Okay, excellent. Thank you guys for joining us. Super excited to have Protagonist management with us. Congratulations on your phase III data with J&J, oral IL-23. I feel like the first time I worked on that program, I just saw the iterations you guys went through to nail down the bioavailability. Right. Everything else. But maybe let's kick it off there and we can jump into your pipeline as well. Yeah, no, absolutely. I mean, so, you know, the oral IL-23 blocker, now it's called Icotrokinra. I'm still trying to learn that. Me too. We have worked on the oral IL-23 program for almost a decade, and it was in 2017 that we inked the partnership with J&J. Right. As you can tell, it has been quite a journey. We initially had a first-generation drug. Right. It was oral, but it was gut-restricted. So the learning we had from that was like, we need to make our peptides orally bioavailable. And the gut-restricted idea was logical. The idea was that, hey, for IBD, gut restriction could be useful. There will be adequate tissue concentrations, things of that nature. But ultimately, all of this led us to PN-235, which is referred to as JNJ-2113, and now Icotrokinra, which has the perfect combination of potency, oral stability, as well as oral absorption. Got it. And remind me again, Dinesh, what were you guys doing for the gut restriction? It's so over there, the physicochemical characteristics of the peptide would be of such nature that it's not necessarily absorbed in any meaningful way into the bloodstream. So in a way, it was kind of a lower barrier. We just had to worry about engineering excellent potency equivalent to that of the biologics. Got it. And create oral stability. But then with Icotrokinra, there is the additional challenge of like, okay, how do you also kind of engineer oral absorption kind of characteristics into your peptide? Got it. Excellent. Well, I know the phase III data was exciting, and you guys have clearly met the bar. It's easily the most efficacious oral for psoriasis now. They'll be on the market in short order. There were some comparisons made with injectables and whether it's as effective as injectables. Can you maybe characterize that? And I have some follow-ups on the way I was looking at the data as well. Yeah, no, absolutely. And I think it's a great question. The agenda that J&J and Protagonist has had in this program was that we want to come up with the best oral psoriasis drug, right? And by best, we mean the best efficacy as well as best safety. Now, with our IL-23 blockade, we inherit the safety characteristics, right? The safety of our IL-23 blockers is kind of like unmatched, so to speak. And in our oral drug, we are also capturing biologics-like efficacy. I mean, at the end of the day, ICO does have. See, ICO is easier to say rather than the whole thing, Icotrokinra, right? So let's just call it ICO. ICO does have STELARA-like efficacy at the end of the day. But injectables were never the comparator over here because we are differentiating by having an oral, and this turns out to be the only oral IL-23 blocker that is out there. So the scarcity value is going to be huge in terms of the demand of the drug and even competition, right? We don't know of any other oral IL-23 that is out there. Right. I guess if we compare versus some of the TREMFYA trials, I think on PASI 90s, you guys are in the mid-40s, they're like around 68%-70%. Is that a reasonable cross-trial comparison or not? Yeah, cross-trial comparisons are adequate. I think the other thing we found in the phase III study is like instead of week 16, if you focus on week 24, now our scores are increasing by about 15% more or something like that. So when we talked to the KOLs after we got the results, they were like, look, you guys should be celebrating. This is the best oral psoriasis agent that is going to be out there. And if I have to tell my patients that, hey, here is an oral drug, it's an IL-23 blocker, so safety will be amazingly good as well. And you may have to wait a little bit longer, but you will get to the same efficacy endpoint. Right. You know, the Frontier, our phase II study. It was a FRONTIER 1, FRONTIER 2 study. FRONTIER 1 was a 16-week readout. FRONTIER 2 was like, you know, long-term extension up to 52 weeks. What we found is like the compliance was amazingly good. 97% of the patients expressed satisfaction with the drug. Improvements in terms of PROs, like itching and those sort of things, those were dramatically self-evident within 16 weeks or something. Wow. I guess just as I think about sort of the prospects here, one thing that's confused a lot of people is the TYK2 launch has underwhelmed, and the assumption generally is maybe even a slightly better efficacy may not perfectly correlate, but the difference this time around is it's not a new player launching your oral IL-23. This is J&J using its existing rebate structure on TREMFYA and perhaps rolling it over, so I guess for you sitting here from a Protagonist perspective, what visibility do you have on J&J's conviction and willingness to actually look to, I don't want to use the word transition the franchise over to the oral, but make a pretty serious dent? Because they can single-handedly control that with their rebate structure. Yeah, I think those are great points. And what I would say is like