Morgan Healthcare Conference. My name is Tess Romero, and I'm one of the Senior Biotech Analysts here at JP Morgan. Our next presenting company is Upstream Bio, and presenting on behalf of the company, we have CEO Rand Sutherland. Rand, over to you.
Tess, thank you so much for the kind introduction, and we appreciate your moderating this session, and of course, appreciate the opportunity and the invitation from JPM to participate in this year's conference, so my name is Rand Sutherland. I'm the CEO of Upstream Bio. It's my privilege to share a bit more about our story with you today. Please do take a note that I will be making forward-looking statements. Drug development is a complicated and risky business, and there is risk associated with it, so Upstream Bio is a clinical stage company. We are working in immunology with a specific focus on severe respiratory diseases, and we are doing so by developing a drug in the TSLP pathway.
Now, of course, we know that TSLP biology and even clinical and commercial opportunity has been de-risked by Amgen's Tezspire, but we are taking a different approach than any other drug in development targeting TSLP in that we are targeting the receptor for TSLP. By doing so, our molecule verekitug, which is a fully human IgG1 targeting the receptor, has demonstrated unique pharmacology. That pharmacology manifests itself as significant suppression of disease-related biomarkers, the ability to be dosed as infrequently as every four times per year or two times per year, and importantly, has shown that now not only in preclinical and early clinical studies, but now in mid-stage clinical studies, including our recent data readout in chronic rhinosinusitis with nasal polyps.
So because of what we hope is a transformative potential of this molecule, we are studying it not only in CRS with NP, but also severe asthma and chronic obstructive pulmonary disease. And I will get in a little bit to the details of those studies and to the timing as we progress. Now, I don't need to tell anybody here that these are significant diseases with substantial remaining unmet need. There is still room for differentiated assets in these diseases, and therefore there is also significant commercial opportunity associated with a differentiated profile as well. Now, our company is still relatively young and relatively small. We've got a great leadership team, but importantly, the folks who aren't depicted here on this slide are all together comprising a company where there's a ton of deep experience in drug development, specifically in respiratory diseases.
We've got a lot of experience in product development as well, and we've got a team that has been executing at an extremely high level, has been allowing us to pull our timelines forward and working with this molecule, generating some great data. So I'm proud to be part of this team, and we are working hard to bring verekitug to patients as quickly as we can. So as I mentioned, as far as we know, verekitug is the only known drug in development that targets the receptor for TSLP. As I mentioned, it's a fully human IgG1, and it binds the TSLP receptor and prevents formation of the full TSLP receptor, IL-7 receptor alpha receptor complex, thereby preventing downstream JAK-STAT signaling and fully abrogating actually any signaling through the TSLP pathway.
As I've mentioned, our data not only from the preclinical space, but from phase I have demonstrated a very differentiated profile that's perhaps most notably marked by complete, that is, 100% receptor occupancy, receptor occupancy being of all free TSLP receptors for up to 24 weeks after the last dose. Now, this is associated with significant suppression of disease-associated biomarkers, specifically exhaled nitric oxide and blood eosinophils. And importantly, this is also associated with a very potent profile, and we'll get into the fact that even a small amount of verekitug, again, is enough to maintain effect for up to 24 weeks after the last dose. So this pharmacology has allowed us to move this drug into development with every 12-week and every 24-week dosing intervals. And again, as I will show you, may also provide the opportunity for differentiated efficacy versus other TSLP ligand-targeting molecules.
Now, one thing that we've also learned about TSLP is that it has a very broad set of inflammatory effects. And so by blocking TSLP signaling, not only do you downregulate Type 2 immunology, but you can also downregulate Type 1 signaling and even some of the mechanisms that go to drive fibrosis and the development of airway remodeling in diseases like severe asthma. And so this very broad degree of immunomodulatory effect has been associated in Tezspire's development program, actually with a very broad patient population with regard to eligibility not being defined by any specific eosinophil or other biomarker subsets. So the hope here is that we have a very efficacious molecule that can be used by a very broad population of patients with disease in whom we will see significant suppression of disease-associated biomarkers and therefore substantial improvements in meaningful clinical outcomes.
