Protagonist Therapeutics, Inc. (PTGX) Earnings Call Transcript & Summary

Welcome to the Protagonist Therapeutics June 30 Conference Call. [Operator Instructions] As a reminder, this call is being recorded today, Monday, June 30, 2025. I will now turn the call over to Dr. Corey Davis of Lifesci Advisors. Please go ahead.

Thanks, Julian. Hello, everyone. Thanks for joining us on our call today. With me from Protagonist are Dr. Dinesh Patel, President and CEO; Dr. Newman Yeilding, chief Scientific Officer; Asif Ali, CFO; and Dr. Sam Saks, Clinical Development Adviser. We also have Dr. Kirk Ways, an endocrinologist with expertise in metabolism and a clinical adviser to Protagonist on its obesity development program, who will be joining us for the Q&A session of the call. Earlier today, Protagonist issued a press release announcing the formal nomination of a triple receptor agonist development candidate for obesity. Copy of this press release is available on the company's website. As can be seen on this first slide, we will be making forward-looking statements on this call. These may include statements relating to the safety and efficacy in the therapeutic and commercial potential of our investigational product candidates. For further information relating to risks and uncertainties related to our business, please see the periodic reports we have filed with the Securities and Exchange Commission. This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, June 30, 2025. Protagonist undertakes no obligation to revise or update any forward-looking statements or reflect events or circumstances after the date of this conference call, except as may be required by applicable securities law. With that, I'll now turn it over to Dinesh Patel, Go ahead, Dinesh.

Thank you, Corey, and good afternoon, everyone. We have gathered today to deliver on our guidance of announcing a novel, well-differentiated oral peptide-based, anti-obesity development candidate. As a reminder, we define a development candidate as a novel chemical entity with adequate preclinical characterization and proof of concept and one that is ready to move forward into IND-enabling studies. PN-477 is our novel anti-obesity development candidate, and it is a triple agonist with remarkable potency against the GLP, GIP and GCG receptors which are all well validated incretin and non-incretins biological targets in the obesity field with each target offering unique characteristics to optimal body mass composition. While our initial guidance was just about a well-differentiated oral anti-obesity agent, and the unique oral stability characteristics of 477 is, in fact, the most differentiating aspect of our candidates, we are opting to pursue parallel development of both a once-daily oral and a once-weekly subcu injectable formulation of 477 with the intent of offering maximum optionality to patients, payers and practicing physicians for treating this chronic condition. As you can see, PN-477o and PN-477sc, the oral and subcutaneous forms, respectively, of this novel triple agent are a great addition to Protagonist's broad and diverse R&D pipeline of early and late-stage assets shown below. Moving to Slide 4. Obesity represents one of the biggest, probably the biggest health care challenges of our lifetime. Obesity rates have exploded in the U.S. and worldwide over the past half century, such that today in the U.S., almost 3/4 of our population is overweight or obese with nearly 40% qualifying the criteria for obesity with a body mass index or BMI of at least 30. This obesity epidemic is being met for the first time with new therapeutic agents, and there are 2 major drugs in the market and both are injectables. These 2 agents, namely semaglutide and tirzepatide are collectively treating slightly over 1 million patients which is a big number, but represents less than 2% of the total drug treatment eligible patient population, clearly implying that there is a lot of unmet need and significant room for improvement with new therapeutic agents with superior properties. There are numerous challenges and limitations with the current anti-obesity drugs, including accessibility and availability, magnitude of efficacy as well as tolerability and mode of administration that could be affecting overall utility and compliance. Both approved agents are weekly injectables and is well established that avoiding a needle through an oral agent is a highly desirable feature in new medicine, especially for treating a chronic condition where you are expected to continue treatment for the rest of your life. So it was very compelling for us to apply our proven expertise in the field of oral peptides to the discovery of novel and oral anti-obesity agents. I would also point out that while the field of anti-obesity drugs is very, very crowded with hundreds of clinical studies underway and for all the right reasons, it appears significantly less crowded the moment you shift your attention from injectables to oral agents. And with a focus on orally stable peptides as anti-obesity agents, we then turned our attention to the next important question. And this is, which is the best biological target or set of targets we should focus on with our oral peptide approach. So as mentioned before, going to the next slide, there are only 2 major drugs on the market. Semaglutide is a mono GLP receptor agonist marketed by Novo Nordisk. And tirzepatide is a dual GLP/GIP receptor agonist marketed by Eli Lilly. Both drugs have reported impressive weight loss, but there is significant room for improvement and to address the huge unmet need. In that context, several new agents targeting both incretin and non-incretin mechanisms are being pursued, but almost all of them are largely injectables. While the science is still evolving and a lot remains to be proven, the most noteworthy development in our mind is the triple agonist as exemplified by retatrutide from Eli Lilly, which is currently in Phase III studies. Not surprisingly though, retatrutide is once again an injectable, and we concluded that an oral triple GLP, GIP, GCG receptor agonist with the right balance of absolute as well as relative potencies against the 3 receptors and the right type of physiochemical and pharmacokinetic characteristics so that it could serve as an orally stable agent could lead to significant improvements that are highly desired in the current therapies. This decision of developing an oral triple agonist agent is based on an extensive survey of both the approved and emerging therapies and in consultation with the key opinion leaders or KOLs in the field. So based on this rationale, we set out to discover an oral triple agonist peptide using our proprietary peptide technology platform. And the outcome of this intensive and dedicated effort over the past 18 months is PN-477, an orally stable singular peptide with very impressive absolute potencies and an optimal balance of relative potencies against the 3 targets. Some of the improvements we are seeking with our oral triple agonist approach are first and foremost, providing a more convenient option that is an oral agent. Second, addressing the large population of patients who may require a greater magnitude of weight loss than currently achieved by the approved drugs, including the possibility of more effective treatments for the various comorbidities associated with visceral adiposity. Third, a triple agent could potentially offer improved tolerability, specifically gastrointestinal or GI tolerability, which may have contributed significantly to approximately half of the patients discontinuing treatment within the first year of therapy with current agents. And fourth, a triple agonist could help improve fast mass loss and reduce lean mass loss, leading to a more favorable fat-to-lean mass ratio and driving optimal body composition. And finally, while not listed here, we are also hoping to achieve longer durability of response with our candidates. Lower dosing or less frequent dosing would be very desirable, especially if it could lead to more convenience and lower tolerability issues in a maintenance treatment setting. So our CSO, Dr. Newman Yeilding, will walk you through the extensive preclinical data package and this will make it clear that PN-477 has great potential as a best-in-class oral anti-obesity agent that has captured the various desired characteristics that I described on the previous slide. Before I hand it over to Newman, one final point is that in our continued assessment of the evolving landscape, we also concluded that while an oral once-daily drug would be a highly preferred choice, it would be ideal to develop the same peptide PN-477 in parallel, both as a once-weekly subcu administered drug as well as -- in parallel, both as an overall as well as a once-weekly subcu administered drug to offer maximum optionality to patients, payers and physicians and to maximize the chances of addressing the huge global patient population in an uninterrupted and most cost-effective manner. With that and without any further delay, I will now turn it over to Newman.

