Therapeutics Virtual KOL Event. At this time, all attendees are in a listen-only mode. As a reminder, this call is being recorded, and a replay will be made available on the Galectin website following the conclusion of the event. I'd now like to turn the call over to Michael Cozart of LifeSci Consulting. Please go ahead, Michael. Thanks, Tara. Again, good afternoon, everyone, and thank you for joining today's KOL webinar. As Tara mentioned, my name is Michael Cozart, and I'm a Managing Partner at LifeSci Consulting. Today, we will discuss belapectin as a treatment for MASH cirrhosis and portal hypertension, an indication with a significant unmet medical need. Joining today's call are two key opinion leaders, Doctors Naga Chalasani and Naim Alkhouri. Today's call will last approximately 30 minutes and will include a brief Q&A session. To start, I would like to introduce Joel Lewis, Galectin CEO, who will provide a brief overview of the company. With that, Joel, I'll turn it over to you. Thank you for joining us. We are honored to have Dr. Naga Chalasani and Dr. Naim Alkhouri with us today to discuss the results of our clinical trial, Navigate. They have both been involved in the development of belapectin and its related trials for many years, and I believe have a unique perspective on the potential impact of our program. We are confident that today's presentation will highlight the importance of Galectin 's program in a high unmet medical need. At this point, I would like to introduce Dr. Khurram Jamil, our Chief Medical Officer. Khurram. Thank you, Joel. Galectin-3 is a lectin protein that has been demonstrated to be pro-fibrotic across many organs in the setting of chronic injury or inflammation. It becomes significantly upregulated in the injured tissue and contributes to disease progression by activating hepatic stellate cells, which are responsible for collagen production and scar tissue formation inside the liver. Belapectin is a Galectin-3 inhibitor and has been studied in multiple phase IIb trials to date. Before we share the results from the clinical trials, I would like to give a brief overview of preclinical findings for belapectin that provide a strong rationale for its development as a therapeutic agent in MASH cirrhosis and portal hypertension. Belapectin was evaluated across a number of animal models that mimic the biological features of MASH cirrhosis in humans. Next. In a well-established mouse model of MASH, belapectin led to a notable reduction in Galectin-3 staining, particularly in macrophages. This is critical because Galectin-3 activity in liver macrophages is a key driver of inflammation and fibrosis. In a separate rat model of cirrhosis, belapectin again showed anti-fibrotic effects, including decreased hepatic fibrosis and, importantly, significant reduction in portal pressure, which is a key driver of complications in patients with MASH cirrhosis and portal hypertension. Based on observed anti-inflammatory, anti-fibrotic, and hemodynamic effects in preclinical studies, belapectin was advanced to human trials for further evaluation. Now, I will invite Dr. Naga Chalasani, Professor of GI and Hepatology and Director of Terence Kahn Liver Research Program in Indiana University School of Medicine, to share his expert opinion on the current state of management in patients with MASH cirrhosis and portal hypertension. Dr. Chalasani? Next slide, please. Thank you, Khurram. Let me just start by saying I really don't have any conflicts of interest with Galectin Therapeutics. I have been involved in the Galectin-3 program for over 10 years from the very first dosing here happened at IU many years ago. I'd just like to highlight that MASH cirrhosis is a significant unmet need. It's a growing segment of the MASH or cirrhotic population. It is the most common cause for cirrhosis in the U.S. and one of the most common causes for liver transplantation. Yet, really, there are no therapies. We tell patients to take care of themselves and put them on beta blockers. I think it's just been a great unmet need. There is, just from some of the epidemiological estimates, there may be as many as 5 million U.S. adults with MASH cirrhosis, and there may be as many as 3.3 million people with MASH cirrhosis and portal hypertension. That is sort of the population that are potentially addressable by belapectin. Next slide, please. When you take care of patients with cirrhosis, you always worry about portal hypertension. Portal hypertension is one that sort of is the platform upon which you have complications such as variceal bleeding or ascites and encephalopathy. Shown here, though, is the cartoon of esophagus where you see no esophageal varices, and then you get small to large varices and eventually variceal bleeding, which can have a very high mortality rate even in well-equipped medical centers. I have always said, if you can prevent varices, you can prevent the development of variceal bleeding. Arguably, you can prevent other complications such as ascites or hepatic encephalopathy. Next slide, please. As all of you know, there is a lot of interest in developing pharmacotherapy for NASH or MASH at a high level. There are two groups of patients. One is the non-cirrhotic MASH, which is stage two and stage three MASH, which is at risk to develop cirrhosis and complications. That is where medications like resmetirom or GLP-1 agonists like