Spyre Therapeutics, Inc. Common Stock Citigroup’s Biopharma Back to School Summit 2026

Sure. Broadly, our goal is to develop products that elevate the standard of care in autoimmune diseases. In general, our approach to doing that is developing what we think are best-in-class monotherapies, long-acting optimized antibodies against what we think are the best biologic targets in each indication. Then in most cases, we are quite interested in evaluating how these best-in-indication or best-in-class antibodies can be combined together to hopefully do better than we are able to do with the monotherapies alone. I would say in inflammatory bowel disease, that approach and strategy is most mature. That is where we started. We have the three, I would say near top, if not the top three mechanisms in the space, long-acting antibodies against each of them.

Over the last few months, including this week, we've shared data from each of them that I think shows that they're at least as good in terms of best-in-class molecules, in terms of efficacy and better dosing than anything else in each of those spaces. At least I think in our Alpha-4 case, maybe can even do better than the first-generation products in terms of efficacy. Then there, we've actually, since about April of this year, we've been enrolling the combinations of those assets, which we think have a realistic probability of delivering efficacy that's above and beyond each of them individually. Beyond IBD, we're first exploring where TL1A should work. I think everyone who has TL1A is interested in its pipeline and a product potential. What indications will TL1A be excellent as a monotherapy, or is it a combination component in these different indications?

We're looking at a basket of rheumatic diseases. We reported RA results recently where the drug is certainly active and well-tolerated. We didn't think it was sufficient to advance as a monotherapy in phase III, though we do think it looks like a potentially good combination component. Then later this year, in the fourth quarter, we'll have both psoriatic arthritis, PsA, and axial spondyloarthritis, AxSpA data, where we'll be making the same evaluation. Is this good enough to advance as a monotherapy, or does it make sense to combine with the other great mechanisms in those spaces? Then, we're also expecting data from others as well that inform our strategy. I think in total, there's 7 TL1A proof of concepts this year. I've just talked about a few of them. We'll see the HS data shortly. We know it's positive from Merck.

Then we expect to see atopic dermatitis as well as MASH from Roche as well in the upcoming months. Again, in each of those indications, we should evaluate whether we think it makes sense to advance our molecule on its own or whether we should consider combination therapies. We made an initial bet in HS already, which is that we might be able to leapfrog the monotherapies by combining TL1A with bimekizumab or IL-17AF, and we think that's a really exciting trial. Again, like our IBD strategy, combine the best mechanisms in the space, and hopefully we can do better than anything else that's out there today.

Yeah. I think the obvious hint in terms of our certainty about which one is best is given by the fact that we're testing them head-to-head right now.

I mean, we don't know which of these combinations is best. I think we look at the biology of these and know they're quite orthogonal in terms of how they're benefiting patients with IBD. We've tested these in a variety of animal models and see that all three are additive with each other, so I think there's good reason to believe that they'll be additive clinically as well. In terms of which one, we don't know. That's why we're testing them head-to-head. I think we feel very increasingly good about the safety of all of these. Until recently, I would have put Alpha-4 and IL-23 above TL1A in terms of our certainty of the safety, though I think in recent months, both in our randomized phase II data as well as Merck said in phase III that their TL1A was well-tolerated.

I think at this point we feel pretty good about the safety of all of them, and the efficacy of all these is good as well. I have a slight bias towards our Alpha-4-containing combinations because I think it's an elegant solution to a gut-predominant disease to have one agent that's acting in a gut-selective manner and the other being a broader immune suppressant, so you're functionally getting double suppression in the target tissue and then only single suppression everywhere else.

As much as I am hopeful that our combinations could deliver much better efficacy than monotherapies today, I think it is unlikely that we are getting to majority patients in long-term remission forever with our combinations. I would love if that were the answer. I just think that is quite unlikely, meaning I think it is still likely to end up being a cycling market, but IBD is a cycling market that is highly concentrated to the best products. If we look over the last decade, the top three drugs have taken almost 70% of the revenue here, and those top three drugs have changed. But as soon as you beat the prior standard of care on efficacy without a safety downside, those drugs take the lion's share of the market.

I think it is credible that our combinations have the possibility of beating today's standard of care by a meaningful amount. I frankly think all three of them have a decent shot at that in terms of being those next-generation top-tier products. I think it will make sense to advance more than one if they are all in that top tier.