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

Good afternoon, ladies and gentlemen, and welcome to the Galectin Therapeutics conference call to discuss the initiation of the adaptive Phase IIb/III belapectin clinical trial, the NASH-RX trial. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to hand the conference over to Mr. Jack Callicutt, CFO of Galectin Therapeutics.

Thank you, and good afternoon. I'm Jack Callicutt, Chief Financial Officer of Galectin Therapeutics, and I'd like to welcome you to our conference call to discuss our NASH-RX clinical trial. Joining me this afternoon are Joel Lewis, CEO and President; Dr. Harold Shlevin, a member of our Board of Directors, currently a Consultant to the company and our former CEO and President; and Dr. Pol Boudes, our Chief Medical Officer. Before I turn the call over to Joel, I'd like to remind you that certain comments made during this conference call, particularly those anticipating our future financial condition and results of operations, results of clinical trials and our strategic plan, constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements, by their very nature, are subject to certain risks and uncertainties that may cause actual results, events and performance to differ materially from those referred to in such statements. These risks and other risks are discussed in our Securities and Exchange Commission filings, including our Form 10-K for the year ended December 31, 2019. A transcript of this presentation will be made available on our website. I would now like to turn the call over to Joel Lewis.

Thank you, Jack, and to everyone joining us today. My name is Joel Lewis and I'm honored to be the CEO and President of Galectin Therapeutics. Before we go any further, I want to take the time to specifically thank and acknowledge several groups of people. First and foremost, I want to thank the investigators and patients who participated in our Phase II trial. And in advance, I want to thank the investigators and patients who will participate in our NASH-RX trial. Simply stated, without your commitment, there is no way we would be where we are today, nor would we have a future. In early-stage biotech, we spend a lot of time analyzing. We analyze everything, including our research, funding, trial protocols, cost projections, competitive landscapes, too many things to mention on this call. However, in its essence, every single analysis is driven by data. And without the patients and investigators and their commitment, there is no data. Actually, I've already discussed my goal of increasing our exposure to NASH patients and advocacy groups with our Chief Medical Officer, Dr. Pol Boudes. And I personally invited some of them to this call today. Hopefully, you were able to join us. With that said, I also want to thank our coprincipal investigators, Dr. Naga Chalasani and Dr. Stephen Harrison. I think it's safe to say that in recent months, we all have a renewed respect for FDA registration trial and the important role they play in discovering innovative therapies. What is probably less understood is that innovation is not only discovered in preclinical lab setting, it is driven by clinical trial design. New drug approval is solely dependent on the power of data derived from an adequately designed regulatory trial. We believe our collaborative efforts with Dr. Chalasani and Dr. Harrison resulted in a protocol that gives us the best chance to achieve that goal. Finally, I wanted to acknowledge that our collaboration would not have been possible without extensive input and appropriate challenge from the FDA. Designing a trial with the goal of addressing an unmet medical need demands critical oversight. The importance of that oversight becomes amplified in a protocol designed to replicate a subset analysis into large patient cohorts, which then, if successful, adapt into an even larger Phase III trial. Among many enhancements, the comments we received were instrumental in reducing subjectivity by utilizing centrally-read test results and improving patient safety by reducing invasive procedures. We are grateful to FDA for the comments we received and for working with us through iterations of the protocol. Our goal for the call today is to allow everyone participating to hear directly from our new Chief Medical Officer, Dr. Pol Boudes, and to get a better understanding of our innovative trial. Additionally, Dr. Harold Shlevin will speak about his transition and his commitment to the successful enrollment of our trial. Finally, we will spend some time answering your questions. However, on a personal note, I want you to hear directly from me. I urge you to read my comments in our September 2 press release, which you can find on our website. What I want to say today is simply this. I'm excited. We are entering a trial with a clinically relevant endpoint, progression to esophageal varices using endoscopy. Not only is that endpoint easy to understand, it's already part of the standard of care for NASH-cirrhotic patients. There are potentially no liver biopsies unless one is required to diagnose NASH-cirrhosis before entering the trial. However, many NASH-cirrhosis patients have already been diagnosed through biopsy confirmation, and it will not be necessary to repeat this invasive procedure. We also don't need to perform HVPG as we did in our Phase II trial. HVPG, which measures portal pressure, is difficult for patients for many reasons. It's invasive and uncomfortable, but more importantly, it's not part of standard care for NASH-cirrhosis. Not having this procedure as part of our trial is a big advantage for patients and investigators. While anyone would be enthusiastic about running a biotech ending a Phase II -- entering a Phase IIb/III adaptive trial with an endpoint easily articulated to patients, investigators, potential partners and investors, excitement from my perspective requires more. I'm also excited for 2 additional reasons: our science and our people. Galectin, and specifically Galectin-3, have been implicated in many diseases. Dr. Boudes will discuss the mechanism of action with our compound, belapectin, in NASH-cirrhosis. Additionally, as you may be aware, there's an investigator-initiated trial currently being conducted by Providence Portland using belapectin in combination therapy with KEYTRUDA in both melanoma and head and neck cancer patient. I personally believe more research is warranted to expand our understanding of Galectin inhibition, and I want to echo our Chairman's sentiments from his May 10, 2019, letter, his goals and my goals. The best way to realize the full potential of belapectin is to fully enroll and analyze our NASH-RX trial. In the past few months, I have not only gotten a better understanding of the detail involved in conducting a large registration trial. I am fully aware of the expertise and commitment necessary for success. One of the silver linings of not being able to travel is the greater premium placed on regular formal communication. Every morning, we conduct a web-based conference call with every employee. While you can't hear those calls, what I will tell you is I'm beyond impressed with every single person. The collective ability of every team member to collaborate via web conference and move between 50,000 foot strategic planning down to 1,000 foot level detail is simply inspiring. While I've always been impressed by our small group and their ability to achieve goals beyond their number, my confidence in their ability has far surpassed my expectations. Combined with our Board, including its 2 new members, Rick Zordani and Dr. Elissa Schwartz, I am truly excited about our team. And I could tell you that besides being honored to be in my role, I'm fortunate to be in it. I do want to comment on one thing from our recent press release. If I did not fully believe in the company, there is simply no possibility that I would have suggested that 80% of my compensation be paid in the form of stock. Some of the CEOs I admire the most align themselves with our company's success. Not only am I excited about the company, I believe we will succeed. An overview of our company is on Slide 5. Our NASH-RX trial was launched this year in June and the first patient was randomized in August. I am sure you all know that the NASH market is projected to be huge in coming years. We are very encouraged by the results from our preclinical studies and most recently the NASH-CX trial, which will be covered a little later in the presentation. Additionally, we have a significant patent portfolio covering both composition of matter and methods of use in many indications in the U.S. and in other countries around the world. Finally, we are fortunate to have a very dedicated, qualified and experienced management team. I believe the qualifications of our management team speak for themselves, and I truly enjoy working with each of them. I want to reiterate the Board and my thanks to Harold Shlevin for his leadership of the company over the past few years. And now I will ask Harold to make some comments. Harold?

