All right, good afternoon, everyone. Sorry we're getting started a few minutes late, we still have 28 minutes. Rand had to chase me down because my associates were socializing. Anyhow, so thanks everybody for joining us for the discussion with Upstream Bio. It's very much my pleasure to welcome Rand Sutherland, the CEO, and welcome you to Miami.
Yeah, thank you. It's beautiful.
Thank you for being here. I thought we could just start at a high level if you could provide an, you know, sort of a high-level framework for the company and your vision.
Sure. Upstream Bio is a clinical-stage company. We have a single asset called verekitug, and we are focused on developing that asset in a number of immunological diseases, principally focused on severe airway diseases right now. Verekitug is the only known drug in development that targets the receptor for TSLP. As you know, we'll probably talk about, that confers upon it some very specific and unique pharmacology that gives it the potential to be differentiated from other assets in the space, both on dosing frequency and potentially on efficacy as well.
These are conclusions derived from data that we've generated as part of our clinical development program to date. While TSLP is actually expressed at the epithelial surface in the skin, the gut, and the lung, we've, you know, focused on the lung principally because we believe the biology is most de-risked there. There actually is an example of a commercialized, successfully commercialized product in Tezspire. Again, we believe because of our differentiated pharmacology, we can, if successful, develop this and add additional value for patients.
Excellent, excellent. Could you just go into a little bit more detail on why targeting the receptor matters and the differentiation that you expect?
Absolutely. What we've learned from the development program to date, both from the preclinical perspective and now the clinical perspective, is that targeting the receptor appears to really benefit from the fact that the receptor is expressed at very low levels versus the ligand. Furthermore, it appears to be refreshed at a far less frequent rate than the ligand as well. Even though verekitug is an IgG1, it has a normal, you know, IgG1 half-life of around 20 days, because the receptor is expressed at such a low level, it takes very little drug to fully occupy free TSLP receptors. Even after several half-lives, there is enough drug in the system to fully block signaling through the TSLP receptor.
What we've seen preclinically is that even in the very early stages, when plotted against a therapeutic threshold of 1 microgram per ml, it appeared that Q12 week dosing could actually be on the table on the basis of some of the preclinical data. As we've moved again through, into clinical development, what we've learned actually is that the EC50 and the EC90 for verekitug is over 300-fold lower actually than the similar EC50, EC90 for Tezspire. It's really a very potent molecule, and, you know, this potency translates to the ability to dose it quite infrequently in our clinical trials, and we're testing Q12 and Q24 week dosing intervals in our severe asthma program.
On the basis of data we've generated with regard to both fractional exhaled nitric oxide and blood eosinophils, it appears that this potency could also translate to the potential for differentiated efficacy in that our effects on both FeNO and Eos are greater than those observed with Tezspire.
Excellent, excellent. And how are you framing it from a safety standpoint given, you know, the prospect of greater efficacy and what you just described?
Right. What we've learned from our program so far is that there are no unexpected or untoward safety signals that, you know, have prevented the program from going forward. We, you know, have reported from our Phase I program thus far, sort of the overall safety profile. As we've moved into Phase II, of course, we're monitoring this very closely. We have an independent data monitoring committee who is also doing this.
You know, we have seen nothing in the way of a signal so far that, you know, has limited the program. What we have learned from modulating TSLP biology, you know, courtesy of Amgen and AstraZeneca's work, is that the safety profile of Tezspire seems to be quite bland, and we have observed a similar profile going forward. Of course, it's something that we are very much focused on and, you know, we'll be monitoring as part of our development program.
Very good. Could you talk about the big opportunities that you see commercially?
As I mentioned, we've elected to focus in severe airways diseases, you know, not just on the basis of the biology and the fact that there's been substantial de-risking there, but also commercially. You know, we do believe that if you have a product that is differentiated on efficacy or differentiated on dosing interval or convenience, that the experience in the marketplace thus far would suggest that a differentiated profile allows you to come in, it allows you to take substantial share, and do that not by eroding the share of others, but by actually growing the overall market, largely because there's still substantial under-penetration of biologics in severe asthma.
I would say the same is true in CRS with NP, and although we are in the very early days of biologics being prescribed in COPD, I would estimate that the same would be true there. For all those reasons, we've focused on airways diseases. We want to come in with a differentiated profile, again, potentially on dosing interval and efficacy, and we'd like to really bring something that adds value. If we are able to do that, that will be a successful entry into sizable commercial opportunities.
