Good morning, everyone. Welcome to the 43rd Annual J.P. Morgan Healthcare Conference. It is my pleasure to be hosting Shattuck Labs today. Joining us today is Dr. Taylor Schreiber, the CEO of the company, who will be leading the presentation. Please note that we will have the Q&A session as the second portion of this session, and Dr. Schreiber will be able to address any questions that you might have. And with that, Dr. Schreiber, the floor is yours.
Great. Thank you very much and thank you to J.P. Morgan for the invitation to present at this year's healthcare conference. I'm pleased to present to you the DR3 blocking antibody program we're developing here at Shattuck. These are my forward-looking statements.
So, we'll start with an introduction in the biology of the TL1A and Death Receptor 3, or DR3, axis. And this axis may be familiar to many folks in the audience due to the recent activity from the business development side that really was precipitated by the phase II data originally presented by Prometheus Biosciences, one of the first companies developing a TL1A blocking antibody.
These data were published in the New England Journal of Medicine last year, and what you can see on the far left panel of this graph here is that monotherapy with their TL1A blocking antibody, now being developed by Merck and referred to as tulisokibart, was able to deliver a 25% placebo-adjusted complete remission rate in patients with treatment refractory ulcerative colitis. A nd this included a number of patients who had failed prior biologic therapies.
A nd seeing this result in that patient population with a monotherapy antibody like this is really uncommon in this disease and precipitated the interest of Merck, and most encouragingly, these data have now been replicated across two other randomized phase II clinical trials, one with an antibody now being developed by Roche, and the third with an antibody partnered between Teva and Sanofi.
It's uncommon that an emerging axis like this has three consistent clinical remission rates in this 20%-27% range in such close succession to one another, and that serves as a strong point of validation for targeting the TL1A and DR3 pathway. Now, so far, all of the efforts to inhibit the signaling between TL1A and DR3 have focused solely on the ligand, TL1A.
And with some TNF receptor ligand pairs, there's a very good reason to focus on either the ligand or the receptor, because in some cases you may have a ligand that binds multiple receptors. That's the case, for example, with TNF- alpha. Or you can have a receptor that binds multiple ligands, and you might not want to interfere with more than one of those interactions.
In this case, TL1A is the only signaling ligand to DR3 and does not cross-bind any other receptors. The only wrinkle to that statement is that humans have evolved a soluble decoy receptor called DcR3. This is not a signaling receptor, however. This is something that humans evolved as a secondary means to neutralize inflammation that's driven by TL1A.
And so, when you look at the simplicity of this axis, what we expect is that the current safety profile that has been seen with the three phase II and phase III stage TL1A blocking antibodies would predict not only the safety profile of future TL1A blocking antibodies, but also antibodies developed against the receptor DR3.
Our perspective on why you might want to think about targeting DR3 instead of TL1A begins with understanding where and how is TL1A expressed versus DR3.
And in the figure on the left here, what we're showing you from a publication is that the source of TL1A is primarily tissue-restricted antigen-presenting cells. When those antigen-presenting cells turn on TL1A, and I'll go through how that happens, that then provides a co-stimulatory ligand which can activate nearby T cells which express DR3.
And so the starting principle here is that TL1A is primarily localized to cells that reside in tissues, whereas DR3 is primarily expressed by lymphocytes, which are present both in the peripheral blood and traffic in and out of those tissues.
Now, the discovery of TL1A was made in 2002, and from 2002 through the mid-2010s, there were a large number of publications that came out which really defined what were the rules of this axis, what did it do, and what were the outcomes of DR3 signaling in an inflammatory setting.
The figure on the right comes from a great paper that was published by Richard Siegel's group at the NIH, and what he generated here in the top panel were mice that overexpressed TL1A. And what he showed, and others have shown, is that those animals are predisposed to developing severe inflammation and inflammatory bowel disease, but you can completely reverse that phenotype if you cross those mice onto a DR3 knockout background.
And so, this is representative of a number of data points in those early publications proving that all of the inflammation driven by TL1A is mediated by DR3 signaling. If you go through all of those preclinical data points, you'll find examples of TL1A or DR3 driving inflammation in models of i nflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis.
You won't find an example where interfering with DR3 signaling is inferior to interfering with TL1A signaling. In fact, you'll find several data points showing that either genetic deletion or pharmacologic inhibition of DR3 signaling provides a stronger protective effect from inflammation than doing the same thing with TL1A.
