Okay, great. Just wanted to thank everybody for coming today to this Piper Sandler Annual Healthcare Conference. I'm Joe Catanzaro. I'm one of the biotech analysts. It's my pleasure to welcome Shattuck Labs and their CEO, Taylor Schreiber. I'll hand it over to Taylor, and he'll tell you a bit about the company.
That's g reat.
Thanks, Joe. Thanks to Piper Sandler for the invitation to join. Many of you may know Shattuck from our oncology program, which we pivot away from in October of this year. So today's talk, albeit short, will be focused entirely on our current lead program, which we call SL325. This is a monoclonal antibody that blocks the receptor for TL1A, which is known as death receptor 3. Many folks will likely be very familiar with the Prometheus data for Merck's antibody tulisokibart that was recently published in the New England Journal. The results that were found in that study were really striking, where you saw a placebo-adjusted complete remission rate in the range of 25% in a population of ulcerative colitis patients that were largely experienced with multiple biologic therapies.
And so many folks are, I think, correctly viewing interfering with this signaling axis as being complementary to the well-established anti-alpha-4 beta-7 and anti-IL-23 therapies in the IBD setting. And if you look around the landscape today, everybody is focused on TL1A. And TL1A binds a receptor, which is known as death receptor 3. And this is a pretty simple axis. TL1A is the sole signaling ligand for DR3. And DR3 does not bind any other signaling ligands than TL1A. So from a safety and specificity standpoint, there's no reason to believe that interfering and antagonizing DR3 will be distinct from blocking TL1A. The only other wrinkle to the axis is that humans evolved a decoy receptor, DcR3. This is a soluble receptor that presumably evolved because it became advantageous in larger order mammals to develop a secondary means of quelling inflammation that was driven by TL1A.
DcR3 also binds Fas ligand and LIGHT, which are the other two TNF family ligands that can drive inflammation. The way that this axis works, the rules for the axis were really all defined sometime between 2002 and the mid-teens in the 2000s. The figure on the left illustrates one of the points, which is that TL1A is primarily expressed by antigen-presenting cells, and so that it is a ligand that is turned on in tissues. It can also be expressed by epithelial cells in those tissues. DR3 is a receptor that is almost completely isolated to lymphocytes and innate-like lymphoid cells. One of the unique aspects of TL1A signaling through DR3 is that it can co-stimulate a wide range of immune responses, a wide range of effector T cells.
So it can activate innate-like lymphoid cells, CD8-positive T cells, and CD4 cells that are polarized down the Th1, Th2, Th17, or Th9 lineages. And the unifying mechanism for how this axis works is that DR3 signaling sensitizes lymphocytes to interleukin-2 in an antigen-dependent manner, and so that's what we're looking to interfere with here. And the figure on the right was published by Richard Siegel's group. He's one of the investigators that's been studying this for a long time. He was at the NIH, now at Novartis. And the result here is showing in the top panel something that's reported in a number of other publications, which is that if you overexpress TL1A, animals will become hypersensitive to developing inflammatory bowel disease, mouse models of inflammatory bowel disease.
That can be completely neutralized if you cross those TL1A transgenic mice onto a mouse strain that lacks DR3. This is one of many data points that proves that this is a monogamous receptor-ligand pair. If you look across all of that preclinical literature, you will not find any examples of autoimmune mouse models where interfering with DR3 is inferior in terms of the resolution of inflammation that it provides to interfering with TL1A. You will find a number of publications that show that interfering with DR3 is more potent in interfering with inflammation than TL1A. This is an example of a paper that was published by Fabio Cominelli's group at Case Western. That's another one of the investigators that's been looking at this axis for decades.
What he's looking at here is a strain of mice that is prone to developing spontaneous Crohn's disease-like ileitis. What the panels on the top of this figure are showing you is that if you cross these animals onto a DR3 knockout background, the animals are almost completely protected from developing inflammation. What the bottom panel shows you is that if you cross that same mouse strain onto a TL1A knockout background, the animals are only partially protected from inflammation. Why is this? This is, again, an older publication. What these investigators were doing is they were taking biopsies from the GI tracts of patients with Crohn's disease and looking at where TL1A was expressed versus where DR3 was expressed. These are flow cytometry plots.
And what the panel in the far top left shows is that somebody in this room or somebody without Crohn's disease, about 3.5% of the cells that you take from a biopsy of someone's GI tract will express TL1A. The next panel over in the top middle is showing you that if you take a biopsy from a patient that has Crohn's disease, but you biopsy an area of the bowel that's not actively inflamed, you don't find any more TL1A than you find in a patient that doesn't have Crohn's disease. If you move 2 centimeters down the bowel in that same patient and you biopsy an actively inflamed area, that's where you find TL1A to be upregulated. And then if you look at the panels on the bottom, it's showing you how DR3 is expressed in those very same patients.
And so first of all, if you look at the second from bottom panel on the left, it's showing you that a patient without Crohn's disease, you find about 8% of cells in that patient's biopsy express DR3. So DR3 is more abundant than TL1A at baseline. Then you look at the biopsies from the Crohn's disease patient, and you find that DR3 is evenly upregulated in both the inflamed and adjacent uninflamed areas of the bowel. And this was, as I mentioned, an older publication. We now have the benefit of checking this data against some of the very large registries that have been assembled. And what we were showing you here is that that early finding is corroborated by these very large patient registries.
So the panel on the top left here is showing you in patients with Crohn's disease or ulcerative colitis, you find much more DR3 present in the transcriptional levels in those patients than you do TL1A. That's looking at the red curve versus the blue curve in the top left. Perhaps more importantly, when you look in the blood of those very same patients, you find that TL1A is not present in the blood. That's what that blue curve is showing you that overlaps zero expression. And you find very high expression of DR3 in all of those patients. And that is because DR3 is expressed on circulating lymphocytes, both in the blood and in tissues, whereas TL1A is isolated to the tissue itself. Another important difference in the biology of TL1A versus DR3 is that TL1A is not constitutively expressed.
