Galectin Therapeutics Inc. Aktie

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 your moderator, Michael Cozart of LifeSci Consulting. Please go ahead, Michael.

Thanks, Tara, and good afternoon, everyone, and thank you for joining today's KOL webinar. My name is Michael Cozart, and I'm Managing Partner at LifeSci Consulting. Today, we will discuss belapectin as a treatment for MASH cirrhosis with portal hypertension.

Joining today's call, in addition to Galectin management are two leading key opinion leaders, Dr. Naga Chalasani, Professor of Gastroenterology and Hepatology, Adjunct Professor of Anatomy, Cell Biology and Physiology and Director of the Terance Kahn Liver Research Program at Indiana University School of Medicine; and Dr. Naim Alkhouri, Chief Academic Officer at Summit Clinical Research in San Antonio and the Director of Steatotic Liver Program at North Shore Gastroenterology in Cleveland. As Tara mentioned, today's call will include a brief Q&A session should time allow.

And as we get started here, we'd like to introduce Khurram Jamil, Galectin's Chief Medical Officer, who will provide not only a brief overview of MASH cirrhosis with portal hypertension, but also belapectin's ability to address this significant unmet medical need.

So with that, Khurram, I will turn it over to you.

Thank you, Michael. Yes, I'm really excited to join two distinguished experts today as we review the evolving treatment landscape and discuss key results from our clinical program.

Prevalence of MASH cirrhosis continues to rise in the United States, largely driven by increasing rates of obesity and type 2 diabetes. MASH cirrhosis is a progressive and life-threatening condition that can culminate in hepatic decompensation, liver failure and ultimately, the need for liver transplant. In fact, MASH cirrhosis has become the leading indication for liver transplant in the country. It's estimated that more than 5 million individuals in the U.S. are living with MASH cirrhosis. By contrast, fewer than 12,000 liver transplants were performed last year, underscoring the profound gap between disease burden and available definitive treatment option.

This stark imbalance highlights the magnitude of unmet medical need for patients with MASH cirrhosis and portal hypertension. Our goal is to address a significant unmet medical need with belapectin and provide a viable treatment option to our patients.

Galectin-3 is a protein which is upregulated in multiple chronic inflammatory conditions and is well known to be a key driver of fibrosis. Belapectin is a complex carbohydrate that binds with galectin-3 receptors to reduce its expression. Data from animal and human clinical studies have shown that targeting galectin-3 can lead to reduction in fibrosis and inflammation, thus offering a novel approach to treat MASH cirrhosis and portal hypertension.

Multiple preclinical studies have shown that belapectin reduces galectin-3 expression, collagen deposition, portal pressure and overall fibrosis. These strong mechanistic foundations form the basis for our clinical development program.

The economic burden of MASH cirrhosis, combined with absence of FDA-approved pharmacological therapies have created a significant market opportunity in these patients. With the potential to prevent the progression to more severe complications, belapectin could potentially significantly improve patient outcomes. In a blinded market research, we received extremely positive feedback from both treating physicians and payers. The total addressable market is substantial with estimates suggesting a multibillion-dollar opportunity. We believe that our clinical development efforts will pave the way for belapectin to become a key player in this therapeutic area.

At this point, I'd like to invite Dr. Naga Chalasani, Professor of Medicine at the Indiana University School of Medicine, to present an overview of the treatment landscape and share the top line results from our clinical program.

Thank you, Khurram. For the opportunity to be here. What I'd like to first share with you all is to give a bird's eye view on what happens to people with cirrhosis. Once again, I reiterate there may be anywhere from 3 million to 5 million people in the U.S. with varying degrees of cirrhosis.

So when you have cirrhosis, initially, it starts as compensated, meaning liver is still working and no portal hypertension, meaning there isn't a portal pressure buildup. As the time goes on, a couple of things will happen to these patients. One, they become decompensated, which basically means the liver isn't working well and you get complications such as ascites or other encephalopathy. Along the way, you also develop called portal hypertension, which is pressure buildup in the portal circulation. Portal hypertension comes a bit before decompensation.

