Good afternoon and welcome to the Attovia Therapeutics virtual KOL call and ATTO-1310 clinical development update. At this time, all attendees are in a listen-only mode. A live Q&A session will follow the formal presentations. To our covering analysts, please use the raise hand feature to be added to the queue. As a reminder, this call is being recorded and a replay will be available on the company website after the event. I will now turn the call over to Tao Fu, founder and CEO of Attovia Therapeutics. Please go ahead, Tao.
Good afternoon, everyone, and thank you for joining us. I am Tao Fu, founder and CEO of Attovia Therapeutics. We are hosting a virtual KOL call and clinical development update for ATTO-1310, our lead clinical asset and the next-generation precision itch therapy targeting IL-31. Today, we are sharing the top-line 12-week results for our phase I-B study in chronic pruritus and high-itch atopic dermatitis. Earlier this afternoon, we issued a press release with these results, which is available on the investor section of our website. I'm pleased to be joined by two of the world's leading experts in itch and atopic dermatitis, Dr. Brian Kim and Dr. Jonathan Silverberg. Also with me are Hubert Chen, our Chief Medical Officer, who will present the data, Steve Chan, our CFO, and Petter Veiby, our Chief Scientific Officer, who will join us for Q&A. Steve, over to you.
Thank you, Tao. Before we begin, I would like to remind everyone that today's presentation includes forward-looking statements, which are subject to risks and uncertainties. Please review the disclosures on this slide and in our SEC filings, including the disclosures regarding cross-trial comparisons. Back to you, Tao.
Here is our agenda for today. I will start with a brief overview of ATTO-1310. Dr. Kim and Dr. Silverberg will then share their perspectives on the significant unmet need in chronic pruritus of unknown origin, or CPUO, and in high-itch atopic dermatitis. Hubert will walk through the top-line 12-week results of our phase I-B study, followed by our phase II plans.
I will come back at the end to share what we believe these data mean for ATTO-1310, and then we will open it up for questions. Shifting to the focus of today's call, ATTO-1310, I would like to explain why we believe this molecule is differentiated. ATTO-1310 is a next-generation precision itch therapy. It is an anti-IL-31 antibody fused to a half-life extended Fc given subcutaneously. IL-31 is a key driver of itch. Nemolizumab, which targets the IL-31 receptor alpha, has validated the IL-31 pathway and has seen strong commercial uptake.
When we designed ATTO-1310, our goal was to create a next-generation IL-31 medicine with a differentiated product profile across several key attributes. First, rapid itch relief. We targeted IL-31 ligand itself rather than its receptor. Cytopoint, an anti-IL-31 ligand antibody used in dogs, can deliver itch relief within hours, and we believe ligand targeting can produce faster onset. Second, deep efficacy. The ATTOBODY platform gives us ultra-high affinity and potency, and by targeting the ligand, we believe we can avoid the reverse dose efficacy seen with nemolizumab in multiple phase II studies, where the highest dose performed worse than lower doses. Third, a benign and differentiated safety profile, including the potential for fewer dermatitis adverse events. Last but not least, quarterly maintenance dosing compared with nemolizumab, which is primarily a monthly drug. Before we hear from our experts, let me share how we think about our phase I-B study.
Our week four interim analysis, which we previously shared, gave us a clean signal and the confidence we needed to advance into phase II. In addition to a favorable safety and immunogenicity profile, we saw rapid deep itch reduction by week four after one single dose in two different pruritic conditions, one with skin lesions and one without. We identified active doses to take forward to phase II, which is already underway. Now, with the full 12-week follow-up data in hand, I am very pleased to say that these data reinforced our confidence that ATTO-1310 can deliver the compelling target product profile we set out to achieve that we believe is significantly differentiated from nemolizumab. First, target engagement and drug exposure support quarterly dosing. Second, clinical activity was durable, extending beyond week four through week 12 after just one dose.
Third, the favorable safety and immunogenicity profile remained consistent through the full follow-up. We also have preliminary clinical and biomarker data suggesting a potentially differentiated safety profile. With that, before Hubert walks through the data, it is important to spend time on the diseases themselves and the patients we are trying to help. We are very fortunate to have two leading experts with us today to discuss this unmet need in CPUO and high-itch atopic dermatitis. Dr. Brian Kim is Vice President and Chief Biotechnology Officer at Northwell Health and Professor at the Feinstein Institutes for Medical Research. He was previously Professor and Vice Chairman of Research at Mount Sinai. Brian is one of the leading scientists in the field of neuroinflammation and itch, and he has helped design multiple pivotal trials in dermatology for agents like dupilumab. Brian will speak on CPUO.
Dr. Jonathan Silverberg is Professor of Dermatology at The George Washington University School of Medicine, where he is a Director of Clinical Research and Contact Dermatitis. He was lead investigator for the nemolizumab phase III ARCADIA program, and Jonathan will speak on high-itch atopic dermatitis. Thank you both for joining us today. Brian, over to you.
Thank you, Tao. So, I will be speaking about chronic pruritus of unknown origin, or CPUO. This is a disease that is very near and dear to my heart. It is a disease that I see most in my clinic, and we have gone through a very interesting journey where it went from, is it a disease, to now what I think you will be convinced after today that it very much is a disease. So it is chronic itch lasting for greater than or equal to six weeks, where there is no clearly defined cause. It's typically associated with aging. It is much more prevalent within the elderly, and it's a generalized itch in nature, but highly prevalent, affecting 2 million to 5 million patients and adults in the U.S. There are no FDA-approved treatments yet, and its disease burden is quite tremendous.
