Apogee Therapeutics, Inc. (APGE) Earnings Call Transcript & Summary

Thank you for standing by. My name is Kathleen, and I will be your conference operator today. At this time, I would like to welcome everyone to the APG990 Phase I interim readout presentation. [Operator Instructions]. I would now like to turn the call over to Noel Kurdi, VP of Investor Relations. Please go ahead.

Thank you, operator, and thank you all for joining us today. During this call, we will be making forward-looking statements related to our current expectations and plans for the company as well as our clinical and preclinical programs. These statements represent our views as of this date and should not be relied upon as representing our views as of any subsequent date in the future. Looking at our agenda today, our CEO, Michael Henderson, will begin the call with an introduction to today's APG990 Phase I healthy volunteer trial interim results and our planned combination strategy for this program. Following our Chief Medical Officer, Carl Dambkowski, we'll discuss the scientific rationale for APG279, our combination of APG777 and APG990 and the APG990 Phase I interim results. Kristine Nograles, Senior Vice President of Clinical Development, will then walk us through the plans for the APG279 clinical development program. Before moving to Q&A, Michael will summarize our vision for building a leading I&I company. The subsequent Q&A will be led by Michael, Carl and Apogee's CFO, Jane Henderson. I will now turn the call over to Michael.

Thanks, Noel, and thank you all for the time today. We're excited to share positive interim results for our third program, APG990 and the implications for our combination program of co-formulated APG777 and 990 which we refer to as APG279. Apogee was founded to create best-in-class therapies for people living with I&I disorders with an initial focus on atopic dermatitis, asthma, EoE and COPD. Patients living with these indications have limited treatment options, often requiring injections as frequently as every 1 to 2 weeks. We believe these patients deserve new options with better efficacy and more convenient dosing. Today's positive interim results for 990 bring us one step closer to achieving this. Atopic dermatitis is a future $50 billion market, and we believe that Apogee is well positioned to transform the treatment paradigm. All of our programs including our combination approach, have the potential to be dosed every 3 months or longer during maintenance, but just a single 2-milliliter injection. Patients and their physicians tell us this innovation alone would be transformational, but we also have 3 key efficacy readouts in atopic derm starting in the middle of 2025 through 2026 that each have the potential to unlock greater efficacy as well. First, in the Part A portion of our Phase II study reading out in the middle of this year, we are testing 30% to 40% higher exposures of drug levels of 777 compared to Ebglyss. Multiple pieces of evidence suggests these higher exposure rates could lead to better efficacy. Second, in the Part B portion of our Phase II study, we are testing even higher exposures than in Part A to fully explore the potential of the IL-13 mechanism so we do not leave any remaining efficacy on the table. With our combo, which will be the focus of this call, we will be attempting to demonstrate better efficacy than the market-leading biologic DUPIXENT and are testing our combination head-to-head. Lastly, we are well capitalized to move as quickly as possible to bring these therapies to patients with cash into 2028, that should enable us to deliver each of these important readouts. This is an enormous opportunity. That cannot be overstated. And we have the capital and team in place to move quickly. The next several quarters should be very exciting for us. APG279 is our combo program for atopic derm, that combines 777 and 990, two antibodies that have been engineered for best-in-class properties against clinically validated targets and share an overlapping epitope with similar potency to lebrikizumab and amlitelimab, respectively. Both antibodies are Fc-Engineered for extended half life. For 777, [ vinyl ] Phase I PK they were treated at a 77-day human half-life that is 3x longer than lebrikizumab. For 990, today's Phase I interim data demonstrated an approximately 60-day half-life. That is 2.5 to 3x longer than amlitelimab. The exceptional PK demonstrated by both molecules, along with successful co-formulation and high concentration could enable every 3- and 6-month dosing for 279 with just a single 2 mL injection. By combining two of the most validated targets IL-13 and OX40 ligand, 279 also has the potential to achieve best-in-class efficacy in atopic derm. At our R&D Day last December, we announced preclinical proof of concept for 279, which, as you can see here, demonstrates broader inhibition of type 1, 2 and 3 inflammation compared to monotherapy. Later this year, we're excited to put 279 to the test in the head-to-head trial against DUPIXENT with initial data expected in the second half of 2026. Now I'll hand it off to Carl to dive deeper into the scientific rationale behind 279.

