Out, from the phase III program, in the coming weeks, I think in the fourth quarter, but it seems like it probably will be in the earlier part of fourth quarter. But I'm not gonna. You know, we don't need to get into those details. But, you know, how should we think about the entire phase III program that J&J has put together? Because it is clearly one, not just about getting this product approved, but sort of maximizing the commercial potential, and I think it might be helpful for you to sort of just walk through, you know, how the different pieces fit together.
Yeah, it's a real pleasure to be here. In the context of 2113, the short answer is, like, it's a one-product portfolio within the J&J universe, as you can tell from half a dozen different studies, clinical studies that are being conducted right now, and hopefully many more to come. But before we dive into the details, as you know, we, as a company, have always been focused on peptide therapeutics. We have two different assets in phase III studies, one partnered with J&J, another with Takeda, and now we have a discovery pipeline that is promising three new clinical development candidates over the next twelve months.
So, what I say very proudly and in a very satisfying manner is, like, the next ten months are very eventful. There are about ten different disclosures we would be making over the next ten months or so, and J&J-2113 is at the center of that. As you know, this is a partnership that occurred all the way back in 2017 when we just had a preclinical program around oral peptide-based IL-23 receptor antagonist. You know, this is a great example of a great partnership between a biotech and a pharma. We couldn't have hoped for or found a better partner than J&J.
They are making a huge commitment to this asset, and I think the asset truly deserves it. Five different phase III psoriasis studies, one phase II study in ulcerative colitis, and as you know, IL-23 pathway blockers, they are a product in a portfolio play. They create a presence in both derm as well as IBD. In derm, psoriasis, psoriatic arthritis are the key indications, and in IBD, of course, ulcerative colitis and Crohn's disease. So I think the way the data will be unfolding is, like, by year-end, we should have a good understanding of the clinical outcome of the phase III ICONIC-LEAD and the ICONIC-TOTAL study, both of those studies.
And that, if positive, then. And phase II was very positive, and the phase III ICONIC-LEAD is sort of like an extension and a larger scale repeat of the phase II study, so to speak. So we are very optimistic. J&J is very optimistic, but the results will speak for themselves. But that should lead to a path of registration, so to speak. And then, the other studies, like the ICONIC-TOTAL or the pustular psoriasis study, or even the superiority studies with Dupixent, the oral TYK2 that is in the market, right? Those are basically a form of label extension and label expansion, rather, that sort of thing.
Because at the end of the day, the way we want to stage this is, like, this is the best oral play in psoriasis. So if you compare what is out there in the psoriasis space, it's Otezla is there, and then the TYK2 inhibitor from BMS is there, right? That's why it's like, let's go head-on with a superiority study with Dupixent or Sotyktu, and let the results, you know, do the talking. So it's like it's a great, healthy start. The ICONIC-LEAD study will start the process towards the NDA filing, and then the rest of the studies will prove the true capability and expansive capabilities of this oral IL-23 blocker.
And I think the head-to-head studies against Dupixent are sort of noteworthy because it's not common that you see a sponsor sort of take on. Right an on-brand asset in a head-to-head, and clearly, you know, sort of a measure of their confidence. And one thing I would quickly add is, another attractive feature about that study is, like, J&J is now raising the bar for the whole field of psoriasis. Historically, people have focused on PASI 75 as a primary endpoint. Here, the focus is on PASI 90 as a primary endpoint, right? So, which is, in a way, great for the patients.
You did mention that they're starting a UC study. I guess. You broadly hinted at sort of the broad applicability of the IL-23 pathway. I mean, what's your sense, and I know it's a little hard because, you know, they control the program, but, you know, the breadth of how far they can go with this, because certainly it can--should be able to go beyond psoriasis and ulcerative colitis. Is sort of the Stelara label or the Tremfya development pathway sort of a roadmap, do you think?