Thanks, Dinesh, and good afternoon, everyone. Here at Protagonist, we're very pleased to formally announce the progression of our triple-G agonist PN-477 as a development candidate for the treatment of obesity and the comorbidities associated with obesity. Over the next few slides, I'm going to lay out how we designed PN-477 and the attributes that it exhibits in our preclinical studies. And just to make the presentation a little simpler, I'm going to call each of the receptors by the 3 letters of its ligand so GLP, GIP and GCG. We used proprietary protagonist capabilities to engineer PN-477, focused on delivering key attributes that I'll show in the next few slides that include potency and the balance of potencies against all 3 receptors, peptide stability that we believe will facilitate oral delivery, preclinical efficacy and models that are likely to predict efficacy in humans, pharmacodynamics, improving glycemic control consistent with improving comorbidities associated with obesity like type 2 diabetes. And finally, pharmacokinetics, it gives us confidence that PN-477 will deliver the desired target weight loss and pharmacodynamic effects with either once-daily oral dosing or with once-weekly subcutaneous dosing. PN-477 is a highly potent triple GLP, GIP, GCG receptor agonist designed to provide the weight loss profile of retatrutide with the GI tolerability of tirzepatide. We based this design on careful review of the literature and detailed input and advice from key thought leaders in the field of obesity. And I'm going to highlight a few of the key features that we believe are important to achieving this target product profile. And you'll see from this description that the beauty of our technology is that it gives us great control in engineering the relative balance of potencies between the receptors. So first, compared with reference products, PN-477 is the most potent agonist against all 3 receptors, which we envision will translate into dosing advantages. Second, you can see that we engineered the relative potency balance of GLP to GIP to be skewed towards GIP with a similar SKU as tirzepatide, and that's shown as a 17-fold SKU in green in the table. And the SKU is intended to potentially mitigate GI tolerability issues as has been suggested with the clinical data with tirzepatide. And then third, we engineered GCG potency to be generally comparable to retatrutide as a key booster of energy expenditure. And we believe that this potency profile may offer the optimal combination of total body weight loss, improved GI tolerability and improved fat-to-lean mass ratio. This table also shows detailed information on the EC90 concentration, the concentrations achieving 90% of maximum receptor activation for human receptors on the left, for mouse receptors on the right and benchmarks those potencies versus semaglutide, tirzepatide and retatrutide. In later slides, I'll be showing how PN-477 benchmarks versus retatrutide in the mouse DIO model. That's the diet-induced obesity model in which mice are maintained on a calorie-rich diet-induced obesity. But before I get there, I just want to highlight that these are not mice engineered to express human receptors. So the impressive results that I'm going to show are achieved despite the relatively lower potencies of PN-477 in mice than in humans as shown in this slide. One of the profound differentiating features of PN-477 is that we've engineered it to be stable in GI matrices shown here, simulated gastric fluid on the left, simulated intestinal fluid on the right. You can see that the remarkable stability of PN-477 clearly distinguishes it from the reference compounds. And it's easy to understand why stability in the GI tract would be important for an orally administered drug, and we're seeing this as a key advantage and is very enabling as we progress our oral formulate -- in our oral formulation development. We observed very nice dose-proportional weight loss in DIO mice shown here of up to 50% of body weight. This is the standard preclinical model for assessing weight loss and it has good translation into humans, benchmarking against retatrutide administered the highest dose reported in the literature, and that's shown in red. The 3 and 10 milligram per kilogram doses achieved weight loss lower than retatrutide, while the 30 and 90 milligram per kilogram doses achieved weight loss greater than retatrutide. Again, these impressive results were achieved despite PN-477's relatively lower potency in mice versus humans. As Dinesh mentioned, we intend to initiate parallel development of subcutaneous PN-477. And this slide shows that at equally molar doses, weight loss with PN-477 administered subcutaneously is comparable to that seen with retatrutide with PN-477 in the green line producing approximately 48% weight loss at 14 days, while retatrutide at the same dose produces 40% weight loss. So combined with the data that I showed you on the previous slide, these results suggest that PN-477, in fact, does offer promise as both an orally and a subcutaneously administered product. Now in a separate DIO mouse experiment, Slide 12 shows that PN-477 not only leads to comparable weight loss as retatrutide, but also the quality of weight loss leads to comparable improvements in body composition. In this experiment, mice were dosed with PN-477 retatrutide at 30 nanomolars per kilogram every 3 days for 3 weeks, and we used echo MRI to assess changes in body weight composition over this time. And shown in this table, you can see that mice lost approximately 30% of their body weight over these 3 weeks. And in that time, they lost 65% to 70% of their fat mass while losing only 13% to 17% of their lean mass. So this shows a preferential loss of fat mass and a significant change in body composition. And specifically, what that means, you can see that the lean mass to fat mass ratio was 1.3 to 1.4 at baseline. So that means that they had approximately 30% greater lean versus fat mass at baseline. But by day 22, that ratio increased to 3.3 to 3.9, which approximates the normal fat to lean mass composition in normal mice. So these results suggest that PN-477 like retatrutide leads to a preferential loss of fat mass. Again, in a separate DIO mouse experiment, Slide 13 shows that PN-477 improves glycemic control after a glucose challenge. In this experiment, mice were challenged with 1.5 grams of oral glucose after administration of either PN-477 or retatrutide. And you can see that compared with vehicle, glucose elevations are blunted as measured by the glucose AUC over 2 hours and the magnitude of effect was comparable to retatrutide with both oral or subcu dosing, retatrutide is shown in the red bar. These results indicate that PN-477 results show -- that PN-477 results in better glycemic control and suggests it has potential as a treatment for type 2 diabetes, which as you know, is a frequent comorbidity of obesity. So now moving on from mice, we've further extended our findings into higher species that may be more relevant to informing the pharmacokinetics that we will achieve in humans. The left-hand graph on this slide shows that in normal cynomolgus monkeys oral dosing of PN-477 at 6 milligrams daily for 7 days leads to progressive weight loss of up to 11% and notably, even after dosing cessation, the weight loss in these animals was generally sustained over the next 6 days. The right-hand graph shows the PK profile in these animals showing trough PK levels of PN-477 each day with references to the human GLP EC50s and 90s. And I'm going to highlight 3 important features of this PK graph first. PN-477 levels increase or accumulate for the first 4 days, and that's consistent with its long half-life in cynos, leading to increasing weight loss. Second, based on its potency, these trough levels are anticipated to provide good activity with each receptor based on their EC50s and -- EC50/90 values. And then third, PN-477 has a long half-life as demonstrated by the drug washout after day 8, and we project that it will have an even longer half-life in humans. So these are all features that strongly suggest that PN-477o will be suited for once-daily human dosing. Regarding the sustained weight loss post dosing, and the accumulating drug levels that we observed in plasma, we also envision potential possibilities with maintenance regimens at lower or less frequent doses in a human setting. So I'm going to now transition to subcu dosing in higher species since we're planning to develop the subcutaneous presentation -- in Slide -- thank you. Slide 15 in the left-hand graph shows that after a single dose of PN-477 subcutaneously, cynos lost 13% of body weight over the subsequent 7 days, and that's shown in the purple line. And this magnitude of weight loss is similar to the 11% we saw with oral dosing that I showed you on the previous slide. Moreover, it benchmarks favorably versus the 7% weight loss with the comparable dose of retatrutide and that's shown in the green line. So looking at the PK profiles on the right, also shows that high levels of PN-477 are sustained through 4 days after a single dose. And with the half-life projected to be substantially longer in humans, this PK profile suggests that PN-477sc, in the subcutaneous form, will be suitable for once-weekly human dosing. And then finally, on Slide 16, the left-hand graph shows that normal Beagle dogs lose approximately 10% of their body weight after a single subcu dose of PN-477, that's shown in the purple line, which again benchmarks favorably versus the 5% weight loss achieved by comparable dose of retatrutide. And as in cynos, the PK profiles on the right showed nicely sustained PN-477 levels through 6 days post dose. And this again, strongly suggests the PN-477sc, the subcutaneous form will be suitable for once-weekly human dosing. We were struck that as we extended our observations from the mouse DIO models into higher species, specifically the dogs and the cynos that we were observing features that suggest a more profound weight loss effect of PN-477 and retatrutide at equivalent doses. Since each of the targeted receptors in these higher species show greater homology to the human receptor, this may reflect higher potency of PN-477 for dog and cyno receptors. And if true, we're hopeful that this observation could translate into better efficacy in humans. So in conclusion, the data that I've shared with you today shows that PN-477 has the potential to be a best-in-class triple agonist anti-obesity peptide with convenience of once-daily dosing oral or once-weekly subcu dosing. We engineered this novel potent stable triple-G agonist with careful attention to the balance and potencies for the 3 receptors in a way that's intended to achieve the optimal combination of total body weight loss, improved GI tolerability and improved fat-to-lean mass ratio. We've shown that PN-477 benchmarks well versus retatrutide with either oral or subcutaneous dosing that it does, in fact, lead to preferential loss of fat mass versus lean mass similar to retatrutide and that it produces glycemic control that may have the potential to treat type 2 diabetes. In higher species, normal dogs and cynos, PN-477 yields PK profiles and weight loss kinetics after oral and subcutaneous dosing that supports once-daily -- once-daily dosing of PN-477o and once-weekly injectable dosing of PN-477sc. And finally, we find the apparently greater weight loss of PN-477 in higher species in DIO mice to be notable. And while the cause of this observation is speculative at this time, it raises the possibility that a similar effect could be seen in humans. So based on these results, we've initiated IND-enabling studies and look forward to initiating clinical trials next year. Thank you for your attention. I'm going to turn it back to Dinesh now.