semaglutide are appropriate. There is the cirrhotic population. They are at risk for complications and liver cancer, decompensation, needing a liver transplant, and mortality. There are very few programs that are showing promise in the cirrhotic population, one being belapectin. Today, though, when we have patients with cirrhosis, how we manage them is vaccinations per guidelines, good nutrition, screening for varices, and liver cancer, but there are not any liver-targeted therapies. Next slide, please. Belapectin is first in class and best in class for that's been investigated in patients with MASH cirrhosis. The phase II trial that we published a few years ago showed some promising results. As I have already said, there may be as many as 3.3 million U.S. adults with MASH cirrhosis and portal hypertension. This brings an important market opportunity. Khurram, you want to sort of touch on what this might mean from a market standpoint? Yes. Thank you, Naga. We recently conducted a third-party market research. Both payers and treating physicians were interviewed and received very positive feedback, which, again, reinforced the significant unmet need in these patients. Both payers and physicians reiterated the clinical and economic benefit of preventing varices and stopping progression of disease in these patients. Based on the feedback received, we believe there will be likely a very high adoption rate upon approval that translates into a significant market opportunity with peak sales for belapectin estimated to be up to $18 billion. We feel very encouraged by the feedback received and the high unmet need that we have observed from these treating physicians for their patients. I'll hand it back to Dr. Chalasani to walk us through the phase IIb data. Next slide. Yeah. As I said, I was involved in the GT-026 trial with late Dr. Stephen Harrison and Dr. Peter Traber. These are just a couple of figures from the paper we published in Gastroenterology many years ago, which, by the way, cites quite well. It has been cited over 300 x so far. To your left is the primary endpoint. On the x-axis, you see three treatment groups: placebo, 2 mg per kg, and 8 mg per kg of belapectin. On the y-axis is reduction, or actually HVPG pre- and post-treatment. What you see here is in patients, subgroups of people with no varices at baseline, 2 mg per kg had a significant reduction in HVPG relative to placebo at the end of treatment. It had to complement this particular observation in the same subgroup of people who had no esophageal varices at baseline. Those people who were on 2 mg per kg, they had significant reduction in the development of esophageal varices. This observation that the 2 mg per kilo seemed to be effective in patients with MASH cirrhosis and no esophageal varices at baseline was encouraging, and that led to the subsequent study that Dr. Alkhouri will present. Next slide, please. I'd just like to call upon Dr. Alkhouri, who is a leader in the field. He has tremendous expertise in the MASH as a subject matter expert, as well as he is an outstanding clinical trialist and knows this space as well as belapectin quite deeply. Naim? Thank you very much, Dr. Chalasani, for the kind introduction. Thank you to the Galectin team also for giving me the opportunity to present the results from the NAVIGATE trial. The NAVIGATE trial looked at a specific patient population. These were patients with MASH cirrhosis based on the liver form criteria, and they had evidence of portal hypertension based on the Baveno criteria and non-invasive test. All these patients did not have varices based on endoscopy at baseline. It is important to highlight that the assessment for varices was done through a central adjudication of endoscopy videos by expert endoscopists. The trial design was basically as follows. Patients were randomized to belapectin, the established dose that Dr. Chalasani showed you some results with in the earlier slide. This is 2 mg per kg of lean body mass, and this is an infusion every other week. We had an experimental dose of belapectin at 4 mg per kg lean body mass, and then placebo. You see the sample size was 357 patients. They were treated for 78 weeks. Next slide. These are the key inclusion criteria. Again, they all had MASH cirrhosis, no varices on the baseline endoscopy. They had compensated cirrhosis, Child-Pugh score five or six, and they all had evidence of portal hypertension. This is key because this is basically an advanced patient population with MASH cirrhosis. Portal hypertension was defined as platelet count less than 150,000 or having at least two of the following: AST - ALT ratio more than one, spleen size more than 14 cm, collaterals by imaging, or liver stiffness by transient elastography more than 20 kPa. The primary endpoint was a composite endpoint in the intent to treat population, and I'll share with you what it exactly included in the next slide. We also did this incidence of varices in the per protocol population. This is the completers analysis. The composite secondary endpoints included hepatic decompensation events such as ascites, variceal bleeding, or encephalopathy, all-cause mortality, the proportion of patients with large varices or red whale sign, varices requiring treatment, increase in MELD to more than 15, and needing liver transplantation. Next slide. The intent to treat population included all randomized