Thank you, Michael. I'm thrilled to be here this morning to discuss our combination for atopic dermatitis and the APG990 data supporting this approach. We know that atopic dermatitis and other inflammatory diseases are heterogeneous with broad cytokine involvement. Clinical data from DUPIXENT and Ebglyss which target type 2 inflammation as well as multiple preclinical and translational medicine studies support the type 2 inflammation and IL-13 specifically, is a key driver of atopic dermatitis pathophysiology. Amlitelimab, on the other hand, which targets OX40L has broader inhibition, inhibiting Type 1, 2 and 3 inflammation, but both biomarker and clinical data support that this inhibition is partial showing lower clinical efficacy compared to DUPIXENT and Ebglyss in non head-to-head studies, targeting IL-13 with greater exposures than Ebglyss may allow for improved clinical outcomes a hypothesis we are testing in our ongoing Phase II trial of APG777 with a readout midyear. Beyond that, though, we believe there is further potential in combination therapy. JAK inhibitors like RINVOQ illustrate this potential. They show deep inhibition of all 3 inflammatory subtypes and deliver strong clinical efficacy. But JAK inhibition also leads to safety liabilities as evidenced by their black box warnings. APG279 could provide a significant improvement in clinical outcomes without the safety liabilities of JAK inhibitors. APG279 broadens the inhibition profile compared to biologic monotherapy approaches to include not just type 2, but also Type 1 and 3 inhibition potentially approaching JAK-like efficacy. At our R&D Day last December, we shared data demonstrating preclinical proof of concept for APG279 including the potential for broader and deeper inhibition of type 1, 2 and 3 inflammation. As you see in the [ heat ] map on the right lebrikizumab and dupilumab both provide deep type 2 in emission, while Amlitelimab provides broad inhibition across types 1 through 3 inflammation, but not the depth at Type 2. Only APG279 inhibition approaches JAK-like activity on key inflammatory biomarkers. Importantly, our GLP toxicology study of APG279 in nonhuman primates supports that we may be able to achieve this JAK-like inhibition of key inflammatory markers while maintaining the well-tolerated profile that has been exhibited by APG777 and APG990 individually to date. In this 3-month toxicology study, APG279 was well-tolerated with no findings at any dose level including the highest dose tested of 150 mg per kg of each individual monotherapy. In contrast, a non-head-to-head GLP toxicology studies, JAK inhibitors approved for AD saw cytopenias decreased organ weight, increased thymoma, tachycardia or hypotension. The APG279 toxicology study results with no toxicity observed at any dose level is a key outcome for the combination and supports our goal to approach JAK-like efficacy with APG279 without the safety liabilities. We not only want to have the potential for APG279 to be safe and to deliver best-in-class clinical efficacy, but we want it to be patient-friendly as well. We have achieved an APG279 co-formulation that is stable at high concentrations, injectable and a comparable time to DUPIXENT and retains the potency of the 2 antibodies. Based on this and the best-in-class PK we've seen for APG777 and APG990 we believe we will be able to target a dosing regimen of APG279 as a single 2-milliliter injection given every 3 and 6 months in the maintenance setting of atopic dermatitis. Now we'll walk through the APG990 Phase I healthy volunteer data supporting our ability to potentially have APG279 delivered as a single 2-milliliter injection, just 2 to 4x per year. When designing the Phase I study for APG990, we laid out clear goals for what we needed to achieve in terms of safety, PK and exposure targets particularly with regards to APG990's potential for use in combination with APG777. Regarding safety, all tested doses up to 1,200 milligrams were well tolerated based on all available data at time of data cutoff. Moving to our second goal. We observed a well-behaved PK profile across all cohorts. While our target was at least a 21-day half-life, we exceeded this by a wide margin with an approximately 60-day half-life. With regards to maintenance dosing, our results today support the potential for every 3- and 6-month dosing with relatively small doses of APG990 enabling APG279 to potentially be delivered as a single 2-milliliter prefilled syringe or auto-injector, every 3 and 6 months in the maintenance setting of atopic dermatitis. We're pleased with these results for APG990 and what they mean for our APG279 combination program and patients with inflammatory conditions. The data we'll discuss today is from our ongoing Phase I single ascending dose healthy volunteer study, which is testing doses up to 1,200 milligrams. The trial is fully-enrolled, and today, we'll be presenting interim data on safety and PK. Demographics were generally well balanced across cohorts. APG990 has been well tolerated with a favorable safety profile across all cohorts, including doses up to 1,200 milligrams. The safety profile is in line with expectations for therapies targeting OX40L and is supportive of continued development. Adverse events have been mild and generally unrelated to study drug. There have been no cases of pyrexia or chills. There have been no serious adverse events and no dose-dependent trends in AEs. APG990's PK profile has been favorable. The half-life of APG990 is approximately 60 days which is approximately 2.5 to 3x longer than amlitelimab's published half-life of 20 to 24 days. Moreover, APG990 generally demonstrates dose proportionality and low variability.. Here, we have modeled exposures from an APG990 every 3- and 6-month dosing regimen. As you can see from the blue traces, both regimens are modeled to have comparable exposures to that of amlitelimab. Importantly, based on the best-in-class PK profile we've seen for APG990, we have achieved these exposures at relatively low doses. This leads to the potential for APG279 to be dosed in a single 2-milliliter injection every 3 and 6 months in the maintenance setting of atopic dermatitis. I'll now hand over the call to Kristine Nograles, our Head of Clinical Development, who will discuss the APG279 clinical development plans including our plans to launch a Phase Ib study this year, putting APG279 head-to-head versus DUPIXENT.

