 7.4%. Um Which should correlate with histological improvement. And you can see here the more weight you lose, the more reduction in liver fat you achieve. So again, similar effects of those two diet interventions compared to standard of care with respect to see Otto sis weight reduction, insulin resistance improvement. Um and really suggesting that the weight reduction is more important than the macro nutrient content of the diet. I will say that there are data on the mediterranean diet, which is what we actually generally recommend for these patients. Um That is independent. There are benefits to the macro nutrient content independent of of weight loss. But this is just what this particular study found. So this I thought was important even though mostly because endoscopic methods of weight reduction are sort of gaining speed. The biggest issue with them of course is that most of the time or at least as far as I know, insurance doesn't cover this. So it's still going to be difficult to employ on a wider scale. But it is a pretty nice study basically. They looked at a comparison of endoscopic uh sleep gastro plasticky plus lifestyle modifications for 72 weeks compared to standard treatment, which is lifestyle modifications. And they actually did sham endoscopy in these patients. And the complete study will look at the 40 people that were actually randomized, but they had a pre specified analysis that would look at the results. Once 21 of these people reached that 72 week time point, lifestyle modifications you can see here in the green box are pretty restrictive actually. Um and uh fairly specific in the recommendations. So it wasn't just like the hepatology ist recommendation here. You can see weight loss over time, much like you see with bariatric interventions or even diet interventions, you get a peek weight loss early on and then you start to lose some of it over time at the 72 week period. But compared to the grave are the gray line, which is the lifestyle modification alone in the sham endoscopy, there was a nice reduction in in in weight and um Even 12% at the 72 week time point, This correlated with nice improvement in liver enzymes that's supposed to be -42.7. Um and reduction in ferreting for whatever that's worth and mostly related to inflammation. So looking at histological changes. Again, huge grain of salt with this because they didn't even they didn't even have enough people to compare within the between the groups. So what they did is they looked at weight loss versus no weight loss And more more than or less than 10%. And you can see significant differences in all the histological parameters. Again, not surprisingly, this has really previously been shown, but I think this is important because it does offer another mechanism of more sustained or at least more sustained potentially than lifestyle intervention alone, but that will have to, you know, sort of stand the test of time um you know, in the future. But interesting nonetheless, and randomized control trial in this population is hard to do with sham endoscopy and everything. So from a diagnostics perspective, there really wasn't much presented at the meeting. Um Just for perspective, I want to introduce the fast score. So basically um the reason why this particular score was developed is because we were at a bit of a loss in identifying people who had more than or equal to F to fibrosis. In the context of Nash specifically Naville activity score greater than april to fort. Why? Because that's what you need to enroll in clinical trials. But also those are the patients that are more at risk for liver related outcomes down the road. So this was developed really to identify people. But in this particular study um that's a subgroup analysis of the semi tied trial. They looked at fast score as a marker of histological improvement so that at some point of course we can unload the doing the biopsy thing because it's just not a practical thing um really either for diagnostics or for to the to assess treatment response. Although it's currently still required until we have more data on the biomarkers. So basically um the fast score as I just showed you in the slide before is a combination of the liver stiffness measurement with the cap score which is the fat measurement on fiber scan and A. S. T. Which we find that correlates much better with fibrosis than does A. L. T. So this post talk analysis basically looked at the fibrosis responders versus non responders and then compare them and to bring us a little bit back in case some of you don't know these are the semi tied Um phase to be data. And Nash presented actually deliver meeting in 2020 but then subsequently published actually the same month in the New England Journal of Medicine by Phil Newsom. You can see really nice improvements in national resolution and the 0.4 mg, sub q daily arm compared to placebo. And the issue really with this study was that there was no significant difference in fibrosis. And as you might be aware of your hepatology, it's nothing special about Nash is just that the more fibrosis you have, the more likely you are to have a liver related outcome. And so improvement and fibrosis would be what we're really looking to achieve ultimately. So here are their data on the left. You can see changes in fast score from baseline two weeks 72 this is a subset analysis of 161 patients. You can see that there's a dose dependency to the change and the fast score. The dark blue being the 1610.4 mg dose. And then over to the right, it's separated by primary endpoint. So the primary endpoint that they met was the resolution of nash. You can see a very big improvement in the fast score, especially in