subjects except for two of them that were adjudicated as having varices at baseline. The per protocol or the completer population included all the subjects that completed 18 months of therapy and had an EGD at baseline and 18 months. The composite primary endpoint included the following: any subject who developed esophageal varices or if they had intercurrent events or they dropped out without an EGD or developing intercurrent events. The intercurrent events included liver events, again, ascites, encephalopathy, and variceal bleeding, adverse events leading to discontinuation, the need for TIPS shunt, or the use of a GLP-1 agonist or non-selective beta blocker for more than 12 months. Next slide. These are the baseline patient characteristics in the NAVIGATE trial, typical for MASH cirrhosis populations. Older adults, very high rates of type two diabetes and metabolic syndrome features. You can see their platelet count was low. Average was around 130,000, and the liver stiffness was around 24 kPa. The majority had enlarged spleens. You can see the average spleen diameter was around 13.9 cm. Having low platelet count, high liver stiffness, and enlarged spleen, these are all indicators of more advanced disease. It's also important to highlight that approximately 40%-45% of patients were on a statin, and approximately 23% of patients were on a GLP-1 agonist. Next. This is the primary endpoint in the intent to treat population. If you look to the right, you see the total. This was, again, the primary endpoint, composite endpoint. You can see that numerically, patients in the 2 mg dose had lower events, so they're less likely to meet the primary endpoint, but this was not statistically significant. When we broke down this composite endpoint into the three different components, we looked at subjects with new varices. Again, numerically, you see with the 2 mg, there's less new varices, but this was not significant. There was no difference in the number of subjects that developed intercurrent events and also no difference in the patients that did not have end-of-treatment EGD and no intercurrent events. Next slide. More importantly, this is the per protocol analysis or the completers analysis. Here we are looking at the incidence of varices, and we show statistically significant lower rates of developing varices in the established 2 mg dose of belapectin every other week. You can see varices developed in 11.3% of patients with belapectin 2 mg versus 22.3% in the placebo arm. Again, this was statistically significant. Next slide. We also looked at changes in liver stiffness from baseline to 18 months of therapy. You can see here in the table that there was a reduction in liver stiffness by vibration-controlled transient elastography between 2.9 kPa-3.1 kPa. This was more than what we saw in the placebo arm. This was only 0.7 kPa. We also looked at the percentage change in liver stiffness, and you can see with the belapectin arms, it was around 12% reduction compared to only 3% in the placebo arm. Next. More importantly, we looked at worsening in liver stiffness because, as we mentioned earlier, with belapectin, we are trying to prevent progression of the disease. We defined liver stiffness worsening as increase by 30% from baseline or increase by 10 points kPa from baseline. When we looked at increase more than 30% from baseline, significantly lower number of patients progressed based on liver stiffness in the belapectin 2 mg arm compared to placebo. You see the p- value at 0.03. A similar story emerged also when we looked at increase in lPa by 10 points or more from baseline, 4.3% in the belapectin 2 mg arm versus 12.5% with the placebo arm. Almost three-fold reduction in the progression based on VCTE. Next slide. In terms of safety summary, there was no difference in the percentage that discontinued the study due to adverse events in the placebo arm compared to the two belapectin arms. When we looked at treatment emergent adverse events, they were reported in approximately 95%-97%, but no difference between placebo and belapectin arms. Also importantly, when we looked at treatment emergent serious adverse events, there was no clear signal, no difference between placebo and belapectin. Next slide. We also looked at the incidence of new varices in patients treated in the United States versus outside of the United States. Interestingly, we saw significantly lower number of patients that developed varices in the United States. You can see this is, again, completers analysis per protocol population, but the incidence of varices was at 6.7% compared to 21% in the placebo arm. If you remember, in the entire cohort, it was around 11%. Definitely patients treated in the U.S. did the best. Again, incidence 6.7%. This was not the same when we looked at patients treated outside of the U.S. That percentage was 18.9% with the 2 mg dose of belapectin. You can see the sample size. We had more patients treated in the United States than patients treated outside of the United States. Next slide. We next looked at concomitant medications, specifically GLP-1 receptor agonist, non-selective beta blockers, statins, and ACE inhibitors because of their known potential effect on portal hypertension. You can see that in the United States, more patients were likely to be on a GLP-1 receptor agonist, and more patients were likely to be on a statin. There was no