ACRIVON THERAPEUTICS CORPORATE R&D AND KOL EVENT - ACRIVON THERAPEUTICS INC

Good afternoon, everyone, and welcome to today's webcast. My name is Adam Levy, and I'm Chief Financial Officer and Head of Investor Relations at Acrovan Therapeutics. This afternoon, we are excited to host a key opinion leader panel to discuss our recently announced acquisition of two INI assets, ACR525, formerly known as AQ280, an oral JAK1 inhibitor, and a PKC theta inhibitor preclinical program. As a reminder and point of context, this acquisition represents Acrobon doing exactly what we said we would do. Specifically, INI has long been part of our strategic narrative because of the suitability of our AI-driven AP3 platform in this space, and this deal reflects the execution on this strategy with what we believe is a highly differentiated oral JAK1 inhibitor. Next slide. I'd like to remind you that certain statements made during this call, including those made by participants in the KOL panel, may constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 21E of the Securities Exchange Act of 1934, as amended. Next slide, please. Here is our agenda for today. Peter will provide an introduction and together with Mansoor provide an overview of the I&I assets we have acquired. We will then have brief presentations led by our esteemed KOLs who I will introduce shortly. These presentations will cover EOE unmet need as well as current standard of care. Following the discussion, we will have a brief Q&A session. Please submit questions on the text panel you see on your screen. On the next slide, you see our esteemed KOLs, both thought leaders in eosinophilic esophagitis. Arjen Bredenoord. Dr. Bredenenoord is a professor of gastroenterology and hepatology at Amsterdam University Medical Center. He's the former president of the European Society of Xenophilic Esophagitis, URIOS, a member of the UEG Scientific Committee. Evan Dellen. Dr. Dellen is a professor, Department of Medicine, Division of Gastroenterology and Hepatology, and Director, Center for Esophageal Diseases and Swallowing at the School of Medicine University of North Carolina at Chapel Hill. Joining the call today from Ackermann will be our Chief Executive Officer, President and Co-Founder, Peter Blum Jensen, who is the inventor of the AP3 platform, as well as our Chief Medical Officer, Mansoor Razamursa, who has led numerous guideline-changing studies. We also have Eric Gamelin, our Chief Development Officer, on the call. He has a distinguished career and accomplishments both in oncology and INI, including prestigious appointments by the French Ministry of Health. With that, I'll now turn the call over to Peter. Thank you so much, Adam, and thank you to everyone calling in for this corporate webcast today with our expert key opinion leaders. We are super excited to share with you all today how we used our generative AI-driven AP3 platform to identify what we believe is a very differentiated, highly selective oral phase two ready JAK inhibitor, as well as a selective preclinical PKC theta inhibitor. Next slide, please. For those of you who are new to Acrobon, we have a pioneering platform called Acroboron Predictive Precision Proteomics, or AP3 in short, which we leverage for all our precision medicine discovery and development. The platform was specifically designed to enable streamlined development to phase two clinical POC without relying on genetic alterations or any clinical information. What you see in the middle is that the concept is based on the central dogma that But instead of relying on genetic alterations and inferring from them, or for that matter, transcriptomic alterations, and infer from them how a drug might act in a diseased cell, we directly have developed tools with our generative AI to measure how a drop regulates the intracellular signaling pathways at a global level. So everything we do is drug-centric and directly enable us to match the mechanism of action with any drug of any modality, regardless disease type, with the disease-driving pathways. ACRON actually means exact or accurate to symbolize that exact or aggregate match with the drug MOA. And we have a number of proprietary tools that we've developed and keep developing and expanding in that context. Next slide, please. So here's an overview of our generative AI phosphoproteomics platform. Notably, in contrast to most AI-driven and AI-based life sciences companies, our generitive learning is applied primarily to a massive amount on the left side of proprietary in-house generated data. As such, we have profiled dozens and dozens of compounds, whether it's leads or hits or approved compounds, and we have all this existing in the cloud in an AP3 interactome accessible to all scientists at Akron. We have generated a data portal, an AP3 data portal that converts all multimodal data from the left side, whether it's MS data or biological data or structured data into AI enabled or amenable data for our proprietary AI