Spyre Therapeutics, Inc. ($SYRE)

Good day, and thank you for standing by. Welcome to the Spyre Therapeutics SPY001 Part A induction top line results conference call. [Operator Instructions] Please note that today's conference is being recorded. I will now hand the conference over to your speaker host for today, Eric McIntyre, SVP of Investor relations. Please go ahead.

Thank you, Olivia, and thank you all for joining. We're thrilled to be speaking with you this morning. As you saw today, we issued a press release outlining positive top line induction results from Part A of our SKYLINE trial of 001 for the treatment of moderately to severely active ulcerative colitis. Press release and slides that we'll be using today during our call and are available on the Investors section of our website. I would remind everyone that during this call, we'll be making forward-looking statements related to our current expectations and plans for the company and our clinical programs including the IBD market opportunities, the best-in-class potential of SPY001 and its safety and efficacy potential and that of our product [indiscernible] and combinations thereof for the treatment of IBD as well as the expected timing of our additional data readouts. These statements represent our views as of this call and are subject to certain risks and uncertainties covered in our SEC filings and should not be relied upon as representing our views as of any date in the future. Please review our forward-looking statement legend carefully. On the call today with me are Cameron Turtle, our Chief Executive Officer; and Deanna Nguyen, Senior Vice President of Clinical Development. Following our prepared remarks, we'll have a Q&A session during which Sheldon Sloan, our Chief Medical Officer; Scott Burrows, our Chief Financial Officer; and Kate Tansey Chevlen, our new Chief Commercial Officer, will also join. With that, let me turn the call over to Cameron.

Thanks, Eric, and good morning, everyone. We're excited today to be sharing the first patient data from our ambitious development program that aims to address the substantial unmet need in autoimmune diseases by developing potential best in indication products with uncompromising profiles across safety, efficacy and convenience. Today's call will focus on our efforts in inflammatory bowel disease, the condition that causes substantial morbidity for more than 2 million American patients and represents a $25 billion and growing global market. Despite the scale of this market, today's standard of care leaves much to be desired. The half dozen approved therapeutic classes are unfortunately capped at what physicians call the therapeutic ceiling. Shown here is an approximately 25% placebo-adjusted clinical remission level leading the substantial majority of IBD patients with incomplete responses and continued disease activity. Today's drugs are also dosed inconveniently with subcutaneous injections as frequently as every two weeks and even long-term maintenance IV therapy both of which impact patients' lives and reduce adherence. In addition, many of these therapies carry safety concerns or monitoring requirements that further increase patient burden. Fortunately, the blueprint for breaking the therapeutic ceiling in IBD is increasingly clear. Advanced combination therapy has been shown in randomized trials, such as J&J's VEGA study shown here and real-world cohorts to provide additive efficacy without apparent safety downside for the first time, opening the possibility of providing long-term remission to the majority of IBD patients. With this future in mind, we believe success will ultimately be determined by the thoughtfulness of combination construction. Spyre is unique in that we design our combinations from the ground up, selecting validated mechanisms with the best safety and efficacy profiles, engineering next-generation molecules with potential best-in-class properties and designing them to work together as a convenient product. The results are combination products that we believe will stand apart. Certainly from what exists on the market today in IBD, but also other combination products in development. If any of the Spyre combinations are successful, we believe they will set a new bar for product performance in IBD across efficacy, safety and convenience. Today, we'll start with proof-of-concept data for our first component targeting alpha-4 beta-7, which we believe is the ideal backbone for IBD combination therapy as this gut selective mechanism and well-tolerated class safety profile have the potential for lower off-target immunosuppressive risk relative to drug classes that reduce systemic immune activity. Further, we believe that an anti-alpha-4 beta-7 antibody is likely to provide additive efficacy with cytokine blocking agents such as our anti-TL1a or anti-IL-23 molecules given alpha-4 beta-7's unique mechanism of blocking immune cell trafficking to the gut. This hypothesis has been well supported by real-world studies using vedolizumab in combination with other advanced therapies. Our approach to inhibiting alpha-4 beta-7 is an optimized version of vedolizumab, SPY001, which targets the same validated epitope with comparable potency and [ match effector ] function financing to ensure gut-specific activity and avoid off-target immune suppression. Our design improvements to the molecule include sequence modifications to meaningfully extend 001's half-life relative to vedo and a high concentration, low viscosity subcutaneous formulation to enable maximum target coverage and patient convenience. With this optimized product, we aim to learn from prior vedolizumab data and test whether increased target coverage during induction could lead to improved efficacy. Specifically, we saw an induction data from Phase III trials and real-world cohorts that maximal efficacy of vedolizumab was observed in patients in the highest quartile of drug trough concentrations. So we aim to achieve 001 exposures in this fourth quartile for patients during our 12-week induction period. Though our final PK analysis is not complete, preliminary data suggests that the substantial majority of 001 dose patients had week 12 concentrations in this fourth quartile of vedolizumab exposures. We, therefore, believe that we're effectively testing the exposure response hypothesis in this study. On the back of the Part A results that we'll share now for 001, our conviction in this exposure response hypothesis for alpha-4 beta-7 has substantially increased. Specifically, the SPY001 Part A induction results suggest a potentially best-in-class anti-alpha-4 beta-7 product profile. The molecule was well tolerated as expected and across all key efficacy measures, outperformed results from vedolizumab in precedent trials. In fact, as we'll show later, we believe the 001 efficacy compares favorably to data for precedent trials for mechanisms of action even outside the alpha-4 beta-7 class, suggesting that 001 could be one of the leading monotherapeutic products in development today. But without getting too far ahead of ourselves, I'll turn the call over to Dr. Deanna Nguyen, who will go through the trial and data in more detail.