the 0.4 mg group. And you even see it in the fibrosis improvement without worsening of nash. But of course the placebo group had a pretty significant response in this um study. Again, not terribly surprising because you're gonna see this if you look at A. L. T. Two and it's just easier. Um Other things noted in this trial where that other markers that are relevant to nash such as weight loss. Um The egg, the app rescore which basically is liver chemistry ratio and platelets um fit for and some markers of nash activity all correlated with improvement in the fast score. So in conclusion the reduction of the fast cars associated with an improvement histological nash activity and also another important um Biomarkers of disease or co morbidity. And they're proposing that a 25% reduction in fast score may be associated his logic response in trials over 72 weeks. Of course this is pulled kind of out of the air. Um okay but in any case it does seem that response is it's not just a a static marker. It could be used as a dynamic marker as well. Okay so as I mentioned we can't do biopsies on everybody. So what do we know as far as what correlates with histological improvement? So this table includes of course it constantly is changing. Doesn't include every single biopsy trial to date but it includes um every biopsy trial today with final information. Um You can see the L. T. Improves where every single time when there's improvement in histology and that's either national Resolution or fibrosis pdF F. Which you're going to see a lot in the next in the subsequent slides also improves but it's really mechanism of action specific and more tightly correlates with national resolution and not so much of fibrosis. And so it's just important to remember that as we're looking at some of these earlier phase trials. So here's an example um in the Obaida colic acid uh study the regenerate trial which is published a couple of years ago. This is just as a reminder, the first phase three trial and only phase three trial and Nash that has shown that has met its primary endpoint. It is still being considered by the F. D. A. Was not approved with its initial submission probably related to um side effects. The risk benefit analysis not being a subsequent are sufficiently in favor of a beta colic acid. But the point here really is that if you separate groups out by improvement in fibrosis, which is the circles, you can see more improvement in a LT. Not surprisingly you see this in placebo as well but the magnitude is higher in a beta colic acid and this is sort of a dose dependent phenomenon which is important and suggests that the drug is having a role on the bottom. This is a smoothing spline plot which basically looks at uh it plots the percent change in a. L. T. On the X. Access to the probability of fibrosis improvement on the y axis. And you can see that the more LT improves, the more likely you are to have fibrosis improvement again. Not terribly surprising. So I'm moving on to uh some emerging therapeutics data. So there's a lot under development right now and this isn't even including everything. But as the con the concept being that there are multiple ways to attack this disease, um, I would argue that the higher up in the cascade, you hit it, the more likely you are to have improvement because there's a lot of biological redundancy um, with respect to inflammatory signaling, an activation of Stella it sells. So not surprisingly here, we have the pipeline for Nash where you see of course many trials failing from Phase one to Phase two as you would expect and then from Phase two to Phase three, although the big problem we're having right now is that we're seeing a lot of drugs dropout in advanced development and I think that that is in some ways predictable and really requires us to be a little bit more um, circumspect before we allow trials to move into advanced development. So these are the trials we have in Phase three actively, there are multiple that are about to start that are not actively enrolling yet. Although I'm missing one actually. Um you can see the ones I drew the line out. Those are the ones that have already fallen out. Okay, so we're gonna be, we've mentioned briefly abated colic acid we're going to touch on or as Mitterrand. Uh they have not read out yet and will not read out their final Phase three until 2024. Uh Aram called nothing new is presented or below picked and nothing new is presented. So this is kind of an interesting study. This is a drug called L. P. C. N 11 44. It's an oral pro drug of endogenous testosterone. And so in cross sectional studies of men with fatty liver disease is an association with low testosterone and higher degrees of scoliosis. And so based on that. The lift trial was designed which is a phase two randomized controlled trial of male subjects with nash in any degree of fibrosis. Um What's being, what was presented an easel is the is a 12 week pre specified analysis looking at um changes in hypnotic fat content and L. T. This is a design as a 12 is a 36 week biopsy study though which is of course not completed. Uh Maybe completed, violate breaker for sld. So here you can see at the upper right absolute changes in liver fat M. R. I. P. D. F. F. Um And just the 30% relative reduction I mentioned earlier is being sort of the threshold where beyond which we start to see histological improvement for absolute that that number is 5%. So here you can see in treatment group A. Which is I should have mentioned before. Sorry. Just the lipo seen 11 44 by itself. And then treatment B. Is the 11 44 combined with uh D alpha two Kafir All okay, so this has vitamin E. In it. You can see in both cases nice