Hello again, everyone. I'm Etzer Giroud, Senior Biotech Analyst at Barclays. It's my pleasure to welcome Protagonist Therapeutics to our fireside. With me today, I have Dinesh Patel, the Chief Executive Officer and President at Protagonist. Dinesh, maybe just to start off, for those maybe less familiar with the story, if you could just provide an overview of Protagonist, and then we'll move into Q&A.

Sounds like a plan. First and foremost, thanks for inviting us. And I have to mention that this does take me down memory lane. You know, protagonists, we did our IPO back in 2016, and Barclays was one of the bank that helped us achieve that component of going public. So thanks for that as well to Barclays. So yeah, right from the get-go, we have focused on creating innovation through novel peptides. So that's our bread and butter, and we have expertise both for injectable peptides, but also for oral peptides, and we have been able to put it to good use over a period of time. Maybe over a period of time is a bit of an understatement, because we have been doing this since 2008 when nobody cared about peptides. It was an unknown entity. Of course, now over the past few years, the landscape has changed, and we are glad that it has changed. But, you know, fast-forwarding from 2008 to now, what has then happened is, like, we have two wonderful assets which showed outstanding Phase III data last year, and on the heels of that, we are assuming, hoping that they get approved this year. So the first drug I'm talking about is Icotrochindra or Icotide. This is an oral I-23 blocker, and this is the first and only. So there is amazing scarcity value as well. And this is a journey that we started with J&J all the way back in 2017 when it was just a preclinical program. So we have come a long way, And now the first indication for which approval will be seeked is for psoriasis. And then the drug is also in phase three studies in all the other three indications where out of 23 blockers have had 100% success, right? Namely psoriatic arthritis, UC, and Crohn's. The other asset then is rasputide. This is a weakly injectable mimetic of the natural hormone hepcidin that is in charge of iron homeostasis and and we felt that hey polycythema vera that's a disease it's characterized by excessive red blood cell production right excessive erythrocytosis so it made sense to come up with an erythrocytosis specific agent and again that there is no such thing that is out there right now so we are the first and only over there as well and that is something uh unlike the j and j deal which was partnered at a pre-clinical stage here we partnered with Takeda in January of 2024, when we were already in a phase three setting on our own. It's a rare disease indication, right? So it is something we could take forward further. Takeda is an amazing partner. They have a focus in the heme space, and we are so glad we have joined hands with them as well. And about a week ago or so, we announced that we received priority review. So that is going to hopefully accelerate the approval by a few months. And with ICO, the NDA was filed in July of last year. So it would be an amazing coincidence if both drugs get approved, let's say, sometime in the third quarter of this year. So we are looking forward to that. So that's the outcome of, you know, 16, 18 years, whatever you want to call it, or at least 12 plus years of efforts in these programs. And now what we have, since we believe we are validated, we have proven ourselves multiple times, we are going for the second act like a repeat performance right and the the next wave of assets is again continuing in the eye and eye space with an oral io17 program the drug is in a phase one study in healthy volunteers we also have preclinical studies going on in the io4 program and it's like hey if you can create an oral you know Ico is like whatever you want to call it is it's it's an oral equivalent to a sky easy or Trump fire you know pick one so similarly could there be an oral bimzelex right that's the idea with the 17 and then over the last few years as we all know the entire obesity space gets a lot of attention and chemically speaking the two approved drugs are injectable peptides. So that was like an invitation for us. It's like, okay, can we create some solid differentiation through oral peptides? And the first thing that we have is an oral GGG. It's the one of its kind. And over there, we will get into clinical studies in the second half of the year, that sort of thing. And we also have an oral GLPGIP, a dual. We have acknowledged our presence in the amelian agonist program as well so we want to create a whole portfolio of different assets and then at last but not least in the heme space the second act is the oral hepcidin so that's that's basically the story in a nutshell great as you think about

you know the preclinical evaluation of all of these assets prior to moving them into the clinic how are you measuring sort of success and then the ability for those assets to translate to the clinic you're looking at exposure particularly it's peptides and so yeah it's that presents a challenge in of itself so how are you measuring what success looks like prior to going into it's a fantastic question and it's fair