This is a publication here that was from Fabio Cominelli's group at Case Western, and he studies a mouse model that is highly prone to developing Crohn's disease-like ileitis. What you can see here is in the top middle panel, the animals that are crossed onto a DR3 knockout background, so this is a genetic deletion of DR3, are completely protected from developing that inflammatory disease.
In the bottom, he crosses those same animals onto a TL1A knockout background, and what you can see is that there's some degree of protection, but not nearly as much as what you can see when you cross that same strain onto a DR3 knockout background. So, now we'll transition over to some of what's known in humans with inflammatory bowel disease about where you'll find DR3 and TL1A.
This, again, is an older publication, but a very well-executed one. And in the top left panel here, what these authors have done is they've taken biopsies from the ileum of somebody without Crohn's disease in the left or in the middle and top right panel, somebody with Crohn's disease.
And the number in the box there, 3.5%, what that is telling you is that in somebody without Crohn's disease, you take a biopsy from that patient's ileum, and 3.5% of the cells that you find in that biopsy will express TL1A. Now, in Crohn's disease, this is a discontinuous inflammatory disease. And so, you'll have areas of the bowel that are inflamed, and then you'll move 2 cm down the bowel, and you'll find healthy tissue.
And so, if you take a biopsy from an inflamed part of a Crohn's disease patient bowel, what you'll find is about 8.5%, 8.4%, 8.5% of those cells will stain positive for TL1A. So that's telling you you've doubled the amount of TL1A in response to inflammation in that tissue. But if you go 2 cm down the bowel to the uninvolved adjacent healthy tissue, there is no upregulation of TL1A whatsoever.
If you look in the bottom panels here, you'll see the corresponding expression of DR3 in those same patients, and so first of all, in a patient without Crohn's disease, you take that same biopsy and you find 8% of those cells will stain positive for DR3, so that tells you right away that DR3 is more abundant than TL1A at baseline.
T hen you look at those same corresponding tissue biopsies in the inflamed and adjacent uninflamed tissue, and you see 18.8% and 17.4% of cells staining positive for DR3, so DR3 is both more abundant and evenly upregulated in the actively inflamed and adjacent uninflamed areas of a Crohn's disease patient's GI tract.
Now, this paper is showing you data on the protein level, which is wonderful to see, but of course, this was a relatively small number of patients and an older publication.
So, what we then did is we pulled data from the Mount Sinai Crohn's and ulcerative colitis patient registries. This is a database of over 2,500 patients. And what the panel on the left is showing you is that, as that figure I just showed you from the older publication predicted, DR3 is much more abundant in the GI tracts of this cohort of patients with ulcerative colitis and Crohn's disease than is TL1A.
And as I mentioned a few slides ago, DR3 is expressed by circulating lymphocytes, whereas TL1A is tissue-restricted. And so, on the right panel here, if you look at the corresponding expression of DR3 and TL1A in the peripheral blood, you find loads of DR3, whereas you find almost no TL1A at all. And so, why is this? In addition to being a tissue-restricted ligand, TL1A is not constitutively expressed.
Here are a couple of publications on the left which show you that TL1A can be turned on by a variety of different innate immune signals, but TL1A is not expressed in the absence of those signals. The figure on the right here is showing the kinetics of how TL1A gets turned on in response to one of those innate signals.
What you can see is that when you expose an antigen-presenting cell to lipopolysaccharide, which of course mimics barrier disruption that might occur in the gut of a Crohn's patient, you reach peak expression on the mRNA level within six to eight hours of exposure to that signal. 24 hours later, there is no longer any continuing expression of TL1A. It's tightly regulated on the transcriptional level.
In addition to that, when those transcripts are turned into protein, that protein makes its way to the cell membrane. There's a membrane proximal protease cleavage site on TL1A that leads to clipping of the protein shortly after it's expressed on the membrane. This is the reason why you can find soluble TL1A in our blood, and it's also the reason why humans evolved a soluble decoy receptor to neutralize that shed TL1A.
The broader point that I'm making here is that when you're targeting TL1A, you are targeting a moving target in the tissues. The red line in this figure here is showing you the expression of TL1A across the GI tract of a patient with Crohn's or ulcerative colitis. You'll find it in the actively inflamed areas. You will not find it in the adjacent uninflamed tissue.
The problem there is that that means there is no means of retaining a TL1A blocking antibody in the adjacent uninflamed tissue. The reason that's a problem is that both ulcerative colitis and especially Crohn's disease are migratory diseases.
