Shattuck Labs at UEG Congress: Innovative IBD Treatment Insights

On Wednesday, October 8, 2025, Shattuck Laboratories (NASDAQ:STTK) took center stage at The United European Gastroenterology UEG Congress UEG Week 2025. The company outlined its strategic focus on developing SL-325, a novel DR3 blocking antibody for treating inflammatory bowel disease (IBD) and other autoimmune conditions. While highlighting the potential advantages of targeting DR3 over TL1A, Shattuck also acknowledged the challenges in developing this innovative therapy.

Key Takeaways

• Shattuck’s SL-325 aims to provide a novel treatment for IBD and autoimmune diseases by targeting DR3, which may offer superior efficacy compared to TL1A.
• The company anticipates completing its Phase 1 study by the first half of next year, with plans to initiate multiple Phase 2 trials.
• SL-325 is designed to avoid immune complex formation, addressing a common issue with TL1A blocking antibodies.
• Shattuck is exploring additional indications for DR3 targeting, including rheumatoid arthritis and atopic dermatitis.
• Caution is advised for diseases with seasonal patterns like asthma.

Operational Updates

• Phase 1 Study: Expected to complete in the first half of next year.
• Phase 2 Trials: Prepared to launch multiple placebo-controlled Phase 2 trials post-Phase 1, focusing on IBD and comparing efficacy against anti-TL1A therapies.

Future Outlook

• Efficacy and Immunogenicity: Key questions include whether SL-325 offers a superior immunogenicity profile and efficacy compared to existing anti-TL1A therapies.
• New Indications: Beyond IBD, potential applications include rheumatoid arthritis, atopic dermatitis, and fibrosis.
• Cautious Approach: Advised for diseases with seasonal or relapsing-remitting patterns, such as asthma.

Important Quotes

• "DR3 is a much more stable target than TL1A, and that could lead to higher efficacy." - Taylor Schreiber, CEO
• "With DR3, you don’t have to worry about immune complex formation." - Taylor Schreiber, CEO
• "Our phase one study is moving along swiftly right now, which is great, and our phase one data will definitively answer that superior immunogenicity question." - Taylor Schreiber, CEO

For a comprehensive understanding of Shattuck’s strategic direction and insights shared during the conference, readers are encouraged to refer to the full transcript.

Full transcript - The United European Gastroenterology UEG Congress UEG Week 2025:

Martin: Okay. Our next session is with Taylor Schreiber, MD, PhD, CEO of Shattuck Laboratories. Doctor. Schreiber is leading the efforts to advance a new target in IBD known as DR3. I say new target even though the pathway itself is a very prominent one that we are all familiar with t l one a.

And so doctor Schreiber, if you’d like to say a couple of introductory remarks on shatter labs and t l one a.

Taylor Schreiber, CEO, Shattuck Laboratories: Sure. Well, thanks, Martin and David for hosting the session today. Chadik, as you mentioned, is focused on developing what is the first in clinic and potentially first in class death receptor three blocking antibody. DR3 is the sole signaling receptor for TL1A. As you mentioned, Martin is a well known target to probably most people who are listening in today.

And there are a number of reasons we believe why targeting DR3 may provide superior efficacy to what has already been super exciting data seen to date from multiple TL1A blocking antibodies, and I suspect we’ll get into that.

Martin: Fantastic. And so, DR3, any reason to believe that targeting the receptor for TL1A could be substantially different from targeting the cytokine itself?

Taylor Schreiber, CEO, Shattuck Laboratories: Sure. So as I just mentioned, one consideration you always have to be mindful of when when picking to block a ligand, in this case, a soluble cytokine like TL1A, versus a receptor is is is one of them promiscuous? I. E. Does one side of the axis bind multiple targets and and does the other side only bind a single target?

There’s many examples of receptor ligand pairs where where one end is promiscuous and the other end is not, and so it can be very obvious to go after the receptor or the ligand. In the case of t l one a and d r three, this is a monogamous receptor ligand pair. T l one a only binds to d r three, and and d r three has no other signaling ligands. So from a safety and specificity standpoint, there’s no reason to believe that what has been learned in the clinic so far to date regarding the safety profile of TL1A blockade will not predict the safety profile of DR3 blocking antibodies so long as your d r three blocking antibody lacks, the ability to engage with Fc gamma receptors, which ours does not. And so then, you know, what are the reasons to believe that there could be differential safety and efficacy or efficacy profiles and tolerability profiles between the two?