to admit that we almost torture ourselves with exhaustive preclinical evaluation and to your point it's like hey is it gonna work as an order because let's face it with peptides you're going to be limited with the oral bioavailability component now we make up for that with just outstanding picomolar like potency which also gives us amazing specificity right and now advances are being made in terms of enhancing oral bioavailability but one thing that we do is we go through a lot of preclinical models where our drug will be administered orally and then we would like to see that preclinical proof of concept being achieved in animal studies when our drug is administered orally so that's kind of a generic way of describing it and it's fair to say that we take at least three to four months longer than what the typical preclinical assessment would look like because we want to make sure that we

pick the right candidate yeah great and maybe on a cotra canra and psoriasis We've seen at least one successful superiority study. We also have iconic ASCEND comparator, the Skitunumab. How do you plan to leverage those, again, studies as you think about initial launch in psoriasis, you think about the types of physicians that you're going to want to target? How do you ultimately want to leverage those data sets?

I mean, these are extremely important questions, but but I have to be very upfront about it J&J is the best entity to do to be answering these questions they are the ones doing the heavy lifting but as you can imagine they have done some amazing things right they like you pointed out went for a head-to-head superiority study with the only approach to inhibitor Ducra and our data is fantastic the primary endpoints were achieved and you know whether that makes it to the label or not that that's between J&J and the regulatory agency they also went ahead and kind of did a subpopulation analysis and presented amazing data in the adolescent population and as you know now by the end of the month they are completing this head-to-head study with their own injectable Stellara uh to me what all that is telling me is like obviously they are big believers of I could kinder or I could type now uh and uh they uh could be gearing this towards like you know first line therapies something like that right right um maybe a question on

on resveratide, but not necessarily on the injectable program, but again, when you think about the potential for an oral hypside and functional mimetic, how should we think about the positioning relative to resveratide in terms of, you know, cannibalization is always something that people are going to talk about. Could they be complementary? How do you think about an oral agent versus sort of the injectable agent?

Rasputide is like a kid that is completing college and is pretty soon going to have a job and have his own income, whereas the oral is like still maybe in junior high or something like that, right? That kind of thing. But jokes apart, it's like there is enough time delta between the two drugs, and Rasputide is an outstanding drug. It's the first drug of its own kind uh erythrocytosis specific mechanism takeda is a fantastic partner so uh we don't see any uh overlap or you know uh that kind of uh yeah overlap or one thing taking away the market from the other right yeah if it doesn't anything it's a continuity of dominance first with Rasputide, and then hopefully with the

oral herbicide. Great. That makes sense. We've had questions around the competitive landscape, or evolving competitive landscape for, you know, with Fertide, people have talked about some upcoming data sets from, like, silence therapeutics. Maybe your thoughts around the competitive landscape, just broadly, and PV, and then you're thinking around, like, what that ultimately, that space evolves to. Yeah, I

And I mean, in a way, we are flattered that people, other companies are also embracing the core mechanism of Habsidin, right, as a way to offer treatment in polycythema vera. And whether it is silence or whether it is, you know, disc medicine, and these are great companies, and we wish them all the best of luck. What I would say, though, is like let's pick the Trump-6 mechanism and other mechanisms of that type. Those are mechanisms whereby you are trying to really enhance the production of endogenous episodic. And that could have its pluses, minuses, limitations, things to watch out for, that kind of thing. whereas our approach is very clear we have we used have sagging as a starting point rather than as a drug because I I'm a medicinal chemist by training so for me upside is a great starting point and then it's like okay what do we fix let's create a mimetic that is a more potent more stable has drug like properties and that is what we achieved with rest for tight and it is titration to affect things like that, right? So one of the things to watch out for, quote-unquote, longer-acting drugs would be, like, keep in mind that the biggest side effect that one should be concerned about over here is exaggerated pharmacology, right? Because now you are making the patient anemic, and that is not desirable. So I think with a weekly injectable that we have, we are in a very balanced position if you will and we titrate from low to high and then find the balancing act of which is the right dose, that kind of thing and measuring whether your drug is continuing to have the effect or not is a very simple blood test, you measure the hemocritical levels so I think we are happy with that we are and the other component is of course we are

