Galectin Therapeutics Inc. (GALT) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Galectin Therapeutics Virtual KOL event. [Operator Instructions] 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. And 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 2 key opinion leaders, Drs. 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's CEO, who will provide a brief overview of the company. So 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 profibrotic across many organs in the setting of chronic injury or inflammation. It becomes significantly upregulated in the injured tissue and contributes to progression by activating hepatic cells itself, 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 you 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 current state of management in patient 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 am -- had been involved in Galectin-3 program for over 10 years from 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 NASH 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. And yet really, there are no therapies. We tell patients to take care of themselves and put them on beta blockers, but I think it's just been a great unmet need. There is -- there -- 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's 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's sort of is the platform upon which you have complications such as variceal bleeding or ascites encephalopathy. And shown here, though, is the cartoon of esophagus, there you see no esophageal varices and then you get small to large varices and eventually variceal bleeding, which can have very high mortality rate, even in well-equipped medical centers. So I've always said if you can prevent varices, you can prevent development of the variceal bleeding. Arguably, you can prevent other complications such as ascites or hepatic encephalopathy. Next slide, please. So as all of you know, there is a lot of interest in developing pharmacotherapy for NASH or MASH. At a high level, there are 2 groups of patients. One is the noncirrhotic MASH, which is Stage II and Stage III MASH, which fears that risk to develop cirrhosis and complications. That's where things -- medications like resmetirom or GLP-1 agonists like semaglutide are appropriate. And then there is the cirrhotic population. They are at risk for complications in 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. And today, though, when we have patients with cirrhosis, how we manage them is vaccinations up or guidelines, good nutrition, screening for varices and liver cancer, but there aren't any liver-targeted therapies. Next slide, please. So belapectin is first-in-class and best-in-class for -- that's been investigated in MASH patients with MASH Cirrhosis. The Phase II trial that we published a few years ago showed some promising results. And 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. And 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. So again, we feel very encouraged about the feedback received and the high unmet need that we have observed from these treating physicians for their patient. I'll hand it back to Dr. Chalasani to walk us through for the Phase IIb data. Next slide.

As I said, I was involved in 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's been cited over 300 times so far. To your left is the primary endpoint. On X axis, you see 3 treatment groups: placebo, 2 mgs per kilo and 8 mgs per kilo 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 mgs per kilo had a significant reduction in HVPG relative to placebo at the end of treatment. To complement this particular observation, in the same subgroup of people who had no esophageal varices at baseline and those people who were on 2 mgs per kilo, they had significant reduction in the development of esophageal varices. This observation that the 2 mgs per kilo seem 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 subject matter expert as well as he is an outstanding clinical trialist and he knows this space as well as belapectin quite deeply name. Naim?

Thank you very much, Dr. Chalasani, for the kind introduction, and thank you to the Galectin team also for giving me the opportunity to present the results from the NAVIGATE trial. So 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 noninvasive tests. All these patients did not have varices based on endoscopy at baseline. And it's 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 milligram per kilogram of lean body mass, and this is an infusion every other week. And then we had an experimental dose of belapectin at 4 milligram per kilogram lean body mass, and then placebo. You see the sample size was 357 patients. They were treated for 78 weeks. Next slide. So 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 5 versus 6, and they all had evidence of Portal Hypertension. So this is key because this is basically an advanced patient population with mass cirrhosis. Portal Hypertension was defined as platelet count, less than 150,000 or having at least 2 of the following: AST to ALT ratio more than 1; spleen size more than 14 centimeters; collaterals by imaging or liver stiffness by transient elastography more than 20 kilopascal. The primary endpoint was a composite endpoint in the intent-to-treat population, and I'll share with you what is exactly included in the next slide. And then we also did this incidence of varices in the protocol population, so this is the complete analysis. The composite secondary endpoints included hepatic decompensation events such as ascites, variceal bleeding or encephalopathy, old course mortality. The proportion of patients with large varices or red sign, varices requiring treatment, increase in MELD to more than 15 and needing liver transplantation. Next slide. So the intent-to-treat population included all randomized subjects, except for 2 of them that were adjudicated as having varices at baseline. The appropriate record or the completer population included all the subjects that completed 18 months of therapy and had an EGD at baseline at 18 month. And 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 a nonselective beta blocker for more than 12 months. Next slide. So these are the baseline patient characteristics in the NAVIGATE trial. Typical for MASH Cirrhosis population, so older adults, very high rates of type 2 diabetes and metabolic syndrome features. And you can see their platelet count was low. Average was around 130,000 and the liver stiffness was around 24 kilopascal and the majority had large spleens, so you can see the average spleen diameter was around 13.9 centimeters. So having low platelet count, high liver stiffness and a large 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. So 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. And you can see that numerically, patients in the 2-milligram 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 3 different components, we looked at subjects with new varices. And again, numerically, you see with the 2 milligrams, there's less new varices but this was not significant. And 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 protocol analysis or the completers analysis. And here, we are looking at the incidence of varices, and we show statistically significant lower rates of developing varices in the established 2-milligram dose of belapectin every other week. So you can see varices developed in 11.3% of patients with belapectin 2 milligrams versus 22.3% in the placebo arm. And again, this was statistically significant. Next slide. We also looked at changes in liver stiffness from baseline to 18 months of therapy. And you can see here in the table that there was a reduction in liver stiffness by vibration control transient elastography between 2.9 to 3.1 kilopascal. And this was more than what we saw in the placebo arm. This was only 0.7 kilopascal. 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. So we defined the liver stiffness worsening as increase by 30% from baseline or increase by 10 points KPA from baseline. So when we looked at increase more than 30% from baseline, significantly lower number of patients progressed based on liver stiffness in the belapectin 2-milligram arm compared to placebo, and you see the P value at 0.03. And a similar story emerged also when we looked at the increase in KPA by 10 points or more from baseline, 4.3% in the belapectin 2-milligram arm versus 12.5% with the placebo arm, so almost threefold reduction and the progression based on VCT. 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 2 belapectin arms. When we looked at treatment-emergent adverse events, they were reported in approximately 95% to 97%, but no difference between placebo and belapectin arms. And 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 and patients treated in the United States versus outside of the United States. And interestingly, we saw significantly lower number of patients that developed varices in the United States. So you can see this is, again, completers analysis for protocol population. But the incidence of varices was at 6.7% compared to 21% in the placebo arm. And if you remember, the entire cohort, it was around 11%. So definitely, patients treated in the U.S. did the best again, an incident 6.7%. This was not the same when we looked at patients treated outside of the U.S. So that percentage was 18.9% with the 2-milligram dose of belapectin. And you can see the sample size so 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 agonists, nonselective beta blockers, statins and ACE inhibitors because of their known potential effect on Portal Hypertension. And 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 nonselective beta blockers or ACE inhibitors. So this is a new analysis. We think that potentially, there's 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. But again, maybe the combination has potential in this advanced population with Portal Hypertension. Next slide. So key takeaways from the NAVIGATE trial. Number one is belapectin as the established 2 milligram per kilogram 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 milligram. 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 have Michael to share questions that we have received in the portal and walk us through, Michael?

