Gossamer Bio, Inc. (GOSS) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the Gossamer Bio GB004 Investor Day Conference Call. [Operator Instructions] I would now like to hand the conference over to your speaker today, Faheem Hasnain. Please go ahead, sir.

Welcome and thank you to all of you who are joining us today on the webcast. This is a second in a series of 2 webcasts to highlight the promise of what I've been calling priorities 1A and 1B for Gossamer. The 2 clinical assets that are currently marching through their respective proof-of-concept Phase II clinical trial, seralutinib also known as GB002 for the treatment of pulmonary arterial hypertension and GB004 for the treatment of inflammatory bowel disease. In case you weren't able to join us in December, our seralutinib webcast is archived in the past Events section of our Investor Relations website. Now we've got a great agenda today for our GB004 Investor Day. We're grateful and excited to be joined by 3 of the top experts in the field of IBD and cellular physiology and have kindly agreed to share their insights with you. To start, Dr. Bill Sandborn of UCSD will go over the current treatment landscape for patients with UC and where he sees the biggest unmet needs. Dr. Silvio Danese of Humanitas University Milan will then cover how the field is evolving to look beyond Mayo score endpoints to attempt to achieve deeper and more durable remission for patients. And then Dr. Cormac Taylor of University College Dublin will then give you an overview of one of his labors of love for the past 20 years, HIF biology and its relevance in inflammatory diseases such as inflammatory valve disease. Following our extraordinary lineup of experts, the Gossamer team will review the GB004 program before we open up the call to questions. But before we really get going, I want to take an opportunity to set stage and layout customer's vision for the GB004 program. Because I do see this presenting a unique opportunity set compared to other program development. And as many of you know, I and many of the Gossamer team are very familiar with drug development in IBD. The 3 gastroenterologists that led ozanimod's development in IBD at Receptos, 2 of whom you will hear from later, are here with me at Gossamer driving the development of the GB004 program. Now in many ways, I see this as an extension of what we were successful in doing with ozanimod in UC, bringing it an effective oral therapy to a large group of patients in the treatment gap. Those patients whose disease is uncontrolled by 5 ASAs and potentially reliant on steroids, but who are unwilling or unable to go on to systemic biologic therapies. GB004, like ozanimod, is an oral therapy that could lead to better outcomes for these patients who desperately need more treatment options. But in many ways, GB004 has the potential to be a much more revolutionary therapy for the treatment of IBD. GB004 has a differentiated mechanism of action aimed as a promotion and repair of the epithelial barrier. GB004 is also important for what is not. It is not a semicenter in contrast to most of the other therapies available or in clinical development for IBD. Driving more patients towards deeper, more durable disease remission while avoiding the liabilities of systemic immunomodulation is our ultimate treatment goal for GB004. In ulcerative colitis, we see this manifesting itself as an opportunity to establish an oral continuity of care for patients failing 5 ASA therapy and to reduce their reliance on steroids. And with GB004's unique and complementary mechanism of action, plus a potentially differentiated safety profile, we see GB004 as a potential backbone of therapeutic regimens for patients following 5 ASAs across the severity spectrum. And Mario Orlando, from our teams, will give a more in-depth view of this positioning later in the presentation. Our ship UC Phase II study is the first step in achieving that goal. And I'm very pleased with the progress our team has made in getting the study up and running despite the incredible challenges with anemic. We look forward to sharing the top line results from this study in the first half of next year. Now with that introduction, I'd now like to turn the call over to our first presenter, Dr. Bill Sandborn, to provide an overview of the treatment landscape for UC. Bill?

Thank you, Faheem. Welcome, everyone. In next slide, please? All right. So ulcerative colitis is a chronic inflammatory disease of the colon. It presents with a variety of debilitating symptoms, including bloody diarrhea, fecal urgency that can have a profound negative affect on patients. [indiscernible] both of which contribute to a disruption of local immune homeostasis in the colon and you'll hear more about this from Cormac Taylor in a few minutes. [indiscernible] untreated tends to colo-relapsing and remitting disease course and the goal of medical therapy is to induce remission and then maintain remission overtime and professor Danese will talk more about that in a few minutes. It's estimated that about 1 million people in the US have ulcerative colitis a similar number have crohn's disease and the prevalence continues to increase. This is a young age bond set condition and then patients of course age with that and people are living longer. Next slide, please. So let's think through the therapeutic landscape. We have some older drugs which are oral. These include the 5 aminosalicylate or mesalamine drugs, steroids and thiopurines. So let's talk about each of those a little bit. The aminosalicylates. You might know some of the drugs like Asacol and Lialda. They're generic at this point. Quite safe, some very favorable risk to benefit ratio in patients with mild to moderate ulcerative colitis, and there's sort of mainstay of first-line therapy. The oral -- the problem is that from a negative standpoint, about at least 50% of patients are either primary or secondary nonresponders. And many of these drugs were developed in an earlier era when outcomes for lucror. And if were to apply today's outcome lasers to the treatment, the remission rates were probably more in the range of 25% rather than 50%. Steroids work quickly and are also still in use for patients who need a rapid control of symptoms, but they have well-established side effects and cannot and should not be used repetitively or for flown courses. So they're not a maintenance there. And finally, there is a label unapproved use of thiopurines. These include azothiopurine and [indiscernible] they are thought to have some steroids bearing potential, again, not approved. So it's investigator initiated studies. The studies are very old, poor quality. And we've come to understand that there are considerable side effects on these medicines, including a fourfold elevation risk of skin cancer or 4 fold elevation risk of non-Hodgkin's lymphoma, myelosuppression and the infection risk. So lots of side affects. Moving to the right side for moderate to severe disease, we have a number of classes of approved drugs now, the TNF blockers in [indiscernible] adalimumab and [indiscernible] They work pretty quickly. A number of limitations. They're either intravenous or subcutaneous injections, sort of a modest effect on healing the mucosa the black box warnings around serious infections, including herculeses and fungal infections. And then they're quite immunogenic. So loss of response among patients initially respond, you see quite a large rate of patients eventually getting antidrug antibodies. You can block that to some extent by co-administering an immunosuppressive, like cases Bioprint, then you're getting the additive safety kit with the safety problems with TNF blockers plus the safety problems with thiopurines. Then we have anti endocrine therapy with anti alpha 4 beta 7 vatelizumab. Even though this is administered intravenously in the United States, and then there's a subcutaneous version in Europe. It's got targeted, even though it's intravenous, but it is parenteral. And it has quite a good sticky profile and which has made it attractive. And it sort of sets the stage that if you have -- you've got targeted therapies, but you can transition from differential therapy an oral therapy that there's a real sort of need in market for that. We'll hear more about that data. Then we have the anti cytokine ustekinumab, which OCI Nerleukin 12 and 23. It's generally comparable and efficacy to anti-TNF agents. It works in -- to some degree in patients who've previously failed antidrug. It's relatively safe, but it is a systemic and finally, you have an oral class of drugs, Janus kinase or JAK inhibitors. Tofacitinib is -- seems like endlessly in the news for concerns about toxicity. We've just heard in the last week or 2, the final results of the big cardiovascular safety trial, where it showed that both the 5- and 10-milligram doses had risk for base events or cardiovascular events and for malignancy. So it is used in ulcerative fits in patients who have failed biologic drugs. But oral medicines that would have a better safety profile would be very welcome. Next slide. So then we have a pipeline of new agents that are coming along. Faheem mentioned S1P modulators like ozanimod, which are in the upper left, these are oral medicines. They're pretty well tolerated, but I think you have some reduction in lymphoma counts and you can see a reduction in heart rate with the first dose. Some of them have some drug-drug interactions. There's so rare but real risk of macular edema. So there are systemic immune modulating drugs and do have some side effects. In the upper right, interlink on 23 blockade, recall that we have a marketed drug, ustekinumab that Loci Nerleukin 12 and 23 and then psoriasis, blocking interlukin 23 has been better than blocking 12 and 23. We're still seeing this play out in splits. The only data that we have so far is a Phase II study with mirikizumab, where there's estimately an effect compared to placebo, but it looks like there's still going to be lots of opportunity for patients that didn't respond. In the lower right with endocrine [indiscernible], the systemic integrin blockers like anti-Madcam antibody have and anti beta even antibody etrolizumab have either been discontinued or failed in late stage trials. So I think the parenteral energenic locos were really just intend up with [indiscernible] and eventually biosimilar vatelizumab. There are some gut targeted oral strategies that we'll talk about in another slide. And finally, in the lower left, we have Jack and TYK 2 inhibitors. So this is trying to build on the efficacy profile that was seen with systemic JAK inhibition, but see if the safety profile can be cleaned up. So there's TYK2 inhibitors being studied and then of a have inhibitors filgotinib and you've had acitinib. These are still systemically active drugs, and we'll sort of have to see how the safety profile plays out as those drugs report out their Phase III data. Next slide. And then there's an emerging strategy of going for organ specific treatment. And I think GB004 is a great example of that. So you understand the biology of the target around inflammation and/or epithelial barrier function and try to treat it with a drug that is restricted to the gut to improve the safety profile while getting good efficacy. There has been some other strategies that are duct targeted interleukin 22 as a target. These are parenterally administered drugs, so they won't necessarily be -- they're not oral in that sense and could have some off target. People are trying to increase T regulatory sales in the gut with the idea that they will express interleukin 10, which has an inflammation down regulation. So 1 strategy is to enter to administer low dose interleukin 2, others are to directly try and administer interleukin 10 to the COSA. It's early days on those proof of concept, and we're looking forward to seeing any pilot data. There are a couple of strategies of giving oral integrin inhibitor peptides and waiting to see how that plays out. And then people are trying topical JAK inhibitors. So you get the idea that organ specific delivery is becoming a thing. And then really the concept of instead of having all the drugs really being more immune suppressive to try and restore that potential bare function as attractive. And if you can mix organ delivery and feel barrier restoration, that's very attractive. Next slide. So despite all these emerging therapies, there are opportunities for improvement. One is to improve on the efficacy rates that can be done through novel mechanisms of action. I think the, in a way, the lowest hanging fruit for cubing this goal is combination therapy. But this is different than oncology, where there's more of a tolerance for toxicity if you start to combine drugs you need the combination to be acceptably safe. And this is where having one or more of the agents be gut targeted with safety profile that would come with gut targeting is really attractive. And then we should always be looking to see their companion diagnostics. We've talked about improving safety further with the organ specific approaches. And then really, having oral drugs that fit in after mesalamine, especially applying sort of a modern bar for remission for mesalamine, I think there's quite a lot of patients that aren't in full remission on mesalamine and don't necessarily want parenteral biologic therapy, and this is a real opportunity. Next slide. So I will stop there and turn the program back over to Faheem and Silvio and Danese