And when -- in the life of a patient with cirrhosis, development of portal hypertension is a -- I would say, an ominous milestone. Portal hypertension shown in the pictures here can develop esophageal varices, which can bleed, as you can see on your right side figure, blood squirting from an esophageal varix and this is catastrophic. If somebody bleeds from esophageal varices, there could be as much as 20% mortality during that just hospitalization. Overall, in the life of a patient with cirrhosis, decompensation or portal hypertension are not good events to develop.

Next. So currently, there are no approved treatments for MASH cirrhosis. We know both resmetirom and semaglutide have been approved conditionally, subpart H for Stage 2 and Stage 3 fibrosis patients, but not for cirrhosis. Today, how we manage patients with MASH cirrhosis is lifestyle interventions, really no data that would dramatically change the natural history. Bariatric surgery, when it is done, can change the natural history. But especially when you have portal hypertension, the risk is high. So it is not done frequently. And mostly, we manage comorbidities such as diabetes and hypertension, so on and so forth. And then also as we have patients with cirrhosis, we screen for the development of varices with periodic endoscopies as well as screen for liver cancer as patients with MASH cirrhosis are high risk for liver cancer.

So I've been involved in the belapectin program from at least for about 10 years or so. The very first patient, human being, dosed with belapectin actually happened at our center, I would say, about 10 years ago. So this is a Phase IIb program published in Gastroenterology. I'll just call this GT-026. This is sort of the first, I would say, pivotal study that compared placebo versus 2 mgs per kilo versus 8 mgs per kilo. And the primary endpoint was hepatic venous pressure gradient change at the end of 12 months. And hepatic venous pressure gradient change is sort of the gold standard for portal hypertension.

What we saw in that study was 2 mgs per kilo group had a significantly -- significant benefit when you look at HPVG change. And also, we saw a significant reduction in the development of varices with 2 mgs per kilo, not with 8 mgs, and there is a good pharmacokinetic explanation why that is the case. This led to, of course, a high-impact publication also discussions with the agency and launching the NAVIGATE trial, which I think is largest -- it's one of the largest trials in the cirrhosis space with some of the design intricacies I'll share with you.

Here, everybody had MASH cirrhosis to start with. Patients also had portal hypertension, non-invasively unless -- unlike our GT-026, here, we did not do hepatic venous pressure gradient, but we used surrogates that were agreed upon by the agency and all patients had endoscopy at baseline and showed no esophageal varices. So this is a group of people with MASH cirrhosis, have portal hypertension, but they have not developed esophageal varices yet.

A brilliant aspect of this design -- this study is that for the first time, there is a central adjudication of endoscopy, three expert endoscopists evaluated baseline and end-of-study endoscopies in a blinded fashion. And what happened with NAVIGATE is now being protocolized by other trials in the cirrhosis space. The trial design briefly shown here, this is a 78-week trial and 2 doses, 2 mgs per kilo, 4 mgs per kilo and placebo. And once again, really robustly sized, well-powered trial.

And these are key inclusion, no surprises here. Primary endpoint was in the ITT population, composite primary endpoint. And then also of primary interest is the incidence of varices in per-protocol population. There were a number of composite secondary endpoints. And then once again, just to walk you through ITT, intention to treat, population is all randomized patients minus two individuals who had varices at baseline. Per protocol is all participants who received the study medicine and also for 18 months and also had end-of-treatment endoscopy at 18 months.

And the composite primary endpoint is what we ended up after discussions with the agency. This is any subject who developed esophageal varices or had an intercurrent event or dropouts without an endoscopy or intercurrent events. And may seem complicated, but actually it makes sense. And the intercurrent events included for this program, if any participant developed liver-related clinical events or AEs leading to discontinuation, people requiring a TIPS shunt for variceal bleeding or using GLP-1 or nonselective beta blockers for longer than 12 months.

These are the baseline demographics, well matched across three groups. Shown here, the composite primary endpoint in the ITT population, the primary endpoint was not met, but you could see a numerical difference, almost a 10 percentage point lower with 2 mgs per kilo. However, though, if you look at the box, the dotted box on the left, in patients who develop new varices, the same thing what we have seen with GT-026, it seems to be reproducible. With 2 milligrams per kilo dose, the development of new varices seems to be significantly lower.

