Thank you for standing by and welcome to the Upstream Bio phase II VIBRANT Top-Line Results Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. As a reminder, this call is being recorded. I would now like to introduce your host for today's conference, Meggan Buckwell, Director of Corporate Communications and Investor Relations at Upstream Bio. You may begin. Good morning and thank you for joining us today. Before we begin our formal comments, let me remind you that during today's webcast, we will be making forward-looking statements that represent the company's intentions, expectations, or beliefs concerning future events. These statements represent our views as of this date and should not be relied upon as representing our views as of any subsequent date in the future. Additionally, please note that this presentation includes comparisons of verekitug against existing treatments and product candidates in development based on third-party published data. Head-to-head clinical studies have not been conducted between and these products, and differences exist between trial designs and patient characteristics. Caution should be exercised when comparing across studies. With me today are Upstream Bio's CEO, Dr. Rand Sutherland, and Upstream Bio's Chief Medical Officer and Head of R&D, Dr. Aaron Deykin. Looking at our agenda today, Rand will begin the call with an overview of the results, an introduction to Upstream Bio, and our plans for our lead asset,. Aaron will then review the Phase II VIBRANT clinical study top-line results in detail, after which Rand will conclude the call and management will take questions. I would now like to turn the call over to Rand Sutherland. Thank you, Meggan, and thank you all for joining us today. We are thrilled to share the top-line data from the Phase II placebo-controlled randomized VIBRANT Trial of verekitug in chronic rhinosinusitis with nasal polyps, or CRS with NP. As Aaron will share in detail in a few minutes,, administered just once every 12 weeks, had clinically and statistically significant effects at the end of this 24-week study on the primary endpoint of endoscopic nasal polyp score, as well as key secondary endpoints, including the nasal congestion score. Remarkably, this trial also demonstrated a significant impact of on the need for steroids or surgery in study participants. V was also generally well tolerated, with no serious adverse events reported, consistent with previous studies. These trial results further extend the consistent body of preclinical and early clinical data from our development program, which together suggest the potential for to deliver meaningful clinical benefit at a significantly reduced dosing interval versus other biologics. These are the first placebo-controlled data for an extended dosing interval agent in the TSLP pathway, supporting our intent to develop in this and other indications, including severe asthma. I'd like to put the data in context of the current landscape of approved or investigational treatments for CRS with NP, with a focus on TSLP. This comparison is for illustrative purposes only, since head-to-head studies with have not been performed and study methodologies may differ. With these caveats, administered every 12 weeks, equivalent to four times per year, demonstrated improvements in absolute and placebo-corrected endoscopic NPS at 24 weeks that were generally consistent with those seen with tezepelumab, which requires administration every four weeks, equivalent to 13x per year, to achieve this effect based on published studies and product labeling. Agents targeting other pathways demonstrate clinical profiles that either require far more frequent injections per year to achieve similar clinical benefit, as in the case of dupilumab, or demonstrate significantly lower treatment effects in the context of twice-yearly dosing, as seen in published trials of depemokimab, a YTE-modified anti-IL-5. Before I turn the call over to Aaron to review the trial results in further depth, I'd like to provide a bit of context about Upstream Bio, about our molecule, and about CRS with NP. Upstream Bio is a clinical-stage immunology company, and our initial focus is on severe respiratory diseases. We are developing, the only known antagonist of the TSLP receptor. V 's unique pharmacology has been evaluated in preclinical and early clinical studies and is characterized by rapid, complete, and sustained occupancy of the TSLP receptor for up to 24 weeks after the last dose. Our corporate strategy is aligned with our focus on severe respiratory diseases and is designed to maximize the value of across multiple indications with unmet need. VIBRANT, our phase II trial in CRS with NP, is now complete. VALIANT, our Phase II trial in severe asthma, is on track to report top-line data in the first quarter of 2026. VENTURE, our Phase Two trial in COPD, is actively enrolling participants. TSLP biology also