Immunology Symposium. We're delighted to have Teva with us. Certainly a lot to talk about, and with us is Dr. Eric Hughes, Chief Medical Officer. So Eric, there's a lot to talk about, not just regarding duvakitug, but also your IL-15. But maybe I'll just start with a high level question, and that's just more broadly regarding your immunology R&D efforts. I wanted to ask you about your approach to pre-clinical research here, and how you're thinking about molecular targets. It seems like a big focus is on already validated targets. You mentioned a TSLP/IL-13-directed treatment you introduced to the investor community last year as just one example. So just talk about your overall approach to validated targets and to your design of more optimal molecular entities. Yeah ... based on validated targets. 'Cause I know it's... Look, obviously Teva's evolved considerably, and it's a big. Yeah. A rea of focus of your R&D organization, so I'd love to get your thoughts there. Yeah. Well, thank you, David, for having me, first of all, and, you know, it's great that you guys are having an immunology-based investor call symposium. That's. I think that's a perfect focus for a lot of drug development. But, you know, getting back to your question about, you know, what's the focus and what's our thinking, you know, you gotta remember that, you know, we have a great antibody engineering group and protein engineering group down in Australia. And, you know, remember, we also make a ton of biosimilar drugs as well. So they have a great knowledge base of a number of different targets, not only, not to mention our innovative stuff. So, you know, it's a great mix of knowledge and, you know, things to build upon. Then for immunology, one of the great things about the immunology and the development area here is that there's a lot of tools to play with. You know, the immune system is very complex, and bringing together different components of that really is a chance for, you know, not only increasing your probability of success, but really having build upon great efficacy that we've seen in a number of different targets. So you mentioned TSLP and IL-13. That's a natural combination of targets to bring together, and we bring that same kind of, you know, thought process together with other ones. You know, we have TL1A. We can build upon TL1A. There's 23s, there's 17s, there's 31s, 33s. There's all kinds of different combinations you can envision, but that's a great way of increasing your probability of success and build upon, you know, our expertise in antibodies and protein engineering. Okay, that's helpful. And I guess... So, there's absolutely early-stage research efforts. But I guess my question here is, what's your appetite for to seek out novel targets? Really more in by the inorganic approach. So in other words. Yeah. You've got your internal capabilities. What about inorganic approaches, BD/M&A approaches to bolstering your immunology business? Yeah. Yeah, so, Richard and I are very clear on this. We're agnostic as to wherever the innovation comes from. You know, innovation comes from everywhere around the world right now. You know, it's almost like a commodity at this point. So, you know, we approach BD and our internal as one and the same, so we don't, we don't care where it comes from. You know, getting back to the TSLP, IL-13 program, that was a great collaboration with Biolojic Design. We used AI technology to bring the two together in a way that couldn't have been done in a mouse. Yeah. You know, that was engineered in a computer where we actually used each tip of the antibody to bind a TSLP or an IL-13. So that's a real great innovation, not only speeding up the combination, but doing it in a way that couldn't have been done before, where you're binding one or, or the other, or both, depending on the concentration of the environment you're looking at. So that's a great example of innovation. It's a great example of speeding drug development, and it has the potential to make a better combination in a better way. Because, you know, I also... I think like a drug developer, I want a, I want a molecule that binds things well with high potency, but I also. Mm-hmm. W anna be able to make it. I need to make it generate the antibody, have low COGS, and have the profile of an antibody when we make the final product. Okay. So I wanna spend time on 408, your IL-15-directed antibody. So that's obviously been in the news just given the agreement with Royalty Pharma. I'll start off at a high level. Just briefly remind us of the potential timeline for filings in each of vitiligo and celiac disease. Yeah, so we're really excited about the acceleration of this program. You know. Yeah IL-15 is a great target, it has great biology, a basis for going into