The itch is typically quite severe, long-lasting, continuously on a daily basis, and strongly associated with anxiety and depression. As you see here in the picture on the left, this is a patient of mine who you can tell he is itchy just by looking because you see scratch marks where he can reach, and not where he cannot. So, we have been working on this disease for a while. There is a relatively simple way in which you can actually get to the diagnosis, although it is a diagnosis of exclusion. You take a very simple medical history. There are physical exam findings that you can exclude to rule out dermatologic conditions and basic laboratory tests.
This is a schematic that we published a number of years ago, but CPUO, although a diagnosis of exclusion, is one we can very consistently diagnose in the clinic, and in fact, this is what I do most of my time as a clinician and dermatologist. Where are we at now in 2026? Well, we ourselves were able to instigate a phase III clinical trial with dupilumab, which blocks the IL-4 receptor alpha in CPUO. Here are results in the phase III study. Although it did not meet its primary endpoint based on the proportion of patients reaching itch reduction at 24 weeks, a 4-point reduction, if the primary endpoint were 12 weeks, it would have actually met the primary endpoint. This is study A. Now, just to frame this, at week 12, these patients have received now seven injections of dupilumab.
Also, nemolizumab, which blocks the IL-31 receptor, the pruritogen or itch cytokine, is now in phase II clinical trials as well, which I'll speak to a little bit based on my own experience later as well. Nemolizumab is a very promising agent, of course. There is remibrutinib, another drug that we are quite familiar with. It is a BTK inhibitor that is now FDA approved for chronic spontaneous urticaria and inducible urticaria that is also going into CPUO in phase III clinical trials. Then what you are hearing about today is ATTO-1310, which targets not the receptor, but now IL-31 ligand with positive phase I-B data now. So, we believe now the pipeline is rich and promising and exciting for chronic pruritus of unknown origin, which is in stark contrast to over 10 years ago when we first were exploring this disease and indication.
So, dupilumab in CPUO, we have anecdotally found in a case series fashion from our own clinic that patients with CPUO can respond. This was very important for us, even though this is simply a case series, not a randomized controlled trial, but this was really gathering evidence that we can actually pharmacologically intervene in this condition. This drove the conviction that, in fact, this is a tractable condition, and I think increasingly, we will see this more and more with a number of different therapeutics in this space. We also have great experience with nemolizumab in the clinic off-label for CPUO as well, but here is also a potential problem with nemolizumab, which there were some hints of in the clinical trials for atopic dermatitis, where we saw aggravation of atopic dermatitis as a flare, as a side effect potentially in the clinical trials.
I'll come back to this in the real world as well. Even in the clinical trials, we saw what was some concern about dose-dependent aggravation of asthma, and there was some debate about whether this was simply theoretical, somewhat unpredictable, or whether there was actually a biological explanation for what could be going on and whether this is actually there was a real phenomenon. We actually were concerned that this could be a real phenomenon of nemolizumab, notwithstanding its efficacy for itch in the setting of atopic dermatitis, and as well as prurigo nodularis. One of the things that one has to be aware of with IL-31 is that the ligand binds its receptor, which is comprised of two subunits, the IL-31 receptor alpha, which is bound up by nemolizumab, and oncostatin M receptor beta, or OSMR. These two then can signal IL-31.
Why is this relevant? One of the concerns we had early on based on preclinical data was that if you actually sequester IL-31RA by way of nemolizumab, what can actually happen is you free up the OSMR receptor, which then binds its other partner, which is GP130, and this can actually signal another cytokine called oncostatin M or OSM, which can be pro-inflammatory. When I brought this up and we wrote this editorial, a lot of people thought this might actually be theoretical. We do not think this is the case. In fact, if you talk to many providers now after nemolizumab was approved, one of the things that does happen is these aggravations, particularly in atopic dermatitis.
What we have also observed, and others will attest to this, is even in patients with chronic pruritus of unknown origin, or CPUO, so not atopic dermatitis or prurigo nodularis, we can actually see the development of a de novo rash, as shown here in my patient on the right, on the knees. Surprisingly not itchy. It looks itchy, but it is a rash. I believe this is actually caused by exactly what I described, the biology here. Some people call this a nummular dermatitis. Some people refer to this as a psoriasiform dermatitis. It is not entirely clear what this is, but this is something that is seen with nemolizumab, and much more observed post-approval. What' s unique, I think, about what you are going to hear about today is that IL-31 itself can be targeted as a ligand.
You do not have to go after the receptor, but if you can do it very effectively, that's potentially a very unique strategy that harvests all of the advantages of blocking IL-31 itself, but also avoids potentially some of these hazards about blocking the receptor itself. This is data. This is actually cytokine levels from the serum from our patients in our clinic with CPUO who we have found to have elevated levels of IL-31, the ligand, which is essentially the target that you want to go after. In summation, CPUO has become a disease unto itself. It's well-recognized across the fact that there are so many clinical trials. It is a tractable condition. It's morbid, it's highly prevalent, and a unique opportunity to really alleviate the suffering of many, many patients with severe pruritus throughout the U.S. population. Thank you.
Thank you, Brian. Jonathan, over to you.
Thank you, Tao. I'll be discussing the burden of itch in atopic dermatitis and some important patient subsets that I think that are highly clinically relevant for this, you know, drug development. First, just to understand that itch is the most burdensome symptom in atopic dermatitis. Perhaps there's no surprises here, but these are data from a study where we looked at U.S. adults in the population with atopic dermatitis, and by far, the most burdensome symptom was itch. Even amongst those patients where itch wasn't their most burdensome symptom, it was their second most burdensome symptom. When we look at the importance, or the burdensome nature of itch stratified by the severity of the disease, what it turns out is when you're looking at a patient with just mild AD, it's all itch, itch.