supports future expansion into other therapeutic areas, including dermatology and GI. V targets the receptor for TSLP and blocks its assembly. It is the only agent known to do so, and inhibiting TSLP has been shown to reduce both type 2 and non-type 2 inflammatory processes, providing broad anti-inflammatory effects. The TSLP receptor is both expressed and renewed at lower rates than the TSLP ligand, and our data have shown by virtue of targeting the receptor, is approximately 300-fold more potent than, an antibody targeting the TSLP ligand. On the basis of preclinical and clinical data supporting 's highly potent inhibition of the TSLP receptor, our clinical programs have been designed to test the translation of this potency to both dosing interval and efficacy in CRS with NP, severe asthma, and COPD. CRS with NP is a TSLP-driven upper airway inflammatory disease, which causes significant and disabling symptoms. These symptoms have a major impact on quality of life, and severe forms of the disease can require recurrent surgery and courses of systemic corticosteroids, which can cause substantial morbidity in the form of osteoporosis and other complications. Because of overlapping disease biology, the majority of patients with CRS with NP will also have comorbid asthma. In recent years, novel biologics have been approved for the treatment of CRS with NP, and while sales of these therapies in CRS with NP now exceed $1 billion annually, they are projected to grow in coming years, driven by the arrival of additional agents and expanded use in both surgery-experienced and surgery-naive patients. Our market research indicates a high degree of interest among both allergists and ENTs for the use of biologics in this indication, with a strong belief that TSLP inhibition could be a highly efficacious mechanism of action in this disease. With that introduction, I would like to turn the call over to Dr. Aaron Deykin, Upstream Bio's Chief Medical Officer and Head of R&D, to take us through the details of the top-line VIBRANT p hase II data. Thanks, Rand. First, let's start by reviewing the VIBRANT study design. VIBRANT was a phase II randomized, double-blind, placebo-controlled, parallel group clinical trial designed to assess the efficacy and safety of in adult patients with moderate to severe CRS with NP. Eligible participants who were enrolled from the U.S. and four European countries had a documented history of nasal polyps requiring prior NP surgery or systemic corticosteroids in the past 24 months, had a bilateral endoscopic nasal polyp score at screening of at least five, had ongoing CRS with NP symptoms despite standard-of-care treatment, and had a nasal congestion score, or NCS, of at least two during screening. Eighty-one participants were randomized in a one-to-one allocation to either 100 mg of or placebo subcutaneously administered once every 12 weeks over a treatment period of 24 weeks. The trial was designed with widely accepted and standardized endpoints. The primary endpoint was the change from baseline in nasal polyp score, NPS, at week 24. This primary endpoint has been used in several registrational trials for other biologic treatments for CRS with NP. The sample size provided greater than 85% power to detect a clinically meaningful treatment difference of 1.5 points on the NPS. Secondary endpoints included the NCS, sinus opacification on CT scan evaluated using the Lund-Mackay score, or LMK, total symptom score, or TSS, difficulty with sense of smell score, or DSS, and percentage of participants requiring systemic corticosteroids or nasal polyp surgery. Safety was carefully monitored and characterized in collaboration with an independent data monitoring committee. Now, reviewing the disposition of the ITT population, 81 patients were randomized, with 40 randomized to receive placebo and 41 randomized to receive, providing ample statistical power to detect a meaningful change in the NPS over the 24-week treatment period. We do note one subject was a screen failure but was randomized in error to and was not dosed. All participants in the arm completed treatment, and five subjects, all in the placebo group, withdrew from the study. As a result, the discontinuation rate from this study was lower than anticipated, with 75 participants, or 93% of those enrolled, completing the trial. Now, as we look at the baseline characteristics for the participants in this study, we see that they were consistent with the design and were generally balanced across the dose groups. We did note a slightly higher baseline eosinophil count in the placebo group, but do not believe this affects the interpretation of our results. Furthermore, as we'll detail further shortly, the characteristics of the population studied in are similar to those included in recent studies of other biologics for CRS with NP. Now, considering safety, we're very pleased to see that was generally well