Thank you for joining us. I'm Paul Choi, and I cover biotechnology here at the firm. It's our pleasure to welcome Spyre, and we have Cameron here on stage with us. Maybe to kick it off, Cameron, can you just give us a brief overview of Spyre and just sort of the key programs and technologies under any main company?
Yeah, of course. Thanks for having us at this great event, as always. The background for Spyre, we launched the company a couple of years ago with a pretty straightforward goal, which was to address what we saw as the unmet need in inflammatory bowel disease, which I think we view in two dimensions. The first being, most importantly, efficacy here, as the disease that we've been working on for decades and have come up with about a half dozen therapeutic classes that have been approved to treat the disease. They're uniformly capped at what the physicians in this field describe as the therapeutic ceiling, which is that we can't really get above about a 25% clinical remission rate with any individual drug. What that leads to is physicians having to cycle through many different medicines over time to try and keep patients in remission.
The second issue is that despite this being a disease that affects 2 million people in the U.S. and being a $30 billion global commercial market, the product profile of products on the market today are also still lacking relative to other INI categories. They're dosed as frequently as every two weeks subcutaneously, or patients still have to go in to get intravenous therapies. Our goal at Spyre was trying to address both of these dimensions of unmet need simultaneously. On the convenience side, we've engineered all of our antibody therapies with half-life extending modifications that lets us take molecules that were dosed every two weeks, and we think we can dose them twice a year.
On the efficacy side, we believe the blueprint to follow here is beginning to test these therapies as combinations, which has been now kind of shown in a few studies in this space that you can actually unlock a very different level of efficacy than we get with individual therapies. We think we're uniquely able to combine these long-acting antibodies together to get combinations that are really targeting a product profile that no one else can go after in this space.
OK, great. One of the questions we often get is just understanding how was the company started and just kind of what is the structure between Spyre and the Fairmount Funds. Also, is there sort of maybe understanding the separation between indications and firewalling of data and technologies and so forth? Can you maybe just give us an overview of that?
Yeah, so the background here is the investor group that launched Spyre is called Fairmount Funds, and they've launched a handful of companies over the last few years. I think largely use part of the strategy that I described in terms of engineering improved versions of what they and we think are the best biologics in different indications. I think the fundamental principles on what we're looking for in an antibody are quite similar in terms of excellent potency and selectivity, great pharmacokinetics, and then really strong developability and manufacturing properties as well. We do share kind of the origin of all these antibodies.
Once I think they get into the kind of the spinoff companies and we take them each into the different therapeutic areas, I do see more divergence in strategy because, of course, every therapeutic area is different. For example, in inflammatory bowel disease, I think this focus on combinations is different than you see in other indications where perhaps the individual therapies are actually quite good on their own and we can kind of approach near maximal efficacy in different therapeutic areas. That's the basics. In terms of sharing, we obviously do learn a lot from what has been done before in this space. There are kind of both formal and informal interactions between the companies that help us, I think, all execute more efficiently.
OK, great. You've talked a little bit about focusing on IBD as sort of the broad therapeutic category, but you also have, in the past, talked about three primary targets here. Maybe you could just briefly go over that before going into some of them individually.
Yeah, sure. Again, in general, we're not testing new targets in IBD. We looked across, and there's about a half dozen, as I mentioned, approved classes in IBD. There's really three of them that get to that therapeutic ceiling of efficacy and don't have any substantial safety liabilities. Those are the three that we picked. That's alpha-4 beta-7, which is the number one class in IBD overall. That's Takeda's ENTYVIO. It's a gut selective mechanism that we think is an excellent individual agent and a backbone for combos. The second molecule is TL1A, which we don't yet have approved TL1As in IBD, but multiple phase threes ongoing now. I think it's fair to say that the phase two data for TL1A perhaps shows the best monotherapy efficacy of any biologic class. Then lastly is IL-23, and specifically the p19 subunit of IL-23.
The same target as risankizumab from AbbVie or guselkumab from J&J , which is one of the most rapidly growing classes in this space and again shows excellent efficacy and an excellent safety profile. We think these are the three best biologic classes to have. What we've done is taken those targets, engineered what we think are the best possible versions of biologics against those targets. As I mentioned, we plan to test them together. I think it's a reasonable hypothesis that the best monotherapies combined are likely to create the best combos when put together.