Thank you. Dr. Danese, please, go ahead.

And thank you very much for this kind of indication. I will try to give you a small overview on how the feel this moving bill gave a fantastic overview about how the fit is moving in terms of drugs and strategies. And I would like to give you an overview on how clinical ambition is evolving. With potential new concepts in the field of reseated collation. One of this is something that will probably emerge. That we are defining for now disease clearance, which is not yet established, but is made of several components, and I will drive you through this. Please, next slide. So the concept of disease clearance is not new. In other disease areas where inflammation occurs such as in psoriasis, this is quite established. And if you go to next slide, we see that there are multiple measures. One of this is passive according to the different values that could the range between 0 and 100. And dermatologists are very ambitious. Because they talk all the time before they were talking about improvement, 30%, 50%. Now they introduced this wore buses clearance because their drug have been able to totally clear the scheme from psoriasis plaque. And I think this is something very unique in the field of chronic chronic in new mediated diseases. Next slide. Actually, what they show is that in their field, they can correlate very nicely the concept of disease clearance with the quality of life of patients. Next slide. So let's look at what could be disease clearance in patients with ulcerative colitis. And when you look -- this next slide, when you look at what I always like to define clinical ambitions? There are these layers that is appear in our landscape. Every time that we treat clinically as a patient. We always look, and this is according to the to target recommendation from IO IBD, we always look at symptoms of our patients. This is very well-established because we won't let a patient stays well. But also, we want to achieve endoscopic targets. And this is quite relevant because if we are able to held the gap, then it means that we are changing the structural damage of the intestine, and this probably is going to be associated with better outcome. But of course, there are other measures that we can add on. And this is something very new, for instance, histology. Now it is a regulatory requirement. And the same is in the evolution of clinical practice. The use of biomarkers, such as CRP and fecal calprotectin in order to be able to tightly monitor our patients in order to have the disease biologically, fully under control. Next slide. So I always like to say that when you look at this graph, before, we were thinking just -- and this is in the history of how drugs have been evolved in the drug development process before we were just looking at symptoms. And of course, you can improve symptoms in a large majority of patients. But the more you become clinically ambitious the more you want to go down with the depth of remission, then, of course, the bars, the number of patients that are really able to achieve those tight control through the different layers. So from just symptoms to symptomatic remission to endoscopic remission to up to histologic healing, that means that we have no inflammation at all in the gap of course, you will have less and less stations because this means challenging a lot -- asking a lot to the drugs that we have available in order to achieve this very deep remission. Next slide, please. So now let's look at the link altogether between -- next please. To all the different layers that they just give you, and let's think about a multidimensional new definition of remission. Because as I said, we are moving through lies. But what about instead of layers altogether, putting all the pieces together to see how many patients can achieve, at the same time, not only a BI dimension, but maybe a 3 dimension, putting together symptoms structural damage with endoscopy and [indiscernible] So at with some of the data that has been replicated in multiple data sets. This is a met analysis, looking at how mucosa feeling correlates in the long-term outcomes for us. And this is very well-established because you see that achieving you cause are healing by endoscopy or actually endoscopy hearing will lead to long-term clinical remission is associated with less need for colectomies for the patients. Long term, of course Michael [indiscernible] and also clinically long-term student Fermison. Next slide. Well, it's also true that on the other side, while we have some patients that can achieve endoscopic remission, only 1/3 of these patients will have complete absence of symptoms. And this is being replicated now in multiple data set as you see here, in all the papers that have been reported in this meta analysis. Next slide. What about histology? If we go deeper and deeper, this is very well established. Think about cancer. In cancer, no bad self means during the disease. Can we use the same concept of alternative colitis, if we do not have neutrals anymore. If we have completed this appearance of the bad cells that we give continuous inflammation in our patients, can we cure as well the disease? Can we totally change the disease cost? Next slide. Well, endoscopy and histology, not always correlate properly. Probably we are still evolving in our field because now we are learning how to do proper biopsies, how to do proper assessment of the histological. But this is what you can see in the correlation of multiple data set available in these big metanalysis looking at 44 studies. Next slide. In this paper, it is extremely interesting to look at how many patients that still have an estatic remission of 0 or endoscopic remission of 1 still have active disease as histology. So this is the 2 dimension. As I was mentioning, 2 dimensions show you if you put together at the beginning, endoscopy and symptoms, 1/3 of patients. Here, you see that endoscopy and histology, overall, another set of patients still have active inflammation while having totally absence of symptoms or endoscopy emission. Please to next why we care about histology? And why healing of the PTL cells is fundamental also histological level? Well, for sure, because there are multiple that are set showing that in the long term, even though there is a lot of learning in our field. But for sure, patients are more likely to be symptom free, they have reduced the relapse risk. They have reduced risk of getting collectomies of hospitalization and overall of colorectal cancer. This is very well-established because inflammation in the big inflammation, if the disease is not properly controlled at the histological level is one of the biggest driver for concept, which is one of the major concern of our patients. So this is why histologic killing is one of the key aspects that we are taking, and we are caring a lot in our field at the moment. Next slide. Let's look from a regulatory perspective in the ustekinumab registration trial, how good -- how it was possible to achieve histological healing. Well, this was actually the first paper in which the first registration timing, which from a regulatory perspective, histology and in this case, association of histology endoscopy with a new definition of because the healing was considered. And you see here that there is a nice correlation in the long-term when you think about clinical response, clinical remission and stride remission in the long term maintenance. So this gives us the perfect flavor on how it's important to go deeper into remission at only for Roman endoscopic perspective, but also from a histological perspective with this new definition of combining in 2 dimensions, the 2 aspects together. Next slide. How can we achieve disease clearance or histological feeling or endoscopy killing with vedolizumab? Well, this is one of the latest studies reported the headwind studies comparing vedolizumab versus adalimumab in patients with incentive colitis. You see that you can achieve endoscopic improvement in 40% of patients in the right bar with vedolizumab red and in 27% with adalimumab in BRU. But if you go to the next slide, you see that depending on how ambitious you want to be and -- or depending on the theological score that you read, you can achieve bars that are much lower in terms of geo core for histological inflammation or the robot histological index. You see here that once again, you pick differences between the drug, but there is a substantial proportion of patients that do represent a big unmet medical need. So I think this slide is very important because this is the flavor on how much there is a gap of a met medical need for which we need more drugs that are able to achieve histological control of inflammation. Next slide. And this is my final slide. Considering the 3 dimensions, moving towards a new concept that takes into account not to dimension at the same time, but simultaneously, symptomatic control endoscopy killing and histologic healing. And I think this is very important because even if this means that we'll have less and less patients, even if it means that we go deeper and deeper, but probably these are the patients that are technically or potentially chewed for in a long term. Of course, this is a concept that is now undergoing systematic review with the international organization of IBD, but we'll see nice data later on. And probably in the future, we will have a first dimension that will be molecular feeling. I see a lot of companies and biotechs that now are looking into this because it's not enough to achieve just the inflammation control, the disease clearance, but probably also the healing of at the molecular level will be also necessary. And with this, and I think that is my last presentation with our thinking about how we can reset our loads. Thank you very much.