difference in non-selective beta blockers or ACE inhibitors. This is a new analysis. We think that potentially there is synergy between belapectin and GLP-1 receptor agonist and potentially statins. We know semaglutide as the example of GLP-1 receptor agonist did not work by itself in patients with compensated cirrhosis. Again, maybe the combination has potential in this advanced population with portal hypertension. Next slide. Key takeaways from the NAVIGATE trial. Number one is belapectin at the established 2 mg per kg dose significantly reduced the incidence of new esophageal varices at 18 months of treatment in patients with MASH cirrhosis and portal hypertension. When we looked at categorical changes in liver stiffness, we also noticed a similar trend with basically less progression with belapectin 2 mg. These findings validate the prior favorable observations from the GT-026 trial. Also, the safety profile looked very promising with really no differentiation between placebo and the belapectin arms in terms of the percentage that discontinued medicine or developed significant adverse events. So belapectin has the potential to address the unmet need in these patients with advanced MASH cirrhosis and portal hypertension. Next. With this, I want to thank you for your attention and to hand it back to Khurram to moderate the Q&A. Thank you, Naim, and Dr. Chalasani as well for sharing the clinical data. I'll invite Michael to share questions that we may have received in the portal and walk us through. Michael. Yeah, thanks, Khurram. So a couple of questions that the audience has. Maybe we start with, so NAVIGATE is one of the few trials that have used centrally adjudicated endoscopy videos to track variceal development as a primary endpoint. So Dr. Alkhouri, from your perspective, what are the strengths and challenges of using this kind of clinically meaningful endpoint in a cirrhosis trial? Yeah, this is very important because endoscopists do not always agree on the presence, especially of small varices. This was a very rigorous way to do this. Endoscopists were required to spend enough time in the esophagus looking at varices in the stomach. They took the videos, and each video was read by two central endoscopists with great experience in reading varices. If they agreed, we went with this reading. If there was any disagreement, then we had a third experienced endoscopist do the adjudication. This is a more rigorous way. It increases the likelihood of identifying varices. The issue is that sometimes you do not get agreement between different endoscopists. That can create sometimes discordance. That is why we did the adjudication, and we had a third endoscopist read this. It increases my confidence that when we identify varices, we are finding real varices and increases my confidence that we are not missing varices. Wonderful. Thank you for that. Maybe Dr. Chalasani, this question for you. How do you interpret the results of NAVIGATE in the context of the earlier GT-026 trial? Yeah, thank you, Michael. I think the NAVIGATE trial validates what we found in GT-026 trial. As I said, 026, the Gastro paper showed efficacy. Really two key takeaways from the gastro paper. One, two mg per kg works better. Number two, the population that is best served by belapectin is the group without esophageal varices. They have portal hypertension, but no esophageal varices. Navigate, really, that's what NAVIGATE reproduces, that in patients without esophageal varices, 2 mg per kg reduced the development of esophageal varices. You also see some signal with reduction in non-invasive fibrosis markers. I think they validate each other. To me, it gives me a lot of confidence that belapectin, given at 2 mg per kg, seems to work for that population with portal hypertension and yet have not developed esophageal varices. Wonderful. Thank you for that, Dr. Chalasani. Obviously, another question from the audience. People are always concerned about safety of investigational assets. Maybe, Dr. Chalasani, back to you. How would you compare the safety profile of belapectin recorded in trials to date with perhaps other pharmacological therapies in development? Yeah, thank you once again. As I said, when I was talking about my slides, the first dose, human dose of belapectin was given at our institution, at our research unit. After that, I think we have dosed many dozen patients, and many have gone on for longer than a year or a year and a half of this therapy, very well tolerated and safe relative to we have not seen any safety signal with this compound. Also, tolerability is really important. GLP-1s are, for example, FGF21 agonists are a promising class of agents, and yet there is GI intolerance. There is the signal with potentially with gallstones, so on and so forth. We have not really seen anything with FGF, excuse me, with belapectin. Really, the tolerability is one. We have not seen the bone adverse events or muscle loss. From a safety standpoint, which is really important from the regulators and the prescribers and patients' perspective, I think this stands out, in my opinion. Wonderful. Dr. Alkhouri, a question for you. How do you interpret the relationship between LSM progression and variceal development as observed in the trial? I guess further, what does this suggest about the use of NITs to assess treatment response in cirrhosis specifically? Yeah, I think