improvements in liver fat. And what was interesting here is that they didn't pre specify that people had to have low testosterone before entering. And about 46% of people had did not have low testosterone. So you gonna tell patients with testosterone levels of greater than 300 are noted here. And even they had improvements and liver fat. So that's kind of interesting I think. Um And again here relative changes uh On the on the left. Uh so exceeding the 30 are people who responded on the left uh to greater than 5%. And then here responders greater than 30% against this is a responder analysis. So 75% and 70% respectively of the treatment groups had a achieved achieved this benchmark ketosis reduction. So moving on to liver enzymes, you can see here that there was a a significant difference between A. L. T. And A. S. T. In those that were treated with either the 11 44 alone or that combined with vitamin E. Um for L. T. N. A. S. T. Respectively. And then also longitudinal E. There seemed to be actually a benefit to the uh be treatment which had vitamin E. Incorporated particularly in A. L. T. So um in summary uh the L. P. C. N. 11 40 for reduced liver fat by P. D. F. F. A. L. T. N. I. S. T. At the 12 week mark, irrespective of gonna gonna tell status, it's possible the addition of vitamin E. Uh was additive. However, it's a little bit unusual. They chose uh an ice, a form of vitamin E. That's not really well studied um for unclear reasons, but in any case may have had some added benefit and the magnitude of change in the pdF F. Reduction and L. T. Are suggestive of a future histological benefits. So we'll see what the 36 week trial shows. So this was also an interim analysis. This is the this is the meeting of interim analyses. So I cosa beauty is a structurally engineered fatty acid. It's sort of um like uh casa petn OIC acid but it's um the potency of it is higher. And so you're able to give a lower dose of it. Um And so this was studied basically in people with nash and fibrosis. Um And this is a 16 week in term analysis. This is this is designed to be a 52 week trial. Um And again we're looking here just at L. T. G. T. Triglycerides and then some markers of fiber genesis and inflammation. So in this 16 week interim analysis you can see dose dependent improvement over placebo. In the liver enzymes are corrected values against placebo GT as well. Um Here at the bottom you can see those numbers uh those in numerical format. And then to the right you can see some fiber genesis and inflammation biomarkers. So you're gonna see these biomarkers used in the majority of trials with Nash of Nash right now, proceed three is emerging to be an important harbinger of um fibrosis improvement. And you can see a nice reductions in both in both groups and a dose dependent manner compared to placebo. Uh Crp not really clear how much of a change that really had. Um And then here this is again uh P. Three and P. Temp one and hyaluronic acid which are components of the elf score. And the score is noted here. So was there was a reduction in the F. Score which is a uh for those who don't know it's a it's a marker, it's a serum marker of fiber genesis that's currently undergoing evaluation by the FDA. So not surprisingly this is essentially fish oil on steroids. You see uh improvements in lipid parameters and home I. R. Was so mild improvements in insulin resistance as well. So here the lipid parameters on the bottom right? So not surprisingly was improved on all fronts really. So with respect to safety and cholera bility um It was fairly well tolerated. Um Most of the t of the adverse events were diarrhea and nausea. That's what you also get with higher dose fish oil. There was no dilly but again I hope not at 16 weeks. Um no increase in weight again, not terribly surprising at that short time frame. Um so the in summary I Costa Beauty like to dose dependent reductions in markers of inflammation including proceed three really liver enzymes and then reduced triglycerides. Um It does meet the threshold of 17 units and LT response which has been shown in other trials to correlate with histology and it's reasonable to continue uh development of this. Um presumably when the when the final results are in and there is an improvement in histology. Um I will note though that studies of the ghost of you tape for display academia also report nausea and diarrhea. So I I don't really I'm not sure I believe that it was unrelated to the study drug the nausea and the diarrhea and nausea that we're seeing in this trial. The other thing too is their dislike Houdini. A trial was stopped because of QT prolongation and um a dog toxic toxicology studies so that that was not reported here either. So that needs to be demonstrated to be safe as well. So if Rocks Afirman is a drug that's gotten fair amount of excitement and here is basically a very small study um interim results too. So what if Rocks Afirman is is a long acting FGF 21 analog? There are a lot of these on the underdevelopment right now each one is quite different. But in a nutshell what this one does is it mimics The Biologic Activity of FGF 21. It's modified so that the half life has increased. You can give it less frequent and it and it hits all of the sub receptors of FGF. So has some potential benefits. Um A very small amount of people received a biopsy. Okay so all their conclusions on biopsies really need to be tempered greatly. Um so here you can see again five in the placebo and 12 and the if rocks affirming group underwent liver biopsy on baseline characteristics, there was some imbalance, there were less uh the ones the body weight in the if rocks affirming group was significantly lower at least