Well, good afternoon, everyone. Thank you very much for joining us. Very excited to be here for the I&I, or Inflammation Immunology, corporate panel. Obviously a packed room because we have several very high-quality companies up here. My name's Tyler Van Buren, Senior Biotech Analyst. I'm joined by my colleagues, Yaron Werber and Peyton Bohnsack. With us on the panel, we've got AnaptysBio, Dan Faga, the CEO; Apogee, Michael Henderson, the CEO; Celldex, Anthony Marucci, the President and CEO; and Spyre Therapeutics, Cameron Turtle, the CEO as well. So what we're going to do is we're going to start with some general thematic questions. Feel free to chime in as you'd like before we go into some company-specific questions.
I'd like to start things off by just talking about the explosion of the growth that has occurred in the I&I space for biologics treating I&I diseases or small molecules, and where you guys believe there are still the highest unmet needs and how you view areas of differentiation within the I&I space.
Who wants to crack it?
You go first.
Certainly, there's a big need in the CSU space, the CIndU space. There are a number of indications out there that still can everybody hear me?
I think the mic is out.
You told me this would work.
Sure. Take this one.
It'll fix it.
Is that better?
No.
Tap. Is it on?
All right. I'll try to screen. So there are a lot of indications. Now it's working.
Well, that I think that's his.
Thanks, Dan. So there are a number of indications such as CSU and CIndU, EoE, PN. Atopic dermatitis still has a big need even though it's pretty well served by a number of companies that are out there. So last four or five years, you've seen an explosion in interest in I&I. Certainly, I think we're just scratching the surface with some of the molecules, both biologics and small molecules that are out there.
Yeah. Happy to add on a little bit. I think we're obviously going to be a bit biased all in our answers. So I don't think what I say will be that surprising. But when we look at a lot of the I&I conditions, especially atopic derm, for instance, still single-digit penetration in terms of people that are treated, huge unmet need. And where do patients in these markets evolve? It is deeper responses, longer dosing, especially for 40% of these patients that are pediatric. A shot every few weeks, it's really hard. And improved options that can take that out to every three, six months, I think, is really where we want to be pushing as well as for the broader population.
I can add my IBD bias where I think one of the large I&I indications, having remission rates that are in the 25% or less rate for most monotherapies, is quite poor across the I&I landscape. And I think that's been really one of our core strategies for Spyre is addressing that with hitting multiple mechanisms at the same time. It's probably one of the only ways that we expect that you can really deliver a step change in efficacy in that space. Certainly, a long way away from what we've seen in other I&I indications where you're pushing substantial majority response rates for most patients. So I think IBD is still trailing a long way behind.
I get to go last, which is always the most fun. As the immune cell modulator company on the podium here, we're focused on the treatment of systemic and heterogeneous diseases. To Cameron's point, in many diseases, we're talking about AD, colitis, RA. They're very low efficacy ceilings. The reason is these diseases are complex and you need to target multiple pathways to get broader outcomes for patients, deeper responses, and hopefully more durable outcomes to restore immune balance. We'll get a lot more into this. But it's going to take, in many diseases, more than one approach to raise the bar of 10%, 15%, 20%, 25% response rates that are sufficient for patients, unlike diseases like psoriasis where they're more simplistic in what's driving disease, and you're seeing PASI scores of 90% with one single cytokine blocker.
A lot to come, but the understanding of disease biology has progressed enough where I think we could take more sophisticated approaches moving forward.
Yeah. That's actually pretty much a good lead into our next kind of thematic question, which is given that there are some developments in treatment paradigms for inflammatory conditions, especially in psoriasis, but some, not so much, especially in UC. How would you say that this has changed in terms of designing clinical trials over the last 10 years, changes of the efficacy bar? And then have you really seen any changes from either quality of life or patient perspective or FDA-required endpoints? And maybe I'll kick it to Dan first since you started last.
Yeah. Well, there's a consistency in how we're looking at proof of concept designs here in RA and AD. There's a commercial bar that's not necessarily the same as the regulatory endpoints in phase three. So ACR50, ACR70, EC90, IGA 0/1, I guess, is where we're moving in AD with the FDA. So the bars are distinct. But what we're doing in our trials is we're looking across multiple lines of therapy. And by taking a top-down approach, we hypothesize we can see similar response rates, whether you've been on a biologic or not in the front line. So there's consistency there. And then the second component is off-drug durability, whether mechanistically, half-life generate, what have you, can patients see longer-term outcomes once they achieve whatever their peak efficacy will be? So those are features that we built into our phase two trial designs for all these diseases.
So for indications that we're going after, I think the bar is pretty well set. The CSUs only are still going to be approved drug. Can you not hear me still?
AnaptysBio. Fran. Appreciate it. So depending on the indications, really do me in today.
It's Yaron's fault.
Can you do this thing again?
There we go.
All right. Everybody hear me now?
No.
No.
Very great.
Forget it.
There we go. Put three mics in front of you. One of them's going to work.
Let's do it.
There you go.
All right.
Anaptys, you got to make this one really good.
I'm ready to go home. For CSU, it is planned out. Xolair is the approved drug. There are other drugs that have tried going after CSU, so the bar is very well established. For indications such as CIndU, there's nothing been approved. So I think we're going to have to clear that path for everybody else that's going afterwards. And PN and EoE, it's kind of middle of the road. Some of it's been cleared with Dupixent getting approved in both of those indications. But I'm sure as we will learn as we go through our clinical development, there may be other markers that are as important as clearing eosinophils. So still to be determined.