Shown in more detail here, there is about a 50% reduction in the development of esophageal varices, new onset of varices. And also this is important. If you look at medium-sized varices or large varices, once again, you see a treatment effect. And of course, the trial was not powered for these outcomes, so one should be cautious. Nonetheless, what you see in the NAVIGATE is it basically validates what we saw in GT-026, the 2 mgs per kilo dose given every 2 weeks is reducing the development of varices, esophageal varices in people with portal hypertension who did not have varices at baseline. That validation in two studies is generated a fair bit of confidence for me as somebody who has been involved in this program.

This population had -- this was not powered or studied long enough to pick up a signal with the liver-related events or MACE. So I would stop at that for that slide. Safety was excellent. Adverse events, treatment adverse events or treatment-related SAEs, there was no signal. Certainly, there was no signal for any drug-induced liver injury.

So with that, I'm going to pass on to Dr. Alkhouri.

Thank you, Dr. Chalasani, for this excellent overview, and thank you to the Galectin team also for having me on this important call. So over the next few slides, I'm going to review some exciting and new biomarker results at 18 months from the NAVIGATE trial.

First, I just wanted to remind you of the patient population that these patients have MASH cirrhosis, but also signs of portal hypertension. This was actually part of the protocol. So in addition to liver stiffness and platelet count, we also wanted some patients to have enlarged spleen. So we looked at spleen size. Many of these patients also had collaterals, whether it was on physical exam or imaging. So this is an advanced patient population, again, not only with compensated MASH cirrhosis, but with signs of clinically significant portal hypertension.

So in this table, we are showing you the baseline platelet count. And this is on the lower side. I encourage you to compare this to other MASH cirrhosis trials and see the baseline platelet count. Of course, the lower the platelet count, the more likely the patient will have clinically significant portal hypertension and the higher the risk of decompensation. Also, baseline liver stiffness was around 23.5. So this is on the higher side. Spleen size, normal spleen size is typically less than 11 centimeters. So you see the average spleen size was around 13.8 for the cohort. As I said, these patients are compensated, so a relatively low MELD score and Child Pugh score by design. But over 55% of these patients had signs of clinically significant portal hypertension or probable portal hypertension based on Baveno criteria. They also had elevated FIB-4 index, ELF score and the AGILE-4 score, which is really a combination score that includes your liver stiffness, but also other variables like AST, ALT, platelet count and the presence of diabetes or not. So again, advanced patient population at baseline.

So first, we are showing you changes in liver stiffness measurement by transient elastography. This is done with the FibroScan machine. And remember, the goal with belapectin in NAVIGATE is to prevent disease progression, but yet we are able to show actually a reduction in liver stiffness here compared to placebo. There was a slight increase in the placebo arm and 8.4% decrease in liver stiffness with belapectin.

We then looked at progression of liver stiffness and worsening liver stiffness, and we showed actually significantly less progression with belapectin. So if you look at increase in liver stiffness by 30% or more from baseline, which we consider clinically significant, and this is beyond the variation coefficient of liver stiffness on transient elastography. We showed that actually less patients in the belapectin arm progressed and increased liver stiffness by 30% or more. We also looked at an increase by 5 kilopascal units or more in liver stiffness. In a cirrhotic population, this is considered also clinically significant. We have what we call the rule of 5, and we showed that less patients treated with belapectin increased their liver stiffness by 5 points or more.

We then looked at the ELF score, enhanced liver fibrosis score. This has three biomarkers of extracellular matrix deposition and turnover. And we divided patients based on their ELF score into ELF less than 9.8, ELF between 9.8 to 11.3 and then ELF of 11.3 or higher. We had several studies showing that having an ELF above 11.3 in patients with compensated cirrhosis predicts actually decompensating events. And what you see here is that there's a progressively higher percentage of patients that developed varices based on the ELF criteria. But also, we showed significant reduction with belapectin. To me, personally, I was most impressed by patients with ELF above 11.3, and you see about 43% developed varices in the placebo arm compared to only 22% in the belapectin arm.