Thanks, Newman. So moving to our R&D pipeline. As you can see, 2025 has been a remarkable year so far for Protagonist with an amazing range of accomplishments with both of our lead assets. Both rusfertide partnered with Takeda and icotrokinra partnered with J&J are progressing towards NDA filing this year and hopefully towards regulatory approval and commercialization next year. In the discovery camp, we have delivered today on our guidance of nominating a well-differentiated oral anti-obesity agent and have actually expanded the program by deciding to pursue the clinical development of both the oral and injectable options with the intent of providing maximum optionality. While our guidance on the other discovery assets, namely the oral IL-17 peptide antagonist 881 and the oral hepcidin program, they remain unchanged, I would like to caution though that going forward, Protagonist will be inclined to provide less details on discovery assets, and we will probably hold off on new discovery announcements until after the assets are nearing or have already begun clinical studies. This is for a number of reasons reflecting both the maturity and growth of Protagonist as a company and also reflecting our desire to preserve confidentiality of our highly innovative projects and development candidates going forward. Getting back to the obesity program. In closing, I would like to congratulate and sincerely thank our extremely talented and dedicated pool of employees, advisers and consultants on yet another highly innovative and well-differentiated development candidate namely a potential best-in-class oral GLP-1, GIP and GCG receptor triple agonist peptide PN-477 with the expanded optionality of an injectable for treatment of obesity. And with that, I will now ask the operator to begin our Q&A session. Operator?

