Good morning all, good afternoon all, and welcome to the Do the Key Tug Anti-TL1A Phase 2B data presentation from ECHO. My name is Adam and I'll be your operator today. If you'd like to ask a question during the Q&A portion of today's call, you may do so by pressing star followed by one on your telephone keypad. I will now hand the floor to Chris Stevo to begin. So Chris, please go ahead when you are ready.

Thank you very much, Adam. Good morning and good afternoon, everyone. Thank you for joining us to discuss these important data. We'll be making forward-looking statements in the course of this call. Any statements we make are only as of today, and we do not undertake any obligation to update these statements beyond this call. If you have questions about our forward-looking statements or risk factors, please see our SEC filings under Forms 10-K and 10-Q. And with that, I will turn it over to our host, Dr. Eric Hughes. Go ahead, Eric.

Thank you, Chris. And good morning, good afternoon, and good evening. And thank you all for taking the time to talk about this Imduva-Ki-Tug program. If I can have the next slide. Before we get started, I know that Imduva-Ki-Tug is the star, you know, what R&D is doing to support our pivot to growth strategy at TEVA. You know, we have really stepped up. We have a number of programs in clinical development right now. Our Alanzapine LAI program and schizophrenia has now achieved its last patient, last visit, and will be presenting that data in the second quarter of this year. Our DARI program, it's phase three program now. Duva-Ketug we'll talk about today and ulcerative coitus and Crohn's disease, but Emrah-Solman, anti-IL-15, and anti-PD-1-IL-2 are all in clinical stage development at this point with multiple system atrophy, celiac disease, vitiligo, and our oncology about what we're doing. like Duva-Ketug and the excitement around the T1A mechanism at the ECHO. You know, one of the important themes of the ECHO conference was that we still have a long way to go with inflammatory bowel disease. You know, there's over 4 million people with ulcer, and less than 50% of those patients achieve a clinical remission. 5% of people with Crohn's disease and 20% of ulcer, at least one surgery in their lifetime. So there is a long way to go to control the next slide. Do the key to, again, this new mechanism of action by targeting T1A. Well, T1A is an amplification signal across multiple different inflammatory signals in the body. You know, T1A is secreted by a number of cells, immune cells as well as mucosal cells. And that cytokine, T1A, then amplifies many different pathways in the immune system. It also might have a direct as well. But why is this important? Well, these pathways have been implicated in a variety of different indications. Here we have a list that goes all the way from Crohn's disease all the way down to idiopathic pulmonary fibrosis. And there's many different things that we have the potential in the future. And it's important to note that, you know, many marketed products today only attack one of these pathways and can be indicated in a few of these indications. But the potential of a molecule or a treatment that can treat across many different indications is very exciting. So what differentiates Duva Ketog in the way it was designed? Well, when we developed our antibody here at Teva, you know, we specifically targeted the interaction between TL1A and a DR3 receptor. This is the receptor responsible for the inflammatory signal. We also proactively designed it so that it maintained the binding to the DCR3 receptor. This is a decoy receptor that the body uses to maintain a natural homeostasis during inflammatory responses. So we strategized and selectively made the compound block DR3 while maintaining the DCR3 decoy pathway. Can I have the next slide? Now, I'll be passing this off soon to our guest speaker, but I just want to briefly remind everyone what the design of the Phase II study for DuVu-Ketug in ulcerative colitis and Crohn's disease was. You could see that there were a total of approximately 240 patients enrolled. They were equally divided between ulcerative colitis and Crohn's disease. After a loading dose, they received either a high dose of DuVu-Ketug, a low dose, or received placebo. The primary endpoint was at week 14, and those people who responded and then some of the placebo patients who got re-induced went on to a long-term extension trial. Just as a reminder, in ulcerative colitis, the primary endpoint was clinical remission by the modified Mayo score, and for Crohn's disease, it was the endoscopic endpoint for the primary endpoint. Next slide. Let me introduce my co-presenter today. We're very excited to have him with us. It's Professor Dakul Jayrath. Professor Jayrath is a gastroenterologist and a professor of medicine in the Schulich School of Medicine and Dentistry, and holds the John and Susan McDonald Endowed Chair in Inflammatory Bowel Disease Clinical Research at Western University in Canada. Professor Jayrath leads the IBD Center at University Hospital, London Health Sciences Center, and is Director of the IBD Clinical Trials Unit, the Director of the IBD Fellowship Program, and is the Research Chair for the Department of Medicine at the Schulich School of Medicine and Dentistry. In addition, Professor Jayrath is Coordinating Investigator for our Dubokito IBD Phase II Clinical Trial. I will now hand it over to Professor Jayrath to walk us through the data and to discuss his perspective on the data in both the ulcerative colitis and Crohn disease. I'll then come back to summarize and open the call for questions and answers. And with that, over to you, Professor J. Rath.