We have not elected at the moment to pursue, you know, skin disease, atopic dermatitis, or others, and similarly are not pursuing eosinophilic or other gastrointestinal diseases, but those are certainly, as I mentioned earlier, earlier areas where there's human genetics and human disease biology to potentially support a role for TSLP, and areas that could be a focus for life cycle development over time.
Got it. Okay. Very helpful context. Turning to the Phase II CRS with nasal polyps readout, could you please frame that for us and what to watch for?
Sure. We've taken an approach with chronic rhinosinusitis with nasal polyps as an indication that very much relies on our differentiated potency to, you know, allow our 100 milligram Q12 week to be tested versus placebo in a program that is designed not really to further inform dose selection or to be exploratory in nature, but really to potentially support registration. Our Phase II trial, which we'll read out, which is completed, by the way, enrollment, and which we'll read out in the second half of this year, is designed with the endoscopic nasal polyp score as the primary endpoint. Of course, we know that that's a registration-enabling endpoint.
The nasal congestion score is a, is a key secondary endpoint, along with a number of other very important, as we've learned now from Dupixent and from Tezspire and others, a number of very other important endpoints, including the Lund-Mackay CT score, and other measures of sort of overall patient symptoms and quality of life. You know, our trial is anticipated to read out in the second half of this year. We have very carefully designed it, not only with those endpoints in mind, but with inclusion criteria in mind that will allow us to have a study population that very much looks like the registration programs of other assets, and hopefully will give us data that, you know, are very comparable and allow some meaningful cross-trial comparisons.
Now, in terms of what we hope to achieve, you know, we've gone into this trial, designing it, empowering it to achieve a Dupixent-like effect or better in terms of these key endpoints. That would allow us to detect an effect with our drug, verekitug, that could very much approximate that that we've seen with Dupixent, and what we've seen with Tezspire just recently.
Excellent. Obviously, that scale is zero to eight.
Yes. Than nasal polyp score.
Yes.
Endoscopic score.
and that, maybe you could just talk about sort of absolute and placebo-adjusted rough benchmarks there for Dupixent.
Yeah, I think we'd like to see, you know, to be competitive around a two-point reduction in the endoscopic nasal polyp score versus placebo and around a one-point or so reduction in the nasal congestion score.
Excellent. Okay. Great.
That's, by the way, of course, all in the context of a Q12 week dosing interval, which is quite different from that of both Tezspire.
Yes.
Tezspire and Dupixent.
Yes. Excellent. Oh, and then just actually on the timing, that 12-week, you know, dosing, could you just remind us, so between the completion of enrollment, obviously you're looking at a readout later this year, but could you just remind us on, you know, the actual timing of what, you know, when we might expect a press release?
Sure. I mean, I think the way to think about this is it's a 24-week observation period. Every patient contributes, participant contributes 24 weeks. You know, last patient in plus 24 weeks gives you a general sense of when the last patient is out. Of course, there are follow-up periods for a variety of reasons, and then work needs to be done to, you know, close and lock the database and do the analyses. I'll leave the arithmetic to you. You know, we have not changed our guidance from the second half of this year, but we have, you know, now this new milestone of having completed enrollment.
Okay. Very good. Congrats on that.
Thank you.
And then just to, I guess, follow on there. Why was this the first indication that you decided to study in Phase II?
I think, you know, a number of considerations can come into play when you make indication selection decisions. A couple were important here. The first is simply sort of speed to meaningful data. Now, that's not to say that all the preclinical and the early clinical data that we have thus far are not meaningful. In fact, we believe we've achieved proof of concept in asthma. We wanted to really get a very robust, and we believe versus the competition, you know, differentiated data set as soon as we could. One advantage that you can take with nasal polyps is the fact that it's a 24-week study, not a, you know, annualized rate of exacerbation study like you might have to, like you do have to do in asthma.
The sort of overall time period is shorter, the sample size is smaller, and we, you know, also elected to just take our, what we call internally our no-regrets dose, the 100 milligrams Q12 dose for it is a single dose versus placebo. All of those allowed us to move more quickly to data, data that we believe will be robust and definitive in this indication, and also data that we believe on the basis of a lot of learnings from drug development programs over time that will very much have a read-through to efficacy in severe asthma.