years ahead of

everyone else so we are going to have for a number of years

right uh uh the space to ourselves great um maybe switch gears to pna1 or l17 um you have um healthy volunteer um study that you know we'll get an update on on this year how are we thinking about what success looks like for for that study and and how that study hope ultimately helps inform What a phase 2 program would look like for for an oral 17. Yeah, no oral is 17 881

That's like our second act if you will right as my kids have been telling me all my life Anybody can get lucky once can you do it again? Whether it's creating another successful company or another asset or that we will await it one The preclinical data has been outstanding like we were talking about or we went through like a very exhaustive evaluation. And you are asking a great question, what would success look like? Because we are doing just a phase one study in healthy volunteers. Very comprehensive study, though. And the idea would be like, we want to get definitive ideas about the dosing regimen. What is the ideal dosing regimen, right? So if we believe the drug is working, then that would enable us to go for a full-fledged phase two study in psoriasis patients. Now, what we are looking for, the antibodies, I mean injectable antibodies have taught us a lot, right? It's like what should be the level of target inhibition that you should be achieving that would translate into efficacy. So what we have done is like based on that and we have achieved amazing BIMI-like potency, right? Picomolar kind of potency against the target and another characteristic we have, which is BIMI-like is we have activity against both A and F isoforms. We don't know if anybody with an oral approach that has that right. So we have made it as foolproof as possible. But getting back to your question, this has given us an understanding of what are the drug levels we need to achieve through oral administration that would give us the confidence at a translation level that, okay, this should lead to efficacy in patients. And so that is what we are striving for in a phase one study. Now, the other thing to keep in mind is like our peptide, it's almost like hundred times smaller in size compared to the big antibodies and so in theory one could assume we may have better tissue penetration skin penetration that sort of thing and that could give us an extra advantage in terms of overall you know efficacy scores down the road having said that we are not counting that in our quote unquote mathematical model of like what the drug levels we need to achieve based on what the antibodies have taught us and in order to

feel pretty assured of efficacy right and you know one of the questions that we get around the oral 17 program is how how much of this um does protagonists want to execute on their own versus ultimately finding a partner for a large indication how are you thinking about business development around oral 17 is this an asset that you can take to the finish line yourself or do you ultimately view sort of maybe the same roadmap as we've

seen with another fantastic question and I'll give a slightly detailed answer so as you know with the money we have in the bank and then we have also kind of admitted that we will be most likely opting out let's say that out of the Takeda thing which is gonna bring an influx of another 400 million dollars than the 75 million upon approval as a milestone payment and another 50 million from J&J if I go gets approved right so and then the revenue streams we are not even and revenues are perennial so there is a lot of money will the company protagonist have the financial capability to fund its own studies, not just up to clinical POC, but even in phase three studies, even for larger indications, the answer is yes. Are we going to do that? The answer is no. Here is the reason why. It's not only about money, right? It's look at the amazing strength that a farmer brings to the table, right? It's like I go by the end of the day, counting all the four indications, it's being evaluated in 7,000 plus patients. What an amazing job, right? Think big. Pharma can do that. As long as we get our cut, a fair cut, we will be okay. So our approach would be, you know, in simple terms, it is like, we will take all of our assets to clinical POC. But after that, I'm a big believer of pharma partnerships because of the things I mentioned about now we may have a higher participation with J&J when we did the deal it was at a preclinical stage the arrangement was we discover we do the preclinical and I and D enabling and phase one studies and after that phase two and beyond they take care of it now we may say you know what no phase two let's do a 50 50 cost sharing phase three let's do a 30 70 cost sharing so we could get more creative so that we can retain more back-end economics but at the end of the day for big indications yes we would love to have a pharma partner for the niche indications the rare disease indications like our oral hypsidine that is where we definitely can have a mindset of like let's do it alone all the way through the finish line so it's those kind of things but the beauty is we envision we'll be doing all these things without, you know, never say never, but most likely never having to raise money from outside, right? So we are not going to dilute away the shareholders for the foreseeable future.