[Operator Instructions] And our first question comes from the line of Roger Song with Jefferies.

Great. Congrats for this nomination of DC. So a couple of questions from us. Maybe first is we see the half-life is pretty long in monkey and then you also alluded maybe in human the half-life will be even longer. So can you just give us some -- your thoughts around that? And then how likely the subcu can be monthly beyond weekly and then oral, how likely it will be longer? And then the second question is related to the bioavailability. We know that oral peptide, the key thing is to be viable as chronic therapy. So how do you think about the bioavailability for 477?

Yes. Roger, those are both excellent points. And our comment on anticipated higher half-life in humans is basically [ coursed ] on the extensive translational data that we have for this category of drugs in general. And you see the sustained -- sustainability that is out there, especially in the dog and cyno. And -- so that's what it is based on. And you are absolutely right. We didn't spell it out, but now we can respond to your question. And it's like, yes, if you look at the data, both the cyno and dog data, the cyno PO and subcu data carefully, there are hints of being optimistic of transitioning from a once-daily oral dose to a once-weekly oral dose down the road, especially in the maintenance arm of the therapy. And similarly, for the subcu, one could envision transitioning from once-weekly subcu to once-monthly kind of subcu dosing in the maintenance arm of therapy. And that would be such a welcome addition, as you can imagine, it will be very efficient, effective and may even lead towards lower tolerability issues based on less frequent dosing. Now again, these are speculations. They are very logical, but at the end of the day, this is something that we look forward to proving in a human clinical setting. And your other question was about bioavailability. So like being in the field of discovery and development of oral peptides for more than a decade now, one thing we have learned is like with oral peptides, you don't chase bioavailability. What you chase is how many fold above you are about, let's say, the EC50 numbers, for example, in this case. And with each target or each disease indication, it will be a different type of requirement. And as you saw, we have pretty remarkable results with oral dosing, whether it is in DIO mice or whether it is in cyno. So we feel very confident about the future prospects. The other component, as you know, this is just reminding everybody that if you look at our oral IL-23 blocker icotrokinra, recall, that we were -- we protagonists were responsible for discovery, preclinical development and Phase I human PK studies, right? So we have a ton of experience in terms of what kind of PK levels are desired for a successful outcome with an oral peptide agent.

