Good afternoon, and welcome to the Galectin Therapeutics Virtual KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player. 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. Dr. Naim Alkhouri, Chief Academic Officer at Summit Clinical Research in San Antonio and the Director of Cirrhotic Liver Program at North Shore Gastroenterology in Cleveland. As Tara mentioned, today's call will include a brief Q&A session, should time allow.
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. With that, Khurram, I will turn it over to you.
Thank you, Michael. Yeah, 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 two 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 this 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 multi-billion 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 pertinent 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 3-5 million people in the U.S. with varying degrees of cirrhosis. When you have cirrhosis, it initially starts as compensated, meaning liver is still functioning, and no portal hypertension, meaning there isn't a portal pressure buildup. As the time goes on, a couple things will happen to these patients. One, they become decompensated, which basically means the liver isn't working well, and you'll get complications such as ascites or other encephalopathy. Along the way, you also develop portal hypertension, which is pressure buildup in the portal circulation.
Portal hypertension comes a bit before decompensation. 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, a blood squirting from an esophageal varix. 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. Currently, there are no approved treatments for NASH cirrhosis. We know both Resmetirom and Semaglutide have been approved conditionally for compensated stage 2 and stage 3 fibrosis patients, but not for cirrhosis.
Today, how we manage patients with NASH 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. Mostly, we manage comorbidities such as diabetes and hypertension, so on and so forth. 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 NASH cirrhosis are high risk for liver cancer. 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, and I would say about 10 years ago.
This is a phase II-B program, published in Gastroenterology. I'll just call this GT-026. This is sort of the first there, I would say, pivotal study that compared placebo versus 2 mg per kg versus 8 mg per kg. The primary endpoint was hepatic venous pressure gradient change at end of 12 months. Hepatic venous pressure gradient change is sort of the gold standard for portal hypertension. What we saw in that study was 2 mg per kg group had a significant benefit when you look at the HVPG change. Also we saw a significant reduction in the development of varices with 2 mg per kg, not with 8 mg, 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 NASH cirrhosis to start with. Patients also had portal hypertension non-invasively, 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. This is a group of people with NASH 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. 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 two doses, 2 mg/kg, 4 mg/kg and placebo. Once again, really a robustly sized, well-powered trial. These are our key inclusion. No surprises here. Primary endpoint was in the ITT population, composite primary endpoint. Then also of primary interest is the incidence of varices in per-protocol population. There were a number of composite secondary endpoints. Then once again, just to walk you through, ITT, intention to treat population, is all randomized patients minus 2 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. 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. It may seem complicated, but actually it makes sense. The intercurrent events included for this program, if any participant developed liver-related clinically events or AEs leading to discontinuation. People requiring a TIPS shunt for variceal bleeding or using GLP-1 or non-selective beta blockers for longer than 12 months. These are the baseline demographics 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. 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 2 studies is generated a fair bit of confidence for me as somebody who's been involved in this program. This population had. You know, this was not powered or studied long enough to pick up a signal with liver-related events or MASHes. I would stop at that for that slide. Safety, it was excellent. Adverse events, treatment-related adverse events or treatment-related SAEs, there was no signal. Certainly, there was no signal for any drug-induced liver injury.
With that, I'm gonna pass on to Dr. Alkhouri.
Thank you, Dr. Chalasani, for this excellent overview. Thank you to the Galectin team also for having me on this important call. Over the next few slides, I'm gonna 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. 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.
This is an advanced patient population, again, not only with the compensated MASH cirrhosis, but with signs of clinically significant portal hypertension. In this table we are showing you the baseline platelet count, and this is, you know, 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 cm, so you see the average spleen size was around 13.8 cm for the cohort.
As I said, these patients are compensated, so relatively low MELD score and Child-Pugh score by design. Over 55% of these patients have 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. Again, advanced patient population at baseline. First we are showing you changes in liver stiffness measurement by transient elastography. This is done with the FibroScan machine. Remember the goal with belapectin and NAVIGATE is to prevent disease progression, but yet we are able to show actually 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 the belapectin. 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 five, 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. 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. What you see here is that you know, there's a progressively higher percentage of patients that developed varices based on the ELF criteria. 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. 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 the Baveno criteria. We showed that less patients treated with belapectin achieved this outcome, so placebo arm was at 14.3 versus 8.2 with belapectin. 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 the Baveno criteria and the change in the category after 78 weeks of treatment. 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 mg 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. We went from 42% to close to 57%. We looked at the AGILE 4 score, and this is important because it's a combination. It's not just dependent on liver stiffness, but it has the AST to ALT ratio and the platelet count. We looked actually at preventing worsening in the AGILE 4 score by 20%. 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.
We also looked at disease progression here and preventing an increase by 20% or more in YKL-40. We showed that this outcome was achieved in less patients treated with belapectin. We also looked at a decrease by 20%. Here you see that 33.8% of patients treated with belapectin decreased their YKL-40 by 20% or more, versus only 23% in the placebo arm. We looked also at PRO-C3, another fibrosis biomarker. You know, 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. Looking at ELF, looking at YKL-40, looking at PRO-C3, and you get the idea that, you know, patients treated with belapectin decrease their PRO-C3 in a significant manner compared to placebo.
We looked at patients at the highest risk of having fibrogenesis. These are patients with ELF above 11.3. We looked at changes in these patients in PRO-C3, a 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. 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. We showed here reduction in the ratio. 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 IV collagen buildup. Type IV collagen, very important in liver fibrogenesis. 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. I think key takeaways, you know, I think we've shown you in the previous slides that belapectin at the 2 mg/kg 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. 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 a 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.
Yeah, absolutely. Thanks, Khurram, and thanks 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?
I mean, really there is. I've been part of MASH clinical trials 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 or enrolling cirrhosis for either prevention of clinical outcomes in a longer duration or improvement in fibrosis. But this prevention of varices, variceal bleeding is a very unique aspect of the Galectin belapectin program. I think it has a niche approach here.
Wonderful. Thank you. For Dr. Naim Alkhouri, another question as well. There's 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, you know, 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. That's why we believe that the combination of blood biomarker, a 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. 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-40, of course, MR elastography. Again, if I have to pick two, these would be the two.
Wonderful. Thank you so much for that. Another question perhaps for both of the KOLs. Are you still relying on liver biopsy to establish cirrhosis in clinical practice or have non-invasive modalities sufficiently replaced biopsy for diagnosing cirrhosis and portal hypertension? Maybe Dr. Chalasani, we'll start with you and then go to Dr. Alkhouri.
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, you know, iron, you know, 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. We have several programs now that are enrolling trials based on non-invasive tests. 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. 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, 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. Perhaps turn it back over, Khurram, for closing remarks.
No, thank you again. Every time I listen to Dr. Alkhouri and Dr. Chalasani, I learn a few things. Thank you again, and look forward to continuing to share the data in public domain and excited to share our progress on the program from regulatory point of view and other aspects in coming weeks and months. Thank you again for joining today.