Welcome, everyone. Hope you're having a great day three at the J.P. Morgan Healthcare Conference. I'm Bhavana Balakrishnan, an associate here in the healthcare investment banking team. Welcome to the presentation of Morphic Therapeutic. Today with us, we have Praveen Tipirneni, MD, who's the Chief Executive Officer, Bruce Rogers, PhD, who's the President of Morphic Therapeutic, and we have Marc Schegerin, MD, who's the Chief Operating Officer and Chief Financial Officer. We'll have time at the end for questions. For now, over to you, Praveen. Great. Well, thank you. Thank you to the J.P. Morgan team. Thank you, Bhavana. Thank you, Phil Ross. This year, it's actually a particular thrill to just be physically standing here. Some of you may know that this last quarter, I had a cardiac-related medical event, spent 3 weeks in the ICU and several more weeks in the hospital after that. Actually, there were dozens, as you can imagine, there were dozens of medical interventions, things that are actually like household names to us here at this conference, so both devices and medicines that were applied. It really made me think that, you know, what we do in this industry is important. Actually, I'm physically standing here today because of it. Before, before we dive into Morphic's accomplishments and what may lie ahead, let me just note that we will be making forward-looking statements and, you know, you should consult our SEC filings to understand all the risks and uncertainties. Okay, now let's get down to business. I thought we'd start with the big picture first. Before we focus specifically on MORF-057, our recent success, what we're hoping to do with the EMERALD-2 data and some of our pipeline, let me just frame the discussion by taking a macro, long-term view of the IBD treatment paradigm. As I noted in a conference call when we announced the top-line results for EMERALD-1 data, this is the way we look at the future of treatment paradigms in IBD. As probably many of you know, that the efficacy rates in IBD is still fairly low, so there's quite a bit of progress yet to come. And here are the various horizons and the way we think about it. Injectable biologics, the last few decades, the dawn of oral therapies, this is where we are today. Safe, oral, and effective. This is the future. This is the promise of 057 and ultimately, combinations to really break through the efficacy ceiling. And I'm gonna spend actually quite a bit of time, for the first time in our presentation, I'll be talking about combinations, in the slides to come. What we're talking about today is alpha-4 beta-7. This is a very well-validated mechanism for IBD. Vedolizumab is a monoclonal alpha-4 beta-7 inhibitor, approved for the treatment of ulcerative colitis and Crohn's. As you can see in that diagram there, it's a fairly very straightforward mechanism, preventing the T cell migration out of the bloodstream and into the gut, which causes the inflammation. That's the pathology of the disease. The antibody, Entyvio, also vedolizumab, also called Entyvio, continues to experience growth, and it's increasingly earlier and earlier line deployment based on its remarkable combination of efficacy and tolerability profile. An oral alpha beta seven inhibitor would be a gigantic leap forward for patients. It was a bit tongue-in-cheek, but if you remember last year at this, presentation conference, we asked, and we found random IBD patients in this conference themselves and asked them the question of what target product profile that they, would prefer, and all roads lead to an oral alpha beta seven. So this is what the ideal would look like, the holy grail of UC treatment, an oral, safe, effective drug. This has been so far lacking. But as I touched on earlier, this—if you can get a well-tolerated oral application, it actually unlocks a much bigger market, the era of combinations. We've seen glimpses. Actually, I came from the antibiotic world, and people always talked about, I was at Cubist for 13 years, and everyone in antibiotics talks about combinations, and it never happens. Like, it's just too complicated. But here, we've been talking about it for a long time, and this future is coming much faster than you think. And so we think, the first well-tolerated, safe, efficacious oral would be the ideal back form for a combination treatment. So let's all take a walk down our development just memory lane here to understand why we feel particularly confident in the ongoing and upcoming studies in UC and Crohn's. What I hope you'll see is a uniquely consistent, sequentially correct track record that we've shown on the path toward an oral effective IBD drug. But what I'm gonna do is very quickly go through all of the MORF-057 data holistically. And the reason I do that is so you can see its remarkable internal consistency. Now, let's start with the molecule itself. You need a potent molecule. In this case, MORF-057, low nanomolar potency across a range of in vitro assays. But the harder part, you know, what really... Why it was so difficult to make this molecule, and the standard that you should