As they get more severe, there now become other sequelae of the itch, like now they're scratching their skin, and they have open sores, or they have the secondary sleep disturbances or secondary skin pains. This is a study that looked at predictors of how patients view their own severity of atopic dermatitis, and what was found was that there are a number of different patient-reported outcome measures that are associated with or can predict patients' self-report of AD severity. Really, what is at the top of that is the severity and intensity of their itch. Why does that matter? Because what ultimately drives patients' treatment decisions is their perception of the severity.
I can look at the patient and say, "Oh, your skin looks pretty bad." But if they think that their disease is mild because they're not all that itchy, they're not changing therapies, and they're certainly not going to be stepping up to an advanced systemic or biologic therapy. On the flip side, if the patient sees themselves as having really severe disease because their itch is super bad, but I look at the skin and I say, "Oh, it doesn't look so terrible," they're still going to want to exercise an option to step up therapy. Understanding that itch is the major driver of patients' perception of their own disease essentially translates to understanding that itch is the major driver of their treatment decision-making.
Now, from the study that I just showed you, it's important to also understand that there's a weak to moderate correlation at best between patient-reported outcomes of itch severity, like the NRS itch, with clinician-reported outcome measures, b ut it's particularly striking in atopic dermatitis because you have such weak correlations between the severity of itch and the lesional severity scores. Whether you're measuring by an Eczema Area and Severity Index, objective SCORAD, body surface area, or even validated vIGA scores, tools that we are using routinely in clinical trials are missing the severity of the itch. It's important to understand this because the itch and other symptoms are really following a different longitudinal course than the visible signs.
It also tells us that, as clinicians, when we're looking at the skin, we may be underestimating the severity of the disease if we're not routinely asking about itch, which is why there's been such a big push in the field that itch become almost like a vital sign in atopic dermatitis that we ask every patient at every encounter. Because I regularly encounter patients whose skin looks they have clear disease, but it looks pretty good otherwise. It doesn't look like the worst of the worst lesions, but they're absolutely miserable when it comes to their itch. Now, let's talk a little bit about this concept of itch-dominant atopic dermatitis, or high-itch atopic dermatitis.
This was a fairly simplistic approach at classifying or phenotyping patients clinically with atopic dermatitis, to say, if we divide patients by the severity of their itch versus the severity of their lesions, right? A priori, we came up with four different groups of patients. Those patients who've got mild to moderate itch and mild to moderate lesions, those who've got mild to moderate itch but severe lesions, right? Then those who may have severe itch but mild to moderate lesions, and of course, the most severe would be the severe itch with the severe lesions.
We looked at how commonly this occurred across our large registry cohort of patients. What was fascinating was, there are some slight differences depending on which lesional severity scores you are looking at, but really, very consistent pattern that between about 25%- 33% of patients with atopic dermatitis, now this is the adult population, but of adults with atopic dermatitis, had this severe itch, mild to moderate lesions. This is a common subset of patients. Okay, so it is common. Why should we care?
When we started to look at the burden of disease and their outcomes, what was fascinating was those patients with itch-dominant atopic dermatitis had more frequent flares, fewer periods of clearance or remission, a higher number of itch triggers, and more unpredictable course of their itch, more unstable longitudinal course, or more persistent really severe itch over time compared to those with mild itch and mild to moderate lesions. In fact, they actually looked much more similar to those who had severe itch and severe lesions than those who had mild itch and mild lesions. They had poorer quality of life. They rated their disease as being more severe overall. What became clear was that this was a missed population, right?
What was also interesting, these patients were less likely to be stepped up to advanced systemic or biologic therapies, indicating that this is still a relatively untapped patient population. I think that is true even today, where we have got so many of these patients still out there being undertreated right now, with a big opportunity in terms of therapeutic development. This high-itch subset really warrants specific therapy, and is really going to benefit from a clean biologic regardless of the lesional severity. There are no approved systemic therapies that are targeting this itch-dominant/high-itch atopic dermatitis. Why is that? Well, we have obviously got topicals that are approved for mild to moderate atopic dermatitis, and they have been shown to work on itch, but of course, it is a very different patient population when you are treating more targeted lesions.
Also, when you look at the value of the topicals on itch, they tend to be pretty slow when it comes to the itch, right? But patients certainly, when it comes to itch, want faster responses wherever possible. You know, as I always say, I have atopic dermatitis, so I am very sensitive to this issue. I've got one-pound jars of topical steroids floating all over my house. They are greasy and gross. They trash your clothing. They trash your linens. They are uncomfortable to put on a lot of the times. It is hard to be adherent with them. They sting, they burn, especially the non-steroidals that are out there, all sting and burn, right? Even the ones that are supposed to not sting and burn, sting and burn. This is a big issue that comes up.
Really, what patients need is something that is going to give them more robust control of the itch, more widespread control of the itch, because when they are putting on topicals, the topicals, they are usually treating an individual lesion. But here, if they have got full-body itch, the topicals are just not possible or practical to use there. We need something that is going to give them a better dosing regimen, that is going to give them more stable control of the itch, something that is going to be able to treat their itch even beyond the visible lesions, something that is going to be able to prevent flare-ups of itch, and something that is going to be able to address especially that more extensive nature of the itch.
I think for all those reasons, there is a really big opportunity in this patient population for a clean but highly effective biologic agent to be used here that is going to give you not only the rapid onset of effective itch, but give you that long-term management of itch for those patients, given that this is a chronic disease, and something that gives them really good control over their disease and over their itch. For that, you really need infrequent dosing. They do not want to have to even patients who technically like the idea of orals and market research studies, but that same patient, when they come back after a few months and they are still taking the same medication once a day, every day for six months, nine months, and they miss one dose and they start itching again, they are not happy, right?