Yes. Thanks, Khurram. So a couple of questions that the audience have. 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?

Yes. This is very important because endoscopists don't always agree on the presence especially of small varices so 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 their videos. And each was led by 2 central endoscopists with great experience in rating varices. And if they agreed, we went with this reading. If there was any disagreement, then we had third experienced endoscopist do the adjudication. This is a more rigorous way. It increases the likelihood of identifying varices. But the issue is that sometimes you don't get agreement between different endoscopists. So that can create sometimes discordance. But that's why I did the adjudication, and we had the third endoscopist treat this. So it increases my confidence that when we identify varices, we're 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?

Yes. 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. There are really 2 key takeaways from the gastro paper. One 2 mgs per kilo works better. Number two, the population that's 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 mgs per kilo reduced the development of esophageal varices. And we also see some signal with reduction in noninvasive fibrosis markers. So I think they validate each other. And to me, gives me a lot of confidence that belapectin given at 2 mgs per kilo seems to have worked for that population with portal hypertension and yet they 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. So 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?

Yes, thank you once again. As I said, when I was talking about my slide, we -- the first dose, human dose of belapectin was given at our institution, at our research unit. And after that, I think we have dosed many dozen patients and many have gone on for longer than a year or 1.5 years of this therapy. Very well tolerated and safe relative to -- we haven't seen any safety signal with this compound. And also, tolerability is really important. GLP-1s are -- or for example, FGF21 agonists are a promising class of agents and yet there's GI intolerance, and there is the signal with potentially with gallstones, so on and so forth. We haven't really seen anything with FGF -- with belapectin. And really, the tolerability is one, and we haven't seen the bone adverse events or muscle loss. So 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?

Yes. I think this is important to understand that with belapectin, we are trying to prevent disease progression, and that's why we looked at increase in liver stiffness by 30%. We looked at also increased by 10 kilopascal unit. And we showed that smaller percentage of patients treated, especially with the 2-milligram dose progressed based on liver stiffness. We know that there is a correlation between liver stiffness and Portal Hypertension. The Baveno criteria basically established the higher the liver stiffness, the more likely you have Portal Hypertension. That inverse is true also for platelet count. So the lower the platelet count, the more likely you have Portal Hypertension. So 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's the development of varices. But the hope is that this will translate into less outcomes in the future. And then we see less decompensating events like ascites encephalopathy and, of course, variceal bleeding. And I do believe that if you develop less varices, you'd be less likely to develop bleeding. But again, the hope is we will see it also with ascites encephalopathy or MELD needing liver transplantation.

Wonderful. Thank you for that. We have time for -- 2 minutes -- we might -- or 2 more questions. We might just go slightly over. So Dr. Chalasani, why, from your perspective, do you think this population has remained underserved despite the increasing disease burden?

Yes. 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. And 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 NASH space. And yet there isn't a Phase III trial in the 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. So they have a lower limit for the platelet count. So most studies, they want the platelet count, for example, to be more than 100,000. So 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 to ALT ratio, liver stiffness at least above 20. So I want to highlight that this is really a unique patient population, and there is a lot of interest in MASH Cirrhosis. But with other therapeutic targets, there is concerns about the point of no return and that may be a metabolic -- purely metabolic drug may not be effective. So 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. And this is the key feature of this trial that, again, patients are progressing less.

Understood. No, I appreciate that. And perhaps one last question. Maybe Dr. Alkhouri, we'll 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? So perhaps building a little bit on what you just mentioned. Anything else to add?

Yes. I mean, maybe I can give some more granularity. I mean, there's other agents, for example, FGF21 agonist and they have Phase III trials in MASH Cirrhosis. But again, they're doing biopsies before and after. They're looking at disease regression, but they're selecting a less sick patient population. So of course, these trials are still ongoing. We don't 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. And this is by design and not to take away anything else from other agents. I think they're very promising. But again, this is a more advanced patient population. We're trying to prevent the progression of their disease. I think also the endoscopic endpoints, and this is 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. But 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. Well, 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 is 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. And again, we appreciate the KOLs' time very much as well as the management team of Galectin.