Good day, and welcome to the PN-943 phase II data readout conference call. All participants will be in a listen-only mode. Should you need assistance, please signal a conference specialist by pressing Star then 0. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press Star then one on a touch-tone phone. To withdraw your question, please press Star then two. Please note this event is being recorded. I would like to turn the conference over to Jami Taylor, Vice President of Corporate Affairs. Please go ahead. Thank you, Matt. Good afternoon, everyone, and welcome to the Protagonist Therapeutics conference call and webcast to discuss top-line data from the phase II IDEAL study of PN-943 in moderate to severe ulcerative colitis. Turning now to slide two. We are joined today by Dinesh Patel, PhD, President and Chief Executive Officer, Scott Plevy, MD, Executive Vice President and Head of Gastroenterology at Protagonist, and Bruce Sands, MD, MS, the Dr. Burrill B. Crohn Professor of Medicine at the Icahn School of Medicine at Mount Sinai. Dr. Sands is a principal investigator of the phase II IDEAL study, the topic of our discussion today, and a consultant to Protagonist. Also with us on the call today are David Liu, PhD, Chief R&D Strategy Officer, Suneel Gupta, Chief Development Officer, Samuel Saks, MD, Clinical Development Advisor, Paula O'Connor, MD, Senior Vice President of Clinical Development, and Asif Ali, Protagonist Chief Financial Officer. Earlier today, we issued a press release outlining new data from the phase II IDEAL study of PN-943 in moderate to severe ulcerative colitis. This release, as well as this webcast presentation, will be available in the investors and news section on our website at protagonist-inc.com. The slides for this presentation today are also posted to our website. We'll now turn to slide three in the presentation deck. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for purposes of federal securities laws. They include statements about our plans and expectations regarding various programs. Actual results may differ materially from those indicated by our forward-looking statements, so we encourage you to review the Risk Factors section of our most recent periodic report filed with the SEC. Next slide, please. I'll now turn the call over to Dinesh Patel, president and CEO of Protagonist. Dinesh? Thank you, Jami, and thank you all for joining us today. The purpose of today's call is to share the top-line data from the IDEAL phase II study of PN-943, as per our prior guidance of doing this sometime in the first half of the second quarter, and to announce our ambitious and well-justified future plans based on the positive results that we have obtained from this study. It's a momentous day indeed, not just for Protagonist, but also for the broader pharmaceutical community, for clinicians, and especially for patients. The severity of unmet need in ulcerative colitis, or UC, persists even today, despite the introduction of new therapeutic agents over the course of recent decades. Today's announcement represents what we consider could be a leap forward in the potential treatment paradigm for UC on multiple levels. At the outset of our work in UC, we sought to develop what we loosely refer to as an oral ENTYVIO as a safe and effective therapeutic option for patients. Specifically, we refer to PN-943, an orally administered and gut-restricted peptidic entity working through blocking α4β7 Integrin, a biological target with robust clinical as well as commercial validation in the arena of inflammatory bowel diseases, or IBD. Today, the Protagonist team is pleased to announce the results from the phase II IDEAL study with PN-943 that places us closer than ever before towards achieving this ultimate goal. I'm glad to report that we have now successfully achieved the clinical proof of concept for an oral gut-restricted approach for ulcerative colitis via blockage of the integrin pathway. As noted in our press release, we look forward to expeditiously advancing PN-943 in a phase III registration study, pending regulatory guidance. This decision is based on the results that the 150-mg twice-daily dose of PN-943 has been found to be both safe and effective and showed efficacy levels similar to vedolizumab in similar studies. What further assures us is the strong concordance we have observed between the primary endpoint of clinical remission and various secondary endpoints, including histological remission and endoscopic improvements. We believe the results of the IDEAL study may be paradigm-shifting and of broad scientific relevance in understanding IBD pathogenesis and gut-restricted drug development via intervention of the integrin MAdCAM pathway. Based on its convenience of oral administration, the increased optionality of combination therapy that comes with an oral drug, and the favorable efficacy and safety results observed to date, we believe that PN-943 has the potential to become a first-in-class foundational oral medicine for individuals living with moderate to severe ulcerative colitis. There are more than 700,000 individuals living with ulcerative colitis in the U.S. alone, and many are not well-served by today's treatment options. Current therapies have important limitations and liabilities, including many that require burdensome injectable routes of administration. We believe that PN-943 as an oral therapeutic candidate with a potentially highly favorable efficacy and safety profile, has the potential to provide a significant new treatment option to the UC community, and we believe that our approach may have tremendous commercial opportunity. With that, now let me turn it over to Dr. Scott Plevy, our Executive Vice President and Head of Gastroenterology, who will walk us through a top-line summary of the phase II data. Scott? Thanks, Dinesh. It is my pleasure, and I'm very excited to share this data from the phase II IDEAL study of PN-943 in moderate to severe ulcerative colitis. We'll begin on slide five, and I'd like to start by level