Now, as I mentioned, these are substantial commercial opportunities, even with the fact that now in severe asthma, for example, there are seven approved biologics, there is still increasing epidemiology, there is still substantial unmet clinical need, and associated with that, a market dynamic in which novel entrants, if they are meaningfully differentiated, can come in and take substantial share and do that actually more by driving penetration into eligible patients than by eroding the share of others, and so the magnitude of these various markets is highlighted here. I won't go into these details other than to say these are multi-billion-dollar markets, and even CRS with NP, which is still a relatively newer market compared with severe asthma and COPD, is one that now numbers in the over $1 billion of biologic sales annually in the U.S. and is projected to grow over time as well.
We are targeting these three indications: substantial unmet need, substantial clinical opportunity, and I think substantial opportunity to impact the care of patients. And as I mentioned, again, we're doing that with a molecule that has very unique and very, I think, differentiated pharmacology. There's a lot of information on this slide. I won't go through it in exquisite detail other than to say that one of the other things that marks this molecule is a very clear and consistent through line from the preclinical days about the potential for this molecule to be differentiated because of its potency. We've seen this in preclinical assays looking at cell proliferation, looking at cytokine elaboration. We've seen it in animal models of allergen challenge.
We've seen signs of potential extended PD and association with a very unique PK/PD profile in not only the phase I in healthy volunteers, but also our phase I in patients with asthma, and we've now, of course, moved that and have really validated all of these previous observations in a very robust phase II placebo-controlled trial in chronic rhinosinusitis with nasal polyps. Now, I did allude earlier to the fact that we've spent a lot of effort on improving our formulation and our product development activities as well, and it's important to note that we have a formulation currently of 200 mg per mL, which allows us to give even our highest dose of 400 mg in a 2 cc injection, so briefly on our MAD study, this was a fairly characteristic and classical multiple ascending dose trial in patients with asthma.
These were not patients with severe asthma, but rather a group of asthma patients who were selected to have evidence of sort of high Type 2 inflammatory signals, and of course, in these types of studies, you're looking for essentially a signal-seeking type of approach to identify and fully understand the pharmacology of your molecule, so across the four dose regimens that you see here, ranging from 25 mg given once to 200 mg given every four weeks, three times, and 300 mg given every 12 weeks, two times, we enrolled eight patients per cohort, two allocated to placebo and six to drug, and of course, carefully monitored safety and looked at pharmacodynamic and other pharmacology endpoints as part of this. What was very reassuring and very important for the progression of the program, of course, was the fact that this molecule has a very clean safety profile.
This is actually typical not only of programs that target TSLP, but really broadly of biologics in the Type 2 space in severe asthma and related diseases, and so we were reassured to see that here. Now, what was also very helpful in terms of understanding the pharmacology and allowing us to understand how we might move forward here are some of the data shown on this slide. On the left, we're showing you the results of our receptor occupancy assay, which is essentially a competitive binding assay in which we make the receptor compete either for verekitug or for TSLP.
What we showed here is that even at a 25 milligram single dose, we could rapidly, that is, at two weeks after the first dose and for a period of up to 12 weeks after that last 25 milligram dose, see 100% free TSLP receptor occupancy, an observation that actually persisted and increased in its duration as we increased the dose and dose regimens as you see here. So these very early data, which then were actually reflected in the changes that we saw with regard to the expression of exhaled nitric oxide and blood eosinophils, very much showed that by blocking signaling through the TSLP receptor, we could have magnitudes of reduction of FeNO, exhaled nitric oxide and blood eosinophils that was quite significant, but also have those persist for a duration that very much overlapped the persistence of receptor occupancy.
A very nice signal here of a significant suppression of up to 54% in exhaled nitric oxide at week 12 and reductions in blood eosinophils that ranged from about 40%-65% at week 12 as well. We know that both of these biomarkers are very tightly related with the kind of inflammation that drives disease in severe asthma and related diseases. And particularly with regard to exhaled nitric oxide, significant suppression of expression of that biomarker was associated with substantial improvements in clinical manifestations of disease. So we emerged from this study with, I think, the potential for a profile that was not only going to be unique in the TSLP space, but potentially across all of the different target space in severe asthma and related diseases.