tools. They're shown in the blue periphery or ring in the middle of this figure, and you can see that it enables network mapping, pathway mapping. We have various tools that also are specifically developed to understand at high resolution how a drug activates or inhibits signaling pathways inside a cell. This is what enables us on the right side to do patient responder prediction, do indication finding, identify rational drug combinations, et cetera, before we enter the clinic. Today, as you can see highlighted in bold, we have used our platform to prioritize an asset that is a highly selective JAK1 inhibitor. And we have also mapped all the global PD effects of that drug and identified both a sensitive indication as well as rational drug combinations for this asset. Next slide. Here we'll hand it over to our chief medical officer, Mansoor Mirza. Mansoор, please. Thank you. Thank you, Peter. While here you see our updated pipeline now incorporating our INI franchise, we remain on track. for our pre-specified interim analysis of ACR36A trial, and we'll not discuss that further today. We recently updated on the exciting activity of our first-in-class V1 PK-MET inhibitor, ACR2316, in AP3 predictive tumor types, including endometrial and lung cancer. I am very excited about the ongoing clinical benefit now over 65 weeks in heavily pre-treated lung cancer patients as well as a confirmed cr in squamous lung cancer i encourage you all to join the late breaking oral plenary presentation on acr 2316 by dr tim yap at the upcoming triple meeting in barcelona We also recently updated on our potentially first-in-class CDK11 inhibitor development candidate ACR7280, which has shown complete regression in preclinical AML in vivo models, also on an AP3-predicted sensitive tumor type. But today, our focus will be entirely on our new INI programs identified using our AI-driven AP3 platform as highly differentiated based on head-to-head profiling against approved JAK inhibitors and dipolemab. Next slide, please. So, as Peter mentioned, it is our AI-driven AP3 platform that enabled us to identify this exciting asset. You will see on the next slides how we profiled it extensively head-to-head against other approved JAK inhibitors and dupilumab and found it to have highly differentiated, attractive features and desirable global pathway effects. It shows a highly JAK1 selective profile and orally available. Very importantly, it has desirable suppression of non-SMART TGF beta signaling. Many inflammatory disorders also led to fibrosis. So obviously, this could be potentially of additional benefit. Moreover, in contrast to a couple of other JAK inhibitors, we do not see any obvious activation of pro-apoptotic BAT signaling, which could be a potential safety advantage and which has been linked to rhabdomyolysis for some JAK-inhibitors. Finally, we noticed, based on our AP3 profiling, broader anti-inflammatory effects beyond IL-4 and IL-13 signaling pathways, which are inhibited by dupilumab. Phase 1 data were very encouraging. We saw dose-dependent PD effects in preclinical models, as well as a dose-dependent reduction of the inflammation marker CXCL10 and dose proportional predictable PK in phase 1 supporting one's daily oral dosing. Consistent with high selectivity of ACR 5 to 5, initial phase 1 safety was very favorable. Based on these data, ACR5 to 5 is now phase 2 ready and our initial target indication is eosinophilic esophagitis. We, of course, also see a broader INI opportunity, both as a single agent as well as in combination, given the high JAK1 selectivity and oral availability. Based on AP3, we see opportunity to combine with other agents, like our acquired preclinical selective PKC theta inhibitor, as well as IL-23 inhibitors and TNF antagonists. Importantly, the asset is wholly owned with no milestone or royalty obligations, and there is extension opportunity beyond the composition of matter expiration of 2038. Peter. Peter, would you take next slide, please? Thank you so much, Mansoor. Next slide, please. Yeah, so as we mentioned, it is really the AI-driven AP3 platform that uniquely enabled us to identify this as a very attractive JAK1 selective inhibitor. And what we did here is outlined here, we profiled this acid, hetriate against approved JAK inhibitors mentioned here, as well as dupilumab, the IL-4, IL-13 directed antibody. And based on that, we were able to, in different disease-relevant cellular models, both interferon-alpha stimulated and Th2 polarized cells using IL-4 and T-cell receptor activation, we were able to uncover the drug-regulated pathway mechanisms using our mass spec-based AP3 phosphoproteomic profiling. And on the right-hand side, you can just see an example of what you can see with this unbiased approach. We saw a very, very dramatic reduction of a lot of the key or core cytokine-regulated pathways including primarily as you can see the size of the dot here implies the magnitude of the effect blue is down