setting. As a reminder, in our previous small phase II PROPEL study with the first generation oral peptide α4β7 antagonist PTG-100, we reported a delta versus placebo for clinical remission of 11% at the 900 mg QD dose, supported by a dose-dependent increase in histological remission in this study. These results compare favorably to results from the registrational vedolizumab trial, as well as studies from other approved drugs in ulcerative colitis, including tofacitinib and ozanimod. I'll ask you to remember this important point. The low dose of PN-943 of 150 mg BID in the IDEAL study was modeled to replicate the 900 mg QD dose of PTG-100, as PN-943 is three times more potent compound. Slide six, please. Now, for a successful phase II proof of concept study, there are three major goals. Number one, to make a decisive decision, a go/no-go decision to move into a large phase III registrational program based on efficacy and safety. Two, to execute the phase II study so that the results can power registrational endpoints in phase III. Three, to derive critical information on dosing for phase III. On this slide, we give three examples of successes in this phase II to phase III transition in ulcerative colitis. For vedolizumab, ozanimod, and recently upadacitinib, phase II deltas for clinical remission of 10%-20% versus placebo were used to initiate and power successful phase III programs. We will now show you data from IDEAL that unequivocally supports all of these metrics for advancement into phase III with PN-943. Slide seven, please. To review the study design, IDEAL is a phase II trial of PN-943 that was conducted at 122 sites. In the 12-week double-blind placebo-controlled treatment period, which we'll focus on today, participants were randomized in a 1:1:1 to PN-943 at 450 mg BID, 150 mg BID, or placebo BID. Key inclusion criteria were moderate to severe ulcerative colitis, defined as a three-component Mayo score comprised of stool frequency score, rectal bleeding score, and centrally read Mayo endoscopic score of 5-9, and prior inadequate response to at least one conventional medical therapy or a biologic excluding vedolizumab. The primary outcome measure, which is on the bottom of this slide, is the proportion of subjects receiving PN-943 450 mg BID achieving clinical remission defined as stool frequency score of less than or equal to one, rectal bleeding score of 0, Mayo endoscopic score of less than or equal to one at week 12 compared to placebo. These secondary outcome measures include clinical remission at the 150 mg BID dose, and then comparison of both doses for endoscopic and histologic improvement and remission. 358 subjects were screened in this study, of which 169 were randomized between June 20th, 2020 and January 19th, 2022. As we previously disclosed, sites in Russia and Ukraine were closed. Patients from these countries who completed the week 12 evaluation are included in what we call, and I'll keep on referring to, as our modified intention-to-treat analysis or mITT, which comprises 159 subjects. This, at that time, was pre-specified as our primary population for efficacy analyses. Slide eight, please. The overall geographic distribution of patients was predominantly from Eastern Europe, reflecting the consequent predominance of bio-naive patients that I'll show you on the next slide. Slide nine, please. Looking at baseline demographics and disease characteristic results, 86% of the subjects enrolled in the study were naive to biologic therapies. There were qualitative imbalances among the treatment groups for baseline biologic and corticosteroid use, neither of which affect the overall interpretation of efficacy. Slide 10, please. Now we're getting into the important, data results. Although the pre-specified primary endpoint, clinical remission 450 mg BID versus placebo, was not met and there was minimal differentiation from placebo in this high-dose group, a consistent treatment effect was observed in the low-dose group, 150 mg BID versus placebo across multiple endpoints. Shown on the left side of this slide in the modified intention-to-treat, or mITT group, the placebo clinical remission rate was 14.5%, which was slightly higher than we predicted, but is consistent with most expectations in the predominant biologic-naive population. For clinical remission at the 150 mg BID dose in the mITT population, an absolute remission rate of 27.5% was seen compared to this 14.5% in the placebo group for a delta of 13%, and a P value of 0.08. On the right side of this slide, we show you that in the bio-naive population, which again was predominant in this study, an absolute remission rate of 30.2% was seen at the 150 mg BID dose with a statistically significant delta of 16.2% versus placebo. Slide 11, please. Moving to key secondary outcome measures, we'll start with histology. This is an important correlation endpoint as it is a quantitative measure which is centrally read and completely independent of the Mayo score components. For histologic remission in the modified intention-to-treat population, there is a 23% delta for the 150 mg treatment group versus placebo with a significant P value. For histologic improvement, there is a 20% delta for 150 mg versus placebo with, again, a significant P value. Let's go to slide 12. On slide 12, here are the secondary endpoints for the centrally read endoscopic results in the mITT population. Starting on the right, endoscopic improvement was defined as a Mayo endoscopic score of 0 or one at week 12. Of note, some publications define this as endoscopic remission. In this analysis, we see a 26.7% difference in endoscopic improvement between 150 mg BID and placebo with a highly significant P value. On the right-hand side of the slide, we look at a very stringent definition of endoscopic remission, of a Mayo endoscopic score of 0 at week 12. Here we see a notable numeric difference favoring 150 mg over placebo, that did not reach statistical significance. Slide 13, please. To summarize our efficacy results, PN-943 at 150 mg BID