Yeah. Fingers crossed. I think what we're seeing and what we're hearing from patients, physicians, but also payers now is that there is a need for more durable, longer-term responses, minimizing breakthroughs, minimizing relapses, minimizing the breakthrough itching that really drives a lot of discomfort for patients. So as we think about our trials and our mechanism lends itself well to it, both IL-13 showing a lot of durability, but also the YTE piece, we're excited to show that we can better control both more deeply through things like IGA01 and EC90, where we think higher exposures could lead to deeper response, but also just more durable responses with time.
Yeah. IBD has seen evolution in the last few years. I think the most recent guidance was 2022 on UC and Crohn's. I think the major, most interesting changes were modification to the endpoint to the modified Mayo, which removes a global assessment, makes it a more objective measure of disease course. Also, an acceptance or a recommendation to move to a mixed population, including both naive and experienced patients in those cohorts. And then lastly, an acceptance of a treat-through style design, which again, I think makes it viable as a, again, extended half-life set of antibodies here a readily doable strategy because we expect these drugs to have long durability. And so a treat-through design makes a lot of sense for our antibodies in particular.
So one of the things I want to ask about is the reimbursement landscape, especially as you're going into I&I. In some cases, you're first to market. In some cases, you're fast followers, potentially best in class. One of the challenges in I&I and in Part D, especially with the IRA, is the best drug doesn't always win out. Sometimes it's a reimbursement and formulary question. Can you maybe, Dan, we'll start with you. How do you design that into your phase 2, and really into your phase 3 trial design? Now, in some cases, you're going to be first in class, but in well-established markets too.
Yeah. Look, it's a good question with biologics. And with IRA, maybe there's slightly more protection there, but it's still capped. We did initiate a second trial before we had our first phase 2 trial readout with a novel mechanism. So we have an RA trial that we initiated the middle of last year. We started also a colitis trial at the end of last year and have parallel tracks with readouts that, generally speaking, are around the same time. And to your point, in one, there's other competition with similar mechanism action RA. In UC, we're first in class. There's other diseases we want to pursue. At some point, you have to pause for right now. The real question I think you're asking is, how do you go broad quickly if it makes sense?
What we're going to be looking for is translational data as an outcome of multiple trials that we're assessing. Are there correlations both in peripheral draws and in the biopsies to the outcomes, but also signatures of agonism and depletion of different immune cells to other correlative diseases? The biggest question for us is, how many can we go at one time? Do we stay within one therapeutic area within autoimmune, which is four, five, six different therapeutic areas? The scaling for a biotech company is challenging with the breadth of where we can go, knowing that we want to do as many things as possible in parallel.
Yeah. So for us, I think it's been well established. Xolair is out there in the market. Dupixent's out there in the market for its indications. What we've been told by payers is that for urticaria, they just consider urticaria to be the space rather than CIndU and CSU. And I think also because we're targeting tryptase, which is a biomarker, I think the reimbursement there will be pretty easy as well.
In your case, Xolair will be biosimilar, and Dupi has been priced in a way for a much broader I&I market than just taking the last sort of opportunity in urticaria. I know it's way too early to talk about pricing. Can you think about dynamically, how do you handle that?
Well, so.
Without asking about pricing, can we?
I think the way we see it is that Xolair is going biosimilar. But what we're also looking in the field is that many patients on Xolair are being dosed well above what their label price has been. So I don't think there's that huge of a difference between a Xolair and a Dupixent and anything else. So I think for our modeling purposes, we're good as far as.
Yeah. So when we look at atopic derm and the indications we're going after, we don't anticipate launching into a biosim world or really an IRA world either, pretty heavily commercial pay. So we think that lebrikizumab, when it gets approved, assuming this year, and Dupixent are both kind of in that 2037, 2038 plus sort of entry from all that we can tell and all that they're saying. So we'll have ample time, similar to how Skyrizi came onto the market, to establish themselves. So I think that bodes well for our lead programs. And then for COPD, which we're going to be targeting with 808, I think they're sometime before we have to worry about IRA exposure because that is the only indication really where Dupi is exposed.
I think biosimilar entry in IBD is happening and will continue to be happening in this space. I think, in general, the only real answer to it is the answer that we gave about the unmet need in the space as well, which is that on most of the monotherapies, which will be the biosimilars, there's a therapeutic ceiling in that low-20s response rates. I think you really need to beat that by a meaningful margin to not be thinking about second-line patients who are getting cycled through biosimilars in IBD. I think the most likely way we do that is with combination therapies, again, as the answer to get through that first-line edit.
All right. Company questions?
Yeah. So I guess we'll go in alphabetical order, it looks like. So Dan, we're starting with you again.
You're lucky. You're not last this time.
Yeah. Over the past year, over the past year or two, AnaptysBio has begun switching from single cytokine targeting agents to more of these broad targeting immunomodulating antibodies. What was the rationale behind this decision? And then why do you think that these antibodies will have more effect than, say, a single target? So AnaptysBio has been discovering antibodies for autoimmune and oncology conditions for 18 years. We've been around for a long time. We've had a lot of success in programs that are now commercial. For checkpoint agonists, we've been developing these drugs for 10, 12 years. It's taken a while to find the right optimal outcomes and potency for these targets. We're not the only ones that have been focused on this for this period of time. Name your big pharma. Going back to Celgene, when it existed, was focused in this world.
So it's not a novel idea. What's been hard is getting potent antibodies. What I ended up doing when I came in a couple of years ago is refocusing the company to develop these drugs. And I mentioned it a little bit earlier. The understanding of disease biology and these autoimmune conditions is very different than it was even five years ago. The complexity of a disease like AD, also of colitis, and the understanding where we're going matches up well the biology and diseases with the mechanisms of actions of where we're now targeting our immune cell modulation, specifically the checkpoint agonists. When you look at the landscape in Step Out, Lilly, Sanofi, Amgen, J&J, Gilead, a big segment of the autoimmune space of the big players are all moving in this field to take top-down approaches with targeted therapies that have broad immunological outcomes.