Thank you, Dr. Danese. Now Dr. Taylor we'll turn it over to you.

Many thanks, faheem. So if I get up to the next slide, please. So Hello from Dublin. If we go to the previous slide, and those of you who visited Dublin, may be familiar with this bridge, it's called Ha'penny bridge and plays an important role in getting people from one side of the river to the other. I'm using it as an analogy for -- to bridge between the bench and the bed side and the importance of that and in the future of medicine, but of course, I do realize it's more than a hip that, that cost. So I guess that's what we're here. So if I can start with the next slide, what I'd like to cover in the next 10 or 12 minutes is the impact of our understanding of how organisms deal with oxygen deprivation or hypoxia. In order to start, I guess, at the very beginning, this slide on the vertical axis depicts the atmospheric oxygen over the course of the history of the planet, as shown on the horizontal axis. And as we see, while living cells evolved in the primordial soup, and we had a life on are quite early in the existence of the planet. It was almost an imaginably long period of time before oxygen actually started to accumulate. And this is a result of the evolving blue Green algae of the oceans, which photosynthesize and produce oxygen. Now for the next 1 billion years or so, that oxygen was all absorbed into the bedrock of the planet, but eventually, when that was saturated, we started to accumulate oxygen in the atmosphere of the planet. So we see that happening at just over 1 billion years ago. Now it has to be said that the first appearance of oxygen in the atmosphere was actually a disaster for Life on Earth. Most living organisms could not deal with the toxic effects of molecular oxygen or O2 in the atmosphere. However, of course, eukaryotic cells, which came on, went on to be the basis of the metazoans, the animals, the multi cellular organisms. Not only were able to withstand the toxic effect of oxygen, but actually to utilize its inherent chemical energy. So really, it was sort of like going from metabolic candle light to nuclear power. And that allowed us to become much more interesting organisms single cell bacteria and pro carriots, but to be multi cellular organisms like we are today. Now the evolution of that into mammals in humans was a key part, which occurred during the Cambrian explosion. This an explosive period of evolution on the planet. But the payback for this dependence upon oxygen for molecular energy is that we need to have a constant supply of oxygen to all cells of rebody in order just to maintain normal physiologic function and life. Now you don't have to stop breathing to realize the effects of oxygen deprivation as a cell tissue and organism level. So in the next slide, one of the things that is key to this dependence upon oxygen is that actually there are many situations, both physiologic and pathophysiologic where our tissues and the cells in those tissues get challenged with what we call hypoxia or oxygen deprivation. Now it might become -- it might be because you go to high altitude, such as the top of mount AVRS, that's depicted in this slide where the atmospheric oxygen concentration is about 10% compared to 21% at sea level. And if you ascend to those high altitudes, those low oxygen concentrations, well, your body is not going to be able to deal with the decrease in oxygen supply. But of course, that's not what mountain climbers do. They go to base camp. They allow their bodies to adopt to a relative drop in oxygen concentration, and that induces a response, which allows those mountain climbers to then a sense to higher altitude. And what's interesting and what's been demonstrated, and as I'll show you in the next few slides is that we've recently started to understand the mechanisms by which adaptation to low oxygen levels occurs. Now at the cellular level, in the next slide, what we know now after about 25 years of research in an explosive area of biology is the molecular mechanism by which cells respond to a drop in oxygen concentration. And it all centers around the transcription factor called HIF ONE alpha, which you see depicted in the middle of this red cell here. This call is depicting Normoxia, physiologic normoxia, which is a normal healthy state, where the amount of oxygen that we take into our body actually exceeds the demand of oxygen by our body. So there's spare oxygen that's not being used to make energy. And that spare oxygen is sort of a signal to cells to tell them, okay, we're not hypoxic. And in those situations, that oxygen is used by a family of enzymes called PHDs or proly roxolid enzymes. They're depicted just below the oxygen on the first arrow. And what they do is they destroy any HIF that gets made inside the soul. So every cell in your body right now, provided you're a physiologically normoxic is generating lots of hit but provided there is excess oxygen available that HIF gets degraded, switched off and is never functionally active within the cell. So what happens when the experience hypoxia at the cellular level? In the next slide, you'll see that when oxygen demand exceeds supply because we go to high-altitude or alternatively because the oxygen supply to a tissue has been diminished due to a block and a blood vessel or multiple other pathophysiologic states. Then all of the oxygen that's available to the cell is used to make energy. The hydroxylases are no longer active, hit then becomes stabilized because remember, normally, that's broken down in an oxygen dependent manner. So HIF now accumulates within the cell. It goes to the nucleus as depicted into the yellow area at the lower part of the cell there, and it switches on a whole family of adaptive genes. And in the next slide, you'll see that these genes include things that promote blood vessel formation, the growth of new blood vessels into the hypoxic tissue, thereby increasing blood supply, factors which will increase the diameter of the blood vessels there, again, increasing the oxygen and blood supply to that tissue. And also proteins such as erythropoietin, which will increase the amount of red blood cells in the body, thereby again, helping us to increase our oxygen supply, adapt to the hypoxic state. And in the next slide, you see, that really works as a very neat sort of molecular reflex because the activation of hip increases oxygen supply to the body, we reset a situation where oxygen supply exceeds demand, thereby going back to a state where the HIF within the cell becomes degraded because once again, there's spare oxygen available for the Polo hydroxylase enzymes. And this pathway, which was first identified in the early 1990s, the HIF transcription factor was identified by Gregg Semenza and the mechanism linking oxygen levels to HIF expression by Peter Rattles and Bill Calin has really been kicked around a lot -- in a lot of labs over the last 20 or 25 years. So it's a very robust, well understood biochemical pathway. Now in the next slide, one of the really interesting things that's very pertinent to today's presentation is that we now have not only an interesting biochemical pathway, but also one that is extremely druggable. And the Prolyl hydroxylase inhibitors, which we're hearing about today, GB004 being one of them, are pharmacological inhibitors of the hydroxylases, which trick a cell, a tissue or indeed an organism into biochemically thinking it's hypoxic by inhibiting these enzymes that are normally only inhibited when the cell oxygen levels drop, thereby increasing HIF and stimulating or activating this adaptive pathway to conditions of hypoxia. Now the first sort of clinical application of these drugs in the next slide was in the treatment of anemia. So these drugs have recently, in some countries, been approved for the treatment of mainly chronic kidney disease associated anemia. And it should be pretty clear, the administration systemically into the bloodstream of Prolyl hydroxylase inhibitors, results in the increased expression of erythropoietin within the body, which is used to generate new red blood cells and thereby overcome anemia. And these drugs have proven very effective clinically and in the treatment of anemia. And this, I would have always thought of as the sort of low-hanging fruit in terms of the potential therapeutic applications of these drugs among a number of other conditions, including inflammatory conditions as I'll get to in the next couple of slides. So in the next slide, I wanted to just remind you that the architects of this pathway, the discoverer of HIF, Gregg Semenza, Bill Kaelin Bergreen have [indiscernible] and also the identifiers of the hydroxylases as the regulatory pathways. We're awarded the 2016 Alaska basic medical Research award. And then more recently, as most of you will know, in 2019, there were recipients of the Nobel prize in physiology or medicine for their discoveries of how these cells sense and adapt to oxygen availability. You also noticed that when people go from the LASCAR to the nobel, they sort of transmogrified from being pictures to get actual cartoons or super human beings we signed a thing on that. All right. So if I can move on to the next slide, to address the disease, which you've heard a lot about already, the inflammatory bowel disease is a chronic inflammatory condition of the gut. I won't go into any more detail as Bill has done a wonderful job and Tivo in outline [Audio Gap]

Operator, I'm wondering if we lost Dr. Taylor's audio.