We know that this class of drug requires titration. The current products require titration for maximal tolerability. And when we have a longer half-life, that enables a more straightforward titration because you get to the steady state at 5x the half-life. So if you have a longer half-life, that means you're necessarily going to sneak up on your effective dose by virtue of that if you take the product once a day. So that's part of why we emphasized the half-life differences.

Our next question comes from the line of Srikripa Devarakonda with Truist Securities.

Congrats on the progress. So one of the questions was you showed with the daily oral dosing in monkeys, you showed sustained weight loss for 6 days, even after treatment cessation. Curious if you were able to see the data beyond 6 days? Are you seeing plateauing? And how do you expect this to translate into patients? And also, where do you see the oral being used versus the subcutaneous? And what would you need to see to make that decision?

Yes. So, Kripa, what I would say is like our intent today was to offer more than adequate preclinical data package to kind of support our optimism of this being like a best-in-class agent. And I think the data package supports that. As you can imagine, there are so many experiments that one could be undertaking in a preclinical setting. And in a way, we are doing all of that. So many things are in progress. So for some of the things, if you are seeing a data cut after a few days or something like that, either the experiment may be ongoing or we may be designing another set of experiments towards that sort of goal. Now in terms of where an oral could be used and where a subcu could be used, I mean, my mindset is like oral is ultimately going to win the day, especially in a chronic setting, the oral sort of comes across as a clear winner. And with an oral, one could also expect a different set of pharmacokinetic, pharmacodynamic characteristics versus an injectable that could down the road without getting into details lead to better performance and better tolerability. So time will tell, we'll find that out in a human setting. And finally, though, in terms of what could be used when, we will just see. In a way, we wanted to take that question out of the equation. And talking to the KOLs, we were like, okay, this is easy enough for us. Let's just develop both an oral and a subcu and that is -- and that way, it's like one can have their pick and choose whatever is to their liking.

What the KOLs told us was, hey, there's a bunch of agents that are oral. There are a bunch of agents that are subcu and the maximum flexibility for their patient population, what they'd like to get used to is 1 drug substance that they can use in either setting under the appropriate circumstances.

Yes. So the idea is single chemical entity, same chemical entity, both oral and subcu. And something that is very cutting edge, triple agonist with the potential for being best in class. So we try to check as many boxes as we can. And now we will try to run as fast as we can.

And our next question comes from the line of Brian Cheng with JPMorgan.

Newman, just going back to your comments earlier about the more common weight loss you have seen in dogs and cynos versus mouse model. On that point, have you done work to see if there is more prominent observations in terms of lean mass versus fat mass ratio in dogs and cynos compared to mouse? And I have a follow-up.

No, we don't have any data in cynos or dogs on lean and fat mass loss. Our data there is limited to the mouse model. That's where we have good capabilities as well, just to be able to assess...

And I would add that, just to clarify, the cyno and dog, these are normal non-obese species. So when you keep that in mind, you might find our observations even more remarkable.

Yes, that's a good point.

And we think that the greater activity is may be explained by the receptor potencies we showed you in the presentation.

Both the absolute and relative potencies because we have gone out of our way to engineer the appropriate relative potencies of GLP versus GIP and GLP versus GCG. And I think as Newman mentioned, the technology will allow us. And this is very proprietary to us, right? Our technology platform will allow us to engineer any kind of relative potencies we want to. So once again, this is something an exhaustive consultation with the KOLs and all that. This is the optimal balance we were striving for. And we are kind of seeing the glimpse of superiority in higher species.

And as we think about the next year clinical trial design, are both formulations heading into the clinics at the same time? And do you have a sense of the doses and also the dose range that you'll be targeting?

Yes. So a lot of that is pretty clear in our heads. But it's fair to say that at a practical level, we might see the subcu weekly clinical studies starting a little ahead of the oral.

And our next question comes from the line of Julian Harrison with BTIG.

Congrats on all the progress. I noticed retatrutide has been associated with some treatment-emergent cardiac arrhythmia. So I'm curious if you've had a chance to reflect on that. And then if cleaner safety is part of the proposition here, how is 477 designed to achieve that? And how soon will you be able to confirm adequate cleaner safety in the clinic?