Yeah, you've already toplined your alpha-4 beta-7 program a little while back. Maybe people know it more, the target, at least as you mentioned, is commercial stage, Takeda's ENTYVIO. Just kind of remind us briefly what you showed there with your lead program.
Yeah, so ENTYVIO , as you just highlighted, it is the number one product in IBD. It's a gut selective mechanism, extraordinarily safe, and tracking towards about an $8 billion peak sales level for that molecule. The main weakness with ENTYVIO from our perspective is its product profile, which is that it's either delivered every eight weeks intravenously or every two weeks subcutaneously, neither of which we think is the best you can do. What we showed with our phase one data for SPY001, our molecule targeting alpha-4 beta-7, that we had a half-life that was more than three times that of ENTYVIO in humans. What that lets us do in combination with our high concentration formulation is dose this molecule, we think, as infrequently as twice a year.
We will test both quarterly and twice annual versions, which we think can achieve similar, if not potentially even better efficacy by covering the target better during the induction setting. We think just a meaningful step up in convenience compared to the current product, as well as the potential to optimize the efficacy as well.
You talked about exposure levels being meaningfully higher than the commercial stage product. What does that mean potentially clinically in addition to the convenience? I think in the past you've talked about quartiles of exposure.
Yeah, maybe more broadly first. I think kind of the first assumption for half-life extension is that the advantage you get is only in convenience, that you can kind of extend the dosing interval. However, I think one of the things that is generally true for long half-life drugs is that you can actually get the same C-min or AUC exposure, kind of what you're looking for to ensure you're covering the target without having to push the C-maxes, those peak exposures, as much. You actually narrow the peak to trough ratio for any individual molecule, generally letting you get better coverage without some of the safety risks that you might have with really high peak exposures.
What we are able to do with our molecule is kind of just with our planned dosing schedule here, without more frequent doses, actually with much lower frequency dosing, we're still able to achieve better average target coverage, a greater AUC, even without pushing the peak levels dramatically higher. In particular, what we're looking to do is what vedolizumab showed in both their pivotal study and their real-world data is that individuals that were in the fourth quartile of exposure, so the highest quartile of exposure as measured by C-trough, so the people that had the highest, lowest levels, if that makes sense, had the best responses. Again, because we have these long half-life molecules, we can get everybody into that fourth quartile without meaningfully pushing the peak exposures.
We think that can provide kind of the optimal risk-benefit profile for patients in this disease.
OK, great. Maybe turning to your next program, your TL1A-1002, that top line. Not too far off. Can you maybe just remind us first what kind of data you plan to share with the 002 program? Just secondly, what does the potential medical conference schedule look like for that data?
Yeah, so this is a similar Healthy Volunteer study, so just escalating dosing of this antibody. We'll plan to do a disclosure quite similar to what we did for our Alpha-4, which is initially we'll present this just as a company presentation in the upcoming weeks here. We're still on track to announce the data in this second quarter, in the upcoming weeks here. We'll follow it up with a more detailed presentation at a medical conference over the upcoming quarters. In general, what we're looking for is kind of what we typically want to see across all of our antibodies, which is really four, I would say, key properties, which is first and foremost safety, of course. This is a phase one Healthy Volunteer study. That is the primary endpoint. Second, we want to look at pharmacokinetics.
This is, again, we're kind of engineered long-acting, what we believe long-acting versions of anti-TL1A antibodies. We've seen in our non-human primate studies that they have between two- and three-fold the half-life of the first-generation TL1As, and we'd want to see that recapitulated in humans. Third here, we're interested in pharmacodynamics. As opposed to alpha-4 beta-7, where we measure receptor occupancy, but it hasn't exactly correlated with efficacy for alpha-4 beta-7. For TL1A, I think it's fair to say that it has. There's three first-generation TL1As. They've all used one of two different pharmacodynamic measures. They've all selected doses for phase two based on those pharmacodynamic measures and seen that they had, we think, similar induction efficacy when they're able to saturate these pharmacodynamic measures and then carry those doses forward into phase two.
