Hello again, everyone. I'm Etzer Darout, a 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.
Yeah.
First and foremost, thanks for inviting us. I have to mention that this does take me down memory lane. You know, Protagonist, we did our IPO back in 2016, and Barclays was one of the bank that helped us achieve that component of going public.
Thanks for that as well to Barclays. Right from the get-go, we have focused on creating innovation through novel peptides. That's our bread and butter.
We have expertise both for injectable peptides, but also for oral peptides. 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. 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. On the heels of that, we are assuming, hoping that they get approved this year.
The first drug I'm talking about is icotrokinra. This is an oral IL-23 blocker, and this is the first and only, so there is amazing scarcity value as well. And this is a journey with J&J that we started all the way back in 2017.
When it was just a preclinical program. We have come a long way and now the first indication for which approval we'll be seeking is for psoriasis. The drug is also in phase III studies in all the other three indications.
Where IL-23 blockers have had 100% success, right? Namely psoriatic arthritis, UC, and Crohn's. The other asset is rusfertide. This is a weekly injectable mimetic of the natural hormone hepcidin that is in charge of iron homeostasis. We felt that, hey, polycythemia vera, that's a disease, it's characterized by excessive red blood cell production, right? Excessive erythrocytosis. It made sense to come up with an erythrocytosis-specific agent. Again, there is no such thing that is out there right now.
We are the first and only over there as well. That is something unlike the J&J deal, which was partnered at a preclinical stage. Here, we partnered with Takeda in January 2024 when we were already in a phase III setting on our own. It's a rare disease indication, right? 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. About a week ago or so, we announced that we received priority review, so that is gonna hopefully accelerate the approval by a few months.
With icotrokinra, 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.
We are looking forward to that. That's the outcome of, you know, 16, 18 years, whatever you want to call it, or at least 12+ years of efforts in these programs. 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? The next wave of assets is again continuing in the I&I space with an oral IL-17 program. We also have preclinical studies going on in the IL-4 program. It's like, hey, if you can create an oral, you know, IL-23 is like whatever you want to call it. It's an oral equivalent to a Skyrizi.
... or TREMFYA, you know, pick one. Similarly with [Derby] and oral BIMZELX, right? That's the idea with the IL-17 .
Over the last few years, as we all know, the entire obesity space gets a lot of attention. Chemically speaking, the two approved drugs are injectable peptides.
Right.
that was like an invitation for us. It's like, okay, can we create some solid differentiation through oral peptides?
The first thing that we have is an oral triple- G. It's the one of its kind.
over there, we will get into clinical studies in the second half of the year, that sort of thing. We also have an oral GLP/GIP, a dual. We have acknowledged our presence in the Amylin agonist program as well. We want to create a whole portfolio of different assets.
At last but not least, in the heme space, the second act is the oral hepcidin.
Right.
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 know, looking at exposure, particularly it's peptides, and so-
Yeah.
That presents a challenge in and of itself. 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.
To your point, it's like, hey, is it gonna work as an oral? 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? Now advances are being made in terms of enhancing oral bioavailability. One thing that we do is, we go through a lot of preclinical models where our drug will be administered orally. We would like to see that preclinical proof of concept being achieved in animal studies, when our drug is administered orally.
That's kind of a generic way of describing it. It's fair to say that we take at least 3-4 months longer than what a typical preclinical assessment would look like, because we want to make sure that we pick the right candidate.
Right.
Yeah.
Great. Maybe on icotrokinra in psoriasis, we've seen, you know, at least one successful superiority study. We also have ICONIC-ASCEND comparator, the secukinumab. How do you plan to leverage those, you know, again, studies as you think about, you know, initial launch in psoriasis? You think about the types of physicians that you're gonna wanna target. How do you ultimately wanna leverage those data sets?
I mean, these are extremely important questions, but I have to be very upfront about it.
Yeah.
J&J is the best entity to be answering these questions.
Got it. Sure.
They are the ones doing the heavy lifting. 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 approved TYK2 inhibitor, Sotyktu, and our data is fantastic. The primary endpoints were achieved, and you know, whether that makes it to the label or not, 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.
