All right. Good afternoon, everyone, and welcome to the H.C. Wainwright 27th Annual Global Investment Conference. My name is Matt Keller. I am a VP in the Equity Research Department, and it is now my pleasure to introduce our next presenters. Please join me in welcoming Joel Lewis, the President and CEO, and Khurram Jamil, CMO of Galectin Therapeutics. Guys, the floor is yours.
Thanks, Matt. Hi, I'm Joel Lewis, President and CEO of Galectin Therapeutics. Due to time constraints today, I'm going to hand over the remainder of the presentation to our Chief Medical Officer, Dr. Khurram Jamil.
Thank you, Joel. Good afternoon, everybody. I'm really pleased and excited to be here today and look forward to sharing the latest on our belapectin program for patients for NASH cirrhosis and portal hypertension. Our presentation contains a forward-looking statement. I encourage everybody to look at our corporate website for more details. Our lead program is in patients with NASH cirrhosis and portal hypertension. Portal hypertension means increased pressure in veins that bring blood from your liver to the heart. As the pressure increases, it's a harbinger of worse outcomes. It leads to complications in patients with cirrhosis. Those complications include ascites, development of esophageal varices, hepatic encephalopathy, so on and so forth. The reason we selected specifically the development of esophageal varices as a primary endpoint and clinical outcome is based on multiple natural history publications in cirrhosis.
As the disease advances, the development of esophageal varices is the first complication or first sign of progression of disease and also a sign that the patient has now developed from a compensated cirrhosis to cirrhosis and portal hypertension. In fact, clinically significant portal hypertension. Among many things that are unique to Galectin Therapeutics and our program, this clinical endpoint is also a unique thing compared to many biopsy-based endpoint studies that you may have observed in NASH and even NASH cirrhosis patient population. As we all know, there's no FDA-approved treatment to reverse portal hypertension in patients with NASH cirrhosis. Now, belapectin is a complex carbohydrate. It selectively binds galectin-3 proteins. Galectin-3 proteins are very well documented to be increased or up-regulated in multiple chronic inflammatory conditions and chronic fibrotic conditions. These studies have been done not just by Galectin Therapeutics, but multiple other large, well-known academic centers.
Specifically, in the context of NASH cirrhosis and portal hypertension, an increase in galectin-3 has shown to correlate with macrophage activation, increased collagen buildup, and indeed development of complications. We have conducted multiple animal model studies and shown that if you give belapectin, then it led to a decrease in galectin-3 levels, a decrease in collagen burden, and an improvement in portal pressure. Based on these encouraging preclinical studies, we embarked on our clinical program. Before I share updates and key data from our clinical program, just a few words on the epidemiology of this patient population. Based on a very well-documented, well-referenced epidemiological study that was published earlier this year, it's estimated that 1%, up to 1% of the U.S. population may have NASH cirrhosis and portal hypertension.
Given there is no approved treatment, if this condition is not reversed, then invariably over coming years and decades, these patients end up on the transplant list. Now, based on some of the most recent liver transplant data, overall in the country, we transplant less than 10,000 liver transplants a year. You can compare literally hundreds and thousands, if not millions, of patients who have portal hypertension due to NASH cirrhosis with a very small amount of patients who may end up on liver transplant or who may get liver transplant. Indeed, that underlines a very high unmet need to give a therapy that can reverse this condition and reverse portal hypertension. One of the challenges over the years has been when to treat cirrhosis.
If you give an anti-fibrotic therapy too late, meaning when they have already varices developed, then we know they have thick fibrous septa in the liver, and it's too hard to undo that burden or that damage. Indeed, trials that were done five, ten years ago showed that it probably is too late to give an anti-fibrotic therapy at that stage, and the only hope, opportunity physicians have, is to give symptomatic therapy at that stage. On the flip side, if you treat too early, say compensated cirrhosis, they don't have portal hypertension, then for any clinical outcome, you have to wait many, many years before you can have any meaningful dent in preventing or reducing the incidence of clinical outcome.
With that mindset, we have deliberately chosen a patient population which not only has cirrhosis, NASH cirrhosis, but has portal hypertension, so we can show in a reasonable time frame some meaningful impact of our therapy. Just to carry on from the epidemiology data I shared earlier, if we estimate roughly 1.7 million patients who exactly meet our target indication, which is portal hypertension on top of NASH cirrhosis, and using some of our market research studies from last year, based on positive feedback from payers and treating physicians, we believe there is significant market opportunity with belapectin. Even using very conservative estimates for uptake, the market opportunity is many billions of dollars annual peak sale. Now, shifting to our clinical data, GD26, one of the large Phase IIb studies published in 2022 by Dr. Chalasani in Gastroenterology, the primary endpoint was improvement in hepatic vein pressure gradient.
