Good morning, everybody, once again, and welcome to our first annual I&I Summit. I'm Yaron Warber from the BioTech team, and it's a great pleasure to moderate the next session with Upstream Bio. With us today, really needing no introduction, is Rand Sutherland, who is the Chief Executive Officer. Rand, good to see you. Thanks for joining us. You too, Yaron. Thank you. Thanks for having us. This is an exciting time in Upstream. This is one of our top ideas. You just showed about two months ago positive phase 2 data with chronic rhinosinusitis with nasal polyps for verekitug. For everybody on the call, this is a drug that is an antibody that hits the TSLP receptor. It is unique. It is the only one, and that confirms a very long Pharmacodynamic activity. That was Q12 weeks. We will come back to that in a second. That really sets up the data for asthma, which I believe is expected to phase 2 about 450 patients or so, roughly phase 2 testing Q12 and Q24 weeks against placebo. Again, that is coming in Q1. Maybe we will start first. For the audience, if you have questions, feel free to email me or put it into the chat that I could see, and I'll read it for you. Maybe, Rand, on CRS with nasal polyps, the data looked very good, again, with Q12 week dosing. This was the 24 weeks, and we'll get next year the 52 week data. It really did not show a plateau in terms of effect at 24 weeks, even though patients at that point only got essentially three doses, right? Zero, 12 weeks, and 24 weeks. What does that mean about the Pharmacodynamic activity sort of as a potential read-through into asthma? Yeah, it's a great question. I think we've generated data actually since the preclinical days. It really speaks to the potency of this molecule. You've alluded to it. I mean, what we even saw in early clinical development was that for up to 24 weeks after the last dose, we had 100% occupancy of free TSLP receptors with associated reductions in Exhaled Nitric Oxide and blood eosinophils in our asthma multiple ascending dose study. We were very happy then to validate that and recapitulate that in our CRSwNP study. This, of course, was a much larger, much more robust placebo-controlled trial, as you mentioned, of 100 mg Q12 weeks, 24 week trial, and really showed efficacy that meets or exceeds that of available biologics, all at four times a year dosing. I think the thing that for me was really exciting about the data is that not only did we have a very internally valid set of endpoints, all of which were hit with a significant magnitude, statistical robustness, including a reduction in the need for steroids and surgery, but also, I think, validation, again, of that picture that has emerged now over many years of the molecule and its potency. There's no other mechanism by which that degree of efficacy could have been delivered at Q12 weeks other than potency. We're not FC engineered, YTE modified antibody. We're a straight fully human IgG1. Again, really strong and I think very exciting data that speak to our differentiation versus all of the other molecules that target the ligand TSLP. I think also giving us strong reason to believe for good data in severe asthma as well. Now, we need to wait for the data, but I think the profile has been confirmed now in a Sizable, robust clinical trial. In one indication that's very much a type 2 driven disease, we know that severe asthma is also very much a type 2 driven disease. We know that biologics that have been approved in both indications generally work with a commensurate level of efficacy across the two indications. We will see what happens, but I think very strong potential for read-through, again, with the Q12 weeks and potentially the Q24 week dosing interval as well. Now, on the issue of is there room to run with the nasal polyps data, it is true that the Endoscopic nasal polyp score did not plateau. It is also true that it's not measured as frequently as other things like the Nasal congestion score. I do think we believe, and we've seen with other programs that when you progress from a 24 week to a full 52 week study, that there generally is a little bit of incremental efficacy that's gained by a further observation time. That's very useful. When you're looking at also, you showed a 76% reduction in SCS use, essentially, essentially steroid use and also reduction in surgery as well. When you're looking at that data out to 52 weeks, does that normally continue to improve, or you typically see the vast majority of the response upfront? I mean, I think it's hard to answer that question. There's not been a ton of experience over time with clinical trials. I think looking at 24 week versus 52 week continuation of additional incremental efficacy there, I mean, look, it's already a 76% reduction. Could we get to 100%? I guess potentially, but we would need to see the data. This is much less of a continuous variable than is something like a Nasal congestion score and Endoscopic nasal polyp score. We were, I think, surprised actually to demonstrate a statistically significant 76% reduction in the need for systemic steroids or surgery. That was a big part of the reception of Tezepelumab's data in CRS with NP. The fact that they were able to demonstrate that was a much larger trial, again, a different approach to modulating TSLP. We were happy to see it. We'll be monitoring it, obviously, very closely in our longer phase three program. Yes, if we can do more than 