What we are excited to see in our, what we hope to see in our Healthy Volunteer study is that at doses that we achieve with our molecules, we get full saturation of these pharmacodynamic measures as well. One is a total TL1A assay, and one is a free TL1A assay. I think it is fair to say now that they both work, and we would like to see that our molecules are able to saturate both of those as well. Lastly, what we are also interested in for TL1A is that we know this can be an immunogenic target, meaning that you form anti-drug antibodies against your therapeutic antibody. What we really would like to see and what we really do not want to see is that either of those first two properties are affected by immunogenicity. That is really the key questions.
Like, do we see the pharmacodynamics of our molecule affected? Do we see cs that lead to clearance of your antibody? Or do you see that we say lose coverage of these PD measures over time as ADAs form? Those are really the four properties that we're looking for. We'll share those data in the upcoming weeks here.
Great. As you think about what your product or products, since you're working on multiple TL1As here, just kind of ideally would look like, as you think about the Merck/Prometheus data that we've seen to date or the Teva data that was presented not too long ago, maybe just sort of help us contextualize what are the strengths and weaknesses of the competing programs out there and just how do you hope your program fills or meets these gaps?
Yeah, so I think in general, as I mentioned, I think we believe that all of the first-generation TL1As were able to saturate the target during the induction portion. The first three months of dosing in IBD, you typically have higher levels of drug on board to kind of capture these acute flares. I think it's fair to say that the placebo-adjusted efficacy across the three first-generation molecules was quite comparable in that first three-month period after they all kind of saturated the target based on the same PD measures. I think in general, we'd like to recapitulate that with less drug. I think that's generally an advantage here that we can dose less. It's advantageous when we move into combination therapies as well that you don't have to have as much of any of them individually.
We want to be able to see match that safety and efficacy of those first-generation products with lower drug levels. In the maintenance setting, I think the answer might be a little bit different. I think for the first-generation TL1As, for the two that have reported maintenance data, we've seen dose responses for both of them where the highest doses tested were actually the best, most efficacious. As the large pharma acquirers of those molecules took over to run the phase three programs, at least one of them actually increased the dosing frequency of the molecule, went from a four-week dosing interval to a two-week dosing interval, I think also suggesting that they thought they might have underdosed it in the maintenance setting and did not fully capture the maximal efficacy there.
What that lets us do, if our molecules perform the way we expect, where they have at least in vitro, we see compared to that Prometheus molecule about tenfold the potency. Again, somewhere between two- and threefold the half-life in non-human primates. We will see that in humans shortly. We think we actually may be able to get greater target coverage in that maintenance setting, again, without pushing the C-max. We think there might be additional efficacy to be had for these molecules in that longer-term maintenance setting with more potent, longer-acting antibodies.
I mentioned earlier that you are testing two candidates at this current stage. Just maybe briefly, what are the differences between your two children here, so to speak? I guess as you think about it, what are the criteria or metrics that you're most focused on in terms of candidate selection for the next stage of your UC program for your TL1A?
Yes, so I think, as always, totality of data is the answer. I think the reality here is that we think both of them are excellent based on their preclinical characterization. All those properties I mentioned are true for both of them, kind of long-acting, highly potent, highly selective antibodies that we can, both of them we can formulate at very high concentrations as well. What we are really looking for is, does that diverge when we get into humans, which is always possible on PK, PD, or immunogenicity, we see a separation between the two. If that's the case, if we see one that's meaningfully better than the other, then we would just take the better one forward. I think that's the easy case.
If we see that they're both excellent molecules, I think we could consider actually taking one molecule into our inflammatory bowel disease phase two study and the second molecule in our rheumatology study that we've disclosed as well. The advantage there is both some commercial advantages as we get to market related to IRA and then also the ability to have some partnering optionality as well that we wouldn't have to say indication split if we wanted to partner one molecule but retain the other for ourselves. I think that those are kind of the range of outcomes here. We either have one that we like meaningfully better than the other, and then that one gets used in both indications.
Or if we like them both, we could actually decide to bring one into our ulcerative colitis trial, which is testing both the monotherapy and combinations, as well as our rheumatology study.