Because I agree, I just don't think you're going to get there with these types of systemic heterogeneous diseases without a broader approach. You're going to ultimately need combinations or have therapies that hit in multiple different ways that knock down different escape mechanisms within these more complex diseases. Yep. So kind of talking about that, let's talk about your lead program, rosnilimab, which is a PD-1 agonist, as you mentioned. Could you give us some of the rationale for going after RA and UC specifically? Is there increased PD-1 in these diseases? Why do you think that this is going to be a bar for success? And when we can find and when we'll hear about data from both the UC program and from the RA program as well? So in arthritis and for UC, there's a significant percentage of T cells that are activated in these conditions.
80% of T cells in the synovium are PD-1 expressing. 40% in the lamina propria. The site of inflammation in the large intestine in UC are expressing PD-1 positive T cells. In addition, systemically, you see multifold increases of activated T cells in the blood. So we have different ways we're going to engage within the immune system just in targeting T cells. There's correlations between reduction of TPH, PD-1 positive high T cells, reductions with clinical remission in UC. There's animal data that we generate. So we're really excited about what we've done in UC. And then on the flip side, in arthritis, Eli Lilly does have really compelling proof of concept data from the phase 2A data they read out at ACR a year and a half ago, which instigated their phase 2B trial initiation as well as ours.
And just to kind of put a point on efficacy ceilings, if you're on a biologic in second line today, it's a $10 billion market. There's four or five classes of biologics that all look the same in terms of the outcomes. Lilly's ACR50s at week 14 were 57% on an absolute basis versus 20% with other classes. That's a breakthrough in efficacy. If it could be anywhere near recapitulated in the phase 2b, even if it's half of that, it's a major breakthrough in this disease. So that's the type of efficacy that we're talking about that's potentially possible here with this type of approach. Data will be, sorry. Yeah. Mid-2025, an RA trial, 420-patient phase 2b, and then for colitis into 2026.
Great. All right. We'll move to Apogee with Michael. So can you start by walking us through the YTE half-life extension technology employed by Paragon to create your assets and then also their antibody capabilities in general? And Cam, if he misses something, please provide back.
Yeah. I got it. Yeah. One sec. Cameron would probably do a better job, but I'll try. So I think it's funny, actually. We're all YTE antibodies mostly up here. So YTE, it's a really elegant mechanism that MedImmune created back in the day, Xencor with LS, where when an antibody gets taken up into the cell, whether or not it binds to FcRn dictates whether or not it gets disposed of or if it binds to it, recycled. And if it's recycled, it can exert its function by being recirculated back into the bloodstream to continue going. So IgG antibodies, for instance, have a higher FcRn affinity than IgA. That's why we use IgGs for backbone therapeutics. So Paragon technology, we tried YT. We also try LS.
We try everything to get to the best antibody that we can against the targets we're going after that have the most optimized PK profile formulatability. We showed an improved formulation for our lead drug and just the best manufacturability as well to then take forward into these patients because we feel that these markets are large enough. The more that you can do to optimize fully what you're taking forward, the better result you can get.
Did he get it all?
I think he covered most of it. Yeah. I mean, I think the answer is test of a range of different Fc modifications and then choose the one that delivers the best half-life improvement. I think we typically err towards the YTE if all else equaled because there's an established set of validation around the YTE modification, multiple approved products, dozens in the clinic, and that they routinely show a two- to fourfold increase in half-life relative to the wild-type counterparts without clear downsides on ADAs or safety or other attributes. So I think that tends to be our approach for both of the antibodies that Apogee and Spyre have inherited license from Paragon.
Yeah. Speaking about a full change in half-life, Michael, you guys presented very exciting data this morning for APG777. So it'd be great if you could provide the highlights from the half-life exposure and biomarker data.
Yeah. No. Thank you. We were really excited today to present interim data from our phase 1. So we reported a 75-day half-life for APG777, about a threefold improvement over that of lebrikizumab, also an improved formulation. So we're at 180 mg per mL, so 360 mg in a 2-mL injection versus lebrikizumab at 250 mg, so 44% greater. I think for us, that allows us to do a few things. One, in the induction phase, which is the first 16 weeks of therapy, we can now test higher exposures, which recent European data suggest could lead to improved efficacy, including on those stringent endpoints that drive deeper response like EASI-90, IGA 0/1. So we'll be doing that in the induction phase of our phase 2 while still cutting the number of injections in half.
Then in the maintenance phase, it allows us to test transforming the paradigm from an every current two-week, maybe every four weeks with Lebrikizumab when it gets approved, out to every three or six months. So we think a transformational approach for patients and something that when we talk to physicians and patients and look at how other I&I markets like psoriasis have matured has led to a winning strategy historically.
Anthony, let me maybe move to c-KIT and talk about mast cells. So far, you've released data both from CSU, a little bit of data from CIndU, and you've released a little bit of data on PN. And you're also talking about going to EoE next. Can you talk about so essentially, there's a commonality on mast cell depletion. Can you talk about the biology and why it potentially can work in these indications?
So we think mast cells play an important role in a number of diseases. So we certainly think diseases like CSU and CIndU and PN and EoE are mast cell-driven diseases. So if you target the mast cell, we think we can have efficacy and safety benefit in those clinical indications. So the phase 2 data from the CSU study, which we announced last week, we achieved a 50% UAS7, meaning there was zero itch, zero hive, in more than 50% of the patients at 150-milligram dose and 37.5% with the 300-milligram dose. And then there's another measure in CSU, which is looking at the UAS7 less than or equal to 6, which is basically well-controlled patients. And so with the 150 and the 300, we achieved a 60% rate. So when you compare that to Xolair, which is the approved drug, Xolair had a UAS7 of 36%.