Now, that's not to say it's a one-to-one and linear, and it's not to say that we don't need to do the trials, but we have learned from the biologics experience that there's a high degree of comorbidity between severe asthma and CRS with NP, and that there can be directionally similar improvements in these indications seen potentially not only in patients with comorbid disease, but also the diseases individually, largely because Type 2 inflammation plays such a role in driving both.
Yeah. Makes a lot of sense. That's great. Have you talked about, you know, how you might pursue Phase III , assuming the data are compelling?
Sure. That would obviously be, you know, determined by the data and by discussions with regulators. I think, you know, one strategic question is how quickly do you move versus how well-informed do you move? We do have an opportunity from our severe asthma program to learn, because in that Phase II trial, also robustly designed, powered, and with regulatory endpoints, enabling endpoints in mind, we are taking a total of three doses versus placebo forward. There could be information that comes out of that program that informs our Phase III in nasal polyps. We are, you know, continuing to think and strategize about that.
Obviously, once we see the data themselves from the nasal polyps trial, we'll, you know, also be able to make some more informed decisions and choices. You know, of course, regulatory input is very important as well. I think we've got a number of different paths we could follow depending on the data, depending on, you know, how much we think we could gain additional information from the asthma program, and we'll make those decisions with data in hand.
Got it. Okay. Very good. And so let's talk a little bit more about that Phase II asthma readout that's expected second half of 2026. You know, you've shown compelling MAD data to date. But can you talk a little bit more about, you know, the efficacy, that one should expect, based upon, you know, biomarker translatability that we've seen in the past?
Sure. Maybe just to step back and do a high-level overview of our asthma MAD data, because they really are quite impressive. You know, what we learned from that trial, which was a four-cohort trial in which patients, eight patients were put into each cohort, six randomized to drug, two to placebo, conducted in a blinded fashion in patients with asthma with an elevated degree of Type 2 inflammatory tone. What we learned is that first, no matter which dose or dose regimen patients received, there was a 100% occupancy of free TSLP receptors at two weeks. A very rapid onset of effect.
That, you know, translated to a, you know, contemporaneous significant reduction in both fractional exhaled nitric oxide and blood eosinophils greater than those observed in the Tezspire program in Phase II and Phase III. There was really substantial durability of that effect as well. Even the 25 milligram single dose completely blocked free TSLP receptors for 12 weeks before there was evidence of any off effect. With multiple dosing, we actually saw 100% receptor occupancy for up to 24 weeks in some cases after that final dose.
You know, we believe, based on what is known to date, that the only mechanism by which TSLP can signal is the TSLP receptor itself. Again, based on some of the comments I made earlier about the relative expression and turnover of the TSLP receptor, we believe that we can, for quite a durable period of time, fully block signaling through that receptor.
What that allowed us to observe and then ultimately model, on the basis of these data, was an effect in parts per billion on fractional exhaled nitric oxide that ranged from about 27 to low fifties, which is, you know, greater overall than that observed with Tezspire, and then a % change from baseline of around 50%, which is approximately double that observed in the Tezspire program.
When we looked at that, you know, a little bit more rigorously in formal PK/PD modeling to then enable dose selection for, for asthma, what we observed on the basis of the modeling was that both 100 milligrams Q12 weeks and 400 milligrams Q24 weeks kept patients, modeled patients, a modeled population well above the EC90 for FeNO for really virtually the complete duration of that, 48-week period, except for a couple of days at the end of dosing interval for the Q24 week regimen. We have a hypothesis in, in, in asthma that these two dosing regimens could essentially be equivalent from the standpoint of their ability to reduce asthma exacerbations, symptoms, et cetera. We're testing that hypothesis, and we'll see if we're right.
You know, if that's the case, and if these incrementally greater effects on fractional exhaled nitric oxide and blood eosinophils translate to the clinic, then there is the potential, again, that we could be differentiated not only on dosing interval in ways that are very meaningful, but also potentially on efficacy as well.
Yeah. Yeah. Very exciting. That's great. All right. In terms of just taking that next step, if you could talk about the Phase II trial design in asthma, and, you know, timing, et cetera.
Sure. The Phase II trial in asthma is a three-dose regimen versus placebo. We've got the 100 Q12, the 400 Q24. We're taking what we're considering a lower dose, 100 Q24 forward, all three versus placebo, in a trial that's designed to read as its primary endpoint, the annualized rate of asthma exacerbations. We will be looking at lung function, asthma control, other important endpoints as well. This is a multinational global study. Our team has been working, you know, hard to execute this, not only with a, you know, a great degree of speed, but also a very high degree of focus on quality. Enrollment's going very well, and we are well on track to complete this in a timeline that will allow us to read out in the second half of next year.
