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 Acrivon Therapeutics. This afternoon, we are excited to host a key opinion leader panel to discuss our recently announced acquisition of two I&I assets, ACR-525, formerly known as AQ280, an oral JAK1 inhibitor, and a PKCθ inhibitor preclinical program. As a reminder and point of context, this acquisition represents Acrivon doing exactly what we said we would do. Specifically, I&I 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's 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.
Arjan Bredenoord. Dr. Bredenoord is a Professor of Gastroenterology and Hepatology at Amsterdam University Medical Center. He's the former President of the European Society of Eosinophilic Esophagitis, EUREOS, a member of the UEG Scientific Committee. Evan Dellon. Dr. Dellon 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 Acrivon will be our Chief Executive Officer, President, and Co-Founder, Peter Blume-Jensen, who is the inventor of the AP3 platform, as well as our Chief Medical Officer, Mansoor Raza Mirza, who has led numerous guideline-changing studies. We also have Erick Gamelin, our Chief Development Officer, on the call. He has a distinguished career and accomplishments both in oncology and I&I, 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 II-ready JAK inhibitor, as well as a selective preclinical PKCθ inhibitor. Next slide, please. For those of you who are new to Acrivon, we have a pioneering platform called Acrivon 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 II 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 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 drug regulates the intracellular signaling pathways at a global level. 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. Acrivon actually means exact or accurate to symbolize that exact or accurate match with the drug MOA. We have a number of proprietary tools that we've developed and keep developing and expanding in that context. Next slide, please. Here's an overview of our generative AI phosphoproteomics platform.
Notably, in contrast to most AI-driven and AI-based life sciences companies, our generative learning is applied primarily to a massive amount of, 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 Acrivon. 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. Mansoor, please.
Thank you. Thank you, Peter. Here you see our updated pipeline, now incorporating our I&I franchise. We remain on track for our pre-specified interim analysis of ACR-368 trial and will not discuss that further today. We recently updated on the exciting activity of our first-in-class WEE1/PKMYT1 inhibitor, ACR-2316, 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, ACR-7280, which has shown complete regression in preclinical AML in vivo models, also on an AP3 predicted sensitive tumor type.
Today, focus will be entirely on our new I&I programs, identified using our AI-driven AP3 platform as highly differentiated based on head-to-head profiling against approved JAK inhibitors and dupilumab. Next slide, please. 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-SMAD TGF-beta signaling. Many inflammatory disorders also lead 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 BAD 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. Our phase I 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 I, supporting once-daily oral dosing. Consistent with high selectivity of ACR-525, initial phase I safety was very favorable. Based on these data, ACR-525 is now phase II ready, and our initial target indication is eosinophilic esophagitis.
We, of course, also see a broader I&I 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 PKCθ 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. 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. What we did here is outlined here. We profiled this asset head-to-head against approved JAK inhibitors, mentioned here, as well as dupilumab, the IL-4, IL-13 directed antibody. 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. 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-related regulated pathways, including primarily, as you can see, the size of the dot here implies the magnitude of the effect. Blue is downregulation, not of levels, but of activity, and red is upregulation. You can see the most dramatic downregulation was actually identified for the very important pathways driven by IL-4 and IL-13. We also could directly, out of our over 100,000 quantified mapped phosphorylation sites, we can go in and directly pull out the downregulation of, for example, phospho-STAT6, a key readout of these pathways. You can see the dose-dependent reduction of that compared to IL-4 stimulated control cells.
Our pathway mapping showed a differentiation against other inhibitors, and very importantly, also high selectivity against JAK2, JAK3, as well as TYK2, which could suggest potential for improved efficacy and safety over other JAK inhibitors. Here is 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 KaiSR 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 anti-fibrotic mechanism. In the middle, you are seeing the pathways from and crosstalk with JAK1 and TGF-beta receptor one signaling in particular, and phosphorylation of STAT3.
In the bottom, you can see a very, very significant downregulation of the phospho-STAT3. We will run it in many quadruplicates, these samples. You can also see dupilumab has a similar effect on STAT3, but we do not see the same dramatic effect on the non-SMAD TGF-beta signaling pathways, while other JAK inhibitors do not show that potentially beneficial effect. We also, very importantly, are able to reconstitute our proprietary drug-regulated data against publicly available data. In doing so, we can reconstitute or map the drug-regulated 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. You see here as an example, brepocitinib and ACR-525 highlighted beneath from the rectangle shown and stippled up from the global view of all the drug-regulated sites.
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. 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. As you see here, ACR-525 does not inhibit that site significantly, while a couple of the other assets do inhibit that site very, very dramatically. We do think this could be potentially releasing a pro-BAD 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.
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. 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. You can see that it seemingly is the absolute most selective inhibitor of those we have tested for JAK1 versus JAK2, which we actually really are excited about. The readouts are based on, for JAK1, interferon-alpha signaling through phospho-STAT1, and in the case of JAK2, we used GM-CSF-stimulated PBMCs and looked at phospho-STAT5 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 I data. Mansoor, will you briefly cover this data, please?