We had above 51. So definitely one of those leaps. And again, let's go with the YTE here. We have a YTE antibody as well. And there's 23.5 days of half-life. And we think that dosing those patients less frequently and continuing that, downing of tryptase, controls the disease better for us as well.
When you look at the biomarkers and when you look at your 12-week data, it looks like the efficacy continues to improve. So it hasn't plateaued yet at 12 weeks. We'll see the 52-week data probably in Q4 or so this year. What are you expecting from that data? I know you can't say a lot, but I mean, preclinically, do you expect a plateau? I mean, it'll plateau at some point, or would it continue to get deeper or slower?
Yeah. So the only thing I can tell you is that we saw the phase 1 data where we treated patients for 8 weeks, and then we followed them out for 24. And a large majority of those patients at 24 weeks still had UAS7s zero for their disease. So they were not dosed for 16 weeks, and it still maintained their response rate. So we're hopeful that with the 52-week, you'll get that deepening of response and certainly that deepening of control. So we'll look forward to seeing that data.
Just remind us at week 8, what was the UAS7?
It was in the 50s.
Right. So you're already deeper now at 12 weeks. All right. Cam, over to you. Spyre. So for your lead candidate, SPY001, also known as Super Vedo, it'd be great if you could briefly highlight the recent NHP half-life data presented at ECCO, how it's evolved over time, and what you expect from the phase 1 interim update by year-end.
Yeah. So 001 is our alpha-4 beta-7 targeting antibody. What we showed at ECCO was updated data on the program, which shows that it has very similar epitope, identical epitope to vedolizumab, and similar potency and selectivity as well. But the half-life was a bit over 3 times the half-life of vedolizumab in two preclinical species. So that was in transgenic mice that expressed the human FcRn as well as non-human primates. We showed a bit over tripling of half-life compared to vedolizumab. And that really is one of the main concerns with vedolizumab. Today, it's dosed every 2 weeks subcutaneously, and it's one of the top products in the space with a tripling of half-life as well as improvements to the formulation that we've done for alpha-4, the 001 program as well.
We think we have a reasonable shot at dosing at least every 8 weeks, if not quarterly, with this molecule. It's completing talks now, and we'll go into the clinic in the second quarter of this year. And we're expecting to report out human data by the end of the year, which will hopefully validate the human half-life. And then we'll let us inform our dosing for phase two going forward and hopefully prove whether or not we have an every 8, every 12-week drug, which we think makes it a very interesting molecule to take forward into phase two program from there.
So if the phase 1 data are successful by your end, what sort of phase 2 program do you intend to run from a high level, and when might we be able to receive data?
Yeah. So I think the most important phase 2 to run here, as I probably alluded to previously, is testing these molecules in combinations against the monotherapies. I think we saw that as Vedo defining what the future of IBD is likely to look like. And our intention for our phase 2 study is to immediately test the contribution of the monotherapies as well as the possibility of a combo being superior to each of the monotherapies. And our intention is to start that study next year, start with the alpha-4 beta-7 program initially, and then as our additional agents are available as they finish their phase 1s, to add those same drugs to a same platform-style phase 2 study where we sequentially add cohort to that study. So that's the intention.
And so we should be able to start that study in the middle of next year. And we expect approximately a year from starting the phase one for each program until we'd be able to incorporate it in the phase two.
Great. I guess moving back to Anaptys, we're going to switch over to the ANB032 program, which is a BTLA agonist monoclonal antibody. And it's currently in a phase 2b trial for atopic dermatitis, and data have been guided for year-end 2024. I guess, could you tell us how enrollment is progressing in the trial? Are the data still on track for year-end? And then we've also previously heard that the company has indicated that it's looking for Dupixent-like efficacy in Dupixent experienced patients. Is this still the defined bar for the phase 2? And then could you also go over some study-powering decisions and the overall clinical profile you would look for advancing to a phase 3?
We are incredibly excited about this drug, the BTLA agonist. So it has multiple mechanisms of action that are implicated in this disease. AD is known to be a TH2-driven disorder, but it's also driven by TH1, TH17, TH22 cells. OX40 ligand by Sanofi was incredibly de-risking for our program. They showed that reductions of 50% of IL-13 show better responses than DUPI over a six-month period. And I think we're going to see data later this week at AAD, their 52-week data represented by their phase three program that they're looking at every three-month dosing given the mechanism of action here. BTLA targets TH2, TH17, TH22, at least it's not hard in terms of reductions of the cytokines, but we're also targeting TH1 cells with the mechanism. And that's half the story. BTLA is also present on dendritic cells.
The relevance here is that we've shown by modulating the dendritic cells directly, which are increased tenfold in inflamed skin in AD, we're seeing a reduction more than half of the presence of antigen such as OX40 ligand or CD40. So the target's gone. And by modulating these DCs, we're seeing an inducement of Treg expansion. So there's a lot happening here mechanistically that's exciting relative to others in the space. And for these reasons, we think there's a real chance to significantly change the efficacy profile in the short run, whether that's three months or six months relative to DUPI. But a safe TPP that we think is compelling, there's nothing in the second line in a market that today, Sanofi's penetrated with DUPI 9% that translates to $6 billion U.S. revenue today. So this is going to be a huge market over time with increased penetration.
There's nothing in the second line. More than half the patients that take this drug don't achieve EASI-75 or anything else in the Th2 pathway. So the market's there, but there's nothing being developed for it. So a feature of our trial is 25% of the enrolled patients will have Dupixent experience or other IL-13 experienced patients. The mechanism for BTLA should work indifferently between front line or second line given the biology of this disease. So if we see something that's compatible between the front line and the second line, there's a clear path to second line development for us. It doesn't mean that we also can't have a higher bar in the front line. The second feature of our trial design is a six-month off-drug period. So we dose through 12 weeks. The primary endpoint's at 14, but we're going to be observing through 36 weeks.