As you know, now by the end of the month, they are completing this head-to-head study with their own injectable, Stelara.
To me, what all that is telling me is, like, obviously, they are big believers of icotrokinra now.
They could be gearing this towards like, you know, first-line therapy, something like that, right?
Maybe a question on rusfertide, but not necessarily on the injectable program. Again, when you think about the potential for an oral hepcidin functional mimetic, how should we think about the positioning relative to rusfertide in terms of, you know, cannibalization is always something that people are gonna talk about. Could they be complementary? How do you think about an oral agent versus sort of the injectable agent?
Rusfertide is like a kid that is completing college and is pretty soon gonna have a job and have, you know, his or her own income, whereas the oral is like still maybe in junior high or something like that, right? That kind of thing. Jokes apart, it's like there is enough time delta between the two drugs.
rusfertide is an outstanding drug. It's the first drug of its own kind, erythrocyte-specific mechanism.
Takeda is a fantastic partner. We don't see any overlap or, you know, that kind of yeah overlap or one thing taking away the market from the other.
Right. Yeah.
If at all anything, it's a continuity.
... of dominance first with rusfertide and then hopefully with the oral hepcidin.
Great. No, that makes sense. We've had questions around the competitive landscape or evolving competitive landscape for, you know, rusfertide. People have talked about some upcoming data sets for, from like Silence Therapeutics. Maybe your thoughts around the competitive landscape just broadly and PV, and then your thinking around like what that ultimately that space evolves to.
Yeah. I mean, in a way, we are flattered that people, other companies are also embracing the core mechanism of hepcidin, right?
as a way to offer treatment in polycythemia vera, and whether it is Silence or whether it is, you know, Disc Medicine. These are great companies and we wish them all the best of luck.
What I would say, though, is like, let's take the TMPRSS3 mechanism and other mechanisms of that type. Those are mechanisms whereby you are trying to really enhance the production of endogenous hepcidin.
That could have its pluses, minuses, limitations, things to watch out for, that kind of thing. Whereas our approach is very clear.
Yeah, we use hepcidin as a starting point rather than as a drug, because I'm a medicinal chemist by training. For me, hepcidin 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.
That is what we achieved with rusfertide, and it is titration to effect, things like that, right? One of the things to watch out for, quote unquote, "longer acting drugs" would be like, keep in mind 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.
I think with a weekly injectable that we have, we are in a very balanced position, if you will. We, you know, titrate from low to high and then find the balancing act of like, which is the right dose, that kind of thing. Measuring whether your drug is continuing to have the effect or not is a very simple blood test. You measure the hematocrit levels. I think we are happy with where we are. The other component is, of course, we are years ahead.
of everyone else, so we are gonna have, for a number of years, right, the space to ourselves.
Right. Maybe switch gears to PN-881 or IL-17. You have a healthy volunteer study that, you know, we'll get an update on this year. How are we thinking about what success looks like for that study and how that study ultimately helps inform what a phase II program would look like for an oral IL-17?
Yeah, no. Oral IL-17, PN-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 love PN-881. The preclinical data has been outstanding. Like we were talking earlier.
We went through like a very exhaustive evaluation. You are asking the great question, what would success look like? Because we are doing just a phase I study in healthy volunteers. Very comprehensive study, though. The idea would be like, we want to get definitive ideas about the dosing regimen. What is the ideal dosing regimen, right?
If we believe the drug is working, then that would enable us to go for a full-fledged phase II 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.
What we have done is, based on that, we have achieved amazing bimekizumab-like potency, right? Picomolar kind of potency against the target. Another characteristics we have, which is bimekizumab-like, is we have activity against both A and F isoforms.
We don't know of anybody with an oral approach that has that right, so we have made it as foolproof as possible. 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.
That is what we are striving for in a phase I study.
Now, the other thing to keep in mind is like, our peptide, it's almost like 100 times smaller in size compared to the big antibodies. So in theory, one could assume we may have better tissue penetration, skin penetration.
that sort of thing. 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 are the drug levels we need to achieve.
based on what the antibodies have taught us in order to feel pretty assured of efficacy.
