Hey everyone, we're back. Happy to have Rand Sutherland here, CEO of Upstream Bio, for our next fireside chat. Maybe to kick things off, Rand, I'll kick it over to you for a brief intro of the company, and then we'll get into the Q&A. Sure, thank you, Alex. First, thank you for having us. We're super excited to tell our story. Obviously, we just released some what we think are great data, and we're happy to talk about the company and what we think our molecule, Viraqita, can deliver for patients. Upstream Bio is a clinical-stage company. We're developing the only known antagonist of the receptor for TSLP that's in clinical development. As we've learned throughout the course of both preclinical and clinical development with this molecule, by virtue of targeting the receptor, it has very unique pharmacology, and that pharmacology is really marked by two things, both of which are driven by potency. The potency of this molecule allows us, we believe, to be able to dose it maybe every 12 or 24 weeks, and those are dosing intervals we're testing in our clinical trials. Also, on the basis of the potency of the molecule, potentially delivering efficacy that could meet or exceed that of really all other biologics in the space as well. On the basis of all of this, we've taken the molecule forward in three indications. The first is chronic rhinosinusitis with nasal polyps. The second is severe asthma. The third is chronic obstructive pulmonary disease. We're currently in phase 2 in all three of these indications, and for us, phase 2 means large placebo-controlled, randomized, potentially dose-ranging trials using regulatory endpoints with the goal, of course, of supporting BLA with these trials as one of two pivotal studies if possible. We're doing all of this with substantial funding. We are funded on the basis of a successful IPO last year through 2027. That's allowing us to read out these nasal polyps data, read out our severe asthma data in the first quarter of next year, and make substantial investments in phase 3 and also material and device for commercialization. Great. You mentioned that obviously you're the only TSLP receptor antagonist, and you've done a lot of preclinical work to understand what biology that unlocks for you. Maybe can you just tease out a little bit more, you know, what you've done and what gives you confidence that there's really something unique here versus all the other TSLP ligand antagonists out there? Sure. As you just said, I think it is important to distinguish the fact that everybody else targeting TSLP goes after the ligand. We uniquely are targeting the receptor. We think that's a meaningful difference for a couple of reasons. The first is that we've done some pretty extensive computational biology to understand the relationship between targeting the receptor and the ligand. We know now that the receptor is expressed at a much lower level than is the ligand. It's also turned over at a far lower frequency. We've shown in both preclinical and clinical data that within two weeks, Viraqita can fully occupy 100% of free TSLP receptors and do so for up to 24 weeks after the last dose. We know that TSLP is the only ligand for the TSLP receptor. We know that there are no alternative receptors for TSLP. By fully shutting down signaling through the TSLP receptor, we believe that we're having a very significant effect on TSLP signaling. Because it takes so little drug to fully occupy those receptors, we believe that the major reason for potency is the fact that even with a small amount of drug, there's enough around for many, many weeks to block signaling, whereas it's just hard to give enough of any antibody to fully mop up all of the circulating and frequently refreshed ligand. Great. As you mentioned, you just put out your phase 2 data for chronic rhinosinusitis with nasal polyps. Maybe before we jump into the data, could you just talk a little bit about this indication? I think, while there's clearly a lot of strategic interest here, it's one that I think a lot of investors are less familiar with. Yeah. It is probably, just from a pure epidemiology standpoint, the least prevalent of the three indications that we're targeting. Obviously, severe asthma and chronic obstructive pulmonary disease (COPD) are much more prevalent. As a disease, chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly type 2 enriched form of sinusitis that not only causes near total opacification of the sinuses with sinusitis and mucus and cellular debris, but also results in the proliferation of these tissue masses called polyps. Those polyps further add to the obstruction. They can be visible to the naked eye, even in the nasal passages, and can also be measured and counted, if you will, using the endoscopic nasal polyp score. It is a disease that's associated with a high degree of symptom burden. Patients often can't smell, they can't taste, they have difficulty sleeping. It's the type of disease that historically has been treated with surgery and systemic corticosteroids until the recent advent of efficacious biologics. It is one also that is marked by a need for multiple courses of steroids and often multiple surgeries as well. It is a disease with a high degree of morbidity. It is a disease that drives a fair amount of healthcare utilization through these surgeries and systemic corticosteroid courses. It is one that, again, is very much enriched and driven by type 2 inflammation. Where that is important for us is not only is this then a disease that needs to be treated, but it's one that's marked by a lot of biological synergy with severe asthma. In fact, if you just look at the epidemiologic overlap, many patients, probably 50%, 60%, 70% of those with nasal polyps will also have asthma, and a significant proportion of patients with severe asthma will also have nasal polyps. A lot of overlap. In general, the biologics that have been approved or studied in both indications work equally well, sort of commensurate with their overall level of efficacy. This is one where we hope very much that the data that we've just read out in nasal polyps will also provide substantial read-through to our program in severe asthma. In terms of the trial design, how does this compare to historical studies for Tezepelumab, obviously the TSLP drug, and then Dupilumab, your IL-4 receptor alpha antagonist? Yeah, it's a great question. The approach that we're taking here with this as sort of our temporally first indication is a pretty traditional one. We've done preclinical studies. We've studied the molecule in phase one in healthy patients and patients with asthma. Now in nasal polyps, we're taking an approach where we're doing a phase 2, potentially followed by a phase 3. Again, recognizing that the phase 2 has been designed in a way to follow FDA guidance, everything from study design, registrational endpoints, and all the way through to analysis, which we can get to in a bit. We've taken a pretty rigorous approach