Thanks, Cameron, and welcome, everyone. Over the next few minutes, I would like to walk you through the SPY001 Part A induction results from our SKYLINE platform study in patients with moderately to severely active UC. The overall study design for the SKYLINE study is shown here. And as we have previously described, this is a platform study with an induction maintenance [indiscernible] design, investigating each of our 3 monotherapies and 3 pairwise combinations conducted in 2 parts. Part A is an open-label evaluation of our investigational monotherapies, whereas Part B is a placebo-controlled evaluation of our combinations as well as our monotherapies. We have said previously that enrollment was ahead of schedule, and today, we're thrilled to announce that Part A recruitment is complete. After open enrollment, there's approximately 130 participants across the 3 cohorts. We're starting to enroll patients in Part B in various countries across the globe. And the excitement continues to build with investigators as we leverage the infrastructure built in Part A to begin testing monotherapies in combinations. The focus of today's discussion is the first readout of the trial, the SPY001 Part A induction data. And as a reminder, each of our monotherapies was added to the study after its interim Phase I study results became available beginning with SPY001. You can see here on the slide that participants were enrolled using standard eligibility criteria for moderately to severely active UC trial, and these criteria are largely consistent for Parts A and B, including allowance for failure of up to 3 classes of advanced therapies. And in addition to using specific objective criteria to ensure patients have active UC, our team is leveraging our experience in executing UC trials to minimize placebo response rate. The objective of Part A is to demonstrate proof-of-concept, safety and efficacy for our 3 monotherapies. Though these Part A results are open label, we are using clinically validated and objective endpoints that correlate closely with placebo-controlled results in UC. Our primary endpoint is changed from baseline in RHI, the Robarts Histopathology Index. And RHI is clinically validated instrument for measuring histologic disease activity in UC and is scored from 0 to 33 based on inflammatory infiltrate, neutrophil infiltration and epithelial alteration or erosion. One key secondary endpoint was endoscopic improvement, reflecting the proportion of participants who had a mildly active or normal endoscopy, meaning a score of 1 or 0 in week 12 by central reading. As a reminder, every participant enrolled in the study had to have a moderate or severe and endoscopic score, meaning a score of 2 or 3 at baseline. Another key secondary endpoint was clinical remission, which is a composite endpoint that includes an endoscopic component as well as a symptomatic component as reflected by patient reports of stool frequency and rectal bleeding. Importantly, both histology and endoscopy have blinded center readers for the SKYLINE study. That means that global experts with GI pathology or endoscopy expertise are reviewing the histology and endoscopy images, unaware of whether the images are coming from participants at baseline in Week 12 or another time point such as the end of maintenance. Baseline characteristics we're in line with our expectations and with precedent studies in moderately to severely active UC. The first cohort enrolled in North America and Europe, given the quicker regulatory approval time lines in these regions, hence the advanced therapy naive predominance, which is comparable to the VARSITY study. Disease severity at baseline was typical with more than half of participants with the baseline endoscopy score of 3 and a mean baseline modified male score of 6.8. As you can see on the left side of the slide, 43 participants were treated with SPY001 and 41 completed the induction treatment period. Two participants early terminated before week 12 due to withdrawal of consent. One participant dropped out of the study due to personal circumstances and a second after a nondrug related adverse events that we'll discuss on the next slide. Overall, SPY001 was well tolerated with few treatment-emergent adverse events. The benign nature of this profile appears consistent with that of the anti-alpha-4 beta-7 class broadly, which is considered one of the safest advanced therapy classes and IBD. The most common treatment emergent adverse events, meaning occurring in at least two participants was back pain. No AEs were deemed drug-related, and there are no deaths or at first events of special interest. As mentioned previously, there was one serious adverse event in a participant in the induction treatment period which was deemed not related to study [ drug ]. That SAE was chest pain in a 68-year-old male with a history of coronary heart disease and angina, diabetes, hypertension and hypercholesterolemia who presented with chest pain and ruled out for an MI. Now turning to efficacy. SPY001 met its primary endpoint in Part A, with a change from baseline in RHI in week 12 of negative 9.2 with a p-value of less than 0.0001. Certain prior studies have required a baseline RHI score of 10 or above for inclusion so we prespecified a sensitivity analysis of that subgroup in our study. When we look at that subgroup, our change from baseline was even larger at negative 10.6. For our key secondary end points, 40% of participants achieved clinical remission, 51% achieved endoscopic improvement and though not shown on the slide, we observed a mean change of negative 3.7 in modified male score from baseline to week 12. So our sample size limits our ability to interpret subgroup analyses. We were also encouraged to see little difference in clinical remission or endoscopic improvement rates among patients who had or had not previously been exposed in approved advanced therapy. Beyond these top line measures, we observed consistent and substantial improvements in both endoscopic and disease symptom measures between baseline and week 12. As shown on this slide, our study population had moderately to severely active disease at baseline and following two doses of SPY001, the population had dramatically improved across all measures. Lastly, we'll highlight the time course of improvement observed during this induction period, as shown by the change from baseline in both partial male score and level of fecal calprotectin, a biomarker of intestinal inflammation participants receiving SPY001 improved rapidly and consistently. And taken together, we believe these data are clear that SPY001 significantly benefited UC participants enrolled in this cohort. And with these data in hand, we're thrilled to be progressing into Part B of the SKYLINE study, in which SPY001 will be tested as a monotherapy at two dose levels and as part of combination with an anti-TL1A and an anti-IL-23 with a large number of sites activated globally. I'll now turn it back over to Cameron.