demonstrated concordant treatment effects across multiple key primary and secondary endpoints with statistically significant differences in clinical remission in the bio-naive population, as well as histologic remission and improvement, as well as endoscopic improvement in the modified intent-to-treat analysis. Comparing our results to the induction data for vedolizumab in their registrational trial for bio-naive patients, we conclude that we are well within the vicinity of vedolizumab-like efficacy in an oral drug as we plan for phase III. There are many caveats of this comparison in that our primary endpoint was at week 12, while vedolizumab was at week six. Also, vedolizumab used a more lenient definition of remission where a rectal bleeding score of one could be considered remission, as well as the presence of friability on endoscopy. Overall, we find our efficacy results to be highly encouraging. Based on these robust and concordant clinical, histologic, and endoscopic outcomes, we are excited to rapidly advance PN-943 into phase III registrational studies, and we have found our dose at 150 mg BID. Slide 14, please. That's the efficacy component. Now let's move on to a top-line summary of our safety analysis. There were no drug discontinuations in either treatment arm related to adverse events, which were infrequent. There were no serious adverse events that were related to drug. The safety signal was overall similar for the 150 mg BID dose group compared to placebo. On the right-hand side of this slide, I wanna comment on frequent treatment emergent adverse events that occur in greater than 10%, for the infection and infestation category. This is a bit of an eye chart, but here there is a potential signal for increased upper respiratory and mucosal infections in the ineffective 450 mg BID treatment group, which for efficacy reasons will not be moving forward. We believe that 150 mg BID is a safe dose to study in registrational studies. The take-home message is that adverse events at 150 mg BID are infrequent and have not affected dosing in these patients. We believe this is a safe dose to study in phase III. Furthermore, we believe that the favorable safety profile that we have seen with PN-943 is an important advantage with our approach. Safety is an extremely important consideration in the treatment of ulcerative colitis, a chronic disease where patients require many years of treatment, and we believe our safety profile may be a key point of differentiation to other available drugs. Slide 15, please. On this slide, we are gonna take you through our data on PK and receptor occupancy. On the left side of this slide, we show dose-dependent increase in serum levels of PN-943, noting that PN-943 is minimally absorbed. On the right side, we show peripheral blood T cell α4β7 receptor occupancy. There is a general trend towards slightly higher receptor occupancy at the higher dose with large and overlapping error bars consistent with wide inter-patient variation. Interestingly, receptor occupancy was in the 30%-40% range for the effective 150 mg BID group. These results demonstrate that for the gut-restricted, locally acting mechanism of integrin blockade of PN-943, there are no correlations between clinical efficacy and dose-related serum PK or blood T cell receptor occupancy. Next slide, please. Next, let's review our dose response results that we just presented to you. In the IDEAL study, the 150-mg BID dose of PN-943 was superior to placebo across all measures. By contrast, the higher 450-mg BID dose showed limited effectiveness roughly comparable to placebo. An inverse dose response or bell-shaped dose response in phase II ulcerative colitis studies has actually been a frequent occurrence across multiple therapies that block the α4β7 Integrin MAdCAM pathway, as well as anti-cytokine-based therapeutics such as the IL-23 pathway. This phenomenon has actually been observed as early as 1997 in the original Remicade phase II Crohn's disease study, but still not fully understood mechanistically. Decisions were justifiably made to move into phase III trials based on an identification of effective dose from these phase II programs. Specifically, this has been observed with antibodies targeting, anti-α4β7 Integrin, such as vedolizumab and etrolizumab, and one that targets the counter receptor MAdCAM-1 ontamalimab. Furthermore, the anti-IL-23 antibody mirikizumab also exhibited a bell-shaped response in phase II. One possible scientific explanation is based on the role of regulatory T cells that dampen inflammatory responses. In fact, the authors of two publications for etrolizumab and ontamalimab have specifically described Treg involvement as a potential biologic mechanism to explain the observed bell-shaped responses seen in phase II. In chronic inflammatory diseases like UC, the objective is to block inflammatory effector T cells but not anti-inflammatory Treg function. Slide 17, please. To illustrate specific examples, I'm showing you a recently published exposure response relationship between serum vedolizumab levels and clinical remission from the pivotal phase III programs in Crohn's disease and ulcerative colitis. In large numbers of samples, these data show that there are, in fact, diminishing returns with greater drug exposure in terms of clinical efficacy. In essence, what we're seeing at high serum concentrations of vedolizumab, a bell-shaped exposure response curve. In the same study, the investigators also demonstrate that T regulatory cells are less sensitive to the effects of inhibitors of the α4β7 Integrin MAdCAM pathway, suggesting that higher drug concentrations will begin to block these anti-inflammatory Treg functions. Importantly, the confluence of data and information suggests that PN-943 is uniquely active in the local GI tissue, and it's interesting to speculate that local concentrations may affect activation, trafficking of inflammatory cells, and at higher doses, immunoregulatory cells as well. Next slide, please. Here's another example of a dose