Exactly. So, for example, if the psoriasis study is a success, then it's a given that there is a natural extension to psoriatic arthritis, right? The translation ratio from psoriasis to psoriatic arthritis is almost 100%. Similarly, in IBD, I mean, you know, when you talk to the IBD KOLs, they're like: "Hey, first, do the UC study." right? And then if the UC study works, then you can think of both UC and Crohn's. And now J&J is a company, by virtue of having that experience with Stelara and Tremfya, they have so much translational knowledge from preclinical to clinical, from UC to Crohn's, all those kind of things.
So all that material, you know, one should be able to put to use. So the UC study is a proof of principle study at the end of the day. What is more critical is what are the next steps after that, right? There are three scenarios. One is, like, let's say, the study doesn't even work at the highest dose, then obviously it's a no-go in IBD, in my opinion. But if the study works, and if preclinical data is any indication, the study should work. Because, if you recall, there were two types of preclinical studies that were done with this molecule.
One was a colitis study, and the other was the ear inflammation study. The ear inflammation study is sort of like has connectivity to the derm conditions, right? And in the phase II psoriasis study, the data has been excellent. The colitis study is sort of a prelude to the IBD indications. Now, if you look at the minimally efficacious dose that was required to achieve efficacy, in the colitis study, if anything, it was five- to tenfold lower than what was required in the inflammation study. So our optimism for the UC study is for a reason, but that is the preclinical thing.
Pretty soon, the clinical data will be out there, and it will do the talking. But if the UC study is positive, then there are two scenarios, right? Take the drug forward in a phase III UC study, or also take it forward in a phase 2b/3 Crohn's study, based on all the translational knowledge and know-how that helps. So from that viewpoint, the UC study, in a way, it is a phase 2b study, but it is of paramount importance in that regard because it sets the stage for the next steps. That truly dictates what is the true scope of 2113 .
Is it in derm, or is it both in derm as well as IBD indications? And as you know, I mean, just last year alone, the combined sales of Skyrizi and Tremfya and Stelara were north of $14 billion or something like that. So this is a huge market opportunity that we are talking about, whereby with something like 2113 , you know, a company like J&J can think of, you know, connectivity or extension of their franchise, and also an important transition from injectables to orals down the road.
Maybe it'd be helpful just given sort of the now that you've sort of done a nice job characterizing the magnitude of the opportunity, the economics for Protagonist in the relationship with Janssen, because those are obviously milestones as well as sort of downstream ones.
Yeah, so far, we have already benefited by, you know, garnering north of $170 million or something like that from J&J. There are another $700 million in milestones. I would say, out of those, $215 million are near term that could be achieved over the next two to two and a half years. For example, if a phase III study is positive, that triggers a $115 million milestone. NDA filing is another $35 million, approval is another $50 million, so the numbers add up. But the biggest piece of the pie over there is the 6% to 10% royalties that we have, right? J&J has already, last year in their enterprise review day, categorized this drug in their largest bucket, which is the $5 billion-plus bucket.
So we will see what the real product profile is, but whichever way you do the math, anywhere from $5 billion to $14 billion, which is the, you know, Stelara, Tremfya combined sales for last year, right? Six to 10% of that is a lot of money, and 10%, that triggers at, anything above $4 billion, so.
I do want to turn to rusfertide, because there's a lot of ground to cover. You know, earlier this year, it was in January, you signed a partnership with Takeda for rusfertide, which is in phase III for polycythemia vera. Just maybe a quick update on the phase III program for PV. And then, one of the interesting elements of the partnership with Takeda was, you know, this sort of opt-in or opt-out window that you get-
Right, right
when you get the phase III data from the VERIFY study.
Yeah.
And maybe just walk through, sort of the thinking behind the opt-in, opt-out, and sort of what would sort of make you choose to go down one path versus the other.