over the years since 2017, we have seen the commitment and determination and dedication that J&J has had for this program. As I mentioned before, this was the third peptide that went into the clinical study, right? So they were very persistent that if we were just a biotech on our own doing this thing, I don't know if ICO was even going to be in existence or not. Then if you look at the amount of efforts they are putting, right? Five phase III psoriasis studies. Right. Who the hell does that? And what kind of transition happens down the road, things like that, it's like, you know, that's something that J&J can answer. But as they say, the writing is on the wall, right? I mean, if you look at what they're doing with TREMFYA, now they have a sub-Q administration in place. They are moving TREMFYA towards the pediatric adolescent kind of population, things like that. An oral pill will be amazingly attractive for that kind of population and all population in general, right? The KOLs basically say, look, psoriasis is something different. Patients love the idea of having an oral agent. And especially if you guys are clearly superior in terms of efficacy compared to, you know, based on cross-trial comparisons and comparing it to Otezla or SOTYKTU. Efficacy and safety is such a given with IL-23, which is not necessarily the claim that could be made with TYK2 inhibitors, right? When you combine all that, this is like, and again, like I said, the scarcity value, this is the only oral IL-23. If you want an oral IL-23 blocker, this is the one. Got it. Remind us the royalty structure and does it tier based on sales thresholds? Yeah, so we do have, when we did the deal in 2017, and you know, there were several bidders. And thank God we chose J&J, even though they did not offer the highest upfront. It was $50 million, not shabby. But the milestones were around $1 billion, roughly speaking, and we have earned about 1/3 of those. And 2/3 are still pending. So this was not like buy a buck still. Things were very reasonable in terms of the milestone structure. And the royalty was 6% to, is 6%-10%. It's tiered. But the beauty is the 10%, it kicks at $5 billion, no, sorry, over $4 billion. And it's tiered basically from 6%-10%. I think at a practical level, if we think about the scope of IL-23 blockers in general, and especially an oral IL-23, it's fair to assume that we'll be tilting towards the higher end of the 6%-10% spectrum. Got it. Okay, excellent. Excellent. Excellent. Maybe switching gears a bit in the sort of latter half of the presentation. I know you have an oral IL-17 as well. I want to come to that in just a second. But since obesity is the topic of the hour for everybody, is this an oral GLP? We haven't shared the exact detail of what the target is, but the way we are looking at the obesity space is like, you know, we have kind of three different types of drugs, right? At Protagonist, rusfertide, the hepcidin-mimetic. That's for the rare disease polycythemia vera. Over there, one would say, okay, the target population in terms of the number of patients is 10,000-100,000 patients. With ICO, it's in immunomodulatory diseases. Over there, you're talking about 1 million-5 million kind of patients. But when it's obesity, it's like you're talking billions, right? So it's pretty clear that this is not going to be a winner, a single winner takes it all kind of thing. That's why we believe that the targets that are already out there as validated targets, whether it's GLP or GLP-GIP or GLP-GIP-GCG, whatever, Amylin, we are focusing on targets that are validated. But as usual, our agenda would be to come up with the best oral drug that one could envision in the space. But just to be clear, the molecule, like one synthetic cyclic peptide, what have you, would engage one protein, or do you want to have two different things combined? How are you thinking about that? Or all of the above. Could one molecule interact with two different peptides? One peptide could definitely interact with two targets or even with three targets. So that's something we would be engineering. In the obesity program, just to be clear, we are envisioning announcing a development candidate by middle of next year, but that is just going to be the beginning, so to speak. Our intent is to create a whole portfolio because let's face it, you know, the science is still progressing. Our understanding and observations are still, you know, being refined. Got it. So we don't, I mean, you know, the Amgen story, for example, right? So the best thing to do right now is like pursue various different approaches and then we'll sort out over a period of time. Got it. Like which is the ideal oral obesity agent? And I think a lot will also depend on what are the comorbidities that one wants to target over there, right? That may influence what kind of combination of activity you want against one or different types of biological targets. Got it. Is it fair to assume for bioavailability reasons and everything we've learned off of your oral IL-23 that cyclic peptide is a path forward now? Cyclic peptides offer definitely an advantage in terms of absorption over linear peptides. And you know, Protagonist historically started with what we refer to as DRPs, DRPs, disulfide-rich peptides, which are of course cyclic in nature, right? That