Right. You know, one of the questions that we get around the oral IL-17 program is how much of this does Protagonist want to execute on their own versus ultimately finding a partner for large indication? How are you thinking about business development around oral IL-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. I'll give a slightly detailed answer.
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.
$75 million upon approval as a milestone payment, and another $50 million from J&J if icotrokinra gets approved, right? The revenue streams.
Revenues are perennial. 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 III studies, even for larger indications? The answer is yes. Are we gonna do that? The answer is no. Here is the reason why. It's not only about money, right? Look at the amazing strength that a pharma brings to the table, right?
It's like icotrokinra, by the end of the day, counting all the four indications, it's being evaluated in 7,000+ 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. Our approach would be, you know, in simple terms, it is like we will take all of our assets to clinical POC.
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 IND-enabling and phase I studies.
After that, phase II and beyond, they take care of it. Now we may say, "You know what? No, phase Ii, let's do a 50/50 cost sharing. Phase II, let's do a 30/70 cost sharing.
We could get more creative so that we can retain more backend economics. At the end of the day, for big indications, yes.
We would love to have a pharma partner. For the niche indications, rare disease indications, like our oral hepcidin, that is where we definitely can have a mindset of, like, let's do it alone all the way to the finish line .
It's those kind of things. 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? We are not gonna dilute away the shareholders for the foreseeable future.
Right. Great. Maybe, with that, we could spend the next few minutes on obesity. Obviously, dominated now by the injectable peptides. You've had an opportunity to see all of the commercial dynamics, what's happening in the clinic 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 treatment paradigm for obesity?
Yeah. Look, I think in obesity it checks all the boxes for us, right? The two approved drugs are injectable peptides, so we are like, "Yeah, 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.
Second is, through our approach, we should be able to offer some very strong differentiation. 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.
We may just be scraping the surface. This may just be the humble beginnings. As usual, you know, so many undertakings are there, that kind of stuff. Even then we said, "You know what?" We consulted a lot with the KOLs. What came at the top of the chart was like, "Hey, can you create an oral triple?" The answer was, "Yeah, we can do that." That is what we have chosen, right? An oral triple GLP-GIP-GCG. In talking to the KOLs, we also gained an understanding of what could be the relative potencies of GLP-GIP-GCG that could be considered optimal. Could that translate into not just better quantity of weight loss, but also better quality of weight loss?
I'm referring to better tolerability, which could be achieved through better GIP agonism and, you know, better lean muscle mass preservation that could be achieved through the GCG component of energy expenditure, that kind of thing. We have tried to optimize those components also as much as possible. We believe we are the only or one of the very few oral triples that is out there.
In talking to the KOLs, it also occurred that, hey, some of the markets with some patients for some periods of times may belong to injectables. We are developing both a weekly subQ and a daily oral. The PK characteristics are fantastic. We see drug accumulation. We do believe that down the road, maybe the weekly subQ could transition to monthly subQ in a maintenance setting.
Same way, the daily oral pill could be a weekly oral pill or something like that.
We like what we are seeing. 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.
We have already announced we have a dual, right? And we have already acknowledged our presence with Amylin mono and polyagonist, that kind of thing. We'll 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? If it is, let's say, NASH, MASH kind of liver centric indications, maybe the GCG component does become important over there. That's where the field is leaning towards. 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.
Yeah
At the end of the day.
Yeah. Yeah, no, great. 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? Is this really based on just what the analogs that you've seen in clinical development and being able to assess exposure and then initial, you know, whether it be 28-day weight loss and then assuming that maybe that would be durable? How would you-
whether it is a 13-week weight loss.
Yeah. Yeah
that kind of thing. No, exactly. It's like we are observing, we are learning from others. Why not, right? Knowledge is free.
Yeah.
that would be the idea. By the way, that is another general advantage with our approach.
Like in a phase I 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 iron levels and the related biomarkers.
We will get a good understanding of where we are going. I think then if you add up everything that's in our R&D pipeline, the clinical POC is just gonna sneak up on us.
Right.
It can come sooner than what most people may be anticipating.
Great. 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.
Thank you.