Hey, good morning, everyone. Happy to have Cameron Turtle, the CEO of Spyre Therapeutics, with us for our next presentation of the morning. Maybe, Cameron, I'll kick it off to you, maybe a quick overview of Spyre, and then I actually want to switch things up and maybe talk a little bit about HS and rheumatology to start.
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.
Yep. As you allude to, one of the foundational elements of Spyre is combinations, and obviously there's a lot of different datasets out there now since when you were first founded as a company. I guess, where are we now, just broadly in that field, in your view?
Yeah. I think in many of these autoimmune markets, we've been working on various targets for 20 - 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. J&J 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. I definitely want to get into IBD, but I do think the sort of thinking about combos is a good jumping-off point. Obviously you have alpha 4 beta 7, IL-23, and TL1A, and you've recently announced that you're moving into HS with your other TL1A antibody, and that follows after top-line data from Merck with tulisokibart for that program. We just saw that they're going to have a late-breaker at EADV for HS. I guess maybe to start, what are you expecting for the tulisokibart data at a high level? Then I want to talk about the way you're thinking about HS development.
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.
At the same time, if TL1A is the best mechanism in HS, and we think we have a potentially best-in-class TL1A molecule, including, we have hundreds of patients of exposures on it as well from our various studies. I think that we actually could have a relatively rapid path for that monotherapy as well, that we will be making a call on in the next few weeks as we see of those data and decide, do we want to advance just the combination, or should we also be advancing our monotherapy?
I guess, this data set represents kind of a decision point for you to pursue the combo with IL-17 as well, or are you still going to plan to have those data end of next year or early 2028?
The combo is going.
Yeah.
I think we're very excited about the combination. HS, like I described with IBD, it's a serious unmet need disease where as rapid growth we're seeing with the therapies in this space, we're still not doing all that well. It's like IBD, a space where physicians are using combinations already in the real world. We have early proof of concept that they're doing better than they do for monotherapies as well. If TL1A and IL-17A/F are the best two mechanisms, I think that's probably a good idea for a combination. In some of our basic biology work, we see these are hitting different aspects of the biology of the disease as well, and we think we could see additive efficacy between them. We think the combination is a great program, and that's definitely continuing.
I think the question is, could there also be rationale to have a rapid path from TL1A monotherapy there too? I think that this might be one of those indications, since it's a relatively immature market, where we're not yet sure how much better combinations can be as we are in IBD. I think it could actually make sense to do both here.
Yeah, for sure. I guess moving on from the balance of this year, your big two additional updates are from psoriatic arthritis and axSpA. I guess, this comes off of a lack of a large enough signal in RA to proceed with [SPY072]. I guess, sort of where do we go from here with rheumatology? Are you more or less excited now about these other two indications after the RA update?
Yeah, I think the RA data shows that it's clearly active on-
Yeah.
arthritic disease, clearly providing a benefit, very well tolerated as well, kind of similar to placebo in terms of the adverse effect profile. There actually aren't very many mechanisms in the arthritic diseases that do that have a demonstrable benefit without a safety downside. Most of the agents don't have that. Then we also see that many mechanisms that work very well in PsA and axSpA, I think, point to the IL-17 and IL-23 classes, which have kind of comparable data in RA. They're active but not quite good.
I think we still think it's very possible that TL1A could look nice in PsA and axSpA as well. In some ways, I actually may be even more encouraged about the combinations in those agents there where we already have the IL-23 and the IL-17, which would be the logical combination components in those indications as well. I still think kind of plenty of path forward in rheumatic disease as well, and we'll see those data over the next few months. We'll also see data in atopic dermatitis and MASH.
Yeah.
I don't have quite as high expectations for those, but we'll see, and if those are promising, then of course, we'll be interested in those indications too.
Externally, as is Roche and Merck.
Both of those are Roche, yeah.
Roche. Okay.
Atopic derm and MASH, yeah.
Yeah. I guess you alluded to, is the bar to move forward lower in axSpA and psoriatic arthritis given the prospect of combinations here, or no?
I think the bar for monos is about the same.
Yeah.
We show kind of the existing commercial landscape for products in the space. We are not particularly interested in things that have lower efficacy, but better convenience. I do not think that is something that is our highest use of investor dollars. I think if we saw something that matched the existing monotherapies in the space from efficacy, and we have a cleaner and/or more convenient profile, that is something that we would be excited to move forward. Then there is probably a bar that is, I think, slightly lower that you would consider combining it with, again, the leading mechanisms in the space, IL-17 and IL-23, and potentially have the leading product when you combine those things together. Outside IBD, PsA is actually the other indication where we have seen combos add up relatively well with the J&J AFFINITY trial.
I actually think we feel that those are a pretty plausible path forward, too.
Yeah. I guess, are you committed to moving forward in rheum and IBD on your own if these data look solid in your view?