response in phase II that was advanced into phase III. These are results from an extensive dose-finding phase II study of the anti-MAdCAM-1 antibody ontamalimab in ulcerative colitis, showing a clear bell-shaped dose response. Next slide. On slide 19, here is a bell-shaped dose response curve determined in a phase II study of the anti-IL-23 antibody mirikizumab. Notably, Lilly, who makes mirikizumab, recently reported positive phase III data in ulcerative colitis, achieving the primary endpoint of clinical remission and all key secondary endpoints with statistical significance. In conclusion, the history of the IBD field, illustrated by the data I just presented, gives us confidence that our demonstration of unequivocal clinical efficacy of PN-943 at the 150 mg BID dose is a robust signal for advancement into phase III. Slide 20, please. Let me make a few preliminary conclusions here and begin to discuss next steps. PN-943 at 150 mg BID appears to be a safe and effective dose. There was 27.5% absolute clinical remission in this group versus 14.5% in placebo for a delta of 13% in our modified intent to treat analysis. There was a 16% delta in the bio-naive population, which was statistically significant. There was strong concordance with efficacy across multiple key secondary endpoints with statistically significant differences in histologic remission and improvement as well as endoscopic improvement at the 150 mg BID dose. This data serves as confirmation of the clinical effect with the bioequivalent dose of PTG-100, 900 mg QD in PROPEL. Essentially, we have shown that the bioequivalent dose of PN-943 of 150 mg BID is clinically effective in two separate human experiments now. Taken together, these results show that PN-943 exerts a gut-restricted mechanism of action in the local tissue environment, and the data is confirmatory of our original TPP of vedolizumab in a pill-like efficacy. The safety analysis was similar for the 150 mg BID dose of PN-943 versus the placebo group. There was not a correlation between clinical efficacy for the gut-restricted PN-943 and blood PK as well as blood T cell receptor occupancy. We had demonstrated an inverse dose response consistent with several other modalities in the integrin pathway as well as anti-cytokine pathways. In final conclusion, the IDEAL study supports further development of PN-943 in UC registrational trials. I would like to finally comment that as a long-time researcher in gastroenterology drug development and as a clinician, I am extremely enthusiastic for these impactful study results. My excitement is unqualified to move PN-943 forward as a much-needed oral therapy for IBD patients. At this point, it is my great pleasure to introduce my colleague, Dr. Bruce Sands from Mount Sinai, who is a leading expert in the IBD field and someone who is well-positioned to comment further on what we've presented today and put this in the context of unmet needs in ulcerative colitis. Bruce? Yes, Scott. Thank you very much. Yeah. It's a pleasure to be here. I think it's worth sort of just looking backward at the journey that we've been through in treating our patients with ulcerative colitis. If you think about the days when I was training in the eighties and nineties, really we had conventional medications. We had 5-aminosalicylates. We know they work fine for patients with mild to moderate UC. There's so many patients who, in actuality, don't achieve mucosal healing on those agents and lose response. We know the downfall of steroids and their side effects. We know that the thiopurines are largely not very effective in ulcerative colitis and have a great number of side effects, including malignancy. Obviously the field was very happy when we had biologic therapies, namely the anti-TNFs, which clearly brought the field forward for the treatment of patients with moderate to severe UC. The field also recognized a few things about these agents, their safety profile being a little bit off-putting to both clinicians and patients with risk of malignancy and infection, certainly. Loss of response because of immunogenicity over time. The need for some patients at least for therapeutic drug monitoring to adjust dosing and lots of complexity in explaining all that to patients. Subsequent iterations of biologics with other mechanisms really did present a lot of progress. Namely with ENTYVIO, we finally had a safer biologic therapy, maybe not quite the equal efficacy of anti-TNFs, although in ulcerative colitis, when compared to HUMIRA, ENTYVIO seemed to be superior to HUMIRA in the VARSITY study that we published just a couple of years ago, and clearly has a better safety profile, but still suffers from the need for parenteral dosing. We have STELARA, of course, that's also parenterally dosed, seems to have a good safety profile. We have tofacitinib, XELJANZ, and that has black box warnings. I would note that all these agents really do not have effect sizes that exceed 10%-15%. By and large, we're seeing these sorts of effect sizes in approvable drugs. More recently, of course, we have the example of RINVOQ, just approved, and that is more effective than any of these agents, but also bears this black box warning. Finally, another oral therapy, we have ozanimod or ZEPOSIA. That would seem to be a somewhat safer oral agent. It does, in a different mechanism of action, affect trafficking. But it still comes with a lot of safety baggage in terms of cardiac conduction risk, use in older patients, drug interactions, that clearly people have to be aware of. Very important in our ulcerative colitis patients, not clear safety in women who wish to become pregnant because we have a younger patient population. The way I'd summarize it is the agents that have the convenience of oral dosing, by and large, don't have the safety profile that we would like. What we most like is the safety profile of ENTYVIO. I think there really is an important niche for, in our armamentarium, for an agent that looks like the safety profile of an ENTYVIO, but can be dosed effectively