They really do not want to think about their disease, and that really happens when you get good control with an infrequent dosing regimen, so they just do not have to pay attention to their disease as much. Of course, with a highly effective drug on itch, of course, you want the lesions to improve as well. IL-31, I think, is a ripe candidate for targeting in this high-itch or itch-dominant atopic dermatitis patient population. Why? Because we have seen for years now that serum IL-31 is elevated in atopic dermatitis. The more severe the disease, the higher the elevations of IL-31, b ut particularly, that IL-31 correlates very well with the intensity of itch. We know, of course, that it is pathomechanisms and how important it is in the pathomechanisms of itch in atopic dermatitis.
We' ve seen this, both correlation-wise as well as in vitro studies, et cetera, that IL-31 is a key cytokine for itch in atopic dermatitis. Even amongst those patients where there may even be not this great correlation with IL-31 with the lesions, but there is a stronger correlation between IL-31 and their itch. Nemolizumab is obviously an approved therapy targeting the receptor for IL-31, has been shown to reduce itch in atopic dermatitis, and has been, I think, effective overall in the field. I think particularly in this itch-dominant or high-itch atopic dermatitis patient population, I think still major opportunities there to even get better control of itch. I think IL-31 pathway really can be explored further in order to understand its role in this high-itch atopic dermatitis patient population.
To conclude, itch is the most burdensome symptom of atopic dermatitis, really at every severity level. Itch correlates only moderately or weakly with lesional severity scores. This itch-dominant or high-itch atopic dermatitis patient population affects between one in three to one in four patients across the adult AD patient population. This subset of patients has a lot of unmet needs and is right now really undertreated. Lesion-based thresholds, like the EASI of 16 used in clinical trials, can underestimate the burden of atopic dermatitis because it's really missing that symptom component from the itch. High itch with mild to moderate lesions in atopic dermatitis may benefit from biologics, and particularly, I think IL-31 inhibition may be a promising approach there. With that, thank you for your attention.
Thank you, Jonathan. Hubert, over to you.
Brian, Jonathan, thanks for that valuable background. As a clinician myself, I always find it insightful to hear from those in the front line seeing these patients. Before I jump into the results, I want to give a brief overview of our phase I study. The first two parts consisted of a SAD and MAD in healthy volunteers. This data has been previously presented. Today's focus is on the latter two parts, the phase I-B portion of the study in patients with AD and chronic pruritus. In both parts, patients were required to have high itch scores of at least seven out of 10 on the Peak Pruritus Numerical Rating Scale, or the PP-NRS. The chronic pruritus cohort required symptoms for at least six months, involvement of at least two body parts, and no identifiable cause.
In each patient population, we explored two dose levels, 4.5 mg and 9 mg/ kg. Our goals for the phase I-B study were to assess safety and immunogenicity, look for rapid introduction by week four after a single dose, establish evidence for clinical activity in two pruritic conditions, one with and one without skin lesions, and to identify active doses that we could bring forward into phase II. As such, each cohort consisted of 12- 14 patients each and used the same design. Patients were randomized 2:1 to a single subcutaneous dose of ATTO-1310 or placebo. The primary endpoints were safety, pharmacokinetics, and immunogenicity. Clinical activity was exploratory. Rescue medications were not permitted for the first four weeks. An interim analysis was conducted at week four before rescue therapy was allowed to assess the early activity of a single dose.
Follow-up was continued through week 12 with an optional week 16 visit. After week four, topical steroids and antihistamines were permitted as rescue therapy. Today's top-line data presentation focuses on week 12, where we now have a complete dataset. Here are the baseline characteristics for the chronic pruritus and AD cohorts. Patients with chronic pruritus were older than those with AD, with a mean age of about 60, consistent with the diagnosis of CPUO, which is a condition associated with aging. In fact, all the patients in the chronic pruritus cohort met diagnostic criteria for CPUO. Overall, the baseline itch scores were approximately 8.5 and balanced across all treatment groups. In AD, due to a small number randomized, we had an imbalance in skin severity at baseline, with the placebo tending to be a little more severe.
With the 12-week follow-up, we were pleased to see that the pharmacology in both chronic pruritus and AD patients continue to support the potential for quarterly dosing during maintenance. Here, we show serum concentrations of ATTO-1310 on the left and target engagement on the right. Drug concentrations remained above the in vitro IC90 through week 12 after a single subcutaneous dose, with 95% suppression of free IL-31 that also extends out to about 12 weeks. At the interim analysis, we only had preliminary biomarker data. The complete dataset now confirms what we previously saw, strengthening the pharmacologic rationale for quarterly maintenance dosing. In patients with chronic pruritus, we are excited to see that the itch reduction observed at week four extended out to week 12 and appeared to deepen after just a single subcutaneous dose.
This slide shows the proportion of PP-NRS responders in each dose cohort, with the new data beyond week four highlighted in orange. As a reminder, the PP-NRS identifies patients with an itch score that drops by at least four points from baseline, which is considered clinically meaningful and is the endpoint commonly used in anti-itch drugs for anti-itch drug trials. Given that these are small numbers, we believe the most reliable way to look at this data is to pool the two active doses together, which is shown on the right. As you can see, the responder rate continues to increase after week four. Despite the small sample size, we achieved statistical significance as early as week two, and the response continues to deepen through week 12. By week 12, 14 of 17 active treated patients, over 80%, were responders.