regulation not of levels but of activity and red is up regulation you can see the most dramatic down regulation was actually identified for the very important pathways driven by il4 and il13 and we also could directly out of our over 100 000 quantified map phosphorylation sites, we can go in and directly pull out the down regulation of, for example, phosphostat 6, a key readout of these pathways. And you can see the dose-dependent reduction of that compared to IL-4-stimulated control cells. So our pathway mapping showed a differentiation against other inhibitors and, very importantly, also high selectivity against JAK2, JAK3, as well as TIK2, which could suggest potential for improved efficacy and safety over other JAK inhibitors. Next slide, please. Here's an example of some of the data and what we can do. We uncovered here, shown on the left side in the pathway map, again, this is a measure of activity states of signaling pathways using our in-house developed proprietary Kaiser method presented at the recent AACR meeting, where we are seeing a very dramatic reduction of non-SMAD TGF-beta signaling pathways, as Mansoor mentioned. We think this could be a potentially desirable antifibrotic mechanism. And in the middle, you're seeing the pathways from and crosstalk with JAK1 and TGf-bета receptor 1 signaling in particular and phosphorylation of STAT3. And in the bottom, you can see a very, very significant downregulation of the phosphostat 3. We will run it in many quadruplicates, these samples. And you can also see dupilumab has a similar effect on STAT4, but we don't see the same dramatic effect on the non-SMAT TGF beta signaling pathways, while other JAK inhibitors do not show that potentially beneficial effect. Next slide. We also, very importantly, are able to reconstitute our proprietary drug-regulated data against publicly available data. And in doing so, we can reconstitute or map the drug-related signaling pathways, potentially also leading to liabilities or adverse event. On the left side, you see an annotation top left of various types of biological functional classes of mechanisms, and you see here as an example, brecocitinib and ETR525 highlighted beneath from the rectangle shown in stippled up from the global view of all the drug-regulated sites. And what you notice, based on the legends in the bottom, that we see a rather dramatic effect on apoptosis pathways and on MAP kinase pathways indicated with the black and purple arrows, respectively. And in the middle, you can see, again, we pull out directly from the global high-resolution phosphoproteomic data. we can directly look at the phosphorylation of, in this case, an inhibitory phosphorylation site of BAD called serine-134. And as you see here, ACR525 does not inhibit that site significantly, while a couple of the other acids do inhibit that side very, very dramatically. And we do think this could be potentially releasing a probad apoptotic activity. So we think that this ability to map these pathways gives us an opportunity to really assess potential safety liabilities prior to entry into a clinical trial. And we are happy to see that we don't see this potential linkage to the few cases of rhabdomyolysis that have been mentioned in the past. Next slide. Here we also see, based on biochemical as well as cell-based IC50 assays, the very, very high degree of selectivity of this particular oral inhibitor versus other approved JAK inhibitors shown on the left column. And you can see these numbers represent the potency ratio of inhibition of JAK1 over JAK2 biochemically in the middle column and cellular to the right. And you Can see that it's seemingly is the absolute most selective inhibitor of those we have tested for JAK 1 versus JAK 2, which we actually really are excited about. And the readouts are based on, for JAK1, interferon alpha signaling through phosphostat 1. And in the case of JAK2, we used GM-CSF-stimulated PBMCs and looked at phosphostat 5 readout. Next slide. I will just say that a number of preclinical studies have been done, including various allergic inflammation in vivo mouse models, as well as various ex vivo whole blood models. And also we have the initial phase one data. Mansoor, will you briefly cover this data, please? Thank you, Peter. So on the left, you see a few of the preclinical studies. ACR 5 to 5 has been shown to dose-dependently reduce the disease, relevant biomarker, phosphostat-3 in an ovalbumin-induced allergic inflammation mouse model, as well as the EOE Th2 inflammation markers, SPARC and eotoxin, in ex vivo stimulated whole blood from human donors. I'm particularly excited about the initial clinical data. On the right, you see the dose-dependent deduction of the inflammation marker CXEL10 and the dose-proportional well-behaved PK from the phase 1 in healthy volunteers. In summary, PD biomarker changes are consistent with JAK1 selective inhibition. There was a limited effect on reticulocytes consistent with minimal JAK2 