This one always sort of makes my head spin, but you've sort of developed a multi-pronged phase II strategy, which is thinking about sort of a multi-arm monotherapy and a multi-arm combination trial of testing your various candidates. Can you maybe just at a high level just walk us through how that phase II development plan is going to proceed?
Yeah, so it's an interesting problem that we had to solve in that we have three potentially best-in-class monotherapies in IBD. As I mentioned earlier, we think it's quite likely that the combination of the best monotherapies makes the best combinations. To develop a combination, really, in any space here, you need to show that the combination beats the two monotherapy components of it, and the monotherapy beats placebo. We could have decided, hey, we're going to go run three combo studies where we test placebo, the two monotherapies, and the combination of those monotherapies. We would have to do that three times to develop all three of our potential combos.
Instead, what we think is a far more efficient way to do this is to share the placebo arm and to share these individual monotherapy arms and do this in one platform study. That means only one placebo arm, only one of each of the monotherapies, and then we get to test three combos in a single study. I actually think we're the only ones that can run a study like this because we believe all of our molecules will have these extended half-lives and the ability to dose on a quarterly or twice-annual basis. Whereas I think we see other players in this space that kind of they objectively cannot do that, where they're mixing molecules with different half-lives, different dosing approaches, and they're not able to combine them into a blinded study where they're all dosed on the same interval.
We think this is a really efficient way for us to, and we only have to activate sites once. Kind of the timeline for this does not look as long as you would have taken if you ran three separate individual studies. Here, we think we can efficiently get six active arms, all of which I think are either the best potential monotherapies in this space, and we think have high probability the best combinations in this space in one study that we think we can execute over the next couple of years.
Investors can look to commercial analogs in terms of ENTYVIO for the alpha-4 beta-7 space, and SKYRIZI and TREMFYA for the IL-23 space, where all these drugs are a billion-dollar plus, if not meaningfully more, and just look at very strong adoption here. I think one of the questions we get is just, what is the logic, I guess, of TL1A in rheumatoid arthritis? People say, how does it differentiate from TNFs, which are obviously multiple ones are approved for that space? Just understanding how TL1As and sort of what the logic there is in RA, given that TNFs are approved as well.
Yeah, I think so when we started working on TL1A, I think we had a similar view as many of the other owners, which is that it's probably unlikely to be a single indication product. For the same reason that TNF went from being something with one or two indications to a dozen-plus indications for it. TL1A is in the same superfamily as TNF. It's many of the same pathways and has this potentially interesting anti-fibrotic aspect of it as well, which opens up yet another set of indications. We think kind of when we're looking across the more than a dozen indications where TL1A is implicated, the science was really strong across many, actually.
We think it's strong gist in the rheumatology space, where, again, I mentioned the mechanistic overlap with TNF, but there's also very strong human genetic data, human tissue data, animal evidence as well that suggests that TL1A plays a key role in these rheumatologic diseases. When we look at RA in particular, yes, it's fair that there are biosimilars entering this space, but it's still a $20 billion commercial market. It still has some of the same properties that I described in inflammatory bowel disease, where patients are cycling through multiple drugs here. They're not getting to complete remission, and they're not staying on it in perpetuity. When we test the potential of a quarterly, if not twice-annual drug, even with similar efficacy as the existing drugs, it's one of the preferred choices for a physician as soon as the patients have failed other classes.
We think this is really a meaningful opportunity on the commercial side. I actually think that's borne out with what we've seen in some of the trials that have actually been able to enroll in RA over the last few years. Despite the fact that you have multiple classes available, even enrolling a mixed population of patients that are naive to any therapies or failed other things, these studies enroll quite well, which is often a good indication that there's still substantial unmet need here, that patients are willing to take a chance at placebo if they're to get a chance at a new active drug. If they had good options that they were satisfied with, they would just not participate in those studies.
The fact that we've seen these studies enroll reasonably well over the last couple of years, I think suggests to us that there really is an opportunity here that we can go after.
Great. You went with one of my questions, which was thinking about development, that there are no TL1A experienced patients outside of the clinical trial setting, but there are obviously biologics, including TNF experienced and/or JAK and oral experienced patients. It seems like you're thinking about development in both those populations.
