Spyre Therapeutics, Inc. Common Stock Wells Fargo 21st Annual Healthcare Conference

Thanks for having us. Welcome.

Sure. We're interested in what we hope to elevate the standard of care across a range of the large autoimmune markets. We started initially in inflammatory bowel disease, working on what we think are the three best biologic targets and engineering optimized versions of each of those antibodies. Then what we think is quite exciting is the possibility of combining these together in pairwise combinations, which we think has the potential to provide additive efficacy without safety downsides. We have the ability, we think, uniquely, to combine these in elegant co-formulations. We've expanded that strategy outside of IBD to explore the biology of TL1A and a range of other indications as well, in rheumatology initially, and then just recently, we also announced an expansion into dermatology and HS as well.

And really across all of these, the goal is let's see how well these molecules work individually and then ideally, in the long run, push the bar again by combining what we think are the best mechanisms in each of these indications. I'm sure we'll hit all of them individually.

Sure. So in IBD, we started with three classes of molecules, none of which our molecules are first in class. So we really do get to learn from the first generation set of molecules against each of these mechanisms. So the first one, alpha-4 beta-7, same target as Takeda's ENTYVIO, second TL1A, and third now IL-23. In the study that we're running, this platform SKYLINE study, we initially explored them as individual monotherapies to provide preliminary safety and efficacy. I think for two of the three, we largely expected, based on the dose exposure response and target engagement to the first generation molecules, that it was unlikely that we could do much better.

Meaning on both TL1A and IL-23, it looked like the first generation molecules likely saturate the target in the induction setting for sure, and that we thought that a long-acting version, we could probably do the same amount of efficacy with less drug. Basically, in a long-acting antibodies, we can give quite a bit less drug and get to full saturation. I think that's what we've seen with both our TL1A data set that we delivered a few months ago, and then the IL-23 data in the last week, that these perform like the in-class molecules in terms of safety and efficacy, and then we have the ability to dose them much less frequently in the maintenance setting, and then we can deliver a lot less drug in the induction setting.

Which is actually very helpful as you get into combination therapies in terms of the ability to get both antibodies into a single injection, having lower drug loads is key. On the third of them, the alpha-4 beta-7, that was one where we looked at the exposure response data for ENTYVIO, both in their phase III studies and in the real world, and we saw that they had a pretty steep exposure response relationship, meaning that we thought with higher target coverage, we might do better. Though all of these are relatively small 40 odd patient cohorts, I think our data for our alpha-4 beta-7 molecule does look like there might be greater efficacy to be had with higher dosing on that target.

Great. Yeah. Then, so you asked again about the second part of this study now in terms of the combinations.

We think this is both an innovative study in terms of its efficiency and a platform design to get all of these answers in one trial. Then it's also robust in terms of answering what's key for combination therapies, which is contribution of components. That's really the key goal of the study, and that's why in this second portion of the trial, we have a placebo group, we have all three of our monotherapies, and then we have all three of these pairwise combinations as well, and we expect to read that all out together next year, which will help us prioritize which of these combinations we think is the optimal one to advance to pivotal studies.

Yeah, so. Yeah, we finished, I think back in April, we announced that we had completed enrollment of the part A portion.

Those were the monotherapy arms that we just described, and initiated enrollment in part B. Part B does include, as I described, all three monotherapies, actually two doses of the monos, and then high doses of the combination. Really we're testing do these monotherapies beat placebo as we would expect based on the class, and then how much do these combinations add together? The goal is to show monos beat placebo, combos beat the monos, and then we'll have the ability to prioritize which of these combos should advance, and in what order, I think, is the main question.