All right. Good day, everyone. Welcome to day two of Cantor's Global Healthcare Conference. For the next session, we have the pleasure of hosting Protagonist Therapeutics. From Protagonist, we have Dinesh Patel, President and CEO. Dinesh, thank you so much for coming to our conference. It's a real pleasure. Thanks for inviting us. Great. There's a lot going on in Protagonist right now, but maybe just to level set expectations, start off with a brief overview of the current state of the business, some of the key priorities for the next one to two years, as well as you did announce a recent share buyback as well. Maybe talk about that as well. Yeah. As you know, we have been around for a while, but all along, right from the early beginnings in 2008, we have been focused on peptide therapeutics. There has been a long and deep level of dedication and commitment, which has allowed us to build a very unique expertise. Now if you fast forward it to this year, then it has culminated in the approval of two drugs. One is ICOTYDE, the oral IL-23, the first of its kind, partnered with J&J. The drug is doing amazingly well. It was launched a day after St. Patrick's Day, I guess, sometime in March. More recently, over the past few days, our second drug, MIMRYLO, the hepcidin mimetic for polycythemia vera, got approved, that is partnered with Takeda. We seriously could not have asked for a better, cleaner outcome. The label is very broad and clean. We believe the drug is really poised to do incredibly well. Again, it's a first of its kind as well. Until then, there has been no erythrocytosis specific agent for polycythemia vera, and that is the hallmark of the disease. With the confidence that we gained from these two drugs, as of the end of second quarter of this year, we had around $850 million cash. The MIMRYLO approval, the combination of a milestone and the opt-out fee, it amounts to $275 million. That takes us over $1 billion in cash, that sort of thing. It is that kind of cash position as well as the promise that we see in the two drugs, the ability to generate future revenues, that prompted us to announce the share buyback that we announced, I believe that was yesterday or the day before. Time flies, I guess. $300 million, that sort of thing. The whole idea is like, look, we have proven ourselves, we have validated ourselves with two peptidic drugs. We are all set for a repeat performance with multiple programs in our R&D pipeline. R&D is our number one, number two, number three priority. That is where money is going to go first. But we believe that we are in one of these fortunate situations where we don't see a need to go out and do an equity raise in the foreseeable future. We can fund our own R&D. In spite of funding our own R&D, we still will be left with adequate amount of cash to do share buyback. I think from two very different directions, the whole idea is to go for repeat performance, come up with new drugs that will benefit patients, and also create tremendous shareholder value. That's great. rusfertide approval, we talked about the label being better than expected and pretty broad. I know Takeda will commercialize this drug, but where do you see this asset being used by physicians? Takeda had a $1 billion-$2 billion peak sales forecast. Seems to be before the phase III data and before you saw the label as well. Maybe just talk about that as well. Yeah. I think the way the deal is structured, Takeda is in 100% charge of the commercialization, and they will be the main spokespeople about the commercial forecast and those sort of things. As you pointed out, the $1 billion-$2 billion estimate they made, A, pharma companies, they are meant to be conservative. B, it was before the outstanding phase III data that was splashed as an American Society of Clinical Oncology plenary session in 2024. And C, before we got this amazingly broad and clean label. We will just have to see how they want to manage all that. Having said that, though, this is a first of its kind drug. Until now, there has not been an erythrocytosis specific drug that is out there. So there is going to be effort geared towards creating the awareness, making people aware of this kind of a new treatment that is available right now. I would not be surprised if in the first few quarters, the takeoff could be slower than anticipated. But in terms of what happens after that initial phase, I would say you could expect a hockey stick-like phenomena because the label is just amazing. There is no black box warning, in spite of all the drama during the clinical studies and all that kind of thing. There is no issue around carcinogenicity. The phase III study, if at all anything, had more cancer events in the placebo arm compared to the treatment arm. So that is about as clean as things