Excellent.
These data, if positive and if we're successful in our negotiations with regulators, could be one of two potentially registration enabling studies. That's a path, by the way, that's been followed fairly frequently in our space, where a well-designed, robustly positive Phase II can serve as one of two pivotal studies.
Excellent. Excellent. That's great. Maybe we could pivot to the opportunity in COPD.
Sure. We do not to date have any data generated in COPD, but we were very much influenced and I think encouraged by the data that were reported with the Tezspire program, now last year with Tezspire and COPD. We're also, I think, really excited to see Dupixent now approved in COPD. And, you know, I, as a pulmonary physician, believe that biologics are gonna transform the care of this disease, at least for a subset of patients. We'd love to be a part of that. What gives us confidence? You know, as you'll recall, the tezepelumab trial was really, I think it could be called a proof of concept study in COPD. They were very bold. They took sort of a broad range of patients, sort of across a wide range of eosinophils, did the study.
And although they were, we think, not adequately powered to reach their primary endpoint, when different eosinophil sort of strata were looked at, it became clear that in patients with eosinophil counts of 150 and up, there was a significant effect on COPD exacerbations with a magnitude actually of reduction of COPD exacerbations that was actually slightly greater than that reported in the Dupixent Phase III programs. That is very encouraging. I think, again, it validates the TSLP pathway in another severe airways disease. We saw those data and were very much encouraged to move quickly to get our own program going. We have not fully disclosed the design of that trial yet, but as with our other two programs, it will be designed to support registration if positive. It will be an exacerbation primary endpoint study.
It will have very important secondary endpoints that are meaningful in the field. We've thought very carefully about how to handle the eosinophil question and are striking a balance whereby we believe we will enroll a population that enriches our probability of success from the standpoint of the biology and what we know to date, but also allow us to explore the full range of eosinophil criteria or concentrations, just to understand whether or not we might be able to work across the broad, broad range of patients. It's interesting, there are probably about 30% of patients with COPD who have eosinophil counts of 150 or less. You know, if the mechanism is relevant to those patients, there's an opportunity to help them. Of course, from the business standpoint, a potential additional commercial opportunity versus just 150 and up.
That's great. Very interesting. So then let's pivot back to the drug itself. So, verekitug is not a long-acting antibody.
Correct.
Obviously, you, you're showing a very impressive, impressive duration of effect. Could you go into some detail on that, please?
Sure. I, a lot of it, I think, is, you know, as we've had the chance to talk about, simply by virtue of the fact that we target the receptor and, and what that means. And we've shown data to support that. I, I think it's important to highlight a distinction between other molecules that are, you know, aiming for extended dosing intervals, because, you know, first, at least in the TSLP space, all of those are targeting the ligand versus the receptor. and so that's important. And to our understanding, all of them are achieving their extended dosing interval by virtue of FC, you know, engineering and, introducing a YTE mutation to extend the pharmacokinetics of the molecule. So, depending on the molecule, you know, maybe this extends the PK, the half-life, three to four-fold.
And if you're developing these molecules and you've extended the PK, you know, to that extent, you can then make choices about how far you wanna push the dosing interval, and, you know, sort of use one to potentially model the durability of efficacy that you're, you're gonna see over time. I think it's gonna be really important as these different approaches move forward to look at what others are doing and look at the durability of efficacy and, and really ask, okay, is there coherence between the delta PK and the delta dosing interval, or could there be evidence that there is a loss of either pharmacodynamic or, or clinical effect starting to emerge at the tail end of the, of the dosing interval? You know, it's a long way of saying that we believe how you get to Q24 weeks, Q6 months matters.
We believe on the basis of our data so far that we will have a durable effect over the course of that period. We are testing the hypothesis that clinically that will translate to durable effects, again, not just with exacerbations, but on meaningful clinical symptoms as well.
Yeah, that's very helpful perspective. Excellent. And then could you touch on IP protection and the company's cash runway?
Sure. We have composition of matter protection through 2034. We just recently had a patent granted around our formulation that expires in 2042. Those two will kind of run alongside each other. I think if you just think of sort of a base case scenario in which, let's just say with a 2030 launch, we relied on 12 years of biologics exclusivity, then we would have in that base case scenario protection into 2042. Of course, we're continuing to innovate. We will continue to protect our intellectual property, where there is an opportunity to do so and, you know, move to extend as much protection as we can over time.