On a placebo-adjusted basis, the PP-NRS response rate is about 60 percentage points. This is versus 21 for dupilumab in part A of their phase III trial at the same time point. Impressively, we achieved this with one single dose, compared to dupilumab, where patients would have received seven injections by this time point. On this slide, we are showing the more stringent threshold of an absolute PP-NRS of less than two. Clinically, these patients are considered itch-free or nearly itch-free. At week 12, eight of 17 patients treated with ATTO-1310, or about 47%, reached a PP-NRS of less than two, compared to none on placebo, which is statistically significant. To put this into clinical context, these patients came into the study suffering from a severe itch for at least six months, with a PP-NRS of over eight.
With a single dose, nearly half of them have achieved itch-free or nearly itch-free status. This is exciting to see and gives us confidence that ATTO-1310 is highly active and will have a profound impact in patients with CPUO. As Brian highlighted earlier, these patients have a high unmet need and currently no approved therapies. Turning to high-itch AD, we are pleased to see that the itch response observed at week four was maintained through weeks 8 and 12. As you can see, responder rates in the active treatment group remained around 45%-50% out to week 12. Again, this is after a single dose, which is quite encouraging. We did, however, gain four additional placebo responders after week four. With only eight placebo patients in total, a few additional responders can have a large impact.
As a reminder, the study was designed to focus on itch reduction at week four, before rescue medications were permitted. After week four, three of eight placebo patients used rescue therapy, compared to none of the 18 patients that received ATTO-1310. I would note that in our phase II studies, patients requiring rescue therapy will be counted as non-responders. Separately, we also noted that half of the placebo responders, three out of six, came from a single site. While we can't attribute the elevated placebo response to any single factor, these observations provide important context when interpreting the data with such a small placebo cohort. Importantly, when we look at the more stringent itch and skin lesion endpoints in the following slides, you'll see that this placebo effect is significantly reduced, and the clinical activity of ATTO-1310 can clearly be seen.
Here, we're now looking at the more stringent PP-NRS less than two endpoint, which, as a reminder, represents patients who are essentially itch-free or nearly itch-free. This is a much higher bar than achieving a 4-point reduction from baseline. What's particularly encouraging here is that we see a clear separation between ATTO-1310 and placebo. At week eight, six patients treated with ATTO-1310 achieved this threshold, compared to none with placebo. At week 12, five patients continued to meet this threshold, compared to just one placebo patient. We think this is important, and it shows that patients who got placebo didn't achieve the same deep itch reduction as those that got ATTO-1310. We were also excited to see substantial improvements in skin lesions, as measured by physician-assessed EASI score.
As you can see, we observed approximately 50% or greater reductions from baseline by week four, which were generally maintained through week 12, and continued to see separation from placebo. We see a similar picture with the EASI 75 on the right, with evidence of deeper response at the higher dose. Notably, placebo response remains low. I think it's remarkable that we saw these sustained improvements, not just in itch, but in underlying skin lesions with just a single dose. Here, we pulled the two active doses, looking at reduction in skin lesions. We see impressive reductions across multiple EASI thresholds. By week 12, 44% of treated patients achieved the EASI 75, 22% achieved the EASI 90, and 17% achieved EASI 100. We also saw 39% achieve clear or almost clear based on the vIGA.
What's particularly reassuring is the consistency of response across these endpoints, with relatively little placebo response. Just to remind everyone, the EASI and IGA are the primary endpoints commonly used in AD trials. When we take a step back and look at the totality of the data, we saw sustained itch relief with patients achieving itch deep responses, substantial improvements in skin lesions, all persisting through week 12 after a single dose. We believe that the combination of depth and durability is particularly impressive across the higher bar itch and physician-assessed skin lesion endpoints. This gives us high confidence in ATTO-1310's clinical efficacy in AD, and when we move to a much larger phase II study, we will see a robust treatment effect. Before moving on, I wanted to briefly highlight one particular case that exemplifies the type of patient who may respond particularly well to ATTO-1310.
This is a 49-year-old female in the 4.5 mg/ kg AD cohort. She had severe itching with a baseline itch of 9.9, but moderate lesions with an EASI score around 11. This is the itch-dominant AD phenotype that Jonathan talked about. She previously failed dupilumab and didn't respond up to two additional experimental treatments. According to the PI, she had been miserable for years. As quoted here, she felt relief within hours after receiving a single dose of ATTO-1310, and she's remained itch-free with clear skin for almost five months. Notably, statements were made by the site prior to unblinding, so they were unaware of her treatment assignment. While this is just one example, it illustrates the profound impact that's possible with ATTO-1310 in patients with high-itch AD. Finally, we assessed whether the safety findings from the first four weeks remained consistent through the rest of the study.
As you can see here, over the remaining 12 weeks, we observed very few events. Overall, ATTO-1310 was generally well tolerated in both patient cohorts. There was only one serious event, a worsening of preexisting hiatal hernia that was deemed unrelated to study drug, and there were no AEs leading to study discontinuation. As you may know, an increase in dermatitis AEs was observed in the nemolizumab trials. Notably, we did not see any of this in any of the patients treated with ATTO-1310. Turning to immunogenicity, we continue to observe low rates of anti-drug antibodies in the phase I-B study, similar to what we observed in the healthy volunteers. Across the entire phase I study, we observed six of 77 participants with treatment-induced ADAs at any time point, representing 7.8%. Importantly, we didn't see any impact on PK, target engagement, tolerability, or efficacy in any of these participants.
Before concluding our phase I results, I want to highlight an important biomarker observation. As you know, TARC, or CCL17, is often used as a pharmacodynamic biomarker in AD. It's known that nemolizumab, which targets the IL-31 receptor, raises TARC levels in AD patients. Shown on the left are data from nemolizumab's original phase III study conducted in Japan, and as you can see, there was about a threefold spike in TARC at about week eight. In contrast, on the right are biomarker data from our phase I-B study. Not only did we not see an increase in TARC, but we observed about a 50% decrease at week eight. While these data are preliminary, they provide evidence that there may be important biological differences between targeting IL-31 ligand versus targeting its receptor.