Sure. So I will give a general answer, maybe Newman, you can -- or Kirk can talk to the specifics, he is on the call. But the way we look at it is like the GCG receptor is affiliated with energy expenditure and one needs to make sure that one doesn't go overboard with that component. And as you can see from the relative potencies, that's probably our least potent component. So just kind of a touch of the increased energy expenditure component, which I think could be helpful. But maybe, Kirk, you might want to weigh in?

Yes. I mean just looking at the blood pressure changes relative to dulaglutide in the type 2 study that was done with retatrutide, the blood pressures were reduced. Heart rate did go up about 3 to 4 beats per minute with the drug and with retatrutide, with dula was about 1.7 increase, and those were not statistically different. The arrhythmias that we reported as adverse events in that study ranged in the retatrutide groups from about 4% to 8%, dula was about 7% and placebo was about 9%. So really didn't see much of a signal so far in those trials for any adverse event of hitting the glucagon receptor.

To your point, certainly, we will be tracking that in the clinical trials. And to Kirk's point, we see the increase in heart rate as being sort of the -- that's the signal that we're looking for.

So if I'm understanding you correctly, the heart rate increase portends potential risk of arrhythmias.

No, I wouldn't say that. I would say that -- yes, sorry.

Sorry, Kirk, you were saying something?

Yes. The heart rate increase that's seen in the 2 Phase II studies with retatrutide is in the range that's seen with the GLP-1 agonist and the GLP/GIP agonist tirzepatide. And those agents have cardiovascular outcome studies. The GLP-1 agonist at least have cardiovascular outcome studies, where they actually reduce risk and have not been shown to be associated with any clinically relevant arrhythmia. So the expectation here, again, looking at the Phase II data for retatrutide just regarding the pulse rate increase is pretty similar to what you see with the GLP-1 and those have proven cardiovascular safety reduction or risk reduction rather, pardon me.

And our next question comes from the line of Tara Bancroft with TD Cowen.

It's great to see such an exciting new asset. So I know it's early to be thinking about the market for these, but we can't help ourselves. And I want to expand on Kripa's earlier question anyway, which is at a higher level in the market, how do you see these fitting into the treatment landscape? Like if it's so potent for all these targets, maybe is it -- do you envision it more as an initial therapy before maintenance? Or are you confident that could be titrated for longer use? Or would it be competing most with tirzepatide, retatrutide or all of them together, do you think?

Yes. I mean -- so it's a great question, and Tara, you're right. It's too early to -- well, never too early to ask a question, but a bit too early to speculate on all that. But keep in mind the magnitude of weight loss is directly proportional to the dose. So there is no harm in starting with a lower dose and then inching upwards as necessary. And in fact, that's kind of a step-up dose titration is almost mandatory with the obesity drug. So I think our biggest appeal is that this is a single entity that is both oral as well as subcu and we look for like what should we strive for so that we will compete and stand out in the future, not in the present. And it was with that mindset that we chased what seemed like to be almost impossible about a year ago. And as you see, we have achieved remarkable relative potencies -- both absolute and relative potencies against the 3 targets. And the results, I think, have manifested themselves in the DIO studies and also in the higher animals, higher species like dog and cyno. So I think we are at a very good place. And then once again, getting back to your commercial thing, the fact that we have both oral and subcu even widens the choices that makes the entry easier for early initiation, early adoption, transition, all of that.

I would remind you that we did all the preclinical and Phase I work for icotrokinra -- ico, let's put it that way. And so we have a great team on the pharmacokinetic side, and we're going to design our early Phase I and early Phase II studies to give us maximum information to the points you're saying about how to use each unique product with regard to its pharmacokinetic and pharmacodynamic profile.

And our next question comes from the line of Douglas Tsao with H.C. Wainright.

And I guess, Dinesh, when we think about the subcu and oral programs, do you think it's possible that over time, we could see the 2 products with slightly different profiles, and therefore, maybe one is more appropriate for one patient group than another? Or is it really your intent to really have the 2 products have very -- as close to profile as possible to really just sort of give patients an optionality in terms of sort of how they administer the drug?

Doug, it's a great question, and we'll find the real answers in a human setting because from a scientific perspective, you can imagine that with an injectable, you are kind of "starting out" with maybe a higher kind of concentration and PK characteristics in the beginning, whereas with an oral -- and you saw we pointed out on the observation of drug accumulation with oral dosing. So it's almost then starting out in the opposite category, if you will, right? You start out with lower drug levels and then inch up higher. But once again, we'll find out the real answer in a clinical setting and at a practical level, we have covered all bases.

You nailed it, though, Doug, in terms of the brackets, of the boundaries. And on either side of the boundary, it's a good idea to have the subcu. On the one hand, it's just another choice for patients who want a different format of taking their drug and some prefer subcu than oral. On the other hand, there are important differences in safety and efficacy that relate to how and when they should be used and that's what our Phase I studies and the Phase II studies will be designed to figure out.