Thank you, Joel. Leading Galectin over the past several years has been a privilege, and my time at the company has been extremely rewarding on both a personal and a professional level. However, none of this would have been possible without the dedication and commitment of our team. I want to thank each of them for their past efforts and their commitment to the future of our company. We have made significant progress over the past few years so that we are now enrolling patients in our NASH-RX trial. It is underway. As you will hear many times in this call, the goal of the trial is to illustrate that our drug, belapectin, has the ability to prevent the development of varices for NASH patients with compensated cirrhosis. There are numerous NASH drugs at various stages of development, but very few, if any, are targeting the compensated NASH-cirrhotic patient. Patients with compensated cirrhosis are at an advanced stage of liver disease, and many of the approaches that may stop or prevent progression of early-stage NASH, such as the change of diet or an increase in exercise, are not effective in these patients. Since there are no currently approved therapies for this condition, these patients frequently advance to decompensated cirrhosis, where the only hope of a cure is a liver transplant. So we are targeting a population on the spectrum of the progression of NASH, where the medical need is indeed the greatest. Unlike many of the trials in the NASH space, we are not relying on a biopsy-driven endpoint, which can be difficult to interpret. Rather, based on data flowing from our NASH-CX trial, our endpoint is to prevent the development of esophageal varices. We have confidence in this endpoint as a result of the Phase II NASH-CX trial results, which demonstrated the ability of belapectin to prevent the development of varices in patients with NASH-cirrhosis who did not have varices upon entering the trial. Preventing the development of varices or slowing the development of large varices, which can be complicated by life-threatening bleeding, is where we are focused. If we are successful in demonstrating this, it would indeed be a major medical breakthrough and more in which we feel would be well accepted by the medical community as being clinically relevant. This is not only innovative and exciting but it is why a career in the pharmaceutical industry is so personally satisfying, as you get to help people each and every day. I feel now is the right time for me to relinquish the reigns of management of the company and enter retirement, which is something that I have wanted to do for several years. At the same time, I made a commitment to the company to stay through the start of the new trial, and I believe in honoring my commitments. I could not be more thrilled that Joel has agreed to take on the CEO role. Having worked with Dick and Joel over the past few years, I am extremely confident the organization will be guided by strong and accomplished leadership. Joel has both the vision and the passion for helping patients and to see this trial through. While I am entering a new life phase, I will remain on the Board as well as continue to be intimately involved in the trial as an active consultant. I agreed to take on this consulting role to help assure rapid start-up and execution of the trial through full patient enrollment, and importantly, to help assure a smooth transition of the leadership reins of the company to Joel. On a personal note, retirement will allow me to spend more time with my wife, Barbara, both at the beach and eventually returning to our favorite pass time of traveling and cruising. So with that, let me turn the call over to Pol, who will walk you through the characteristics of belapectin and its mechanism of action and the results of our Phase II trial, and the design of our NASH-RX trial as well as share with you his personal passion for what the company is doing. Pol?