There’s two prongs to that answer, and and one relates to efficacy, the other relates to immunogenicity. So I’ll answer first by giving our perspective on why the efficacy could be different. And what that relates to are significant differences in how and where TL1A is expressed versus DR3. So TL1A is not a constitutively expressed ligand. It gets turned on in short waves, and it only gets turned on in response to different innate immune stimuli.

So if if you were to take a biopsy of of any someone’s gut who doesn’t have inflammatory bowel disease, you would find that there would be little to no expression of d r of t l one a in that biopsy. And if you do the same thing, you take biopsies from a patient that does have, let’s say, Crohn’s disease, and you biopsy the actively inflamed part of a Crohn’s disease patient’s bowel, what you’ll find is that about eight to 10% of the cells in that biopsy will be expressing TL1A. And in that same patient, if you move two centimeters down the bowels, you remember Crohn’s disease is a discontinuous inflammatory disease. You have inflamed followed by neighboring uninflamed followed by downstream inflamed tissue. If you biopsy the uninflamed tissue, you’ll find that t l one a is not upregulated just as is in the case in a patient without inflammatory bowel disease.

In those same in that same patient though, if you look for DR3, what you’ll find is that about 18 to 20% of the cells in the actively inflamed biopsy will be positive for DR3, so about double the amount of cells that are positive for TL1A. And that same proportion of cells will be expressing d r three in the neighboring uninvolved tissue. Now the reason for and and so d r three is both more, it has a broader pattern of expression and is more abundant in patients with IBD. Now the reason for that is that the cells that express DR three are primarily lymphocytes and innate like lymphoid cells. And when a lymphocyte has decided that it is going to express d r three, it expresses it for as long as that cell lives.

The amount of d r three on the surface can fluctuate over time, but those cells generally don’t turn d r three off. So it represents a stable target. TL1A gets turned on, as I mentioned, in response to innate immune stimuli in short pulses. So it gets turned on for twelve to twenty four hours at a time, then it gets turned off again. And then if if there’s another inflammatory stimulus, it can go up again and come down again.

And so you’re you’re constantly chasing these waves of inflammatory ligand with TL1A, and and you’re not fighting that sort of kinetic battle if you’re instead blocking d r three. So this is analogous to a number of other receptor ligand pairs. And for those folks who who have followed oncology, as an example, you’re probably familiar with the fact that there are both p d one and PD L one blocking antibodies. And the efficacy of PD one blocking antibodies is generally higher than the efficacy of PD L one blocking antibodies. And one potential reason for that is that with that receptor ligand pair, p d one represents the more stable side of the axis.

Just like t l one a, p d l one is a is an inflammatory ligand that achieves pulsatile expression patterns just within the affected tissue, in that case tumors. So just to summarize, we think DR3 is a much more stable target than TL1A, and that could lead to higher efficacy.

Martin: Great. And one point that we also wanted to know about TL1A is because of that transient expression, you could potentially have high local concentrations, whereas the DR3, you would be able to suppress across the board broadly in all in all tissue locations, the binding. Would that be a correct way of assessing it?

Taylor Schreiber, CEO, Shattuck Laboratories: Yeah. I I think what we have modeled and and what our data are showing is that because d r three is more abundant, your first dose target mediated clearance effect is higher than what you see with t l one a as as the less abundant target. But then with our antibody, once it binds d r three, it doesn’t cause d r three to internalize, and binding is highly durable. So what that means is that by the time you give that second dose, there is no free d r three left. So you have rapidly decreasing clearance with d r three blocking antibodies with repeat dosing.

Whereas with the TL1A blocking antibodies, because TL1A is rapidly turned over, you see more steady clearance with each dose.

Martin: Right. And we were hoping you could also talk about that free versus bound concept. So with the DR3, it being bound, does this prompt any additional receptor to be expressed on the surface? And then with TL1A, as that gets bound, how does that affect the concentration of TL1A, total concentration?