Yeah, we think for a proof of concept study in a novel indication, that's the right approach to go after, is to test a relatively broad indication first. We think this has potential application in a relatively broad population. We'll share the full details of the study actually in the upcoming weeks here where we say, OK, here's exactly what we're going for in designing the study. We think that's the right idea for a proof of concept.
Maybe just briefly, just to close out the discussion on RA, the thinking has evolved with more agents becoming available as well as biosimilars. I guess just in terms of where rheumatologists are currently, is there a focus on any particular measure now that the market has become more mature? Historically, we focused on ACR50s or ACR75s. Now we're focused on maybe DAS scores and other things like that. Just kind of what, I guess, would you look to show down the road as you lay out your clinical trial program?
Yeah, I think you've just highlighted the two that we think make a lot of sense as well. I think you typically see the DAS scores used earlier in development and then focus on the ACR scores as primary endpoints as you get later. We think that's a reasonable approach to follow.
OK, great. I want to talk maybe a little bit about your last program, 003, which, again, has some commercial precedence here in terms of SKYRIZI, which is a multi-billion-dollar drug, as well as TREMFYA. Just remind us, what is the status of the program and what sort of rough timing for the top line of your IL-23 program might be?
Yeah, so that molecule is in phase I as well. We started that in Q1 of this year. We would expect to kind of do a similar type of announcement that we just talked about for TL1A in the second half of this year. In that case, I think we're less interested in pharmacodynamic measures for IL-23, as none have really been validated, as I described for TL1A. There, we're mostly, it's a safety and pharmacokinetic study in particular. Are we able to achieve that quarterly, twice-annual dosing interval in IBD that we think makes IL-23 really an ideal combo target as well for us? I think that's really our primary interest in that molecule.
OK, great. I want to spend a little bit of time talking about the combo arms in your basket trial. For investors who are unfamiliar with the space, there is sort of a precedent here, which is that J&J ran a study a few years ago testing two drugs. They also have data expected, I think this quarter probably or fairly soon, for a new combination program. Can you maybe just sort of remind us of the background and why sort of combinations make sense here?
Yeah, to kind of walk back, as I mentioned at the outset, we really have not seen kind of meaningfully different clinical remission rates for different monotherapies despite decades of trying. A little over two years ago, J&J reads out their VEGA study where they combined their TNF and IL-23 together and functionally saw additive efficacy. They saw a 47% clinical remission rate on the combo versus mid-20s for each of the monotherapies. I think it is fair to say that has lit the field on fire in terms of showing that there is just a different level of efficacy that is possible in this space. I think now every strategic who is interested in playing in this space in the next five or 10 years knows this is likely to be the future.
I think what J&J has followed that study with is really two large studies, now one in ulcerative colitis and one in Crohn's disease, which I think are finishing imminently.
These are the two DUET studies.
That's right. Two DUET studies, the same combination, TNF and IL-23, now testing multiple doses of it against both monotherapies and placebo in both Crohn's and ulcerative colitis. Very large studies run in these two indications. Now it's a refractory population, whereas in VEGA, these patients were all naive to prior biologics. In DUET, they're all refractory. They've all experienced and failed the prior biologic therapy. I think it really will help us answer kind of which patient populations are combos best in, now on the Crohn's side as well as the refractory ulcerative colitis side. I think really just help us understand kind of is it only differentiated in the naive population, or do we see that same kind of separation or additivity of efficacy in the refractory population?
Though I think we can all expect that the response rates are not going to be as large in a refractory population. I think we know that well from every monotherapy class, that the numbers are all going to come down, but we're still interested if you see a delta between the combination and the monotherapy.
Right. You talked earlier in referencing the VEGA study about low 40% response rate for the guselkumab-SIMPONI combination versus 20% for the monotherapies. Maybe just remind us what historically biologics have looked like in terms of the refractory population. Clearly not as good as you would expect in a naive population. So just should we think about the DUET studies coming out as, again, probably likely to be lower than we saw in VEGA, but just kind of what differential would, I guess, clinicians potentially view as meaningful?