orally. When I look at the data from the IDEAL study, I note a few things. One is it, to me, seems to replicate the data from the PROPEL study. We now have two proof of principles demonstrating that this orally dosed agent can achieve the outcomes that we expect in terms of efficacy. There seems to be good safety. We're seeing effect sizes that really seem quite similar to ENTYVIO. We're seeing the convenience of oral dosing. I find it believable that the lower dose is the more effective dose. Scott outlined for you very nicely all the different agents that we've explored over the years that seem to have a bell-shaped dose response curve and a plausible immunologic explanation for this. In fact, I think, Scott, you may have missed one, which was the example of abatacept, a completely different mechanism, which really also seemed to have lesser efficacy and didn't seem to work. Again, the explanation was potentially differentially affecting T regulatory cells that could down-regulate inflammation. I think when I put it all together, I'm also enthusiastic about moving this forward into the next phase of study and understanding that you've found an effective dose that looks very much like ENTYVIO, but is orally dosed and also seems to be quite safe. From all these perspectives, I think this could be a very important contribution to the treatment of patients with ulcerative colitis. I'll stop there and pause. Thank you, Bruce, for that excellent summary and overview. This is Dinesh Patel again. Thanks for putting things in perspective, both for us and everyone else on this call. In closing, I want to emphasize how pleased we are with the outcome of this phase II dose-finding study with PN-943. Turning to slide number 22. To summarize the points that have already been made here today, first and foremost, we believe we have oral ENTYVIO-like efficacy in hand. Second, we believe we are well justified to move forward with a phase III registrational study. Third, Protagonist as a company will continue to innovate novel medicine to address unmet need of patients, driving the advancement of paradigm-shifting, cutting-edge science and leading the development of first-in-class oral drugs for IBD with clinically proven and well-established biological targets like α4β7 Integrin and also interleukin 23. I'll also add that what we have announced today is further validation of our proprietary peptide technology platform. This platform and the experienced R&D team that innovates it and develops it have proven to be among the most prolific drug discoverers in this industry today. We now have, as a company, three different maturing assets, all emerging from our platform, two of which are fully owned by us, and the third one is partnered with Janssen. The hepcidin mimetic rusfertide has moved into a registrational study for polycythemia vera and the oral gut-restricted integrin blocker, PN-943, as we are announcing today, we intend to move it into a phase III registrational study for ulcerative colitis after our dialogue with the regulatory agencies. Finally, the oral IL-23 asset, PN-235, is partnered with Janssen, and they are currently evaluating it in a 240-patient phase IIb psoriasis study. As we prepare now for the phase III study with PN-943, we will expeditiously assess, determine, and pursue the best of the many options that are available to us to support the financing of this effort, including potential partnerships and collaborations. Our cash position remains strong with cash and cash equivalent securities totaling $305 million as of March 31st of this year. In addition, in April this month, we received a $25 million milestone payment from Janssen Biotech in connection with the initiation of the phase II trial evaluating PN-235 in psoriasis. In closing, we are sincerely grateful to the clinical investigators who have participated in this study and to the patients who have made these scientific insights and this outcome possible. I want to extend my personal thanks to the truly world-class drug development and discovery team at Protagonist, and more broadly to all those who have shared and supported our vision for a safe and effective oral therapeutic agent that would ultimately transform the treatment landscape for IBD. We are committed to the mission of Summit today, impacting and significantly improving the quality of lives of those individuals who can benefit from an approved therapy such as PN-943. The results we have shared today further strengthens both our conviction and commitment. This now concludes our formal remarks, and we will now open the line for questions. We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then two. At this time, we will pause momentarily to assemble our roster. Our first question will come from Anupam Rama with J.P. Morgan. Please go ahead. Hey, guys. Thanks so much for taking the question. Just two quick ones from me. Can you remind us of the rationale for dose selection criteria here for phase II? Why did you choose 450 mg at the higher end? I know you talked about that, the rationale for inverse dose response, but how do you know that you're not leaving some efficacy on the table with a dose kind of in between 150 mg and 450 mg? And do you think you'll study multiple doses in phase III? And then Dinesh, just a quick clarification point on your final closing comments. To be clear, you are gonna be looking for a partner to help potentially fund a registration study, or would you be willing to take this on yourself as well? Thanks so much. Thanks, Anupam. Both are great questions. First of all, in terms of the rationale for 150mg BID versus 450 mg BID, the thought process was that 150 mg BID, as Scott explained, is kind of equivalent to the 900 mg effective dose of the first generation drug PTG-100. Then the question remained, "Hey, could we achieve higher efficacy by going to higher doses?" Today we know that that will not be the case if you went threefold higher. Now, if there is a sweet spot in between or at a slightly lower dose, all that