Okay, great. We'll get started. Good afternoon. I'm Eric Joseph, Senior Biotech Analyst with J.P. Morgan. Our next presenting company is Morphic Therapeutic, and presenting on behalf of the company is CEO, Praveen Tipirneni. There's a Q&A after the presentation, just raise your hand, we'll bring a mic to you. For those tuning in online, feel free to submit a question via the digital conference book. With that, Pravin, please. Great. Well, thank you. Thank you everybody in the room here for attending. We really appreciate the interest. It's always a pleasure to be at this conference. I love this conference. I'm so glad it's back in person, and a chance to see all the investors, the colleagues, the partners and everything. I'd like to thank J.P. Morgan for inviting us here. Thanks, Eric. Thanks, Phil Ross. This actually is probably the most exciting year in Morphic's existence. Imminently next quarter, we announce proof of concept data on our phase 2 MORF-057 IBD compound for ulcerative colitis. Today I'm gonna talk about that, but also for the very first time, we're gonna announce some new data and some new programs of our early pipeline. It's been a really productive last year and this year actually is certain to be even more exciting. Before I get into that, let me just say that we are a public company. I will be making forward-looking statements. Just check our disclosures for all the usual risks associated with it. Morphic Therapeutic, just to step back for a second, is a company completely focused on a particular target class, and that target class is the integrin target class. What is an integrin? The integrin is a key cell surface receptor across many different diseases and therapeutic areas. It's the only receptor actually in the body that signals bidirectionally. It takes stimuli from the extracellular environment to make changes intracellularly, takes stimuli from the intracellular environment to make changes extracellularly. As you can imagine, the only receptor in the body that signals bidirectionally. I used to ask the audience how many more there were, and there were lots of comments, but it is actually the only receptor that does that. You can imagine that the pathology associated with that receptor is significant, and it is. The diseases that span the pathology of the integrin receptors span autoimmune, fibrotic, cardiometabolic, cancer, some very devastating diseases, and those are all the diseases that Morphic can address. There are expensive, complex biologics that have shown blockbuster efficacy in targeting integrins, but not any orals, and that's the key to what Morphic is about. As you know, as you can see there, a lot of chronic diseases where an oral would be a huge advance for patients. There, as you can see a picture of the integrin, it's a alpha-beta heterodimer, but also there you see in the active site, MORF-057. Just a note. Why are there no oral integrins? Why is Morphic the only one who can make specific integrin inhibitors? This is what we call MInT Platform, our technology platform. In previous years, I've talked about the promise. This year I will talk again and again and again about how much this platform has actually delivered, and it's a combination of technology and actually great people, and it starts with the structural knowledge. Morphic Therapeutic is the only company in the world that's able to elucidate the chemical structures of the integrin class across the target class. Nobody else is able to do that. We are the one game in town that is able to come at this target class in a structure-based drug discovery manner. From that, we have very focused chemical libraries that has just built up over the years, a whole slew of assays against the various integrin targets. Really uniquely, we marry that with the computational chemistry of Schrödinger. An exclusive partnership with Schrödinger, also one of a kind computational chemistry company. That one of a kind partnership in the integrin class has really been productive for both companies. By being the only one that is able to make specific inhibitors of the integrin class, we have very high-quality probes. I mean, this biology space, much of it has been largely unexplored. By having very high-quality specific probes, we can interrogate that biology in a way that no 1 else can. From that, and I'll talk about some of the new findings that we have today, we start to be able to validate a number of targets that have never been tractable previously, and that's led to our a number of our novel drug candidates. On the right there you see the the baseball card of our alpha four, beta seven compound. In previous years, you'd see these on the back of our business cards, but nobody's using them anymore. That leads to our proprietary pipeline. All of these compounds were discovered by our team at Morphic. That includes alpha four, beta seven, that MORF-057, which I'll talk about today. That's the one, that's imminently next quarter we're gonna be announcing phase 2 data. We have next generation compounds. These compounds are at picomolar level potencies, potency levels rivaling a biologic. There are a number of other indication applications for next generation α4β7, but these backup and next generation compounds are just remarkable chemistry. Talk about our αvβ8 program, and we are