The reason we're all talking about the importance of every 1-month, 2-month, 3-month plus dosing is because patients, if they come off the cytokine blockers today, return to baseline in 3 months and definitely by 6 months. So we'll have a relative built-in control for what you expect out there in the commercial markets to what we are potentially going to observe with the BTLA program over time. 160-patient trials on track to read out by year-end.
Perfect. Then I guess regarding your ulcerative colitis program, you guys are doing this as a monotherapy and not as a combo, like Cameron kind of mentioned. What was the idea of not testing an Entyvio-like style? Do you really want to just show that this rosnilimab has a whole bunch of efficacy in this indication? And then why are you using only two dose levels versus the three that are in the RA study?
Yeah. First, we want to establish proof of concept in what the potential is in this disease. It's similar in RA. It's also similar in AD. We need to establish a baseline profile. You could always stack against that in the future over time. Those options are available. An important component of all of these trials that you see is not excluded from this, but I'll speak to the entire portfolio of phase two programs, is the translational insights we're going to generate. We're going to take biopsies across all three diseases in sampling of patients, correlate that with what we're seeing through the blood draws, and then to the outcomes overall. There could be subpopulations that make more sense. I mentioned a cell type called TPH. This is 2%, 3%, 4% of the activated T cells in disease. It's less than 1% in a healthy individual.
So there's small percentages of cells that correlate to outcomes based on literature. We'll see how that translates in our studies and what's happening actually at the site of inflammation, including the gut. So I think the story needs to be written still on are there super responders that are not here over time, and where more specifically should you target combination therapies in these diseases? I think that's to come. I think that's to come at all autoinflammatory diseases over time. We're 10 years behind, 10-plus years behind the oncology world. So to be determined. But Cameron already spoke to the need here and what the baseline efficacies are. And we want to see what the drug can do on its own given the breadth of immunological outcomes we expect.
Cool. So Michael, following the APG777 data this morning, can you briefly describe the phase 2 AD design that you went over and what you'd like to see with the 16-week proof of concept data in AD patients expected next year?
Yeah. So we're excited to announce this morning, along with the data that we've accelerated our phase 2 trial. So first half of this year, we'll be initiating an integrated phase 2 A to B. When we think about the risk profile in here and how much de-risking we feel happened with the phase 1, for us, it's about how quickly can we get to BLA and make this option available to patients. So we've done an integrated design that will give us that critical 16-week data topline second half of next year, 2-to-1 randomization with maintenance and OLE, which we think will be very attractive to patients who will get active drug. And it's greater than 90% powering within that. We didn't want to wait on that as one might typically do before launching the larger 360-patient fully optimized dose-optimizing regimen, which is the part B.
So that will start as soon as the part A finishes enrollment so that all those sites that we spend so many months activating will be under one protocol. And that hockey stick of enrollment growth, we won't have to reset on. We'll just keep that flowing through to the part B. So what this gives us is kind of the best of both worlds with 16-week data in atopic derm. It is the hallmark. Patients want fast relief. And the R-squared, when you look at phase 2 versus 3, it's like 0.99. We have yet to find a phase 3 run on the back of positive 16-week phase 2 that did not hit its primary. So we'll get that data second half of next year, and then data will just keep flowing from that study.
Maintenance of every 3 and 6 months, OLE, then the part B optimization regimens as well, which will set us up well to kick off phase 3 studies.
Okay. So continuing on the phase 2 program, why have an asthma study initiation next year given the history of lebrikizumab in that indication, and how do you guys expect to have a differentiated clinical strategy that could lead to a more successful outcome?
Yeah. So when we look back at the study that was done with lebrikizumab and asthma, it was by Genentech. They used what was effectively a five-fold lower dose. That same dose in atopic derm also didn't look good. Dose higher. We now know that every bit of exposure matters. You drive much deeper and greater efficacy. In fact, what looks to be best-in-class efficacy.
A post hoc in January actually just showed that even at that very low dose, the high EO, greater than 300 group, with an exacerbation, which is what Dupixent ran, still hit. So for us, it's about fully unlocking that atopic derm opportunity. And that high EO had an exacerbation, which you kind of need to if you're going to show an improvement on it. That's the right study to run. And post hoc analysis from that shows that even at a low dose, it hit.
At a high dose, it could hit even better.
Anthony, maybe back to you. Your latest data last week on CSU said that the activity was the same, whether patient is Barzol refractory or Barzol naive. And to your point earlier today, the efficacy looks superior to Barzol. I guess as you're thinking about phase 3 and you'll run 2 phase 3 studies, is there any reason to even do even a separate phase 2 go and head-to-head against Barzol to completely replace that drug? Or do you see it getting positioned ultimately probably as a second-line agent after oral antihistamines anyway?
I think in the U.S., we don't need to do it because I think it'll be positioned behind Xolair since it's coming off. We do think it's important to have in the phase 3 both the naive population and the biologic experienced and refractory because we do want that whole label. And I think that'll be important. And the reason why I think that'll be important is that Xolair, we believe the patient population between the U.S. and the E.U. is about 750,000 patients. We believe Xolair has an effect in half of that population. We can possibly go after the whole population because we would be upfront in that experienced and refractory population. In Europe, I don't think it's going to make sense for us to do a head-to-head versus Xolair because that will require it for us to move forward.
The economics in Europe aren't going to. You're not going to make me spend $125 million to get a little bit more upfront. I'll take the second line.