can get. And then, of course, it is a drug for all comers. There are no restrictions or pre-requirements like, hey, you need a derm exam or some sort of screening, or you have to be on certain number of phlebotomies or some sort of treatment with a cytoreductive as a prior requirement. So it is all very broad utility, we would believe. The requirement being erythrocytosis, which by the way, when you look at the real-world data, it is like 78% of the patients are not controlling their hematocrit. So I would say this is a clean drug, very mechanism, erythrocytosis-specific drug. And at last but not least, this is the first drug ever that has the symptom improvement in the label, right? The fatigue improvement, which is one of the big condition that affects the quality of life of these patients. So we have got on that claim as well. Got it. That's why I say we couldn't have asked for a better outcome, and the drug deserves it. No, that's great. Congratulations on that. You're not stopping on rusfertide and PV. You do have an oral hepcidin as well in the pipeline. I guess, talk about the rationales for developing an oral formulation for PV as well. Yeah. I think all along what we are finding is that for indications that require long-term treatment, whether it is in obesity or in the inflammation and immunology space, or whether it is in a rare disease like polycythemia vera, the average kind of duration for a PV patient to stay with the disease is around 15 years or something like that. Whenever there is that extended utility, there is a high demand and preference for an oral pill, right? Taking an oral pill also psychologically, it doesn't remind you of having an illness or something on a regular basis. It just becomes part and parcel of the norms of daily life, so to speak. We, Protagonist, have the ability to come up with oral drugs for this kind of chronic indications. I think MIMRYLO is going to have wonderful solo presence for a number of years, at least five years, five to seven years, that kind of thing, and it's only fair that the next option would be something like an oral pill. Okay, great. Maybe we can move on to ICOTYDE. The launch has been very impressive. I guess, what has been some of the surprising aspects for you as you see the drug launching, as well as J&J really talking positively about the asset and being one of the biggest asset for them in the 99 right now? Yeah, I think with ICOTYDE, we don't want to get too carried away, but it's probably fair to say that success was expected. If you look at the phase II data, if you look at the phase III data, if you look at the scale at which J&J is developing this drug in other indications also, right? Psoriatic arthritis, UC, Crohn's, and fortunately all IL-23 blockers, they have had 100% hit rate for all four indications. It's a unique drug of its kind. There is nothing in the rearview mirror for the foreseeable future. It's the only oral IL-23 blocker, and the data is just amazing. So we are just glad to be assured that it is exceeding what were already our high expectations. Okay. I know before the launch, there was a lot of debate around food restrictions, whether that will be an issue in the real world, how will compliance be managed, and how the real-world efficacy may look similar or different than what's been shown in the clinical trials. What's the feedback been? Yeah. I think in the spirit of differentiation, we kind of pull out all little things. But I think at the end of the day, things are put into context when the drug find its utility in real life. Looking at the receptivity of the ICOTYDE once-daily oral pill, the appeal of like, "Hey, you have the safety and efficacy of an injectable, but the convenience of a daily oral pill," that appeal is so strong. By the way, what is the food requirement, right? At a practical level, it's basically take the pill with some water or coffee, and don't eat solid food for 30 minutes. I can't even remember when was the last time I had to put solid food in my mouth in the first 30 minutes after I woke up. So what food requirement, I would say, right? I guess there will be more competition down the line with new orals launching as well. Takeda has a XELJANZ TYK2. How do you see that? I guess, what differentiation do you think ICOTYDE will have, just from a profile perspective- Yeah compared to a XELJANZ TYK2? On the commercial front, we get it, like J&J is No, I think it's a great question, and these are the things we think about all the time. The biggest thing I would emphasize is IL-23 pathway blockade has turned out to be one of the most effective, efficacious, and safe. Safety is of paramount importance when it comes to chronic indications. One just cannot make that claim for kinase inhibitors, which is what TYK2s are for