So, as inflammation spreads from one part of the GI tract to an adjacent part of that patient's tissue, it will set off a race as to whether that newly expressed TL1A has the opportunity to interact with locally more abundant DR3, or whether it is immediately neutralized by a TL1A blocking antibody that is passively diffusing through that tissue.
As you can see in the yellow line, orange line on the top, that's not a race that you're fighting if you instead are targeting DR3, because DR3 is constitutively and stably expressed both in actively inflamed and adjacent uninflamed parts of the bowel.
This is not a unique relationship between a receptor and a ligand. If you look at PD-1 and PD-L1, for example, PD-L1 is a tissue-restricted inducible ligand. It gets turned on in tumors in response to interferon gamma, whereas PD-1 is constitutively expressed by antigen-experienced lymphocytes, and many folks believe that this expression difference may underlie the superior efficacy that's been seen with PD-1 blocking antibodies.
So, now to transition over to the SL-325 program. We have a number of different antibodies that are targeting DR3. 325 is a monoclonal antibody that has recently completed GLP toxicology studies and will go into the clinic this year. 425 is an equivalent antibody to 325 but contains a YTE half-life extending mutation. You'll see when we share our nonhuman primate data later whether that is a desirable attribute to have or not.
In addition to the monoclonals, we have a variety of bispecifics leveraging our DR3 targeting moiety that we think will provide some very unique opportunities for development relative to what can be achieved with a TL1A blocking antibody. 325 is a very high affinity antibody. It binds to DR3 with a 1.3 pM binding affinity, and we selected an epitope that does not cross-bind the decoy receptor.
So, that native interaction between shed TL1A and DcR3 will remain intact. We have shown in a variety of different in vitro potency models that 325 both directly interferes with a trimer-to-trimer interaction between TL1A and DR3, and that it also prevents trimerization of DR3. This antibody also does not cause internalization of DR3 from the membrane.
This is an example of one of those in vitro potency assays where we've controlled the activity of SL-325 against Merck's antibody tulisokibart as well as the Roche antibody that they acquired from Telavant. Ultimately, the indicator of whether TL1A has provided co-stimulation to a lymphocyte is whether that lymphocyte begins to proliferate and secrete cytokines such as interferon gamma.
Here, what we're showing you is the amount of interferon gamma that is produced when lymphocytes from patients with ulcerative colitis or Crohn's disease are stimulated with TL1A. So, the orange figures on the left are showing you that when you stimulate these patients' lymphocytes with a CD3 and a CD28 bead, you titrate in SL-325. SL-325 provides absolutely no agonist activity on its own. The first blue bar shows you what TL1A agonism looks like in these patients.
When you titer in SL-325 in the setting of TL1A, you rapidly neutralize all co-stimulation that is driven by TL1A in these UC and Crohn's patient lymphocytes. This is what the competitive landscape looks like today. No surprise, the success of the Merck and Sanofi, Teva, and Roche antibodies has precipitated significant interest in the axis, and that's led to the development of a number of me-too follow-on antibodies against TL1A.
There is no company other than Shattuck today that has a DR3 targeted antibody, and we don't believe that there's a good reason for that. It's true that in any given antibody discovery campaign, your chances of successfully finding a good antagonist are lower if you decide to build an antibody against the receptor than the ligand.
However, clearly we've proven here that it is achievable, and we're very excited about what DR3 targeting may provide. In addition to the points that I've mentioned already, one of the potential issues with TL1A targeting is that when a TL1A antibody binds to serum TL1A, it stabilizes that serum TL1A and slows its degradation.
And so, if you look at the concentration, not of free, but of total TL1A in patients treated with one of these antibodies, it goes up approximately three logs. Pfizer had a nice publication on that data point from their antibody that is now being developed by Roche.
And when you have high concentrations of an anti-TL1A antibody bound to serum TL1A, that is by definition an immune complex. That's the reason that some of these antibodies have such high rates of ADA.
When you're targeting a membrane-restricted receptor such as DR3, there is no risk of immune complex formation, and that is advantageous both with regard to the monoclonal and especially the bispecifics that are under development at Shattuck.
What we're hoping is that DR3 targeting, because of the fact that it can more broadly suppress TL1A signaling across the GI tract of patients with UC and Crohn's, is that this antibody as a monotherapy will close the gap between the approximately 2/3 of patients that have some degree of clinical response to a TL1A inhibitor and the 25% or so that are able to achieve clinical remission, and so we're very excited about this program.