inhibition. As mentioned, the PK was dose proportional and predictable with a T half life of 12 hours. So far, the initial data suggests ACR 5 to 5 to be safe and tolerable with no serious adverse event. Can I give you back, Peter? Thank you so much, Mansoor. Next slide, please. And just a brief introduction beforehand and the microphone over to Dr. Ardian Bredenor. Our pathway profiling has shown, as I showed you earlier, very dramatic reduction of IL-4, IL-13 signaling as well as potential beneficial effects on TGF-beta signaling, and as you can see here, these are central players in eosinophilic esophagitis, but I'll let the expert Arjan Bredenor expand on this from here on, please. Arjan? Thank you so much, Peter. So, the pathophysiology of EOE is complex with food activating multiple inflammatory cells and cytokines that are then all involved in the disease cascade. Typical features of EOE are epithelial mucosal integrity impairment and type 2 inflammation. A key role here is reserved for alarmants such as TSLP and cytokines IL-4, IL-5, IL-13, and then these activate subsequently more immune cells and via THF-beta activate fibroblasts, eventually resulting in fibrosis, more epithelial barrier dysfunction, and more inflammation. So these cytokines and alarmants, they signal via the JAK-STAT pathway. Also, there are several critical SNPs within the Jak-STAt signaling pathway affected in EOE patients found in genetic studies. JAK inhibitors are also effective for atopic dermatitis, in which the pathophysiology has many resemblance to that of EOE, and there are case reports showing efficacy of JAK-inhibition in EOEs. Next slide, please. So, EOe is an attractive first indication for ACR525, downstream signaling of alarm in CSOP, cytokines IL-4, IL-13, IL5, and as listed, IL9, 15, oncostatin, and they're all mediated through the JAK-STAT pathway, and thus, they can be inhibited through a JAK inhibitor. And while dupilumab only inhibits IL-4 and IL-13, and tezopilimab inhibits TUSP alone, with the JAK inhibitor, you can inhibit the inflammation in EOE much broader. Next, please. Yes. So, in an EOE model with an air-liquid interface that resembles human esophageal epithelium, we were able to show that IL-13-induced esophagial epithelia resistance disruptions and permeability increase were reversed with ACR525 to a similar degree as with dupilimab. And this data has been presented this year at the annual meeting of the American Gastroenterology Association. On the right, you can see that oncostatin M-induced epithelial resistance disruptions and permeability increases, similar to IL-13. And these were also reversed with ACR525, but not with dupilumab, demonstrating the broader inhibition that was obtained with ACRI525. So, there's a huge increase in EOE over the past 25 years, and you can see in multiple studies from basically all the countries in which these studies were performed in North America, in Europe, and Australia, that there is a very significant increase in the EOEs. on the next slide, this is highlighted further. So the annual incidence in the US is now estimated to be 120,000 patients with the current prevalence of over 500,000. And just some more figures here that the prevalence in 2009 was 28 per 100,000, but then in 2022, it was already 163. So that meant a total increase over 30 years of almost 500%, an average annual growth of more than 14%. So, these are really impressive numbers. There's a huge increase in incidence of EOE that we are currently seeing. Next slide. EOe leads to esophageal obstruction, and that basically cause an inability to pass solid food in patients eventually. This leads to a profound loss in health-related quality of life. EOE is a chronic disease and will lead to fibrostenosis eventually, as you can see in the figure on the right. It requires long-term treatment for symptom control, but also for prevention of esophageal scarring. Next slide. And so with this, I'd like to hand over to my colleague, Dr. Evan Dallin, who's presenting from Chapel Hill. All right. Hi, everyone. Thanks for the opportunity to speak. And with that background on EOE, I want to take you through what the current treatment algorithm is based on the most recent guidelines from the American College of Gastroenterology. So after an EOE diagnosis is established, there's this concept that you want to treat inflammation and assess for fibrostenosis, essentially esophageal scarring, stricturing, and narrowing in all patients. And all patients should have an anti-inflammatory therapy given. And in general, we make a branch point between pharmacologic therapy and diet elimination therapy. And this is essentially decided with a patient-shared decision-making model. There are certain patients who really prefer not using any medications and try to eliminate foods that might trigger EOE. As a food allergy condition, this can be an effective treatment, but it's quite restrictive. And I would say, in general, the minority of patients