But I wouldn't be surprised. I think your hunch is correct, I wouldn't be surprised if the difference between oral and subcu extends beyond just the difference of administration. And then at a practical level, like I said, for Protagonist as a company. And even for patients, it's irrelevant because we have both choices.

Our next question comes from the line of Geoff Meacham from Citibank.

Thanks for the question and for all the detail. I had a couple of quick ones. The first is can you talk about what you've done preclinically on looking at things like GI or liver or other toxicities and maybe how that compares to some of the assets that you've tested? And the second thing is, when you think about receptor engagement for 477 within the 3 modalities, I guess, 2 questions. One is, have you compared to other orals in development? And then, b, is there a minimum on any of those modalities that you need to hit that you think the threshold that -- to see differentiated weight loss?

So I'll give short answers and then Kirk and Newman will elaborate. In terms of comparing other orals, so the small molecule orals that are out there, they do not have any appreciable potency against the mouse receptor. So that is a handicap right there, and that's why we didn't pursue that. In terms of the GI effects and things of that nature, we haven't conducted specific studies, but it's fair to share that in dog or cyno, Newman, we didn't see any kind of GI -- observable GI effects, right?

Yes. So we didn't see any -- in the cyno and dog studies, we did -- we didn't see any GI tolerability issues. We obviously are going to do standard tox package. So we'll certainly learn if there are any tox issues as we do our IND-enabling studies. I am going to -- you asked about GLP-1 agonist comparisons. And I didn't show you the data, but we also included semaglutide as a control at doses that are relevant for weight loss of semaglutide. We did use that as a GLP-1 agonist. And we didn't show it to you because we thought that well -- retatrutide is clearly the higher bar and we saw that in our experiments and but yes...

And the oral small molecule GLP-1, they don't have activity against rodents.

That's correct. That's correct.

Also remember that small molecules in general have much less potency. And so are much more common to have off-target effects. In our case, we're informed about 2 kinds of effects. One, the pharmacodynamic effects, the known pharmacodynamic effects, we were informed on that by the development of the existing product either on the market or in development. But in terms of off-target effects, our experience teaches us that peptides have a very limited chance of off-target effects because of their high degree of potency.

And our next question comes from the line of Jon Wolleben with Citizens.

Congrats on what looks to be an exciting molecule. Hoping if you could comment a little bit about manufacturing costs? You commented a bit about bioavailability in the context of efficacy, but how do we think about the logistics and feasibility of manufacturing the 2 different subcu and oral options?

Yes. And again, Jon, I mean, obviously, as you know, it's the same API. So the API manufacturing basically is a common component. And in a way, we have in terms of our experience, our network with the contract manufacturers, all that -- those kind of things, we have almost had a head start. We are ahead by almost a decade compared to most of the companies. So we feel very comfortable with the -- not just the COGS component, but also the scalability component in the scheme of things. And yes.

Okay. And then when you talk about the optimal combo of weight loss, tolerability and lean mass preservation, we're seeing the field kind of shift, I think, over time because the retatrutide data was so astounding weight loss wise, but now kind of an appreciation that a lot of these co-morbid benefits are seen at lower weight losses, we may not need 25%-plus weight loss. And tolerability remains a big issue for many molecules. So how do you think about the actual -- what is the combination that you think is going to be optimal for most patients?

Yes. So the beauty over here is like if you create a triple agonist, you certainly are covering both -- all kind of patients, right, the full spectrum. Because at the end of the day, the effect is correlated directly to the dose. We showed you a beautiful dose-proportional data where we are reducing weight anywhere from 11% all the way to 50%. So it's just a matter of choosing the right dose for the right patient.

And our next question comes from the line of Yun Zhong with Wedbush Securities.

Sorry if I missed it, but could you remind me if the oral and also the subcu, they have the same binding profile or different binding profile, in terms of receptor and potency, please?

It's the same chemical entity.

The potency assays that we did were -- they are in vitro assays.

Yes. The reason why I asked was -- I assume probably for oral and the subcu, the ideal binding profile might be -- may be different. But I think then will you be able to share data across 2 different formulations so that may be in terms of time line and capital use, there could be a little more efficiency when you develop both formulations going forward?

Yes. So I think as I mentioned in response to a prior question, we will be slightly ahead with the initiation of the subcu formulation in comparison to the oral, but there is not a significant difference between the 2 time lines, I would say.

I see. And on the subcu, I think on several slides, you actually showed data which seems to be better than Lilly's asset. And although you are benchmarking to the data, it looks like using the word comparable, but is it realistic or reasonable to expect that your subcu formulation might show better efficacy than Lilly's assay, please?

I mean, we are quite optimistic about that observation because that's an observation that we have made in higher species like cyno and dog where there is much closer homology to the human targets, right? So yes, so that's an observation, we cannot ignore, but we also cannot ignore the fact that these are preclinical studies. So the real finding will be in a clinical setting. But I think it's -- those observations in higher species compared with our deliberate engineering of the optimal relative and absolute potencies when you add all that up, there is reason to be optimistic about, let's say, better performance by our drug candidate compared to retatrutide. But the real telling will be for the clinical studies.