moving this into a new indication. We talked about this compound and this target before, but not in this particular way. Finally, for the first time, we're gonna talk about our targets in pulmonary hypertensive diseases and where they are. Let me start with the discovery pipeline. Our αvβ8 program. We've talked about this program before, it's on our website, and the really unique thing about the integrins is how it's able to suppress TGF-β specific to particular tissues. In this case, what we talked about previously is our IO indications where αvβ8 inhibition of TGF-β in Tregs. Today, I'm gonna talk about the IO program, but also I'm gonna talk about its applications in myelofibrosis. This data, our αvβ8 program, small molecule inhibitor, enhancing checkpoint inhibitor response, in a number of models. As you can see here, this has been on our website for a long time, very dramatic effects in the EMT6 model, the gold standard model here on tumor burden as well as survival. Really fantastic data, as good as anyone has ever seen before. That data set has deepened across many, many models. I'm not gonna go through this data in detail because we have many times in the past, but it's on our website, and it's shown, dramatic efficacy. What we're doing is we are not advancing this program in the IO space, due to the requirement of the combo here, as well as a number of competitor molecules, biologics that are reading out pretty soon, hopefully. We wanna have a better understanding of the landscape here before we advance it in, in IO. This program also has potential applications in myelofibrosis. Myelofibrosis is an application that Morphic can take all the way from discovery to commercialization. A very, as you guys all probably know, a devastating bone marrow disease, megakaryocyte proliferation and multifactorial etiology, but Key part of it does include TGF-β. It's a blockbuster rare disease indications. Jakafi has $1 billion plus sales alone. To date, there are no disease-modifying therapies except for a very invasive allogeneic hematopoietic stem cell transplant. It's largely underserved still. I mean, the standard of care is still at a pretty nascent state. There's still toxicities associated with it, you know, intolerance and resistance to therapy, as well as no disease-modifying agents. Our alpha-beta eight inhibitor has the potential to actually increase red blood cell counts. That diagram on the right, TGF-β has a key effect here in that proliferation, both in the direct proliferation of osteoblasts as well as in the feedback toward the hematopoietic stem cells. Blocking that specifically, in the bone marrow has the potential for a really important therapy in myelofibrosis. You guys are gonna announce a lot more data on this in the coming weeks and months, we are very excited because of this program and one that we can actually take all the way to market ourselves. Let me talk about an integrin we haven't talked about before, and we're not gonna actually name the specific integrin for competitive reasons. This is a fibronectin integrin suppressing the activation of TGF-β, and it has applications across a number of pulmonary hypertensive diseases. I'm gonna name some of the effects that this inhibition of this molecule has, and any one of these is remarkable from a therapeutic benefit, reversing remodeling in the pulmonary vasculature. Directly, so not a function of hemodynamics, but directly preventing right ventricle fibrosis. Third, improving cardiomyocyte metabolic efficiency. Just imagine that. Three distinct effects. Each one of them would be a huge advance. This molecule has the potential, this target has the potential to do all three. You see on the right there, the effect, and I'll show the actual data in a second, the actual effect on pulmonary hypertension, pulmonary hypertensive diseases and That vasoconstriction reversing that fibrosis. Here you can look at some of the data here in the Sugen/hypoxia model. Picture is worth 1,000 words, and you can see on the right there, actually on the left, I guess, for you guys, that the control, the vehicle, and then treatment with our small molecule inhibitors. Quite a dramatic effect. Then, in the other two panels there, you see the effect on cardiac output, and you see the effect, which is dramatic on vascular remodeling. We think that there's a key role for this target and this molecule in pulmonary hypertensive diseases. Now the other thing about this, because, you know, you can potentially see benefits in cardiac output by decreasing that afterload and then vascular remodeling, and other people have. Nobody has shown a direct beneficial effect on the heart. Here, this is the, this is the data associated with the pulmonary arterial banding model. You band it, hold the blood pressure constant with the band, and then seeing the effect after treatment with our small molecule. As you can see, quite a change of the cardiac output there at the same pulmonary pressures. That's a very direct effect on the heart. That is a very, a huge advance, in terms of pulmonary hypertensive diseases. You see the same thing on the next panel. That's a measure of systolic volume as well. We are very excited about this program. It has potential across a number of cardiac and pulmonary diseases. We will be announcing much more