We lost his line. He disconnected.

Okay. Maybe we'll just give it a second and see if we can get them back on. Barrett, if we're unable to get Dr. Taylor back on, maybe we'll jump into your section?

Glad to. Here, I think we'll get started with your section, and then we'll get Dr. Taylor to pick up when we can get them back on the line. Excellent. Well, we can move to Slide 71. All right. Well, thanks. Well, thank you, Dr. Taylor. I'm sure he'll be back on the line. I've got to say that when I first started studying GB004, I was encouraged by the type of research that was going on in the HIF pathway, a former fellow mine, actually, Dr. Hendrik. So you'll see cited and Professor Taylor literature was working with me years ago when I was at another company and doing research in this. And I think really the amount -- the distance has come from the basic science now to the clinic is really impressive, and I'm looking forward to really unlocking this evolutionary key to preserving ATP in a way that we can treat inflammatory bowel disease for patients. It's really amazing. So well, thank you to Dr. Taylor, Dr. Danese, Dr. Sandborn. And just turning briefly to our clinical development of GB004. Looking back Angaston licensed the program in mid-2018, and we knew one of our first tasks was to develop a tablet or a capsule formulation in order to move closer to a commercial formulation and to avoid some of the initial tolerability issues that were being observed with the liquid formulation used in the Phase I studies in healthy voluntaries. Now while this formulation was being developed, we had the opportunity to run a short clinical trial in patients with ulcerative colitis. That even with this non optimized liquid solution formulation, would allow us to potentially accomplish several key objectives. First, we could evaluate the safety and tolerability of for patients with active ulcerative colitis. And given, as you heard, this impact of the systemic HIF stabilizers on EPO and VEGF concentration. Which we didn't want. We were also very interested in ensuring that our targeted approach avoided these increases in plasma concentrations of these markers.

Hey, Barrett. Dr. Taylor is back on. So maybe we just give it back to him to pick up where he left off.

To be continued. Thank you.

Dr. Taylor?

I apologize his line just disconnected. I think he's dialing back in I'll be right back.

Apologies for the technical difficulties. We'll get that sorted out shortly.

Dr. Taylor has joined.

Dr. Taylor, can you hear us? All right. Dr. Taylor, if you can hear us.

This is Dr. Danese not Dr. Taylor. Can you reconnect me? I don't hear anymore.

We can hear you, Dr. Danese I think we're just waiting for Dr. Taylor to come back on the line. Barrett, I would say -- there we go. Dr. Taylor.

I'm back in there. Apologies, guys. I don't know what happened there. It seems to have got cut off.

Okay. We can pick up from where you left up.

Okay. Was that on this slide with the inflammatory bowel disease?

I believe so.

Okay. So apologies for that technical glitch. So what I'd like to do now is relate what I spoke to earlier on in relation to the hypoxic response in cells to inflammatory bowel disease and really answered the question, why do we think that inflammatory bowel disease may be a useful target for drugs that regulate the HIF pathway. So in the next slide, if I can identify a study, which we recently published where we've investigated the impact of hypoxia and the presence of hypoxia in inflammatory bowel disease. So in this recently published study, what we were able to demonstrate was that if we measured the oxygen tension in inflamed tissue taken from patients with active inflammatory bowel disease and compared that to adjacent healthy tissue, as shown in this slide. If I can draw your attention down to the middle panel where we look at the oxygen levels, which we measured using an endoscopic approach, we were able to demonstrate a significant reduction in oxygen tension in the inflamed tissue in ulcerative colitis. And in the lower panel, we have what's called a western block, for those of you who haven't done biochemical sciences, but this clearly demonstrates an up-regulation in the HIF transcription factor between the A, which is the adjacent healthy tissue and the eye, which is the flames tissue. And here, you can clearly see an upregulation in the HIF pathway. So the take-home message from this slide is that the colonic mucosa in inflammatory bowel disease is indeed inflamed. So we asked the question in the next slide, what the impact of this hypoxia is on inflammatory processes within the gastrointestinal tract. In the next slide, I'll just show you 1 slide from this paper, which we published over 12 years ago now, where we were able to demonstrate that activating the hypoxic response, the HIF dependent response with a hydroxylase inhibitor is profoundly protective in experimental colitis. So here we see a cross-section of a healthy mouse colon without an induced IBD or colitis. In the next panel, we will see in the next slide, please. You see what happens when we induce colitis in the colon of this mouse, you see DSS colitis. You don't have to be a gastroenterologist to take to see the breakdown in the architecture of the tissue. There's a large infiltration of immune cells. And this is a classic histological features of inflammation in the gut. Now if we pretreat these animals with the hydroxylase inhibitor, as you'll see in the next slide, and this was the prototype hydroxylase inhibitor called Demag. I think things have got significantly better now in terms of the drugs that can be used to activate the HIF pathway. But what we saw was a profoundly protected phenotype. So mice that received the hydroxylase inhibitor is -- are profoundly protected by the treatment for this. Now if I can go to the next slide, which I think is a key aspect of this, we were also able to recapitulate this result using genetically knockdown Mice it pro Ehid oxalate 1 isoform. So this is really just a genetic a version of the previous slide. But what I wanted to point out is that we think the main mechanism by which these hydroxylase inhibitors are protecting the mouse colon under these conditions of colitis is through enhancing the epithelial barrier. And in the lower panel here with the black arrow, you see that there is a very robust epithelial barrier. Even though these mice have been exposed to DSS colitis, and we can recapitulate these results in using the pharmacological inhibitor. And this is shown in measuring barrier function of the gut on the right-hand panel where you see in the wild-type mice, if you're exposed to DSS, you get an increase in leakiness. And this is prevented when we block, in this case, genetically the prolonged oxalate. So in the next slide, I think probably one of the most important things and one of the most important points that I'd like to get across is that this work using the hydroxylase inhibitors has proven to be extremely robust. It's been reproduced by many international studies using different models of Calin next slide. I have to get a new slide. I had a second slide because of the number of studies that have reproduced this work. And this is a growing list. So the preclinical evidence for protective effects of hydroxylase inhibitors in IBD models is extremely strong. In the next slide, I'd just like to outline because you don't have plan to get into all of the mechanism here, but what we know is that under conditions of -- in a healthy gut, the barrier, the epithelium prevents, as you can see here in pink, prevents the bugs, the top from infiltrating into the lower compartment, which is the tissue -- the body's tissue. In inflammatory bowel disease. Next slide, this leakiness results in the microbiome, the bugs getting through the epithelia layer into the underlying tissue and causing an inflammatory response, which causes further leakiness in the go and what we know happens with the treatment with a hydroxylase inhibitor. Next slide. Is the truly inhibition of the pro of hydroxylases, it promotes hair activation, essentially tricking those intestinal epithelial cells into thinking their hypoxic of when they're not. And it turns out that the activation of this adaptive pathway results in an enhanced barrier function. In the next slide, thereby getting to the stage where we seal the roof, if you like. So just treating the inflammation is a little bit trying to, like, if you've got a big leak in your roof trying to just bail water out of the house, whereas if we treat with a hydroxylase inhibitor and enhance the barrier function, we believe that we're enhancing the protective effect by promoting barrier restitution. I will say there is a significant amount of data, as outlined in the dotted line here that HIF also has modulatory effects on immune cells in the submucosal compartment. Next slide, please. So to summarize, we believe that the treatment of the intestine with hydroxylase inhibitors in these murine models of colitis. Are effective primarily by the directed healing of the intestinal mucosal barrier and thereby preventing the movement of antigens, such as the microbes in the gut into the submucosal [indiscernible] thereby causing inflammation. On the final slide, I just wanted to show that I do believe that this -- I should say here, there's some reviews here that if people would like to get some more information on the basic science behind this. On the next slide, I'd just like to say that the possibility that I see as a pharmacologist and training of combining these barrier protective effects with the immunosuppression drugs, which we heard about earlier on, particularly from Bill, represents another therapeutic potential, I would see, where the synergy of combining a barrier protective and an immunosuppressive agent, maybe a use. And this is something we did in the next slide, in a proof-of-concept model where we combine the prolyl hydroxylase inhibitor with cyclosporine, and we're able to show in the very lowest panel there, the bottom panel, the combination of cyclosporin and Demog virtually fully reversed the pathological effects of DSS in a model of colitis. I'd just point out the lowest panel there, you can actually see the stool being formed in the intestine, despite the fact that these mice have experienced exposure to DSS and colitis. So I'll leave it there, and apologize for the technical hiccup and maybe it was the Irish telephone lines, and I'd be happy to take any questions later on.

