Next, I'd like to invite to the podium Dr. Alina Allen. She is a hepatologist and the director of the Maslil Clinic at the Mayo Clinic in Rochester, Minnesota. She will present the Maslil debrief. Thank you very much for the invitation and for this opportunity. These are my disclosures. I'd like to start with a disclaimer. Maslil abstracts on the clinical realm comprised about 500 from the about 2,500 total abstracts in this meeting. So I had the great privilege to sift through all of them and choose what can be presented in 30 minutes. So there were massive scientific gains. And I apologize to those that will not be mentioned here for this reason. But I know there is impactful science out there which will not make it to the slides. I'd like to congratulate all researchers and also to thank you to the authors for sharing their slides for this presentation. So what are the major themes in 2024 Maslil research at ASLD? If you're looking for an elevator speech for the question, what was hot in Maslil in 2024? Here it is. It was a lot about omics, from genomics, metabolomics, proteomics. Much needed data in pediatric Maslil, which I was very happy to see. Of course, data on drug therapies continue to dominate the space as we need therapies here. And there were two flavors of this. Available drugs from completed trials and real-world experience. And also new mass-specific drugs making their way to the finish line. And I'll leave this towards the end of the talk. So let's start with the area of genomics. And I'll start with resmeterome effects on NASH with liver fibrosis in patients with NASH genetic risk alleles. This is a study presented by Dr. Naga Chalasani. And I think it is important, now that we have resmeterome in our clinical toolbox, to know whether we need to be concerned about a patient's genetic makeup. This is a post hoc analysis of the Maestro NASH trial, which by now you are all familiar with. This studied resmeterome 100 milligrams and 80 milligrams compared to placebo. The paper has been published in NEJM earlier and led to the approval of this drug. What this study did was testing the SNPs in PNPLA3, HSD17B13, and TM6SF2, as well as other genes. But I will focus on the ones mentioned here in red. These were genotyping patients consenting to DNA collection in this study and genetic testing for the response to resmeterome on serial liver biopsies and MRI PDFF was analyzed. The biopsy, the PDFF, and other biomarker responses were analyzed within each treatment arm, comparing wild type, heterozygote, and homozygote for each genetic risk alleles. The outcome of NASH resolution is what I'm showing here. And what you see are bars for proportion of responders from two 80 milligrams and 100 milligram of resmeterome in orange bars and placebo in the blue bars. And these are stratified by genetic phenotype. So on the PNPLA3, you can see that the responses between those with no mutation, heterozygote, and homozygote mutations was essentially similar. The same story was seen in HSD and TM6SF2 genes. So there was no apparent impact in genetic risk markers on NASH resolution in resmeterome and the placebo population. For the fibrosis improvement outcome, the data is presented in the same way, proportion of responders here, and the message is similar. There's no apparent impact in genetic risk markers on fibrosis improvement in resmeterome and placebo. So to me, this was good news. I think we can be agnostic to genetic makeup for resmeterome treatment. What about terzapatide? This is a study that I will present just a few big line summary features of, because you will see this presented by Dr. Arun Sanyal and the late breaker. But this study looked at the PNPLA3 variant specifically in those treated with terzapatide. And this is another post hoc analysis from the Synergy NASH phase 2 trial, which evaluated terzapatide in 5, 10, and 15 milligram doses compared to placebo in adults with MASH and F2 and 3 fibrosis. Again, the paper was published in the England Journal earlier this year. In this specific study, we look at 131 participants who completed the study on treatment and had PNPLA3 genotyping. These are the numbers, 33 wild type, 65 heterozygote, and 33 homozygote for the GLE, which is the one with higher risk. The treatment groups were pooled on the terzapatide doses and compared to placebo by genotype for MASH resolution, fibrosis improvement, changes in liver fat by MRI PDFF, and changes in body weight. From the MASH resolution perspective, what you see here is a proportion of responders in placebo in gray and terzapatide in blue. And this is the overall response. And this is the response by PNPLA3 strata. And as you can see, there was a signal for greater terzapatide treatment effect in those with CC genotype versus those who had G allele. This was not seen in the outcome of fibrosis improvement, which seems to be similar across the strata. Also not seen in the outcome of more than 30% fat reduction by MRI PDFF. And also not seen in the responses in body weight. So the study concludes that terzapatide treatment was associated with improvements in MASH disease activity, fibrosis, liver fat, and body weight across all three PNPLA3 genotypes. However, the terzapatide treatment effect for MASH resolution was greater in those with the CC genotype compared to the G carriers. Fibrosis improvement, reductions in liver fat and body weight were similar across. So these data suggest that the G risk allele may be related to MASH independently of its effect on liver fat. Again, there were three 3GG carriers. I think this is an important signal that, in my opinion, needs to be studied in larger cohorts. But it's very interesting. Staying in the realm of genome, this