Thank you, Carl. We will now discuss next steps for clinical development of APG279 in atopic dermitis. Supported by today's positive Phase I interim results for APG990 and favorable combination toxicology showing no adverse findings for APG279 we plan to initiate a Phase Ib study of APG279 head-to-head against DUPIXENT. This study will evaluate the safety, PK pharmacodynamic effect and efficacy of APG279, which combines APG777 and APG990 to target orthogonal mechanisms that are both clinically validated and well tolerated in AD. We expect to initiate this study later this year and plan to randomize 50 to 75 patients with moderate to severe AD to either APG279 or standard of care DUPIXENT. We selected DUPIXENT as a comparator arm in this study as we believe that it is important to demonstrate the potential for improved efficacy over currently available treatments. Efficacy readouts will be at week 16 and 24 providing 2 opportunities to demonstrate the potential for better efficacy with APG279. We expect to report initial data from the Phase Ib study in the second half of 2026. Our goal is that this Phase Ib study will demonstrate 3 things: First, that APG279 has an acceptable safety and tolerability profile to progress to later-stage trials. Second, that APG279 shows broader pharmacodynamic effect on key AD biomarkers of types 1, 2 and 3 inflammation; and third, that APG279 demonstrates a promising efficacy profile compared to standard of care DUPIXENT early in the clinical program prior to progression to later phase trials. We are very excited to initiate Apogee's first combination program this year. We believe we have the potential to show improved clinical outcomes when taking an orthogonal approach with two of the most validated targets IL-13 and OX40L in patients with AD while minimizing the injection burden to every 3-month dosing or better in the maintenance setting. I'll now turn the call back over to Michael for closing remarks.

Thanks, Kristine. We are building a next-generation biotech company with plans to deliver innovative medicines across 3 waves of innovation. Our nearest term opportunity is to prove the potential of APG777 as a best-in-class therapy for moderate to severe atopic derm, starting with readout of Part A of our Phase II trial in the middle of this year. Beyond atopic derm, IL-13 is implicated in more than 10 other indications. These represent opportunities for us to extend the impact of 777 for a greater number of patients. We've announced the first 2 of these indications that we will pursue, asthma and EoE and initiation of proof-of-concept studies and those indications is expected to begin this year for asthma and next year for EoE Finally, we are at the forefront of bringing the innovation of combination therapy to I&I. As we detailed today, APG279 has the potential to approach JAK-like efficacy in atopic derm, and we expect to begin a proof-of-concept trial, testing 279 head-to-head against DUPIXENT this year with a readout in the second half of next year. We've seen quarterly dosing transform other I&I markets such as psoriasis. We believe Apogee therapies can similarly transform the atopic derm market and are excited that with today's data, both our monotherapy and combination approaches have the potential to be dosed as a single 2 ml injection, just 2 to 4 times per year. We've been excited by the momentum seen thus far across our clinical programs. And as we look ahead to the next 2 years, that momentum continues. We expect 7 additional clinical trial readouts over the next 24 months, including the 16-week proof-of-concept readout for Part A of our Phase II trial of 777 in the middle of this year with additional readouts next year. Today's 990 readout is an important step in this combination approach. We look forward to continued progress in these programs with multiple data readouts to come.