tolerated, with a profile consistent with that we've seen in our previous studies. Overall, the incidence of treatment emergent adverse events, or TEAEs, was similar across the treatment groups, and TEAEs related to study treatment occurred more frequently in the placebo group. No severe AEs or serious AEs were reported, and no Grade 3 or greater injection site reactions were observed in this study. Now, the most common treatment emergent adverse events, that is, events occurring at 5% or greater in the population in this study, were upper respiratory tract infections, sinusitis, nasopharyngitis, nasal polyps, and headache, all of which are associated with CRS with NP itself. Now, turning to efficacy, we are very pleased to report that in the study, administered just once every 12 weeks had clinically and statistically significant effects at the end of this 24-week study on the primary endpoint of endoscopic nasal polyp score, as well as key secondary endpoints, including the nasal congestion score. Specifically, we observed at 24 weeks a placebo-corrected reduction from baseline in NPS of 1.8 points, in NCS of 0.8 points, in the LMK of 8 points, in TSS of 4.3 points, and in DSS of 0.9. Now, consistent with FDA guidance, these results are based on the observed data without consideration of intercurrent rescue systemic corticosteroid use, and in this regard, the estimates of treatment effects are considered more conservative than results using an approach which censors data observed after systemic corticosteroids. It's an important point to keep in mind, as notably, this trial also demonstrated a significant 76% reduction in the need for steroids or surgery in the study participants. Now, considering the trajectory over time in NPS and NCS, we again see that at week 24, -treated patients achieved a clinically meaningful 1.8 placebo-corrected reduction in NPS change from baseline and a 0.8 placebo-corrected reduction from baseline in NCS. I'd highlight here that these do not take into account or adjust for the impact of rescue systemic corticosteroids. Looking at the NPS, we see that the majority of the effect is apparent at week 12, although we do see continued improvement to week 24, and as it does not appear that a plateau in NPS has been reached, a study of longer duration, such as we plan for phase III, will clarify the potential for additional effects of on NPS over time. With NCS, we observed reductions occurring as early as two weeks, where a statistically significant difference between groups was first seen. Importantly, this effect was maintained throughout the dosing interval, and these observations are consistent with the rapid and sustained suppression of inflammatory biomarkers that we have seen in our prior trials. When we analyzed the data in clinically relevant subgroups of patients, we also observed that the effects of on NPS were robust. Our analysis shows that point estimates for the placebo-corrected NPS over 24 weeks are consistently documented, favoring in these subgroups. Now, when considering the VIBRANT trial in the context of other studies completed with other biologics, it's first important to compare the population studied. As demonstrated here, the baseline characteristics of the VIBRANT participants are very consistent with those enrolled in other studies, including age, disease duration and severity, presence of comorbid asthma, and the need for prior surgery. We do note slightly higher baseline eosinophil counts as compared to some trials, as well as a lower rate of recent treatment with systemic corticosteroids. We believe the latter may reflect a change in CRS with NP management driven by an increased use of biologics versus systemic corticosteroids in recent years, but overall do not believe that either of these aspects meaningfully affect the interpretation of our results. Now, putting our results in the context of others and with the caveat that this comparison is for illustrative purposes only,, again administered every 12 weeks, equivalent to four times per year, demonstrated improvements in both absolute and placebo-corrected endoscopic nasal polyp score at 24 weeks that are generally consistent with those seen with tezepelumab, which requires administration every four weeks, equivalent to 13x per year, to achieve this effect based on published studies and product labeling. Agents targeting other pathways demonstrate clinical profiles that either require far more frequent injections per year to achieve a similar clinical benefit as compared to, for example, in the case of dupilumab, or demonstrate significantly lower treatment effects in the context of twice-yearly dosing, as seen in published trials of depemokimab, a YTE-modified anti-IL-5. In summary, administered just once every 12 weeks had clinically and statistically significant effects at the end of this 24-week study on the primary endpoint of endoscopic nasal polyp score, as