at many practices, particularly in adults, would pursue this. But there are some who want to do this. and if they do that, they might do an empiric elimination, where the statistically most likely foods to cause EOE, like dairy, might be eliminated. But the traditional diets are very restrictive, right? This would be like the six-food elimination diet, dairy, wheat, eggs, soy, nuts, and seafood. So you can see why many people opt for pharmacologic therapy. And right now, the guidelines position either proton pump inhibitors or swallowed topical corticosteroids that coat the esophagus as your first-line treatment. Now, no matter which of these treatments you decide, patients are going to do an endoscopy to assess the response to those treatments and assess for fiber stenosis. If there are strictures and symptoms of dysphagia or trouble swallowing, on the right side there, esophageal dilation can be performed as an adjunct parallel kind of treatment. And if people are responding, then they would maintain their therapy and continue monitoring. And if they don't respond, this is when you might change your therapy or step up to a biologic like dupilumab and then again assess response. We know that EOE being a chronic condition, if any treatment is stopped, the disease universally recurs. People don't grow out of the EOEs and it's a chronic disease. So long-term treatment is needed. Next slide. So with that kind of treatment algorithm, why do we still need new therapies? Well, there are a lot of issues with our current therapies, and there's a large unmet need. So those first-line therapies I told you about, responses are suboptimal. 50% or more may be non-responders to those initial treatment attempts. There's adherence difficulties. The medications, particularly PPIs, which are off-label, and the topical steroids, both for the U.S. and Europe, are twice daily dosing. And that obviously can be difficult to do long-term. And as I mentioned, the diets are quite restrictive. Depending on the medication, there are concerns for side effects. And I would say even more concerning is even if you get into remission with those first-line treatments, the loss of response is frequently observed. So by a year of therapy, many people who previously responded have flared up. Of course, biologics right now are positioned as a step-up therapy and second-line injections. Dupilumab, which is the one that's approved now, of course, requires frequent injections. The dose is twice as high for EOE as it is for its other allergic indications. And there are no advanced small molecule orally available medications at either the first or second line for EoE treatments. So there's quite this large unmet need, and in particular, a highly specific oral JAK1 inhibitor, if it's proven to be safe and effective, would fill an important treatment gap and an unmet need in this condition. So I'll turn it back over to Peter now. Next slide, please. Thank you so much, both Ariane and Evan. Very, very insightful. Just two words on our preclinical PKC Theta program. PKC theta plays a critical role in T-cell activation, as I'm sure some of the audience know. And here's just a diagram on the left side showing its role in the APC antigen presenting cell T-cel synapse and in signaling. It's a central mediator of the interaction between APCs and T-cells, and it's going through NF-kappa-B pathways and AP-1 pathways. And it's actually recruited to the polar side of the attraction with the APC in the T-cel PKC theta. So it's a very, very critical mediator. However, there are two decades of very strong preclinical evidence from various in vivo studies of mouse colitis, allergic airway disease models, rheumatoid arthritis studies, et cetera, to uncover the key role of PKC theta in these types of T-cell immediate inflammation. And most importantly, there's actually convergence with the JAK-STAT pathways, so the nuclear translocation of STAT converges with the NF-CAP or BNAP1 in the nucleus to further assist and aid and potentially synergize with both Th2 and Th17 activation. Next slide, please. so since it is a preclinical program we are still very excited about it and we decided based on ap3 data and insights to also acquire this asset the current leads have shown very very potent inhibition and potent activity in various immune cell models and critically important extremely high selectivity over PKC delta, which is very similar structurally, and so far we have promising candidates showing low clearance, etc. On the right side, you can just see the convergence illustrated here in this graph. I mentioned it already that STAT converges with in the nucleus with the nuclear functions of NF-kappa B and AP1 pathways downstream of PKC theta so given the high selectivity uh for these programs uh and and that's critically important also for pkc theta we think there's a really unique opportunity here for combination opening up for for broader potential not only for the single agent jack one