So this is a figure showing you how TL1A is induced. And there's a variety of stimuli that are listed in the figure on the left, including interleukin-1, different toll-like receptor agonists, Fc gamma receptor stimulation that can cause antigen-presenting cells or epithelial cells to upregulate TL1A, but they do not express it in the absence of those innate-like signals. The figure on the right is showing you what the kinetics of TL1A expression look like. This is at the transcriptional level. And what you see is that TL1A gets very rapidly turned on. You reach peak mRNA levels within about six hours. But then there is no expression continuing 24 hours later. And this is how many of the pulsatile co-stimulatory ligands of our immune system are controlled.
In addition to being tightly controlled at the mRNA level, there's a secondary means of controlling TL1A expression at the protein level, which is that when TL1A protein makes its way to a cell membrane, there's a membrane proximal cleavage site that clips TL1A from the membrane shortly after it is expressed. That is the reason why you find soluble TL1A in patients. It's also the reason why we evolved to have a soluble decoy receptor to get rid of it. When you look at DR3, again, as I showed you in the prior slides, it is stably and constitutively expressed by immune cells. The situation this presents is illustrated in the figure on the left here, where both ulcerative colitis and Crohn's disease are diseases that migrate throughout the bowel.
Because TL1A, the expression pattern of TL1A is shown in the red curve here, because TL1A is not expressed in adjacent uninflamed areas of bowel, there is no means to retain a TL1A blocking antibody in an area of the bowel that's not actively inflamed. Because DR3, on the other hand, is constitutively expressed in both inflamed and adjacent uninflamed areas, and stably expressed, antibody blockade of DR3 has the opportunity to provide more durable inhibition of inflammation driven by the axis. One.
What you'd expect. Pancolitic patients are typically harder to treat, and one potential reason for this could be that in pancolitic patients, because the entire length of the colon was inflamed, that's the sort of patient where there was a means of retaining a TL1A blocking antibody throughout the inflamed area, and this is not novel biology. Many co-stimulatory ligands and receptors are differentially expressed, PD-1 and PD-L1 being a good proxy here where almost the same groups of cells that express DR3 are the cells that express PD-1. PD-L1 is a transiently expressed ligand in tissues, and this may contribute to the superior efficacy that has been seen with PD-L1 inhibitors versus PD-1 inhibitors, so SL325 is the lead monoclonal that recently completed GLP toxicology studies.
We also have a half-life extended version of that monoclonal. And then one of the attributes I'll get back to at the end is that there's a unique opportunity to develop bispecifics in for IBD patients when you're anchoring to DR3 versus TL1A. So 325 is a very high affinity antibody, 1.3 picomolar, binds to both monomers and trimers of DR3. It competes with the TL1A binding site on DR3. And this antibody leaves the decoy receptor untouched. When we look at the in vitro potency of this antibody head-to-head against, in this case, tulisokibart or the Roche antibodies, you see about a log improvement in potency, in terms of its ability to interfere with TL1A binding to DR3.
And then one of the things that you always have to be thinking about when you're making a choice to build an antagonist to a TNF receptor as opposed to a ligand is that in any particular antibody generation campaign, there's some risk that you'll inadvertently end up with a receptor agonist when you were trying to build a receptor antagonist. And there's a number of ways to test for this, in vitro. This is one of them using in the panels on the left in blue, where we're taking lymphocytes from a patient with Crohn's disease or a patient with ulcerative colitis, stimulating those cells with CD3 and CD28 beads to mimic antigen source, and then increasing the concentration of 325 in those patients. And you don't see any activation of those cells with the antibody alone.
The first red bar shows you what co-stimulation, using TL1A looks like in terms of stimulating interferon gamma production from those lymphocytes. And that can be completely neutralized, as you titrate in SL325. And so this is what the competitive landscape currently looks like. Everybody has been focused on the ligand instead of the receptor. And, hopefully I've laid out a case for why we believe that, going after the receptor will lead to higher rates of clinical remission, than have been seen so far with the TL1A blocking antibodies. Another factor in going after the receptor is that we've seen pretty high rates of immunogenicity with some of these TL1A blocking antibodies. In the early Roche antibody studies, over 80% of patients had ADA. And the reason for that is that the TL1A blocking antibodies are binding a soluble factor.
And that antibody is then floating around in the blood in a complex with TL1A. By definition, that's an immune complex. And that leads to ADA formation. I think you'll also be limited in ever developing bispecifics that are well tolerated against TL1A. And Amgen tried this. They made a TL1A by TNF bispecific, took it through a phase I trial, and 100% of patients had ADA. That antibody was discontinued because in that case, you now have a two-pronged immune complex that's floating around. When you're going after DR3, this is a, as I said, stably expressed membrane-bound receptor. And it's expressed by the same cells that express alpha-4 beta-7. It's expressed by the same cells that express IL-23 receptor. And those are the two other pillars of therapy in IBD.
And so these are things that we're excited to move forward as the pipeline advances, a nd all of those initiatives will be supported by the first in human experience that we will soon have with SL325. So as I mentioned, we've recently completed the GLP toxicology study. We're really excited about the profile that we've seen there. It's corroborated all of the preclinical studies that we've completed so far.
IND is on track for the middle of 2025. We'll be enrolling about 70 patients in a healthy volunteer initial single ascending dose followed by multi-ascending dose study. We expect to have that study fully enrolled by the first half or during the first half, I should say, of 2026, with data along the way. And that will set the stage for our phase II studies in UC and Crohn's disease patients. I'd be happy to answer any questions you have.