study presented by Dr. Naga Chalasani looked at associations between muscle and biological age and its acceleration as assessed by methylation clock. I chose this study because of the recent emerging data correlating metabolic diseases, including muscle, with senescence and aging and degeneration. In this study, they aimed to examine the relationship between muscle, then biological age, and its acceleration in a cohort of multi-ethnic adults and to assess the interactions between the biological age and its acceleration and PNPLA3 risk allele on muscle risk. It evaluated 885 participants in the multi-ethnic study of atherosclerosis, or MESA. The muscle diagnosis was based on CT images of the liver. And there was also methyl analysis in the circulating DNA. There were four different methylation clocks that were assessed. They found significant relationship between biological age and biological age acceleration by one of those clocks, named Hanum. And what I show here on the left is the biological age and muscle associations. And on the right, you can see the biological age acceleration and muscle association. The difference between the models is listed here. Note that the impact or the association decreases the more elements are included in the model for adjustment. There was also evidence of interaction of PNPLA3 risk allele with biological age, noted here on the left, and its acceleration by Hanum clock, noted on the right. So the study concludes that biological age and its acceleration by Hanum are significantly associated with muscle. There is an interaction between PNPLA3 G allele and biological age and its acceleration for increasing the risk of muscle. Whether this interaction promotes muscle progression and increases the risk of liver-related events needs to be examined and further studied. But I think this is very interesting. Moving to proteomics, you saw a glance on the previous presentation. As we're starting to scratch the surface in metALD diagnosis and distinction between that and muscle, this is a study, again, looking at the UK Biobank, presented by Dr. Niharika Jakkar, in which over 9,000 patients had muscle and almost 900 patients had metALD. Note that metALD here was defined based on self-reported questionnaire. So there's a caveat there. They assessed the protein levels for comparison across individuals utilizing normalized protein expression, or NPX. They saw signals that can potentially differentiate proteins among muscle versus controls, here on the left, and between metALD and controls. Some were upregulated. Some were downregulated. I'll leave details more for the paper. But I think the signal is that there could be distinct proteomic profiles that could differentiate muscle from metALD. Retinol-binding protein 5 and oxytocin neurofizin 1 were found as potential metALD markers in this study. Plasma proteomics, in addition, can identify high-risk patients. And I think this is important data to consider with the caveat that it needs to be validated in metALD defined by biomarkers rather than self-reported questionnaires. So definitely more to come, I think, in this space. We're going to metabolomics, here, in a very special population, that of children. This is an analysis presented by Helena Huno, who is a PhD candidate in Dr. Miriam Voss's lab at Emory University, with a fantastic presentation. And she used an unsupervised machine learning analysis of youth enrolled in NASH CRN. The objective was to identify muscle metabolotypes in children. And they used an unsupervised machine learning clustering analysis using clinical and laboratory markers that associate with muscle pathophysiology. They also used high-resolution metabolomics analysis for the metabolome profiling in the serum. And the hypothesis was that there are distinct muscle metabolotypes driven by inflammation, insulin resistance, and lipid partitioning. What they found was three clinically distinct metabolotypes in pediatric muscle. The top listed here in green is what they called early mild, which is characteristic of children that tend to be younger, have a lower HOMA2IR score, a lower triglyceride and LDL level. The second metabotype was adipolipid SBP in children with a higher waist circumference, a higher level of VLDL, higher systolic blood pressure, and higher uric acid levels. A third type was the inflammatory fibrotic, with a higher signal for liver disease severity, as illustrated by higher ALT, AST, and on histology, a higher proportion of MASH and advanced fibrosis. How could this impact practice? One thing to mention before we move is that the higher proportion of Hispanic ethnicity in those with early mild and inflammatory fibrotic phenotypes. So how could this impact practice in the future if we were to consider this for clinical care? Those children with an early mild phenotype could be focusing more on prevention. Those who have an inflammatory fibrotic phenotype, and thus are at higher risk of hepatic complications, would have a care pathway that would focus on nutrition therapy to decrease inflammation, avoid sugars and fructose, as well as alcohol when of age, follow up by hepatology, and also maybe focus on antifibrotic medications if these will be available soon. For those with adipolipid SBP phenotype, the risk may be higher in extrahepatic complications and cardiovascular disease. Therefore, the care pathway there, in addition to the nutrition therapy for obesity and heart health, would focus on early CVD surveillance and maybe metabolic drugs such as metformin, GLP-1, agonists, and statins. So I found this interesting. I think further research is needed to validate these findings and to disentangle these pathways and amino acid, energy