Spyre Therapeutics, Inc. Common Stock Stifel 2026 Virtual Immunology and Inflammation Forum

Yeah, that sounds great. Yeah, so background for Spyre is that we're interested in seeing if we can elevate the standard of care in some of the largest autoimmune markets. The way that we think about this is the relatively similar playbook across all these indications, which, first, let's see if we can find the mechanisms that provide the highest benefit-risk ratio in each of these indications individually, engineer what we think could be best-in-class versions of those antibodies, maximum potency, long-acting versions that we can co-formulate together, which we think might be the optimal product profile in the long run.

In many of these unmet need indications, we're interested in seeing if combining the top mechanisms in the space has the ability to provide additive efficacy without meaningful safety downsides, which we think has the opportunity to just create products that are substantially better and provide a much better option for patients with these serious diseases. Now, in each of the indications we're looking at, we're at a different stage of this playbook. We're furthest ahead in inflammatory bowel disease, where we started with what we thought were the best biologic targets in the space. I think over the last few months, we've shown that our versions of these antibodies are at least as good from an efficacy perspective as the first-generation products with that improved dosing profile and maybe better.

We've actually been testing these combinations for the last few months in the SKYLINE Part B study, and we're excited to read out those combination data next year. Outside of IBD, as I know we'll talk about, we're kind of working through those stages as well, where we're testing how good TL1A is in each of these indications individually. We think we've engineered a potentially best-in-class TL1A with improved properties to the first-generation molecules. Depending on the results that we see from the various indications over the last few months and in the next couple of months, we'll decide whether we want to advance our TL1A as a monotherapy or potentially as a combination, or in certain circumstances, we even could consider doing both the monotherapy and the combinations.

Yeah. I think in many of these autoimmune markets, we've been working on various targets for 20 to 30 years, trying to find which ones do best from a benefit-risk ratio. In some of them, we found targets that largely put the vast majority of patients into remission and keep them there for an extended period of time, and I think that's an amazing accomplishment for the field. However, in a number of these indications, we haven't done all that well. We've tried dozens of different mechanisms of action, and we still get a minority of patients into remission immediately, and then over the long run, we actually tend to lose those remissions over time for these individual mechanisms. In the serious enough diseases, what you tend to have happen is that physicians in the real world try to solve that.

These patients are having very costly consequences of their disease, and so physicians start testing combinations in the real world and seeing if they can get them into a better place from an efficacy perspective, despite meaningful payer pushback. Of course, they don't like folks testing multiple expensive drugs at the same time, nor do some physicians or patients are a little cautious about testing mechanisms that haven't been formally studied together. I think that's usually a good indication of places where it makes sense for our industry to run well-controlled trials and test whether combinations work better or not.

Yeah. I would say that the main starting gun in IBD, certainly, and I actually think it translates to a lot of broader I&I was the VEGA result.

Johnson & Johnson ran this groundbreaking study testing their two drugs together in ulcerative colitis patients. They functionally doubled the remission rate in those patients when they combined their two agents together versus them individually and without meaningful safety downsides. I think it really just told the field that we can do a lot better for these patients if we combine targeted therapies together, and this has really kind of launched the space. I think what's unique about Spyre is kind of right place, right time when that happened.

We were basically working on long-acting versions of an alpha-4 beta-7, a TL1A, and an IL-23 at the time, and had the ability to pick antibodies that weren't just great individually, but we could co-formulate them at high concentration. We ran our entire toxicology program with the combinations in mind and showed that they weren't just well-tolerated individually, but well-tolerated together. Then we designed what I think is one of the most innovative and efficient development plans for combinations as well in terms of one large platform study that lets us develop these things highly efficiently together. I think it ends up with a set of products in IBD that are potentially head and shoulders better than others in development. Co-formulated, four shots a year, best mechanisms in the space.

Whereas most of our competitors, when VEGA came out, started combining what they had on hand, and that was a mix of different agents with different dosing profiles, different half-lives, even mixes of orals and injectables. That ends up just with products that are, I don't think, close from a product profile perspective relative to what we're developing.

Yeah. So I think broadly, we thought when we initially picked indications for TL1A outside IBD, there was not a ton published in HS. But between some Merck publications and presentations, then we replicated a good amount of that data internally, we actually were reasonably convinced that TL1A could be a very active agent in HS, and so that's why we launched this trial that you're talking about. But I think, we're very interested to see the presentation next week from Merck at EADV. I think for that study to have been successful and hearing some of the commentary about their encouragement around those data is that they could have data from an efficacy perspective that's close to BIMZELX. If that's true, BIMZELX is the leading product in the space. So far, TL1A appears to be better tolerated, actually, than IL-17A/F.

If you have near similar efficacy and better safety, this could be the leading mechanism in HS. Tulisokibart is a great molecule, but I think ours has a number of differentiating features in terms of about a log fold more potent in a variety of assays, and then also about three times the half-life of that molecule. The data we have already seen from Merck, the top-line announcement that it was positive, very encouraging for us to be running the combination study that we are doing. I think it very well could be the top two mechanisms in this space that we are currently testing together. I think we would have the leading product in the space that could leapfrog these monotherapies there.