Thanks, Deanna. Before providing a few comparisons of these 001 results with the broader UC landscape, I first wanted to take a moment to acknowledge the team behind these data. As you see on this slide, completing enrollment of over 130 ulcerative colitis patients across 3 investigational agents in 10 months represents an unparalleled pace in this disease area. This outcome reflects tremendous execution by our team and our partners and also substantial investigator and patient enthusiasm for even our monotherapy product candidates as long-acting versions of some of the best mechanisms currently available. As we now transition into Part B and introduced 3 combination arms to the study, we believe enthusiasm will only increase from here. To begin to put our 001 data into perspective, we first want to compare the population that we enrolled relative to populations enrolled in benchmark alpha-4 beta-7 trials. As shown on this slide, the 001 Part A cohort had comparable disease severity as the VARSITY, GEMINI and EMERALD studies by either baseline modified Mayo or endoscopy scores. The population of advanced therapy naive participants in our cohort was comparable to VARSITY though somewhat higher than GEMINI or EMERALD. Acknowledging the uncertainties with cross-trial comparisons, with similar trial population, the 001 efficacy results were meaningfully above benchmarks reported in precedented alpha-4 beta-7 trials across all key end points. We're particularly excited about our 51% endoscopic improvement rate, given the purely objective nature of this endpoint. This value compares favorably to vedolizumab data in the GEMINI study despite that study not requiring central endoscopy reading as well as to the MORF-057 result in the EMERALD study with a very similar trial design as our own. Overall, we believe these results support the hypothesis that increased target coverage of alpha-4 beta-7 with SPY001 due to its extended half-life and higher induction dosing will lead to greater or faster efficacy than other agents in this class. As we begin to look beyond the alpha-4 beta-7 class, our SPY001 results continue to compare favorably. There are fewer benchmarks for RHI given the novelty of this end point but the change from baseline of 9.2 that we observed is larger than any previously reported up to week 12 in precedent trials. Turning to our first key secondary end point, we're showing on this slide the absolute clinical remission rates for relevant approved and investigational therapies in UC. As you can see, the 40% clinical remission level observed in the SPY001 cohort represents one of the largest response rate seen in precedent UC trials to date across mechanisms. Whereas clinical remission includes stool frequency and rectal bleeding components that could be impacted by the open-label nature of our trial, endoscopic improvement represents an objective endpoint that is difficult to bias. On this slide, we show the absolute endoscopic improvement rates observed in the prospective industry-sponsored trials of approved and investigational therapies in UC. Again, our 51% rate of endoscopic improvement is one of the highest rates ever observed. Combining the well-tolerated safety profile and efficacy data shown in today's top line data, and our ongoing development of maintenance dosing as quarterly or twice annual subcutaneous injections, we believe SPY001 is one of the most promising single agents in development in IBD. With the completion of Part A screening announced today, we've begun screening patients for Part B, which includes both placebo-controlled dose ranging of SPY001 to potentially enable streamlined pivotal development as well as combinations with SPY001, with SPY002 and 003. Speaking of our combinations, we believe the SPY001 data provide increased confidence in our approach, given our continued belief that better components will lead to better combinations. The efficacy data that we've shown for SPY 001 is higher than that reported for either combination component in the VEGA trial, which enrolled an almost entirely naive population with comparable disease severity as our cohort. And additionally, on certain endpoints, our SPY001 monotherapy [ master ] even exceeded the efficacy of J&J's combination. If our anti-TL1A or anti-IL-23 agents were to provide additive efficacy on top of SPY001 as has been observed for other IBD combinations, we believe SPY001-containing combos could outperform other combinations in development. We further believe that advanced combination therapy will dramatically reshape the IBD market. Gastroenterologists treating IBD patients have shown the top-down therapy, meaning the use of the most effective products first leads to substantially better long-term outcome than step-up therapy in which more efficacious products are reserved for later line use. In addition, top-down therapy has been shown to be cost-effective due to the high cost of caring for uncontrolled IBD. If the top-down treatment paradigm continues, we believe that advanced combination therapies are likely the winning approach. This improved efficacy can be conferred without substantial safety concerns and delivered in a convenient product priced as a single agent, we believe combos are likely to displace branded monotherapies in the treatment paradigm and become the leaders in this large market. We further believe that Spyre is uniquely designed for success in this future. With this first patient set of patient data in hand, we've officially entered the [ prove it ] period for what we believe is one of the most ambitious and high potential pipelines in biotech. From here, in the SKYLINE-UC trial, we expect to readout SPY002 data midyear with 003 coming in the third quarter. For these two agents, we're targeting comparable efficacy and safety as in class comparators as these mechanisms don't share the same dose or exposure response opportunity that we've tested with SPY001. For our efforts outside IBD, in the SKYWAY trial of our potentially best-in-class anti-TL1A antibody, we expect accelerated RA top line data next quarter after that sub study over-enrolled with more than 140 participants randomized between two doses of SPY072 and placebo. Again, the team here continues to deliver ahead of schedule. We also remain on track with both PsA and [indiscernible] substudies with top line data expected in Q4. We expect to provide an update later this year on [indiscernible] to expect the Part B data from the SKYLINE study. With that, we're done with our formal presentation. I'll turn the call back to the operator to begin Q&A.