And so here we're showing how verekitug at its very early stage stacked up with regard to a number of important attributes here on the left versus tezepelumab, Tezspire, dupilumab, Dupixent, and mepolizumab, Nucala. And what these data demonstrated was that by targeting a unique MOA, targeting the TSLP receptor, we could potentially dose this drug either two times a year or four times a year, do that, as I mentioned, with our CMC advances in a commercially viable presentation, and with administration see basically class, top of class effects both on exhaled nitric oxide and blood eosinophil suppression as well. I also mentioned earlier that we hope to do this in a broad population. We are continuing to test whether or not this drug will work in patients independent of blood eosinophils or other biomarkers.
So hold the phone there, but I think we understand a good bit about TSLP biology and would anticipate being able to move forward with a profile similar to Tezspire's from that regard. Now, the other thing that we emerged from our MAD study with was a trove of data, a trove of data that allowed us to do very robust pharmacological modeling, PK/PD modeling. And we also had the advantage that the Tezspire development program had done some really great work and had actually provided some sense of how to move forward here.
By using very similar, if not analogous approaches to those used in the tezepelumab program, we were able to model not only what we thought the maximal effect of verekitug on suppressing exhaled nitric oxide would be, but also to get a sense of potency and understanding exactly how much verekitug would be needed to achieve a 50% or 90%, the EC50 and EC90 for suppression of exhaled nitric oxide. What we observed first was that verekitug generated in this quantitative modeling an Emax or a maximal effect, predicted effect on exhaled nitric oxide that was about 1.5 times greater than that observed with tezepelumab, but that importantly, the EC50 and EC90 for the molecule were over 300-fold lower.
This is sort of the reflection of the potency and the manifestation of the potency is a lot of the early signs that I've already shared with you and that we will see validated as we move forward to the phase II data from CRS with NP. So we were able to sort of do some quantitative comparisons as to what we might expect versus tezepelumab. And of course, ultimately, we want to use these data to make dose selection for subsequent studies. And so we did that and actually modeled a number of different dose regimens. And what you see here on the top left are the 100-milligram Q12-week dose regimen and on the lower left, the 400-milligram Q24-week dose regimen.
You see what the results of that modeling are with the line representing sort of the median member of a modeled population plotted out against the EC90 for exhaled nitric oxide. Now, that of course is a very, very conservative threshold for efficacy. In many drug development programs, you see an EC80 or an EC50 used. Here we wanted to be as conservative as we could and with that showed that our 100-milligram Q12-week dose keeps the vast majority of the population well above the EC90 for the entire 48-week modeled period. Similarly, with the 400-milligram Q24-week regimen, we keep the population above that EC90 for all but about the last couple of days. We believe that in our hypothesis is that in both of these cases, we will be able to see significant efficacy in terms of reducing asthma exacerbations.
Of course, we're doing the trial now to figure that out. One of the things that actually gives us some comfort as well is that we know that Tezspire is an efficacious molecule and we see when we compare the levels of coverage that we get with verekitug versus the levels of coverage obtained with the marketed dose of tezepelumab that there is significant coverage comparably there as well. So again, we feel that this is well-understood biology associated with significant improvements in clinical outcomes as reflected in that program. But our hypotheses again here are that we have the potential for differentiated efficacy, the potential for differentiated dosing. And if we can do that in a broad population and hit all three of those sort of achievables, then that's a really compelling potential profile for verekitug.
And so we were reassured and I think given even more comfort by the data from our phase two trial in chronic rhinosinusitis with nasal polyps. This was a fairly typical trial for the space, one in which we look at potentially registration enabling or registration supporting endpoints, including an endoscopic nasal polyp score, a number of symptom indices, and even clinically important outcomes like need for surgery or steroids. In this case, we elected to take our 100 milligram Q12 week dose forward versus placebo because that was our sort of highest coverage dose regimen and allowed us to move more quickly than we would have been able to move with multiple dose regimens. Our primary endpoint here was the endoscopic nasal polyp score and a number of key secondary endpoints, many of which I've already mentioned. And we received data from this trial.