[Operator Instructions] Your first question comes from the line of Seamus Fernandez of Guggenheim Partners.

Congrats on the excellent profile of 990. Maybe the first question is really, if you can just help us understand it seems like the company has continually executed their profile of recruitment and then study and then data presentation faster in most cases. And it seems like second half of 2026 might be a little bit long. Are you just kind of providing extra cushion for execution of that study versus DUPIXENT or are there specific workup dynamics that need to be executed on before the official initiation of the 279 study? And then 2 just very quick additional questions in terms of controversies that investors have been dealing with. First, just hoping that you could provide -- I know you have done this in the past, but maybe to remind investors, all of the dynamics that you've brought into play for the 777 Phase -- 777 induction Phase II to really manage the placebo response in that study and what your expectations are along those lines? And then just the second question on a similar topic. Maybe just to remind investors how challenging it is to actually generate assets with a profile like what you are delivering in -- with 777, 990 and your anti TSLP as well.

Great. Thank you, Seamus. I appreciate the questions. And we'll endeavor to hit on all of them, but let us know if we miss anything. First, on the timing piece, we continue to be excited by the enthusiasm that we see from the physicians and sites and patients that are enrolling in our studies -- that did allow us in the past to move up the upcoming 777 Part A readout from originally second half of the year to middle of this year, which we continue to be very excited about. I think it's just too soon to comment on the guidance beyond what we already have around 279. We will look to provide updates in the future if and when we have the sufficient data to do so. We're just kind of use that as the point though that between Part A middle of this year and then Part B in 279 coming next year by 3 efficacy readouts in atopic derm that could prove us to have potentially a best-in-class drug by the end of next year, which we're very excited about that setup. Your second piece, I'll hand to Carl on the Phase II and all that we've done to mitigate placebo rates. I will say that to help assist investors, we have added a few slides just to our corporate deck online in the appendix where we've shown recent trials really actually every trial since DUPIXENT with similar inclusion exclusion criteria to us in terms of EASI baseline of 60 and above. And right investors can go there and see that trial is designed in that way, actually a pretty consistent placebo responses. While there were -- last year, some placebo responses that we're seeing higher and some less severe patient populations or in different protocols, we endeavor to stick to what lebri and dupi and others have done, and that has some across a variety of endpoints led to pretty reliable placebo responses over the past 10 years. So again, right, the data doesn't lie, encourage folks to look at that because I think the charts speak for themselves. Beyond that, we have taken a number of measures in our trial, and I'll hand it to Carl to hit on some of those.

Yes. And so since the beginning of the design of the trial, we've really been thinking about how we make sure that we have a reasonable [ pool ] placebo rate for APG777, [ 279] . There's kind of 3 key areas that we focused on in doing that and probably a lot of other details we could add to this. But from a high level, the first piece is really site and region selection being very rigorous about what areas and then what sites within those areas that we allow into the study based on historical data and historic ability to execute successful trials. And so that's been really important to us. Second, as Michael mentioned, really rigorous thought around IE criteria and not making any sacrifices in terms of trying to have an easier IE criteria to enroll which potentially wouldn't be as comparable to what we've seen in the past with dupi, lebri and others. One example of that is making sure that patients are EASI 16, both at screening and baseline. It's just a small example of the way we thought about that. That's obviously the most difficult criteria to enroll in terms of EASI scores, but we think we'll lead to the best trial outcomes there. And then I think the final overarching piece too is just really intense oversight of sites. We think this is really important in terms of not only our relationship with them, so they have aligned goals with us, but also making sure that we're always looking for them and us to be aligned with enrolling the right patients at the right sites, at the right pace. We have a importantly a large and very experienced clinical operations team to make sure that we're doing everything on an almost minute-to-minute basis to ensure success for every patient enrolled in the trial.

