Shattuck Labs, Inc. Common Stock 12th Annual Cantor Fitzgerald Global Healthcare Conference

My pleasure. Thank you, Prakhar.

Sure. Shattuck is exclusively focused on blocking an immune receptor known as DR3. Many people will be more familiar with the sole ligand for DR3, which is known as TL1A. There are a number of companies that have developed TL1A-blocking antibodies, the leaders of which these days are Merck, Roche, and Sanofi. The enthusiasm for the axis has come initially from phase II efficacy data in ulcerative colitis and Crohn's disease for all 3 of those antibodies that was suggestive that blockade of this axis could be best in disease, better than the other approved therapies there. Now we have evidence from Merck that the class is active, not just in IBD, but in other diseases with the first evidence of activity in a skin condition called hidradenitis suppurativa.

We, to this day, are the only company with a disclosed antibody that is blocking the receptor for TL1A, known as DR3. There are two fundamental advantages of going after the receptor that could lead to higher efficacy. One derives from the fact that DR3 is the more stably expressed target in the axis. The second is due to the fact that all anti-TL1A antibodies have extremely high rates of anti-drug antibodies, and those are secondary to TL1A as a target, not the antibody engineering.

Yeah. It's a very common question we get. I think there's two fundamental reasons. One is that the academic history of folks that have studied this axis for a long period of time is quite narrow. The first company that developed a TL1A-blocking antibody back in the early 2000s was Human Genome Sciences. When they did that, they sent some of that antibody to two academicians. One was Steph Targan, the other was Fabio Cominelli. Steph Targan was later the scientific founder of Prometheus, and I think it's quite likely that his experience initially with that HGS antibody contributed to the choice to focus continually on TL1A. Also, the proof of concept, although today it seems like almost everybody knows about this axis, it came very recently.

Up until the Prometheus phase II data just a few years ago, all we had was a failed clinical trial of Teva's antibody in asthma. The other reason, obviously, we see this all the time, once something works, there's a sort of a herd mentality to focus on what works. The other reason is that it's a much more significant engineering challenge to build a good DR3 blocking antibody relative to TL1A. The reason for that is that when you're trying to build a TL1A blocking antibody, all it needs to do is provide steric hindrance of TL1A binding to DR3.

When you are building a DR3 blocking antibody, because your antibody can cross-link two subunits of DR3 and DR3 itself can signal, if you get the wrong epitope, the wrong affinity, the wrong Fc engineering, your antibody will cause residual agonism of DR3, and you have to engineer around that very carefully.

Yeah. Our view, first of all, is that everywhere TL1A antibodies work, DR3 blockade will work better. One aspect relates to target stability. I alluded to this, but DR3 is constitutively expressed by lymphocytes and endothelial cells. When a lymphocyte has undergone a fate decision where it decides to turn on DR3, that cell never turns DR3 off again. You can block it and have it stay blocked. TL1A, on the other hand, is not constitutively expressed. It is an inducible ligand by tissue-resident antigen-presenting cells. It gets turned on and off in short pulses. What that means is that when you are trying to block TL1A, you are chasing a moving target.

This is why all of the TL1A antibodies are moving very high doses forward in their phase III clinical trials, because you need to keep a very high concentration of the serum for there to be a gradient that actively drives lots of antibody into tissue to sop up that rapidly cycling target. That is simply a kinetic battle you do not have to fight when you have instead chose to block DR3. The other reason relates to ADA. As I mentioned, all of these antibodies have very high rates of ADA. We have published data that leads to accelerated clearance over time, and with accelerated clearance goes efficacy. This is the reason why none of the TL1A antibodies show accumulating clinical remission from induction to maintenance.