Thank you, Harold. And thank you for your leadership and your continued commitment to the success of the belapectin program. So what is belapectin? And how does it work? Belapectin is a potent Galectin-3 inhibitor. It targets and disrupts the function of Galectin-3, a major player in the progression of inflammatory and fibrotic diseases. As shown on the left-hand side diagram, Galectins constitutes a family of proteins and Galectin-3 is the most important of them. It acts as glue or a binder, if you prefer, and promotes cell-to-cell interaction and cell-to-matrix interaction. By doing so, Galectin-3 brings all the actors of inflammation and fibrosis together. We know, for instance, that Galectin-3 is up-regulated in human fibrotic liver diseases and we also know that the disruption of Galectin-3 markedly reduces liver fibrosis. This has been demonstrated in Galectin knockout models and in animal models of fibrosis when treated with belapectin. On the right-hand side is the depiction of the central role played by Galectin-3, represented in green in the illustration, on inflammation and fibrosis. An important player to note is the macrophage. First, because this cell is the main producer of Galectin-3. Second, because macrophages, whether a resident in the liver and they are then called Kupffer cells, or recruited from the circulation, are activated in cirrhosis. And third, because belapectin is captured and absorbed by macrophages, and thus can reach its target in the liver parenchyma and inhibit Galectin-3, also at its site of production. Currently, there is no medical treatment for NASH-cirrhosis. The only option is a liver transplantation. We all know the inadequacy between the availability of livers and the number of patients listed for transplantation. We also know that with the current NASH epidemic, the problem is only going to get worse. There is a continuum of progression from fatty liver to NASH to cirrhosis. NASH could be stopped before the cirrhotic stage, either through lifestyle and diet changes or medical therapies. Most of our competitors have clinical development programs that are indeed targeting the early stages of NASH using liver biopsies and histologic readings at the main outcome of efficacy. In contrast, we are targeting NASH at the cirrhotic stage. Notably, we do this because we think this is the stage where the medical need for our treatment is the most pressing. Furthermore, results from the NASH-CX trial indicate that we may be able to prevent the progression of the disease for this patient group. Cirrhosis can be divided into a compensated stage and a decompensated stage, as depicted on the slide. This staging is mainly driven by the development of portal hypertension. Portal hypertension is an increase in the portal vein pressure that is explained by the degree of fibrosis that is present in the liver. The portal vein drains the gastrointestinal blood into the liver. There, this venous blood is processed, detoxified and assimilated in different nutrients. In cirrhosis, the liver becomes fibrotic, stiff, if you prefer, and it offers resistance to the venous flow. This venous blood then stagnates in the portal vein, the portal pressure increases, and this increased pressure itself will also rupture the venous circulation in other organs. One of the most dangerous consequence of this phenomenon is the development of esophageal varices, as illustrated on the images on the right-hand side of the slide. A normal portal pressure is less than 5-millimeter mercury. When the portal pressure is raised between 6 and 10 milligram approximately, generally no esophageal varices are present. When the pressure increase above 10, then small varices appear as you can see on the image at the center. With further increase in portal pressure, varices become larger and larger and potentially rupture and lead to severe internal bleeding as illustrated on the image on the right. It is evident that such bleeding is immediately life-threatening, which explains, in part, the decreased survival of such cirrhotic patients who have reached this stage of the disease. What we are trying to achieve in the NASH-RX trial is to prevent the development of esophageal varices in patients with compensated cirrhosis or as mentioned on the slide preventing the progression of the disease from stage 1 to stage 2. With that background, let me review our previous clinical trials with belapectin. This trial, also known as NASH-CX was both a proof-of-concept to demonstrate the efficacy of belapectin in compensated cirrhosis and a proof of concept for choosing the appropriate outcome measure of efficacy in future studies. The study was randomized, double-blind, placebo-controlled in a large number of cirrhotic patients, 162, who were dosed with either a placebo 2-milligram or 8-milligram infusion of belapectin, administered every other week for 26 infusions over 1 year. The patients enrolled were diagnosed with NASH-cirrhosis, and this was documented by a liver biopsy. That cirrhosis was at the compensated stage, and their portal pressure was above 6-millimeter of mercury, which meant they had portal hypertension. For this portal hypertension to be documented, we asked patients to have their portal pressure directly evaluated by measuring the intravenous pressure with a catheter inserted in the different places in their hepatic veins. This is an invasive procedure that can only be performed in highly-trained hepatology centers. We also performed esophagogastroduodeno endoscopy to record the presence or absence of esophageal varices. At baseline, approximately half of the patient had varices and the other half had no varices. Our main objective was to see whether belapectin, through its documented mechanism of action, could decrease portal pressure in patients with NASH-cirrhosis. We were also interested to see whether this effect, if present, could be translated into a positive outcome on esophageal varices. The results of the trial are presented on Slide 12 and they were both comforting and exciting. The belapectin 2-milligram group demonstrated a statistically significant reduction in portal pressure from baseline to week 52 when compared to placebo. The change in the placebo group were, as could be expected, with an increase of nearly 1 millimeter in portal pressure over a 1-year period. This is consistent with the progression of the disease. The 2-milligram belapectin group saw a decrease in portal pressure, slightly above 1 millimeter, for a differential of around 2 millimeter with the placebo group. The 8-milligram groups also saw a trend in decrease in portal pressure, but this was not statistically significant compared to placebo. This slide translate in clinically relevant way as a consequence of decreasing portal pressure with belapectin. Over 1 year for patient presenting with no esophageal varices at baseline, significantly fewer varices developed in the belapectin 2-milligram group compared to the placebo group. The size of the effect was also notable with 18% on placebo developing varices, but no patient on belapectin developing varices. This translates into a 100% reduction in the number of patient developing esophageal varices. We believe this difference highlights a striking effect size that defines our next step in the belapectin program. In summary, in patients who have not yet developed varices, the decrease in portal pressure seen with belapectin was associated with the prevention of development of esophageal varices. Let's summarize the medical landscape for patients now that went through the results of the NASH-CX trial and show that belapectin has demonstrated efficacy in the clinically meaningful endpoints where no current therapy exists. We know that portal pressure gradient greater than 10 milligram -- 10 millimeter, sorry, is associated with increased risk of decompensation and mortality. Furthermore, for patients with compensated cirrhosis and portal hypertension without varices, there are no specific therapies indicated for -- either for reducing portal hypertension and/or directly treating the underlying liver disease. Beta blockers may improve outcomes in patients with portal hypertension and varices, but likely do not prevent the development of varices or disease progression in early-stage cirrhosis patients. As a consequence, practice guidelines, whether in U.S. or in Europe, do