Taylor Schreiber, CEO, Shattuck Laboratories: Sure. So with with DR3, we don’t see changes in the in the per cell expression pattern of DR3 when that cell is fully occupied with our antibody three two five. So it it it seems to be essentially inert other than blocking the ability of d r three to interact with t l one a. And there is no shed form of d r three, so our antibody does not bind any soluble proteins that we can detect. Just as as a note for for those that are familiar with the axis, there is a a another member of this axis, which is called decoy receptor three.

That is a soluble protein, but decoy receptor three is encoded by a separate gene than d r three. It’s not a shed form of d r three, and our antibody does not cross bind decoy receptor three, so that remains untouched. Now decoy receptor three doesn’t exist in rodents. It evolved in primates. And whenever you see, you know, new evolutionary changes like that, you know, you you have to ask yourself why.

So what decoy receptor three does is it it binds to and facilitates the clearance of soluble t l one a light and fast ligand. Those are all TNF ligands that can be shed. So when TL1A is expressed, it’s initially anchored to the membrane, but then there’s a membrane proximal protease cleavage site that leads to shedding of of the extracellular domain of TL1A, and that is still capable of signaling. So it’s likely that humans evolved decoy receptor three to rapidly get rid of shed t l one a. So that tells you a little bit about how important this axis might be in driving different inflammatory processes.

Now when a patient is treated with a t l one a blocking antibody, those antibodies, depending on whose antibody we’re talking about, can bind either trimers of t l one a or trimers and monomers of t l one a, both when that t l one a is expressed on cell membranes as well as the shed forms of TL1A. And so what all of the developers of the TL1A blocking antibodies have shown is that within a week or so of getting the first dose of a t l one a blocking antibody, the total concentration of t l one a in the blood increases by two to three logs. So it goes from, you know, in in folks pre dose from about a hundred picogram per ml into the microgram per ml range. And what is actually being measured in that case are immune complexes between this the shed t l one a and the anti t l one a antibodies. And so your total concentration of t l one a goes way up.

Now immune complexes are a dominant generator of immunogenicity. And so when when immune complexes form, they often are internalized, processed, and presented on MHC, and that results in the generation of anti drug antibodies against, whatever the the protein components are in that immune complex. And this is the reason why every t l one a blocking antibody developed to date has seen rates of anti drug antibody formation in excess of sixty five percent of patients. In some cases, it has been one hundred percent of patients. And so this is a concern with the the Pfizer antibody that Roche is now developing.

They recently published a paper in The Lancet that demonstrated that even though there wasn’t a particularly high rate of neutralizing, anti drug antibodies, that high rate of ADA led to accelerated clearance of Vimcabart over time, and that accelerated clearance was associated with loss of response. So this is something that that IBD, clinicians are very used to from their experience with TNF alpha directed agents that cause the same sorts of immune complex related immunogenicity. It’s the reason why patients often cycle from one anti TNF agent to another, and it’s a reason for loss of response. So with with d r three, you don’t have to worry about immune complex formation.

Martin: Right. So if I could summarize the three differentiators that we are hearing so far in terms of targeting d r three versus t l one a. First one would be increased broad expression of DR3 allows you to intercept the signal before you start to have that inflammatory spike that you would with TL1A. The second one would be that you are able to shut down you are able to allow decoy receptor three to continue performing its natural inhibitory functional TL1A. And the third would be reduced immunogenicity potential because you’re not generating those soluble immune complexes.

Would that be correct? Would there be any other differentiators that we’re missing?

Taylor Schreiber, CEO, Shattuck Laboratories: Those are those are the key things, Martin.

Martin: Fantastic. Okay. So that is the background on the TL1A versus DR3. Let’s talk a little bit about what you’re doing here. So SL three twenty five, tell us a little bit about this antibody development history, and why has nobody else done a DR3 blocking antibody?

Taylor Schreiber, CEO, Shattuck Laboratories: Yeah. So 325, as I’ve alluded to, this is a human d r three blocking antibody. It’s a very high affinity antibody measured at at less than two picomolar. And this antibody lacks any Fc gamma receptor binding activity, so it is it is completely null from an Fc binding perspective. It does still bind neonatal Fc receptor.