Yeah, look, we think about advancing programs from the financial and the operational bandwidth to do additional things. I think we've shown so far, this company is only three and a bit years old, the ability to scale rapidly and take on, frankly, fairly complicated, large phase II trials. A more rapid and challenging growth trajectory than most biotechs do. I actually think our ability to scale and do larger studies that follow on from here, I'm not overly concerned with as well. We're currently running trials in 35 + countries with north of 300 sites. It looks like a phase III operational capacity that we're already doing now with the size of the phase II's that we're doing.
Great. We're, weirdly enough, almost in the fourth quarter, which means that people are starting to think about 2027, and you're going to have an insane amount of data next year from the SKYLINE study. I guess maybe to set this gauge on the UC readout next year, do you want to sort of walk through, at a high level, the data that you've generated from the monotherapy components for all three of your combo monos?
Yeah. We're running the SKYLINE study in UC, is what we call the study, and it's a two-part study. In Part A, it is each of these monotherapies in an open-label setting. Then Part B, which is enrolling now, is the combos against the monos against placebo. In the Part A component, these were 40 odd patient cohorts across alpha 4, TL1A, and IL-23. Since it was open-label, we used an objective primary endpoint, which was the Robarts Histopathology Index, a centrally read objective measure, not something that's fudgeable in an open-label context. I think we saw highly statistically significant benefits there that also, there haven't been that many studies that have used RHI, but I think the three deltas that we reported from week zero to week 12, some of the highest reported improvements on the histopathology of any agents in the space.
When we look at the more classical endpoints that we'll use in Part B and going forward in phase III, clinical remission, endoscopic improvements. For the TL1A and our IL-23, we think that these performed right in line, basically, with those classes, which was our expectation. We think with both TL1A and IL-23, the first-generation products, they saturated the target with their dosing. Though we could do it with a lot less drug, which we think is very helpful as we get into combinations, we didn't think there was much opportunity to do better on efficacy, and we saw efficacy that was in line on those two targets. On alpha 4, beta 7, we might have done better.
I know we looked at data from ENTYVIO in both its phase III studies and the real-world setting that suggested that higher exposures of the drug could lead to greater or faster efficacy in the induction setting. We tested a higher level of exposure with SPY001 compared to ENTYVIO, and we saw efficacy levels that look superior compared to what is seen with ENTYVIO, with all the caveats that are necessary for a small open-label study. That said, if we had seen all three were in line efficacy in class, I still think we would have the three most interesting combinations in development in terms of the product profiles we could deliver.
If we have the alpha 4, beta 7 that is differentiated on efficacy versus ENTYVIO, and then the other two are in line with those classes, I think it gives us even higher probability that these are the three most valuable products in development in IBD, and I think have the potential to deliver a product profile that's superior to most things in the space.
SKYLINE, there's a lot going on in this study. Multiple arms, one shared placebo arm. Can you walk through what exactly we're going to get next year in terms of what are the arms for each mono, what does the combo arm look like, what are the doses, et cetera?
Yeah. It's one big readout.
Yeah.
I think that is the utility of this trial, is that we have a shared placebo, and each of the monos serves as a comparator for two of the combinations, right?
Yeah.
We have three combos and three monotherapies. That is the value of this study, is being able to do it all in one and not have to have a huge number of placebo patients across all of them. It will be one big readout, two doses of each of the monotherapies. The high dose will be the combination dose. Really, this is the proof of concept for us, which is which of these combos is best. In terms of the bar that we want to see or what we think is exciting would be about a 10 percentage point delta of clinical remission improvement on the combinations relative to the best monotherapies.
Yeah.
The reason this is our bar, really, it is a market-back view on what is important in this space and what has mattered over the last few decades in IBD. I know when we look at this space, it is a remarkably concentrated market because the physicians call it top-down treatment, meaning you use the best drugs first, and what that often means is you never use the less efficacious drugs. If we look back 10, 15 years, top three drugs took 70% of the market. Today, it is actually about the same. They are different drugs, though. 10, 15 years ago, it was HUMIRA, REMICADE, STELARA. Those three drugs lost by about 10 percentage points on clinical remission to ENTYVIO, TREMFYA, and SKYRIZI by about 10 percentage points on clinical remission.
We see 70% of the market going from those three to these three, and we think the transition to combinations is reasonably likely to look similar, that if you can beat the current standard of care by a clinically meaningful amount, about 10 percentage points on clinical remission, that that market is going to relatively rapidly move to those more efficacious products. Especially given the case that today those branded drugs are competing against biosimilars. They're still favored to take that huge position. When we'll be launching combinations, existing branded drugs are still going to be branded, and we expect to be in a similar price point as the existing branded drugs with clinically meaningfully better efficacy, frankly, and better convenience as well for our combos. We think this is an opportunity to really deliver something that's quite a bit different and move this market quickly.
I think that all makes sense. You want to put that delta in context with the DUET study, particularly in UC, because I think there's some important differences around how you're enrolling your trial versus that trial in particular.
Yeah. It is quite different. I think J&J ran two studies in UC, right? They ran the VEGA study that I referenced earlier, and then they ran the DUET UC study. You saw quite divergent results, right? The VEGA study was run in completely naive patients. They had not seen advanced therapies before, and they had the result that I mentioned, almost a 25-point difference on clinical remission, a dramatic improvement on the combination versus the monotherapy components. In the DUET trial, everyone had failed a prior therapy, and we know in the UC side, almost three-quarters had failed a prior TNF, usually HUMIRA or REMICADE as the leading TNFs in the space.