[Operator Instructions] Our first question comes from Sam Slutsky with LifeSci Capital.

Appreciate the questions, and congrats on the great data. Just two for me. I guess, first, given the strong data, does this open up the possibility of developing 001 as a monotherapy to approval? If so, would you have to run a head-to-head versus vedolizumab? And then were you able to look to see if any single site or region particularly drove the high response rate or was the data pretty consistent across sites?

Yes. Thanks, Sam, for both those questions. Actually, the first one is the one that we've debated quite a bit internally as these data started to become clear in terms of is 001 a viable commercial product. And I think from the data that we've seen today, if they were to hold in larger placebo-controlled studies, I think the answer is absolutely yes. We're differentiated on efficacy, very clean on safety. And I think we have the most convenient product as a monotherapy, I think that this could be a very successful monotherapy product. However, we still also think that it's very likely that TL1A or IL-23 will provide additive efficacy on top of this result. And if we see increased efficacy beyond this, I think that product, those combination products would be even more attractive in this field. So I think the short answer is we likely have multiple things that are going to be attractive commercially coming out of this, and the Part B of this study will both enable a streamlined monotherapy development with two doses against placebo as well as help us see how much better those combinations will be to help us pick which agents go first into pivotal development. In terms of will we require a head-to-head study? I don't think it's been the case that you've ever required head-to-head studies to get drugs approved in this market, but certainly head-to-head superiority have substantially shifted the market. And think differentiation on the order of 10% in clinical remission is enough to massively shift the market. So again, as we see more data, what we can decide what the most attractive way is to advance this. And then maybe the last question on regional differences. I mean, of course, it's a small trial of substudies or subgroup analyses are always challenging, but maybe Deanna, I'll ask you to comment on whether we saw anything different in different regions.

Sure. Yes. Thanks for the question. We did see consistency across the sites and across the geographic regions.

Yes. So I think we showed both the naive versus refractory subgroups, but we didn't see anything different when we looked at, for example, the U.S. versus rest of world [ either ]

Our next question coming from the line of Tyler Van Buren with TD Colin.

Big congratulations on the data, which are absolutely tremendous. But the -- so can you elaborate on your confidence that you're likely maxing out the alpha-4 beta-7 exposure with this dose? And given that the SPY001 monotherapy remission rate is already approaching that of combo in VEGA at the 47% level, how are you currently thinking about the theoretical upper bound for remission rates that combination regimens can achieve in the future?

Thanks, Tyler. Yes, great questions. I think when you test a higher dose and seem to support the idea that, that higher dose has better efficacy. I think always the questions was, is there something even beyond this? I think we tend to believe we're getting close to the level of plateau here for a couple of reasons. Most obviously, is that when we look at that highest exposure quartile of vedolizumab patients, we see remission in a very similar range to what we're seeing with this exposure where we're putting most patients into that range. Now when we see the full Part B data and we have our full PK analysis, we'll conduct sensitivities where we look at exposures and efficacy within our cohort though I'm skeptical that there's going to be any dose level where we say near complete remissions just by having higher drug levels of alpha-4 beta-7. And I think that gets to the main hypothesis here, which is that blocking any individual mechanism is quite unlikely to fully cure this disease in any individual patients. And the way that we're more likely to get substantial incremental efficacy from here is by blocking orthoganal pathways. And that gets to your second question, which is how much better do we think they can be. That's why we're running the experiment. I think so far, we've seen on different end points, a level of additivity between mechanisms on clinical remission, I certainly think that starting with a higher baseline here on alpha-4 beta-7 is obviously a great start. And I think IL-23 and TL1A have orthogonal ways of benefiting this disease that I suspect will provide additive efficacy on top, but we'll have to see in the Part B data just how much that is.

Our next question coming from the line of Akash Tewari with Jefferies.

A couple on my end. Can you go over the steroid tapering protocol for the patients on background TCS? I know European doctors can sometimes be more aggressive and did efficacy differ in those populations. Also, we're seeing Mayo improvements as soon as two weeks with your data, which is impressive. Can you go over -- I know you were targeting kind of quartile 4 exposure from the Rosario analysis. Can you comment about how much more exposure patients were receiving out of the gate versus the VARSITY trial?

Good question. Maybe I'll take the last one first, which is that we haven't said exactly what we're dosing here, but that initial dose that we're providing is kind of a multiple of where vedolizumab starts with that initial IV dose. And so I think we are getting quite a bit of drug on board right away within a lower dose at a later IV. And so I think that may be what's driving that fast efficacy in terms of getting exposures up very rapidly. In terms of steroid tapering and whether we see any difference in steroids by efficacy, Deanna, would you mind covering that and maybe comment on both kind of how we're handling it in Part A and then Part B as well as reintroduce the combos?

Sure. So Part A, patients were not tapering during the induction period. But for Part B, we will have a paper starting at week 6 just like the VEGA study since we will have combinations in Part B, and we want to minimize the time when a patient may be on triple immunosuppression. So in Part B, by week 12, patients should be off steroids and therefore, that should help with the placebo response rate. In terms of the Part A data that we just showed today, if you saw we had 40% of patients in steroids, which is commonly seen in other studies, and therefore, the effective [indiscernible] is similar to what you observed with other studies.

