Good day and thank you for standing by. Welcome to the Spyre Therapeutics SPY001 Part A Induction Top-Line Results conference call. At this time, all participants are on a listen-only mode. After the speaker's presentation, there will be a question- and- answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising that your hand is raised. 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, Livia, 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 SPY001 for the treatment of moderately to severely active ulcerative colitis. Press release and slides that we'll be using today during our call 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 candidates 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-Shevlin, 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, a 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, leaving 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 downsides, 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 result 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 matched effector function silencing to ensure gut-specific activity and avoid off-target immune suppression. Our design improvements to the molecule include sequence modifications to meaningfully extend SPY001'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 in induction data from Phase 3 trials and real-world cohorts that maximal efficacy of vedolizumab was observed in patients in the highest quartile of drug trough concentration. We aim to achieve 001 exposures in this fourth quartile for patients during our 12-week induction period. Our final PK analysis is not complete. Preliminary data suggests that the substantial majority of SPY001-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 result that we'll share now for 001, our conviction in this exposure-response hypothesis for alpha 4 beta 7 is substantially increased.
Specifically, the SPY001 Part A induction result suggests 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 SPY001 efficacy compare favorably to data from precedent trials for mechanisms of action even outside the alpha-4 beta-7 class, suggesting that 001 could be one of the leading monotherapy products in development today. Without getting too far ahead of ourselves, I'll turn the call over to Dr. Deanna Nguyen, who'll go through the trial and data in more detail.
Thanks, Cameron. 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 3-2 design investigating each of our three monotherapies and three pairwise combinations conducted in two 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 with approximately 130 participants across the three cohorts. We're starting to enroll patients in Part B in various countries across the globe.
Excitement continues to build with investigators as we leverage the infrastructure built in Part A to begin testing monotherapies and combinations. The focus of today's discussion is the first readout of the trial, the SPY001 Part A induction data. As a reminder, each of our monotherapies was added to the study after its interim Phase 1 study results became available, beginning with SPY001. You can see here on the slide that participants were enrolled using standard eligibility criteria for a moderately to severely active UC trial, and these criteria are largely consistent for Parts A and B, including allowance for failure of up to three classes of advanced therapies. 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 rates.
The objective of Part A is to demonstrate proof of concept, safety, and efficacy for our three monotherapies. Though these Part A results are open-label, we are using clinically validated and objective endpoints that correlate closely with placebo control results in UC. Our primary endpoint is change from baseline in RHI, the Robarts Histopathology Index. An RHI is a clinically validated instrument for measuring histologic disease activity in UC, and is scored from zero to 33 based on inflammatory infiltrate, neutrophil infiltration, and epithelial ulceration 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 one or zero at week 12 by central reading. As a reminder, every participant enrolled in the study had to have a moderate or severe endoscopic score, meaning a score of two or three, 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 central 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, at week 12, or another time point, such as the end of maintenance. Baseline characteristics were 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 timelines in these regions, hence the advanced therapy-naïve predominance, which is comparable to the VARSITY study.
Disease severity at baseline was typical, with more than half of participants with a baseline endoscopy score of three and a mean baseline modified Mayo 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 non-drug-related adverse event 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 in IBD. The most common treatment-emergent adverse event, meaning occurring in at least two participants, was back pain.
No AEs were deemed drug-related, and there were no deaths or adverse 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 artery 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 -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 pre-specified a sensitivity analysis of that subgroup in our study. When we looked at that subgroup, our change from baseline was even larger at -10.6.
For our key secondary endpoints, 40% of participants achieved clinical remission, 51% achieved endoscopic improvement, and though not shown on the slide, we observed a mean change of -3.7 in modified Mayo score from baseline to week 12. Though 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 improvements observed during this induction period.