Yeah, no, that's it. It's a fantastic question, so rusfertide, you know, we completed enrollment by the end of the first quarter of this year. The primary endpoint is at 32 weeks, so basically, the last patient will be completing 32 weeks by the end of the year. That is why we feel confident that in the first quarter of next year, we should be, you know, able to kind of share the highlights regarding the outcome of the study. And over there also, the phase II data has been fantastic. You know, P value of zero point zero zero zero something is a good number to have.
and in a way, the phase III, there are many similarities with the phase II , so our confidence is, of course, very high. Of course, Takeda also has a lot of confidence. That is the deal we inked with them in January of this year. It's interesting that with J&J, we did the deal in 2017 with a preclinical asset, and then the next major deal we do is with Takeda this year in 2024, and now it's a different kind of deal and deal structure, right? It's a co-development, co-commercialization kind of deal structure, which had a $300 million upfront, and then the many other favorable terms, including the opt-in and opt-out that you are referring to.
I guess, you know, Takeda is a very, very fair partner, and it respected the phase II data we have. It sees the opportunity the same way that we see in PV. This is a huge opportunity, and we were able to convince them that, you know, we, Protagonist, should be able to have this opt-in, opt-out structure. Because right away, we are stepping in with a co-development, co-commercialization approach, meaning opting in. But at some stage, you know, Takeda would have ideally wanted to just out-license it, and at some stage it makes sense for us to do that, then we have the ability to opt out.
That will be, you know, that decision will come four months after the NDA filing. So from our viewpoint, it was like, that is a decision we have to make that in the future, when we know a lot more about the drug, right? The outcome of the phase III study, the true market opportunity, and then based on the NPV kind of, math, we can then make a decision about, like, whether we stay opted in or we decide to opt out. So it's a decision we can make in the future, and we have plenty of elements that will guide us toward the right decision.
Dinesh, you know, people say imitation is one of the most sincere forms of flattery, and we've certainly seen competitors.
Yeah
following you in terms of the importance of hepcidin, right, for PV. I'm just curious, you know, from your perspective, why you still think, and obviously Takeda agrees, that the rusfertide approach, right, you know, basically a hepcidin mimetic, should prove durable. Also maybe, I guess, the long-term vision, because I think some of the early discovery programs that you've talked about are oral hepcidin products.
Right. Right. No, I think, look, this is one of those areas where I truly believe, the more, the merrier, so to speak. And whether it's a Takeda partnership that brings a validation or some sort of followers that make us more validated as well, that's a great thing. But in terms of like, you know, the who will grasp what kind of market opportunity, time will tell. But first and foremost, our back-of-the-envelope math suggests that we are at least four and a half to five years ahead of everyone else, right? All other mechanisms that are. So rusfertide is a synthetic peptide.
It's a mimetic of the natural hormone, hepcidin, and hepcidin is the master regulator of iron homeostasis. What all the other approaches are doing is directly, indirectly, they are increasing the production of endogenous hepcidin by, let's say, fivefold, sevenfold, something like that. You know, one of the company has illustrated a good proof of principle with that kind of approach. Having said that, I would like to believe that the way we started the program is gonna serve us in a much better way. Because from my viewpoint, and I'm a medicinal chemist by training, hepcidin was always a starting point for drug discovery, but it didn't have enough oomph for a pill or strength to be a drug in its own right.
That is why we took on the approach of coming up with a mimetic. So our drug, rusfertide, in comparison to hepcidin itself, is much more potent, much more stable, has much better PK properties, which are very, very important, right, from a drug delivery perspective, those sort of things. So I think we have those advantages as well. But the other thing we will also add is, like, you know, like I said, rusfertide is four and a half to five years ahead of everyone else, and, hopefully other companies will succeed as well.
We have our own second-generation plan, which is focused on oral hepcidin, which is something we are promising in the first half of next year as a development candidate ready for IND-enabling studies.
And, You know, one of the other early-stage programs that I think I wanted to highlight was, or talk about, was the IL-17 antagonist. You know, that's a target that's continued to get a lot of interest from both monoclonal antibodies as well as other oral programs. What do you think it is, or how do you see the opportunity? So this is the reverse, right? You're not necessarily in the lead. but what do you think that you're gonna bring to the table that differentiates? You know, Your IL-17?