And the major concern when you’re developing a TNF receptor targeted antibody as opposed to a TNF ligand targeted antibody is that a TNF ligand targeted antibody like the anti t l one a’s, all your only design consideration really is to find an epitope that interferes with t l one a binding to d r three. There’s other small design tweaks that certain folks have applied about whether they bind trimers and monomers and whether they bind a site that also interferes with TCOI receptor three binding or not. But really the major objective is just to bind an epitope that blocks d r three binding. When you’re going after the receptor side of the axis, the in our opinion, the design goals are to pick an epitope that interferes with trimerization of the receptor, an epitope that also interferes with t l one a binding to d r three, pick an epitope that is not shared with decoy receptor three, and fourth and and perhaps most importantly, and and this represents the biggest challenge, find an epitope and overall antibody characteristics that do not cause residual agonism of d r three. This is the principal challenge, and and I would assert the principal reason why we are the first to develop a d r three blocking antibody, is because many antibodies that bind TNF receptors all all antibodies with the bind TNF receptors will at a minimum be able to bring together two subunits of d r three in this case.

And whenever you are clustering multiple subunits of a TNF receptor, there’s always the risk that those cytoplasmic domains come into inappropriate configuration where you can trigger residual signaling. And so you can inadvertently end up with an agonist when you’re trying to develop an antagonist. This is something that you can study and and make yourself aware of with very sensitive preclinical assays, which we did. And many of the antibodies that we developed ended up having residual agonist activity and and were triaged at various points in development. We found several candidates that did not have those activities that we chose to bring into nonhuman primate studies.

And if you were to have a d r three agonist, the way that you would see that in vivo in primates, meaning both nonhuman primates and humans, is that within five to eight days after administering your d r three targeted antibody, you would see proliferation of various t cell subsets. And and you might see increases in cytokines. You might see changes in activation markers on on t cell surfaces. And so our data confirmed that that none of those signs were seen with three two five in primates either. So, you know, we we have a pure d r three antagonist on our hands.

And you can look at you know, this is not the first time that this challenge has been encountered in the industry. If you look at another TNF receptor ligand pair is is BAF and BAF receptor. Right? Benlysta is an anti BAF antibody that has been commercially available for over a decade. Worked in some indications, didn’t work in others.

Now you have companies like Novartis and Jade who are coming very late to the scene with BAF receptor targeted antibodies. And those antibodies seem to be active in Novartis’ case and Sjogren’s, for example, where Enlista previously failed. Right? You can look at OX40 and OX40 ligand where you have rocotinlimab that, you know, is the OX40 targeted antibody that that we’ll see, may have a differentiated profile from some of the OX40 ligand targeted antibodies. And and in general, the receptor targeted antibodies come a little bit later than the ligand targeted antibodies, but but there is a pattern emerging that they can be more efficacious.

Martin: Fantastic. And so far, are you aware of any other developments in progress for d r three antagonist, barring any surprises from China, but any other competitors that you are aware of that are looking at the same mechanism?

Taylor Schreiber, CEO, Shattuck Laboratories: Yep. Nobody has a disclosed program, and we are we are not aware of anybody going around and talking about it. We are aware of of one highly experienced antibody development pharma company that did prioritize, d r three, over t l one a for the same reasons that we have. And, the antibody that they developed ultimately had some of the agonist issues that that I was speaking about earlier in the same assays where our antibody does not. So, there are efforts, no doubt, ongoing, at at multiple companies, but I think, you know, evidence that one of the world’s, you know, most, experienced antibody developers encountered that issue, it gives us some degree of confidence that that this isn’t going to be a simple follow fast follower story.

Martin: Right. And speaking about fast followers, so you are now tell us about your timeline. So when can we expect to see first clinical data from this program? When can we expect to see it starting to advance into IBD? What are your thoughts on IBD advancement in terms of selecting between UC and Crohn’s disease?

Taylor Schreiber, CEO, Shattuck Laboratories: Yeah. So, you know, the key questions that we have to answer are, number one, is it true or not true that targeting d r three has a superior immunogenicity profile than targeting t l one a? Our phase one study is is moving along swiftly right now, which is great, and our phase one data will definitively answer that superior immunogenicity question. We expect this phase one study to be complete in the first half of next year, and we are prepared to move immediately into multiple placebo controlled phase two trials. The second question obviously is how does the efficacy of d r three targeting stack up to anti t l one a’s?