not recommend beta blockers for the prevention of esophageal varices in these patients. Belapectin was safe and well-tolerated in NASH-CX trial. For instance, we only saw a dropout rate of 6% over 1 year of treatment, which suggests the drug was well-tolerated in this patient population and patients were adherent. Overall, these results provide strong rationale for our next step, the NASH-RX trial, notably for the selection of the primary endpoint of prevention of varices. In summary, NASH-CX was the first clinical trial to show positive results in the compensated NASH-cirrhosis without esophageal varices, while demonstrated a reduction in portal pressure in a relevant subgroup of patients, an improvement in liver cell death, also called ballooning of hepatocyte on liver biopsy, which is a key component of NASH, and prevention of new esophageal varices. We took these results to discuss our next step with the FDA. And ultimately, the agency indicated its support for "progression to varices as a surrogate endpoint, while progression to large varices or to small varices with a red wale as a component of a composite clinical benefit endpoint." Having identified the surrogate endpoint opened the door for designing a trial with the objective of a drug approval. This also gives us really the identifiable population of potential patients. Based on our experience, we estimate that 50% of cirrhotic NASH patients do not have varices when first diagnosed. It is also important to recognize that contrary to liver biopsies in non-cirrhotic patients, the assessment of varices is also part of the standard of care in these patients and can easily be assessed with an endoscopy. We can design a trial that matches clinical practice. Last, further awareness of NASH should increase the number of cirrhotic patients who will want to prevent the development of varices. Let's now move to the registration trial. The NASH-RX trial is designed to confirm our previous findings in a larger study and can lead to the registration of belapectin. And for that, we choose a seamless adaptive design. So to recap, the patient population will be patients with compensating NASH-cirrhosis. These patients are at the greatest immediate medical need. Currently, this population is not the primary target of most drug developers. We're focused on the prevention of NASH-cirrhosis using liver biopsies as an efficacy endpoint. We have designed in collaboration with our leading NASH experts an innovative, seamless adaptive Phase IIb/III clinical trial. Seamless means this trial was transitioned from Phase IIb to Phase III without interruption. Adaptive means that potential modification has been included upfront and changes to the design will not necessitate we amend the trial protocol. This is something that is always challenging and requires a lot of time, especially for a global trial because amendments need to be approved by ethics committees and regulatory authorities around the world. Potential changes are based on accumulative information, and these adaptation gives us a lot of flexibility. Progression to varices is a potential surrogate endpoint and will be the primary efficacy outcome of the study. As a surrogate endpoint, this can be the basis of an accelerated approval. The progression to large varices itself can be a component of a composite clinical endpoint. The Phase IIb portion of the trial will include 315 patients, 3 group of 105 patients, a 2-milligram and a 4-milligram belapectin groups and a placebo control group. I will now move into the next slide, which represents a schematic description of the trial. Unlike most of the clinical trial focused primarily on earlier stage of NASH, the NASH-RX trial study population will comprise patients with compensated liver cirrhosis who have not yet developed esophageal varices but are at increased risk of disease progression because they have clinical signs of portal hypertension, such as the depressed platelet count, which is called thrombocytopenia and enlargement of the spleen, which is called splenomegaly or an evidence of collateral vessels. Using clinical sign of portal hypertension instead of using an invasive technology to measure portal pressure will be much more convenient for patients and for investigators. All the patients will have an endoscopy at baseline to confirm the absence of esophageal varices. The first part of the trial will last 18 months, and we will repeat endoscopy at 18 months to see what developed the varices. When we have the data from the 18-months endoscopy on the last Phase IIb patients, we will have a blinded interim analysis, run by an independent group. At this point, if we reproduce the results we had seen in the previous trial, the positive risk-benefit of belapectin would be overwhelming and we might have to offer belapectin treatment to all of patients, including those in the placebo group. That would be an ideal scenario. If the result trends in the right directions, based on conditional probabilities, we will move into the Phase III and only select the best dosage of belapectin. While the patients in the Phase II arms will continue into the Phase III arms, we will need to recruit additional patients as well. These new patients will follow the same process as the Phase IIb patients, with an endoscopy at baseline and an endoscopy at 18 months. At the close of the Phase III trial, we will combine the 2 phases of the study and run the final analysis with a large set of 18-month data. Also because the Phase IIb patients will have continued their treatment for a total of 36 months, we will have important additional long-term safety data and additional descriptive efficacy data. Overall, based on our original scenario, we will have a little more than 500 patients in the NASH-RX trial. And based on the different adaptation, this could be increased. By focusing on the development of esophageal varices, we will have a clear objective measure of our results and the clinical significance of these results will be self-evident. This is an important point because many trials in the NASH space are using liver biopsies at the endpoint, which are difficult to interpret in terms of clinical relevance. So as a summary of the NASH-RX trial, the first patient was screened in June of this year. The first patient was randomized in August. It will be a global study. Overall, for the Phase IIb/III, we are planning upfront 100 -- 525 patients of approximately 130 sites in 12 countries, in North America, Europe, Asia and Australia. The Phase IIb part leading to the interim analysis will include approximately 315 patients. We estimate that the recruitment of these 315 patients will take between 12 and 14 months. The key inclusion criteria are highlighted here. The interim analysis for the Phase IIb is expected to be available approximately Q2 2023. The goal of our study is to be able to file for an accelerated approval. For that objective, we will have 2 shots on goal. The interim analysis will give us a first shot at the conditional approval, and we will have a second shot with the Phase III portion of the trial. The efficacy data that will be available are mentioned below. You will notice that whether primary or secondary, the endpoints that we are targeting will be directly clinically relevant. We will not have to translate the results of liver biopsy using the grading of NASH or the grading of fibrosis into a clinically irrelevant study. Primary endpoint will be the development of new biopsies. For this primary outcome, we have put in place a centralized review system of video recording of esophagogastroduodenoscopy. The primary endpoint, the presence or absence of esophageal varices will be adjudicated by expert endoscopies readers. This will help to eliminate viability in the assessment. The secondary endpoint will be the proportion of patients with large varices or red wales, the varices requiring treatments, decompensation events of cirrhosis, all-cause mortality, increase in the MELD score, liver transplant, and we will also look at some biomarkers. An adjudication system will also validate key secondary endpoints such as the type of varices, for example, their size or the fact that they are bleeding or not bleeding or the diagnosis of a cirrhotic decompensation event. Now let me turn the call back to Joel for some additional thoughts and closing remarks. Joel?