Great. Thank you very much, Eric, for the kind introduction and for everyone who's joined the call today. And these data that I'm presenting are fairly hot off. The tale of just having presented these at ECHO two days ago. And obviously, there's been a lot of buzz around the results. So I'm going to start with ulcerative colitis first, and then I will move on to Crohn's disease. And I think, as Eric highlighted, I just want to say two other things that were very novel about this trial. One was the basket design, which allowed concomitant assessment of both ulcerative colitis and Crohn's disease within the same program. And that's really a first in our field. So it was very innovative, number one. And so just starting with the ulcerative colitis cohort, 133 subjects were randomized, 44 to the placebo group, 47 to the 450 milligrams group, and 46 to the 900 milligram group. 89% of the placebo patients completed the trial. All patients in the low dose completed the trial, and all but one subject completed the high dose. So there's a very high completion rate, 99% in the patients treated with duvoketoc. As expected in the placebo arm, it's typically AEs or lack of efficacy, so nothing unsurprising. And there was just one AE that led to a discontinuation in the high dose, so a very high completion rate, which, and this is what one wants to see when, you know, we're looking at drug versus placebo. Next slide. So here are the baseline characteristics of the patients coming into the trial. And I think on a very high level, I would say that these, despite there being, you know, 40 to 50 patients per group, these really reflect the typical moderate to severe population that you'd see in an inflammatory bowel disease trial today. So the mean age was around 40 and slight preponderance of male subjects. No surprise that most of the subjects were recruited in Eastern Europe, and I think that reflects most IBD programs today, and that's related to access of therapies for routine care. Disease duration, about seven to eight years, typical for an IBD study. And I think it's clear that the patients had inflammation going into the trial. 56% had a Mayer endoscopy score of three, and that number is typically between 50 and 60 percent in our program. So this gives a lot of internal validity around the patients going into the trial. 40 percent were on steroids, slightly lower proportion on placebo getting steroids, but these were just chance imbalances given the size of the trial. And then in terms of prior advanced therapies, 69 percent had not been exposed to prior therapies. 20 percent had been exposed to one advanced therapy, 4% to two, and then 7% to three or more. Next slide. So here are the primary endpoint of clinical remission at week 14. Again, this is the regulatory endpoint for ulcerative colitis. This was seen in 20% of patients exposed to placebo, 36% in the duva ketogal low dose, giving a 16% delta over placebo, and in 48% of subjects on the high dose, giving a 27% delta over placebo just for induction. So that's a large effect size at the end of induction for the high dose. So you do see what looks like a dose response relationship in my looking at this. The other novel aspect about this trial, from my perspective as an investigator, is A, the basket design, of course, but B, that there was a Bayesian analysis used So the Bayesian analysis was based on a posterior probability that the response rate in any duva keto dose was more than 90%. And this was observed in 95% of patients on the low dose and 99% posterior probability in the high dose. So these were both highly significant. And the corresponding odds ratios were using a frequentist design was 2.2 for the low dose and 3.6 for the high-dose versus placebo for the primary endpoint of remission. Next slide. We then stratified here the clinical remission rates by experienced to advanced therapies and naive to advanced therapies. And if you look at the middle bar chart here, experience, I think the key thing is the placebo rate falls down to 7%, as expected in an experienced