remains to be seen and those could be the subject matter of future studies. Right now, as they say, you know, the bird in hand is the 150 mg BID dose. I and Scott and Bruce narrated, we believe that we are staring at ENTYVIO-like efficacy with an oral alternative. The intent would be to run towards a phase III registration study as fast as we can with the 150 mg BID dosing. As far as the financing is concerned, keep in mind that we have constantly provided guidance that we are ready for a successful outcome in terms of the initiation activities of a phase III study, largely the CMC-related activities. In the short term, there is no interruption or any change in plans. We move forward and over a course of time, we will obviously be evaluating all different non-dilutive as well as the regular financing options that may come our way. Got it. Thanks so much for taking the questions. Thank you. Our next question will come from Chris Howerton with Jefferies. Please go ahead. Hi, team. This is Kombi on for Chris. Couple questions from me. Could you identify any reasons for the high placebo remission rate? Can you remind us of the powering assumptions heading into the trial for the different dosing regimens? Second question, mechanistically it was hypothesized that dosing at levels greater than receptor saturation may be required for clinical efficacy. How do these results affect that hypothesis? As a last question, are any of the next steps phase III development or meeting with the FDA on capital dependent? Thank you so much. They're all very good questions. Let's get to your first question about the slightly higher placebo with Scott Plevy. Yeah. We saw a placebo remission rate of 14.5%. We were conceiving and hoping that it would be somewhere in the range of 10%-12%, and I think that was a general consensus amongst KOLs in the field. Having said that, nobody is really gonna bat an eye in terms of KOLs in the field and clinical trialists at a 14.5% placebo remission rate in a biologic-naive population. Why exactly it was a little higher than we expected to see, my prediction is as we dive deeper and dice and slice up the data, there's not gonna be a very clear reason for it. I would think of this more within the range than what we would expect to see in a bio-naive population, and consistent with some of the recent clinical trials that you see in bio-naive patients rather than something that stands as an extreme outlier. Very good. Kombi, sorry, can you repeat about your question about the blood receptor occupancy? Yeah. I mean, mechanistically it was hypothesized that dosing at levels greater than receptor saturation maybe required for clinical efficacy. How do these results affect that hypothesis? Yeah. We'll have David Liu take that question. Hey, Kombi. The assumption that you just made was really based on a discussion we've been having with everyone about the systemic drugs. That for them, the supersaturation is required at trough levels that were far and above, that was required for minimal 100% receptor occupancy. That was a condition we felt that was important to be understanding how one thinks about receptor occupancy and systemic drug efficacy. In a sense, all bets are off for a gut-restricted approach, where indeed we are using receptor occupancy in the blood, as we've always said, as a surrogate for whatever happens in the gut tissue. Both target engagement and potentially trafficking back through the compartments back and forth, as well as local activation of cells that are now being inhibited by PN-943. I hope that separates the issues of the systemic drugs and receptor occupancy versus receptor occupancy for us being a surrogate, for exactly what we needed to do, which was to try to define a dose range that would be effective, and meaningful for the phase II, and I think we've accomplished that. I think probably our last question about partnering/financing is similar to what Anupam asked. Look, I mean, the reality is that this is an asset that at the end of the day, at a commercial level, belongs in the hands of a large pharma or a company with much larger and bigger capabilities than Protagonist. So at some stage, we do need to join hands, and we'll be just opportunistic and do a balancing act between what is in the best interest of the stakeholders at any given time. That will dictate the financing outcome. As I also mentioned, we are not starved for cash. $300+ million in the bank right now. In addition, the $25 million we received from Janssen gives us, you know, a pretty good war chest. Our budgeting assumptions had already a baked-in success scenario. We are good as far as initiating the activities is concerned. I think the next steps right now are like, you know, having a dialogue with the FDA, benefiting from their input, structuring the proper study. We are seasoned drug developers. We know what 13% delta means. As you know, Bruce, I think might have mentioned, HUMIRA had a delta of 9%, and that happens to be the largest drug on planet Earth last time I checked. We are good, I think, at this stage. The next steps will reveal themselves over a course of time. We are not gonna do anything out of desperation. Great. Thank you so much, Dinesh. Mm-hmm. Our next question will come from Yasmeen Rahimi with Piper Sandler. Please go ahead. Hey, team. Thank you for taking my questions. I have a number of them. I'm just gonna go one by one so we can get some clear answers. Maybe the first one is a clarification question. So the study enrolled 169 patients, but then the mITT had 159. You mentioned something that 10 patients, I guess, didn't complete 12 weeks due to European sites, so that's why the mITT was 159. Is that correct? Can you clarify what the mITT was and what happened with the 10 patients? Yeah. Hi, hi, Yas. Yeah. Thank you. Let's start there. Yeah. The 10 patients were all from Russia and Ukraine. On March 3rd, we closed those sites. At that time, we said that any patient from Russia or Ukraine who had completed 12 weeks would be included in our primary