Thank you, Dr. Taylor. And I think that allows us to now get back into our normal orders. So Kristen, you're up next. Sorry, Richard. Richard is up next.

Sure. Thank you, Faheem. We'll go quickly through these slides. And so thank you, Dr. Taylor, for your presentation and also want to thank Dr. Sandborn and Dr. Danese for your earlier presentations as this sets the stage as we continue our discussion with a focus on GB004. More specifically, we plan to cover select preclinical data review the early clinical experience and provide an overview of our ongoing Phase II study cause shift you see. So let me begin by this slide pretty quickly just to review several of the key attributes of GB004. It's an oral small molecule hit one alpha stabilizer. If one alpha stabilization represents a new mechanism of action, one that is primarily intended to promote intestinal barrier function and repair as well as local immune modulation. And it's got targeted exposure in non systemic immunosuppression mechanisms are important features of GB004 potentially having safety advantages, which may provide opportunities for combination therapy approaches, as mentioned previously. Next slide, thanks. This slide summarizes the development progress of GB004 and let me just say that its development and IBD is based on strong scientific foundation as discussed by Dr. Taylor. And we've obtained further encouraging biomarker and clinical data in active UC patients in our Phase Ib, which has supported our initiation of our ongoing Phase II study. Dr. Kristen Telemeters next who leads our basic research efforts with GB004 in our biology group that Gossan will be reviewing some of our preclinical data. Followed by Dr. Barrett Loves, who is being our clinical development program. Next slide. Before I turn it over to Kristian and Barrett, I just want to spend a moment to highlight GB004 mechanism of action, building on the science of the HIF pathway. GB004 works primarily by stabilizing HIF 1 alpha and by doing so, directly promotes protective pathways that are critical to the maintenance and intestinal epithelial barrier functional repair. And this is distinct from many of the systemic immunosuppressive therapies as outlined by Dr. Sandborn. GB004 likely also modulates local immune pathways within the gut and this collectively, these effects are expected to lead to increased mecca healing and clinical remission. So with this background, I will turn it over to Kristen to review some of our preclinical data.

Thank you, Richard. We and our collaborators have generated a variety of preclinical data that has helped us to understand GB004 mechanism of action and its potential for treating patients with inflammatory bowel disease. This slide summarizes recent data published by Dr. Simon Kelly at the University of Newcastle, which shows that GB004 accelerates intestinal barrier repair and Lutein in an endoscopic intestinal wood model. In this model, localized colonic wounds were created using biopsy forces in healthy mines. On the far left panel, mice treated with GB004 denoted in last square, demonstrated accelerated closure of the intestine area compared to animals that received vehicle treatment denoted in Block circle. This is captured by endoscopic images on day 2 and the middle panel where GB004 treated animals had greater re-epithelialization compared to vehicle-treated mice. The dotted circle highlights the wound area. On the far right panel, the accelerated re-epithelialization is captured in representative insological images on day 2. The black arrowheads, seen as histology images for the GB004 treated animals denote regions of intestinal wound healing. Vehicle-treated mice do not demonstrate this accelerated barrier repair. Together, these results indicate a strong impact of GB004 treatment on other [indiscernible] barrier integrity repair and improved intestinal wound healing. GB004 has also demonstrated efficacy in mouse models of colitis by improving Ethibel barrier function reducing disease activity scores and driving epithelial reconstitution. On the left side of this slide, are histology images, which demonstrates the beneficial effects that GB004, an have an epithelial barrier protection and the TMBs induced mouse colitis model. The top image is from a healthy naive MOS. Epione middle should round episodial tissue damage that occurs in vehicle-treated TMBs mice. While the bottom image demonstrates treatment with GB004, leading to a significant reduction in tissue damage in this model. Furthermore, treatment with GB004 leads to reduce disease activity scores and normalization of Colon Link which can be observed in the graph on the top right. GB004 also reduced local inflammatory colonic cytokines, including [indiscernible] and TNF-alpha observed on the graph on the lower right. These results suggest that GB004 impact on IBD extends beyond Epicel's healing and includes reduced disease activity and local immune modulation. As I reviewed on the 2 prior slides, GB004 as a HIF stabilizing agent is effective in the treatment of multiple models of colitis and barrier repair. As Dr. Taylor's presentation showed, there are many different pathways that have been alpha impacts that help to drive these results. 2 key pathways in both genes that impact epithelial restitution and barrier functions. On the next couple of slides, I will review data showing how GB004 drives the expression of these genes preclinically, which is termed to the positive outcomes we just reviewed on the prior slide. The first gene that we will look at is Finegan alpha 6 which plays a key role in cell adhesion and migration. These are essential processes to repair damage and explained tissue. Interestingly, deletion of this gene in mice leads to the development of chronic spontaneous colitis. Then I'll review data showing this treatment with GB004 leads to increased expression of genes essential for barrier integrity and function like page judging protein, CD73 and intestinal Trifold Factor III. Importantly, beyond the mechanistic validation this data provides, you can also measure gene expression changes in the clinic, which provides an early pharmacodynamic signal that GB004 is having an impact that may lead to clinical efficacy. Using the intestinal warfarin model, Dr. Kelly Lab investigated key mechanism that accelerated closure on intestinal room and restored the OPEBITA barrier following GB004 treatment. Dr. Kaelin has now found that integrating alpha 6 and then ICR [indiscernible] for cell adhesion and migration was up-regulated following treatment with GB004, functional blockade of this protein in vitro led to reduced cell migration. And the representative of the histological images shown here GB004 treated mice demonstrate more pronounced integrin alpha 6 taming as observed by the brown staining associated with the valumin adjacent flu epithelium in the colon compared to vehicle-treated mice. The significant [indiscernible] is quantified in the bar graph to the right. Furthermore, GB 4 up-regulation of integrin Alto 6 was also observed in colitis mice correlating with approve endoscopy and histology scores with GB004 treatment. Together, this data demonstrates that GB004 stabilization of [indiscernible] alpha is the upregulation of Integra important for epithelial of restitution and leads to accelerated barrier repair and run volume. We have also seen in several in vitro and in vivo models that treatment with GB004 leads to increased expression of genes in the colon required for epithelial barrier integrity and function. On this slide, we share data from results in vivo, TMBs induced colitis mouse models as well as from mouse oregon models, which show that GB004 increases the expression of intestinal TRU pull Factor III or TFF 3, Clovi 1 and SCD-73 for Ntfive. These genes are report for protection of the mucosa, increasing up the bill healing serving the mesodermal pipe junction and modulation of nucleotide and TAVALISSE signal. As I mentioned earlier, was exciting to us about the data on this on the prior slide, does not only do they help us understand the mechanism of actions for GB004 in effect on disease activity and varied functions preclinically, but we can measure changes in the expression of these genes in the clinic. Given the early read of GB reform potential activity in patients. I'm now going to turn it over to Barrett Levesque, who will review the data we collected in our Phase Ib study and give an overview of the ongoing shift you see in the Phase II study. Barrett?