Thanks, Pol. We believe we have an innovative trial design and an experienced team running our trial. A positive result will be very clinically relevant. If the trial shows that belapectin is effective and safe, it will be a medical breakthrough for patients with NASH-cirrhosis. So just to summarize, NASH-cirrhosis is a major unmet medical need with a large potential market. The belapectin NASH-CX trial is the first positive Phase II clinical trial in a subset of patients without esophageal varices. Belapectin was both safe and well-tolerated and improved portal pressure in that subset and it also reduced development of esophageal varices. Galectin Therapeutics is competitively well-positioned in the industry. We have a large experienced global CRO conducting our trial. As Pol mentioned, the first patient was enrolled this June. And we believe that the interim analysis will be complete in Q2 of 2023. Belapectin is also being evaluated in combination cancer immunotherapy at Providence Cancer Institute. Galectin-3 is important in cancer immunity with encouraging early clinical results at Providence Portland. There is a large potential to improve results of cancer immunotherapy. That trial is continuing with the results of the extended cohort expected late this year. The liver and specifically NASH was our first target due to the tremendous unmet medical need for treatment of NASH-cirrhosis. Success in NASH-cirrhosis opens new treatment possibility for belapectin's use in other types of liver cirrhosis and in other forms of organ fibrosis affecting kidney, lung, as well as other organs. Once again, I want to thank everyone for listening this afternoon. And that will conclude the formal part of our presentation. And now I'm going to turn the call back to the operator to take some questions that -- some we've received in advance and we're anticipating some others.