Yeah, I think what we don't know is how refractory these patients are. We know they are refractory, but there's a difference between having failed one prior therapy versus having failed four. We don't know what that distribution looks like. That could tell us if it's going to come down from those mid-20 clinical remission rates down to 10. Could it come down to 15? Could it come down to five? I think there's actually a reasonably wide range of how the monotherapies are going to come down. We don't really know what's going to happen for the combos. It's not going to be in the high 40 as it was in the naive population. What we're really interested in is does it still see a separation from the monotherapies?
I think generally what we think the right way to think about this is that in the pivotal studies, the study to come on the back of DUET, I still think it's a fair assumption that the population will be a mixed population. It will be a mix of naive patients, and it will be a mix of refractory patients. The overall label that they will get and the competitiveness in the commercial market will be looking at that label relative to the label of monotherapies that have been run in that mixed population, and what's the remission delta you see there.
I think we have pretty good precedence in this space that when that delta is in the range of 10%, and I think we've seen some that are slightly lower than that, like in the VARSITY study where ENTYVIO was tested against TNF, it was below a 10% clinical remission delta. We still saw ENTYVIO kind of have a massive increase in uptake with a less than 10 percentage point delta over TNF. Whereas in the case of the new p19s, the SKYRIZI and the guselkumab launches, they showed kind of a 10 or even slightly above 10% delta versus STELARA. Again, we're seeing kind of these really substantial commercial uptakes of those drugs.
I think that 10 percentage point is a reasonable benchmark to think about for the phase three result, which I think is likely to be a mix of the DUET result in the refractory population and the VEGA result in the naive population. I think what we want to see is that that combined delta is in the double digits would be a major effect. The nice thing is we know that in VEGA it was already in the 20s. There's a 20+ percentage point delta. We'll see what it is in DUET, and that will give us an indication, I think, of what the overall product profile will look like.
One thing that comes up when I talk about Spyre with investors is big pharma can do this, and big pharma are working on combination programs like the DUET program, like we've been discussing, other programs at other major pharmas. Can you maybe talk about the strengths or differentiation of your combination approach versus some of these other programs that are in development, because none of these were originally developed as combination programs?
Yeah, I actually think that's key. I mean, I generally find it helpful and kind of confirming that we're doing the right thing to see basically all strategics that want to play in this space are moving towards combination therapy. J&J, AbbVie, Lilly, Takeda, everyone who wants to play in IBD recognizes that this has to be a part of their strategy. I think one of the challenges, which you just alluded to, is that if you didn't plan for combos from the outset, it can be pretty tricky to get them and have them actually end up being a convenient, attractive product profile. J&J, we know what that product profile looks like. It's a monthly subcutaneous combination of TNF and IL-23. It's obviously we and everyone else are standing on their shoulders here in terms of their willingness to make that test.
I think it would be surprising if a TNF-containing combo is the best long-term combo in IBD. I mean, it is, of course, a mainstay product in IBD, but it is far from the highest efficacy in either ulcerative colitis or Crohn's. It comes with fairly substantial safety concerns. It comes with a black box warning and known risks. Those risks may be directly translated to the combinations, or they could get worse when you add additional immunosuppressant on top. I think it's an excellent starting point to see that combination, but I would be surprised if a monthly TNF combo is the best in the long run. In contrast, we know alpha-4 beta-7 beats TNF head-to-head in this space. I think on the efficacy side, it's likely to be superior to that combination. On the safety side, it certainly is as well.
TL1A, we haven't seen yet head-to-head against TNF, but I think anyone looking at the TL1A phase two results and comparing them to the TNF results would conclude that the TL1A is likely superior to TNF as well. I think our combos have a likely improvement in efficacy compared to the J&J combo. I think we really still have the best three targets to combine here, and I think can differentiate there. Then relative to almost everyone else in this space, we're the only ones that can align these dosing intervals and talk about a quarterly co-formulated antibody combination, whereas others in this space are mixing drugs that are dosed every two weeks, four weeks, eight weeks, even some injectables plus orals, which if you survey, no one wants to do both. Some people prefer orals, some people prefer injectables, but no one wants to do both.