We were selected to provide an oral presentation at the European Crohn's and Colitis Congress in February. That is where we will share the data from the recently completed GLP toxicology study with this antibody.
The things that we're looking at there were similar to the things we'll be looking at in the first in-human clinical trial, looking, of course, at safety, the pharmacokinetic profile of 325. Something you can do with 325 that was not possible with TL1A blocking antibodies was measure receptor occupancy. There you're looking at how rapidly do you saturate DR3?
Do you immediately have accumulation, both in terms of Cmax and AUC with repeat dosing as an indicator that you've saturated the peripheral sink? How durable is that receptor occupancy? Patients who are treated with a drug like Keytruda, for example, that's not a YTE-containing antibody, but PD1 remains fully saturated six months after a patient's last dose of Keytruda. Do you see similar things with a DR3 targeting antibody like 325?
We're looking forward to sharing that data in February, and we're really excited for this antibody to enter the clinic in the middle of this year. That will precipitate the first-in-human study that's a single and multi-ascending dose clinical trial that we expect to have fully completed by the second quarter of next year.
And then to proceed into randomized placebo-controlled studies in patients with both Crohn's disease and a separate study in patients with ulcerative colitis. So, I thank you very much for your attention. We look forward to keeping you informed on our progress over the course of this year, and I'd be happy to take any questions.
Thank you, Dr. Schreiber, for this insightful presentation. We are now ready to move into the Q&A portion of our session.
As a reminder, if you're joining us in person today, you can raise your hand, and we will be able to fetch your mic. If you're watching us online, please do use the webcast tool in order to direct any questions you might have. With that, any questions we have from the audience?
Okay. We do have one question online. So, when we think about the landscape, why have other companies pursued the ligand TL1A and not the receptor DR3?
Yeah, it's a great question that we get frequently. I think it relates to a few different aspects. So, for whatever reason, the TL1A-DR3 axis has been less studied on an academic basis than almost any other TNF receptor or ligand you can name. If you go into PubMed today and you search for TL1A or DR3 and you filter out HLA-DR3, you find about 330 total hits.
If you search for almost any other TNF receptor ligand, you'll get several thousand hits. CD40, CD40 ligand, you'll get 17,000. And the reason for that is that since the discovery of TL1A in 2002, there have only been five labs in the world that have continuously studied this axis. Steph Targan, who was the scientific founder of Prometheus, was one of those. Fabio Cominelli at Case Western.
My academic mentor, Eckhard Podack at the University of Miami, Richard Siegel at the NIH, and Aymen Al-Shamkhani and Eddie Wang in the U.K. And that's it.
And one of the earliest companies to build a TL1A blocking antibody was Human Genome Sciences. They shared some of that antibody early on, both with Steph and with Fabio, and that likely had a role with Steph deciding to focus on developing what he hoped and was a better TL1A blocking antibody.
I think those factors played a role. Another, which I alluded to, is that it is more challenging to develop a good antagonist to DR3 because a TL1A blocking antibody, all it has to do is provide steric hindrance of the interaction between TL1A and DR3.
A DR3 blocking antibody ideally does not cause internalization of the receptor, binds an epitope that directly interferes with the trimer-to-trimer engagement, but also interferes with trimerization of DR3, and then most importantly, and maybe the largest challenge, is that with a receptor-targeting antibody like this, you always have to be worried that you pick an antibody that has some evidence of residual agonist activity.
And so, that's just a larger hill to climb than if you're going after TL1A. A nd the final aspect is, until the Prometheus data, there wasn't clinical validation of the target, and so there wasn't a huge amount of effort going into the pathway. Before Prometheus, all we had was a failed clinical trial of Teva's antibody in asthma. S o, I think all of those things contributed.
Thank you very much. And I think we have a follow-up here, and I do think you have touched briefly on that in your presentation, but do you expect to enter the clinic this year?
We do, yeah. So, the IND goes in mid-year. We expect that we'll have initial data from the first few single-ascending dose cohorts by the end of the year and then have that study fully completed by Q2 of 2026.
Right. Any questions from the audience at this stage? And I think we have one final one then. What do you expect to be able to show at any upcoming conferences or events in 2025?
Yeah, so the first one will be our oral presentation at the European Crohn's and Colitis Congress in Berlin in February. That will have our non-human primate data, and we haven't yet provided any guidance for conferences after that, but we'll certainly keep all of our investors informed.
Okay. Thank you very much. I think this wraps up our presentation. Thank you very much, Dr. Schreiber. Thank you, everyone, for attending.
Thank you.