76%, great. Yeah. What are the next steps in terms of moving to phase three for CRS? Yeah. You may have noticed that over the past year or so, we've been pulling forward guidance on completion of our studies, both in CRS with NP and severe asthma. What that's allowed us to do, particularly by pulling the severe asthma trial forward so far, is that we now have the opportunity to actually really get the data from both indications, two different type 2 diseases, multiple different dose regimens versus placebo, and look at those almost contemporaneously to inform phase 3 dose selection in both programs. I think had we ended up with more of a sequential approach, we might have a different answer. Right now, what we'd like to do is get all of these data in-house, look at everything very carefully from the standpoint of efficacy, from the standpoint of PK, any variables there, and really carefully choose a single dose that we could take forward in both indications, and then engage with regulators, see if they agree, and then really try as quickly as possible to execute the initiation of both of those phase three programs. I think we're so fortunate to be getting all these data at the same time and to really be able to inform both programs and then move them forward essentially simultaneously. Yeah. So when we're talking to some of the KOLs, they're alluding, I'm going to switch to asthma now to a certain degree of mechanistically, it's relevant to both, that when you look at real-world patients who have been on Tezi and Dupi on a few doses, let's say, in a commercial setting, they tend to stabilize. There is some suggestion in the literature that they're able to, again, this is real-world data, it's obviously uncontrolled, that they're able to self-extend the duration between dosing. In asthma, there is no concomitant increase back in pheno. They're not relapsing. That's suggesting that once you get the inflammation under control, these mechanisms do a really good job and naturally you can extend. What does that kind of then, do you agree with that if you've been hearing that as well? Yeah. I mean, I think you hear anecdotal reports about these kinds of things. I mean, they are clinical observations. They are clearly off-label approaches to using the medicines. I think that, look, physicians can make decisions based on the clinical scenario in front of them. It gets a little bit at this kind of important issue in developing these drugs of the leading lagging indicator relationship between pharmacodynamic effect on specific biomarkers, for example, and the relationship of that delta and the timing of that delta to the development or reduction of clinical symptoms. There is some lag there. Now, it depends a little bit on the patient. It depends a little bit on the mechanism of action. It all has to be put in the context of the environment and what's driving either allergic or infectious or other kind of triggers and sort of keeping the disease activity at a certain level. It is interesting to say, do I think that that, I mean, we get our extended dosing interval, which we're testing in our trials, from potency. We're not benefiting necessarily from this in terms of how we get to where we are. Now, it may be if these gets approved and we get some real-world data, we may see a similar phenomenon. At this point, we're testing in clinical trials two, we think, very favorable dose regimens for patients. We're hopeful that those will both be efficacious and that we'll be able to choose one to move forward. To be able to do that because of potency and to be able to experience continued durable efficacy and not have to take a risk, if you will, at the end of potentially having some period of instability that comes from holding a dose, I think ultimately that would be the better way to approach care for these patients. Yeah. Those KOL comments come in the context of that they're actually fairly, I would say, constructive, bullish that the Q24 weeks will show very good response similar to even potentially to the Q12 weeks because of the PD effect, as you said, because the TSLP receptor is not cycling quickly. They're alluding to the fact that if patients can get well controlled, then these anecdotal reports kind of contribute to their confidence, so to speak, that in your study, Q24 weeks will work, which we thought it was kind of encouraging. Your study is obviously not powered to look at Q12 weeks versus Q24. They're both powered against placebo. That's correct. What do you need to see from Q24 weeks for that to be the bogey? I mean, does it have to be completely the same as Q12? Is it okay to have a little bit of a decrement? Kind of how you think about that. Yeah. I mean, I think what we are hypothesizing at this point is probably best informed by just going back, taking a step back and reminding ourselves about the data that we've obtained in phase one, both from healthy volunteers and patients with asthma, and then looking at how we've taken those data and done PK/PD modeling to select the doses for the phase two programs. What you see there is that if you model a population at either dose regimen, 100 Q12 or 400 Q24, and plot that over a simulated 48-week period versus EC90 for pheno, a very, very conservative threshold, you see that in the case of the Q12 week dosing regimen, the population stays well above that EC90 throughout. Even with the Q24 week regimen, the population stays above on average