kind of thing. And that has served us well. Got it. Okay, excellent. So development candidate mid-next year, IND filing is 2026? That would be a fair assumption, yeah. Got it. Excellent, and maybe at that point, perhaps let's just switch gears quickly into the oral IL-17, perhaps. Perhaps first bioavailability, do you have a good read on that now, and is the tracking where the oral IL-23 in its more optimized form was tracking? Yeah, the preclinical data is just excellent. You know, we just announced this candidate about two weeks ago, and we also mentioned over there that for the last four months, we were just doing a head-to-head comparison between three finalist peptides because we wanted to choose something that offers us the best readout with respect to all the exhaustive preclinical studies that we did targeting the PK as well as the PD and efficacy models and all those kind of things, so I think this drug has amazing characteristics. The absorption levels are very satisfactory. Potency-wise, even though that may not have been the intent or the target, but our drug has the potency of the best antibody that is out there. I'm referring to BIMZELX basically, so we have engineered activity both against the A as well as the F form of the target, right? Correct. So maybe just remind us quickly. I guess there's multiple things you just touched up on there. I guess the first one, you talked about potency being much higher than the DICE molecule and your potency being more akin to. Seven or several orders of magnitude. See, sorry to interrupt in a way, but I know where you're going with the DICE. Now with our oral peptides, if you think about it, what we are doing is we are saying, hey, we are combining the best of both worlds. What is the best characteristic of an antibody? It's amazing potency, picomolar potency over a small molecule. And what is the best characteristic of a small molecule? The oral component, right? So what we are doing in the oral peptides, it's like, hey, they are oral, but they have the potency of the antibodies. We have done this in IL-23 and we are doing the same thing in IL-17. So IL-23 was your potency similar to TREMFYA? Absolutely. It was picomolar potency, yeah. Got it. Got it. So you should be able to track in the zip code of BIMZELX presumably or close enough, something along those lines. Yeah. Although again, just like IL-23, the approach over here is like, hey, injectable antibodies or nanobodies are not our competitor. We already have a strong differentiation from them by being oral. So our agenda is to come up with the best oral IL-17 blocker that is out there. And you know, with DICE, as you know, now they are focused on the second generation molecule. I don't think potency-wise the two molecules are that different, but the PK characteristics I'm assuming could be quite superior, that sort of thing. But again, there is a scarcity value. Our understanding also was that J&J had a small molecule program and that has also phased out, so to speak. So I think with our oral IL-17, we'll be marching towards a strongly differentiated product. Got it. So okay, so maybe just a quick second then. The DICE molecule, first- gen, they terminated. Second- gen, they're running a trial now. Potency not that different, but do you anticipate their active doses are a little lower than the first gen molecule or are they still going to need close to 1 g in dosing a day? Yeah. Because that was the biggest giveaway on their potency. Yeah. Again, I cannot comment on, you know, what Eli really has in mind and all those kind of things, right? They can best answer that. But in general, what we are finding is like with our peptides, our potency is going to be like a hundredfold or even higher than that better versus small molecules. Did you get a lot of looks for outlicensing on this program? I think we hope the short answer is like, yeah, there are always inquiries, but in this case, we kind of turned those shied away from all that because, you know, now we are in a position to take this asset on our own up to at least a clinical POC, and that will be the right junction, we believe, where we would look at various options. Got it. And maybe just one more follow-up on the DICE molecule determination. Do you think it was efficacy driven or was there some liver safety as well? Is there any buzz on that? Again, I don't have any detailed understanding about it, but you know, when you're going up to 800 mg dose, we know that the PK characteristics are probably not that great, right? Got it. Excellent. On your molecule in specific, I know you're hitting A and the F as well. Could you just remind us of the significance of that and the comparison versus BIMZELX and COSENTYX? Yeah, so I think BIMZELX is the antibody that hits the A, A, AF and FF isomers. And you know, they did a comparative study, I believe it was against COSENTYX, which just hits the A form. And the clinical efficacy was significantly superior by some 20% or more. And that basically gave people the clue that, hey, you should be targeting both A as well as F, right? And now, of course, there is also a nanobody in development, which targets all different, all these three isoforms, dimers, A, A, AF and FF, that sort of thing. So that's the most current understanding, like have activity both against