about this molecule and this target in the upcoming weeks and months as well. Now let me move on to MORF-057. This is our phase 2 molecule in ulcerative colitis. It's in phase 2, and I'll talk about that. As I said, this is an incredible year for Morphic Therapeutic because of the proof of concept that we believe this molecule will show in the next quarter. Stepping back, the great thing about this program always has been is that the α4β7 inhibitor is a well-proven mechanism in IBD. The antibody vedolizumab, Takeda, has shown, right, that the inhibiting the T-cell trafficking with α4β7 has remarkable benefits, both in terms of efficacy and safety for IBD patients. Over 150,000 patients receive vedolizumab. The sales are well over $4 billion, and it's a very straightforward mechanism that panel on the, on the right there, you can see... What you see in that panel is the vascular space, the bloodstream. You see the T-cells in that vascular space. The T-cells express α4β7 attached to the natural ligand MAdCAM transmigrate into that subendothelial space. The pathology of IBD is those T-cells in the subendothelial space when they shouldn't be there. Fairly straightforward that blocking that transmigration, keeping those T-cells in the systemic vascular space, is preventing the pathology. We've shown some of this data before, much better data than we have expected. Here, you're looking at the alpha four beta seven receptor occupancy in our phase I studies across a number of different doses. These were much better results than we expected, much better than even predicted pre-clinically. You can see that they saturate that receptor at very low doses. At 100 milligram BID there, it's completely saturated right from the get go. These are trough concentrations, so 12 hours post-dose, the lowest dose, right before the next dose. This is our data set across all of our data, and you can see there again that we achieve greater than 90% receptor occupancy at very low concentrations. This is really, I think, what made the difference in both ourselves, the market, you know, thought leaders realizing that we got a drug here. We also measured the lymphocyte subsets in this disease. We didn't actually know what to expect. We got very lucky because, at almost the exact same time as we were announcing the data, a paper came out, the Vermeire paper there, that showed the same effects in vedolizumab patients, vedolizumab-treated patients. What you see here is exactly what theoretically you would expect to see, you know, in this patient population, that blocking that α4β7 receptor increases the α4β7 expressing cells in the vascular space. That's exactly what you see on this slide in those first two panels. We measured CCR9, another biomarker in this disease, and it also did exactly what we expected. This was beyond the receptor occupancy. This was further validation that both from the lymphocyte subsets, from biomarkers, from the receptor occupancy, that everything tracked in the right direction for MORF-057. Let me talk about the phase 2a. This is the study that's gonna read out next quarter. We call it EMERALD-1. It's an open-label study. The cohort N equals 30. What we're looking for here is initial indications of clinical efficacy. We also have, in parallel, running a phase 2b study, which I'll talk about. There's a deep translational data set that, on a per patient basis, is much more data than any UC study out there. We met the target enrollment last year. The primary endpoint here, 'cause it is a small study, is the change in baseline in a histopathology index, so histology. This is a centrally read objective histology measure. That's what we're looking for here to get that initial proof of concept. Do we have a vedolizumab here? Actually, I should get rolling on this. What we're looking for is an oral vedolizumab. This is probably the most important slide in the whole deck here of what you should be looking for in this data going forward. If you look at our data, you wouldn't run this study if it was a novel mechanism. It's only because it's well-validated biology. If you look at our data across in vivo, across the rodents, across the primates, and across the human subjects, and across vedo, every piece of data has been consistent. There's no piece of data that where you're scratching your head, what does that mean? You're comparing it to an approved drug, it's all tracking the right direction and all consistent with what you would expect to see. What we're looking for in this study is to match, you know, on the pathologic index vedolizumab, but also what we're expecting to see is there's a huge amount of data. We're looking for all of that to be consistent with all of the data before and with vedolizumab. It's a lot of data. I mean, at some point, you're just essentially It's a lot of data, and if it's all consistent with each other, you really gotta ask yourself that what more data do you need to see for proof of concept. Stay tuned for that. We also have a phase 2B EMERALD-2 study going on in moderate to severe UC. The way to think about this is what now that we have our proof of concept out of the way, scaling up and optimizing and pushing toward registration and approval. This study looks very similar to the UC studies that you've seen out there. Multiple doses at 200 