that EC90, except for maybe the last one or two days of that period. Again, back to this relationship between suppression of important disease-driving biomarkers like ENO and then efficacy as measured both by Symptoms and Exacerbations, we think that there's a reasonable possibility that it may be difficult to distinguish clinical efficacy in these two dose regimens from each other. When we talk about what we would like to see, we couch it a little bit in this 12 versus 24 weeks. We also put it in the context of what we're hearing also from clinicians and others that is clinically meaningful. Actually delivering Teze-like or slightly Teze better efficacy at Q12 weeks is already a major step forward in terms of a competitive value proposition for verekitug. There is probably some incremental value that can be gained going from Q12 to Q24 weeks, but we've also learned that nobody wants to take a trade-off on efficacy for durability. If there's any hint of lesser control or some loss of control at the tail end of the interval, we're going to have to think very carefully. I think we have to think about that very carefully because what we're starting to see now from some of the other approaches to extending the dosing interval, namely FC engineering through the YTE mutation, is that if you push the dosing interval beyond what the PK and the half-life will tolerate, there is a risk actually of losing disease control towards the tail end of that dosing interval. Patients don't want to experience symptoms. They don't want to have an exacerbation. It is going to be very important to have durable efficacy throughout whatever the dose interval is. Again, we believe on the basis at least of our asthma multiple ascending dose data that we can demonstrate durable efficacy for up to 24 weeks after the last dose because we have seen complete receptor occupancy for that period of time, and we have seen that associated with reductions in Exhaled Nitric Oxide and blood eosinophils. One of the questions as we're beginning to kind of move toward that data is, what's the bogey based on prior data? In the phase two data, when you look at, let's say, Dupi and Tezi, they showed responses which were sort of upwards of 60-70%. There was a little bit of a decrement. To give specifics, in the phase two for pathway for Tezi, it was between 62-71% response rates. Seventy-one specifically in the dose they took forward, their dose response was one of these sort of inverse U-curve. That actually was a decrement in phase three to 56%. On Dupi, they were at 70%, and they went to, let's say, 46-48%. What's the bogey for your phase two? Is it phase two-like efficacy from the previous drugs? Is it phase three? In any sense, why was there a decrement from phase two to phase three for those drugs? Yeah. The first thing I'll say is that we have designed our trial to be able to detect a 50% or greater% reduction in asthma exacerbations annualized. We've done that with 85% power. We've powered each of our dose regimens versus placebo. That is a floor for what we hope to detect. That is more of a phase three-like efficacy profile than has been seen with the other two programs that you cited. I think it gets a little bit fraught to start trying to compare this to that. I mean, these are experiments. They're experiments done in different patients at different times with slightly different definitions of the thing that you're measuring. There are different ways of defining an asthma exacerbation, a severe asthma exacerbation, how many days of steroids. There are some nuances there. There is a little bit sometimes of luck of the draw in terms of what the population looks like, in terms of key disease-driving biomarkers. Obviously, Dupixent was very much looking at an eosinophil-enriched population. The baseline or background rate of exacerbations across those studies that you mentioned ranged from less than one to, I think, over two. There are just all these different nuances in the trials that make it, I think, hard to say that because this company saw this, that company is going to see that. I'm not sure it's realistic, and I'd be foolish, I think, to promise 70% efficacy with asthma exacerbations in our trial. If we see it, again, that'll be a powerful endorsement of the potency of the molecule. We're doing a very large, as you said, almost 500-patient trial globally distributed. It's phase three-like in a lot of ways. We've been very carefully monitoring exacerbation rates to make sure that our assumptions about power have held throughout the study. This is a very robust, very large, maybe phase three-like trial in some ways. A long way of saying, I think we have to see, but we're going to be very happy if we can see a 50% reduction in annualized asthma exacerbation rate, keeping in mind that this is happening at four times yearly dosing, right, which nobody else can deliver. Everybody else is delivering that every two weeks or every four weeks. Again, an endorsement of the potency profile of the molecule. Yeah. What about showing a lung function, an FEV1, let's say, improvement? If you look, when we look at the, again, prior study, they were at 120, 130, 140 sort of CC benefit. Is there a chance to show that as well here in the study? Yeah. We are not powered to detect that. I think it's another important nuance for some of these other trials. For example, if memory serves, the phase two Bs for Dupixent were actually 12-week