In summary, our week 12 data extend the findings that we saw at week four, which gives us even greater confidence going into phase II. Not only do we see strong target engagement that persists out to week 12, but we now have data showing that the pharmacology translated to clinical improvement that supports quarterly maintenance dosing.
In fact, we continue to see improvement on itch and lesions out to week 12 after a single subcutaneous dose in two different conditions. That is quite phenomenal. Finally, it is reassuring to see that our safety and immunogenicity profile remains favorable with the longer-term follow-up as we head into phase II. We are now translating these findings into two global phase II studies, one in CPUO and one in high-itch AD, now called the ATTUNE studies, and we are moving quickly toward FPI, with both expected to begin in the first half of 2027.
We also see an opportunity to expand beyond dermatology into other systemic causes of itch and have initiated a phase I-B study in cholestatic pruritus, another condition where the biologic rationale for targeting IL-31 is particularly strong. From there, we believe that there is also rationale to pursue other systemic conditions, such as CKD-associated pruritus. Shown here is the design of the ATTUNE-CPUO trial.
We plan to enroll approximately 300 patients, which would make it the largest trial to date in CPUO. We will be studying two active doses in an induction plus a maintenance phase to test quarterly dosing. The ATTUNE-AD study has a similar design and will enroll patients with AD and itch scores of at least seven. The study has two parts. Part A will allow us to get an early readout while still allowing us to pool the results for the induction phase for part A and B.
Notably, we will have 255 patients across both parts. We have designed the study to help mitigate placebo response, where, one, we will have substantially larger treatment groups designed to minimize the impact of any specific site or geographic region. Two, rescue medications will be tightly controlled and adjusted in the analysis with non-responder imputation. Three, we will be giving additional doses and therefore expect to see deepening in response. This, in addition to careful site selection, investigator and patient training on placebo effect, and central monitoring of diary data and photography. For ATTUNE-CPUO, we plan to activate 78 sites across North America and the EU. We have aligned with the FDA on key elements of study design, and study activation is underway. For ATTUNE-AD, we are planning about 60 sites across North America, the EU, and Asia. The protocol is now finalized, and site selection has already begun.
For both these studies, we are on track to dose the first patients in the first half of 2027.
Thank you, Hubert. Before we open for questions, I want to step back and share what these results mean for ATTO-1310. Simply put, the phase I-B study exceeded our expectations. With the full 12-week data, we now see emerging evidence to support our differentiated product profile. First, efficacy. In CPUO, after one single injection, more than 80% of patients on ATTO-1310 achieved a clinically meaningful 4-point itch reduction at week 12. That is statistically significant placebo-adjusted difference of about 60% with just one single injection. For context, and recognizing the limitation of cross-trial comparisons, dupilumab showed about a 21 percentage point placebo-adjusted differences at week 12 in part A of its phase III CPUO trial after seven injections. Impressively, nearly half of our CPUO patients reached itch-free status at week 12, compared with none with placebo.
In high-itch AD, deep itch relief was sustained through week 12, with about a third of treated patients reached itch-free status at week eight, compared with none on placebo. We also saw robust skin lesion improvement with placebo-adjusted response rates at week 12 of about 32% for EASI-75, about 27% for vIGA clear or almost clear. Again, this was after one single dose. Second, durability. Efficacy was sustained, and by some measures, deepened through week 12 for both itch and skin lesions. Third, dosing. Full target engagement and drug exposure through week 12 after a single dose, combined with the durable clinical activity observed, give us high confidence in a quarterly dosing regimen. Fourth, safety and immunogenicity. The safety profile was benign through the full follow-up. Immunogenicity remained low, and notably, no patient on ATTO-1310 had a dermatitis adverse event, which could represent an important point of differentiation.
Finally, our exploratory biomarker data in high-itch AD showed that, unlike nemolizumab, TARC did not increase with ATTO-1310. While early, these data support our view that targeting the IL-31 ligand rather than its receptor is biologically differentiated. Taken together, these data give us high confidence that ATTO-1310 has a differentiated profile versus nemolizumab, with the potential to enable rapid, deep, and durable itch and skin lesion improvements, convenient quarterly dosing, and a differentiated safety profile. Nemolizumab has done a great job validating the importance of the IL-31 pathway and is expected to exceed $1 billion in sales this year. We believe ATTO-1310 has the potential to be the next-generation IL-31 medicine that can transform the lives of millions of patients who suffer from chronic itch conditions. Our priority now is execution.
Both ATTUNE-CPUO and ATTUNE-AD studies are on track to dose first patients in the first half of 2027, with expected readout in 2028. We also expect cholestatic pruritus phase I-B data in the second half of 2027. Beyond ATTO-1310, we expect ATTO-2306, our IL-13/IL-31 bispecific, and ATTO-1091, our IBD trispecific, to enter the clinic in the first half of 2027. Cash runway fully funds all three assets through the clinical proof of concept and our operating plan into 2030. With that, operator, let's open the line for questions.
Thank you, Tao, and to all of our speakers. At this time, we will be conducting a live Q&A session. To our covering analysts, please use the raise hand feature to be added to the queue. Kindly hold for a brief moment while we pull for questions. Our first question comes from Nat Charoensook with Leerink. Please go ahead, Nat.
Hi, this is Nat Charoensook on for Tom Smith. Congrats on the data. We have a couple of questions. First is for Dr. Silverberg. Knowing that this is a small trial, do you expect to see this high placebo response in PP-NRS4 in the high-itch AD population, and how closely did IL-31 suppression correlate with itch improvement? We have a quick follow-up.