A and F. So by the way, the small molecule, as far as we can tell, the DICE molecule, it did not have any activity against F. So that will be the other differentiation. Again, let's say small molecule orals. We have the absolute level of potency as high as the best antibody that is out there, BIMZELX. And then we also have the spectrum of activity against these three dimers. Got it. And so anytime we talk about the A and the F, we should always be thinking about it on a dimer basis. Would you agree with that? Yes. A, A, AF, and FF. That's how BIMZELX comparisons were shown. Correct. Correct. Okay, excellent. And the timelines now for this program? So, with the candidate nomination about two weeks ago, a year from now, you can expect us to be in the phase I studies. The other thing I would quickly add is, like, because this is such a validated pathway, we are directly going for a three-month IND-enabling tox study so that we can move as rapidly as possible in a 12-week psoriasis study. So we have skipped the customary 28-day tox study, which would have restricted us only to a four-week study. Got it. Excellent. Excellent. And so presumably phase II efficacy type data, that's a 2026 timeframe event? At least the study will get going by that time. In 2026? Yeah. The phase II study, yeah. Okay, got it. Excellent. Maybe just the last one on this. I know we are at time as well. You mentioned nanobody. I'm assuming you're referring to the MoonLake approach? Correct. There was, I remember Merck KGaA had a program that they outlicensed. I guess what happened on the nanobody against IL-17A/F there? Like is there some history there? Again, I'm not privy to all the details, but as far as we can tell with the nanobody approach, what you have is an entity that is about, let's say size-wise, 5x smaller than an antibody. And I think they have been able to capture the same spectrum of potency against the three dimers, A, A, AF, and FF. But dosing would be more frequent? Time will tell. I don't recall the details of the clinical study, things like that. Okay. Excellent. Excellent. Is there anything else we should have touched upon on the pipeline just before we wrap? I know we talked about obesity, oral IL-17, and anything else? Oh, obviously the Takeda program. What's the timeline again? We should mention that. Yeah. At At last but not least, right? Yeah. No, I think it has been a great partnership. The phase III readout is in the first quarter of next year. So that's probably the next thing. Your royalty again on that? So we have an opt-in, opt-out structure. And so if we opt out and give them the U.S. rights as well, rather than doing a co-development, 50/50 co-commercialization in the U.S., under the opt-out structure, then we get 3x higher milestones and the royalty numbers are 14%-29%. Oh wow. Okay. Got it. Worldwide. Excellent. My last question, and this is just before we wrap up. We were looking at another cyclic peptide approach with PCSK9, which Merck has a phase III on next year. But they have a food interaction and they have a lot of DDIs as well. Has that been an observation? And AstraZeneca has an oral PCSK9, which doesn't have that. But that could, the Merck issue could partially be because the PK was not great. So they have a PK enhancer in there. Do you think the cyclic peptide structure has anything to do with food interaction? Is it more to do with the PK enhancer? So it's interesting. And you need that, I guess is really where I'm going with this. Yeah. So over the weekend, I ran into my nephew, he's a cardiologist. And the first thing he asked me is like, so are you working on PCSK9 with all this wonderful technology? And I'm like, no, you know, Merck is kind of taking on the lead over there. So we will let them have fun with it. But the food effect, it will be interesting to see how things unfold. For example, our J&J drug, ICO, also has a food effect, right? So it's a once daily drug. You take it with an empty stomach and after 30 minutes, then you can eat and drink whatever you want to do. So I think even if the food. Do you have the PK enhancer in there? No. With the J&J drug, it's a plain vanilla formulation. There are no enhancers. Okay. Got it. But still, I mean, in general, the absorption will be more with an empty stomach, right? With the food, the absorption will be delayed a little bit. Got it. That sort of thing. So presumably AstraZeneca oral PCSK9 should have similar absorption issues, would it not? Yeah. They claim it doesn't need to. My understanding is like even the oral obesity peptides, right, that are being studied orally. Correct. The SNAC carrier base. Yeah. The semaglutide oral, I believe, also has a food effect. Correct. Yep. So whether this is a common characteristic of all these peptides or is it really going to be different down the road, we don't know. Excellent. But the food effect, again, if it is there, it's very manageable, like I said, right? Especially if you can create a once daily, which is what our agenda is with the oral IL-17 as well, right? Then it's like take it with an empty stomach and then it should be fine. Excellent. Well, listen, thank you again for joining. Congrats again on recent phase three data. Looking forward to a lot of IL-17 updates in short order. Yeah. No, absolutely. Thank you. Thank you guys. Yeah.