And then, Deanna, I'm not sure we've conducted any subgroup analysis of the steroid users versus not, but maybe we can look at that in subsequent analysis.

Our next question coming from the line of Alex Thompson with Stifel.

Great. Let me [ lend ] my congrats on the data as well. Maybe you could talk a little bit about overall trial conduct here as you expand beyond Part A into Part B, expanding sites, et cetera, and sort of your level of confidence in the procedures in place to make sure that these data translate to a broader placebo-controlled setting, just given some of the higher placebo responses we've seen across clinical remission in some contemporary studies?

Yes. No, it's a very good question. Obviously, top of mind as we start Part B and introduce the placebo into this trial. So I think in terms of how I started this in terms of managing the company was bringing on folks that have done it the best in the past few years. So Sheldon here, the Chief Medical Officer, having just run studies for Abivax and Arena with kind of great results there. And then Deanna, who you're hearing from who help run some of the Prometheus studies with some of the lowest placebo rates in the space. Deanna, maybe I'll ask you to comment on the things that we're doing to help manage placebo rates especially in Part B of the study now. But most of those were included in Part A as well.

Sure. So this is a 3-pronged approach. First is our eligibility criteria, where we have criteria that should select patients whose symptoms are from mainly active UC. And then second is, as you heard the steroid taper in Part B, done mainly to avoid immunosuppression with 3 different drugs during the induction period, but also that should help with the placebo response rate. And then lastly, I think, site training, the site training to remind sites to instruct patients on how to accurately report their symptoms and that should also help with the placebo response rate.

Our next question coming from the line of Yatin Suneja with Guggenheim Partners.

It's [ Min ] dialing in for Yatin. Congrats on your strong data. So two questions for me. For the 19% advanced therapy patients, are you guys able to provide some breakdown of any between, let's say, biologics versus oral therapies, such as [indiscernible]? And my second question is for the Part B enrollment, are you guys able to comment on the patient randomization process? So for example, like do we know if the SPY001 cohort in Part B would be rolling a certain capped percentage of ENTYVIO patients, et cetera?

Yes. Good questions, Min. Yes, I think I can handle all those. So in terms of the refractory population here, so in this -- in Part A, we did not allow anyone who had failed the mechanism they would be getting. So there's no ENTYVIO failures in this group. I believe the mechanisms that had been failed among our refractory patients were [ TNF, S1P and JAK ], were the 3 that we saw in this cohort. In terms of Part B, how the study works, this is true randomization. So there's no kind of ability to restrict who goes on to which arm in the trial. We are -- we do have an overall cap on the number of individuals who failed ENTYVIO as well as who failed the P19 inhibitors given that we have both alpha-4 beta-7 and the P19 in this study. And we really don't want to bias the results against either those monotherapies or the combinations that include those components. And we think this is a much better setup relative to prior combination studies where individuals have been failed one of the mechanisms that were included in the combo, and I think that's likely to lead to a lower efficacy result. In terms of the randomization scheme, it's a 2-part randomization where patients first randomized to one of the arms of the study and each of the monotherapies or one of the combo arms and then they randomized between the active arm or placebo.

Our next question comes from the line of Thomas Smith with Leerink Partners.

Congrats on the really stellar data here. Just with respect to the 002 and 003 cohorts that completed enrollment, could you comment at all on the patients that you enrolled into those cohorts and how they compare to 001? Like should we expect similar baseline disease severity, prior treatment experience relative to the 001 cohort? Or are there other considerations from a region or site perspective that would impact that? And then can you also just talk about your expectations for the monotherapy cohorts and whether there's a change at all given the stellar results from 001 this morning?

Thanks, Tom. So for 002 and 003, so these molecules were added to the trial about 3 and 6 months after 001 started. And so the geographic breakdown will be -- will shift a little bit as more countries and sites were added to the trial. By the time we get to and are fully enrolling in Part B, we're going to have 30-plus countries and between 200 and 300 sites going in this trial. So it's really just an expanding base that will look like a big global even Phase III like study when we're in Part B so we'll see a bit of that shift from 001 to 002 and 003. In terms of expectations for the data, I don't think they change with this 001 results today. For TL1A in particular, we've seen 3 first-generation TL1A antibodies report induction data. I think they all show comparable placebo-adjusted efficacy, which, to me, suggests that that's the high end or the kind of the plateau of the dose exposure response there in those 3 drugs have saturated the target. And though we think our molecule has improvement in potency, half-life, immunogenicity and others relative to the first-generation products. I think it's likely saturated in the induction setting. And so I'm not sure there's better to be had in that period. I'm not sure that's true as we get into maintenance for TL1A, but we won't see those maintenance data for this update in [indiscernible]. On IL-23, the answer is similar, I think, particularly for risankizumab, just at the dose level that they dose in the ulcerative colitis population. It's kind of a very high level of dosing, and we see the dose and exposure response there look relatively flat. And so again, we think it's quite unlikely that we see a differentiation on induction efficacy with 003 compared to risankizumab. So that's why we really expect comparable for each of those. But even before this readout, we thought if we were comparable for all 3 of these mechanisms that our combinations would still stand apart because we're the only ones with optimized versions of these 3 great mechanisms. Now that we see the 001 may be differentiated within that class, I think the likelihood of seeing efficacy between these mechanisms that leads to something that is hard for others to match. I think is much higher.