population. and the effect sizes are 22 percent over placebo for the low dose and 29 percent over placebo for the high dose. And as you move to the naive population, I think one of the key points is that we see similar levels of efficacy and delta versus placebo for the high dose. Of course, the placebo rate goes up. So the placebo rate is 28% in the naive population. And the absolute clinical remission rate, 39% in the low dose and 53% for the high dose. So again, giving a 26% delta over placebo. Next slide. Across the secondary endpoints, again, we see higher absolute efficacy for the drug over placebo across all of these. There are no p-values here that this is not adjusted for multiplicity testing. Clinical response between 70 and 80% for the active drug arm versus 50% for placebo. And for endoscopic improvement, which is an MES or 0 or 1, again, we see this dose response relationship of 50% for the high dose over placebo. And then increasingly, we incorporate histology into clinical trial endpoints for ulcerative colitis. And if we look at the hemi endpoint, histological endoscopic mucosal improvement, this is a Mayer endoscopic score of 0 or 1 and a Geboz score of less than 3.1, which is histology scoring scale, allowing just up to 5% of neutrophils in the lamina Again, we see almost double the effect size in active drug arms versus placebo, so that's stringent endpoint. Next slide. Really, just to say about the safety results is there were no dose-dependent effects, and no trends were observed across safety categories, and all the AEs of specialist interest were non-serious and transient. These are typical things that will be effective, expected along the course of an ulcerative colitis trial, so infections, a couple of hematological abnormalities, but really no major safety concerns seen. And there were, importantly, no clinically meaningful changes in laboratory parameters, vital signs, or EKGs seen. Next slide. Then this summarizes the most common AEs that were defined as seen in more than two participants in any treatment arm. These were upper respiratory tract infections, nasopharyngitis, vomiting, and anemia. These are typical things seen in IBD trials, and none of these AEs were serious, and they were all self-limiting. Next slide. So just to summarize the ulcerative crisis section, duvoketic induction demonstrated significant clinical remission rates versus placebo with an effect size of up to 27% in patients with moderate severely active ulcerative colitis. The additional secondary endpoints of clinical endoscopic endpoints supported the efficacy of duvoketic in this population, and it was well tolerated with no emergent safety signals, supporting the further development of this as a potential treatment option for patients and moderate spherly active osteocolitis. Next slide. Okay, and from here, I'm going to move straight into Crohn's disease cohort. So just as a reminder, the structure of the trial, as Eric outlined at the start, was the same. This was a basket design allowing both populations to be assessed in the same protocol with a 14-week endpoint. In this case, 138 subjects were randomized, 44 to the placebo, 46 to the low dose, and 46 to the high dose. There was a high completion rate in the duva-keta-treated patients, 85% overall. 80% completed the trial in the placebo group. Again, typical reasons will withdraw due to lack of efficacy, AEs, or protocol deviations. 80% also completed the trial in the 450 milligram dose for similar reasons for dropout. And 93% competed the trial in the high dose. Next slide. Baseline characteristics of this population are, again, as typically seen in a moderate-to-sphere Crohn's disease population in the trial today. The mean age was 39, slight proponents of male subjects. Most of the recruitment in this case happened in Eastern Europe, about 57%, but a quarter were actually also recruited in North America. The disease duration was about 10 years, so this is a fairly refractory population. They were clearly inflamed, the SCF-CD score, endoscopic measurement of 12, a