vitiligo and celiac disease. You know, we're working to accelerate our vitiligo program. You know, we're targeting, you know, 2031 for that one, and, and celiac, probably 2034. You know, we've got the proof of concept study data coming out in the first half of this year in vitiligo. We have the celiac biopsy data coming out as a proof of concept in the second half of this year. So that's the timelines we're looking at, and the team is really thinking out of the box about how to execute on those. Okay. So, just drilling down on the recently announced development funding transaction with. Mm-hmm. Royalty Pharma. So just wanted to level set a few things here. Just to be clear, Royalty is funding vitiligo development, but not celiac disease, at least as of now. Is that correct? And maybe talk about the extent to which Royalty can opt into funding of further development in celiac- Mm-hmm. I f that's something that, you and, and Royalty Pharma have talked about? ... Yeah, so the deal, which we're really excited about, you know, Royalty Pharma is a great group of scientists really, who actually really dig deep into the program. So for practical purposes, we based it on vitiligo because the pathway to registration is very clear. Yeah. You know, we can, we can lay it out, we can, you know, put deal terms around that. So that's purely why they. It was focused on vitiligo. That will be... You know, if there's more we want to do in the future for celiac, that's, that's gonna be fine if they want to do that. There's other indications that you have to think about, too, alopecia areata or atopic dermatitis, or even eosinophilic esophagitis. So, you know, it, it was practically designed around vitiligo, just, just for the clarity of the, the program. Okay. And then another question on the funding agreement, and then we can talk a little more science and clinical development. So I think and I get this question a lot from folks, from investors, is just on the funding. It's up to $500 million R&D funding in vitiligo, which, you know, I've gotten a few comments is that that sort of is a fairly large cost for a vitiligo development program. So I guess with that in mind, just help us better understand what the phase II-B study would look like, and then what you would need to run in terms of a phase III program. Just to help us understand, you know, what does a mid-stage to late-stage vitiligo program really for systemic, you know, for a systemic option, look like? Yeah. I mean, I don't want to get into too much of the specifics of our phase II and phase III programs. Yeah. B ut I kind of laugh, you know, $500 million for a program. That's actually not too far off from the, you know, the basics of a program. I mean, drug development is very expensive. So, you know, I look at that number, I think, "Well, that's pretty, that's pretty reasonable." And, you know, but you have to just remember that when you do a drug development program, I'll just speak in generalities, you have to get a safety database. So, you know, you need. Yeah. A bout 1,400 patients worth of exposure just for the FDA to approve a drug. You know, you have to do a dose ranging in your phase II-B study, and you have to get those safety numbers in phase III. These programs are all pretty much based on the same principles of what you need for the, for the approval. You know, getting back to the 500, that's pretty much spot on. Okay. I don't think it would be different from any other company. Just to be clear, the phase III would be similar to what AbbVie did with Rinvoq, two essentially identically designed phase IIIs would be required to support approval? They're all, they're all gonna be the same requirements. Yeah. Yeah, they're gonna be very similar. Okay. All right, so let's just, let's just talk about underlying mechanistic rationale here for IL-15 directly treatment, specifically in, in vitiligo. Maybe just help us understand that rationale. Yeah. So this is the part of the science that's very strong. Yeah. We can talk about both vitiligo and celiac if you want. But, you know, in vitiligo, you got to remember that what's happening is there's resident memory T-cells, CD8 positive T-cells, that go and they kill the melanocytes, and the melanocytes are the ones that make the color in the skin. And what keratinocytes do when you get vitiligo, there's an exuberant expression of IL-15 from the keratinocytes themselves in the skin layer. So what we're doing is blocking that signal, and that IL-15 that's being secreted in the skin, is what's drawing and maintaining those CD8 positive T-cells that kill the melanocytes. So, you know, the exciting possibility, obviously, if you block the signal that brings and maintains those CD8 positive resident memory T-cells, you can, you