compare this against any other molecule, is a greater than 3,000-fold selectivity for alpha-4 beta-7 versus alpha-4 beta-1. This drastically reduces the risk of PML through alpha-4 beta-1 inhibition. Very difficult problem. So potency, selectivity, check.... Now let's talk about the consistency of the PK data across mouse, non-human primates, human subjects, and patients with ulcerative colitis. The target here was to achieve oral bioavailability in a class where it's been very difficult to do that previously. We achieved this in all species evaluated, from rodent to canine to non-human primate, notably a consistent dose that covered IC90 at trough in exposures, C90 exposures across all species. These data translated to human subjects, which supported a BID dose in both patients and supporting a BID dose and even possibly a QD dose, and we saw the same consistent results in UC patients. So the PK of mouse, NHP, human subjects, and patients were consistent. Check, check, check, and check. Now let's go to the receptor occupancy. Alpha-4 beta-7 receptor occupancy, inhibition of the target receptor across mouse, NHP, human subjects, patients, that simple mechanism that was described in the previous slide. We developed a MAdCAM-based RO assay and made the system as physiologically relevant as possible. We designed the assay using magnesium rather than manganese. Then we put it to use, and we've published all this. We were able to demonstrate alpha-4 beta-7 receptor saturation in rodents. We were able to saturate the receptor at all time points in non-human primates at 30 mg/kg at trough. We had a positive surprise in our phase 1 subjects, and we were able to saturate at 50 mg BID in ulcerative colitis patients. So again, very consistent results. The inhibition of alpha-4 beta-7 was consistent and in fact improved as we went from mouse to NHP to human subjects to patients. We can saturate the target receptor. Check, check, check, and check. I love doing that. Now, what does that translate into? Let's talk about the consistency of the translational evidence across mouse, NHP, human subjects, and patients. Inhibition of alpha-4 beta-7 leads to the same inhibition of the homing of the T cells as the alpha-4 beta-7 monoclonal antibody across rodents again, non-human primates, humans, and patients with UC. And this was in a very selective pattern. You don't want to be affecting all the lymphocytes broadly. All the beta-7 positive lymphocytes increased, all the beta-7 naive lymphocytes stayed the same. Results were what we were looking for, all good. So that's again, check, check, check, check. Pharmacokinetic. Now let's talk about the tolerability profile. In each of our studies, we had a favorable tolerability profile with 057, which this is very critical to the success of an IBD agent. From assays demonstrating 1,000- to 3,000-fold greater selectivity for β7, to favorable results in rats, canines, and again, both healthy and in patients with UC. Mechanistically, we observed what we expected to see. A selective blockage of α4β7 leads to localized gut suppression without the systemic immunosuppression. Check, check, check, and check. And finally, let's talk about the efficacy, the consistently positive efficacy results. If you block the transmigration of the cells into the gut, the mechanistic slide you saw earlier, what would you expect to see? You'd expect to see clearance of T lymphocytes from the gut. What directly measures that? RHI, the Robarts Histopathologic Index, which directly measures the lymphocyte density in the endothelial space, the exact pathology of IBD. This was the primary endpoint of EMERALD-1. So where we achieved a statistically significant response, 0.0019. And for all, I'll show you in a, in a few slides, but it-- across a whole host of disease measures, beyond that primary endpoint, we performed just as well. 25.7 in Modified Mayo, strong RHI remission rate, excellent absolute changes in RHI, as well as Modified Mayo. So again, consistency across therapeutic measurements, check. 20 checked boxes, all consistent with each other. This is a remarkable level of consistency and provides us with great confidence as we look forward to the results of the randomized EMERALD-2 study of MORF-057, which is enrolling right now, and it's fully on track. So I went through that really quickly. Obviously, the transcript's available, but let me let me go into a few deeper into just a few parts of that. As a baseline note, just in terms of the demographic, demographics, just note that we were treating a moderate to severe population, but it was skewed towards the more severely diseased end of the spectrum with 10 out of 14 patients. These 10 out of 14 patients had the worst possible endoscopy score upon screening. RHI was the predetermined primary endpoint and was met with statistical significance, as you can see there, P = 0.0019. But that's just one data point. We also saw a very strong RHI remission, as you can see there, 2.9%. And then based on that RHI response, we got the response in the Modified Mayo that you would expect to see. 25, the modified