Got it. The company has a strong cash position. Could you touch on that?
Sure. We, you know, had a very successful IPO towards the tail end of last year in October. That was after, you know, a very successful Series A and Series B. The company, you know, was well capitalized going into the end of last year. We actually just reported our 10-K today. As of the end of last year, we had $471 million.
That, you know, gives us runway through 2027, but perhaps even more importantly, runway through a number of really significant catalysts as we've discussed: the nasal polyps readout, the severe asthma readout, the initiation of the COPD study, and really a sort of a significant set of investments in CMC and also device/auto injector investments as well to really be able to launch in a way that is as commercially viable as possible if we make it there.
Excellent. Excellent. And just touch on, you know, the auto injector, just what your plans and expectations are.
Sure. There are a couple of, you know, commercially available auto injector platforms that pretty much everybody uses in our space. We have chosen one of those to move forward. You know, again, are introducing as early as we can in the development program, the device development and also sort of PPQ enabling activities so that, you know, the hope is that we can really launch with commercial material with a prefilled syringe and an auto injector to really give ourselves sort of maximal optionality when it comes to, you know, launch strategies and pricing.
Excellent. I guess finally, just to wrap it up, you know, considering the cash you just mentioned and the market cap at about the same level, it seems like, you know, the market is obviously underappreciating the company's prospects. Clearly, the sector, mid-cap biotech has taken a big hit recently. Maybe you could just summarize, you know, as you see the opportunity, it seems like a pipeline within a product type of opportunity and major markets with maybe even COPD being potentially even bigger than some appreciate because Dupi's launching in a pretty narrow window. If you could just speak to that, that would be great, just how you see that, you know, so building of the building blocks for the commercial potential.
Right. I think the first, you know, question is what, and we've talked a lot about the what could be, and we're doing the trials to figure that out. The next question is when, and, you know, I think we, you can sort of get a sense of when we might be able to come to the market. I think it's important to just then ask when others might come to the market, because, you know, there is competition out there. Although I believe that we are being seen by the market in the same way as many of the peers that you mentioned, you know, there may be, just because of the complexity of the TSLP landscape, you know, people really wanting to wait and see data, before they believe as strongly as we do.
You know, when we look at the others who are developing ligand-targeting, short-acting or long-acting antibodies in the TSLP space, and we contrast where we are from the standpoint of our clinical trials, how they've been designed, and what they will be delivering, we believe that we have a substantial timeline advantage in the order of years potentially versus the competition. While, you know, other companies with maybe more resources, people, or money can always move fast, they can't change the fact that these trials have to be done in a way that allows you to, you know, estimate the annualized rate of exacerbations.
You know, there will always be that need to do these studies in the right way to really have a clear sense of what your dose is. I think also not make risky choices to accelerate. You wanna try to de-risk at every step along the way. You know, our view at this point, and, you know, obviously the landscape will evolve, is that again, we have the potential for this very differentiated profile and we have a significant operational and, and timeline advantage. You know, I think that's important to recognize. Now, you know, what it looks like when, and if we get there, I think is TBD.
You know, I sort of alluded to the fact, and, you know, we have a slide in our corporate deck from Datam onitor that really suggests that these market dynamics have historically and are projected to continue to play out where, you know, as long as there's a significant degree of under penetration and perhaps even, you know, without that, if you are differentiated and, you know, physicians and patients are willing to use the drug, there's an opportunity to take substantial market share. You know, you can look at all kinds of commercial forecasts. We're not in the forecasting business, but suffice it to say it's big for severe asthma. It's even bigger for COPD. As we've learned, I think pretty recently, you know, it's pretty big for nasal polyps as well.
You know, we're gonna focus on, I think right now, making sure that we can get this differentiated profile to move forward, really robustly design a program that gets us through to a successful BLA. We do believe, again, with a differentiated profile, there's gonna be substantial opportunity. In COPD, you know, we believe that those days are just beginning. An opportunity to come maybe earlier to that market than is the case in severe asthma. You know, if everything works out, it looks like we could potentially be on track to be the second long-acting biologic to market in severe asthma. If so, we think that that's a great position to be in, particularly if we can come with a profile that's differentiated and meaningful.
Excellent. That was a great rundown. Thanks so much again for joining us.
Yes, thanks for having us.
All right.
All right. Thank you.