[Operator Instructions] Our first question comes from the line of Ed Arce with H.C. Wainwright & Company.

Let me first add my congratulations to Joel for his new role and best wishes to Harold on his retirement. First question is around the primary endpoint you've discussed in some detail, the prevention of the development of esophageal varices as that primary endpoint. And so I'm wondering if you could discuss given how varices are measured and diagnosed via the duodenum endoscopy, how you're going to work to minimize any sort of variability around that measurement and diagnosis, especially any sort of intra-patient or intra-operator variability, if there is any of that to any significant degree and especially in the follow-up measurements, where there might be some early formation of varices that might not be that easy to detect?

Thanks, Ed. That's a great question. First of all, thank you for the congratulations. And thank you. That was a great question. I'm going to let Pol handle that one. Pol?

Yes. Ed, yes, very good question. I think the underlying fact is that in a pivotal trial, you are trying to make sure that what you measure is measured well, and there is no viability or at least a minimum viability. So for esophageal varices, what we have done, Ed, is to put an adjudication system in place. So the good thing is that you can -- when you do the endoscopy, you can film what you see. You can also record the film and even stop when you have a structure, you want to have more details on. And so what we're going to do is -- what we are doing actually is that we use the film of the endoscopy. We send the film to a central location. And then the film are going to be dispatched to readers, and we have actually 2 sets of readers. So our readers needless to say are very experienced endoscopist, and so we will have a first reading with the first reader. And then the film goes to a second reader and there is a second read. And if the 2 readers agreed, then this is the diagnosis, if you want. Then potentially in case that are a little bit more difficult to diagnose or to make some details about exactly the size of the varices, then we have potentially a third reader and then there will be an adjudication. So I think this system is a very powerful system because there is also a trace. And, for example, if some people have some doubt about what we have done, we can even send the videos to other people to review it if there's a necessity to do that. So we're also doing -- all readers are very, very well trained, but we have also things to facilitate their reading. So we have a class of pictures, if you want, of small varices, medium varices, large varices, all these kind of things. So I think the system is very powerful. And just to come back to what you were saying, I think it's a necessary system also because we want to make sure that we decrease the variability of what we do.

Great. Second question is how -- if you could, discuss how you plan to isolate the benefit of belapectin from any potentially confounding effects from beta blockers, especially given that many of those patients are likely to be on that through the trial?

Maybe I can take this one. So the fact is that the beta blockers are not indicated for this population, patients who do not have varices or even small varices. So in general, our experience is that it will not be a confounding factor. And what we are requesting in the trial is not to be on beta blocker, actually. So we don't think it's going to be a problem because this is not a population where the guidelines are recommended beta blockers. It's different for a more advanced population. So for example, when you have developed large varices, this is where the cardiac nonselective beta blocker actually are recommended. And -- so I don't think upfront that it will be a confounding factor because that's not the population we're looking at.

Okay. So just to be clear, in the patient population that you're looking at in compensated cirrhosis, these patients on beta blockers would basically be -- hit the exclusion criteria for the trial?