mean score and the CDI score above 300. And about a third of the subjects overall were taking steroids, slight imbalance between the groups, but I think that's by chance. Compared to the ulcerative colitis population, the Crohn's population was more refractory overall coming in, meant by 43% had not been exposed to advanced therapies, and 57% had been exposed to advanced therapies, 26% to one therapy, 16% to two, and 14% to three or more. And this was by design because no cap was put on the number of therapies patients could have failed coming into the trial. Next slide. Here are the primary endpoints. So the endoscopic response rate, which is a 50% reduction in placebo, was seen in 13% of subjects in placebo, 26% in the low dose, giving a 13% delta, and 48% in the high dose, giving a 35% delta over placebo. The analysis also was a Bayesian analysis, so the trial was designed that the posterior probability of response rate in any duva-ketoc dose was greater than placebo was over 90% and the observed posterior probability for the low dose was 94% and more than 99% with a high dose. These were highly significant. And the corresponding odds ratio by a frequentist design was 2.4% over placebo for endoscopic response to the low dose and 6.1% for the high dose. Next slide. Similarly, these results were then stratified by patients who experienced or naïve to therapy. In the experienced group, as expected, you would see a very low placebo rate of just 4%, 7% delta for the low dose, but a 44% delta for the high dose, where endoscopic response was seen 48% of subjects versus 4%. In the bio-naive patients, the absolute endoscopic response rate was almost identical to those in the experienced group, but the placebo rate was higher, as expected, giving yield at 25% delta over placebo in the naive patients. Next slide. All of the secondary endpoints support what we saw in the primary endpoints. So we see a dose response relationship endoscopic remission going from 17 and 26% versus 9% in placebo. And then for all the clinical endpoints by clinical remission or response by the CDAI and clinical response by the PRO2, which is just abdominal pain and stool frequency, again, we see absolute higher rates in the drug-treated arm than placebo, and for response, deltas of around 12% of placebo for remission at 10% to 15%. Next slide. Coming to the safety results, these were similar observations, as we've seen in the ulcerative colitis population. Serious adverse events were seen in five subjects in placebo, six in the low dose, and one in the high dose. These were typically self-limiting infections, such as COVID, herpes simplex infection, and bronchitis. And there's one case of perirectal abscess in the placebo group. So these are typical and expected. And there were no deaths. And for AIDS of specialist interest, again, similar to the SES, four in the placebo, five in the duva keto, and three in low dose, or three in the high dose. Again, there were no dose disbanded effects and trends observed. Most of the AEs' specialist interest were non-serious and transient, and there were no clinically meaningful change in the laboratory parameters, vital signs, or EKGs. Next slide. Again, looking at AEs, most common AEs occurring in more than two participants in any treatment arm. These were anemia, headache, and nasopharyngitis. So typical thing that we've seen in IBD trials, and they were non-serious and self-limiting. Next slide. So in conclusion, duvoketal induction demonstrated statistically significant and clinically impactful endoscopic response rates against placebo in moderate to fairly active Crohn's disease. Additional clinical and endoscopic endpoints really supported what was observed for the primary endpoint. The drug was well tolerated. There were no emergent safety signals. And I think importantly, these are the first placebo-controlled data from anti-TIL-1 antibody in patients with Crohn's disease. and they support the further development of Duva Ketug as a potential treatment option in moderate severely crows disease. Okay, next slide.