Our next question comes from Debanjana Chatterjee with JonesTrading.

Congrats on the data. So I mean, just looking at the breakdown of the -- I mean the biologic experience, I mean, advanced therapy experience in live patients, the subpopulations actually look pretty similar here. Could you remind us what is going to be the proportion of treatment experience patients in the randomized portion? And in case that's higher, do you -- how do you expect the overall efficacy trend, which direction should it go if there is a larger proportion of treatment experience patients?

Yes. Thanks, Debanjana. So in this study, yes, we were a little surprised to see these be as similar as they were between the naive and experienced populations here, certainly a strong result compared to what you normally see, which is that the efficacy drops off in the refractory population. And whether that's just small numbers or whether that is due to having kind of the higher exposures of 001 here that actually captures remissions in folks that have failed something else is yet to be seen, but I think certainly encouraging. In terms of Part B, there we will be closer, we're going to be aiming for a 50-50 split between the naive and refractory population, and we'll kind of cap that enrollment to ensure that we're not above 60% of either. So between 40% and 60% of naive and refractory is the target for Part B. And I think given that we didn't see a meaningful result difference between those two populations, I don't expect that much of a shift actually as we get to that population.

Our next question comes from David [indiscernible]

I just had one, maybe it's a little bit less important, but it's similar on the background or experience therapy patients in the future, given this looks like -- or it's vedo like and typically vedo is used sooner. With the treatment experienced patients, kind of how do you -- do you expect a lot of patients who have skipped vedo and gone straight to [ jets ] or a different biologic agent. I'm just kind of curious what the -- what you expect the makeup of the treatment experience patients to be in that study?

It's a good question. Maybe, Deanna, do you want to start commenting in terms of what you think the most likely first- and second-line use will be when we get to Part B?

Sure. As you mentioned, in some countries, vedolizumab could be first-line, but in others not. So we expect in the advanced therapy exposed population to have patients who failed anti-TNF or risankizumab or S1P or others. And as Cameron mentioned in Part B, we will allow a certain number of subjects who have [indiscernible].

Yes. I'll just say, I think we're debating what proportion to include of individuals who have failed vedolizumab and the P19 because on one hand, we think it may make the results of 001 monotherapy or the components that contain 001 could bias the results against it. However, we're also somewhat interested in understanding whether both the high dose of 001 could capture remission and folks that have failed that class previously or perhaps even more interestingly, whether combinations, including a mechanism again, capture remission in folks that have failed monotherapies in the past, which is basically exactly how combinations are used in the real world today in terms of folks that have failed many things and then end up trying combinations. So I think we're taking the balance here of capping that number to avoid the bias, but we'll always have a few that we can start to generate some hypothesis about whether these combos can capture remission in those patients.

Our next question comes from the line of Julian Harrison with BTIG.

Congratulations to these data and all the recent progress. A few questions, and I'll just list them one by one. First, do you expect to see a higher therapeutic index with the 001 versus vedo in Crohn's as well? How translatable do you view these results to that opportunity? Second, my understanding is that even vedo dosed well beyond most conventional PK parameters. So if you could talk about what you think is driving the exposure response relationship here and also [indiscernible], that would be very helpful as well. And then finally, I'm curious to what extent you think the results from DUET have relevance to your overall strategy at this point? Do you maybe view that as less of a swing factor at this point regarding the perception combination regimens in IBD?

Yes. All good questions. Thanks, Julian. The first one on Crohn's. So in terms of the data supporting the idea that higher exposures of vedolizumab could lead to better efficacy. Those data are stronger in ulcerative colitis than Crohn's, though I think it's hard for us to understand why it would necessarily be the case that you wouldn't see the same type of relationship that you see in Crohn's. I think the challenge with Crohn's is that the end points that are used in trials in Crohn's are a bit noisier than the ones in ulcerative colitis. And so it may be the case that you're just not picking up this exposure dose response in Crohn's as we did in UC. We do expect to advance whatever products win from the SKYLINE study here to both Crohn's and ulcerative colitis. And so I think in the long run, we will see whether this translates into Crohn's as well. Two, the mechanism by which we're seeing greater efficacy, I think, is one of the most interesting in the space. As you may know, vedolizumab saturates the pharmacodynamic measure in terms of receptor occupancy at very low concentrations, much lower than where they or we are dosing. And yet, they see a strong exposure response. And when we test that higher exposures, it seems that we might be seeing greater efficacy as well. And so that, it's kind of an interesting question in terms of why that's the case. I think one challenge with the pharmacodynamic measure here is that you're measuring receptor occupancy of alpha-4 beta-7 on T cells in the circulation but many great researchers have shown that T cells are not the only cell types that are driving alpha-4 beta-7 activity. And so it may be the case that kind of measuring it only on the surface of T cells is not sufficient to measure all the activity of vedolizumab. I think there's also some interesting work suggesting that alpha-4 beta-7 might need to be active in the local tissue itself, which there you may need higher concentrations. And I think we do know that at the commercial level of vedolizumab, they may not be saturating and the alpha-4 beta-7 [indiscernible] in the local tissue as well. So I think the short answer is we are not exactly sure of the mechanism by which but by which greater exposure leads to greater efficacy but we thought it was worth testing based on the data from vedolizumab in the Phase III and real-world data. And then lastly, on your DUET question, I think we and everyone I think still remain very interested in seeing those results as kind of one of the largest randomized combo studies in this space. And I think we'll see that now in a couple of weeks in -- at DDW here, I think we'll see both the ulcerative colitis and Crohn's presentations there, which we're certainly excited to see. However, I think our -- kind of how much of a swing factor that is, is probably a lot lower now, given that we know that J&J is advancing that combination to Phase III. We see Royalty Pharma supporting that with a large investment as well. So I think it's pretty clear that, that result is certainly at least good enough and maybe very encouraging to justify a large return on investment for the big pivotal studies for that combination. And we've always thought that the combos that we have here and the trial design that we have here are likely to outperform that, most obviously by replacing the golimumab component, which is not one of the best TNF in the space and replacing it with something like 001 here, the alpha-4 class, which is beating TNF-head-to head or replacing it the TNF with anti-TL1A, which we also think is a superior mechanism, though it hasn't yet [ instead ] head to head. So hopefully, that covered all 3 of your questions. Thanks, Julian.