As shown by the change from baseline in both partial Mayo Score and level of fecal calprotectin, a biomarker of intestinal inflammation, participants receiving SPY001 improved rapidly and consistently. Taken together, we believe these data are clear that SPY001 significantly benefited UC participants enrolled in this cohort. 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 combinations 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 SPY001 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 three 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 introduce three combination arms to the study, we believe enthusiasm will only increase from here. To begin to put our SPY001 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 SPY001 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 populations, the SPY001 efficacy results were meaningfully above benchmarks reported in precedent alpha-four beta-seven trials across all key endpoints. We're particularly excited about our 51% endoscopic improvement rate, given the purely objective nature of this endpoint. This value compares favorably to vedolizumab's 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 endpoint, 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 endpoint, 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 rates 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 of SPY001 with SPY002 and SPY003. Speaking of our combinations, we believe these 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 SPY001 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. Additionally, on certain endpoints, our SPY001 monotherapy matched or 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 that top-down therapy, meaning the use of the most effective products first, leads to substantially better long-term outcomes 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.
If 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 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 read out SPY002 data mid-year with SPY003 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 AS/PsO sub-studies, with top-line data expected in Q4. We expect to provide an update later this year on 127 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.
Thank you. Ladies and gentlemen, as a reminder, to ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Sam Slutsky with LifeSci Capital. Your line is now open.
Hey, good morning, everyone. 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 SPY001 as a monotherapy to approval? If so, would you have to run a head-to-head versus vedolizumab? 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? Thanks.
Yeah. Thanks, Sam, for both those questions. I actually think 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 SPY001 a viable commercial product. 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. If we were 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. If we see increased efficacy beyond this, I think that product, those combination products, would be even more attractive in this field.
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 has substantially shifted the market. I think differentiation on the order of 10% in clinical remission is enough to massively shift the market. Again, as we see more data, we can decide what the most attractive way is to advance this. Maybe the last question on regional differences.
Of course, it's a small trial, so sub-studies or kind of 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. 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.
Thank you. Now next question coming from the line of Tyler Van Buren with TD Cowen. Your line is now open.
Hey, guys. Good morning and big congratulations on the data, which are absolutely tremendous. Can you elaborate on your confidence that you're likely maxing out the alpha-4 beta-7 exposure with this dose? Given that the SPY001 monotherapy remission rate is already approaching that of the 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. Yeah, 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 all these 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 reasons. Most obviously is that when we look at that highest exposure quartile of the 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 see near complete remissions just by having higher drug levels of alpha-4 beta-7. 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 patient. The way that we're more likely to get substantial incremental efficacy from here is by blocking orthogonal pathways. 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 endpoints, 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. We'll have to see in the Part B data just how much that is.
Thank you. Now next question coming from the line of Akash Tewari with Jefferies. Your line is now open.
Hey, thanks so much. 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. Did efficacy differ in those populations? Also, we're seeing Mayo improvements as soon as two weeks with your data, which is impressive. I know you were targeting kind of quartile four exposure from the [SOLARIO] analysis. Can you comment about how much more exposure patients were receiving out of the gate versus the VARSITY trial? Thanks so much.
Yeah, 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. I think we are getting quite a bit of drug on board right away with a lower dose at our later IV. 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 we introduce the combos?
Sure. Part A, patients were not tapering during the induction period, but for Part B, we will have a taper starting at week six, 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. 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, as you saw, we had 40% of patients be on steroids, which is commonly seen in other studies, and therefore the effect of steroids is similar to what you observe with other studies.
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 analyses.
Thank you. Now next question coming from the line of Alex Thompson with Stifel. Your line is now open.
Hey, great. Let me add my congrats on the data as well. Maybe you could talk a little 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? Thanks.
Yeah, no, it's a very good question. Obviously top of mind as we start Part B and introduce the placebo into this trial. 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.
Sheldon here, the Chief Medical Officer, having just run studies for AbbVie and Arena with kind of great results there. Deanna, who you're hearing from, who helps 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. This is a three-pronged approach. First is our eligibility criteria, where we have criteria that should select patients whose symptoms are from mainly active UC. Second is, if you heard the steroid taper in Part B, done mainly to avoid immunosuppression with three different drugs during the induction period, but also that should help with the placebo response rate. Lastly, I think site training, good 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.