well as key secondary endpoints, including the nasal congestion score. Remarkably, this trial also demonstrated a statistically significant impact of on the need for steroids or surgery in the study participants. As we've seen in previous studies, was also generally well tolerated, with no serious adverse events reported. These trial results further extend the consistent body of preclinical and early clinical data from our development program, which together suggest a potential for to deliver meaningful clinical benefit at a substantially reduced dosing interval compared with other biologics. Taken together, the data to date reinforce our belief that the differentiated profile we've observed is driven by 's unique mechanism of action. We are very pleased with these data and look forward to maximizing the impact of for the treatment of severe respiratory diseases. With that, I'd like to now turn it back to Rand. Thank you very much, Aaron. As I hope you can all hear, we are very excited about the positive trial results we're reporting today. How are we interpreting these data? First, delivered significant effects on the primary and key secondary CRS with NP endpoints in this VIBRANT trial. The clinical activity is delivered at a differentiated dosing interval of every 12 weeks, and importantly, s safety profile continues to be favorable. V is the first extended dosing TSLP agent to demonstrate this profile, which is uniquely driven by potency rather than antibody engineering, which simply extends drug half-life without altering potency. Given the role of TSLP in other respiratory diseases, including asthma and COPD, these data support further development of in multiple indications with substantial unmet need and commercial opportunity. As I mentioned earlier, TSLP drives inflammation in all of the diseases in which we are currently testing, along with others, and these data give us confidence that may also demonstrate meaningful clinical effect in severe asthma and COPD. Our rationale for testing in both CRS with NP and severe asthma has centered on a number of data points. First, that TSLP plays an important role in driving inflammation in both diseases. Second, that many patients will suffer from both indications at the same time. Third, by the fact that biologics targeting not only the TSLP ligand but also the IL-4 receptor alpha, IL-5, and IgE all have demonstrated efficacy in both indications. In general, the relative magnitude of effect of these agents on NPS in CRS with NP studies is commensurate with the magnitude of their effect on reducing exacerbations in severe asthma. Taken together, these points, along with the VIBRANT data in CRS with NP, increase our optimism that the clinical benefit of in severe asthma will be, at the very least, similar to that observed in the registrational studies of tezepelumab and dupilumab, while also potentially requiring treatment only 2x or 4x per year. Very soon, in the first quarter of 2026, we will add to our understanding of in this context with the planned top-line data release of our randomized, placebo-controlled, dose-ranging phase II trial in severe asthma. As we conclude, on behalf of the entire team here at Upstream Bio, I would like to thank the participants who enrolled in, along with our clinical trial investigators and site staff who collaborated with us to execute this important trial. Your support and participation have helped us move an additional step forward in the development of a potentially new treatment option for CRS with NP, and we hope for other respiratory diseases as well. Lastly, to our outstanding team here at Upstream Bio, I appreciate all of the work and dedication you have put in to get us to this point. Thank you, and with that, we are happy to take questions. Operator? As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In the interest of time, we ask that you please limit yourself to one question and one follow-up. You may rejoin the queue for any additional questions. Please stand by while we compile the Q&A roster. Our first question comes from Tess Romero with JPMorgan. Your line is open. Good morning, Rand and team. Congrats on the data here, and thanks so much for taking our questions. The first one is, to what do you attribute the stat-fig results you found across various secondary endpoints beyond nasal congestion score, which I think came in ahead of your expectations? Second, looking ahead, what are your preliminary thoughts around the dose used in this study and where you think you could go from a dosing standpoint in the indication? Do you think you might explore Q-24 weeks here, and why or why not? Thanks. Thank you very much. We appreciate the question. I think, as we've mentioned in our narrative this morning, potency is what drives all of this. This is the single defining feature of. At a very high level, it is the attributes of the molecule, the fact that it targets