We then also looked at concordant fibrosis biomarkers. So we looked at basically increase in liver stiffness by 30% or more and achieving liver stiffness more than 25 kilopascal, which is part of the definition of clinically significant portal hypertension based on Baveno criteria. And we showed that less patients treated with belapectin achieved this outcome. So placebo arm was at 14.3% versus 8.2% with belapectin.

And then we looked at also increase in stiffness by 30% or more and increase in the ELF score by 0.5 units or more. Again, this is what we consider clinically significant in terms of change in the ELF score. And we showed that actually only 4% of patients treated with belapectin achieved this outcome compared to 10.7% in the placebo arm.

We then looked at the presence of clinically significant portal hypertension and probable portal hypertension based on Baveno criteria and the change in the category after 78 weeks of treatment. And if you focus on the red section of the bar, you see in the placebo arm, we had about 34% with definitive CSPH at baseline, and that remained at 33% after 78 weeks of treatment. Contrast this to the belapectin 2-milligram arm, where we started with 33%, and that was decreased to approximately 26%. We also with belapectin increased the percentage of patients with no evidence of clinically significant portal hypertension over time. So we went from 42% to close to 57%.

Then we looked at the AGILE-4 score. And this is important because it's a combination. So it's not just dependent on liver stiffness, but it has the AST to ALT ratio and the platelet count. And we looked actually at preventing worsening in the AGILE-4 score by 20%. So this was 20% increase in the baseline AGILE-4, and we showed that less patients in the belapectin arm developed this outcome compared to the placebo arm.

Next, we looked at another biomarker for fibrosis, YKL-40, which is also part of the NIS4 and NIS2+ score. This has been around for a while. And we also looked at disease progression here and preventing an increase by 20% or more in YKL-40. And we showed that this outcome was achieved in less patients treated with belapectin. And then we also looked at a decrease by 20%. And here, you see that 33.8% of patients treated with belapectin decreased their YKL by 20% or more versus only 23% in the placebo arm.

And then we looked also at Pro-C3, another fibrosis biomarker. We've seen these biomarkers sometimes don't move all in the same direction in different trials. But here we're trying to show you consistency. So looking at ELF, looking at YKL-40, looking at Pro-C3. And you get the idea that patients treated with belapectin decreased their Pro-C3 in a significant manner compared to placebo.

And then we looked at patients at the highest risk of having fibrogenesis. These are patients with ELF above 11.3, and we looked at changes in these patients in Pro-C3 fibrosis biomarker, and we showed significant reduction here in the belapectin arm by 18.6% compared to the placebo arm. I think this was absolute change, not percentage.

And then we also looked at the ratio of Pro-C3, which is a biomarker of fibrogenesis and CTX-III, which is a biomarker of fibrosis degradation or fibrolysis, and we showed here a reduction in the ratio. So this indicates that you have less fibrogenesis and more fibrolysis, which is exactly what you want to see in patients with cirrhosis, especially those with portal hypertension.

We also looked at Pro-C4. This is another marker of Type 4 collagen buildup. So Type IV collagen very important in liver fibrogenesis. And we looked here at the percentage of patients that had worsening and increased by 20% or more in Pro-C4, and we showed reduction -- significant reduction in this percentage with the belapectin treatment arm 2.7% compared to 13.1% in the placebo arm.

So I think key takeaways, I think we've shown you in the previous slides that belapectin at the 2-milligram per kilogram dose significantly reduced the incidence of new varices after 18 months of treatment in patients with MASH cirrhosis and evidence of portal hypertension. This is the primary outcome of the trial. I showed you in the previous few slides, several biomarkers that actually improved or at least showed less worsening compared to placebo. We do believe that these findings validate the results from the previous Phase II trial, especially with this dose, the 2-milligram dose. The safety profile looked excellent with adverse events and SAEs, discontinuation rate, all comparable to placebo. So we do believe that belapectin has the potential to address the unmet need in this sick population with MASH cirrhosis and evidence of portal hypertension. Thank you.