Thank you, Kristen. I'm going to speed up, so I want folks pay attention because I think we're going to try to keep -- make up some time here and look forward to showing the rest of these Phase Ib results. Now just returning to the clinical development, as I stated previously, first, with the Phase Ib trial, we could evaluate the safety and tolerability of GB004 in patients with active ulcerative flighted. Next, this trial gave us the opportunity to confirm that the gut targeted PK observed in those previous Phase I studies would hold in patients with UC, given the sometimes significant differences between the 2 groups in both drug absorption and PK. As you see next, a 4-week trial with biopsies at the entry of the study and the conclusion of the treatment would allow us the opportunity to gather important indicators of the pharmacodynamic effects of GB004 at the cited disease and the colon. And finally, we have the chance to observe any chance of preliminary clinical activity in patients. Importantly, because of GB004's mechanism of action, we hypothesized that the histologic evaluation would give us the best opportunity to see early signs of activity. And resolution of that neutrophilic inflammation associated with UC. And in order to give us that best shot at seeing a signal in this small patient population, we designed the first on the globe randomized clinical trial of a novel agent to require that patients have active inflammation on chronic biopsy assessed proactively at entry into the trial. Now we use the [indiscernible] pathology index that we had designed earlier years ago to both screen for patients with active clinic disease and to measure that histologic remission endpoint. And this RHI has been validated. It emphasizes the presence of neutrophils, and these are defining histologic marker of UC. Patients at the entry of the trial were required to have an RHI score of at least 4 and notably to have neutrophils in that colonic epithelium. In our endpoints, we used a stringent definition of histologic remission. Namely a score of 3 or lower with a 0 on both neutrophil components. Now here's the design of that Phase Ib clinical trial. Patients were randomized 2:1 to GB004 placebo. We enrolled 34 patients rapidly, 23 received 120 milligrams of GB004 liquid solution once-daily and 11 received placebo leg daily. Patients were treated for 4 weeks, and these enrolled patients had a mean Mayo score of about 7.5. Our Hi about 14. What does that mean? Well, it will indicate moderately active ITIS, both at the level of looking at the tissue through the endoscope, the colonoscope and under the microscope, where the tissue is the issue, we saw that moderately active disease. Of note, all these patients were on background first-line treatment. That's an ulcerative colitis 5 immuno solicit some on steroids, about half the patients on the study had received steroids in the past. So again, a moderate patient population. Now getting into the results, GB004 was generally well tolerated in the trial. The most frequent adverse events or AEs and the GB004 treated subjects were nausea, Viscusi, that's change in taste, all of which were grade 1 in severity except for one case of Grade 2 nausea. Nearly all of the remaining AEs and the GB004 arm were experienced by 1 subject. Who had a serious adverse event of UC worsening, which was deemed unrelated to the study drug. No effects we're seeing with GB004 versus placebo, namely on systemic EPO or VEGF. Remember, I had mentioned we were looking for that as a key differentiator from systemic PHD inhibitors. And as I mentioned earlier as well, we are in the process of developing a tablet emulation parallel to this 1B trial. We completed this Phase I study in healthy volunteers, evaluating tablets. We found a similar PK profile, a gut targeted PK profile on those studies in that study while improving tolerability at higher doses. So this tablet formulation was moved forward in our Phase II trial. And while these safety results come from a relatively short Phase Ib study, if we're able to avoid some of the side effects in with immune suppression, this could open the door, as mentioned earlier by Professor Sandborn, for potential combinations down the line for patients with IBD. But first, let's look at the PK profile. Here, it's consistent with the gut targeted approach. You see that rapid peak in plasma concentration, minimal accumulation, really minimal exposure in the blood over 28 hours of dosing. You see noting that concentrations of GB004 and the colon and these are assessed by a biopsy, 8 hours after the dose approximately. These were 6.5x higher on the -- in the colon based on Cmax than in the plasma. And if we look at average plasma concentration, these were 65x higher in the colon than in the plasma. And now that's consistent with the gut targeted exposure that we were aiming for. Now how about pharmacodynamic effect? Well, as part of the biomarker plan for the program, we took biopsies as I started at the end of the trial, like I mentioned, and we're tracking changes, for example, gene expression. Now importantly, in the GB004 group, we're looking for changes in barrier function. We're looking for changes in that inflammation in the epithelium. And we saw notably the TI junction protein want a gene associated with barrier Integrity increasing compared to GB004. We're also looking at integrin alpha (sic) . Christian mentioned that earlier, that's a key gene for epithelial restitution. You've got to build the fence before you can mend the fin. And these changes in gene expression were supported or what we observed preclinical to actually said. And given us this confidence that we're having the intended pharmacodynamic effect and seeing these trends that support our mission here. Next, we look at the stool, gastroenterologist that looked at plenty of stool, as we know, and it's a key sign that we can use it as a biomarker for how patients are doing. They're checking it for blood. They're seeing how many times they're going. We're also looking. Do we see changes in the fecal calprotectin. And then we did this is a marker of neutrophil. We observed differences in GB004 versus placebo, decreases in this [indiscernible] cap protective despite a small number of patients, consistent with other studies. And notably, here, pushing the boundaries, looking, is there a biomarker that can show an improved epithelial integrity in the stool? And yes, our team focused on secretory IgA. Secreted by the immune system by the -- in part by the lining of the intestine, and that was also going up. This is a novel way to start looking in the stool in a noninvasive way at improvement in that barrier function. And we saw these trends, which are encouraging. Now hop out back to the tissue and being the issue? Of course, we had set out at the beginning of the trial with a fine [indiscernible] comp that we had we've worked with teams to develop over years to better look for trends in small number of patients in ulcerative colitis disease activity before we go into, as you'll see, our fully powered for clinical remission Phase II study. What gives us reason to believe? Well, you were looking for histology and histologic activity changes based on this validated scale of the RHI, which now you've seen show probably in many investor presentation. With other companies that have utilized it to measure mucosal healing and larger Phase II and Phase III trials. Well, we set out prospectively, we made sure patients have the inflammation. And we found it just 4 weeks with this type of metric, this outcome measure approximately 44 patients. In the GB004 arm, we're achieving histologic remission compared to only 18% in the placebo arm. Now while similar percentage of patients in each arm experienced endoscopic improvement, now that's just a scale of 0 to 3. And so it's not as precise. You note that the 4 GB004 patients with endoscopic improvement also achieved mucosal healing, while none of the patients in the placebo group who had endoscopic improvement at had achieved mucosal healing. And this mucosal healing, used to be described as well, it just has to look better under the endoscope. That's yield. Well, not anymore. And now it's, we need both endoscopic improvement and not just a 1 point decrease in the score, but a true endoscopic improvement, reaching a 1 or 0 or 0 if you start as a 1 and histologic remission. So this is a high bar and indicates that potentially deeper response to therapy that Professor Danese had alluded to earlier. And 17% of GB004 patients experienced this while no patients in the placebo group did. Now moving on to more typical clinical endpoints that include, for example, the patient-reported outcome of rectal bleeding. Again, for patients. Often, it is the stool that's the issue. They're very concerned about seeing blood in the stool, and I know that's the case. And when we look at that clinical response, clinical remission, based on the classic Mayo Score as well as improvement in rectal bleeding or resolution, we see, as you see in the slide here, we see consistent trends that favor GB004. Notably, in only 28 days in this moderate patient population, we saw a patient with clinical remission. I think that may be even different than you've seen in other 28 day study. And notably, we're seeing patients not only improving the rectal bleeding, which you may see in other decks but -- presentation. But we see true resolution of bleeding. And we know here, the patient who achieved clinical remission also achieved that mucosal healing mark hitting, I think, that ultimate treatment goal that Professor Danese mentioned earlier, of disease clearance really only 28 days after entering the study. So we're pleased with these early trends. Of course, we're always looking forward to more data in the Phase II trial, but this gives us support of GB004's mechanism of action working in the UC population and provide us the impetus to move on to a larger study. So we set the bars, as you saw earlier in the slide what we were looking for. We checked these boxes, and we now proceed with our Phase II study. So on the next slide, shift you see. We're shifting gears in the new way to treat ulcerative colitis by leveraging an evolutionary mechanism -- an evolutionary key mechanism to preserving tissues and hypoxic conditions. And we're going to study it, the right way, as a continuation of the way we have been executing trials as a team at Gossamer and GI and other companies going forward rapidly and with high precision. And I think we have a couple of key differentiating factors that we're working with, not only the team that has experience and connections throughout the globe and working with investigators who have many trials to choose from and many of them are our close friends from over the years now. And we're going to bring them and have brought these investigators and patients, a new novel mechanism of action that's not a systemic immunosuppressant. A lot of patients are thinking, do I have to book on my [ cpal ] to make that leap for that [ chasm ] ? And I talked about that to many patients. But we're going to buckle up here. This is going to be -- you're going to read that label, and it's going to be scary, but we're going to think about this in a new way. Do we not have to make that leap that Professor Sandborn mentioned earlier to those types of side effects, particularly in a pandemic, and that has been resonating, and we are often rolling, thanks to patients throughout the globe in enrolling this trial. And we're catering to the unmet needs of a moderate UC population. They're uncontrolled on their first-line 5-ASAs. This isn't a trial trying to compete with live ASAs at first-line treatment. But they haven't yet been treated at biologics. And the patient's treatment options may be limited. They don't want to make that leap. And if they're and their physician aren't ready, we want to be able to step in for patients who may not usually either be on additional treatment or being on a trial and are stuck on steroid and 5-ASAs often. And we're going to build on that translational Phase Ib results that we just reviewed and give patients the chance of that longer treatment period. So all these factors, along with support from our PIs, our key clinical advisers, like Dr. Sandborn and Dr. Danese, this experienced IBD execution, operations, clinical trial team, CMC team. They're going to really look to, most importantly, these patients who volunteer to support this clinical discovery effort across the world, and we're off to a strong start. And what does that start to look like? On the next slide, you'll see the study itself, it's a robust trial design that allows for 2 opportunities to see an impact of GB004 on the efficacy in ulcerative colitis as well as the safety as well as an open-label extension to further evaluate an open-label way, efficacy and safety. So we're enrolling patients with moderately active UC. We have confirmed evidence of modern endoscopic disease based on the central reader Mayo Scores of 5 to 10. We're going to look at clinical remission of standard regulatory grade endpoint at 12 weeks. And also, that time, we're going to evaluate secondary endpoints. That you saw before, response, mucosal healing, histologic remission. But after that 12-week initial period, patients who have experienced worsening could move on to the open-label extension, but if they haven't, we have an opportunity to examine the kinetics of GB004 over a longer period of time. And look, as you saw, for example, in the previous adalimumab trial and ulcerative colitis and others. That -- what is the longer-term effect of GB004 at week 36 on the endpoint. And we're going to be having the opportunity to also evaluate the high hurdles of disease clearance. That combination of mucosal healing and clinical remission, they are so important to patients. So the combination of this effort, I think we are fully behind. We're excited about the data. We're looking forward to working with investigators and patients as we continue to enroll the trial. And we're thankful for the support from folks in doing this. I'll turn it over to Mario.