to the design here. The study was placebo-controlled. We took what we call our no-regret dose of 100 milligrams q. 12 weeks, which provides substantial coverage over the EC90 for FeNO for all of the model period forward. We have used endpoints, including change in the endoscopic nasal polyp score, the nasal congestion score, and a number of other important secondaries to read out efficacy here. Obviously, we still need to have regulatory interactions, but our hope, again, is that this could serve as one of two pivotal studies for BLA submission and NP. As you compare the actual clinical data, obviously cross-trial caveats apply. How does it look relative to, you know, the key comps? Yeah, so, you know, the reason I made the point about the approach and, you know, the way we're going forward here is that it becomes a little fraught when you're trying to compare us with competitors or potential competitors in terms of, you know, what data are available and what approaches were taken. I would say, you know, Dupilumab (Dupixent) took a very similar approach with a robustly designed and ultimately positive phase 2 trial. Tezepelumab (Tezspire) and Depemokimab, however, did not do phase 2 trials with their molecules, partly because they already had data from phase 3 from other indications. When we take all of this into account and we just look at our effects on endoscopic nasal polyp score, they certainly numerically meet or exceed what has been observed with Tezepelumab (Tezspire), with Dupilumab (Dupixent), and with Depemokimab as well. I think importantly, not just from the magnitude of efficacy, but very important for patients is the interval of dosing. We've delivered this efficacy at q12-week dosing. That's potentially four times a year compared with 13 times a year for Tezepelumab (Tezspire) and 26 times per year for Dupilumab (Dupixent). I think the other point I would just make is that, you know, while our delta NPS was minus 1.8 versus, you know, minus 1.7 and 1.6 for Tezepelumab (Tezspire) and Dupilumab (Dupixent), respectively, our values are based on a very conservative analytical approach where we followed FDA guidance and used observed data rather than carrying the sort of worst observation carried forward and analyzing the outcome on that basis. Now, why is that important? What happens in this disease if you're not allocated to an effective treatment is that you will have an exacerbation, a flare, and you will require potentially surgery or systemic corticosteroids. Those, of course, will make you better. The placebo group in an all-data observed data type of approach will often improve more than where you just take the last or worst observation carried forward. We do have and are conducting as part of our continued data analysis, taking different approaches here. When we take a worst observation carried forward approach here, it actually adds another 0.1 to 0.2 units to the effect on our delta NPS. We feel really strongly about the data from the standpoint of efficacy independent of dosing interval. Obviously, we've shown that we can deliver all of this at q12-week dosing, which is, in our understanding, in our market research, and we think, at a top line, a very compelling and valuable profile. Great, thank you. Apologies, there might be a fire drill happening right now, unfortunately. Maybe the follow-up question here is just in terms of baseline characteristics. Do you think that the fact that you had higher eos and lower rates of prior steroid use is a major tailwind in this study as you're thinking about that? Yeah, I think it's probably important to just step back and look at the baseline characteristics as a whole and say that, look, we worked very hard to design this trial in a way that recruited patients that were very similar to those enrolled in other studies. I think if you look at our baseline characteristics and compare those, and we've, of course, done this in our discussions, you know, they are very similar from a sort of disease severity, disease magnitude, and endpoint standpoint. If you actually look at our eosinophil counts at baseline and compare those to the Dupilumab (Dupixent) trial, they're very, very similar. If you look at the counts and you look at how they're distributed between placebo and Viraqita, actually the Viraqita arm had, I think, around 400 eosinophil counts where the placebo group was closer to 500, and the mean was somewhere in the middle. The other thing is you look at the standard deviation, and it's quite large, driven by the size of this trial versus, again, Tezepelumab (Tezspire) and Depemokimab studies of 400 and 500 patients respectively. It's a long way of saying that it's important to look at these things, but we don't think that they're substantially different from other phase 2 trials in this space, and we don't see this as a particular tailwind. I think you can look at the use or lack thereof of steroids in a couple of different ways. One might be to say that this is a population that was disadvantaged and therefore more severe because they didn't have steroid exposure. The other might be to say that that's a reflection of a clinically potentially somewhat more mild population. Again, I think all of this has to be tempered by the baseline endoscopic nasal polyp score, the baseline nasal congestion score, et cetera, et cetera, and that those are really the most important disease state markers to look at in terms of population comparison. Yeah, that makes sense. I think the key question obviously moving forward here is how does this read through into your confidence in asthma, and in particular your confidence in a less frequent dosing regimen with q. 24 weeks? Right. It's a great question. Again, just to take a step back, the thesis in asthma has been the thesis being that we could potentially deliver efficacy as good as Tezepelumab or potentially better at q12 or q24 weeks, based on data generated in our MAT study in patients with asthma that show that if you calculate our Emax for ethionyl oxalic nitric oxide and you look at our EC50s and EC90s, they reflect a far greater degree of potency when compared with Tezepelumab on this important and highly translatable biomarker. These data from our nasal polyp study, particularly once we get the PK analyses, will I think very much reinforce or not. I mean, we need to see the data, but will add a lot of information on the PK. On the basis of the fact that we're talking about the high degree of read-through and shared biology and shared epidemiology, this will be a potentially strong tailwind. We're just a few months away now from data in asthma and should be able to answer these questions definitively then. Yeah, Rand, I really apologize. Apparently, this is not a fire drill in my building right now. I'm going to have to get off. Get out. Hopefully, stay tuned. Hopefully, it'll be settled. Thanks everyone. We'll be back hopefully soon. All right, Alexander. Thank you. Stay safe. Bye. Bye.