efficacy analyses. The ones who have not reached week 12 because of inaccessibility and inability to verify the data would not. We randomized 169 patients. At the time we closed the sites, we pre-specified, and it's in our statistical analysis plan, that our primary efficacy analysis would be on this modified intention-to-treat. The 159 patients who were in the modified intention-to-treat do not include these 10 patients who had not completed week 12 from Russia or Ukraine. Yes, I hope that part is very clear. There is not, there is no suspense there, right? We know what happened and what is happening in Russia and Ukraine and the challenges of continuing with the clinical studies there. That's all there is about those 10 patients. No, no, that's super helpful. Thank you. Sorry. You went way fast during the call, so I might have missed it. Thank you for that. We have so much to cover. A lot to cover. Yeah. Keep going, Yas. Come on. No, I get it. Okay. Second question is actually to Dr. Sands. Thank you're a busy man, for making yourself available. Obviously you've seen a lot of phase IIb's and you've seen phase IIIs, so the fundamental next question that investors are gonna ask is what's the treatment effect gonna be in a phase III study? Typically they tend to weaken. Dr. Sands, given the data that you just saw from IDEAL, like, how confident can we be around what the phase III results could look like and how this could fit into that current treatment? If you could just provide some commentary, please. Sure, I can. My expectation is that the phase III is going to look very similar in terms of delta, assuming that the population is designed in a similar way. The reason I can be assured of that is because this also looks like what they showed in the PROPEL study and more importantly, looks like what we see with ENTYVIO in this population. I'm not sure that anyone could expect much more of this particular mechanism than what we see with ENTYVIO. I think we're matching what we're seeing with that mechanism, and I think that's what, you know, that's the kind of effect size that we'll see in phase III, with the understanding that you'll have more power and more precision of that estimate. That's what I think it will be. I, you know, look to the consistency of the data here. They're all aligned. I don't see imbalances in the randomization that explain the effect. I think there's alignment among objective and subjective outcomes, and that's what we like to see in phase II that predicts success in phase III. Thank you, Dr. Sands. The one data point that doesn't align, at least for the 150 mg dose group, is the data from endoscopy remission. Were you shocked that it didn't achieve stat sig? Is it just 12 weeks is too short? Was the placebo aligned with what we expected? Like, what is that, you know? That seemed a little bit of an outlier. Yeah. Yeah. Yeah. Endoscopic remission. Go ahead, Scott. I'm sorry. No, but go ahead. Oh, you go, Bruce. I'm sorry. That's okay. No, you have to understand that endoscopic remission is a 0, and that isn't really the primary outcome that's incorporated into the primary outcome expected by the FDA. I think it's these endoscopic outcomes, even though they're essentially red, there's a little bit of squishiness to it, and I'm convinced by the fact that you see endoscopic improvement and I think you will also see or you did see histologic that may be similar. In other words, there's concordance between what you see endoscopically and histologically that makes it real for me. I think in such- Yeah. A small study, you can see some variations like this, and it is not very meaningful. All the other things do align. Bruce, I'd like to add to that. That, yes, we'll go over the slide with the data with you in more detail for sure. But on that slide, we showed our definition of endoscopic improvement, which is defined as a Mayo score of 0 or 1 at week 12. Other groups have called this endoscopic remission, and the deltas of the absolute numbers we see for that category are quite frankly, as good as it gets, if you wanna compare this to other studies. What we showed that did not hit statistical significance on the left side of the slide, which we're n umber 12. Which we're trying to get, which we could get up there, as Bruce mentioned, is this extremely stringent definition of endoscopic remission, which is just a score of 0 at week 12. Once again, this data is gonna be comparable to everything else that you're gonna see in phase II and phase III. The P value is 0.002 if you look at the endoscopic improvement definition as a score of 0 or one. Okay. Our next question will come from Douglas Tsao with H.C. Wainwright. Please go ahead. Hi. Good afternoon. Thanks for taking the questions. I'm just curious, going back to the dosing issue, I think you noted that the 150 mg was modeled to replicate what we saw with the 900 mg from PROPEL. Could you just walk through exactly, you know, in what ways it replicates the 900 mg and in what ways there might be some differences? Sure. You know, Doug, as you remember, our second-gen drug, PN-943, is threefold more potent than the first-generation drug, PTG-100. 