And I can take that from here, Dr. Jairath. Thank you for presenting it, and thank you for being one of our co-investigators in the study. And I just wanted to summarize by saying, you know, we believe Duva Ketug has a potential best-in-class profile. You know, we think of this by design because, you know, the basics of drug development, the fundamentals spoke to the results we saw. We designed an antibody that had high potency in vitro, high selectivity for the DR3 receptor, low anti-drug antibodies. We've noted a rapid and profound suppression of free T1A. And as Professor Jay Rath mentioned, you know, the safety profile and the tolerability has been very good today. We're excited by these results, and we're working very hard to be starting our Phase III program with our partner, Sanofi, in the second half of this year. With that, I'll just open the line up for questions and answers, and we can answer any questions you've got.

As a reminder, if you would like to ask a question on today's call, please press star followed by one on your telephone keypad now. Participants are asked to limit themselves to one question and one follow-up per person so we can get to all voices in good time. And our first question comes from Umar Rafat from Evercore ISI. Umar, your line is open. Please go ahead.

Hi, guys. Thanks for taking my question. I have one. I have two here, if I may. First, for the doctor, thank you for the slides. Do you think this molecule is differentiated over the other TL1As? Second, do you think, second, and maybe this one is for Eric, actually, The rate of ADAs, could you remind us, Eric, where that may have tracked in this trial? And more importantly, what was the definition and the cutoff used for defining ADAs? Thank you very much.

So, yeah, I can take a second if you don't mind. So, you know, we didn't have the data. I'm sorry. Yeah. So, we didn't have the data available at the presentation, but since then, you know, we actually have seen ADA rates of about a very low rate at this point. In fact, we had seen below 10% in our first asthma study, but 3% to 5% was very encouraging to see. You know, Umar, I don't have the exact, definitely get that to you later on. But, maybe you can speak to your thoughts about the differentiation of duviquitug compared to other compounds in development.

Yeah, no, thanks for the question. I mean, And, of course, there's no comparative data between the molecules, so, you know, anything here is hypothetical. That said, when the molecule was developed, and my understanding around this, it was specifically developed to preferentially block the interaction with DR3, death receptor 3, because this is an amplification signal, essentially, you know, upregulation of TL1 is an amplifier. And the molecule was designed to preferentially inhibit the interaction with DR3 to dampen down that downstream signaling on a whole range of cells. I mean, this interacts with many types of Tregs and T cells, cytokines and also fibroblasts, but also to try and maintain a natural balance of homeostasis with a decoy receptor. so you know decoy receptors are there to try and maintain some natural homeostasis so the molecule was actually designed with that so in theory this may be differentiating um i think obviously all of that will have to pan out in eventual phase three clinical data across the compounds the next question comes from ash verma from ubs fresh your line is open please go ahead

uh great uh yeah thanks for taking my question i have two so maybe one for dr jared like uh broadly speaking, where do you think the TL1A class as a whole takes market share from existing therapies in IBD? And then second, on formulation, maybe Eric, if you can comment on this. So when you mentioned previously that these, you know, the 450 meg and the 900 can get to a sub-QRO injector, how many ml are we talking about? And I believe your other competitors are maxing out at a dose of 500. So at this 900, are you still confident that you would be able to achieve that? Thanks.

Professor Jaret, did you want to talk about the class in general and its potential use in the future?

Yeah, thank you. Thank you, Ash, for the question. I'll take the first question. So, I mean, with the caveat that these are phase two data, and of course we'd want to, presumably if we see similar effect sizes in phase three, you know, when you look at the, if I take ulcerative colitis first, when you look at the effect size of a placebo of 27% for the high dose, I mean, in my mind, if you look at the comparative field, this is almost Jack-like efficacy, right? So I think if you look at the bar, you know, what's the bar for ulcerative colitis? What's the highest efficacy rates that we see in the clinic today, on comparisons, it's really JAK inhibitors. And I think those effect sizes to me are in that ballpark, number one. And I think the same principle applies with Crohn's disease as well, because seeing endoscopic response rates just after induction with effect sizes of 35% and even higher in bioexperience, 44%. Again, the thing that came to my mind when I saw these data is that this is JAK-like efficacy with potential safety advantages as well. I think that's the first thing. And the second thing to say is also that this trial involved sub-Q induction and sub-Q therapy as well, which I think is also potentially differentiating. So when you look at both by naive and by experienced subjects, you get similar efficacy in osteoclite across both. So, in theory, it could be put anywhere in the treatment paradigm. And for Crohn's disease, even greater efficacy in the experienced population. But overall, as we say in this field, efficacy is king, right? Efficacy trumps everything else. So, in my mind, again, I'm making indirect comparisons, but we do that all the time when we pick agents and where we position them. I think this looks as good as the best agents that we have today with potentially some safety advantages.