Thanks Carl. And then on the last point about how hard it is to generate assets with this profile. We've been at this for about 5 years now, close to $1 billion in capital raised. And we took our time very methodically while in stealth before we entered the clinic with our first asset, 777, to not just add YTE onto an antibody. But to create fully optimized antibodies every since that they're going after validated targets, yes, but with every other improvement that we could discover by testing the head-to-head preclinically to get to the nonobvious, fully-optimized ventral antibodies that we now have 4 of in the clinic. I think that, that has just continued to improve itself out with our readouts, right? Each has exceeded our expectations. When we look at today's readout, there are other OX40s for instance, that have YTE or half-life extension technology in the clinic. And those have netted out in the 30-ish day half range, right? We've seen other antibodies with half-life extension, not delivered to the same extent that we are seeing for our antibodies, not to mention the improvements that we see in formulation. While we're not disclosing the exact concentration of the formulation for 990 today for a number of reasons, including IP and to further protect the moats that we have right now, [indiscernible] 125 and we're saying that we're above 180, right? When we talk about 777, we're at significantly 40% higher than Ebglyss as well. So in everything that we do, we're not just making half or extended antibodies, we're making fully-optimized antibodies and people can look at our IP now and see that we ran the experiments preclinically, including a number of non-human primate experiments to get to those. The last piece, just on that is, right, we endeavor as well to ensure that we can co-formulate our antibodies together. I think that the co-formulation data that we put out today strengthens the proof-of-concept data we released on R&D day and shows that not only is it stable, but we can do it at a relatively high concentration as well with similar attributes to the monotherapies. So we have been very thoughtful about how we've assembled our portfolio and we recognize that we've got to live with these antibodies that we've taken to the clinic. So we've made sure that we're moving forward just with the best antibodies that we feel can be made against these targets.

Really appreciate it and congrats again.

Your next question comes from the line of Alex Thompson of Stifel.

Congrats on the data. I guess maybe can you talk a little bit about your confidence in dose selection for the 279 proof of concept? What are the key considerations there? And are the Phase IIa data for 777 important for sort of finalizing that dose? And then secondarily, I think it's pretty clear what the pathway from line of therapy is in atopic derm right now. But could you talk a little bit at a high level about what the path towards approval might look like for co-formulated combination, particularly if 777 is approved first?

Thanks, Alex. I'll hand it off to Carl to talk about our dose selection with the spoiler that we're not going to disclose much about that at this time.

Yes. Thanks, Alex, for the question. I think that -- I think the key piece for us as we think about dose selection for the 279 Phase Ib head-to-head versus DUPIXENT is really making sure that we walk away from that with a successful outcome with that being a numerical win over DUPIXENT in the trial. And to that end, really, what we want to do is have adequate target coverage for both molecules are both targets within the study design, too. As Michael said, we're not disclosing the exact details of that, but we're going in that with really the goal of making sure we know that this idea that we're taking forward with orthogonally validated mechanisms, we can have a definitive answer on that and so adequate target coverage of both OX40L and IL-13 is really important in that study as well.

And then with regards to the path to approval for the combo, what is, I think, unique about how we're thinking about the -- our combination approach is that we are currently in the Part B of our ongoing 777 study, optimizing the 777 monotherapy dose. That will give us an advantage that when we think about eventual Phase II contribution of components design, for 279 to know what the optimized dose of 777 is and then right, optimizing 990 around that. I think that there is significant regulatory precedent, 140-plus different co-formulations that have been approved by the FDA. We're seeing other leaders in I&I right now, right, start to do co-formulations. And a number of readouts from J&J coming up this year, AbbVie and others are now, Lilly recently as well, talking about the need for co-formulations and as a combination approach to I&I. So we're excited to be at the forefront of bringing combinations co-formulated to atopic derm, and I think that there is a clear path that's derisked by 777 being in the lead. And the last thing that I'll just hit on there is we sometimes get asked about wouldn't it be easier if you didn't have new contribution components or do actives, I think in the future, when you think about 10 years from now, when 777 is out there, hopefully being dosed every 3 to 6 months, the backbone therapy for atopic derm. At that point, we think that additional drugs coming to market will need to prove themselves via active comparator studies or via contribution component studies. So we're excited to do that out the gate, of course, with ours and putting it to the test starting later this year.