An invasive method, but only done in a large academic center in a small clinical research setting. While the primary endpoint wasn't significant, what we observed was patients who did not have varices at baseline, roughly half the patient population in that trial, there was a significant drop in portal pressure at the one-year mark. In the same patient population that had significant improvement in portal pressure, there was significantly less incidence of varices in the 2 mg cohort. Obviously, less varices also in the 8 mg dose compared to placebo. For us, patients who did not have varices at baseline denote they did not have what we call clinically significant portal hypertension.
We chose the 2 mg dose from this trial and also the patient population that seemed to have the most benefit, which is those who don't have varices at baseline, as the basis for our NAVIGATE trial design. NAVIGATE trial design, where also the therapy duration was given for 18 months instead of a 12-month duration. We used the 2 mg dose, the one with positive findings in GD26, a new experimental 4 mg dose, and gave this treatment to three cohorts of patients over an 18-month period. They all had to have a diagnosis of NASH cirrhosis and portal hypertension with no varices at baseline. What's also unique is we had a robust central-blinded review for assessment of esophageal varices. What that means is every endoscopy that was done at the baseline was reviewed by at least two central-blinded reviewers to make sure that they don't have any varices.
If their findings were, there was a consensus, they would be enrolled in the trial. If there was no consensus, they would go to a third adjudication process. This was a robust process which was also agreed with FDA. This is something unique, similar to what we have seen in a NASH trial with biopsy-based endpoints, blinded central review. In terms of patient population, all these patients had a diagnosis of NASH cirrhosis. Portal hypertension was diagnosed based on clinical guidelines and practice of a non-invasive method. This trial was done across more than 100 centers across five continents, so we couldn't implement the HVPG, hepatic vein pressure gradient measurement. Instead, as is known in more registration-level trials, a non-invasive method using liver stiffness measurement, platelet count, or collaterals on ultrasound was used to diagnose portal hypertension.
The primary endpoint was a composite endpoint of varices, and I'll share details in the next slide. We also had an endpoint of looking at varices in the per-protocol population or completer population. The secondary endpoint was a composite endpoint looking at all of these complications in aggregate, not individually. Now, again, the ITT population contains every patient that was randomized through the trial. We excluded two patients who were randomized in error because they had varices at the baseline. We had the per-protocol population, which is all subjects who completed 18 months of therapy as the protocol dictated. Our composite primary endpoint was those who had either varices at 18 months or who had liver-related complications or discontinued the trial due to any adverse event or had TIPS, which is a shunt procedure, or who had more than 12 months' use of GLP-1 or non-selective beta blocker.
The reason the last point is because beta blockers were prohibited in the trial from the onset, but during the trial conduct, the guidelines changed. Now, if a patient has portal hypertension, even without varices, prescribers can give them a non-selective beta blocker. With that change, we had to accommodate, make sure we had a way of capturing that through this intercurrent event. This is the baseline demographic for the patient population, the ITT population, 355. The three highlighted rows refer to platelet count, liver stiffness, and spleen. This corresponds to the guidelines for assessment of portal hypertension. Just to compare the population with some of the recent NASH cirrhosis trials, you can see our baseline platelet count is around 130,000. That's the lowest of most of these trials last one year that have been published in NASH cirrhosis.
Our patient population is a degree more advanced than some of the published trials. Liver stiffness measurement is around 24 kilopascal. This is a result from the ITT population, overall population. We have subdivided that into all three categories, which were used to assess the composite endpoint. Those in the box are specific to the varices endpoint. You can see numerically, roughly 43% less incidence of varices in 2 mg compared to placebo. The 4 mg dose, which is the experimental new dose, also had numerically low incidence, but still slightly higher than the 2 mg dose. The incidence of intercurrent event, I gave the categories in the previous slide, or the patients who had dropped out without any EGD or intercurrent event was comparable and numerically not significant.
The overall result was not significant for the primary endpoint, even though 43% less patients developed varices in the ITT population compared to placebo. If you look at those that completed 18 months of therapy, as the protocol specified from the get-go, there was a significantly less incidence of varices in the 2 mg dose compared to placebo. Just to contrast, there's not a significant difference in varices if you look at 21 in placebo and 12 in 2 mg. This is 21 and 11. This is not some significant math going on here. This is just a difference of one patient in the per-protocol population that tipped the results to statistical significance. Also, all those blinded EGDs were assessed for the size of varices, medium, small, and large.