the receptor, and the aspects of turnover and refresh of the receptor versus the ligand that we think drive not just the top-line sort of primary and secondary endpoints, but really everything that we've shown today. Sure, yeah. Hi, Tess. It's Aaron, and yeah, thanks for your question. You know, really, to extend on what Rand said, I think that the very clear results with efficacy demonstrated across a range of endpoints begins with the molecule itself and the fact that it is efficacious, at least as demonstrated in this phase II study. I'll also point out that a set of results like this really can only occur with a very well-conducted study where variability is reduced and you enroll the population that you intend to, and I think that we've been quite pleased that that's what we've been able to achieve. In terms of the dose considerations, our data here really do validate our model-based understanding of the PK and ultimately the pharmacodynamics of the molecule. In particular, we do not see any attenuation of treatment effect at the end of the dosing interval, and that really suggests to us that with Q-12 weeks, we certainly are controlling disease symptoms very well and completely throughout the interval. That being said, and especially given the validation we have of our PK/PD modeling from this study, there is a substantial probability in our mind that every 24-week dosing could be effective. However, that's really going to be proved out and informed by the coming results from our VALIANT asthma study, where we're doing much more complete dose ranging. Ultimately, we expect to get those results and then contemplate a unified dose to move forward with in both indications. We'll be really looking very carefully at those data. They're going to be coming in the first part of next year. Thank you. Thank you. Our next question comes from Yaron Werber with TD Cowen. Your line is open. Great. Thanks so much and congrats on really solid, solid data. I mean, both on efficacy, I mean, hitting stat-fig on steroid use and surgery in a small phase II is a big deal. Maybe just a question, Aaron. You mentioned, so tezepelumab, I think, is the drug that you're sort of alluding to in the phase III in the Wayne Point study. They did not exclude patients that had steroid use. Have you had sensitivity? You did, so you took a more conservative approach. Have you had a chance to run some sensitivities? What would happen to the endoscopic NPS and potentially NCS if you use the same endpoint and then have a follow-up as well? Okay, yeah. Yaron, thanks for the question. Yes, we did use the statistical approach that's recommended by FDA in their guidance document. Perhaps that might have been conservative in this phase II study, but nevertheless, that is what we did. We do have a sensitivity analysis with respect to the NPS, the primary endpoint, taking an approach that's consistent with what some others have done, which is to censor the data after a patient is exposed to rescue corticosteroids. When we do that, we do add an additional 0.1 to our treatment effect, going from 1.8 to 1.9 on treatment effect on the NPS. Additional sensitivity analyses on the other endpoints are not available right now at the top-line point that we are. Okay. Just a quick question on, there's no plateau in the endoscopic nasal polyp score endpoint at 24 weeks. Do you, I know presumably, release everything in a medical meeting soon or at some point in the future. What are the biomarkers showing you on FENO, as relating to the half-life? I'm kind of wondering if you treat for longer, you'll have even a better effect than the other drugs did. Yeah, so I, you know, we can only speculate at this time. I do think pretty consistently, looking at data in this indication, you do see accumulation of treatment effect beyond 24 weeks and in multiple, with multiple agents. I think that that's a reasonable assumption that when we conduct a longer trial, we will see some additional treatment effect on the NPS. In terms of the biomarkers, we don't have a biomarker available to share at this time, and certainly, we're very eager to see those data when they come in, and we will share them at a medical meeting once we have them. In sum, yes, we do anticipate greater treatment effects in longer studies, and you know, we'll have to wait to see if that actually occurs when we do those studies. Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Good morning, team. Congrats to the great data, and thank you again for a very thorough presentation. I guess question number one is, you did a really nice job comparing the NPS scores across different subgroups. Could you maybe talk about if tezspire has done a similar exercise and whether they found a similar, you know, response rate across all subgroups? If you could just talk about the differences there, that's question one. Then question two is, given this data, how do you think, you know, our favorite question, what the bar for success here is for your asthma study that's reading out in Q1 2026, and I'll jump back in the queue. Yeah, okay. With respect to subgroup, you know, comparing subgroup analyses across trials, I think that's always a sort of a double extrapolation exercise and probably something that has to be done really with a lot of caution, especially because with tezepelumab, the subgroup analyses were all done at their 52-week data. Nevertheless, I would say that generally speaking, there doesn't appear with this mechanism to be a subgroup of patients that doesn't respond, and that's been a consistent finding with our subgroup analyses as well. Yes, do you just mind repeating the other question about the asthma data? I just want to make sure I get the question right. Just like maybe help us understand what your expectations are now that you have seen this data on hand. Yes. With the durability, yeah. Sure, absolutely. Thanks. I think that Rand's slide that he talked to, which of course is a schematic, but it's a schematic representing our belief. We believe that given the efficacy that we've demonstrated in CRS with NP, that we interpret as meeting or potentially slightly exceeding that seen with would indicate that that's the type of efficacy in asthma that we should see. Thank you again for the question. I think we are sitting on a really consistent body of data, starting with preclinical assays, moving into our multiple ascending dose trial in patients with asthma that demonstrated proof of concept, and now these data really illustrate the potency of this molecule. I think we've kind of held our hypothesis back a little bit in NP just to understand what dynamic range could be, but I'll just remind you of the data from our MAD study that suggests that our effects on exhaled nitric oxide and blood eosinophils are really quite substantial and potentially substantially greater than many other agents. I think we feel pretty good. Obviously, we're doing the trial and we have equipoise until we see the results, but that statement about feeling good about meeting or exceeding efficacy on the therapeutic front and doing that with either twice yearly or four times a year dosing, if we can hit some combination of those outcomes, that's going to be, we think, a very strong and competitive product profile. Great. Congrats. Thank you. Thank you. Our next question comes from Matthew Fitz with Blair. Your line is open. Hey, team. Thank you for taking my call. Congrats on a great first phase II readout with verekitug. I was wondering if you could give us a breakdown in the control arm between patients who had surgery versus rescue steroids, and it was 25% across all patients. Do you have a survival analysis on the timing of those events for both arms? Just curious thinking about how that effect might grow between verekitug and placebo out to 52 weeks on that endpoint. Yeah, Matt, Aaron, thanks so much for the question. With respect to the first part, in terms of the breakdown of steroid, you know, systemic steroid exposure versus surgery, only one subject had surgery, and therefore the issues that I was highlighting about the impact of systemic corticosteroids are important, since the vast majority of the cases of surgery or steroids were, in fact, steroids in this trial. We don't, at the current time, have a survival analysis or a time-to analysis of the surgery or exposure to corticosteroid events. That's coming. I could imagine that the difference between placebo and treatment might accumulate over time, as more time at risk for these events will increase with exposure. That's something, of course, that we can only speculate on, and we'd need data from a larger study to confirm, but that's probably a fair guess. Thanks, Aaron. Yeah, quick follow-up. You know, 60% of patients in this trial had asthma and a lot of overlap in the indications. Wondering if you've had a chance to do any subgroup analysis on those patients or look at any other maybe more asthma-specific markers in that population. Yeah, absolutely. Very, very important question. We're very eager to see those data. Those were not prioritized as part of our top line, but they will be coming, and we'll be looking at that and disseminating what we see as soon as possible at an upcoming meeting. Thank you. As a reminder, to ask a question, please press star one one on your telephone. Again, that is star one one to ask a question. I'm showing no further questions at this time. I would now like to turn it back to Rand Sutherland, Upstream Bio's CEO, for closing remarks. Thank you, and thanks to everyone for taking the time to join us today to hear our data and for questions. We look forward to sharing additional progress with you as we move forward, and with that, we'll end the call. Thank you. This concludes today's conference call. Thank you for participating. You may now disconnect.