Congrats again.

Your next question comes from the line of Akash Tewari of Jefferies.

Two on my end on the upcoming data sets from Sanofi and then one on atopic derm for IL-13. So firstly, how is your team framing the upcoming OX40 data in asthma from Sanofi. We internally suspect that efficacy would look more modest than what we've seen with dupi in a biomarker controlled population. Would you consider moving forward with the common approach even if the Sanofi results aren't statistically significant? Number two, if we look at the Sanofi IL-13 TSLP bispecific, it seems like there's strong FeNO reduction has been driven by population and baseline differences. So how much utility is there from combining overlapping mechanisms like IL-13 and TSLP versus OX40 when you think about your combination strategy? And then finally, Michael, in the prepared remarks, you mentioned 777 will be hitting IL-13 more potently than lebri. At the same time, I think your team has been pretty reticent to predict an efficacy benefit as a monotherapy. So what are your latest thoughts on efficacy expectations for your atopic derm data set that's coming up soon.

Great. Thanks, Akash. For the [indiscernible] asthma data, Carl, do you want to speak to our a bit of prognostication.

Yes. And I might take the first 2 kind of in concert, Akash, because I think there's kind of some overlapping scenes there. But on the first one, right, just the expectations for asthma. I think obviously, we're awaiting the Sanofi and amlitelimab data as much as everyone else in terms of what they do in asthma and we'll be responsive to that data overall and what our approach is to. So monotherapy or 279 combination therapy in the future both could be potential options for us given our pipeline, but really will be responsive to that data. I think one of the areas that we're excited to dig into there, right, is just really the patient population. They might be able to have an impact on. We know agents like DUPIXENT, as you mentioned, have really great impact on type 2 high patients in asthma measured by eosinophils. I think one of the open questions for us is whether OX40L can have a broader impact on a non type 2 high or eosinophilic phenotype population overall. So we'll be awaiting that data and responsive to it. And then I think similarly, and this is why I'm kind of grouping them in terms of the IL-13 TSLP data from Lunsekimig and our approach for APG777 and APG333, right? I think a question there too is not just maybe depth of response that you could get there, but breadth of impact that you could have as we've seen TSLP have greater impact on non-eosinophilic phenotype than to be in others. So we'll be thinking about how we do that in our own programs as well. This year for respiratory diseases, we're launching asthma trials and with our monotherapy APG777 and we'll disclose more on our combination plans for APG777 and APG333 at a later time this year.

Yes. And then just to pick back up, we will see -- we're seeing Sanofi launched a number of different Phase IIs with their Lunsekimig. So we will be, of course, responsive to that data as it comes out. And those are studies as you know what should give definitive answers that can't reduced by high FeNO rates at baseline for instance. With the 777 monotherapy. I think that we have been very clear from the beginning, and we'll continue to reiterate that what we have set as the bar as what market research tells us is the bar for us to have what we feel is the leading drug in atopic derm. Then as a physicians, patients and payers are exceedingly clear to us that if we are able to launch this decade with a drug that is equivalent on efficacy and safety to Ebglyss and DUPIXENT but transformational on dosing and every 3 and 6 months in the maintenance setting, that 90-plus percent of patients will act on that drug, the majority to two-thirds of patients are switching over from standard of care to that drug and 90% of new starts are starting on that drug. So we are very excited about that profile because that is the bar that market research tells us should be the bar. As you point out, we are testing higher exposures of IL-13 inhibition versus what has been tested historically by lebrikizumab. While there are multiple data points suggesting that, that could lead to better efficacy, we view that as pure upside and not the base case, given how strong of a profile of equivalent efficacy and safety is.

Your next question comes from the line of Julian Harrison of BTIG.

Congratulations on these early results and all the recent progress. I'm wondering if you could talk a little more about your enrichment strategy for the Phase Ib 279. Any notable differences you would highlight compared to how you approach development for pure Th2 inhibitor?