inhibitor which in and of itself has broader potential than eoe but also for the combination and there's uh obviously these These are all potential indications for this combination. Next slide. So with that, I think we are through the main part of the program and just ending on this slide here that ACR525, based on everything we've done, the profiling head-to-head against other approved JAK inhibitors against dupilumab with the unbiased global proteomic profiling And the unbiased inside cells of the drug mechanism of action and effects, we believe it's highly differentiated, highly selective, and with desirable pathway properties, including the distinct TGF beta pathway suppression and the oral availability, where we have two different oral formulations, one of which is specifically for esophageal esophagitis. patients. And we have this desirable selective pathway potency. We also don't see any signs of pro-hepatotic bad activation, which we think could be an important favorable safety feature. So EOE is targeted as a first indication for ACR525. So with that, I think we are ready to go to the q&a section and are happy to take questions thank you so much thank you peter questions are coming in our first question is from liang chang at jeffries liang asks based a two-part question based on the phase one pkpd data how many doses would you evaluate in phase two, and what exposure or target engagement threshold do you believe is necessary to maximize JAK1-mediated efficacy while preserving the intended safety advantage? So I can answer based on some of the existing data, and also, if needed, I'll let Evan and Ariane maybe supplement. But based on the data we have so far, I think it would be reasonable. There's been two different short phase one studies conducted, and based on those, I think it would be reasonable to approach this with potentially two doses in the phase two study. And in terms of required drug target engagement, we know that plasma concentrations reach several micromolar for several hours, and many of the studies we showed you are down around one micromoler for maximal effects. So we think a drug target engagement that's maybe 60% plus, 50% to 60% plus will be quite beneficial based on all the studies done so far. And that's, of course, primarily based on the preclinical studies, but also very importantly on the PD studies conducted in the phase one. You saw the 60 milligram CXCL10 reduction that Mansoor shared, the dose-dependent reduction of that. And the levels in that obviously shows that we have a very, very potent downregulation of CXEL10. Yeah, so that's kind of how I would answer that. I don't know if either Ariane or Evan has anything to add. Well, I can add that in EOE, the endpoints are rather well established. And there is hardly a placebo effect seen here on the objective endpoints. So typically, a study with a small sample size could give us good information on efficacy. Great. And maybe it's Ariane and Evan. And of course, we are excited about INI because of our EP3 platform and biomarker expertise. So I know that peak erosinophilic counts are one of the measures in biopsies from these patients and histology and symptom scores. But we also hopefully can use our, we have single cell phosphoproteomics and very sensitive technologies developed as well as our multiplex biomarkers platform we are using in our registrational intent trials, inpatient trials, phase 2b, that we can use some of those perhaps for also additional early endpoints in such a study. I don't know if you want to comment on that. I think it's... Yeah, I would say one of the benefits of EOE trials is the ability to get esophageal tissue very readily during the trials, which is sort of a unique aspect of EoE. And It's quite routine to do this, and so to have biomarkers not necessarily systemically in the blood but directly in the organ of involvement, I think, provides this benefit to see very quick responses and changes in that tissue. And finally, too, I think it was Liang from Jefferies, we also, if you recall, have developed already for our ACR2316 that's in Phase II expansion right now, we developed a mass spec-based AP3 PD assay, a global PD assAY, which we use to support our Phase I. And we could see drug target engagement already at dose level 1 with hundreds of PD markers, statistically significantly regulated. So PBMC access is also readily available for all INI patients, obviously. So we have also potentially a meaningful readout there. So I think that's why we are so excited about INI is the good fit with our capabilities. Great. Our next question is from Lee Watzek at Cantor Fitzgerald. Hi, team. Thank you for taking our question. How are you thinking about capital allocation on ACR 525 versus your other programs? How long would a Phase 2 trial run for? Maybe tell us a little bit about trial size and time-dependent endpoints. There we definitely have to refer to the two experts, but our own thoughts so far, discussing