And we’ll get into the other areas where other indications that that are exploring the activity of anti t l one a’s. But today, the only clinically validated place for anti t l one a is in ulcerative colitis and Crohn’s disease. So, one of our placebo controlled, phase two studies will be in IBD, and we will use that data to definitively answer the comparative efficacy question. Folks will have to do cross trial comparisons, but, we’re gonna size and and design our study in such a way that that hopefully that is, not a challenge, for folks who are looking at the data. So it’ll be at least one study in IBD and and then one study in another indication.

Martin: Got it. Okay. So ’26, we will keep an eye out for that data. And then this does follow along with what doctor Dubinsky was saying in terms of comorbidities. The more indications that a drug is allowed in, or is useful in, the more attractive it becomes to clinicians.

What are your thoughts on the most promising new indications for TL1A? And do you have any reason to believe that in certain indications, DR3 might be more efficacious than TL1A?

Taylor Schreiber, CEO, Shattuck Laboratories: Yeah. So they there are the reasons why development of TL1A blocking antibodies began in IBD and asthma, which a lot of people forget, but, are related to the fact that there there is a a well known risk of developing Crohn’s disease, not so much ulcerative colitis. If you are born with specific single nucleotide polymorphisms in TL1A that lead to aberrant expression of TL1A throughout your life. And there are other autoimmune diseases where, there is also a known risk with those same single nucleotide polymorphisms. That includes things like psoriatic arthritis and psoriasis.

It includes things like primary biliary cirrhosis and a number of other diseases. And when you look and and so that sort of is one filtering criteria is is where are these t l one a SNPs driving potentially driving pathology. If you just look at the difference between Crohn’s and UC though, and and the knowledge that anti TL1a works in both Crohn’s and UC, UC doesn’t have an association or a risk association with TL1a SNPs. What it does have is patients are known to have elevated serum concentrations of TL1A at the time of diagnosis relative to non IBD patients. And so that elevated serum t l one a is a second filtering criteria, and you can you can find elevated serum t l one a in a pretty wide range of autoimmune diseases.

It includes asthma, UC, Crohn’s disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, again, primary biliary cirrhosis, and and a number of other, diseases, axial spondyloarthritis. And so you can use that too. And and then you can look at where are their preclinical data that interfering with TL1A DR3 signaling is protective from disease. And, again, of those diseases, there’s there’s strong preclinical data in mouse models of inflammatory bowel disease, asthma, multiple sclerosis, interestingly, and also the arthritities. And so those are all criteria you can look at.

You can also ask, okay, where of of all of these diseases do the downstream effector cytokines, where are they clinically validated? So because t l one a d r three signaling is is upstream of the production of multiple inflammatory cytokines, including IL 17 and IL 23. And so you can look at the places where those antibodies are are already clinically validated and hypothesize that the risk of success or the the chance of success for TL1ADR3 blocking antibody are high. And so the when when you do all of that, you end up with a long list of diseases where in in in many instances, there remains very high unmet medical need. So when you look at, you know, the the fact that Merck and Roche and Spire have all chosen, to go and begin phase two studies in rheumatoid arthritis, I agree.

Those are that is a good choice of a disease to go into. TL1 ADR three is also known to play a role in in the development of fibrosis. Right? So so there’s a number of diseases there. Merck going into their SSC ILD study is probably the first chance we’ll we’ll have to really look at data that might speak to the fibrotic aspect of this axis.

Atopic derm is another this is another place where Roche is going, and that is another disease which which ranks highly on the list based on the criteria that I went through. But so does asthma. Right? And that’s why Teva started in asthma before they went into IBD. I would urge caution, more caution in in thinking about something like asthma.

Because one of the commonalities between diseases like asthma and and atopic derm is that the antigens which drive disease are are not ever present. Right? In in IBD and RA and psoriatic arthritis, they are. And, I think interfering with this axis in diseases that have a more seasonal or, relapsing remitting course is less of a sure bet than going into diseases where, tolerance to a, either self or endogenous microbial antigen has been broken and that that antigen is perennial, in the in the patient.

Martin: Fantastic. Well, thank you so much for for sharing your thoughts on this, Doctor. Shriver. And David, I do apologize we’re out of time for this session. However, we are running now into our Q and A, and so there will be plenty

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