Thank you, Barrett. I'm very happy to be here today to provide our perspective on the commercial opportunity and where GB004 potentially fit in the UC treatment paradigm. And after my great experience and learnings at Receptos, working on zeposia or ozanimod, I'm very pleased and excited to be returning to the UC space with customer and GB004. I'd like to start off by sharing quickly with the interest of time reviewing some key market insights as we start to consider GB004 positioning. I'll elaborate on these insights in subsequent slides. But to summarize, UC is a large and growing market with revenue growth, largely driven by biologics. However, biologics are notably under represented when considering their patient share of the moderate to severe segment. Unmet needs in the UC space include safe, effective and convenient oral options for patients failing 5-ASAs and naive to biologics as well as efficacy beyond that of current biologic options. Given these pressing needs, UC drug development is now focused on retaining efficacy that includes deep and durable remission as well as restoration of the epithelial barrier integrity. Currently, orally administered GB004 is the only HIF-1a stabilizer in development, targeting the restoration of the intestinal mucosal layer and local immune homeostasis with no systemic immunosuppression. And as Barrett has already mentioned, the initial target population being studied in our Phase II trial, or patients failing 5-ASAs, that have not yet initiated biologic therapy. Next slide, please. Let's now review some market sizing data. In 2019, the IBD market was valued at $21 billion, approximately $21 billion, which you see represented 1/3 or approximately $7 billion. Biologic therapies, as you can note, dominated the UC revenue share, representing approximately 60% of UC market value, and this is largely driven by the higher price point of biologic therapies. Let's now view some of the market using patient level data. Next slide, please. Yes. The graphic on the let categorizes UC patients by severity and indicate that of 1/3 of UC patients are -- approximately 1/3 are categorize as mild, whereas the moderate-to-severe segment represents approximately 2/3 of UC patients. However, when patients are categorized by treatment status. You can note on the right hand, the graphic, 60% of patients that have failed 5-ASAs and were biologic treatment naive, whereas only 16% of patients were currently being treated with biologics. So although, biologics dominate revenue share, they're underutilized when considering that moderate to severe patients represent 63% of all patients. Okay. Some of the reasons why this is occurring, key reasons. First of all, safety. This is particularly concerning for both physicians and patients, especially around infections and malignancies, as been previously noted by Dr. Sandborn. In addition, injectable therapies are inconvenient and perceived by patients as being strong medicines. So patients strongly prefer convenient oral therapies. Especially considering that their therapies prior to candidacy for biologics would have included 5-ASAs, thiopurines as well as corticosteroids, all delivered orally. And finally, physicians have reported that migrating patients biologics involves. As Barrett alluded to, fasten you seat belt, a challenging conversation with the patient, which may could evolve to responding emotionally to the notion of moving from convenient perceived safe oral therapy to injections and then a discussion of infection and malignancy risk. This can seem very abrupt for many UC patients who may resist the move to biologics. And this landscape helps to define some clear and unmet needs. Next slide, Please? You can see this graphic illustrative and certainly not too still, but it represents -- given this patient resistant to biologics and the significant size of the patient cohort that has failed by 5-ASAs, there is a significant unmet need and opportunity for a safe, convenient and effective oral therapy for a use prior to biologic use, and potentially, prior to novel oral therapies such as, zeposia or ozanimod. In addition, as mentioned previously, there remains a significant unmet need for more effective therapies for the moderate and particularly the severe segments, targeting deeper remission. Next slide, please. As has been reviewed previously by Dr. Danese novel treatment approaches targeting deeper remission and histologic healing are needed to improve patient outcomes across the severity spectrum. And as has been established, histological remission has been correlated with increased incidents of clinical remission and favorable clinical outcomes. In fact, histologic healing may potentially be the ultimate treatment goal in UC. By primarily targeting the epithelial barrier repair, orally administered and get targeted GB004 represents an advanced approach to address the unmet needs of UC patients with the potential for greater histological healing and improved long-term outcomes. Next slide, please. In conclusion, given that epithelial barrier disruption likely characterizes UC patients at all stages, GB004 has the potential to provide benefit and address unmet needs across the severity spectrum, including mild to moderate patients that have failed 5-ASAs, which is the target population in our Phase II trial as well as potentially expanding treatment options to address the significant unmet needs represented by moderate to severe patients. That concludes my presentation. Thank you. And hip hip hurray. I'd like to turn it back to Faheem for the Q&A. Thank you.

Thanks, Mario, and thanks to all of our presenters. So I think at this point now, we would like to turn it over to any questions that may be in the queue? I believe there are some questions that are set up for either the Gossamer team or the experts that are on the line. Operator?

[Operator Instructions] The first question comes from Joshua Schimmer.

Great. Thanks so much for the excellent set of presentations and the update. I was wondering, this is probably best suited to the KOLs, but perhaps management has some thoughts on it as well, given your experience. I was wondering if you could talk some more about the interaction between the structural versus symptomatic benefits of treatment and which tends to lead versus lag with what's available today and how you would expect these measures to interrelate for GB004. Do you think that 12 weeks is long enough treatment for shift you see to see a compelling benefit on symptoms, which I think is likely to be a Phase III endpoint?

Maybe Dr. Sandborn could go first, followed by Dr. Danese. We could hear you.