Mayo there, 25.7. So the RHI remission was 22.9, sorry. And so very consistent results, highly competitive with the results from the trials of other UC agents. And that was followed by consistent scores in the absolute changes of the RHI and the Mayo scores as well. So in line with the expectations of an alpha-4 beta-7 inhibitor. If we break that down even more, so this is another forest plot here, another depiction of clinical outcomes from EMERALD-1 that again underscores the consistency of the effect in the study. So here, what we're looking at is the two main clinical measures, which I talked about, the Robarts Histopathologic Index, RHI, and the modified Mayo. This is analyzed by prior treatment with advanced therapy, with corticosteroid use at baseline, and the baseline Mayo endoscopy score. In every case, as this is an important slide here, in every case here, you can see that the results are directionally consistent, directionally correct, and the magnitude effect is proportional to what you'd expect for the level- for the baseline status of the patient group. Now, let's go to another way to look at this. So what did... These are all the patients, right? As you can see, about change in the Modified Mayo, 80% of the patients, you know, improved while they were on this study. So again, very, very consistent results. Another way to look at it is that this is, this is, so now we're past the induction phase here. Now we're at week 44. So what you're looking at here, in a longer time point, and this is across symptomatic remission, which is, you know, rectal bleeding and stool frequency. So rectal bleeding and stool frequency. And what you're looking at here is in blue there is the naive patients, and in orange there is the advanced therapy patients, experienced patients. And as expected, in the naive patients, they responded very, very quickly. Again, it's hard to see for me as well there, but even within that first time group, you see the patients improving rapidly. And as you expect in the experienced group, it took a little bit longer, right? So again, what we're seeing here is that the patients are largely all responding in the way that you would expect them to respond. Naive responded quicker, and the advanced therapy patients took a little bit longer to respond, but they all, those 80% of the patients all responded. Now let's talk about the EMERALD-2 study. This is our study that is enrolling currently. Here we've gone through the design of the study. It's a very standard study for UC. I'm not gonna go into all the details now, but just to say that we are very comfortable with our own guidance. It's enrolling well, and we expect to have our results in hand in the first half of 2025. Hold on. Yeah. And if... We previously, people asked us why we did the 2a study, and we said that, you know, we were looking to really understand if we had a drug. We don't know the exact numbers, you know, what, what response will look like and things like that. We want to know if we had a drug, and people were saying, "Why?" And with that study and said it could trigger a number of investments, and one of them being the Crohn's trial. With our confidence from that phase 2a trial, we're really excited to announce today that we are, the launch activities are underway for our Crohn's disease trial, which is, we are labeling the GARNET study. This is, again, a very standard design for Crohn's trial, global randomized phase 2b trial in patients with moderate to severe active Crohn's disease. There's multiple doses. You've seen these doses before in the 2b trial. For UC, 100 milligrams BID, 200 milligrams BID, and a placebo arm. And this, we are... Launch activities are underway, and we will, of course, announce when we have a first patient in the first half of this year. The other thing I want to note here is what is our perspective on the IBD market landscape? And let me just orient you to this schematic here. The y-axis is efficacy, the x-axis is safety, and what you're seeing is the various classes of IBD agents by their relative efficacy level, you know, and safety level. One thing to note is that, as you can see from an efficacy level, they're all in a fairly narrow band, all the classes. A lot of the differentiation actually comes from the safety rather than the efficacy. So far, nobody has been able—no monotherapy has been able to break through that, what we call the efficacy ceiling. So we also kind of looked at the from a schematic perspective, what we call the restricted area, an area that monotherapy has not been able to go, that you really require combination therapy to break into those kind of efficacy levels. And what we think is gonna happen is you're gonna see growth in all those areas. But given this population, remember, this is a young population, they travel, they have jobs just like us, their lives are disabled, but they're not shortened. And so an oral, we actually call it like an injectable penalty, right? Injectable and a safety penalty. If you, if you took away those penalties, you get a lot of the proportionate growth to an