And our next question comes from the line of Evan Seigerman with the BMO Capital Markets.

So at ADA, Lilly indicated they have an undisclosed oral triple-G agonist in development? And just more broadly, given the rapidly evolving competitive landscape, how will you as a company accelerate the development of 477 in a really capital-efficient manner? I want to really get to the core of how you do this in a way that's efficient, yet allows you to remain competitive given how much is going on in the space.

Right. So -- and that is why the -- right from the get-go, we are striving for a huge and significant differentiation. So we didn't settle, let's say, for mono agonist oral peptide. Although that is something we could have easily done if we wanted to. And as you can see from the data, whatever is out there in the public domain in a visible manner, we are at par with it or even superior to it. So that's basically as good as you can get. The other thing is like -- as you know, we have all different assets. Rusfertide is a rare disease drug. It will cater to a small patient population of polycythemia vera patients. Our icotrokinra drug partnered with J&J is in the I&I space. It will cater to a slightly larger population. But in obesity, I mean you're talking about orders of magnitude, more number of patients, right? So the opportunity that exists over here is of such a massive scale and couple that with the strong differentiation we are offering and the optionality of oral and subcu, I think, all those features added together help us differentiate ourselves even though we may be a little bit late to the party. And then finally, the kind of path has been traveled before. So we should be able to expedite the studies and kind of benefit from the early observations, which will make it clear, not just for us, but for others as well, right? I mean, obesity is such a huge opportunity -- and there are several pharma companies that could very well get interested in this program as well.

And our next question comes from the line of Richard Law with Goldman Sachs.

This is [indiscernible] on for Richard. I guess when it comes to thinking about the partnership prospects for this molecule, I know you guys have talked about in the past, right, you're really focused on retaining control up and through Phase II proof of concept. But I think for obesity, we've really seen a lot of pharma companies like to get their toes into some of those earlier-stage assets. So is this an asset that you guys would be potentially open to partnering sooner than Phase II proof of concept? Or just how are you thinking about that opportunity?

Yes. So I think clearly, as a company, we have to keep all options open and entertain all options available at any given time. And -- but just to be clear, and as you said, we have the financial and human resources to move the asset on our own up to Phase II clinical proof of concept. And then at the Phase III initiation, which is after a few years, that will be another junction to weigh all our options then and make the optimal decision at this stage. And historically speaking, I mean, as you know, we have partnerships with Takeda and J&J. So we are pharma partnership friendly, so to speak. But the idea would be like to have the mindset of doing the right deal with the right kind of terms at the right time. And of course, a pharma partner, as you know, it's not just about a pharma company bringing financial resources. They bring amazing capabilities with their experience, expertise, ability to scale. I mean, look at the magnitude at which J&J is evaluating icotrokinra in all different clinical studies. So we appreciate the worth of partnerships. But there is a right time and place for everything.

Our next question comes from the line of Kaveri Pohlman with Clear Street.

Congrats on all the progress. So with 2 formulations, the comments you made previously were that you might -- if there is any opportunity, you might be able to develop them for different settings or different indications. I just want to understand how much of that are you considering in your current cash position and cash runway? And do you think if you plan to pursue basically these could be treated as 2 different assets now? And could you clarify how much cash is allocated to the current operational plan versus 477 related activities? And my second question is regarding manufacturing basically. Are you considering external partnerships or outsourcing for manufacturing going forward?

So Kaveri, I think, you are absolutely right. It's 1 single peptidic entity, but these are 2 clinical development programs. That is pretty clear. And in terms of manufacturing, once again, we have deep-rooted expertise and experience internally. We have an amazing network and relationships with CROs. But this is something that will be strengthened and expanded upon over the coming years, no doubt about it. And in terms of -- but the bottom line is like we feel very confident about managing the manufacturing in a very cost-effective manner and as well as at a scale that will be required to fulfill the demand. Now in terms of the cash guidance and clarity, I will turn it over to our CFO, Asif.

Kaveri, thank you for the question. As a reminder, our public guidance is the cash runway through at least the end of 2028 and that's based on what we reported at the end of Q1, approximately $700 million of cash in the bank. And while we've not -- to your specific question, we've not guided to how much of that is allocated to each of the assets and we're comfortable reiterating that cash runway guidance based on the candidates that we've just disclosed to you today.

Thank you. And with that, there are no further questions at this time. I would like to turn the call back over to Dr. Patel for closing remarks.

So thank you, everyone, for joining us on the call today. We look forward to providing further updates at the appropriate time and be assured, we will continue our strive for novel, differentiated assets through our expertise in the field of peptides. And we will be moving forward in a manner so that we can create maximum value for our shareholders.

Thank you. Ladies and gentlemen, this does conclude today's presentation. Thank you once again for your participation. You may now disconnect your lines.