Professor Jayrath, your comment on the subcutaneous is a perfect segue into the formulation question. And it's worth reminding everyone, Ash, that, you know, this whole program has been done with subcutaneous dosing. So three is like for like. From the very beginning we've been doing that. So to your point, you know, we're still doing the modeling and simulation. We're very excited to see the dose response in the study. That helps our model a lot to determine where we are and where the dose response hits a point of inflection. We have prepared already our pre-filled syringes that are given subcutaneous for Phase III, and that will be the syringe we use in our autoinjector. So to your question, though, the number of injections and how we give that, the schedule is yet to be determined. You know, we're working with Sanofi right now to design the Phase III, and when we make the announcement, you'll be able to see how we're giving it in that program. Thank you for the question.

Thanks. The next question comes from David Amselen from Piper Sandler. David, your line is open. Please go ahead.

Thanks. So, just want to clarify on the Phase 3, and maybe it's too early for you to answer this, but are you going to be testing both doses in Phase 3 or just the high dose? And then secondly, will the presentation be the pre-filled syringe? Or just to clarify, will you have the auto-injector incorporated into the phase three? And then lastly, if I may sneak in one, you mentioned jack-like efficacy. I'm particularly interested in Crohn's, how you see Duva being positioned versus re-invoked, particularly given the safety tolerability baggage associated with Renvoke? Ultimately, do you see the class being positioned ahead of the jacks in Crohn's, given the effect size? Thanks.

So, Professor Jarad, maybe I'll give you the jack-like question first.

Yeah. Yeah. And I know just to comment on that. I mean, I think the first thing to say is that, you know, I think that having endoscopic response as a primary endpoint here was, in hindsight, a very good choice because it's the most objective outcome measure. And we know that endoscopic improvement, response, remission, however you define it, is associated with better outcomes for patients. And, you know, we see a large effect size here at 14 weeks. I think you're quite, you know, and I, you know, the analogy of jet-like efficacy is my analogy, right? This isn't something that I've heard colleagues on Teveline say, but it's my analogy when I look across all of the compounds. And as a reminder, JAKs are, in the U.S., are second-line therapy. They are positioned second-line. That's the label because they have a black box warning. And I think it varies in different parts of the world, but certainly in the U.S., they are second-line agents because of some of the safety concerns. Now, if the Phase III for TL1A produces, again, we need 52-week maintenance data and beyond, but if it produces the same safety that is seen in the Phase II, then naturally, when you're seeing a patient and you've got two drugs with almost similar efficacy, but one has a better safety profile overall, it's obvious which one you're going to pick, the thing with a better safety profile.

Thank you. And the question regarding the phase 3 design and the pre-filled storage. So, you know, our final design is yet to be determined after we have to have our discussions with health authorities, and it has to be the result of our modeling and simulation. So whether we have one or two doses in the phase 3 has not been necessarily – I can't necessarily answer that question, and that's up to the work we're doing. question, you know, we will be going into phase three with our pre-filled syringe. So that's the syringe that goes in the auto-injector, which is developed in parallel. So we're intending to launch with an auto-injector.

Thank you. The next question comes from Jason Gerberi from Bank of America. Jason, your line is open. Please go ahead.

Thank you. Thanks for my questions. So for me, for Dr. Jayrath, I'm wondering, you know, you talked a little bit about the comparisons on Jack. You know, one thing I've heard from some of your peers is, I guess, the value of TL1A having something like an Intivio-like safety profile. And so I guess, you know, based on what you've seen for TL1As collectively and what you understand about the mechanism, just kind of curious how you'd maybe compare the safety of DUVA or the TL1As to Intivio from a potential safety and labeling perspective.