this is important to understand that with the belapectin, we are trying to prevent disease progression. That is why we looked at increase in liver stiffness by 30%. We looked at also increased by 10 kPa unit. We showed that a smaller percentage of patients treated, especially with the 2 mg dose, progressed based on liver stiffness. We know that there is correlation between liver stiffness and portal hypertension. The Baveno criteria basically established that the higher the liver stiffness, the more likely you have portal hypertension. The inverse is true also for platelet count. The lower the platelet count, the more likely you have portal hypertension. Showing that liver stiffness is not increasing, basically, in my mind, validates that these patients are less likely to progress to developing complications of portal hypertension. In this case, it is the development of varices. The hope is that this will translate into less outcomes in the future. We see less decompensating events like ascites and encephalopathy and, of course, variceal bleeding. I do believe that if you develop less varices, you will be less likely to develop bleeding. The hope is we will see it also with ascites, encephalopathy, worsening in MELD needing liver transplantation. Wonderful. Thank you for that. We have time for two minutes. We might, or two more questions, we might just go slightly over. Dr. Chalasani, why, from your perspective, do you think this population has remained underserved despite the increasing disease burden? Yeah. I mean, I think there's been attention to this population, though, at least for the last decade or even longer. If you, those of us who have been in the therapeutic clinical trial space, we know a number of trials done by Gilead and Conatus and so forth. Even Novo had a trial with semaglutide in the cirrhosis population. It's not that there haven't been trials. I think it's just not been an effective agent. Now we are starting to see, and I think that's where the excitement with belapectin, that not only one study, but actually two studies complement each other to identify a population on a dose. To me, that's exciting. You're absolutely right. There is an urgent need. This is the most unmet need population in the MASH space. Yet, there isn't a phase III trial purely in the cirrhotic, focusing on prevention of complications. I want to add to this that we have other MASH cirrhosis trials now, but they're trying to target earlier disease. They have a lower limit for the platelet count. Most studies, they want the platelet count, for example, to be more than 100,000. This will select for a less sick patient population. They don't have strict criteria like what I showed in terms of how to identify the presence of portal hypertension. Here, we are required to have splenomegaly, high AST - ALT ratio, liver stiffness at least above 20. I want to highlight that this is really a unique patient population. There is a lot of interest in MASH cirrhosis. With other therapeutic targets, there are concerns about the point of no return, and that maybe a purely metabolic drug may not be effective. This is what makes belapectin unique in my mind, is that we're actually going to almost the sickest population out there outside of a decompensated MASH cirrhosis. We're trying to show, again, that we're going to slow progression of the disease. This is the key feature of this trial that, again, patients are progressing less. Understood. No, I appreciate that. Perhaps one last question, maybe, Dr. Alkhouri, will stay with you. Based on what you've seen so far, how would you differentiate belapectin's approach versus other investigational therapies in late-stage MASH? Perhaps building a little bit on what you just mentioned. Anything else to add? Yeah, I mean, maybe I can give some more granularity. I mean, there are other agents, for example, FGF21 agonist, and they have phase III trials in MASH cirrhosis. Again, they're doing biopsies before and after. They're looking at disease regression, but they're selecting a less sick patient population. Of course, these trials are still ongoing. We do not have all the baseline characteristics, but my gut feeling is they're going to end up with potentially higher platelet count, potentially lower liver stiffness. This is by design, and not to take away anything else from other agents, I think they're very promising. Again, this is a more advanced patient population. We're trying to prevent the progression of the disease. I think also the endoscopic endpoints, and this is a credit to Dr. Chalasani and the late Dr. Harrison to have the vision to design a trial based on endoscopic endpoints. I think this was a unique feature of the trial at the time. Now we have other programs trying to incorporate endoscopy. To my knowledge, this is really the first trial that was agreed upon with the FDA that an endoscopic endpoint will qualify a medicine potentially for FDA approval. Wonderful. That is the last question that we had from the audience. Certainly, we appreciate everyone taking the time to join today's conversation. If there's an interest in learning more, please reach out to the Galectin Management Team. I'm sure they would welcome the opportunity to have a one-on-one discussion to present more of the data on belapectin. Again, we appreciate the KOL's time very much, as well as the management team of Galectin.