example. That is one. Look at the track record that has been established all the way starting from STELARA more than a decade ago, right? Now TREMFYA and SKYRIZI. So the history is so rich with the established efficacy and safety of IL-23 blocker. Whereas the TYK2s are the new kids on the block. By the way, once again, scarcity value. This is the only oral IL-23 pathway blocker. In TYK2s, we already know there are three to four companies that are out there, that kind of thing. Sure, the mechanism works, but it just wouldn't have the oomph and the whole combination of efficacy and safety and the prior track record that the IL-23 blockers have. Got it. And maybe even looking longer term, there are companies that are starting to develop once-weekly IL-23s now, even in China. I am sure you would have thought about developing that as well. I guess what are the pros and cons? Is it more on the technical side that is a challenge, or the commercial stuff did not make sense? What are your thoughts on that, once-weekly? See, I am a chemist by training, so I am just going to say on the technical side, it is very easy to engineer the once-weekly profile. I don't want to downplay it, that kind of thing. I think the industry just doesn't know yet what is the appeal of an oral pill when it is once a day versus once a week. Informally, when we talk about it, some people could be like, "Well, once daily is easy to remember," that kind of thing. Time will tell. As far as once-weekly IL-23, that kind of thing, you should be rest assured that J&J and Protagonist has thought about everything and anything that one could think of doing, and then, of course, we would both want to preserve our dominance with an oral pill ICOTYDE in that particular category. Now, in the obesity field also, as you know, the once-weekly thing is coming into prominence with an oral. Practically, is it going to differentiate itself versus a once daily oral pill or not? Time will tell. Like I said, chemically speaking, all you have to do is engineer some features in your chemical entity to have drug accumulation, and that will give you a once-weekly. Nothing in the platform stops you right now for developing a once-weekly drug, whether it is for an IL-23 or we will talk about obesity as well, like Triple G. No, not at all. I think with one of our assets, we have already conveyed that, yeah, we can see signs of once daily oral turning into once-weekly oral based on what we have seen pre-clinically. I am referring to our oral Triple G, and that the once-weekly sub-Q could, because of drug accumulation, could transition towards once monthly. Okay, got it. One of the key readouts for oral IL-23 will be in the IBD indications. This is a receptor, right? Obviously SKYRIZI ligand targeting, I think we talked about it previously as well. The benefits of targeting the IL-23 receptor, and how is that translated into the data that you have shown? Yeah, see, we are science geeks, right? All the way back in 2013, it came to our attention that the IL-23 receptor is overexpressed in the GI tissue compartment of IBD patients. At that time, IBD was the only focus for developing an oral IL-23. So we opted for the receptor. That decision was made in 2013, and we believe it has played out very well. If you look at our phase II UC data with ICOTYDE, 30% clinical remission is about as good as it gets, and that is what we achieved in phase II. Right? Then look at J&J's decision. Not only do they go directly into a phase III UC study, but they hop directly into a phase IIb/III study in Crohn's. So the confidence is there, and there is every reason to be so confident. Even pre-clinically, by the way, we did see the advantage of blocking the receptor, and I will give you an example, especially for IBD. For the colitis study, which is like a preview of what could happen in IBD, the minimal drug that we needed for efficacy in the preclinical colitis study, that was an order of magnitude lower compared to the minimal dose that we needed for efficacy in the skin inflammation model. Things are lining up, and 30% clinical remission in the phase II UC is confirming that. But yeah, if you want to take a positive view and a logical view, this could be a great drug in IBD, and maybe the best is yet to come for ICOTYDE. Right. ICOTYDE is matching almost to the level of biologic efficacy, maybe like SKYRIZI and BIMZELX, but maybe there is still few percentage gap. In IBD, do you think you can match SKYRIZI-like efficacy given the advantages of targeting receptor? Or maybe it could be even better in IBD. Time will tell. This is just my confidence and optimism, so you have to take it with a grain of salt. But if you look at the update of ICOTYDE, right? If at all there is a haircut in efficacy, it is not coming in the way. The