Yes. And we do not expect to have many cases like that because the beta blockers are not recommended in this population.

Right. Okay. Fair enough. One more and then I'll just jump back in the queue. It's been a good while now since the initial readout, as you know, of NASH-CX. And I know at the time and for a little while after, there was some degree of work to try to understand why the 2-milligram per kilogram dose did work in patients without varices at baseline, but the larger 8-milligram per kilo dose did not. And so I'm just curious, given it's been probably 2.5 years now since then, if you've come to develop any sort of further insights into why the mechanism of belapectin works in what apparently is more of an optimal dose than a more typical dose response?

Pol, would you like to take that one, too?

Maybe I'll give it to Harold because I know this is a question that has been asked before. And maybe I can add, depending on -- maybe I can add my pitch on this one, if you want.

Great. Harold?

Yes. Thanks, Joel and Pol. So, Ed, as you probably may recall, the results we observed in the clinic mirrored those that we observed in the preclinical animal experiments, right? In that the efficacy variable, no matter what it was, was diminished when the dose was increased above a certain level. Now in designing the original NASH-CX trial, we extrapolated the PK estimates from both the animal experiments, but more importantly, from the pharmacokinetic experiments, which were done in patients with advanced fibrosis but not cirrhosis, right? And what we observed in the cirrhotic population was that the overall systemic exposure of patients to the drug was higher than we would have projected. That's, in part, the rationale for why in this NASH-RX trial, we've lowered the dose. We've also begun to explore, in greater depth, the distribution of the drug and its handling by cirrhotic livers, and we're not ready to present that information yet. But we're also doing, for example, a separate hepatic impairment study, which is a single dose at 4 milligrams in patients with mild, moderate and severe cirrhosis. It doesn't necessarily have to be closed by NASH. And that trial will also come together well before the interim analysis and help further inform about the pharmacokinetic handling of the drug. Does that help a little bit?

Yes, it does.

Great. What I'm going to do in the limited time we have left is we've tried to accumulate some questions, some that have sort of the same theme. So I'm going to try to do my best. Two of them, I'm going to try to combine in my comments upfront before I turn it over to Pol. So one of the questions that we're sort of pulling? Again, there were a lot submitted. Many recent publications on Galectins and their implications in multiple diseases, including other fibrotic diseases and potentially COVID-19, and will the company pursue any of these? And then another question, where my answer is going to overlap and maybe Pol's will, is what's -- since I'm mentioning COVID-19, what's the impact of COVID-19 on our NASH-RX trial? So as the new CEO, I just want to kind of give a broad view of what one of my early goals is. I mentioned earlier in the call that patient outreach is important. And I think that goes into, number one, COVID-19, in general, because we all have to be somewhat flexible, right? We're all on the call now when we can't travel. And so far, that hasn't interrupted our recruitment curve. With that said, I want to make sure that I drive people to, number one, our website, but really just to drive overall communication about Galectin Therapeutics. And that's important on many levels. I want to engage patients, patient advocacy groups, clinicians, researchers, investigators. And to do that, we have to be part of the conversation. I don't know how anybody could discuss a NASH trial without us being part of the conversation. And with all the research that's coming out on Galectin-3 and its implication in many disease mechanisms, I also don't know how we're not part of that conversation. Last year, we redesigned our website, and I'm going to use that to our advantage. I know many of you send me articles all the time. Thank you for doing that. We're going to look at -- first of all, we do look at those articles. We pay specific attention and care the most about peer-reviewed articles. We're a scientific R&D company. So we have to look at peer-reviewed articles. Otherwise, there's a new one every week. But we're going to try to get that research onto our website, and I want to engage everyone in the discussion. And that ranges, like I said, from patients, advocates, all the way to analysts, right? We need to be part of the discourse. So I realize that's a broad answer. We didn't have too much time. So I wanted to try to combine 2 questions. But I'm going to turn this over now to Pol and Harold, Pol first, to talk a little bit about the other disease mechanisms, we have mentioned some of them in our discussion today. So Pol?