Thank you. Our next question coming from the line of Yatin Suneja with Guggenheim Securities. Your line is now open.
Morning, guys. It's Min dialing in for Yatin. Thank you for taking the time, and congrats on your strong data. Two questions from 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 JAK and S1Ps? My second question is for the Part B enrollment, are you guys able to comment on the patient randomization process? For example, do we know if the SPY001 cohort in Part B would be enrolling a certain capped percentage of Entyvio patients, et cetera? Thank you.
Yeah, good questions, Min. Yeah, I think I can handle all of those. In terms of the refractory population here, in Part A, we did not allow anyone who had failed the mechanism they would be getting. 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 three that we saw in this cohort. In terms of Part B, how this study works, this is true randomization. There's no kind of ability to restrict who goes onto which arm in the trial.
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 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 two-part randomization where patients first randomized to one of the arms of the study and of each of the monotherapies or one of the combo arms, and then they're randomized between the active arm or placebo.
Thank you.
Thank you. Our next question comes from the line of Thomas Smith with Leerink Partners. Your line is now open.
Hey, guys. Good morning. Congrats on the really stellar data here, and thanks for taking our questions. Just with respect to the SPY002 and SPY003 cohorts that completed enrollment, did you comment at all on the patients that you enrolled into those cohorts and how they compare to SPY001? Should we expect similar baseline disease severity, prior treatment experience relative to the SPY001 cohort? Are there other considerations from a region or site perspective that would impact that? Can you also just talk about your expectations for the SPY002 and SPY003 monotherapy cohorts and whether those have changed at all given the stellar results from SPY001 this morning? Thanks so much.
For SPY002 and SPY003, these molecules were added to the trial about three and six months after SPY001 started. The geographic breakdown 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+ countries and between 200 and 300 sites going in this trial. It's really just an expanding base that will look like a big global even Phase 3-like study when we're in Part B. We'll see a bit of that shift from SPY001 to SPY002 and SPY003. In terms of expectations for the data, I don't think they change with this SPY001 results today. For TL1A in particular, we've seen three 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 and that those three drugs have saturated the target. Though we think our molecule has improvements 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 at mid-year. 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.
Again, we think it's quite unlikely that we see a differentiation on induction efficacy with SPY003 compared to risankizumab. That's why we really expect comparable for each of those. Even before this readout, we thought if we were comparable for all three of these mechanisms, that our combinations would still stand apart because we're the only ones with optimized versions of these three great mechanisms. Now that we see that SPY001 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.
Thank you. Our next question comes from the line of Debanjana Chatterjee with JonesTrading. Your line is now open.
Hi. Thanks for taking my question and congrats on the data. Just looking at the breakdown of the biologic experience, advanced therapy experience in naive patients, the subpopulations actually look pretty similar here. Could you remind us what is going to be the proportion of treatment experienced patients in the randomized portion? In case that's higher, how do you expect the overall efficacy trend? Which direction should it go if there's a larger proportion of treatment experienced patients?
Yeah. Thanks, Debanjana. 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. Whether that's just small numbers or whether that is due to having kind of the higher exposures of SPY001 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. Between 40% and 60% of naive and refractory is the target for Part B.
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.
Okay. Thank you.
Thank you. Our next question comes from the line of David Nierengarten with Wedbush. Your line is now open.
Hey, thanks for taking the question. I just had one. Maybe it's a little bit less important, but it's similar on the background for experienced 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. Do you expect a lot of patients who have skipped vedo and gone straight to JAKs or a different biologic agent? I'm just kind of curious what you expect the makeup of the treatment-experienced patients to be in the next study. Thank you.
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. We expect, in the advanced therapy exposed population, to have patients who failed anti-TNF or ustekinumab, or S1P, or others. As Cameron mentioned, in Part B, we will allow a certain number of subjects who have failed vedolizumab.