reality is when we talk to the KOLs, they are like at a practical level, all it means is they are going to tell a patient saying, "Okay, here is an oral pill. It does the same thing as the injectable, but now there are no injections. You have to take it once daily." Their skin clearance, instead of seeing 100% clearance at week 20, it may be at week 22. That doesn't come in the way of the patient opting for the oral. Right? Got it. When do you expect the readouts to come for UC and Crohn's? That is up to the almighty J&J, right? Not up to Protagonist. Okay. We are in very trusted hands, and they have been an amazing partner, and we will let them run the show. Okay. Maybe finishing up on the I&I portfolio, you are going after IL-17, TNF, BIMZELX as well. You could have chosen pretty much any target in I&I. Why pick this target? Yeah. If you look at the, in a way, the antibodies are giving us a roadmap of what to do, right? It is like, okay, first there was STELARA, then there is SKYRIZI and TREMFYA. Now there is COSENTYX and BIMZELX, and there are some areas of overlap, and there is a lot of non-complementarity also, in a good way, that kind of thing. Then there is DUPI, that kind of thing. So we are just taking a clue from that. In a way, feel free to beat me down if I am getting too carried away, but our big vision is to really revolutionize the whole landscape of all chronic indications. It is like antibodies are great when you do not have any other option. But for chronic indications where you have to take the drug for almost the rest of your life, why shouldn't there be an oral option? Now we have a technology platform. We have Pro1 expertise that we can deliver an oral peptide for this chronic indication. So that is what we are going after, right? ICOTYDE is the first example. Our oral IL-17 PN-881, as you saw, we loved the phase I data. We are going with full confidence in a full-fledged comprehensive phase II-B study over there. So that is our oral IL-17 play. We have also announced our presence in working towards an oral IL-4 blocker, that sort of thing. So that is the initial runway in the I&I space. Right. What is the status of oral IL-4, like Dupixent? Too early right now. Too- But yeah, we should be announcing a development candidate next year sometime. Okay. Right. Is that basically oral Dupixent? I love how you phrase it. But of course, Dupixent is an antibody, ours is going to be a small peptide. Right. Okay. Maybe just finishing up on BIMZELX. You did present some data recently. I guess surprisingly, it actually looked a little bit better on potency across all IL-17 isoforms. BIMZELX does have some safety liabilities with Candida as well as skin reactions. I guess, does the oral formulation, and given the potency that you have, I guess take care of some of the safety liabilities for the injectable as well? Does oral formulation give you that flexibility? Yeah. That's a fantastic point, and the honest answer is we just don't know, right? Whatever little drama that may be there with an injectable, could it be because when you inject the antibody on day one, you have that huge amount of the antibody, right? Very high concentrations, and then it tapers off over a period of weeks. With the oral, I'm not going to say it's homeopathic, but it's like you have the right amount of dose, you get your Cmax for the first one or two hours, and then it tapers off, and then after 24 hours you take the drug again. It's a more measured approach that way, and there could be pluses, minuses to both kind of scenarios. But in terms of if there are overreactions or that kind of thing, then we believe that at any given time, our drug will have a measured level of blood levels, that sort of thing, compared to an antibody. And whether that works in our favor or against us, time will tell. Okay. That's why we are rolling the dice on a comprehensive phase II-B study. Sure. Talking to the KOLs, Candida infections, they are not concerned about that. It is something that is so easy to manage, that sort of thing. Right. So you are starting a psoriasis trial. Do you plan to start trials in HS or other indications as well? Yeah, absolutely. What we are planning to do is we chose psoriasis because it is the cleanest indication, response rates are higher. Looking at the blinded data, you will get a sense of whether your drug is working or not. Once we get a confirmation about the drug is working, that is when we will start moving in the direction of HS as well. Okay. Got it. When I go back to the history of the company, when you partnered with J&J on the oral IL-23 front, very different stage compared to where you are right now. You have a lot of cash, maybe too much cash. I guess when does it make sense to bring on a partner for oral BIMZELX? Yeah, it's