Sure. Thank you for the question. My expectation would be that not only would we see as good of a result, but we would likely see an even better result, given the loading dose regimen, the more frequent dosing, right? Keeping in mind that all of this was achieved with just a single dose, and for some endpoints, and granted, it is not a head-to-head study, so take what I am about to say with some caution, right? But for some endpoints, it looks like this may even be more effective than nemolizumab at a single dose. I think with repeat dosing, with loading dosing built in, and then just larger sample size, you get more robust confidence intervals. My expectation is we are actually going to see a better efficacy.
Got it. That makes sense. For the company, how do the results look so far at week 16, and when do you expect to share the data?
Well, week 16 is actually an optional visit, so we have incomplete data. So, what we are sharing today is the complete data set for this phase I-B trial. But we are not going to be sharing week 16 data because it is incomplete.
All right. Thank you.
Thank you, Nat. Our next question comes from Parth Patel with Morgan Stanley. Please go ahead, Parth.
Hi, guys. Thanks for taking our question. This is Parth on for Mike. I guess just for the KOLs, how do you guys think about using an IL-31 targeted therapy in both high-itch AD and CPUO, like in combination with other systemic agents? Is that a possibility? And then I guess just in your practices, how many patients do you see with these conditions?
This is Brian Kim. Maybe I'll go first since Jonathan already spoke. I exclusively have treated patients with chronic itch for many years, well over a decade now. Many people thought I was going to ruin my career doing that, but it actually being one of the richest areas in dermatology, because if you think about that includes chronic pruritus of unknown origin, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, brachioradial pruritus, the list goes on and on. It's actually one of the biggest areas of dermatology. Chronic pruritus of unknown origin is almost everything I see in the clinic now. Why is that? Because of the successes towards therapeutics for atopic dermatitis, prurigo nodularis, and all that. Why is everyone so interested in atopic dermatitis? It's just a big market. It's a huge market. It's not an unmet need from the standpoint of that there's nothing there, like CPUO.
It's still an unmet need, but not in the way that you think of conventionally. It's just a gigantic market. Yes, combinations are welcome. Multimodal therapies through different mechanisms of action, welcome in the clinic. We can always use more. There's inflammatory ways to treat itch. There's neurologic ways to treat itch. That's why IL-31 is really unique. It sits right on that axis between the immune and nervous systems, and that's why it has such a different profile from any of the other therapeutics you see out there.
I would agree completely with Brian's eloquent answer. I would just add one point, which is when you're thinking about multimodal therapy, we're comfortable conceptually with the idea and looking forward to the idea of combining clean options. I think if the question is, would I want to combine a JAK inhibitor or something like that with this drug or with this mechanism? The answer is no. We really want clean mechanisms if we're thinking of looking forward to that multi-specific realm. On the flip side, if the efficacy looks so good that it really breaks the efficacy ceiling, whether it's in the overall treated population or in specific subsets, we are certainly open to using a single target and reducing exposure to additional targets.
Thank you for your questions, Parth. Our next question comes from [Annalisa Ferrando] with RBC. Please go ahead, Annalisa.
Hi. Thank you for taking the question. Annalisa on for Brian Abrahams. We were just wondering on the use of rescue meds, if we could get a little bit more color if those placebo participants using the rescue meds were those that ultimately were the responders in the AD, and then if you had any comments on the rates of rescue in the CPUO population.
Yeah. As we indicated in the call, there are three placebo patients used TCS and/or antihistamine rescue after week four, versus none on ATTO-1310, and we believe that contributed to the placebo response. As Hubert mentioned, we would not attribute the placebo response solely to the rescue use. I think the placebo cohort is very, very small, only four per dose. Even one or two patients could swing the result. I would just point out to our analysis in terms of when you look at the lot more stringent itch response, the PP-NRS less than two analysis, when you raise the bar, basically the placebo response went away. At week eight, we have six active responders and none versus placebo, and at week 12, it is five versus one.
It is very similar story when you look at the physician-assessed skin lesion improvements, whether it is EASI-75, EASI-90, EASI-100, vIGA zero to one, we have pretty impressive skin lesion improvement with little to no placebo response. That really gave us a lot of confidence that we have very good anti-itch efficacy. As Dr. Jonathan Silverberg mentioned, when we get into a much larger phase II trial, when the sample size is much larger, the sites are diversified, and we are also having the benefit of induction phase, giving multiple doses, we only expect the effect to become better. On the CP cohort, very similarly, rescue use actually is quite low in the CP cohort, and there is no impact on the clinical activities.
Great. Thank you.
Thank you, Annalisa. Our next question comes from Sam Slutsky with LifeSci Capital. Please go ahead, Sam.
Hey. Thanks for taking the questions, and I appreciate the presentation. Couple for me. I guess first for Dr. Kim, I just want to confirm, by binding the ligand, is the expectation that you won't get the rash seen with nemolizumab with Attovia's asset? And then similarly, I guess by binding the ligand, just rationale biologically for quicker or deeper response versus going after receptor? My last question more broadly for both physicians, but my understanding is that for CPUO and high-itch kind of mild to moderate AD, it's possible to use kind of off-label nemo or dupi at times. Just trying to understand the clinical relevance of officially getting a label for those indications and subsets and what that can mean for uptake. Thanks.
Yeah. Thanks for your question. I think the first thing you're asking is a little bit about the biology. Do I think targeting the ligand is superior? I think it is. That's why I actually wrote an editorial, and that was the figure that I was talking about. The thing that concerned me was the aggravation of dermatitis that was being chalked up as aggravation of atopic dermatitis in the trials. I actually don't think it is. I think it's a different dermatitis. It's distinct, and I think a lot of providers are echoing that now that they're seeing it in the real world. It's amazing what you learn in the real world that you don't see in phase III, by the way.