Yeah, I'll just say, I think we're debating what proportion to include of individuals who've failed vedolizumab in the P19 because, on one hand, we think it may make the results of SPY001 monotherapy or the components that contain SPY001 could bias the results against it. However, we're also somewhat interested in understanding whether both the high dose of SPY001 could capture remission in folks that have failed that class previously, or perhaps even more interestingly, whether combinations including a mechanism can 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.
I think we're taking the balance here of capping that number to avoid the bias, but we'll at least have a few that we can start to generate some hypotheses about whether these combos can capture remission in those patients.
Got it. Thank you.
Thank you. Our next question comes from the line of Julian Harrison with BTIG. Your line is now open.
Hi. Let me add my congratulations to these data and all the recent progress. I have three questions, and I'll just list them one- by- one. First, do you expect to see a higher therapeutic index with the SPY001 versus vedo in Crohn's as well? How translatable do you view these results to that opportunity? Second, my understanding is that even vedo is dosed well beyond most conventional PK parameters. So if you could talk about what you think is driving the exposure-response relationship here and ulcerative colitis, that'd 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? Thank you.
Yeah. All good questions. Thanks, Julian. The first one on Crohn's. 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 in UC and Crohn's. I think the challenge with Crohn's is that the endpoints 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 or 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.
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 either they or we are dosing. Yet they see a strong exposure response, and when we test at higher exposures, it seems that we might be seeing greater efficacy as well. That is 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.
Many great researchers have shown that T cells are not the only cell type 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. I think we do know that at the commercial levels of vedolizumab, they may not be saturating all the alpha-4 beta-7 in the local tissue as well. I think the short answer is we're not exactly sure the mechanism by which greater exposure leads to greater efficacy..
We thought it was worth testing based on the data from vedolizumab in the Phase 3 and real-world data. Lastly, on your DUET question, I think we and everyone, I think, still remain very interested in seeing those results. That was kind of one of the largest randomized combo studies in the space. I think we'll see that now in a couple of weeks 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 how much a swing factor that is probably a lot lower now, given that we know that J&J is advancing that combination to Phase 3. We see Royalty Pharma supporting that with a large investment as well.
I think it's pretty clear 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. 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 TNFs in the space, and replacing it with something like SPY001 here, the alpha -4 class, which has beaten TNF head-to-head, or replacing it, the TNF, with an anti-TL1A, which we also think is a superior mechanism, though it hasn't yet been studied head-to-head. Hopefully that covered all three of your questions. Thanks, Julian.
Very helpful. Thank you.
Thank you. Our next question coming from the line of Paul Choi with Goldman Sachs. The line is now open.
Hi. Thank you. Good morning. Let me add my congratulations as well. Just with regard to the subQ, 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? If during the maintenance portion, you will be allowing or testing the subQ version? 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 perceived at this point and just how that compares to the existing version of Entyvio? Thank you very much.
Yeah, thanks, Paul. First, in terms of the subcutaneous format. To be clear, what we're doing in this trial is we do two IV loads at week zero and week four, and then we transition to quarterly subcutaneous dosing. For Phase 3, I think we have some optionality. Of course, we could maintain what we're doing with the IV load followed by subQ switch, and most products on the market in IBD today have that format in terms of high drug loads via IV, followed by the subQ 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 our combinations.
That's something that we'll be looking at as we transition to Phase 3, 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 de-risked. 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, I believe you were asking about formal quality-of-life questionnaires. We decided to defer to Phase 3 to collect quality-of-life questionnaire answers just to reduce patients and site burden in the contemplated study. As you can imagine, this is a very large Phase 3 study, and we have many sites across many countries throughout the world. In terms of the patient-reported outcomes that you saw today with rectal bleeding and stool frequency, many patients reported reductions in those very quickly after the first dose. 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. From what we've heard anecdotally, patients have had improvement in their quality of life.
Yeah. Thanks, Deanna. Of course, this is just our top-line release of these data. We, of course, measured many other endpoints from kind of softer endpoints like clinical response as well as deeper measures such as HEMI or HEMH. I think as we get into medical meetings in the upcoming quarters here, we'll continue to share those data, which I think were impressive at all levels.