metabolism, and microbiome links to these. Moving on to GLP receptor agonists and Masled, also in pediatrics. This was presented by Andrea Tao at the Children's Hospital of Philadelphia. And this is a real-world study which had the objective to determine the effect of GLP-1 receptor agonists on ALT reduction in pediatric Masled. It was a single-center retrospective chart review of patients younger than 21 who were treated with GLP receptor agonists between 2018 and 2024 with a diagnosis of Masled. Of course, the treatment indication was obesity or diabetes. The endpoint values were collected up to 13 months post-therapy. They found 111 children with a median age of 15 treated for approximately 13 months. And the results were that ALT improved by 23 units at six months and by 18 units post-therapy. And the results are seen here. And I'm highlighting ALT, which started around a value of 78 and ended up around 62. There were also significant improvements in ASD, GGT, triglycerides, and hemoglobin A1c. But interestingly, no improvement observed in weight or BMI. Why? That remains to be determined. But I thought it was an interesting observation. There were even greater reductions in ALT in patients initiated on GLP-1 for an indication of type 2 diabetes, as you can see here. And among the GLP receptor agonists, semaglutide was the most common one, followed by liraglutide, dulaglutide, and exenatide. Side effects reported in 21 children, five had to discontinue the medications. So this is the largest dedicated pediatric study evaluating the effects of GLP-1 on Masled to date. Treatment was associated with significant improvements in mean ALT, AST, GGT, triglycerides, and hemoglobin A1c. So by using ALT as a surrogate for histologic improvement of steatohepatitis, with its limitations, GLP-1 receptor agonists show promising results in treatment of pediatric NAFLD, maybe most beneficial in those with type 2 diabetes. So further prospective studies are needed. And they are highly sought in the pediatric population. We're staying in the realm of GLP-1 in the real world, this time in the adult space. This is a study presented by Dr. Sidney Barrett. This is a study of target NASH, a very large cohort of patients with Masled and MASH of over 6,600 participants. Among these, you can see the breakdown of the over 4,000 patients who met the analysis criteria. You can see it here. And you can see the number of patients by disease severity, a very large proportion of patients with cirrhosis, I would say. Of these, almost 10% were GLP-1 receptor agonist users. Again, a lot of people with cirrhosis. The median duration was between 2.5 to 3.3 years, respectively, on these phenotypes. What they found was that disease progression as defined by progression to decompensated cirrhosis was in non-users of GLP-1 was 1.69 times the hazard of development compared to the GLP users. In the outcome of all-cause mortality, they found that non-users of GLP-1 had a 2.3 times higher risk of death compared to GLP-1 receptor agonist users. So I think important data to find from real world. I think there are caveats and healthy user bias and maybe other potential confounders, but I think important data to know. So we're going into resmedarum, back to resmedarum, but looking into a different angle here. And this was a study presented by Seth Pound looking at liver enzymes reduction from baseline over time in resmedarum treating patients in Maestro Nash study. This was a poster, which I selected because I think it has impact specifically from the question of statin. We know that the label has this warning on maximum dose of certain statins to be used in conjunction resmedarum. So here they looked specifically at the 966 patients enrolled in Maestro Nash, of whom almost half were on statins. And they assessed the direction of ALT in all patients, seen here in the top graph, and then when split between patients on statin and patients not on statin, and specifically looking at ALT levels. What they found were that what was known from the label is that there are liver enzyme elevations in the first four weeks, specifically peaking at week four, which occurred as a delta much larger in those on statins, but they were not associated with hepatotoxicity and they're likely a reflection of lipid changes in the liver that occur adaptively. The statin exposure was within the range of normal variation, not different from placebo, there were no safety issue, and 98% of those doses were within those recommended in the label. But what I'd like to draw the attention more is beyond this delta increase in those on statin is the fact that patients on statin started at a lower ALT and AST, so that the peak really between these two groups is about the same in absolute value. So if you see this in your clinical practice, expect it and know that it does decrease with time and it's not really a sign of hepatotoxicity, irrespective of statin exposure. The efficacy on biopsy, PDFF, and lipid endpoints in patients on statin was equivalent to patients not on statins. Okay, we are moving to the exciting space of clinical trial data, and I will start with a study presented by Dr. Mazen Nuruddin on efruxifermin, which shows that significantly improved liver fibrosis at week 96 in the Harmony study across subgroups and improvements were associated with changes in biomarkers. So efruxifermin is a FGF21 analog administered subcutaneously weekly, which was studied in the Harmony trial, and the data was presented at week 24. Current study extends these endpoints at week 96, so this is what we will focus on. And what you will see is a comparison between placebo and the different doses of efruxifermin, but also comparison between weeks 