We reported these data the day after Labor Day and we're really very happy with the results. So our 100 mg Q12 weeks versus placebo allowed us to meet the primary endpoint of a significant, and I would say that this is both clinically significant and statistically significant reduction in the endoscopic nasal polyp score of a reduction of 1.8 points. We met all of our key secondary endpoints, including a significant reduction in the nasal congestion score and importantly, a 76% reduction in the need for surgery or steroids. This trial was not powered in any way to detect that, so we were very happy to see that. I think as many of you know, that's a very meaningful clinical effect. It's obviously a key driver of healthcare utilization and cost. And so to see that even this early in the program was very reassuring.
It was also very reassuring to see that the unblemished safety profile is continuing. And I think if you just look at the biology of CRS with NP, you look at how much of a Th2-driven disease it is, and you then look at the role of Th2 biology in severe asthma. And even as we're now learning in COPD, you can start to conclude that there is a significant potential here for read-through to other indications as well. Just a little bit more on the trial because people are always asking us, "Well, how did you do versus this agent?
And what are the differences in your trial versus the others?" And I would say that we were very happy to see not only that randomization kind of equally distributed various baseline characteristics between placebo and active, but that the phenotypic characteristics of this patient profile are very consistent with what has been observed in other clinical development programs in this space. Just sharing some specifics here, overall, the incidence of AEs was similar across treatment groups. Treatment emergent adverse events were actually more driven by disease than by placebo, and there were no serious adverse events in the study. And as I mentioned, clinically significant, statistically robust findings across all primary and secondary endpoints, endoscopic objective measures, patient-reported measures, and important sort of summative healthcare utilization measures as well. So a very strong profile, which we were very happy to see.
Now, of course, this was only a study of 24 weeks in duration, so not of the same length and magnitude as a typical phase III trial. We, of course, pending successful regulatory interactions, hope to move forward phase III here and would be conducting a 52-week study, and I think we may even have a sense from the nasal congestion score data on the right that there is still not yet a full plateau that's been achieved and therefore the potential for maybe even a bit of additional efficacy observed over the second half of a, again, theoretical phase III study when we get there.
As would be expected by various phenotypic characteristics, there was, for example, in the case of blood eosinophils, maybe a little bit of enrichment of efficacy in the higher blood eosinophil populations, broader width of confidence limits as the populations get smaller, but in general, very much of an expected behavior of verekitug across all subgroups in this population. And when compared, again, with what is out there, at the time we put this slide together, we actually were anticipating that depemokimab would be approved in CRS with NP, that did not happen. But certainly compared with tezepelumab and dupilumab, not only a magnitude of efficacy that is quite compelling and we think quite competitive, but importantly, with this Q12 week dosing regimen, a dosing frequency that is substantially differentiated from marketed products in this space.
So I mentioned that we have hope that these observations will read through to our severe asthma program. Of course, we need to get the data to verify that. But the reasons to believe are not only the data that I've showed you, but also underlying disease biology, shared epidemiology between these two diseases with comorbidity of one frequent in the other, and importantly, sort of a very consistent set of observations across drug development programs in Type 2 space that suggests that the magnitude of efficacy in one of the indications often comports with the magnitude of efficacy in the other. So we'll see what happens here, but this is our hypothesis going into our asthma data readout, which is going to happen this quarter. So our asthma study, its acronym is Valiant.
It is, again, a very characteristic dose-ranging study in patients with severe asthma, inclusion criteria, definitions of asthma exacerbation, statistical approaches that are very consistent not only with what is consensus, but very consistent with what has been done across development programs in the space. We are taking three dose regimens forward versus placebo. You see those outlined here. It's the 400 mg Q24 weeks, the 100 mg Q12 weeks, and then what we think will be a subtherapeutic regimen of 100 mg Q24 weeks as well, all versus placebo in a range of patients from 18- 80 years of age. Our primary endpoint is the standard registration enabling endpoint of delta and annualized asthma exacerbation rate, and of course, we'll be looking at other important asthma outcomes, including pre-bronchodilator lung function, exhaled nitric oxide, and asthma control/asthma symptoms as reflected by the ACQ-6. We'll continue to monitor safety.