Great. Thanks, Cameron. Speak soon.
Thank you. Our next question coming from the line of Samantha Semenkow with Citi. Your line is now open.
Hi, this is Ben on for Sam. Thanks so much for taking our questions. I have two. The first one, in the treatment-experienced patients, were there any difference in efficacy in patients that failed TNF versus JAK inhibitors versus S1P? The second question we have is, when do you expect to report maintenance data? Nine-ish months would be around early 2027. Is that tracking with the company's expectations?
Yeah, great question. To the second one, yes. The maintenance data point is about nine months afterwards, so I think that's realistic for these. Again, whether we do them one at a time or all together, we haven't committed to yet. 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 N of one and two for those individual mechanisms that have been missed. 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. I think on some of them, it'll be one of one, and others it'll be zero of one. I'm not sure it's worth commenting on those individual N of one examples.
Thank you. Our next question coming from the line of Yinan Xu with Wells Fargo. Your line is now open.
Great. Thanks for taking our questions, and congrats on the great data. I was wondering, how do you think this induction data will translate or carry over into the maintenance dose? Maybe two subcomponent of that, do you think vedolizumab left anything on the table in terms of exposure, in a longer-term maintenance dosing phase? Maybe another component of that is, are we even looking at your second dose's efficacy given where the efficacy is measured? In that, I mean, could we see even better efficacy during the more immediate term after the second dose? If I may, just wanted to also clarify, for the complete remission data, I guess the Entyvio comparison was based on total Mayo score. 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.
I just want to get that box checked. Thank you.
Yeah. Thanks, Yinan. Maybe Deanna, I'll have you answer that last question, but I'll take the first one first. 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 C-trough or AUC basis, there's a much weaker relationship between exposures and responses and remissions in the maintenance setting. 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 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. 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. Maybe some distance into maintenance, you would continue to see deepening of the response remission rates 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.
I'm not sure we're quite there in terms of peak efficacy at week 12 yet. In terms of comparing the remission scoring method, I think we're using the very standard pivotal definition for clinical remission. 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 Mayo score. That's what we used for our top-line data. We don't have the total Mayo score defined remission rates for top line, but we can calculate that later. As you know from other studies from previous publications, that the two often are in relatively similar range. We don't expect the difference in definition to change the results much.
Thanks.
Great, super helpful. Thank you.
Thank you. Our next question coming from the line of David Hoang with Deutsche Bank. Your line is open.
Hi there. Thanks for taking my questions, and congrats on the data. 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 switched patients to mono for maintenance therapy. Secondly, in terms of as you get into Phase 3, 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 2 Part B data help there and maybe allow for a more streamlined Phase 3? Thanks so much.
Yeah, 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 for 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. There, we really don't see that the 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 if 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 their health systems as well, and so maintaining remission is paramount. 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 a superior product on all properties, and I suspect patients will stay on that as long as they can. When they switch, I expect that they would switch to something that tries to be as close as it 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. I think we feel pretty comfortable, at least with this first one, now that that's likely to be the case, and that 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 contribution of the components again in Phase 3.
We may actually get an earlier read on that as we see kind of the J&J Phase 3 design here in the upcoming months, based on whatever they see from the DUET studies, which we'll see even sooner.
Thanks a lot.
Thank you. We have one last questioner coming from the line of Brandon Frith with Wolfe Research. Your line is now open.
Hey, this is Brandon for Andy. Thanks for taking the question. 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 patients continue to improve through week 12. Are there a bigger group of patients responding more quickly upfront, and is there a meaningful tail that continues to improve over time? Thank you.
Yeah. 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 zero and week 12 because you can't subject patients to more than that in the study. 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 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. You may see that in upcoming congresses.
Thank you. There are no further questions in the queue at this time. I'll 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 SPY001 data is excellent as it's on its own and 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 combinations. I think this is the first of our six catalysts in 2026, and so we look forward to catching up with everybody in the upcoming months a number of times. Thank you, and have a great day.
This concludes today's conference call. Thank you for your participation, and you may now disconnect.