with Mansoor and Eric Gamlin on this call, has been also leverage some of our oncology expertise. First, we could imagine, I think, a single arm trial where one could just focus on an early readout for benefit, clinical benefit. But alternatively, and that could be a small study, I think, phase two with just 15, 20 patients, alternatively a maybe placebo-controlled arm of, call it, 25 patients in each arm, again, using the biopsies and the biomarker expertise for early endpoints. The preclinical data, I believe, support 16 weeks dosing initially in the clinic. And in terms of capital allocation, we are a public company and we have shared our public runway guidance and are planning to obviously fundraise as part of routine going forward and plan to do that sometime next year. We also have a lot of strategic activity going on right now, including actually already some in the I&I area. That's all I can share at this point. uh but in regarding trial design arian and evan you've done a lot of that uh any comments yeah the typical duration of um such a phase two trial would be between um 12 and 20 weeks so um that um with a small sample size this would um not be um a study that would take for a very long time. Yeah. And as Aran, you'd mentioned the biologic or objective outcomes that we often measure with EOE trials, including the eosinophil counts in the biopsies and the endoscopic appearance, those can change very rapidly. And so, you know, you can certainly see many changes and even, you Know, great, great improvements or normalization by 16 weeks. Thank you. Our next question is from Mark Tepper. Congratulations, Akravan. This looks like a highly differentiated selective oral JAK1 inhibitor. Are you planning to go for second-line or first-line treatment for the EOE indication? what i learned from uh reading and from from arian and evan is that um if indeed we compare favorably with to pillow map or equally good this would be an interesting opportunity given its oral availability versus the injectable to pillow maps so but i will let the expert uh answer that i think evan alluded that on his slide that there's opportunity in second and potentially eventually of course depending activity going towards front line yes well i would see them a treatment like this being prescribed to patients before any second line or injectable therapies so that would be either immediately after first line or perhaps even as a first-line therapy. Now, most EOE patients typically would have a PPI first, but it could follow after that. Yeah, no, I have the exact same opinion. I think it's much easier, especially for, you know, with the pharmacokinetics, you know, a daily, once-daily medication could be positioned right there after a PPI and with first-line therapies, depending on the efficacy and safety profile. These patients, they have to take medication for years and years, maybe lifelong. And then And the current steroids, which are sometimes rather complex in administration, taken twice a day, then a drug that's simpler to take and can be taken once a day can be more preferable. Great. Our next question is from Jeff Jones at Oppenheimer. Jeff asks, could you speak to the oral formulation described for ACR525 and how this is aligned with the dysphagia challenges seen in these patients? uh yeah i can briefly do that and uh your gambling or mature can also but basically there's both a capsule and a tablet formulation and a bridge study has been done that has shown very very good comparability and and uh one of the phase one studies actually was part of that BRIDGE study. And so there is an easily, call it absorbable formulation where the drug simply can be kind of taken as part of a drink, but you let it just slowly flow down and you get a high local concentration in the esophageal disease lining. So yeah, that's really what there is to that. Eric, do you want to come in? No, in fact, I fully agree with what Peter said and we have the absorbable formulation which will be expected to be easily absorbed by the or swallowed by the patients. So we don't see any problem in our formulation. I would add a question to even, and Arianne, would it be feasible to add this medication on top of PPI? Yes, I think that is feasible, yes. But also just to add to the previous question, if the pill is not very large in size, these patients can swallow a pill. I mean, the first-line therapy for AUE that's most often prescribed is a PPI, is a tablet or a capsule. And our next question builds on the combination theme from an individual. Given how highly selective your JAK1 inhibitor is and the oral formulation, it seems attractive in combinations. Have you used your AP3 platform to identify synergistic combination opportunities the same way you did with your oncology portfolio to identify topo1 and ICI combination opportunities? Thank you. I think I'll take that. Absolutely, yes. And I already mentioned the PKC theta attractive combination opportunity there. We also, based