Great. Yes. So the structural endpoints, I think, is an evolving area, up until very recently, we didn't even do biopsies as recently as the pivotal studies of tofacitinib, we didn't even do biopsies. And then they were done for the first time in a Phase III program with ustekinumab, and it was clear that you could achieve them. The endoscopy endpoints are -- there's sort of a funny misnomer in a way. We recruit patients with a score of 2 or 3 on a range of 0 to 3, and then we declare success with the score of 0 to 1. So the -- and 1 is not entirely normal. And then you have the histology, which ends up because of that, I think, substantially being correlated, but not 100% overlapping with the endoscopy. And then there's a number of patients that don't get all the way to histology remission. My group just reviewed our own data using sort of a treat to target strategy with available results, and then we did a meta-analysis that was published in gastroenterology, looking at what happens with rates of hospitalization, surgery and major complications, if you get to histologic healing in the course of your treatment as opposed to endoscopic improvement. And we found that you had really meaningful incremental clinical benefits in terms of hospitalization, surgery and major complications. If you got to histologic healing. So I think that as was kind of speculated by other speakers that over the next few years, the bar will move to histologic healing for the objective measure of disease. In terms of 12 weeks, I think that most drugs that work, you can see a benefit by 12 weeks that will be different from placebo. Whether you see the maximal benefit, not always, but taking anti-integrin therapy with vedolizumab, is an example, when you block lymphocyte trafficking, the resident lymphocytes have a lifespan of about 90 days. So it takes some time for anti-integrin therapy to work. And yet, you can see a benefit already by 6 weeks, and it plateaus by about 14 weeks. So I would thank, with this drug, which should reach steady state in tissue very quickly. You've got nearly the full 12 weeks of therapy that you would see a benefit by 12 weeks. And then as Dr. Levesque described, there is an extension out through 6 months or so. So there would be the opportunity to see if there's incremental benefits beyond the 12 weeks.

I fully agree with the same concept and probably. It's -- this is a drug that maybe -- will start to kick in even earlier, but 4 weeks would be -- the appropriate time point.

Your next question comes from Josh Schimmer.

Chris, thanks for this terrific overview. I have a few questions, if I may. First, maybe starting with Dr. Sandborn. I'm trying to understand the difference between endoscopic improvement versus mucosal healing. And then specifically, why the Phase II or how the Phase II could show no benefit on endoscopic improvement, but then did show a benefit on mucosal healing versus placebo?

Well, so historically, mucosal healing goes back to about 2000 -- or 2001 when we negotiated the outcome measures for infliximab, remicade for ulcerative colitis with the FDA before the pivotal study started. And in those days, we find mucosal healing as a final endoscopy score of 0 or 1 having started with 2 or a 3. And about 10 or 15 years later, the FDA kind of said, well, wait a minute, this is really a reduction in the endoscopic score. It's not new mucosal healing. And so we're not going to call that mucosal healing. We're going to call that endoscopic improvement. And -- but we are open to the idea of mucosal healing and how we would define that is, demonstrating both endoscopic improvement and histologic remission. And so that bar was laid down, probably 4 or 5 years ago, and then the ustekinumab or stelara program was the first program to get that done. It's still not totally consistent in that exactly what the endoscopic definition should be and what the histologic definition should be. We know what it takes to get an approval for mucosal healing, but how the 2 modalities fully interact is still being sorted out. Now when you come to a small Phase Ib trial like Dr. Levesque that presented. There's a few things going on. Number one, you could have some more mild patients that would have endoscopic -- that may not have much endoscopic disease to begin with, and therefore, they can't improve, but you have some histologic inflammation that's more robust that you can see improve. And then we've also come to see that the reliability of -- so the way these are done, a video recording is made of endoscopy. And then you have a blinded expert reader who knows nothing about the patient status or where the patient is in the course of their treatment, baseline or follow-up, interpret the the endoscopic video and score it. And then for pathology, the glass slides are digitized. And again, a blinded central reader expert pathologist will score the histology. So it turns out that we're surprised by this kind of -- but in the central reading world, it looks like that the histology may be even more sort of reproducible and reliable between readers than the endoscopy, and that may be particularly true, as you have some of the patients on the mild end of the spectrum like we did here. So I don't know what Silvio and Dr. Levesque actually worked a lot on central reading in a previous life, what you guys think about that, but that's my sort of view of it.

Yes. Fully agree on the same view. And actually, there are there are data comparing symptoms endoscopy and histology. And histology seems to be more reliable on a large data set of average on age. The paper is coming out very soon.

Dr. Sandborn and Dr. Danese, I'd agree. And I think in terms of your other question, Josh, mucosal healing is the higher bar. So when we have this problems with reliability as 0 to 3 score with endoscopic improvement, I think in a small data set, more likely to see overlap. By chance, placebo can jump the bar also achieved some numbers. I think the difference being mucosal healing in double edged sword, you have to hit mucosal healing by histologic remission and endoscopic improvement. And when you set that higher bar, as my daughter reaches for in gymnastics, it's the GB004 that's able to leap over it, but not the placebo.

Got it. Very helpful. Maybe for Professor Taylor. In this hypoxic, IBD inflammatory environment shouldn't local HIF concentrations be upregulated, physiologically, based on the pathways that you showed us? And if so, why would this mechanism add meaningfully incrementally to that?

Yes. So I think this is an important point that there is a degree of hypoxia which occurs as a result of inflammation within the context of the inflamed gut. And what we believe is happening is, it's about the degree and the extent to which we activate the HIF pathway. There is a number of genetic studies where HIF has been knocked out, particularly in the context of epithelial cells that show that the endogenous HIF activation that we see with intestinal hypoxia during inflammation does indeed provide a HIF-dependent protective response. But what we're seeing with the pharmacologic agency is that we're boosting and driving up this response. There is a certain amount of adaptation to physiologic hypoxia, which occurs. So if a tissue becomes inflamed and HIF gets activated, it will, through the mechanisms I outlined, increase oxygen supply to that tissue, thereby switching off the HIF response. So really, what we're doing pharmacologically is providing a super boost to the HIF response in the context of the intestinal epithelial cells. And that's doing a number of things. We think that it's increasing the epithelial barrier capacity through a number of mechanisms, including upregulating tight junction proteins within epithelial cells and sealing the epithelial barrier, if you like, but also by preventing the death of intestinal epithelial cells, thereby increasing the density of cells, up the epithelial barrier and keeping the barrier intact or indeed, promoting the healing of the barriers, should I say. So really, what I think is happening, I think your point is well taken, but what we're doing pharmacologically is harnessing and boosting an endogenous protective response in order to, if you like, make it better.

Got it. And last question for Professor Taylor, again. You didn't discuss the potential impact of the hypoxia on the microbiome and whether that could be an exacerbating factor and whether this pathway may, in some ways, have a therapeutic effect by modulating the microbiome, is the reason to think that could be a contributing element to the disease in that therapeutic?

Absolutely, no. Sorry. Yes. No, absolutely. I think this is a really key area of research at the moment. We don't fully understand what components of the microbiome are contributing to good health, but there are examples, for example, of metabolites produced by bacteria such as Butyrate, which can enhance the HIF response and as well as the activation of HIF altering the microbiome by determining the oxygen level that's available through the mucosal. So while I already believe that there is a component by which altering the HIF pathway can impact upon the microbiome and how the microbiome can impact upon the HIF pathway. Probably the best evidence we have for that at the moment is through Butyrate production from bacteria, but it's an area of great interest and a great potential and import in the mechanism of these drugs.

Your next question comes from Tyler Van Buren.

Thanks for all the presentations, very informative. I have a question respect to the SHIFT-UC study, you guys are enrolling the mild-to-moderate UC patients, Mayo 5 to 10 endoscopic score of 2 or above. In the Phase I, I guess you enrolled patients with a Robart score of, I think, it was 4 and above or above 4. Just curious why you're not using the Robarts to enroll patients here? And I guess, secondarily, as we think about the inclusion criteria. Can you just talk about the level of mucosal damage that these patients you'll be enrolling has. And a lot of the animal models, the animals were damaged and then you treated them with 004 to try to improve the epithelial barrier. So do you expect it to matter significantly whether the patient is treated with 004 prior to that damage or after?