The doses you've been testing are 150 q4 weeks or 300 q8 weeks. Can you talk about, so it's the same absolute amount of dose per month. The pricing is essentially equal either way. Would you take both doses into phase 3?
We will take both doses into phase 3. We think that doctors would appreciate the flexibility. There are patients that would prefer monthly, and there are some that would prefer every eight weeks. The delta in difference is not much. We will take both in.
Are you testing those doses in all the other indications, or is PN slightly different?
No. We will test them in all the indications. So EoE is the only one right now. We're using 300 only. But PN, CIndU, we're all using the 150 and 300.
Great. So Cam, we've SPY001. It employs the same epitope as Entyvio as we've been discussing. Maybe we can move to your second candidate in the pipeline, SPY002. It's markedly different from its TL1A predecessors. So it'd be great if you could describe the discovery process for that compound and how it differentiates with respect to its binding against monomer and trimers.
Yeah. So the background for this program was a couple of years ago when the first phase 1 data we're reading out from Pfizer and Prometheus on the TL1A. I think the recognition of the Fairmount and Paragon team that it was probably possible to make an optimized antibody relative to those two in terms of adding the potency, the immunogenicity, the formulability, and the bioavailability. Neither of those molecules really had an optimized set of those things. And so that really was the rationale to launch a broad TL1A discovery campaign within Paragon at the time and now at Spyre, where we think we now have a set of antibodies that do both, that they are highly potent, they have extended half-lives, they are highly formulatable at 200 mg per mL as well, and they bind unique epitopes on TL1A also, which we think is a unique advantage here.
We have nice cryo-EM structures, understanding where the TL1As ahead of us bind on the TL1A trimer. And I think we can explain a lot of their properties in terms of whether they bind the monomers alone, they can bind the TL1A trimer or monomers, as well as their potency by where these antibodies bind. And so I think we have the opportunity coming second, as always, has some disadvantages, but you can also learn from what came before you and I think pick the epitopes that we think are most optimal here and then engineer all those other properties as well for our program.
For the SPY001 program, you mentioned how quickly you guys plan to explore combinations. Imagine you're going to do the same with SPY002. You guys also have IL-23. So how do you think about all the different combinations and which ones might be the best for IBD?
Yeah. I don't think there is an answer today. I mean, we have the same SAP almost everyone else has in this space, and they're the smartest people in the world on this, and they can't tell you which the combos are going to be the best. When we show them our pipeline and say, "What are you excited by?" on one hand, the alpha-4 beta-7 IL-23 is molecules that they have a ton of familiarity with. They've seen Vedo for years. They've seen IL-23s for years. The safety is both incredibly well tolerated, and the expectation is that they're hitting orthogonal biology of this disease and have very rational reasons to have additive efficacy as well. So that's leaving out what might be the most interesting monotherapy, which is TL1A.
I think it'd be crazy not to test the ability of that one to be additive on top of either of these very well-tolerated individual molecules as well. We're not excluding anything at this point in terms of the combination studies. I think it is worth exploring all of these. We may find out that one works better for UC patients versus Crohn's for different subsets of the population, but I think we're going to test that clinically, not in any preclinical model.
Great. Awesome. So I guess we're going to move earlier in the pipeline. So let's talk a little bit about the ANB033 program, which if you give us a little background, it's a CD122 antagonist, and it's being developed for inflammatory diseases. And an IND submission has been guided for H1 2024. Is this still on track? When will we know the development indication, and why are you optimistic about this being used in inflammatory diseases? And then also, I guess we can talk a little bit about ANB1001, which is the BDCA2 modulator, which you got from Centessa.
And what a great set of questions. We don't get to dive into this in a big form too often in the early portfolio. So we have the two checkpoint agonists as part of the immune cell modulatory thesis of AnaptysBio, and we're moving.
The CD122 antagonist and the BDCA2 modulator hit distinctly different immune cells directly and complement what we're doing with the agonists. CD122 is a receptor found on CD8-positive cytotoxic T cells and NK cells. What it does is it's a receptor for IL-2 and IL-15. We're blocking that activity, and we're starving cells from IL-2, T cells that need that for further proliferation moving forward. We're going to see reduction of CD8 cells and similarly on the NK cell side. Then secondary to that, by blocking IL-2, we should help support IL-2 availability for Treg expansion. There's secondary mechanisms of action that could be interesting here, but the primary is reducing CD8-positive cytotoxic T cells and the IL-15s on NK cells. We haven't disclosed the indications. There are other CD122s out there.
Looking at GVHD, alopecia areata, there's a plethora of interesting data that's starting to be generated in the IL-15 space. So there's a lot of choice for us in how we're developing this. So we'll keep it close to the vest. But we do have the most potent in class for the CD122 antagonist. We are filing the IND this first half, and it'll be in clinical development later this year. So complementary to that, we did in-license our first program in the company's history from a group called Centessa, which is a compilation of a number of different subsidiaries over time. They are not focused in autoimmune. This is sitting in their preclinical portfolio and complements what we're doing. BDCA2 is found preferentially on plasmacytoid dendritic cells, which express thousandfold interferon in the setting of disease. The only other BDCA2 that's out there in clinical development is by Biogen.
It's in multiple phase 3 programs in SLE. They also have a late-stage CLE trial that's ongoing. They also start reading out pivotal data beginning in Q2 of next year. We'll be moving our program into phase 1A, 1B minimally in SLE, and there's other indications that we're also looking at in parallel. Our internal data suggests that we have a more potent inhibitor interferon alpha expression, but we also believe that there's a tolerizing aspect of targeting BDCA2 on the PDCs. So very different than ILT7s, which are depleting out the cells. The reason we chose this mechanism over other available ILT7s is these cells are still active and have a secondary purpose beyond the interferon gamma expression if you're reducing it. So there's interesting biology here.