Yes. No, thanks for the question. I think that for the Phase Ib, we're really thinking about making that as comparable as possible to APG777-201, our ongoing Phase II trial there. I think with atopic dermatitis, we're in a space where I guess the disease itself is T2 enriched, but there's nothing in terms of i.e., criteria that we're doing with our monotherapy approach or a combination approach to further enrich that. We know AD is heterogeneous, right? And so you're getting patients that are maybe higher on the T2 spectrum versus have other involvement. IL-13 has been repeatedly shown to be the core driver of atopic dermatitis pathophysiology, but obviously, other contributors there as well. So I don't think any specific enrichment strategy, although its strategy behind that trial to make it as comparable as possible, both to APG777-201 our ongoing phase II trial as well as others like DUPIXENT and lebrikizumab Phase III trial.

Got it. That's helpful. And then another on that Phase Ib. I'm wondering what you expect to be the most informative data points? Is there a go/no-go threshold associated with EASI 75 or IGA you're able to share now?

Yes. When we kind of think about what is meaningful in terms of improvement, when we look at where JAK are, for instance, compared to DUPIXENT, EASI 75. It's a protein 30 points improvement. We don't think the 30 points is necessary to have somebody that's transformational in terms of efficacy, right, as long as the safety is there. We're -- we hear pretty consistent feedback that 10 points of differentiation on 75 -- EASI 75 or [ IGA-01 ] would be -- as one payer, said, guess what, we'll pay for it. We'll go with the profile like that and docs, I think physicians and patients, excuse me, get very excited when it's in that double-digit range. So that's what we'll be looking for. And what's also exciting about the Phase Ib and how we design it as we'll be looking at efficacy at multiple time points, including week 16 and week 24. So we have multiple comparators.

Okay. Excellent. That's helpful. And then a final one for me. I'm just wondering, in light of prior trials of monotherapy, OX40 and OX40 ligand inhibitors. Are there any learnings from those prior efforts you're applying to your plan to develop 279?

Yes. We're still learning from some of those prior trials, and we're excited to see additional data, we hope at AAD around some of those prior studies just to understand if there's anything that we can glean from dose selection or patient selection or geographical distribution and some of the changes that took place between the Phase II and Phase III studies. I think what is important here is we view OX40 ligand as a very exciting add-on just not as the monotherapy. So while we will be learning as much as we can and always exploring how to improve our studies. Nothing in particular kind of jumps out that we would apply to the combination per se, just based off of those monotherapy studies. But of course, we'll continue to be responsive to the data that we are seeing.

Okay. Great. And congrats again.

Your next question comes from the line of David Nierengarten of Wedbush.

I have two maybe quick ones. First off, I assume since they weren't reported, but there weren't any ADA antibodies or anything like that? And then Second, is there -- when you think further ahead, is there a scenario where the combination goes ahead of the 777 monotherapy where you prefer to develop one or the other? I'm just curious how you're planning for different outcomes with the mono versus combo therapy?

Yes. Thanks, David. Carl, do you want to speak to the first point?

Yes. The ADA point, obviously, still early in the study is it, is an interim readout, but we haven't seen any apparent impact from ADAs on PK curves. And though feel confident in the profile we're showing moving forward.

And I think moving forward, we're excited about both drugs, 777 and 279, right? With 777 we -- middle of this year, we'll learn, do we have a potential mega blockbuster in the atopic derm and broader type 2 inflammation market. And again, like equivalent efficacy and safety with improved dosing launching into this decade, give us whatever percent market share, you may, that ends up being a mega blockbuster and kind of the foundational asset for us as a company. Well, we then want to always be thinking through is, how can we continue to offer innovative solutions for patients and drugs that will raise the bar for patients. 279 for us, we feel is the ideal approach of orthogonal mechanisms that could do that. I think part of how quickly 279 shifts into the front line versus kind of take JAK and later-line therapy will depend on just the strength of the 777 data, right? If we end up seeing improved efficacy with 777 mono, then right, you can imagine that 777 mono could persist well beyond any pressures that might come into mid- to late 2030s as we see biosimilars enter and become that mainstay. So just how we think about shifting patients and growing that market will depend on partially the 777 data middle of this year and then also the relative to 279 relative to 777.