Our sample size in this trial ended up being almost 480 patients and that is a large trial. It's certainly a global undertaking to be able to conduct a study like this, but we would just caution that to really be fully powered for these secondary endpoints, including lung function, we would need even more patients than that, so we do not necessarily anticipate being powered for all secondary endpoints. We are fully powered at 85% to detect a 50% or greater reduction in annualized asthma exacerbation rates and again, we are looking forward to reporting these data soon. Also underway is our phase II trial in COPD. Like in asthma, we are doing dose ranging and we are looking at a broad patient population. Also looking at COPD exacerbations as the primary endpoint here and also importantly, looking at a broad range of patients as defined by eosinophil counts.
So not only at patients with 150 or 300 and up, but also at levels below that to really understand whether or not verekitug's potency and unique pharmacology translates to a broad patient population and significant efficacy in COPD as well. It's a little bit early for us to be saying when that's going to be reading out since we just started the trial a few months ago, but suffice it to say that enrollment is going very well. We're actually using a lot of the same sites that we used in our asthma program, and there's just a ton of enthusiasm from investigators that has really, I think, been a significant tailwind for this program as well. So we've got a lot on our plate. We're doing a lot. We're executing really well. We're really excited about the pharmacology of our molecule.
We are very excited by the end of this quarter to read out our data in severe asthma and looking forward to coming back and sharing those with you when the time is right. Thank you.
Thank you, Rand, for the presentation. So I thought I would start our conversation here with a little bit of a bigger picture, strategic one. Why did you focus development of verekitug in the indications that you did? And as you think long term for the business, where are you most excited to take the product?
Yeah, so two great questions.
I think one of the things that's been really important actually for drugs in this space has been the fact that the life cycle and the number of indications in addition to whatever the efficacy criteria end up being can really provide the sort of holistic reason for physicians to choose this drug for this patient at this time. You've seen that, I think, leveraged maybe most successfully with Dupixent and really the ability to move not only across airways diseases, but in multiple therapeutic areas as well: dermatology, GI, allergy, others, and we do think that there's the potential with TSLP biology to do the same. We did, however, look very carefully at where the biology was best understood, where the biology was most de-risked, and where there had maybe been some negative outcomes along the way to sort of choose our initial set of disease states and indications.
We are squarely focused on respiratory disease. That's where we think the opportunity is greatest. The molecule and the pathway are potentially most de-risked and where there's still substantial commercial opportunity. I think we would need to understand more about the potency of our molecule and whether or not that might translate to differential efficacy in atopic dermatitis where other TSLP programs have failed. Of course, in eosinophilic gastrointestinal disease, there may be some opportunities as well. For now, we are funded, resourced, and focused to really spend our time trying to improve the care of patients with these airways diseases.
I think your presentation did a nice job recapping the prior data and what you're thinking you would like to show in your phase two in severe asthma.
But maybe just to put a little bit of a finer point on it, how do you characterize what good data looks like versus what could be a home run for the study? And in this context, can you talk a little bit about what the considerations are from your perspective as investors and analysts try to do some cross-trial comparisons, which we all tend to do from time to time?
Yeah, and which we, of course, say are fraught and shouldn't be done, et cetera, et cetera. Everybody has their position on this. I think, as I mentioned, we understand the biology here reasonably well. We've got a very consistent clinical, preclinical data set. We have an understanding, at least from our phase one studies, of what we think successful dose regimens look like, and we're now testing those.
We are, as I mentioned, 85% powered to detect a 50% reduction in exacerbations. I think if you look broadly across development programs, not only in phase III, but in phase II, perhaps with one notable exception that we often get asked about, somewhere in the 50% or so range of exacerbation reduction is where efficacy lands out at the end of the day. We think it's probably not prudent to try to be promising much more than that. If we see it, that could be good. But I think right now, what would be a great outcome for us is a 50% or so reduction in asthma exacerbations on an annualized basis, doing that at Q12 weeks and being able to demonstrate that degree of efficacy in a broad population.
So we know from our market research and from a lot of conversations with physicians that dosing frequency really matters. If you can deliver best-in-class efficacy and do that with far less dosing, no loading dose, broad population, that's the potential for a very meaningful value creation exercise. And so we would be very happy to see that. If we see greater than that, that would also be, I think, a very good outcome, but one which we would then need to monitor closely through development. Now, you've heard me focusing in this answer on Q12 weeks. I showed you our pharmacology modeling data that suggests that Q24 weeks also we would believe going in has a high probability of success. But what we've learned particularly is the profile of some of these extended dosing drugs that have extended PK through Fc engineering.