Our next question coming from the line of Paul Choi with Goldman Sachs.

Let me add my congratulations as well. Just with regard to the subcu, can you maybe remind us how you're thinking about the sort of quartile of coverage on the PK side relative to the IV version? And then if during the maintenance portion, you will be allowing or testing the subcu version? And my second question is, just given some of the rapidity we've seen on some of the endpoints here in Part A of the study for 001. Can you maybe comment on sort of the quality of life or any other patient measures or patient feedback that you may have received at this point and just how that compares to the existing version of ENTYVIO?

Yes. Thanks, Paul. So first, in terms of the subcutaneous format. So to be clear, what we're doing in this trial is we do two IV loads at week 0 and week 4, and then we transition to quarterly subcutaneous dosing. For Phase III, I think we have some optionality. Of course, kind of -- we couldn't maintain what we're doing with the IV load followed by subcu switch and most products on the market in IBD today have that format in terms of high drug loads via IV followed by the subcu maintenance. However, given the dosing levels here, it's certainly possible for us to use an all subcutaneous induction format as well, that's either with our monotherapies or combinations. And so that's something that we'll be looking at as we transition to Phase III, whether we want to kind of make that switch if we think it's valuable enough commercially to have all subcutaneous induction versus the great results we've seen here with the IV that is certainly very derisked. Two, in terms of the quality of life improvements. I think we showed some of them today, but maybe I'll let Deanna comment on kind of any either anecdotes she's heard or anything else beyond the data that we showed regarding the improvements in rectal bleeding stool frequency that she's heard in conversations with investigators.

Sure. To address the question, and I believe you were asking about formal quality of life questionnaires, we decided to defer the Phase III to collect quality of life questionnaire answers just to reduce patients can [ tight burden ] in the complexity study. As you can imagine, this is a very large Phase III study, and we have many sites across many countries throughout the world. In terms of the patient report outcome that you saw today with rectal bleeding in some frequency. Many patients reported reductions in those very quickly after the first dose and what I've heard from site visits is that some patients felt better, much earlier and actually started even to exercise when they haven't been able to exercise for many years. So from what we've heard anecdotally, patients have had improvement in their quality of life.

Thanks, Deanna. And of course, this is just our top line release of these data. We, of course, measure many other endpoints from kind of softer end points like clinical response as well as deeper measures such as [indiscernible]. And I think as we get into medical meetings in the upcoming quarters here, we'll continue to share those data, which I think were compressive at all levels.

Our next question coming from the line of Samantha Semenkow with Citi.

This is Ben on for Sam. I have two. The first one, in the treatment experienced patients, were there any difference in efficacy in patients that failed TMF versus JAK inhibitors versus S1P? And then the second question we have is -- when do you expect to report maintenance data, 9-ish months would be around early 2027. Is that tracking with the company's expectations?

Yes. Great question. And the second one, yes, the maintenance data point is about 9 months afterwards. So I think that's realistic for these again, whether we do them one at a time or altogether, we have committed to yet, but that's approximately when we'll have those data. In terms of responses by the individual mechanisms that were missed, I think we're getting to a end of one and two for kind of those individual mechanisms that have been missed. So I don't know each of them, but I think you can look at the totality and know that we had a number of good responses in that group. But I think it's -- on some of them, they'll be one of one and others, it will be zero of one. So I'm not sure it's worth commenting on kind of those individual end of one example.

Our next question coming from the line of Yanan Zhu with Wells Fargo.

Congrats on the great data. So I was wondering how do you think this induction data will translate or carry over into the maintenance dose maybe two subcomponents of that, do you think vedolizumab left anything on the table in terms of exposure in longer-term maintenance dosing phase? And maybe another component of that is are we even looking at your second dose's efficacy given where the efficacy is measured? And in that, I mean, could we see even better efficacy during the more immediate term after the second dose? And then if I may, just wanted to also clarify. For the complete remission data, I guess the ENTYVIO comparison was based on total male score. Could you talk about if that's the case, could you talk about how we compare remission based on modified versus total score. Understanding you have more objective measures. So -- but I just want to get that box checked.