Your next question comes from the line of Salveen Richter of Goldman Sachs.

You mentioned the numerical win versus DUPIXENT. Could you just speak to what that might look like with regard to the profile that you're hoping to see in the head-to-head versus DUPIXENT. And then secondly, with regard to the comparison to JAK here, just your thoughts on whether that sets the efficacy ceiling or theoretically could be improved upon with one of your assets, assuming combinations and safety and tolerability holding at higher doses?

Yes, Carl, do you want to speak to the first point.

Yes, happy to, right? I think I mentioned a numerical win versus DUPIXENT, right? I think we see that as at least 10 percentage points better than what DP shows in that study. Again, really based on our discussions with KOLs and blinded market research we've conducted with that is really the bar for a, I would say, a multi-targeted approach, whether a combination or otherwise, to be successful in this space is that 10 percentage points on some key end points.

And then kind of dovetailing that into your second question, right 10 points is a significant improvement versus what's out there. Of course, in some of these endpoints JAKs are doing close to 30 points better than DUPIXENT. Whether or not that 30 points better is kind of maxed out unlimited by the tolerability of JAKs, right? We do know that there is a dose-dependent response. I think TBD, 10-plus points we would be very excited about to have, and we'll see -- we hope that we're figuring out along with you is 30 really the bar by having a very safe and effective combination that we can fully explore that safe, but broad inhibition of the type 2 and non-type 2 pathways.

Your next question comes from the line of [ Richard Wagner ] of Bank of America.

[ Richard Wagner ] of Bank of America for Tim Anderson. As you know, UCB is also taking an orthogonal approach to atopic dermatitis with its bispecifics pairing IL-13 with either IL-22 and IL-17. The company at their earnings commented that they had seen positive Phase IIa in atopic dermatitis with the IL-22 combination. I wonder if you could remind us the biological rationale for your particular combination and your confidence in that approach? And what would be the advantages compared to the UCB bispecifics? And specifically, I'm thinking about mechanism of action. And then related, is there a potential for a safety risk from hitting the type 2 pathway both upstream with OX40 and then downstream with IL-13.

Yes. Thank you for the questions. So for the -- a number of kind of different approaches out there, UCB, of course, from what we understand from their clinical trials and the comments that they made, they ran a small Phase Ib study that included IV dosing only for atopic derm patients and they have had that data for some time and have not yet disclosed it for their IL-13, 17 combo, and they have an IL-13, 22 trial that's ongoing and inset they might share that later this year. Of course, right? We refer to them, and we'll keep an eye on for that data. When we think about IV dosing for atopic derm patients, and even if that later on commerce to subcu, non-half life extended, we don't see that as a progression for patients necessarily right, kind of a step back in some ways. So while we're excited to see additional options being made, we view that as more of a later line option versus a frontline therapy and where we're focused. And when we think about what's really exciting about our approach is right, many years ago, we thought -- do we want to do a bispecific? Do we want to do a co-formulation? And well, how do we get to the best eventual product that can be dosed every 3 to 6 months and where we can titrate against each target and where we can get the broadest coverage of these pathways. And that is with the orthogonal approach because it hits -- it does inhibit IL-17, and also inhibits IL-22 and also inhibits TNF alpha interferon gamma, right, kind of all the different pieces that people are trying to take piecemeal with some of their bispecific approaches. We're able to get all of that with the broad and safe approach of OX40 ligand inhibition and the deep type 2 inhibition that 777 offers. And then to your last question, right, safety risk, we wanted to be as sure as anyone that we were taking a safe drug into the clinic here with our -- with the co-formulation. And to do that, we ran very high dose combination tox of the co-formulation in our preclinical studies up to 150 mg per kg and saw nothing even at that very high dose in nonhuman primates over 3 months. So continue to be as safe as we can and advancing this and everything that we've seen to date on that in a very broad body of preclinical evidence in pharmacology including viral assays, which show our differentiation versus JAK, which we started our R&D Day. And just the ongoing incredibly safe profile of these mechanisms as monotherapies from others in the clinic, supports our view that this should be a safe and hopefully effective therapy.

And that was our final question. Ladies and gentlemen, that concludes today's call. Thank you, everyone, for joining. You may now disconnect.