FEV1 primary endpoint studies, so set up a little bit differently to detect efficacy there. We are, again, primarily focused on the key registrational endpoint of asthma exacerbations in this trial. We think that that is what gives us the greatest potential for using this trial if positive as one of two pivotal studies in regulatory negotiations. We will see what we see, but we have not powered the trial on FEV1 or other key secondary endpoints like asthma control in phase two. Going forward into phase three, this will be a key consideration. Again, depending on the outcome of negotiations with regulators, could very well be something that we will power the trial to detect as well. Yeah. Okay. And again, we're expecting data in Q1. Is it possible to expect that the phase threes will commence next year? We have not provided guidance there. It really is dependent on a lot of things. I mean, we need the data. We need time. I mean, this is going to be probably the single most important decision that we make in the program. We want to get it right. We want to get it right for ourselves, and then we want to be able to go and take thoughtful input from regulators. We will move as quickly as possible. I think we've shown a great track record here over the last months of moving quickly and executing at a very high level, and we have no intent of changing that approach to running the company. Yeah. Maybe just a final question. We do get questions about competition. There is a lot of competition. I think there's a lot of sort of drugs in development, I should say, but many of, and I think it leads to a lot of confusion. Many are not long-acting, first of all, and many are actually at the end are going to atopic dermatitis. They're actually not going toward lung indications. I think that there are a few, I think GSK and ILOS are probably around six months behind based on the YTE modification. I think generally just right out the phase one, and they're potentially planning on going to phase three. And I believe there is Wynward that is a Q6 months, right? That's in phase two now. Can you maybe talk a little bit about the competition and sort of, again, you're the only one hitting the receptor. Everybody else is hitting the ligand. Maybe your thoughts about that. I think that's the key point. I mean, first of all, mechanistically, we take a very different approach than the others. Everybody else, and there's a list, and it's probably better for the companies themselves to explain where they are and what they're doing. We see a lot of ligand-targeting antibodies that in our assessment are not terribly different from each other in terms of their approach to extending half-life or potency. This handful of companies that are chasing this are all kind of going after the same thing in the same way. They will have to execute. They will have to move quickly and have to generate differentiated data, just like us. We're in a position where we're mechanistically different. We've got a clear potency advantage that translates to really good efficacy and extended dosing. We are also in a fortunate position to be able to execute well and to deliver what are potentially registration-enabling data here already in CRSwNP and soon, we hope, in severe asthma. I think we are in a great position. We have a lead. We are differentiated. Of course, we hope for great options for patients. The more successes there are, the better that is at the end of the day. Yeah. Let me sneak in actually one more from the audience. Relating to, you mentioned that there's different ways to define severe exacerbation. And so asthma exacerbation, maybe moderate versus severe. You also mentioned also how many days are on steroids. Maybe how does that, can you speak more about that and how does that get defined or impact the endpoint? Yeah. I mean, it's basically what, well, is it protocolized or not protocolized? Is there exposure to Systemic corticosteroids for how long? Is there a visit in an emergency department or an urgent care? How are the symptom scores measured? There are just all these different nuances that it's less to explain away why there might be differences. It's more to say that once you have done the experiment, the best way to evaluate these studies is to look at the patient populations, to look at the protocol, to look at how the treatment is defined, to look at how the event of interest is defined, how it's treated, actually how the data from that treatment are incorporated or not into the analysis. That was something that we've talked about in the past with our CRSwNP data. That can all be an indicator of, at the end of the day, not just variability in the endpoint itself, but in terms of how you measure it and define the difference. A lot of nuances go into this. It is just very important to look at these within the experiment context before you start reaching out and making comparisons across trials. Yeah. Okay. And the CRS data, I imagine, could be at a medical meeting probably in the earlier side of next year. Is that sort of possible? Yeah. We don't have any finalized plans there, but again, we're working to get those out at a major medical meeting next year. Two target major medical meetings happen in the first half of the year, QuadAI and ATS. Hopefully we'll be at one of those. Okay. Terrific. Ryan, thanks so much. Good to see you. Appreciate it. You too, Your Honor. Thank you. All right. Take care. Bye. Bye.