milligram BID, 100 milligrams, and even a QD dose there. A large study, and the primary endpoint here is one that you're much more typical, the modified Mayo clinical score. One that you've seen over and over. Then it moves into an open-label extension study. A very standard trial. In this one, we are just looking to essentially optimize after our proof of concept study. What is the opportunity here? The opportunity here is a first-line advanced therapy in IBD. You know, you can make this very, very complicated. The, you know, the peak sales now of vedolizumab are expected to be above $7 billion. There are a lot of molecules, not a lot of oral molecules. You can make this complicated, but I always say that if you get a consistent response, you actually don't need a lot of data. What I've said all along is that you actually only have to ask two questions to understand how this could be the first-line advanced therapy in IBD. We did an experiment, and actually you guys can all replicate this experiment, you know, 'cause we did this experiment right here at J.P. Morgan, finding a couple IBD patients. Let me just run this video, and then I'll explain. Do you have inflammatory bowel disease? No. I do not. Do you have inflammatory bowel disease? I do. Ulcerative colitis or Crohn's? Crohn's disease. I'm sorry about that, first of all. If you had a choice between an oral medication you could take at home or an infusion, which one would you prefer? I'd take the oral medication. If you had a choice between being immunocompromised or non-immunocompromised, which one would you prefer? Non-immunocompromised. Thank you very much. Thanks for asking me. Sometimes it really is that simple. Thank you. Now we will answer any questions. I'll have Mark and Bruce come up, and happy to answer any questions that you guys have. Go ahead. Sure. Maybe just building up from the man on the street market research. I guess when you do a more extensive, more in-depth set of market research, ultimately, what type of market share do you think you could draw away from the performance of vedolizumab, assuming all things being equal? I actually have never felt the need for a large market research on this, but Mark has. We have done large market research on it. Do you wanna talk to that, Mark? Sure. Absolutely. It wasn't exactly the same questions that were asked by Praveen at this conference, but we did do that big market research. It's not purely about taking market share from ENTYVIO, to be clear. There's some areas for sure that we can go into that ENTYVIO is not currently very strong in, but of course, that's a part of it. It increases over time, and I think what you see with ENTYVIO is a trend that we would expect to have happen with MORF-057 as well, which is earlier and earlier use. The safety profile is key. In this disease, safety is absolutely top and king. We feel like if we can recapitulate that overall profile and the safety profile as well with an oral pill, it's a relative no-brainer to use that earlier and earlier. It's a multi-blockbuster opportunity in the later stages of use, but as you go earlier and earlier, it really starts to accelerate the commercial potential of it. That's certainly an area that we'll be focused on as well. Big incentive to get there. I guess strategically, how do you pursue it? Independently? Is there a point at which you might look to sort of partner for the sake of going fairly broad with the broad in development with 057? Go ahead, Mark. Sure. I mean, I think that's a multifaceted question. We're certainly very open to those types of conversations. We're a pretty strategic management team on the whole. Ultimately, if you fast-forward 5, 10 years, I mean, the likelihood of us commercializing this drug in Serbia are relatively low. We do at some point think that The rubber needs to hit the road, a very large sort of global I&I juggernaut is probably best to commercialize this drug in Serbia, for example. The question is between now and then, at what time do you sort of maximize the value to our company, to patients, to our shareholders, and capture most of the major value inflection points that we can and capture them entirely ourselves, versus what is the right time to find that big brother, that big partner who can potentially accelerate the drug and obviously get it into the farther reaches of the world as well, once we're commercial, knock on wood. Actually, you get the question I'm sure all the time about, you know, expectations around the upcoming data and how to make comparisons again with the activity profile of avelumab. I guess what, in the view of physicians that you consult with would be basically sort of in line efficacy, if that's a, an appropriate question. Bruce, you wanna answer that? Sure, I'll take that. I think the key thing there is that, you know, we've powered the study to be something that shows a change from baseline on the Robarts Histopathology Index. If you look at the data that's directly comparable to Entyvio, it's the data that came out of their phase 4 studies, actually. It showed that, you know, the mean change from baseline for that drug was about 7.5. Of course, that depends on whether you have a population of naive or previously treated biologic patients. There's some, you know, plus or minus to that, but around 7.5 on