They were getting, as one of the components of the J&J combination, golimumab or SIMPONI, which is another in the same TNF class, and in fact, doesn't quite have the same efficacy as HUMIRA or REMICADE in UC. What you find is that that component did very little in that context. We saw the monotherapy golimumab arm had remission rates in the single digits in that study. It was still additive. It still added on top of TREMFYA alone, but it added a very small number because that agent was not super effective. Our study is quite different. In our study, we're running actually what I think is a more classical study in UC, which is a 50/50 population using about half naive patients in the study and then about half refractory.
Even within our refractory population, we're going to limit the number of patients that will have failed an alpha 4 beta 7 or an IL-23p19 inhibitor. I don't think that population would look like DUET anyways. I think it's quite likely that we're going to see kind of a more larger monotherapy component efficacy, and I still expect we'll see a good amount of additivity between these mechanisms.
Yep. I think you alluded to this in sort of the preamble talking about combinations, but obviously a lot of the competitors, J&J, we talked about DUET, and they're moving forward into phase III. AbbVie is largely built out the same pipeline as you, with expectations of starting a phase III in 2028. I guess sort of how can you maintain your position here in your view moving forward with these big players?
Yeah. I think the products are the differentiation here. If you compare the product profiles that we're looking at relative to the ones that the leading players in the space have, I don't think it's that competitive.
Yeah.
On the J&J side, I think their product profile looks quite good. It's a monthly auto-injector, but they're limited by the fact that one of the components is golimumab in a population where other TNFs are used first. That's a tough setup, and we saw that in the DUET study and their phase III study is a late line study. In the AbbVie case, as you mentioned, they've tried a number of things, and they've largely narrowed to our mechanisms, but they're not quite the same in terms of the product profile.
Yeah
SKYRIZI is a great drug. It's an on-body pump on its own. They need to dose 3.5 g of it in induction just for that monotherapy. Their alpha 4 beta 7 is a repurposed HIV drug. These things are not quite as good as optimized versions of the best biologics in the space that were designed for combos from the outset. From a timeline perspective, J&J is certainly ahead having started phase III already. I think we are neck and neck with AbbVie, and I think we're quite a bit ahead of everyone else, and I think our product profiles are quite differentiated from the rest.
On the IV or on-body point, if you were to move forward with a 23 combo beyond the phase II study, could you do all sub-Q based on the formulations that you have? I know you're doing IV-
We could-
in phase II.
We are doing IV in this study because we were not sure what the dosing would have to be when we started this study. We did not actually yet have our phase I data for our IL-23, and knowing the dosing of SKYRIZI, we thought, depending on our bioavailability and half-life, we might need to dose a lot. Based on what we have seen, both from our phase I data and now in phase II, I think we are quite certain that we can have a reasonable dose of both of our components, and that lets us get to, we could do all sub-Q induction if we chose, or we can do kind of the standard product in IBD, which would be an IV load followed by sub-Q. Either are options for us as we get into phase III.
In terms of other developments in the space, not clear if we will get the tulisokibart data at UEGW, maybe not. Maybe not until ECCO. That phase III data set, we know it is positive, and it is the first phase III among the first gen of the TL1As. I guess, what should we expect to see there, and what are you looking for as you think about TL1A programs?
Yeah, I think we might see Roche data relatively soon actually as well. The two leading TL1As are the Roche and the Merck antibodies. I think we are interested in seeing the phase III data. In some ways, we already have the most important data point from those trials, which is Merck saying that it was well-tolerated in phase III.
Yeah.
I think that is the most critical data point. Hopefully, we'll see the same from Roche. In terms of efficacy, I think the key data point that we will be interested in seeing is the maintenance data points.
Yeah.
Particularly as Merck went to a more frequent dosing in the maintenance setting. I think there's an unanswered question as to whether we've fully saturated TL1A in the maintenance setting with the first-generation agents. I'm quite interested to see the maintenance data, in particular from Merck to see maybe it was underdosed, and we can actually do better in maintenance, which I think would actually bode well for a program like ours with the potency and half-life advantages that we have.
Are you worried to see any effect size regression at induction?
TL1A right now is the leading mechanism in the space, right?
Yeah.
The placebo-adjusted delta is one of the best we've ever seen in the space in phase II. It would have to drop a lot for it to not be one of the top three or five products in the space and make good sense as a combination component. I actually don't worry about that too much.
Okay. Then maybe last question, where are we on the Crohn's disease path forward here?
Yeah, I think we plan to take the winner from SKYLINE forward in both. You know, This has been done a half dozen times in IBD to run proof of concept or one and the other and then advance in both. I think the ideal option would be to run two parallel phase III studies, but if we had to, then we would run a phase II-B/III in a kind of a single seamless design, which has also been done multiple times in this space. I think whichever wins, we will advance in both.
Great. Well, Cameron, really appreciate you joining us this morning.
Thanks for having me.