know, block the destruction of the melanocytes, and then you can allow those melanocytes to come back and grow again in the skin. You know, and maybe you might ask me more questions about this, but one of the differentiating factors then between a JAK and an IL-15, and this is just. Mm-hmm. T heoretical and speculation, is, you know, JAK just turns off the inflammation. We have the possibility of removing the cells that are causing the problem and maybe have more of a persistent effect. That's an exciting speculative aspect of it, but really, the most important point is that we're blocking the signal that maintains these T-cells in the skin. I did want to come back to potential for differentiation versus Rinvoq, but just looking at the treatment landscape, I wanted to ask you about that. So it looks like Rinvoq is headed for label expansion in patients with more extensive body surface area involvement. Mm-hmm. But looking beyond Rinvoq, I mean, it looks like this is a pretty thin treatment armamentarium. Maybe just talk about what's currently available for vitiligo patients with more extensive body surface area involvement, and where systemic treatment would be appropriate. Yeah. So just to review, so right now, the only thing that's approved is the topical JAK- Right ... that, you know, only covers 10% of your, your— you can only do 10% of your body. I believe it's BID, it's twice a day. Right. ... That you have to do that. So it's limited in its scope, and it's limited in its convenience for what you can do. You know, the ones that are in development, there's 2-3 oral JAKs that are in development, again, that you know, potentially provides some systemic coverage, but again, that's a daily treatment. You know, the differentiation, the potential that we're talking about is, you know, we're looking at potentially getting up to a quarterly dosed subcutaneous shot. Mm-hmm. So you have, you know, IL-15, we have a 38-day half-life. We suppress IL-15 for about 80 days. So that potential of convenience of just a shot, maybe 4 times for an entire year, is a real good systemic therapy, you know, to treat both facial and, and total vitiligo. So that's, that's the differentiation, and then the, the, the icing on the cake would be the way in which the molecules work. Instead of just immediately cutting up just the inflammatory response, we're removing the cells themselves that cause this problem over time. Can you talk real briefly about what patients currently use for, in terms of systemic options? I know there's one topical approved, that's Opzelura, and, you know, and then there's a bunch of off-label options, both topical and systemic. But on the systemic side, what's typically used off-label these days? I mean, really, the thing that people use the most that I'm familiar with is the topical, which is, again, 10% only. Yeah. O f the skin surface. But, you know, some you know, UV light therapy is the other thing people do. Right. ... To try to increase it, but, you know, that has limited abilities to change it significantly. There's really not much out there that's really effective. Yeah. So a lot of white space here in. Yeah. ...... For the IL-15. Okay. So I know we talked about potential for differentiation versus Rinvoq. I wanted to get your thoughts on safety. We know that Rinvoq has a lot of language in the label. Yeah. ... On safety. Maybe talk about the safety profile. And again, early days, but how should we think about that? Yeah, I mean, that's a huge differentiation. I'm, I'm glad you reminded me that I didn't say that. You know, you know, JAKs had great, anti-inflammatory activity, but they're, you know, they do have a lot of baggage with the black box that they have with regards to a number of different, systemic, issues. So people actually probably use those mostly in people that they're not gonna have too much potential safety issues. So it's a, it's a limitation. You know, right now it's early days, but, you know, the IL-15 has been very well tolerated in our hands. You know, pretty much like, similar to placebo in our first, celiac program and our phase I stuff. So right now, things look good, and, you know, we'll hope for that. That's a very easy, convenient, safe, alternative for patients. Okay, and then just speaking of celiac, another, you know, similar question to what I asked on, on Rinvoq, what is, what are your thoughts on the mechanistic rationale here of IL-15 directed treatment? Yeah. So again, it, it's very similar. If you think of the skin on one surface and your gut lining on the other surface. Right. ...... These are both really externally facing surfaces. It's those gut lining, it's the epithelial cells of the gut lining that actually secrete IL-15. And, you know, IL-15 has been connected with