on mechanism of action and pathway convergence and both additive effects and semi-overlapping effects, we also believe, for example, IL-23 antagonists could be an extremely attractive opportunity as well. That's an area of great interest right now, as you know, as well as TNF antagonists. But the IL-23 is now the hunt for long-lasting injectables, and I think there's also an oral on the way. But still, the combination desire, I think, is high amongst pharmaceutical-leading INI companies, for example, for the simple reason that we are up against aiming for improved efficacy, lifelong therapies often in big indications. So absolutely. And the AP3 platform is exactly beneficial for that. Just like we did with the approved JAK inhibitors, one of the things we plan to do is just do a profiling against all the approved and existing IL-23 antagonists and profile them with and without ACR525 and get full pathway inside so we directly on bias can see the combination benefit or lack thereof. Very good. Our next question is from Michael Akunowicz at Maxim. Two-part question. JAK1 selectivity. Achillean and Akravan have both profiled ACR5525 and found superior selectivity for JAK1 versus other kinases, i.e. JAK2? What quantitative comparisons can be provided in particular compared to other JAK-1 selective molecules such as filgotinib? And secondly, regulatory differentiation. Could the high degree of selectivity lead to a differentiated safety label, or would the differentiation primarily be a matter of dosing strategy or improved tolerability within the existing JAK inhibitor regulatory framework? I showed it on one of the slides. We actually don't, in our hands with biochemical and cellular assays in our head-to-head studies, see a great degree of selectivity for JAK1 versus JAK2 with, I think it was filgotinib that was mentioned. Is that right, filgotidinib? Yes. And maybe more like in biochemical, actually more one-to-one and 20x or so in our cell-based assays, so much less than the 120x we've seen so far with ACR525. But that said, yes, the high selectivity we are seeing and the lack of pathway effects leading to potential cell death and other features, primarily the selectivity against JAK2, JAK3, and TIK2, and I should add there's also a Kynome screen done just to support the pathway data that shows a high degree of selectivity. Those combined, all those features obviously mean that one could potentially be hopeful that black box warnings either could be avoided or at least reduced, which has been the case for many JAK inhibitors that have those. Can we plan for that? No. It is ultimately a regulatory decision, but that is certainly something that we can be hopeful about. If I may add to the studies, what we have done and seen until now, there are absolutely no serious adverse events. Yeah, there was no SAEs, as you mentioned also, as much as you observed at all. So, and yeah, no effect on reticulocytes that is significant. So, a lot of things that already are differentiated from the initial phase one. Evan, Ariane, any comments on maybe black box or other things? I mean, that's hard to plan for, I guess. Yeah, I think that's going to be primarily a regulatory issue, and we have to see what the safety database looks like as you're going forward. Yeah. But I guess we are slowly, Adam, coming towards the end of our 45 minutes. In fact, we have exceeded it a little bit. Yes, I was going to hand it to you, Peter, for any closing remarks at this point. yeah um we could take a question more if there is but otherwise i'll be happy there's a uh liang from jeffrey's just submitted a follow-up question that we can probably quickly turn to a follow up if 50 to 60 percent target engagement is expected to be sufficient and 60 migs already produces robust cxcl10 suppression what would you expect the second phase two dose to teach you? Is the objective to establish a dose-response relationship for efficacy or primarily to determine whether additional exposure provides incremental efficacy? I think it is. The phase two readiness implies longer, not only clinical activity, but also more safety. So I think It's a combination of the two. You always want to go with the least possible dosage to achieve maximal benefit, and that includes in terms of therapeutic index. So I think that would be our goal with such a trial design. But I want to thank you everyone for joining this meeting. We are super excited about this. As Adam pointed out in the beginning, long planned entry into the INI area, an area we think we are particularly well-suited for with our EP3 platform that was specifically developed to be agnostic and not rely on genetic alterations. And with all the opportunities for sample access that is biologically relevant, whether it be human peripheral blood mononuclear cells or biopsy taking early clinical endpoints. So we are really excited about this. So thank you to everyone and have a great rest of your day thank you ariane thank you evan