oral, effective, safe drug. And then what—if you do have that, we believe what that unlocks is becoming the backbone of future combination therapy, which is where we believe a lot of this growth in the future in IBD is going to come from. Now, let me move past our MORF-057 and IBD to the rest of our pipeline. We've talked about this for many, many years, what we call the MINT platform. We believe that we are the only ones with this platform. It's focused—This platform is focused on the integrins. There's a structural basis for it. It allows us to very exquisitely interrogate the integrin biology, which is unlocking a lot of opportunities across therapeutic areas. What does our pipeline look like today? This is what it looks like today. So we have MORF-057, alpha beta 7. We have a next generation one, which, you know, on specificity, on potency, is even greatly improved over O57. That could be the key to the combinations that we've been talking about. We have a set of non-integrin targets that we're just starting to work on. And then I want to talk a little bit more detail about two particular programs that are advancing rapidly. One is alpha beta 1 for pulmonary hypertensive diseases, and the other one is O88 for alpha-V beta-8. Those are actively moving toward the clinic. So alpha-V beta-8, we've talked about this before, a small molecule integrin inhibitor for myelofibrosis and immuno-oncology. What we're looking at it is for myelofibrosis. We do think that, except for allogeneic hematopoietic stem cell transplant, there are no disease-modifying therapies, and there are multiple deficiencies, from toxicity, resistance therapy over time, and again, nothing actually modifies the disease. And so we think, through TGF-beta, this offers a great potential to help patients here and increase the platelet counts. Let me just show you a little bit of data. And here, what we're showing here is that expression patterns on the, on the left-hand side there. You could see that in patient samples, in healthy donor and myelofibrosis patients, that we isolated the expression patterns to show that this really is driven by alpha-V beta-8 rather than alpha-V beta-6. That's what you see on the left-hand side. On the right-hand side, what you're looking at is effect of an alpha-V beta-8 inhibitor on megakaryocytes and osteoblasts. As you can see there, it's doing exactly what you'd want it to be doing to treat myelofibrosis, enrichment of megakaryocytes and decreased osteoblasts. So trying to get you back to a healthier bone marrow niche. We're very excited about this program, and we're just filling out the entire biology package to advance it into the clinic. And then let me talk about alpha-V beta-1. We had this slide, uh, last year, but we're announcing publicly for the first time what is the actual target. And this slide, even last year, what I told you, right, is that, okay, if you think about a cardiovascular drug, here we're talking about pulmonary arterial hypertension, but it may have opportunities even beyond that. In preclinical studies, this molecule is showing it reverses the remodeling in the pulmonary vasculature. It directly prevents right ventricle fibrosis, so this is not secondary to hemodynamics, and improves cardiomyocyte efficiency. This is early, right? You know, we're... It's advanced to the clinic, it's early. But if these properties continue to play out the way they have been in preclinically, this is the cardiovascular drug people have been looking for for 50 years, right? And so we are very, very, you know, excited about this compound. Let me just show you a little bit of data. It's doing what we expected it to be doing. So this is the rat Sugen model, which is the gold standard in pulmonary arterial hypertension. You're seeing that both in medial wall thickness as well as cardiac output, it's operating the way you'd want it to in a dose-responsive fashion. So we're very excited about these results. And then the second one there, the rat pulmonary arterial banding model. So this is to figure out whether it's a direct effect or an indirect effect, that you hold the afterload of the right ventricle constant and then look at the cardiac output. And as you can see here, a really nice increase there in cardiac output, showing a very direct effect on the right ventricle, not secondary to hemodynamics. So again, another compound advancing rapidly toward the clinic, and we're really excited about what this possibly can do, you know, in patients. So we... It's just been a really exciting year ahead. Lots, lots of data that we will present over the year and continuing to enroll in the Crohn's study and the UC study, and hopefully, you know, we'll have a result as soon as possible. So thank you. One other thing I wanted to say here is that, again, I want to thank actually all the Morphic employees, just 'cause I was out this entire quarter, and they continued, a number of them are here in the room as well. They all continued to run. Actually, in some ways, make myself redundant, but they managed to run the company very effectively, and I'd like just like to