There's peripheral proof of concept out there in this space, and that lupus data is probably best in disease in a robust trial. There's other interesting data that's anecdotal in very small numbers of patients, but their phase 2 data in that disease so far out of Biogen is best in disease.
Yeah. I guess that brings us to the question with you balancing three large phase 2 trials and then going to have another two clinical programs coming in at the end of this year. How are you going to balance this? How are you thinking about cash runway, and what does this in terms of clinical development get you?
Big Pharma can do it, and they're more complicated than us. They're more efficient biotech. At some point, you scale out, right? I think practically speaking, you can't do everything. Then I mentioned earlier in one of the questions, there's other diseases that we'd also like to ultimately pursue. AD development in phase three, that's achievable to do without a partner, and UC, I argue the same. So we ultimately have to make a choice. We can't do them all. We have enough readouts happening across these two different agents in the lead as well as translational data that's going to drive where else we want to explore. At some point, we're not going to be a global player commercializing everything in Europe on ourselves. It's not rational either. We'll ultimately be seeking partnerships on a global basis for one of the programs over the next couple of years.
That's practical to say it that way because you can't do it on your own. We have over $400 million of cash coming into the year and cash guidance out through the year in 2026 across all four programs and the next data catalysts from each of them. It's five different readouts, four programs over the next two years.
That should be exciting. Michael, so people are very excited about the Dupixent COPD launch later this year. They just announced the June 27th PDUFA date. APG808 is targeting the same epitope. And then this morning, you guys also announced that you accelerated those development timelines. So can you briefly go over the profile of that compound relative to maybe 777 and what you expect from the update at year-end?
Yeah. So we're excited to get regulatory clearance last month to start dosing our 808 trial. So IL-4 receptor alpha, we have Dupixent-like epitope. Preclinically, we've shown 5 nanomolar affinity for IL-4 receptor alpha, so improved versus Dupixent and about a little over 2x improvement, so 2.5x in half-life in non-human primates. When we look at Dupixent and COPD, I mean, incredible trial. They took one dose, and they ran two trials, and both trials read out very positively, likely to be the first approved biologic for COPD. And I think people are realizing just how large of an opportunity and how big that unmet need is. We're excited to see what we can do to provide other options for patients. Because this is a receptor-bound target, it does have more turnover by virtue of just being on the cell surface.
It gets taken up into the cell more often, and you get TMDD, Target-Mediated Drug Disposition, which we think a 6- to 8-week half-life could be a great improvement versus an every-2-week option. That's kind of how we think about it. Then in terms of higher exposures, loading dose, different trial designs, I think there's a lot to be trialed to see if anything could be improved upon. We just don't know yet from 2 very impressive studies, but only at a single dose. If we can improve on that, we would, of course, love to.
Okay. You mentioned receptor, which made me think of OX40. You guys have APG990, which is an OX40 ligand, as well as 222, which is a combination of IL-13 and OX40 ligand. So maybe you could go over your thoughts on the OX40 space, what we've learned from the Sanofi and Amgen data when we think about the ligand versus the receptor, and whether you think these are ultimately monotherapy compounds or combination compounds.
Yeah. So similar to kind of as Dan alluded to, we were excited about the OX40 ligand data last year as well. We think it's quite meaningful for that more refractory patient population because there are kind of patients that are more type 1 inflammation-driven, and OX40 ligand is now the first orthogonally evaluated mechanism outside of IL-13, IL-4 receptor that has shown efficacy in atopic dermatitis. Sanofi, they're kind of betting the farm on it. 6 different phase twos ongoing now, asthma coming later this year, alopecia, right, celiac, systemic sclerosis, and a number of others are ongoing. And we're excited to see what it can do. Ultimately, we get excited about it from that combination approach. There's been a lot of talk about combinations. We couldn't agree more. We think that they are the future of I&I.
Like with Vega, it's the first time that there are two orthogonally evaluated pathways that were combined. Lo and behold, like in oncology and like in other areas, they led to more efficacy. We want to be the first to do that with atopic dermatitis. We see really the real upside being maintain that best-in-category seasonal dosing or better, but via a combination approach to see if you can drive even more durable, deeper responses.
What do you think? How do you think Sanofi is going to dose clearance at the end?
I think a lot is TBD there. So they're trialing their phase 3. It is a complicated phase 3 design.
For Atopic Dermatitis.
For atopic dermatitis. They're trialing every 4 weeks and every 12 weeks. They argue kind of that right in their phase 2, they saw some deeper durability. I think if you take a step back and look at all the durability data that exists in atopic dermatitis, the strongest is from Lebrikizumab. Patients in the phase 3 that responded, 36 weeks off treatment in the phase 3, 2 out of 3 maintained response, better than anything else that anybody's put on the board. Next to that is probably OX40 ligand. And I think it makes sense for them to see if they can get patients out to a more deeper, durable state because it is kind of a slower-acting mechanism, right? Patients come in with their skin on fire. They don't want to wait 6 months for any relief. So I don't think it'll become their front line.
But when they were thinking about how do we differentiate from Amgen, we'd already launched their trials. They're obviously making a big deal about safety because OX40 ligand looks to be the safer target so far, right? There's a lot of noise around that. We're excited to just have the OX40 ligand and stay out of the noise. It looks to be safe. And now Sanofi, the owner of Dupixent, is talking about dosing matters, and we couldn't agree more.
They're not testing Q8.
No, they just did Q4 and 12.
With one loading dose for two weeks.