Thank you, Dr. Alkhouri. Belapectin is the first therapy to demonstrate clinical effect of prevention of varices in patients with compensated MASH cirrhosis and portal hypertension.

This is an exciting time for Galectin Therapeutics. With the strong foundation of clinical and biomarker data, we are now focused on advancing discussion with regulatory agency while identifying the right partner to move the program forward. I really appreciate again both you and Dr. Chalasani joining today and walking us through the data. Michael, back to you.

Yes, absolutely. Thanks, Khurram, and thanks both to the KOLs. We do have a few questions that we would like to get responses from. Perhaps we start first with Dr. Chalasani.

When you think about how do the results differentiate belapectin from other MASH drugs either currently in development or on the market?

Really, there is -- I've been part of MASH clinical trial since, I would say, for the last 25 years. There isn't a trial that I know is studying the population that NAVIGATE or Galectin is focused on. There are -- for example, the FGF21 programs are focused -- are enrolling cirrhosis for either prevention of clinical outcomes in a longer duration or improvement in fibrosis, but this prevention of their varices, variceal bleeding is a very unique aspect of the Galectin belapectin program. So I think it has a niche approach here.

Wonderful. For Dr. Alkhouri, another question as well. There has been an increasing emphasis on composite and concordant biomarker signals. From your perspective, which two fibrosis markers do you view as most clinically informative and, I guess, potentially predictive of outcomes in patients with MASH cirrhosis and portal hypertension?

I would say we have the most data today with VCTE, vibration-controlled transient elastography and the ELF score. We have great data showing that your baseline VCTE can predict outcomes, but also more importantly and more recently, the changes in VCTE over time can predict outcomes. I think we have robust data showing that your baseline ELF score is also a very good predictor of outcome.

We've had some issues with VCTE just because patients, especially with MASH cirrhosis, they have higher BMIs. We know BMI may affect the accuracy of VCTE. So that's why we believe that the combination of blood biomarker, serologic biomarker plus an imaging biomarker and showing that both of them are moving in the same direction gives us more confidence that the change we're seeing is a true change. It's not related to the variation coefficient with transient elastography.

So these would be my two picks, I would say, VCTE and ELF. Of course, there are other biomarkers that are very promising. We showed data with Pro-C3, YKL, of course, MR elastography. But again, if I have to pick two, these would be the two.

Wonderful. Another question perhaps for both of the KOLs. Are you still relying on liver biopsy to establish cirrhosis in clinical practice? Or have noninvasive modalities sufficiently replaced biopsy for diagnosing cirrhosis and portal hypertension? So maybe Dr. Chalasani, we'll start with you and then go to Dr. Alkhouri.

No, I think it's -- no, we don't -- we no longer have our patients undergo liver biopsies for the diagnosis of cirrhosis, which in my practice is a dramatic change. 15, 20 years ago when I suspected cirrhosis in a patient with MASLD or NAFLD back then, almost all of them got a liver biopsy. Today, only if there is a diagnostic uncertainty, if there is iron -- concern about an iron overload or suspected overlap with autoimmune hepatitis, otherwise, we just depend very much on the two biomarkers Dr. Alkhouri touched on ELF as well as liver stiffness by VCTE.

I completely agree. And I think even the FDA is in agreement that you can enroll MASH cirrhosis trials now without the need for biopsy. Only if your outcome is histology driven, you have to do a biopsy at baseline. But we have several programs now that are enrolling trials based on noninvasive test. Typically, it's a combination of VCTE, ELF, some programs allow MR elastography at baseline also and looking at the platelet count and imaging, of course. But the need for biopsy has been eliminated in the majority of patients.

Wonderful. Really appreciate the perspectives on all three of those questions. With that, I wanted to thank both of the KOLs again for your time, the responses that you provided during today's call, the perspective on both the indication as well as belapectin, and perhaps turn it back over to Khurram for closing remarks.

Thank you again. Every time I listen to Dr. Alkhouri and Dr. Chalasani, I learn a few things. So thank you again, and look forward to continue to share the data in the public domain and excited to share our progress on the program from a regulatory point of view and other aspects in the coming weeks and months. Thank you again for joining today.

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.