numerically. So here are the results uh deemed to be safe. But again these drugs all cause nausea and diarrhea. You can see here significantly differently than placebo. Um So it's just something to keep in mind with these agents. They clearly do at least this one does cause some weight loss which is beneficial. A minor improvement in hemoglobin a one c. Of 10.4 uh improvement in L. T. Uh and A. S. T. And an improvement in adult connection which generally the FGF 21 do. Uh And this is a favorable effect on insulin resistance and and generally thought to be um uh something that you you know is is beneficial C peptide also reduced. So histological outcomes. Again, massive grain of salt with this. But you can see that it does seem to be an improvement in napoli activity score, which is just an aggregate of inflammation, fat and ballooning on biopsy. Um On national resolution again, these are 25% of 12 people. Okay? Um and then fibrosis um improvement in fibrosis. And so again, so a big thing I forgot to mention by the way this is an F. For population. So this is actually interesting and important really. Mostly because of that the other earlier stage date has already been presented. But so this these are F four. So if you do really improve fibrosis in an F. Four you've made them non psoriatic. So potentially that could be great. But the numbers need to be obviously higher. Um And importantly the noninvasive biomarkers all go in the right direction. So liver stiffness improved, proceed three improved and l score improved. So again adding credibility that this may actually pan out in the longer run. Um So it looked to be safe and well tolerated ish other than the nausea and diarrhea. Um In 35 to 40% of cases there is a signal for fibrosis improvement which is supported by noninvasive tests and again small study. But uh interesting. Okay so these are data from Ray's mataram stories Mitterrand is a thr beta. So thyroid hormone receptor beta agonist, it's in phase three. Interim results have been presented and it improves um National it has a nice national resolution rate. What this is is a um the report of the open label 100 mg group um which does not have a placebo. So these days I'm going to talk about or not placebo controlled. Um This is the part of the mastro maestro snaffled study. So the end point here is really just safety. And so in anticipation of hopeful FDA approval, they need to show safety and cholera bility across the entire spectrum in this particular cohort included psoriatic patients. So here you can see a nice improvements in G. T. A. L. T. Uh and A. S. T. Across the 48 week period. Again, no placebo here. Um here you can see on the right um the cap, which is the fat score on the fiber scan and the M. R. I. P. D. F. F. All reducing um nicely um in in all patients and then more so in those with 5% weight loss and the sex hormone binding globulin high. All that is is people who are sort of in an optimized dose of this drug. That's how they optimize the dozing. Um I think important to note here in this trial the cap score which we use regularly if you have a fiber scan machine really didn't correlate well with PdF F at all. Like we kind of already knew this. But it's important to note because when we tell our patients oh your cap score got better. You know we're kind of not it's not really uh it doesn't really correlate with actual improvement. PdF is much more granular tool. Um And then here this is actually interesting and we'll see if it pans out in the long run. So there really have not been much in the way of studies that have shown improvement and liver stiffness. By M. R. E. Fiber scan we started to see some data with a beta colic acid improvement and liver stiffness. And here they showed a pretty significant improvement in M. R. E. Uh There was one other paper presented which I didn't get a chance to include here that also showed an improvement in MRI so again this will have to be kind of confirmed later on. So this was really well tolerated. It's generally a really well tolerated drug. We now have data on several 100 patients presented for this. Um N. I. T. S. Uh in apple cases of course no placebo exhibited reductions from baseline and that included mari and Elf. Um Again small cohort, no placebo and there's a disconnect between cap and pdF F. Um And so again they made the point that this brings into question fast as a dynamic marker. I would have to agree with that. Um I think you have enough evidence in this that it's probably going to result in histological improvement. So to summarize some of the key takeaways. Um we saw some interim analyses from my cosa mutate uh and lipo seen 11 40 for suggesting that we may see future histological benefit. And we'll probably see the results of these studies uh at A. S. L. D. Or at least one of them. We saw equivalency of the low carb, high fat diet and intermittent caloric restriction and weight loss, metabolic benefit and fat reduction, which is superior to standard dietary advice. Which is, I will admit pretty lame and most of the time people do not get very concrete advice, the safety and tolerable Itty of frocks. Afirman was demonstrated in F four population and cirrhosis. These are of course compensated Sirat IX with an improvement in fiber inflammatory biomarkers and histological improvements in a subset, albeit very small subset of these patients. And we saw encouraging reductions and liver stiffness and other biomarkers that correlated with his logic, benefits and agents that are in advanced development already such as semi tied medical like acid and resume their. Um And with that, I thank you for your attention and I'm happy to take questions in the panel.