Yep. Their phase 2b showed a pretty flat dose-response too. So when we think about combinations, we think there's a lot to be figured out in what's the optimal stoichiometry of the dose. We think that there is a potential to eventually get a co-formulated dose that could be 1-2 milliliter autoinjector, APG777, APG990, the drug for atopic dermatitis.
Yeah. Because the durability looked pretty good to your point in AD.
It did. I think that and Dupi is a great drug. But outside of Dupi, a lot of drugs have good-looking durability. Dupi just has the shortest. So I think that there's that mindset that it's really just that that's all of atopic dermatitis, but it's really Dupi because of that receptor-bound mechanism. So we're excited to see what they can do. Whatever they can do, we hope to then improve upon their durability with an extended half-life version.
Yeah. Anthony, maybe back to you. Dupi didn't look great in urticaria . It is active, obviously, in EoE, but there is some room to improve upon that as well. So can you talk about maybe what do you see preclinically that makes you bullish about mast cells, mast cell function?
So we believe, especially in those diseases where mast cells are important, we believe that we have a biomarker in tryptase, which certainly, if you can knock that down, you know you're knocking down the mast cells. That leads to clinical benefit. And in the diseases that we're pursuing, getting that benefit very, very early, where it's profound, it's durable, and that's exactly what the patients want. So mast cell biology, it can go on and on. We can go into different indications, different therapeutic areas. I mean, for now, we're focusing on just understanding it in the I&I space. In those indications where mast cells are the key driver, we're going to do it with Barzol; in those indications where mast cells play a key role but aren't necessarily the main driver, we'll go at it with a bispecific.
So talking about the bispecific, you're going to be filing an IND this year for your TSLP Siglec-8 bispecific. Where do you see a natural synergy between the mechanisms?
Well, they're different pathways. So we see the fact that there are indications that we're looking at where both TSLP has benefit. We believe stem cell factor has benefit, but we don't want the redundancy. So we see them as two separate pathways, and hopefully, we can get some synergy at them so that you see the full benefit of targeting with each.
That's going to get filed in the second half?
Second half of the year, yes.
What was just the rate-limiting items to filing that?
There was no rate-limiting items. I mean, we're just concentrating on doing the phase 3s and getting those up and running, getting the phase 2s and PN up and running. But there was nothing holding them up. Now we're ready to go with them.
All right. Cam, let's go back to SPY002 just to cap off that discussion. Do you expect it to have a similar half-life and dosing regimen to SPY001 or maybe even 777, or might it be different? And when could we see that initial clinical data to confirm that?
Yes. Last answer is we expect first clinical data first half of next year. So we'll start dosing second half of this year and have the first data first half of next. In terms of expectations, I think the history with YTEs is you basically get longer half-life extension the more soluble your target is. So for cell-bound targets, as Michael alluded to earlier, you get more turnover because the antibody binds to the target and is turned over by that cell type. So within our portfolio of alpha-4, TL1A, and IL-23, we have kind of a span. Alpha-4 is always cell-bound. IL-23 is always soluble. And then TL1A is sometimes both. And so I would expect we get somewhere on the order of doubling for the alpha-4 program, potentially a lot more for the IL-23, and then the TL1A somewhere in the middle.
In non-human primates, we're in the mid-20s for half-life on our TL1A molecules compared to the existing TL1As, at least the leading two are around 10 days in non-human primates, around 20 days in humans. We would expect ours to be probably north of 60 in terms of the human half-life.
That's great. So your pipeline also has SPY004 in it, which is undisclosed but states that it's a novel MOA. So feel free to disclose it here. But if not, what can you tell us about it? Can you?
I actually think it. I'm not going to disclose yet. But I think the answer is that it's pretty similar to how we did the TL1A program, which is that it's an interesting target, genetic validation, preclinical validation, someone else working on a molecule in the space. And if we think their clinical data looks good, then we'll move ours forward as quickly as possible. So it's a strategy that's been okay so far, and so we'll keep doing it for the fourth one.
We have three minutes left, so maybe we'll just end with a final general question. Over the next decade, what do you guys believe will be the most significant development in the I&I space? And try not to speak to your own company.
What if it's the truth?
Fair enough. Anyways, who wants to start?
The most significant? That's hard. I think what you're going to see are a leap like with the immuno-oncology 20 years ago. I think you're going to see a lot of diseases that have been unable to get treated properly. Patients are going to start to benefit from. And there are going to be patients that have been underdiagnosed with so many diseases over time that you're now going to get that full breadth of it. And you're going to see a lot of benefit from some of these drugs coming out.
Yeah. I'll jump in. I think, right, I think in a similar vein, we're going to see a lot more one combination approaches. We've all talked about it. We all believe in it. And we're going to see agents that turn these diseases into drugs with functional cures, right? And that means dosing that you don't think about, right? The ability to not always be thinking about the fact that you have an I&I disorder, but you learn to live with it because you have drugs which make it go away, and you don't have to think about it because they're seasonally or even longer dosing.
Sure. Yeah. I agree with the comments so far. These are complex disorders, like we've been saying. The reason we're talking about combinations on one hand is that you have to turn on or off various downstream effects to get to outcomes across a broader range of patients and/or be able to better diagnose patients that are going to respond to different therapies. It's the things that we've been talking about in the oncology landscape for a long time. What we are focused on is restoring immune balance by bringing the immune system back to homeostasis. That might not be tolerizing for diseases forever, but we should be able to get to longer-term durable outcomes. I think that's where all switching for on this stage right now, novel mechanisms that'll get us to broader outcomes for a longer period of time.
Do you mind to add, Cam?
Not really. I mean, it's basically when you have better products that are more convenient, I also expect the penetrants will increase as well. So I think you just provide more options to patients that are superior to what's out there today, and we'll see patients reaching for them more. I think that's really the future.
Okay. Great. Thank you very much.