And ultimately, Intivio's commercial success was, you know, I guess, underpinned by the Varsity trial and doing head-to-head studies so is that the cost of admission to getting a high level of usage you think in uc given the competitive intensity of the space thanks yeah thank you it's a great great question actually thank you for bringing that up i mean i think the first thing to say from safety i think it's just way too early to make any comparative um uh assumptions about what how this will benchmark against other drugs you know we're gonna use phase two results there's three phase three programs potentially others coming so I think time will tell us about safety signals I think I think your point is exception well made that I think for this whole field it will be very important that TL1As do have a head-to-head trial built in somewhere whether sponsors choose to take that on in their pivotal phase three trial with an active comparator or whether a 3B head-to-head, I think it is essential that there is some way in the development phase head-to-head, both in UC and both in CD. Because I think your point is really well made. Vidalizumab, really, in obstaclitus, it was a major turning point when varsity showed superiority to an anti-TNF. And I think, you know, I think if you see these kind of data in phase 3 for Tier 1A, then there should be a high level of confidence to conduct head-to-head trials in both indications. And I think that would be really important for positioning. I suspect that these would be done as 3B-type studies like Varsity.

Thank you.

As a reminder, that star followed by one to ask a question today. And the next question comes from Chris Schott from JP Morgan. Chris, your line is open. Please go ahead.

Great. Thanks so much. Just two questions for me. Maybe just first on the Crohn side, I think you mentioned Rinvoke, but can you just talk a little bit about how you're seeing TL1A compared to IL-23s, given those drugs emerging as kind of maybe more of a frontline standard of care? And then my second question was on biomarkers and how extensively you're going to look at those in Phase 3. Obviously, we see some great Phase 2 overall data here, but were there any learnings from this study in terms of populations that could see even higher efficacy? or do you think that becomes less relevant just given the strength of the overall phase two program here?

Professor Jayrath, did you want to take the question?

Yeah, I'll take the 23. There's a good question about 23 inhibition, because I think, you know, if we looked at the treatment landscape in Crohn's disease over the last 10 years, it was clear that IL-12-23 inhibition with this tachinumab, certainly in North America and many parts of Europe became first-line therapy. And now that we have three IL-23s almost in the – almost, we've certainly got IL-23 for – one IL-23 for Crohn's. We'll have two more probably followed fairly soon. And a head-to-head in TNF failures demonstrating superiority of IL-23 over istakinumab. I think your comment is right that IL-23 is starting to chip away at the istakinumab first line starts. I think that's probably correct. I think IL-12-23 still has an important role, particularly because it's Q8 and subcutaneous dosing, and there's flexibility in the dosing, which some of the IL-23s don't have. And I think what we're learning as time goes on is, of course, we have some more safety data for IL-23 inhibition. We only have a couple of years of follow-up in IBD, but there is in other indications, and, you know, it's pointing towards a favorable safety class overall. So, you know, I think it would be important coming in in the TL1A landscape to really address that with comparative effectiveness studies, because, to my point around JAX, is JAX our position second line in the U.S., whereas IL-23 inhibitors are not. And, you know, I think it would be important to address some form of comparison to IL-23 inhibition if TL1A is going to take first-line position. I think the second thing to add, though, is that some of the science The science under PIN-TIL-1A development was around potential antifibrotic actions as well. Those need very specific studies to address that, but I think it's one of the potential advantages over other classes as well. But again, the clinical studies will need to be done to show that.

And I can answer a little bit about Professor Jareth, and I'd like to get your opinion But, you know, with the biomarkers, the normal players, genetic readouts, proteomic readouts, biopsy readouts serum readouts in my experience baseline biomarker requires a lot of data especially in disease areas like this so we're collecting that we're hopefully to we'll identify something and we do something that's a little bit unique compared to other programs is that we look at free tl1a as well whether that pans out or not we're not we'll have to get more data but for right now given the data we've seen in both treatment experience and naive patients, you know, we're approaching this as an all-comer program, but we'll certainly be looking at more data in larger patient populations as we move forward to hopefully identify a predictive biomarker or even one that's on treatment response. But, you know, I know that's a perennial question at the meetings, Professor Jay Rath. What are your thoughts about biomarker?