I think these long-acting injectable combinations are likely to be the best product profile in the long run. I think you have to plan for it from the beginning. Otherwise, it's really hard to kind of cobble together agents to get to those profiles.
One other pushback I get in investor meetings is YTE, the technology is sort of broadly known. The IP is somewhat readily available. Why hasn't big pharma figured this out, or why aren't they doing that, I guess?
Yeah, I mean, I think we're seeing more and more. I mean, I think the problem with it is two things. There's a question of why now, which is that the YTE intellectual property has just expired in the last couple of years. It is a relatively new thing that you can go use and not have to license somebody else's intellectual property to go after. Second, it's pretty unlikely that you would use a YTE modified antibody the first time against a target. Because if you don't know that a new target doesn't have an acute safety risk, you don't necessarily want to extend the exposure to that antibody for a long period of time.
It is really an attractive technology to use for a fast follower company to use on a target that has been proven to have a relatively benign safety profile that doesn't have those substantial safety risks to then come forward and go after with. I think, again, in many cases, we're kind of taking the successes of prior companies in this space and building on them, both in the selection of using YTE on known, well-tolerated targets, and then also kind of using this combination strategy that J&J has pioneered with, but we think we have kind of the right targets to pursue it in the long run.
Right. Maybe one other aspect of market development in the future is just the potential role of orals. We've seen some success of oral therapies in the atopic dermatitis space to some degree, some use of JAKs in development there for IBD conditions. Just, I guess, as you think about the oral landscape and the oral clinical stage assets out there, is there anything in your mind that stands out as potentially being truly competitive in this space?
Yeah, so I think we generally start in the commercial market back. When we survey either physicians or patients in this space, we typically test same efficacy, same safety, and would you prefer an injectable or an oral. Once you're out at a quarterly or beyond injectable space, that's preferred to even a once-daily oral. If you go to a twice-daily oral, that difference actually gets pretty broad in terms of how much you would prefer taking two or four shots a year versus taking multiple pills a day. I think that's partially the fact that the IBD population is relatively young. Diagnosis here is often in college age, and kind of remembering that you have to have this disease and need to take a pill every day is just not the preferred approach.
I think it's also fair to say, despite maybe one or two exceptions, I don't think that the orals have quite matched the biologic's efficacy in this space, or actually in other INI spaces as well. In IBD, efficacy is really number one. This is a hard-to-treat INI disease where the consequences of a flare are substantial. The quality of life impact can be dramatic if patients undergo surgery and have had part of their GI tract removed, resected. We think kind of maximizing efficacy here is really critical. I think even at the same level of efficacy, a quarterly or twice-annual injectable profile is actually preferred to an oral. That said, I do expect there may be kind of oral agents that are kind of in the same ballpark of efficacy, and I could see oral combinations being interesting too.
Then you need multiple of them together, and that still ends up being multiple pills a day, which I think will not be preferred to a single shot.
Right. How does your potential theoretical product profiles of a quarterly or semi-annual dosing line up with the sort of typical patient visit schedule or doctor schedule in the UC space or IBD space?
Yeah, quarterly is quite often, and twice-annual is quite often in terms of when patients come in. I do not think anyone would be offended if they did not have to take a shot every time they came in. If they come in quarterly and only need to take a shot twice a year, that's OK too. Yeah, we expect these could be either physician-administered or patient-administered drugs as well. There is kind of lots of flexibility.
OK, great. We're coming up on time here. Maybe just to wrap it up, can you maybe remind us of your cash runway? What does that take you through in terms of your clinical development programs? When could we potentially see one or more of your combinations potentially hit the market here?
Yeah, so I think we've been fortunate to be able to raise substantial capital over the last couple of years. I mean, we still have $565 million on the balance sheet as of the last quarter, which takes us into the second half of 2028. Everything that we've just talked about, kind of the full platform study, which delivers six active agents in ulcerative colitis, plus the TL1A in rheumatoid arthritis, all of that reads out before 2027. We're talking more than a year of runway beyond seven-plus phase II readouts in really large commercial markets.
OK, great. We're exactly at time now, so we'll end it there. My thanks to Cameron and Spyre for joining us.