thank them publicly. So thank you. Thank you, Praveen. Hardly redundant. Hardly. Want to open up for questions, if any, from the audience? Okay, I can start with one. You showed us the landscape slide with a lot of exciting- Mm-hmm. New approved agents and modalities that's coming through. Can you tell us a little bit more about why you feel that MORF-057 is differentiated? Sure, um- ... Mark, you wanna take that one while I try to get back there? Sure, happy to. So one of the things that Praveen mentioned and highlighted in this presentation is the current lack of an available therapy that is safe, oral, and effective. And so that's sort of a glaring kind of lack, given this is a relatively mature, fragmented market. There have been approved drugs, even approved advanced therapies now for a decade, almost two decades. And there are some that have some positive attributes and headed in that direction, but nobody can kind of achieve that trifecta of, say, oral and effective. That said, you know, effective is in quotes for all of us, because none of these drugs, including probably ours, is just curative for UC and also Crohn's. And so there's still a lot of room to improve with respect to true efficacy for all patients, or at least a vast majority of patients, as opposed to making some patients a little better and a minority of patients much, much better, which is what basically all of the drugs do today. And, barring some genius new mechanism, which is yet to be discovered, it seems like combinations of different or orthogonal mechanisms used together could actually be a way to achieve kind of a step function in efficacy. And so it's a combination of sort of step one being a safe, oral, and effective drug, which is a great advance, number one. And number two, the sort of next frontier, which is being able to combine two of these effective mechanisms that are different in the same disease to achieve a step function in efficacy. Of course, most of these, currently approved drugs or other drugs that are in development are somewhat immunosuppressive systemically, and so it may be an acceptable level of systemic immunosuppression used alone, but used in combination may no longer be acceptable. And since this program is completely not immunosuppressive at all, based on its mechanism, it could, in theory, be agnostically combined with any of the other mechanisms without actually adding to that systemic immunosuppression. That's a, you know, two major points of differentiation. One is safe, oral, and effective, doesn't exist, and the second is the combinability with, frankly, most of the other mechanisms that already exist. Yeah. Sorry, could you wait for the mic? Please, one second. Just so that we catch you on the transcript. Thank you. Nice presentation. Thank you. Yeah. When you refer to combination, do you refer to a combined fixed drug product or the two drug product given at the same time to the patient? Well, I think, I think there'll be an evolution there, but, Bruce, you wanna take this? Sure. And I think evolution is a good way to describe this, right? Because, today, most of the therapies that are used as second-line therapies are biologic form, as Praveen pointed out, in his slide. And in combining a biologic with a small molecule is one thing, it's two separate entities. As we start to evolve the space here, and we start to understand which of these combinations of drugs provide the best outcomes, I could see a next generation of these drugs coming forward. And so one of the things you may have noted in our pipeline is that we're still working on alpha-4 beta-7, and we're working on alpha-4 beta-7 to identify compounds that have exquisitely low doses that can be dosed once a day. When you start to have a pill that is 25 milligrams, for example, once a day from a dosing perspective, now I can combine that with whichever mechanism. Today, we just don't know which mechanisms to combine. So I think there's a lot of clinical trial work that has to go on, and as Marc said, it's gonna evolve, and Praveen commented as well, that that's how I see the evolution happening here. I think it's a good strategy because we've seen in a fixed drug combination where people combine the drug too fast, that the practitioner are not prescribing them, but they're- Mm-hmm. prescribing them separately so that they- Mm. It had no commercial or poor commercial penetrability or- Right. Yeah. Yep, we'll build, we'll build that, right? This is, this is an evolving area, right? Mm. The element of combination approaches in IBD is something that's fairly new, right? So the VEGA study, for example, that Janssen ran last year, they showed this, a doubling of an effect in these patients. And will we see more doublings of effect? We really need to study that in combination. Thank you. Given the profile of vedolizumab, can you tell us why you think others have not been able to create another alpha-4 beta-7 inhibitor? We'll go to Bruce. But it is some... Let me just mention that a quote from a competitor, this company got acquired, but when... For some, he's like: "How did you