150 BID, meaning 150 mg twice a day, equates to 300 mg daily dose. When you multiply that by the threefold more potency, you get to the 900 mg equivalent of the first generation drug, PTG-100, which was the most efficacious and effective dose in the first study, the PROPEL study. I could just add that this was all verified in the phase I comparisons using both PK as well as pharmacodynamic markers to show that a threefold lower dose of PN-943, we would see an equivalent response in those parameters to the PTG-100 at 900 mg. Yeah. The threefold more potency has played out in all measures of in vitro, in vivo, potency measurements. I guess just given what you saw with the 150 mg and the 300 mg from PROPEL, that's why you didn't necessarily see utility in testing lower doses in the IDEAL study. You got it. Yep. That is the beauty if you think about it. Again, all this is going to be pending our regulatory dialogue. In a way, we have found the sweet spot, the effective dose. You go higher, we don't want to do that. You get into the bell-shaped response curve. You go lower from the first study, we know that is going to get us to a point of diminishing returns, if you will. Now there is always room for fine-tuning in between those three different blocks, if you will. You know, we can do that separately. The intent right now is to have a dialogue with the FDA about the 150 mg BID dose as the anchoring dose for a registrational study. Okay, great. That's really helpful. Just one final question, and I know, you know, obviously, you know, you're well-resourced. Do you have an initial sense of how much the phase III study may cost? Yeah, I think, you know, again, all that becomes more apparent after we finalize the study design, which again, will be pending the FDA dialogue. I think it will be best to revisit that question and provide clarity on that at that particular stage. Right now, what we do know is that we are geared up both in terms of, you know, having a preparedness of initiating a phase III study. I'm referring to the API, the drug substance, the drug product, the things of that nature, and with the intent of getting going with a registrational study as soon as we can. Okay, great. Thank you so much. Thanks, Douglas. Our next question will come from Julian Harrison with BTIG. Please go ahead. Hi. Thank you for taking my question. We're starting to see ENTYVIO become more frequently prescribed in the first line biologic setting. I'm wondering how important the signal you saw in biologic-naive patients was in your decision to proceed to registrational development. I guess along similar lines, to what extent do you think you can enrich for biologic-naive patients in your next studies here? Great questions and great points. First off, we are fully cognizant that an efficacy and safety profile like we're showing in our TPP could make this an absolutely intriguing option as a first-line option in bio-naive patients. In a registrational trial, a lot of what we will have to do is dependent on regulatory precedent. We also have to acknowledge that there is tremendous unmet need in the majority of patients who at this point, particularly, let's say, in the G7 countries with ulcerative colitis, have been already treated with biologics. What we believe in thinking at a high level about a phase III study, it will be a mix of bio-naive and bio-experienced patients. Bruce kind of alluded to this before when we think about powering a phase III study. What has been shown across most of the drugs we have in IBD is that although the absolute response rates are less in the bio-experienced population, so are the placebo rates, so the deltas are relatively preserved. To really extract the most unmet need that we could address with PN-943, it would be a mix of bio-naive and bio-experienced population in phase III. How much we would enrich for one or the other, we'll see. It's certainly possible that we do more bio-naive than bio-experienced. Got it. Thanks very much. Thanks. Our next question will come from Joseph Schwartz with SVB Securities. Please go ahead. Hi. Thanks. Will you be re-randomizing patients who achieved remission and evaluate their ability to maintain a response on 150 mg of PN-943? When should we expect some maintenance data from IDEAL? Then I have a follow-up. Yeah. The maintenance portion of IDEAL is relatively small. It is double blinded. It's looking at both the 150 mg and 450 mg doses. Patients on placebo who are non-responders go on to 150 mg. Patients on 150 mg who are non-responders will get those escalated. Patients on 450 mg who are non-responders will continue on 450 mg. The problem is it's a relatively small study. We have three groups with all these combinations and permutations. I wanna manage expectations, although I think we could get some interesting sub-analyses out of these. It's going to be relatively small numbers of patients. I feel confident in saying that nothing we will learn in this part is going to mitigate our enthusiasm and speed for moving into phase III, where we could really rigorously test what a maintenance dose will look like. Okay. Makes sense. I'm intrigued by the very plausible hypothesis on slide 16 that says that the objective is to block effector T cells, but not Treg function. Will you be analyzing any data on this front from IDEAL? I think that would be very helpful to close the loop on that biology and convince the community that we understand the mechanism and can reproduce the results in phase III. Did you measure Tregs and effector T cell levels so that you can characterize this phenomenon in each of the doses? Joe, this is David Liu. It's a very important question, and I think suffice to say first is that this is only a hypothesis at this point. We will be developing more information as time goes by, both pre-clinically as well as clinically, particularly gathering and mining any data that we already have, but analyzed in this light of potentially having effects on immunoregulatory cells. Treg is one of them. There are other immunoregulatory cells that have alpha four, beta seven, so those are all under our intent to study. We'll see how that all evolves. That's definitely an important focus for us. I mean, in general terms, one thing we are basically learning over here is for integrin as a target for our approach, clearly the center of action is the GI tissue vasculature and not the blood compartment. Of course, with the commitment we have for nine four three, it will be our intent to do some, you know, preclinical and exploratory studies to develop a better understanding of the whole mechanistic aspects of the behavior of nine four three. You don't have the actual samples from this, the patients studied in IDEAL, to analyze? Yeah. Not from blood. We really don't, that's gonna be a future interest of us. Not from blood. Okay. Got it. Thank you. This concludes our question-and-answer session.