As we've started to see the clinical profile of some of these emerge, what patients and physicians don't want to see is any degree of trade-off for efficacy over time. So everybody's happy to take a drug twice per year, but they want it to work, and they want it to work consistently and of sufficient magnitude. And so we would not make a choice to move something forward solely for dosing convenience and really want to have robust and durable efficacy, whether it's twice or four times per yearly dosing.
And Rand, can you talk a little bit about the decision to test two 24-week doses and one 12-week dose in the study?
Yes. I mean, our real question here is whether or not 100 Q12 weeks and 400 mg Q24 weeks behave the same.
The 100 Q12, sorry, the 100 Q24 is in there really as a subtherapeutic dose. It's to facilitate dose ranging, give us a little bit more patient exposure, and again, to really enable really robust PK modeling to do dose selection for phase three, and I think that's a really important point to make. This program, by the time we get to end of phase two negotiations and by the time we do the work to choose a dose for phase three, and I think our aspiration is to choose a single dose moving forward in both CRS with NP and severe asthma, at that point, we're going to have hundreds and hundreds and hundreds of patients of data, so we're really going to understand the pharmacology of this molecule.
We're going to understand if the assumptions that we made at the end of phase one have held up into phase two, and we're hopefully going to be able to make the kind of decision that really, as much as is possible, de-risk the path to phase three,
and can you maybe talk a little bit about what you're focused on from a study conduct perspective just to maximize the chance of success for the study and anything that you've been watching on a blinded basis?
Yeah, so first, I mean, our R&D team is incredibly meticulous. And this goes really into every single aspect from protocol design to CRO selection to site selection to protocol execution to the way that we interact with investigators and CROs. I mean, everything. It's so important to us to get this right, so it's not glamorous. It doesn't get a lot of talk.
But companies that really focus on this and do it well, I think, have an advantage. So that's the first thing. Study design and conduct and execution have to be flawless. The next thing you have to do is really bring in a patient population that is relevant, relevant in that they need additional care, that they have characteristics as a study population where they can match that of other biologics, are relevant to payers, are relevant to regulators. And if you're a patient that gets included into that trial, could potentially benefit. So we give a lot of thought in the study design around what are the phenotypic characteristics? How do we be sure that we get patients who are going to be appropriate for therapy?
How do we make sure that we monitor that we are getting a broad and diverse population that is really across a wide range of biomarkers, for example? We are, again, meticulous in terms of how we define and how we measure and monitor asthma exacerbations. That's the primary endpoint. And while we are not looking sort of at a patient-level basis at a blinded level, we are looking in aggregate to be sure that the assumptions that we made going into the trial about power and background rates of exacerbation are accurate. Because if those aren't accurate, you can find yourself with an unpleasant surprise at the end of the day. And so we have been monitoring those.
We actually even had the opportunity in our trial to do a blinded sample size re-estimation and determine whether or not we would actually need to change sample size to detect an effect. We did not. And so I think we're in a good place, largely because of the incredible work that the team does and the careful and methodical approach we take to doing these trials. And have there been any protocol amendments? There have been some fairly typical protocol amendments along the way. It's extremely unusual for a protocol never to be amended. They are not meaningful amendments from the standpoint of any of the kind of things we're talking about here.
Okay. Great. Okay.
So I kind of wanted to just kind of press a little bit on the pushes and pulls of your comfort and all else equal, kind of seeing similar-ish efficacy across the Q12 and Q24 week doses. What keeps you up at night about the Q24 week, maybe just not getting quite there as you see it with the Q12 week? Seems like you're pretty confident that they could be similar. Where are you now?
Yeah. I mean, let me just caveat everything appropriately. So we chose our two doses, the two efficacious doses, on the basis of phase one data. Those data are, we think, important, but they are small in magnitude. And so you always take some risk with a small number of patients doing modeling and then making dose selection. But this is how the work is done.