celiac disease for quite a while now. We've done some great preclinical work to show that. But, you know, again, those epithelial cells secrete IL-15, they then drive the maturation and proliferation of these anti-gut lining cells within the gut itself. So we actually did a study, you know, in monkeys a long time ago, and we've published this, where 1% of monkeys actually spontaneously generate celiac disease. Hmm. We took those monkeys, and we actually treated them with and without our molecule, and showed very nicely that we block the maturation and proliferation of intraepithelial lymphocyte cells that destroy the gut lining. With the blocking of IL-15, we not only had the gut recover in those monkeys, but we also blocked the antibody production that is so typical in celiac disease. Now, Novartis has an IL-15 directed treatment, CALY-002. It gained that via the Calypso acquisition. Yep. Can you talk to, you know, potential differences between 408 and the Calypso asset? Yeah. So, you know, I don't have their antibody, but certainly we make antibodies based on patents. And when we look at the potency of the antibodies out there, the other anti-IL-15s, ours is clearly more, more potent. So we have a potent antibody, and we also believe that when you compare, cross-study comparisons, we have a greater reduction in NK cells, which is an effective anti-IL-15 activity. Okay, and then you mentioned eosinophilic esophagitis. I think the Calypso asset is being tested there. So is that something you're considering for 408? And I think you mentioned a couple of other clinical settings, but it seems like EoE would make a lot of sense. Is that something that's in the works? Yeah, I don't want to comment on other people's programs, but certainly, you know, in our hands, we have preclinical data that would suggest that, you know, not only vitiligo and celiac disease are good targets, but atopic dermatitis and alopecia areata are things that we are very confident. You know, there's a lot of related characteristics of these disease areas that would make you think that those would be good areas to go in. Okay. So wanted to spend some time on duvakitug. We're gonna see longer term maintenance data on both UC and Crohn's later this year. Just give us a quick refresher on the design of the longer term extension portion of the phase II, and also help us frame how you're thinking about what would be considered success here. I would think about it as just durability of response at a very simplistic level, but obviously love to get your thoughts. Yeah. Let me say, first of all, it's not just durability response. Sure. That's what these patients need. I mean, they need therapies that... You know, remember, only about less than 50% of patients get a clinical response on an advanced therapy, but then maintaining that therapy is around the same possibilities. At one year, 50% of them have failed. So durability in a chronic disease is super important. You know, with this maintenance data that we're gonna have, you know, by the end of the first quarter of this year, we're looking at a total of 58 weeks of exposure. So they got 14 weeks on the induction, then you add another 44 weeks after that. Mm. So this one-year mark, essentially, is a real good benchmark to see how good you are at maintaining these good responses. So we had some great responses on the induction for ulcerative colitis and Crohn's disease, and this data that we're gonna have this year will show how well do those people maintain that over a full year of therapy. So that, we think that's super important, and that, you know, just to remind everyone, there were two doses they were re-randomized into, and those two doses were given every four weeks. Okay, and just to be clear, those two doses, those are being tested in the phase III? We haven't commented on what the doses are in our phase III yet, but we'll, we'll talk about what the doses were in this phase II. You know, we went in with a 450 and a 900. Right. ... In In this study. That was my sort of not-so-cute way of asking about dosing in phase III. I just kind of had to. Don't worry. I know. Yeah, yeah. Okay. Well, I appreciate still gotta ask. So. No worry. One thing in the phase III, though, you do incorporate a re-randomization of responders, and I wanted to ask you about the rationale for incorporating that into the pivotals, and into the design of those pivotals. Yeah, so I mean, it's acceptable to do either re-randomization or retreaters. We like re-randomization because that's more, you know, reflects more clinical practice. You know. Sure. ... You still get re-randomized potentially into a placebo, but you're basically looking at the response on induction and then acting on that, essentially. Right. It's more, it's more