Yes. Thanks, Yanan. Maybe Deanna, I'll have you comment to answer that last question, but I'll take the first one first. So in terms of the transition from induction to maintenance and how we expect efficacy to translate here. First, the data that we have from vedolizumab is that the exposure response that we showed and cited from both the pivotal studies as well as the real-world is really strongest in the induction setting. Once we look at the maintenance data, either on a [indiscernible] or AUC basis, there's much less -- a much weaker relationship between exposures and responses and remissions in the maintenance setting. So we thought the opportunity here was really what we're seeing today, which is that could we get faster efficacy at week 12 by having more drug on board. In terms of how we think that translates as we move on here. I mean, I think when we show the time course data, it does look clear that we're probably not at maximal efficacy as in these patients are continuing to get better at week 12. And I think we're comparing against the VARSITY and other results that look at week 14. And I think that's an advantage in some ways to those trials that I expect we would continue to see some improvement as we got out a couple more weeks and maybe some distance into maintenance, you would continue to see deepening of the response remission rate in our trial. At some level, though, you eventually get into the standard in IBD, which is that patients lose responses and remissions over time. And that's why this ends up being such a cycling market. But I'm not sure we're quite there in terms of peak efficacy at week 12 yet. And then in terms of the -- comparing the remission scoring method, I think we're using kind of the very standard pivotal definition for clinical remission. But Deanna, maybe I'll let you comment on exactly how we're measuring it.

Sure. As you mentioned, Cameron, by the FDA guidance that was published in 2022, the clinical remission definition should be based on modified mail score. So that's what we use for our top line data. And so we don't have the total mail score defined remission rate for top line, but we can calculate that later. But as you know from other studies from previous publications that the two often are in relatively similar range. So we don't expect the difference in definition to change the results much.

Our next question coming from the line of David Hoang with Deutsche Bank.

Congrats on the data. So maybe first, just a question on -- I was wondering if you had a sense if the community of physicians is comfortable with long-term chronic combo therapies. I'm just thinking back to VEGA which I believe had combo induction therapy, but then actually switch patients to mono for maintenance therapy. And then secondly, in terms of getting into -- as you get into Phase III how do you think that design will go? Do you think you would need to do a factorial type design to show the contribution of a component or would some of the Phase II Part B data help there and maybe allow for a more streamlined Phase III?

Yes. Thanks. Both important questions. In terms of combination use, I think the VEGA was really the first randomized advanced therapy combination in this space, and I think it was a rational approach J&J to use the combination for induction and then drop to a monotherapy. However, that's not really what we see in the real world when combinations, and they do get used pretty regularly as physicians can find a way to get multiple drugs on their patients. And there, we really don't see that physicians achieve remission and then drop off one of the products. They typically stay and this is not just for combos, but monos as well, which is that you can get a patient into remission on a therapy, they stay on that therapy until they lose it because, again, this is incredibly costly disease to the patients, to the health systems as well. And so maintaining remission is paramount. And so I think if combination products come out and they're priced like a single drug and their efficacy is superior and their safety doesn't leave any meaningful downsides, I'm not sure what the argument would be to actually remove somebody from that drug. It's just -- it's a superior product on all properties. And I suspect patients will stay on that as long as they can. And when they switch, I expect that they would switch to something that tries to be as close as they can in efficacy while incorporating other mechanisms, which is why we think kind of multiple combos may be the winning portfolio in the long run. In terms of pivotal design, of course, we're thinking about that on the back of the Part B data here. This SKYLINE study is designed to show contribution of components. Of course, we're using a shared placebo group as well as individual monotherapy components of each of the pairwise combos. The goal here is to show that the monotherapies beat placebo. And I think we feel pretty comfortable, at least with this first one now that that's likely to be the case. And then the combos would beat the monotherapy components. I think if we did that in this trial, I'm not sure that -- and I actually don't think we would have to do a contribution of components again in Phase III. We may actually get an earlier read on that as we see kind of the J&J Phase III design here in the upcoming months based on whatever they see from the DUET studies, which we'll see even soon.

We have one last question coming from the line of Brandon [indiscernible] with Wolfe Research.

This is [ Brandon ] on for Andy. Aside from partial Mayo score, can you comment in more detail regarding the onset of responses through week 12 on the other efficacy measures? I know you said patients continue to improve after week 12, but are patients -- are there a bigger group of patients responding more quickly upfront? Or is there a meaningful tail that continues to improve over time?

Yes, it's a good question. And I don't think we've seen or at least I've not seen time course on all of our endpoints to know if we're kind of capturing them any sooner of course, you are limited by the number of endoscopies and histology measures you can have really at week 0 and week 12 because you can't subject the patients to more than that in the study. So we don't get multiple data points along the way in terms of endoscopy and histology. I think in general, we're very encouraged by seeing the rapid pace of symptom improvement, which is what you can measure on a couple of week basis. Though, maybe I'll let Deanna, if you have anything to add in terms of other measures that we saw move quickly that surprised you or were encouraging.

Thanks. As this is top line data, we wanted to have the data that you saw here, but we will definitely have additional data sets coming in, which will have more granular details about the improvement in symptoms over the first few weeks. So you may see that in upcoming [indiscernible].

And there are no further questions in the queue at this time. I will now turn the call back over to Cameron for any closing comments.

All right. Well, thank you, everyone, for joining this morning. We think this is a great start in terms of our IBD development portfolio. We think 001 data is excellent as it's on its own. And it stands as potentially an attractive monotherapy, one of the most exciting in the space, but also an incredibly strong foundation from which to build our combination. I think this is the first of our 6 catalysts in 2026. And so we look forward to catching up with everybody in the upcoming months, a number of times. So thank you, and have a great day.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.