Great. And maybe with that, we could spend the next few minutes on obesity. It's obviously dominated now by the injectable peptides. You've had an opportunity to see all the commercial dynamics uh what's happening in the clinic with with with different agents i guess how are you thinking about how the set of molecules that you're developing where they can ultimately fit

in the in the treatment paradigm for obesity yeah so look i i think in obesity it checks all the boxes for us right the two approved drugs are injectable peptides so we are like yeah uh we can make a difference over here at a very simplistic level we look for two things when we choose a project it should be an area where there is significant unmet need and second is through our approach we should be able to offer some very strong differentiation so over here clearly the area is getting very crowded but I believe that this is an opportunity of a lifetime of unprecedented level for our industry it could be what AI is for high-tech the whole obesity and comorbidities could be for you know pharma sector and and we may just be scrapping the surface this may just be the humble beginnings and as usual you know so many undertakings are there that kind of stuff but even then we said you know what and and we consulted a lot lot with the KOLs and what came at the top of the chart was like hey can you create an oral triple and the answer was yeah we can do that so that is what we have chosen right an oral triple GLPG IPG CG but in talking to the KOLs we also gained an understanding of what could be the relative potencies of GLPG gip gcg that could be considered optimal and could that translate into not just better quantity of weight loss but also better quality of weight loss so i'm referring to better tolerability which could be achieved through better gip agonism and you know better lean mass lead muscle mass preservation that could be achieved through the gcg component of energy expenditure that kind of thing so we have tried to optimize those components also as much as possible and we believe we are the only or one of the very few oral triples that is out there and and in talking to the KOLs it also occurred that hey some of the market with some patients for some periods of times may belong to injectables so we are developing both a weekly sub-q and a daily oral and the pica characteristics are fantastic we see drug accumulation so we do believe that down the road maybe the weekly sub queue could transition to monthly sub queue in a maintenance setting and same way uh the daily oral pill could be a weekly oral pill or something like that so so we like what we are seeing but the other thing is like you know we are not falling in love with just one asset we want to create a portfolio of assets over here so we have already announced we have a dual right and we have already acknowledged our presence with amylin mono and poly agonist that kind of thing will create a portfolio of assets and I think down the road it will become more clear which could be preferred in which kind of subpopulations and also within when you consider the comorbidities right so if it is let's say Nash mash kind of liver centric indications maybe the GCG component does become important over there that that's where the field is leaning to So I think we are still learning, and we just are taking a very humble approach over here. It's like, let's create a portfolio with different kind of characteristics, and then let's see where we will land at the end of the day.

Yeah, no, great. And you've talked about, you know, potentially achieving maybe early clinical proof of concept with single ascending, multiple ascending dose studies. I guess, you know, this is sort of design, right? but is this really based on just what the analog that you've seen in clinical development and being able to assess exposure and an initial, you know, whether it be 28-day weight loss and then assuming that maybe that would be durable? Or whether it is a 13-week weight loss, that kind of thing.

No, exactly. It's like we are observing, we are learning from others. Why not, right? Knowledge is free. So, but that would be the idea. Yeah. And by the way, that is another general advantage with our approach. Like in a phase one setting, you can get your clinical POC. That is very true in the obesity space. You enroll healthy volunteers with a higher BMI and you will get your readout even with the oral hepcidin. For example, you know, we'll observe the effect on serum ion levels and the related biomarkers and we will get a good understanding of where we are going. So I think then if you add up everything that's in our R&D pipeline, the clinical POC is just going to sneak up on us. It can come sooner than what most people may be anticipating.

Looks like we're up on our time. Dinesh, thank you so much for a great discussion. Thank you for our listeners as well for listening in.

Yeah, no, thank you for the wonderful dialogue. Great questions.