We also know that if larger or medium varices are more likely to bleed and also indicate more severe or advanced disease. For whatever it's worth, numerically, a less number of subjects developed medium or large varices on 2 mg compared to placebo. We also shared recently that patients in the U.S., and two-thirds of patients were enrolled in the U.S. in this large global trial, had also significantly less incidence of varices compared to placebo. You can see the incidence of varices was also lower in the U.S. compared to ex-U.S. This prompted a closer scrutiny. What was the reason behind that? What we observed was in the U.S., across the three treatment groups, the incidence of GLP-1 use and statin use was higher. Obviously, it was higher in placebo still, more than the belapectin group, but that was higher also than ex-U.S.
We believe, based on some recent data from the last two years, there's a potential benefit of statins and even GLP-1 in this patient population that could also play a synergistic role because belapectin acts through a purely anti-inflammatory, anti-fiber action, whereas therapies like GLP-1 act through a metabolic pathway or specifically insulin-resistant pathways. There might be a complementary effect going on here. Now, pivoting to the biomarker, I'll be sharing the biomarker that are more commonly presented for fibrosis, and you'll see that biomarker presented almost in every single NASH cirrhosis trial. You can see here at 18 months in the ITT population, there was roughly a delta of 8% difference compared to placebo. Again, you can compare in some of the recent NASH cirrhosis trials that even the placebo group in those trials shows some improvement.
In our case, the placebo actually had worsening as a percentage of LSM at 18 months. Looking at per-protocol computer population with all available data, the delta is a 10% difference, 1.7% worsening compared to minus 8.4%. I just want to point out this is a more conservative assessment because if you look at the 3.2 kilopascal difference in the 2 mg cohort, 3.2 difference, 24.6 minus 24. If I'm doing a straight 3.2%, 3.2 kilopascal difference of 24, this is more like a 13% difference. What this calculation is actually calculating is a percentage difference from each patient individually and plotting that. I'm here showing a more conservative estimate. Either way, whether you do it straight percentage of 3.4 kilopascal of 24 or individual calculation, the magnitude is unchanged, which is more like double-digit change versus placebo. We also showed in terms of worsening of fibroscan.
Remember, our endpoint, which is the development of varices, is a worsening of condition, not an improvement in biopsy, which we see all the time in NASH trials. It's a worsening of condition. Similarly, looking at worsening of fibroscan, whether by 30% or 5 kilopascal, you'll see the incidence of worsening was much higher in placebo compared to 2 mg. These cut points of 30% or 5 kilopascal are not reinvented, but it's very commonly used in literature, and they're well known to correlate with clinical outcomes. I have the reference at the bottom. Another very commonly used biomarker for fibrosis is the ELF score. Again, while the mean ELF score at baseline was almost identical, 10.6, more patients progressed with a higher ELF score of 13 and above on placebo compared to belapectin. Those cutoffs are based on the ELF-approved label by FDA.
Similarly, patients who had a higher ELF score, now 11.3, means they have cirrhosis. Again, ELF cutoff based on the label. There were nearly twice as many patients in that cohort who developed varices on placebo compared to the 2 mg cohort. These are very encouraging results for us, meaning the sicker the patient population, potentially the most benefit patients can accrue from belapectin therapy. In terms of safety, our safety profile seems very favorable. The overall incidence of adverse events and serious adverse events was similar to placebo. We have not observed any systematic toxicity or dose-limiting adverse events in our program. In fact, there was not a single drug-related SAE or drug-induced liver injury reported in the entire program. To conclude, the 2 mg dose in the NAVIGATE trial showed significantly reduced incidence of varices in the per-protocol population.
The key biomarkers for fibrosis, such as LSM and ELF score, mirrored the clinical findings. Our safety profile is favorable and comparable to the placebo cohort, and there seemed to be a synergistic effect with GLP-1 therapy in the patients who received that, predominantly in the U.S. population. Based on the strong foundation of the clinical and the biomarker data, we're actively advancing our discussion with the regulatory agency to discuss the next steps in the program and at the same time exploring partnership opportunities to help bring this therapy to our patients. With that, thank you again for the opportunity.
I just want to say thank you, Joel and Khurram, for the presentation. If you have any follow-up questions, please follow up after the presentation, possibly in the hallways of Galectin Therapeutics. We want to take a moment to thank everyone, particularly our presenters, for attendance this year, and we appreciate it. Thank you again.
Thank you.
Thank you.