that score. We're also gonna be measuring a lot of other data as well. We'll bring you the same data we looked at in our phase 1 study. Looking at safety, of course, in patients now, PK in patients, receptor occupancy, cell type changes, the things Purvi and I already talked about here today that we've done in healthy volunteers. Then all of the components of the modified Mayo score, the Mayo score, the Geboes score, all of that data will be available, and we'll really put an understanding around that. The focal point from the perspective of how we powered it was really around the Robarts Histopathology Index. Any IBD patients in the room? We can replicate the survey. Are you measuring those? Do you wanna just wait for the microphone one second? Oh, thank you. Go on. Go ahead, Bruce. Your colleague here just answered the question. If you want to give more detail on, if you're measuring the Mayo score or not? Yeah. We're measuring all the components. The modified Mayo, the Mayo, the Geboes, and then the Robarts Histopathological. All of those components will be measured, and so all those component scores will be available. For what particular reason was Robarts becoming primary versus Mayo, considering that's the phase 2b primary? There's a number of reasons that we focused in on this and you know, one of the biggest is that we wanted a score that sort of removed the elements of subjectivity from scoring. Robarts is done in a way where you take an endoscopy of a patient, you take histology as well, and then you bring those all to a central lab to read them. It's that central reading that typically reduces some of the variability. That's important because we're dealing with about 30 patients here, right? If we were dealing with 70 or so patients, which is what our phase 2b study has per arm, now you start to reduce some of that variability, and that's where you can really power and walk into the modified Mayo score. It's also an open label study, right? Everyone knows that they're receiving 100 milligrams of BID in this study. Reducing that variability as much as you possibly can, to keep your placebo rates and things like that down is important. For the central read, are the biopsies all read in order? Are they scrambled together? Or is it pretty apparent to the reader if they're reading a post-treatment one versus a pre-treatment? It's not. It's all blinded, right? There's a trained group of readers, and they actually don't know if they're getting a sample that's pre-dose, post-dose, 12th dose, fifth dose. They have no idea, right? They're getting a sample to read, they provide a read. It has to corroborate with another reader, and if that read is not consistent, a third reader will actually read this and really come to a conclusion of what the actual score on it is. Thank you. In the phase 2a, are you enrolling treatment-naive patients, or are they biologic-experienced? Go ahead, Mark. Sure. It's actually both. We didn't specify by force that it would be exactly 50-50, but the plan was to try to enroll patients and use sites where, on average, we thought approximately there would be a mix. We tried to have a mix between Poland and the U.S., between moderate and severe, younger, older, and also treatment-naive and experienced. How does that compare to the 7.5 number you gave us, which was the mean change for ENTYVIO? Is that also based on that same mix? It is. It's a similar mix. We haven't disclosed the exact entry criteria of our 35 folks yet, our 35 patients. When we do, you'll see that we tried to make those all those parameters as consistent as possible. Last question. The phase 2a is after 12 weeks? Yes, 12. Okay. that seven and a half, was that also measured at 12 weeks? I believe that was 14. 14. That's That's 14. That's enough. Patients had 2 more weeks to improve in that study, but 12 is also a very common endpoint for this induction. The rationale to go up in dose in EMERALD-2, where you're evaluating 200 just, I guess, the anticipated need for that just. Cause you're already saturating, right? No. I understand the question. Yep. Yeah. Why don't we have Bruce ask? Sure, I'm happy to take that. We, you know, we quickly went into this phase 2a study, and because we were saturating receptor occupancy and we had a formulation and a capsule strength that we could utilize, we just quickly started up that study at a saturating dose. In the meantime, we were developing a larger capsule strength to carry into our phase 2b studies. In the context of testing that in another healthy volunteer study, we reported out this data very recently, we decided not only to dose 100 milligrams, but actually go up to 200 milligrams BID to just see what happened. The rationale behind that was, are we maximizing the biologic response? The answer to that question is, we believe we're maximizing the biology, the biologic response. We see a doubling of the exposure of the drug by doubling the dose, but we don't see a further increase in the T-cell populations or of course, we're saturating receptor occupancy. We took the PK data from that study, and we built a PK/PD population model, where you actually, in the context of this, you take data from less than 12 patients, right? You build a model, and you try to estimate what will happen in 1,000 different individuals, not 8 