Yes. There is a lot of science going around Galectin-3. And of course, we are very interested in following the science and seeing what is happening. In a way, it reminds me a little bit about what happened some years ago with the FXR agonist mechanism that was kind of new and people were discovering things. I think Galectin-3 is the same kind of situation where there is more and more science. Actually, the mechanism of action is really fascinating because it seems really to be a central player in things like fibrosis and inflammation. And I'm saying fibrosis and inflammation because as most people realize or do not realize, but chronic inflammation by itself also trigger fibrosis. Now to come back to the clinic, what I think is fascinating, is to see the connection between the decrease in portal pressure and the clinical translation of this effect. Because this is very consistent and very logical. Now if we are able to confirm that in the NASH-RX trial, this opens the door to a lot of things because this antifibrotic effect has been something that has been pursued for quite some time now. The first immediate consequence, of course, is there are other type of cirrhosis. NASH is not the only reason why people are getting cirrhosis. And there will be an immediate translation, if you want, is that also the case, for example, alcoholic cirrhosis or other type of cirrhosis. Now when you add something that is working in a liver disease and it's an antifibrotic mechanism of action, there are other organs that are now in need of antifibrotic treatment. My personal bias is to go to the kidney. And the reason is that I'm also a drug developer, and kidney is a good organ for registering a drug because you have an overall function of the kidney that you can study, which is called the glomerular filtration, the estimated GFR, and this is an accepted endpoint by regulatory authorities. So that's a nice thing. But it's not the only organ. I think the lung also the -- is an organ that is affected by chronic fibrosis, but there are other organs. So I think it's going to be a kind of a very important moment because there could be translation to other clinical program, actually. So the medical benefit can be expanded to other disease that are currently very difficult to tackle. I'd just say a word on COVID and the way we are conducting the operation. I think in a way, we were lucky because we didn't start the trial right at the moment where COVID started because I think that created a lot of uncertainties and people didn't really know a lot about COVID. So I think we were lucky in a way because what we know about COVID and its transmission at the moment is far more important than what we knew at the beginning of the year. We know how to stop the transmission. This is something we didn't know before. So that has implication for the way we manage patients, the way they can visit the center, all this kind of thing. So that's very, very important, and we are dealing with the situation. I mean it's on a case-by-case basis because the center -- the problem in the center might not be the same problem in another center. So we are dealing with the situation as we go, and we are trying to apply solution at the center level, investigators level. And so far, I would say, it's going well. It doesn't mean that we are not going to get problem in the future. But personally, I'm a big believer in vaccines, have always been a big believer in vaccine. So I think, hopefully, this problem is going to be behind us in the near future.

Great. Thanks, Pol. Harold, I don't know if you wanted to comment at all on that. Pol spent a lot of time on it, but I did want to get one of the other questions that was a commonly asked question, was about our cancer trials at Providence Portland. So if you wanted to add anything about COVID or other disease mechanisms, great, but really I do -- before we close because we're pretty close to the end, I just wanted you to touch on our cancer trial at Providence Portland.

Yes. Joel, I'm happy to do that. Just a quick refresher for people. It reflects kind of how we do our science at Galectin as well. We have given out, over the years, the compound to various excellent worldwide investigators because having a Galectin-3 inhibitor in your hand is kind of pretty neat asset to have as a pharmacological tool, which basically nobody else has or is willing to give out. And so we gave it to Providence Portland because they had some good science and rationale for studying the impact of checkpoint inhibitors in preclinical models, together with the Galectin-3 inhibitor. And they've now shown pretty conclusively that in a variety of preclinical animal models across a variety of solid tumor types, that the combination is synergistic in terms of impact on tumor size and tumor progression. Providence is mostly about translating to the clinic. So they took their observations under an investigator-initiated IND with our support into the clinic and they've reported a little bit more than about a year ago now, the first handle of results, which were very encouraging. We had over a 50% objective response rate across the various 3 different doses they tried of the drug. And we asked them to continue the studies, which they were interested in doing as well, into an additional cohort to add to the numbers, right? So that we'd have a sufficient amount of information and massive information to make a reasonably good assessment as to whether or not there was something here that should be pursued from ultimately a commercial standpoint, but that could bring benefit to patients beyond any single checkpoint inhibitor alone. And that's what we call the extension trial, the Phase I trial. They are still on target to report results from that by the end of the year. And I'm pretty encouraged that they will do that. The -- assuming that those results, when combined with the earlier results, remain very positive, that would justify going into what would be a multicenter Phase II trial looking at any one of the indications, which will be either melanoma, more likely and/or head and neck cancer. Head and neck cancers are more resistant to the treatment with checkpoint inhibitors than melanoma, but even with melanoma and despite the great success that agents like OPDIVO, YERVOY, KEYTRUDA and many other compounds, right? The objective response rate amongst the best published data is only on the order of 33%. And in their initial results, we saw objective response rates of 50% in 7 out of 14 of the first patients. So we remain optimistic about that. But as Joel said at the beginning, we are data-driven. And so we have to wait on the results from Providence, and we should hopefully know before the end of the year.

Great. Thank you very much, Harold. So at this point, I'm going to turn it back over to the operator. I want to thank everybody for participating today. I was actually very happy to see the number of participants, and I look forward to speaking to you all again soon. Operator?

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.