a fantastic question. We are very pharma-friendly. We see tremendous advantages of partnering and have each party do what they do best, right? Pharma will be great at late-stage clinical development, commercialization, those kind of things. We are innovators, so we are good at that. But now the company is maturing, the company is morphing, so we have every right and desire to hang on to our assets for longer time periods. As you mentioned, we have enough cash to do that. In a way, our whole approach is very de-risked. The biology is already proven one way or the other, right? By injectables, whether it is in the obesity space or even in the polycythemia vera rare disease space, or of course in the I&I space. There is a lot of de-risking that way also. The idea would be like, I mean, at one end, we'll have the full flexibility of running our shows solo. But at the same time, like I said, at the core level, we believe that it's good to join hands and let two partners work toward their strengths. Especially in the obesity space- we have no desire to do phase III studies over there on our own. Right? But it's a portfolio play, and I think it will be very attractive for numerous pharma companies down the road. Got it. Maybe that's a good segue to your obesity or metabolic portfolio. You have an oral retatrutide. I guess maybe just on the science aspect, how does the potency compare versus retatrutide's potency on the GLP-1, glucagon, and GIP receptors? Yeah. Well, first of all, I mean, I want to acknowledge that, look, the retatrutide data looks amazingly impressive. One could rightfully claim that that is the most potent weight loss drug, and we love it. In terms of the potency thing, I mean, pre-clinically, we were able to show both in cyno and in dogs that on an equal weight basis, our drug is probably more potent. What we have done, the difference is, so retatrutide is a triple, right? GLP, GIP, GCG. In our drug, we have taken the GLP, GIP potency and relative potency of tirzepatide- which is not the case with retatrutide. Now, how much difference that will make down the road, time will tell. But we can certainly claim to be as potent or more potent than reta in a preclinical setting, right? Right. So Is it because you hope to get a safety advantage there? Because I mean, the Triple G- In talking to the KOLs, I mean, GIP is one of those magical targets and where it is like, "Hey, if you have more GIP potency, that could be a good thing." That is what gravitates us towards the tirzepatide, like GLP, GIP relative potency. Right. But you're not offsetting your glucagon potency. No. Okay. With the GCG component, I mean, that could be a different angle in the MASH category. Okay. Reduction of liver fat is a very important component of weight loss as well. But as you know, we are not taking chances on anything. I mean, so we are also developing an oral dual GLP, GIP without the GCG component. Just in case it becomes a liability. Right. amylin is a new flavor, and we are working on amylin polyagonists as well, right? But the whole focus is oral, oral. Okay. And maybe with these peptides, generally in large markets like obesity, scalability is an important aspect, the doses. Novo Nordisk has different peptides that they can obviously launch, but the constraint here is more manufacturing and scalability. So how does the oral Triple G dose fit in? Can you get it below, let's say, a reasonable level unlike companies like, for example Absolutely. Those are the things that you take into consideration right from the get-go. I tell people like, "Look, the scalability or cost of goods components are very different for polycythemia vera," meaning our MIMRYLO drug, right? Because it's a rare disease indication, where the prevalence rate in the U.S. is about 165,000 patients or something like that, which is very different from the I&I space, where the landscape is a few million patients. Versus obesity, where there would be a few hundred million patients, that sort of thing. So yeah, the cost of goods, the scalability, all that, you factor those things early on. And in a way, the key is if you look at the potency of the Triple G, at the end of the day, you're going to need very little amount of drug- Okay right? It's a balancing act. Could this be once-weekly as well? Yeah, certainly. I mean, that is what we have conveyed that the once daily through the drug accumulation could morph into once weekly, and the once weekly sub-Q through drug accumulation could morph into once monthly. Yeah. Okay. I know we're out of time, so want to be respectful of your time as well. Thank you so much, Dinesh. Great overview. Congratulations on all the success so far. Thanks so much. This is such a pleasure, and thanks for the kind invitation. Thank you. This is wonderful.