Based on the modeling that we have, and I think, again, understanding all of the preclinical pharmacology, this model doesn't just include, for example, the MAD data. It really includes everything that we've learned about the molecule over time. So with the caveats that it's still a pretty small data set, I think we feel very good about the precision of that model. Now, whether or not that translates and whether or not we're right, those are still hypotheses. And we just, again, we kind of have equipoise here. We feel really good about the data that we've seen. Again, I just want to point out that all of this was validated in our CRS with NP study, where we had very strong performance of that 100 milligram Q12 week. And so we're not trying to hedge our bets in any way on the 400 Q24 weeks.
It's just to say that if you look at the modeling, there's a little less coverage versus the very conservative EC90. Whether or not that's going to translate to a difference in efficacy or not is something that we'll know soon, but I do, I think the corollary to your question is how necessary is a Q24 week dosing regimen for the success of a potential product here, and again, I think it's important in a circumstance in which there is bulletproof efficacy that does not differ at all from the 100 milligram Q12 week dose regimen. If the efficacy is a little bit less, but the dosing intervals twice as long, our feedback, and I think even our own clinical experience for those of us who have taken care of patients, is that people are not willing to make this trade-off.
You need to give the best efficacy you can deliver, and then you need to make that as convenient for patients as you can, and there's not much room for trade-off of convenience versus efficacy.
A little bit less is a couple percentage points. 5%? What do you mean by that? What would be viewed as materially lower?
I think if we don't get in the 50% reduction range of exacerbations in Q24 weeks, and we do with 100 Q12, I think we're going to have some decisions to make.
Okay. Similar to how we're thinking about it. Okay. Great. Well, maybe I'll just ask a quick sort of market opportunity question here. How do you overall think about the TAM potential peak sales opportunity in these sort of various scenarios? What kind of underpins your confidence here that you have an interesting commercial opportunity?
Yeah.
I mean, I think it's a little early for us to be sort of making any kind of commitments in terms of peak sales and things like that. I think the first thing is these are prevalent diseases. They are prevalent diseases, and let's just take severe asthma as an example. So this is a disease where for many, many years, we've had biologics approved. We now have seven biologics approved in severe asthma. And what we've seen is that as these labels emerge, they have slightly different efficacy profiles. They have slightly different eligible patient populations. They obviously have different targets. And so the beauty of that for clinicians has been that they've been able to make a clinical decision based on the patient sitting in front of them and make a choice.
I think what we've seen is that many of these products have done really well and have contributed a lot of good to the care of these patients. But when you look at overall penetration, it's still, depending on who you listen to, somewhere in the 20%-25% range. Again, here talking severe asthma. So that means that 75% of the patients who could benefit from these drugs aren't getting them. Now, there are, of course, many reasons why that might happen. But what's been really interesting over time is that when novel entrants come in, again, they come in and they take substantial share if they are differentiated in one of those meaningful ways. And they do it largely by driving penetration, far more so than by eroding share of other products.
So I think that gives us hope that even being in the pathway of another marketed product, if we can be differentiated and have a broad patient population, efficacy as good as or potentially better than anybody else, and do that at two times per year or four times per year dosing, that's going to be a pretty compelling profile.
And maybe a last one from me. How should we think about next steps in CRS with NP?
Yeah. I think the beauty of us having pulled our asthma execution so far forward is that you can think about next steps in CRS with NP kind of in the same way as next steps for severe asthma. So we need to read out our severe asthma data this quarter.
We're going to take, as I mentioned, all of these data and do some really deep thinking about what makes sense for the molecule in terms of dose selection. And then our hope would be to essentially simultaneously prosecute the progression of these programs with regulators and hope to get into phase three in each case as quickly as we possibly can. We don't wait for the data to do this. We're already starting the pre-work for this now. There's a lot of planning already underway to get these programs moving forward as quickly as possible. And the data that we have coming out this quarter will be very helpful. But our plan is to go, go, go as soon as we get the data.
And Rand, when's that data going to be? No, you're going to kill me.
First quarter.
All right.
We're going to have to keep it wrapped up here. Thank you so much to the Upstream Bio team and Rand for being here.
Thank you, guys. Appreciate it.