You use this wonderful phrase: imitation is the ultimate form of flattery. So it's like our success in J&J-2113 with J&J then kind of encourages us to imitate ourselves, but in a different category in I&I. And when we look at the slew of targets that are out there, IL-17 is on the top of the list, right? Our approach is very simple. We are not taking any biological pathway risk. These are pathways that are well established, proven by blockbuster antibody drugs. We differentiate by coming up with an oral peptide. So that is where we create the differentiation.
Now, to your point, in IL-23, the interesting thing is, like, we are the only ones with an oral. There is no oral small molecule or anything close to it yet. Whereas in IL-17, it's different. There is an oral small molecule, that kind of thing. But with peptides, what you get, in a nutshell, is you get much, much better potency, you get much, much better specificity, and you get much, much better desired spectrum of activity. So with regard to IL-17 itself, if you look at the small molecules, their potency is about, let's say, fifty-four lower than that of the antibody.
With our oral IL-17 peptide, we believe we will be able to match the potency of the antibody. With IL-17, what has also been shown recently is, like, if you have activity against both A and F isoforms of the target, then you have better efficacy. So small molecules have only activity against A, whereas our peptide is gonna have activity against both AA, AF, and FF isoforms. So that will be the differentiation. It is this approach, basically peptides versus small molecules, if our peptides can make a difference by getting much better potency, spectrum of activity, specificity, which means, you know, much better safety down the road, then that is where we will continue to push the peptides forward, whether it is now in competition with the antibodies or whether it is in competition with the small molecules.
You know, one of the other early-stage programs that you've talked about is obesity, and this is obviously an area of intense interest in the pharmaceutical industry. You're not also not the only one pursuing an oral treatment, and the oral treatments to date have.
Right, right.
You know, sort of pretty mixed results. So what do you think that you're going to be able to do that others haven't?
Yeah. Once again, you know, first of all, the obesity field has started. The two approved drugs are peptides, basically injectable peptides, so that is almost like an open invitation to a company like ours with a proven expertise in oral peptides. And our differentiation would be, like, you know, unlike oral small molecules, we could have much better spectrum of activity, much better potency. And, you know, if you look at the opportunity, if rusfertide for PV is, let's say, for 100,000 patients, if oral IL-23 in I& I is for, let's say, million patients, in obesity, you are talking about, like, maybe 100 million patients or something.
So the opportunity is so huge that there is, it is quite possible that there could be multiple players at the same time. So we will have our own differentiation, but it's not like we have to be so strongly differentiated from everything and anything else out there. I think there is the opportunity of such a scale that there could be many players. But we will clearly have a differentiation from the small molecules by having better potency and better spectrum of activity.
As you know, in obesity now, people are moving from monoagonist to biagonist and triple agonist and all that kind of thing, so these are the wonderful things that we can more easily achieve with peptides, that small molecules have not yet been able to achieve in the oral obesity space.
Okay, and I guess, you know, we only got, like, a minute, but I think it'd be helpful if you perhaps quickly just touched on the Protagonist platform and what you're able to do. You obviously talked about IL-17 and obesity as sort of early stage, as well as the hepcidins, right? Early stages of development. You know, how broad can you potentially take this pathway? Can you look at every sort of monoclonal antibody and turn that into an oral peptide?
I would say, yeah, the sky is the limit, but of course, you know, choosing the right target at the right time is very critical. We don't want to be redundant. We don't want to be too late to the party. The last thing you would want to do is, like, you know, come up with a peptide that works, but you are just winning the battle and losing the war, meaning it's too late, right? We don't want to be in that situation. So selecting timely targets in a timely fashion, making rapid progress, that is what we are trying to replicate, whether it is in I and I, in obesity, in Heme space, or even in other disease areas down the road.
The platform is incredibly versatile and broad.
Okay. Well, I think we're out of time. So, Dinesh, thank you so much. It's great to see you.
Always a pleasure.