24 and weeks 96. So when we look at the outcome of fibrosis improvement by one stage, noted here on the left, you can see that 75% of patients on the higher dose of 50 milligrams achieved this outcome at week 96, so much deeper and more sustained response compared to what was seen at week 24. In the intention to treat analysis, which considers those who did not have a follow-up liver biopsy as non-responders, the differences were 19% in placebo and 49% in efruxifermin 50 milligrams. They used also digital pathology as a comparison to conventional histopathology, and as you can see here, the response rates are again very high, 81%, and what I found interesting was that this would have been caught actually at week 24 as well, so the delta here or the time wasn't as high as in conventional histology. There is evidence of disease reversal after 96 weeks on looking at other outcomes as well. Here you see a two-stage fibrosis improvement, which was achieved by 36% of patients on the higher dose compared to 3% of patients at week 96. There were very good signals of response in biomarkers such as ELF or VCTE or combinations thereof, as you can see here, and they looked at disease response in all sorts of ways from partial reverser to substantial reversal, defined here, to near-complete reversal, which means improvement to F0 or 1 and MASH resolution and liver fat content normalization, and this was achieved by 30% of patients in the high dose versus 0% in those on placebo at 96 weeks. So this is unprecedented antifibrotic activity observed in efruxiferin after 96 weeks, three-quarters of those receiving the 50 milligram dose experienced fibrosis improvement without MASH worsening with early fibrosis response noted at week 24 and sustained and expanded to week 96. The consistent antifibrotic response was seen across high-risk groups such as stage 3 fibrosis, type 2 diabetes, P and PLA3 risk allele carriers. Conventional pathology corroborated by AI-based pathology imaging and circulating biomarkers all showed the same signal of improvement. And almost half of the patients on 50 milligrams of the medication were responders by all three measures of fibrosis, histology, health, or liver stiffness, which is very encouraging. I hope that as we move towards a biopsy-free space in clinical trials, this study will serve as really good data. Lastly, I didn't present this, but the acceptable safety and tolerability profile was also noteworthy, especially with mild to moderate and transient GI events. So this year, late-breaker session in Masl is after this. So I will not be presenting details, so please stay tuned. It's going to be in the same room following this session immediately after. So I'll give you a flavor of what you are about to see, mostly with trial design and what was published for just preliminary results. So one of the studies will be presented by Dr. Mazen Nooradin, and it is once-monthly ephemospermin alpha by Boston Pharmaceuticals in Mash with F2N3 fibrosis. These are results from 24-week randomized double placebo phase 2 trial. And recall that this is a long-acting FGF21 administered monthly, so I'm very excited that we can actually are at the stage to discuss therapy for Mash administered once a month. You can see here the study design, and again, you will hear more after this on the 24-week histologic response on this drug. And I will save, and I have saved the best for last. This is the study that was awaited this year. Semaglutide finished the line, the long line to success from the phase 3 essence trial in patients with Mash and moderate to advanced fibrosis. The 2.4 milligram dose met both primary endpoints of histological Mash resolution and fibrosis improvement. So stay tuned for this highly anticipated presentation given by Dr. Phil Newsom right after this. There are some other very noteworthy late breakers. The first one is the result of the 52-week phase 2B voyage trial of VK2809 in patients with biopsy-confirmed Mash and fibrosis. This will be presented by Dr. Rohit Lumba. Another agent from Aligos, another THR beta similar to the first presentation in a 12-week trial in non-serotic Mash, phase 2A, also presented by Dr. Rohit Lumba right after this. And Ervogastat, a DGAT2 inhibitor alone or in combination with Klesakostat, an ACC inhibitor in adults with Nash, and this will be presented by Professor Quentin Anstey. So we had an amazing year for Masold research in 2024. I was very excited to review all this and present this to you. If we were to summarize the take-home points we will take with us as we get on our planes later today, what we saw this year will be the much-awaited phase 3 trial completed of semaglutide for Mash F2N3. Very noteworthy results in other phase 2 trials of FGF21 analogs, again, administered weekly or even monthly, THR beta analogs that I mentioned earlier, and DGAT2 inhibitors. We learned that genetic background does not impact response to resmetarum treatment, but the PNPLA3G allele appears to decrease Mash resolution interzepatide treatment. We learned that biological age and its acceleration are associated with Masold with a noted interaction with the PNPLA3G allele. We saw early data suggesting signals of proteomic profile differentiating Masold from metALD. We saw distinct metabotypes in pediatric Masold with potential impact in treatment pathways of the future, and I would love to see this in adults as well. And we also saw real-world data on the favorable impact of GLP1 receptor agonists on Masold activity and progression in both children and adults. With this, I thank you, and stay tuned for the late breakers.

Masold research

genomics studies

pediatric data

terzapatide

proteomics

GLP-1 receptor agonists