guys possibly create that molecule without a pro drug, pro drug? That's really remarkable." I said, "It wasn't me, it was Bruce." Right? So he can explain. And I can't take full credit for it. We have a fantastic chemistry team that Blaise Lippa was leading from the beginning of the company as well. And that team really partnered very early on and did a couple of things. Number one, they took advantage of crystal structures, and they didn't just take advantage of crystal structures of alpha-4 beta-7; they solved crystal structures of alpha-4 beta-1. And when you have those two powerful tools, and you couple them with Schrödinger's technology to do FEP calculations and build an understanding, before you ever make a molecule, which of these might not only be potent but selective? Now, that engine that we built at Morphic is really enabling us to explore this, and we had insights into what happens when something binds to this crystal structure that no one else had. And so it wasn't until we actually took advantage of those, and we had to form new crystal structures, right? Because you can't just freeze out a crystal structure. These proteins move, and so you have to be able to take advantage of that and build an understanding, and it's only through iterative structure-based drug design that we were able to accomplish that. Couple that with building a deep understanding of how do you build in high levels of permeability, that led to oral bioavailability. And one of the key chemists on the team at the time, Matt Bersavage, always says, "Man, when am I going to get to give this talk? Because it's a wonderful story to tell." It's really this intricate lacing of the data pieces together that allows us to get there to the small molecule. And the next generation are even more potent, more selective, because we've continued to learn over the course of the program. Thanks, Bruce. A question on your pipeline, your alpha-V beta-8 pathway for myelofibrosis. Can you tell us about how that's differentiated from current standard of care? Sure. Mark, do you want to talk about that? Sure, happy to. So the alpha-V beta-8 integrin activates two of the three different isoforms of TGF-beta. So this is really a TGF-beta-based approach for myelofibrosis and could have applications in solid tumors as well. But initially, we're gonna be looking into making sure we have the right package for this program to go forward very deliberately in myelofibrosis. So the expression pattern of alpha-V beta-8 is selective. It's not expressed all over the body, kind of constitutively. It's expressed in areas that are relevant for myelofibrosis, such as the bone marrow, et cetera. And so what we're really doing is inhibiting selectively in those areas where alpha-V beta-8 is most expressed, the activation of isoforms 1 and 3 of TGF-beta, which we think will help kind of arrest that cascade of inflammatory cycle with ultimate fibrosis in the bone marrow of myelofibrosis patients. Maybe I'll just add one thing to what Marc said, is that I think about this, you know, in a simplistic way, as a disease-modifying approach. Whereas most of the approaches that have been applied in this space have been focused on simply reducing spleen volume, they actually relieve the patient for a short period of time. But getting to the underlying disease, as Marc is pointing out, is really what we need to do for these patients in the future. How are you thinking about the milestones and timelines for bringing this product along? Mark touched on this, right? I think the key is, yes, we were going full bore to go into an oncology study that would have been combining this compound with PD-1, and that landscape has changed over the last couple of years. Very complex space to navigate. So we're not starting from nothing. We have a great compound, and so it's building out this package. And, you know, as we build out that package and determine which of the subsets of myeloproliferative diseases is absolutely right, myelofibrosis is the lead there, we'll guide more toward where we're gonna go from a perspective of entry to the clinic. Another question from me, but probably more high level. Could you tell us about your current capitalization, or like at least which milestones do you think you're funded through? Mark, why don't you take that? Sure, I can take that. So, you know, we have a 10-K in a few weeks, but I think it's no surprise, given our last Q, that we'd have approximately $700 million in the bank at the end of 2023, and that our guidance has been very consistent for the last year or so, should take us into the second half of 2027. So with data coming from our registrational—not registrational, but registrational path, phase 2b trial, EMERALD-2, coming in approximately a year plus or so, we've said that we'd have data in the first half of 2025. It takes us far, far, far beyond that, so. Great. Any final questions? If not, I want to turn it back to the team for any closing remarks. Thank you for your attention. We are very excited about the year ahead. Appreciate the interest. Thank you. Thank you. Thank you.