conducive to what patients would want to experience. Okay. So wanted to ask about the competitive landscape. So we're gonna have MK-7240 data in UC later this year. We've got RVT-3101, that's a Roche's compound. How would you frame the potential advantages of duvakitug versus the other two, TL1As that are in advanced development? Well, first of all, congratulations that you can pronounce all these drugs. That was actually better than I. I spend a lot of time practicing in front of a mirror. Yeah. That was very good. I did that this morning. Yeah. Very good. But yeah, so getting back to our differentiation, I mean, it's... I'm very clear about this. We have greater potency for our TL1A in vitro, in our hands. We have greater selectivity, you know, based on the fact that, you know, we block the DR3, and we maintain the DcR3, and we've reported the lowest anti-drug antibody rate, and it's only about 3%-5%. So in vitro, the fundamentals are great. I think we ran an excellent phase II program on the induction. We posted the best placebo-controlled efficacy in both celiac and Crohn's disease. Ours was the only well-controlled study in Crohn's disease. So those fundamentals are there, and I think that, you know, hopefully, the maintenance data also supports that. So, you know, I believe we have the potential to be best in class, and, you know, hopefully, we have the potential to be, you know, best in disease. Yeah. How do you think the category, the TL1A category, could be positioned relative to the other advanced therapy categories? Mm-hmm. ...... The IL-23s, alpha-4 beta-7s, JAKs? I mean, I guess, my, you know, my question here is two parts. One is, you know, do you see a front-line or second-line treatment paradigm in both UC and Crohn's for the TL1As, and more specifically, do you think these agents ultimately will slot ahead of Rinvoq, given the safety tolerability baggage associated with the JAKs? Yeah. Well, you know, I see a lot of blue sky here because we're not just making. Yeah. A nother 23. We're not making another 17. We're not making another integrated, integrin inhibitor. You know, this is a totally new class of biologic. This is an amplifying cytokine. Mm-hmm. It's a cytokine that affects all these different pathways. So it has the potential of having a direct anti-fibrotic effect. Remember that the DR3 receptor is on fibrotic cells. Mm-hmm. Usually, we're just blocking the inflammation, hoping the fibrosis gets better. Here, we have the potential to have a direct effect. Yeah. So, you know, it is all brand-new science. There's many different pathways we can attack, and it, it might actually have additive effects across a number of different indications. So, you know, to me, it's exciting because it's not just one single pathway we're hitting. It has p- different activity altogether. So I, that's the exciting part about this. I think you mentioned recently about, or at least getting more visibility on other studies you might go into other clinical settings you might go into, but just remind us how many additional studies you could be initiating between now and, say, the end of this year or, you know, first half of next year, beyond UC and CD? Yeah, so we've been very choiceful with Sanofi not to mention the next two indications. Mm-hmm. Trust me, we're working on it, and we have a very clear plan at this point. But just to reiterate, I think that something's very important. You know, we have a very clear strategic plan. There, we bucket the indications that we're gonna go into. Yeah. There's T2 inflammation, there's non-T2, and there's potentially fibrotic buckets. So, we're gonna choose an indication that unlocks each one of those buckets, you know, in a logical way, and, you know, the indications we'll choose to open up those different buckets is based on, you know, the strength of the science, the speed of the regulatory pathway, the probability of success, and the market opportunity to expand the label. So, you know, we're gonna... It's methodical in the way in which we're gonna do this, and it's gonna maximize the potential of the class. Okay, quickly, in the last 30 seconds we have, just remind us when the TSLP IL-13's going into the clinic? So we haven't said when we're gonna actually get into the clinic, but we're gonna submit the IND by the end of the year. So we're moving that forward as quickly as possible. I'm very excited by that. Mm-hmm. There's already some clinical data out there that suggest this is a potentially very powerful combination. All right. Terrific. Well, I wish we had more time, but this was great, Eric. Thanks so much for doing this. Thanks to everyone in the audience, and both Chris and Eric, hope you guys have a great weekend. Thanks a lot. Have a good conference. All right.