The other thing is that, yes, I think the other thing is I think you are actually causing a little bit of another pro-inflammatory pathway to emerge. Fortunately, it's not rampant. Nemo is a great drug. It's not rampant. Are these drugs used off-label? Yes, of course. Dupilumab, nemolizumab, I've done it a lot. These patients are desperate. I think what they need, though, is- Frankly, I think a lot of these agents are being used off-label, and it's contributing to the uptick in the sales that you see, b ut that's not going to move the needle. You need the label. You absolutely need the label. We see this all the time. Once you get the label, it's then everyone out there is treating these patients. I saw this in the early days with a number of different conditions.
I mean, you actually see this even with chronic spontaneous urticaria, when they said, "Oh, what are you going to do with the BTK? Isn't that just another IgE pathway?" Well, look at what Novartis is saying about remibrutinib right now, right? It's very similar to IgE, slightly different properties. It's bringing people out of the woodwork, though. I do not know if I answered all your questions, but hopefully that addressed your questions, what you were getting at.
Yeah, I think just the one, so by going after ligand, the rash related to nemo, possible to avoid that, right?
I think so. Yeah.
Yeah.
Yeah. I am not going to bet everything on it, because you just never know, right? But I think so far, the predictions that By the way, there was a lot of pushback when I made these biological predictions. It was not like people were saying, "Wow, this is definitely the case." There was a lot of pushback. Lofty scientist, academician, but it looks like we were kind of right.
It is true, probably. Thanks.
Thank you, Sam. Our next question, and our final question, comes from Yigal Nochomovitz with Citi. Please go ahead, Yigal.
Hi, this is Joohwan Kim on for Yigal. Thanks for taking our questions. Maybe one for the company and one for the KOL. I thought it was really interesting to see the level of responses, and it looked a little bit like IHC may have been a bit stronger in chronic pruritus versus in high-itch AD, and completely recognizing that it was small cohorts and whatnot, b ut just wondering if you could provide a little bit more color about why that might have been the case, particularly at the later time points.
Yeah, I'm happy to weigh in here. First of all, let us just take a step back. When people are talking about placebo-adjusted kind of amplitude on a phase I, that's really good news, right? I mean, that is always a good sign. What it means is people are squinting towards phase II outcomes in a phase I. I always try to level set. That is a good thing, right? That is not a bad thing, b ut AD is I actually thought the result was going to be slightly opposite. I actually thought CPUO, because if you look at the DUPIXENT trials, what is haunting us with those is the placebo response as you go further out.
I think what happened here is that the advantage in CPUO was that the advantage was what I think you would have perceived as a disadvantage initially, that it was a single dose, and we were looking fairly early. You are getting a very clean signal early on, and you are getting that good differentiation because you have a good asset.
Atopic dermatitis is also a fairly tricky disease because there are a lot of environmental triggers. I do not think people appreciate how heterogeneous atopic dermatitis is. In the early days, people were saying, "Oh, Brian, you are never going to find a treatment for this. It is way too heterogeneous." Now people say, "Oh, it is a homogeneous disease. Why are not you seeing complete separation every time?" Well, it is not. We know that. We know we have itch flares. You heard Jonathan Silverberg talk about high-itch AD.
There is different kinds of AD. I think really, the short answer is the fact that we are talking about phase I data like it is phase II, to me, means that a lot of this is going to look only better in phase II. That is me echoing what Jonathan said earlier.
Got you. Very helpful. Maybe just one for either of the KOLs. I am wondering, in your practice, can you comment how different achieving PP-NRS below two is from achieving a 4-point improvement, just in terms of sleep functioning and other need for medications, and whether the difference is prominent between the two different indications?
Yeah, it is a great question. The answer is there is a very stark difference. Patients who get to that, what we might call either itch-free or little or no itch state, have dramatically improved outcomes compared to those who only have a 4-point response in itch. I mean, just think about it logically. A patient starts with an NRS itch of 10, and you take them down to a six. That is a meaningful improvement, but they still have a six out of 10 itch, and they are still very uncomfortable. It is very clear, and now becoming part of a number of international guidelines and consensus position statements to really set the bar going forward to really be to try to get patients to that little or no itch state.
Because that really comes with this major improvement in terms of sleep improvements, quality of life, associated skin pain, and work performance, just the list goes on and on of improved outcomes. I think that's, from a clinical perspective, a very important endpoint. I think it's also just from a trial readout endpoint, there's a certain nicety of looking at the more robust endpoints because it really helps to sort of sift through some of the placebo responses. When patients get placebo responses, they often get 10%- 20% placebo response, modest responses. They typically don't get to that point where they're getting to itch-free. That really allows you to sort of sift through the noise. I think it becomes an important endpoint in trials as well.
Yeah, I want to underscore what Jonathan just said there. Actually, as you get with really strong assets, as you get more rigorous in the itch endpoint, which people are afraid to get more rigorous because they're worried they can't meet it, but if you do, you do clean up that placebo really nicely.
All right. Thank you very much.
Thank you, and thank you to all of our analysts for participating in today's Q&A session. I will now turn it back over to Tao to close out the call.
Thank you, and this really concludes our Q&A. I'd just like to thank Dr. Kim and Dr. Silverberg for sharing your perspectives today. Most importantly, thank you to the patients, their families, and the investigators who took part in our phase I study. Chronic itch is a major but underappreciated disease burden, and these patients need better options. We are excited about the compelling data we have seen with ATTO-1310, and we are committed to advancing it with both speed and rigor. Thank you all for joining us today.