different individuals, as was the number in this case. That model told us that based on the broader metabolism of the human body, that there's an incremental increase in our ability to ensure that in all patients, we get to saturation of receptor occupancy. It's not a PD argument, it's actually a PK argument to make sure we have it. Of course, we have the safety profile that we need to be able to dose to that level as well. We decided to test it in the context of our dose ranging studies, and it really sets us up for a really nice full dose response curve, 200 milligrams BID, 100 milligrams BID, which we used in the 2a study. Then we're actually using a QD dose as well to finish out the full dose response curve, to be able to build that full PK to PD to now efficacy response level in our phase 2 studies. Maybe just a couple questions on around the pipeline behind MORF-057. Just picking up on the αvβ8 program for myelofibrosis. I guess you characterize this Pravin as a potentially disease-modifying therapy. I guess I don't know. Is it a bit odd to think about where in the, I guess, patient's symptomatology you might expect to have an impact. If we think about sort of the primary axes being splenomegaly and then anemia on the other side, is there sort of one realm where you expect to have more of an impact? Bruce, go on. I think it'll affect both of those endpoints is what we actually anticipate. We're building that full data set out now. You know, the real pivot from solid tumor into a monotherapeutic disease, as Pravin said before, was driven by, you know, there's a complex area of using two therapies, PD-1 plus something, that's really what this trial was. Go to something where we can get to monotherapeutic data, and both of those pathologies should be affected. Again, it's really driven off of the inhibition of the TGF-β pathway. There's been some work already in this space in the clinical setting where the TGF-β pathway inhibition has led to not only those two outcomes, but one additional outcome, that's a true fibrotic change within this population as well. The fibrotic change is really the one that we think is driving potentially the, if you will, halting of disease first. Are we truly disease modifying that, you know, play it out whether it has, but there's a potential to be that for sure. Okay. Practically speaking, I mean, we should be thinking about this as a potential alternative to upfront therapy to Jakafi, or perhaps something that would be in non-responding patients, at least. Maybe perhaps the answer is both, but maybe. You're actually touching on exactly the place where I think that an early entry point can happen here. There's a lot of patients that don't respond to JAK therapies or that cannot take JAK therapies. That patient population is severely underserved within this area, and that's the kind of patient population that we wanna be able to really think about how could we go into. Of course, the other population, as you said, is one you could potentially go into as well. If we can splice out a part of this patient population to get to an early proof of concept, that's really where our discussion's at right now around what does that patient population look like. Okay, great. Hold for any more questions from the floor. Okay. Well, here we go. Terry. I think in the early days of this 30-patient study, you were talking about maybe giving the data earlier if the first dozen or so were consistent. Did that change, or are we to read that the first dozen or so were not consistent? That's good. Good question. Go ahead, Mark. Sure. I'll give it a try. You're absolutely right. Last year, we said there's a possibility of sort of an interim readout. We didn't know what the pace or the kinetics of the enrollment would be, right? If we were in a situation, given that it's open label, that management has, say, pick a number like 15 patients, it told a pretty clear story, the trial is enrolling like molasses, we're gonna have all of the data in 6 months, it's a very uncomfortable spot for us to be in, sitting on that obviously material data for so long. If that had happened, there would have been some sort of disclosure at that point. Because the enrollment, you know, the second half of the trial enrolled in such a short period of time, at the end, the hockey stick kind of kicked in and enrolled in 6 weeks. Right now, we're getting the last half of the data this month, next month, roughly. It would be crazy for us to announce half of the data and then 6 weeks later announce all the data. That's why that's not gonna happen. You saw it kind of at initial 15, and then. It's not about saw it's about the enrollment. I mean, we hadn't seen any data at the time, right? 'Cause you're just enrolling them and, you know, you get your 12-week read for each patient. Back in the fall or so, the whole second half of the trial enrolled in the, call it fall, late fall. We knew that the timeline was basically. Was going to be. Yeah, between half and full is six weeks, basically. Correct. At that point, we're like, "Okay, you don't know the- Might as Yeah. Right. You don't know the data, but you know the timeline. I think we'll leave it there for questions. Thanks very much to Pravin and the Morphic team, and thanks everyone for tuning into the session. Thanks, everyone. Thanks.