Yeah, no, thank you. I mean, look, I think, you know, the holy grail would be that we develop a companion biomarker for any of our drugs. I mean, we're 25 years into advanced therapy starting with anti-TNF, and to date, we don't have one, and so I think if it was easy, it would have been developed, and we're really left with clinical parameters. You know, I think whether other TL1A inhibitors, you know, the companion biomarkers pan out, you know, it's really important that we have to see this within the phase three programs, number one. I think the second thing is that if there is a clear companion biomarker, how would clinicians actually use that? You know, would it be that you only use the drug if you're biomarker positive? And then there's lots of things that influence that, you know, how prevalent is the biomarker in the background population? And what is the true delta that you get? I mean, if you're only getting 5% delta with a biomarker, you probably wouldn't really care much. But if you've got 15% or 20%, or maybe even 10% at least, it may be that we only use the drug if you're biomarker positive and not biomarker negative. So I'm not clear how it would pan out. You know, we'd have to have a really significant effect size with a companion biomarker. And, you know, Crohn's disease particularly, that's really challenging because it's not one condition. Ileal disease behaves differently to clonic disease, to ileal clonic disease and perianal disease and EIM. So, you know, I think part of the challenge is that these are, IBD is a multi-system disease with particularly in Crohn's disease differential behavior according to where the disease presents and when it presents as well. Thank you.

The next question is from Balaji Prasad from Barclays. Balaji, your line is open. Please go ahead.

This is Michelle for Balaji. Thanks for taking our questions. So, first of all, with the JAKLAG efficacy profile, especially in the treatment experience group, have you considered maximize the induction phase opportunity in the drug development process? As in the induction phase, the efficacy is more important versus those in interval. And also, just a quick follow-up on the remission phase data, wondering when should we expect a 52-week clinical data readout?

Dr. Joseph Baerichaner, did you want to answer that question about, you know, what would you prefer, better efficacy or better schedule, you know, two or four weeks or more intensive induction?

Well, yeah, it's an interesting question. I mean, I think the, if we look back over drug development in our field for the last 25 years, we've always had this theory that, you know, by giving, we have either IV drugs or IV induction followed by subcube all separately here. And the notion being that you've got high inflammatory state and you get this antigen sink, and you need to give an IV dosing to get really 100% bioavailability to really kickstart and mop up all that inflammation, then go to sub-Q dosing. I think this program, albeit at the phases, and other parallel programs ongoing in the IL-23 space, which is sub-Q induction, totally challenge that concept, right? It shows that you can give sub-Q induction, and you're getting very favorable efficacy rates for sub-Q induction. So, you know, in the end, I don't think, you know, I guess the question for the phase three is, again, and I'm not privy to that information, is what's the dose selection going through in? And there'll be lots of modeling from here, from the data seen here, and it's getting the, I think it's getting the dose right in the induction phase and trying to get the total area under the curve of drug exposure during that time. But you're absolutely right that we probably believe that if you get really good efficacy induction, that will probably carry out into the maintenance period, particularly with half-life drug and carryover effects.

And I think you said it before that, you know, efficacy is king. So that would be definitely where we want to design the program. Oh, and the second one we'll be having in the December timeframe or November-December timeframe, and it's a 44-week, you know, we're anticipating the last patient and last visit sometime in December of this year. So, thank you for the question.

At this time, there are no further questions, so I'll hand the call back to Dr. Eric Hughes for closing comments.

Well, let me start off by saying first thank you to Professor Jay Rastavi in the conversation today and thank you for being one of our presenting authors of the program here or just last week in berlin at the echo conference i thought it was very exciting to see the data presented and to see it in the context of at the meeting and thank you for everyone for taking the time today we're excited to be working with our partner sanofi to get our phase three program going and at the end of the day we hope to have it that can help relieve people of their ulcerative crisis and disease in the future so very exciting and thank you all again for calling in