Sure. Thank you, Peter. So on the left, you see a few of the preclinical studies. ACR-525 has been shown to dose-dependently reduce the disease-relevant biomarker, phospho-STAT3, in an ovalbumin-induced allergic inflammation mouse model, as well as the EoE Th2 inflammation markers, TARC and Eotaxin, 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 reduction of the inflammation marker CXCL10 and the dose-proportional well-behaved PK from the phase I 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 suggest ACR-525 to be safe and tolerable with no serious adverse event. Can I give you back, Peter?
Thank you so much, Mansoor. Next slide, please. Just a brief introduction beforehand, hand the microphone over to Dr. Arjan Bredenoord. 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. As you can see here, these are central players in eosinophilic esophagitis. I will let the expert, Arjan Bredenoord, expand on this from here on, please. Arjan?
Thank you so much, Peter. 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 epithelium mucosal integrity impairment and type 2 inflammation. A key role here is reserved for alarmins, such as TSLP and cytokines IL-4, IL-5, IL-13. These activate subsequently more immune cells and via TGF-beta activate fibroblasts, eventually resulting in fibrosis, more epithelial barrier dysfunction, and more inflammation. These cytokines and alarmins, they signal via the JAK-STAT pathway. There are also several critical SNPs within the JAK-STAT signaling pathway affected in EoE patients, as 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 EoE. Next slide, please.
EoE is an attractive first indication for ACR-525. Downstream signaling of alarmins, TSLP, cytokines IL-4, IL-13, IL-5, and as listed, IL-9, 15, oncostatin M, they are all mediated through the JAK-STAT pathway, and thus they can be inhibited through a JAK inhibitor. While dupilumab only inhibits IL-4 and IL-13, and tezepelumab inhibits TSLP alone, with the JAK inhibitor, you can inhibit the inflammation in EoE much broader. Next, please. In an EoE model with an air-liquid interface that resembles human esophageal epithelium, we were able to show that IL-13-induced esophageal epithelial resistance disruptions and permeability increase were reversed with ACR-525 to a similar degree as with dupilumab. This data has been presented this year at the annual meeting of the American Gastroenterological 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 ACR-525, but not with dupilumab, demonstrating the broader inhibition that was obtained with ACR-525. Next slide, please. There is 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 EoE. On the next slide, this is highlighted further. The annual incidence in the U.S. is now estimated to be 120,000 patients, with the current prevalence of over 500,000. 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 13 years of almost 500%, an average annual growth of more than 14%. These are really impressive numbers. There is a huge increase in incidence of EoE that we are currently seeing. Next slide. EoE leads to esophageal obstruction, and that basically causes 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. With this, I would like to hand over to my colleague, Dr. Evan Dellon, who is presenting from Chapel Hill.
All right. Hi, everyone. Thanks for the opportunity to speak. 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. After an EoE diagnosis is established, there is this concept that you want to treat inflammation and assess for fibrostenosis, essentially esophageal scarring, stricturing, and narrowing in all patients. All patients should have an anti-inflammatory therapy given. 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 is 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. You can see why many people opt for pharmacologic therapy. Right now, the guidelines position either proton pump inhibitors or swallowed topical corticosteroids that coat the esophagus as your first-line treatment.
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 fibrostenosis. 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. If people are responding, then they would maintain their therapy and continue monitoring. If they do not 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 do not grow out of EoE, and it is a chronic disease. So long-term treatment is needed. Next slide. 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 is a large unmet need. Those first-line therapies I told you about, responses are suboptimal. 50% or more may be non-responders to those initial treatment attempts. There are 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. 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. 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 is 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. There is quite this large unmet need, and in particular, a highly specific oral JAK1 inhibitor, if it is proven to be safe and effective, would fill an important treatment gap and an unmet need in this condition. I will turn it back over to Peter now.
Next slide, please. Thank you so much, both Arjan and Evan. Very insightful. Just two words on our preclinical PKCθ program. PKCθ plays a critical role in T-cell activation, as I am sure some of the audience know. Here is just a diagram on the left side showing its role in the APC, antigen-presenting cell, T-cell synapse, and in signaling. It is a central mediator of the interaction between APCs and T-cells, and it is going through NF-κB pathways and AP-1 pathways. It is actually recruited to the polar side of the interaction with the APC in the T-cell PKCθ. It is a very, very critical mediator. 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 PKCθ in these types of T-cell-mediated inflammation.
Most importantly, there is actually convergence with the JAK-STAT pathways. The nuclear translocation of STAT converges with the NF-κB and AP-1 in the nucleus to further assist and aid and potentially synergize with both Th2, Th17 activation. Next slide, please. 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. So far, we have promising candidates showing low clearance, et cetera. On the right side, you can just see the convergence illustrated here in this graph. I mentioned it already, that STAT converges in the nucleus with the nuclear functions of NF-κB and AP-1 pathways downstream of PKCθ.
Given the high selectivity for these programs, and that is critically important also for PKCθ, we think there is a really unique opportunity here for combination, opening up for broader potential, not only for the single-agent JAK1 inhibitor, which in and of itself has broader potential than EoE, but also for the combination. Obviously, these are all potential indications for this combination. Next slide.
With that, I think we are through the main part of the program, and just ending on this slide here, that ACR-525, based on everything we have done, the profiling head-to-head against other approved JAK inhibitors, against dupilumab, with the unbiased global proteomic profiling and the unbiased insights, inside cells of the drug MOA and effects, we believe it is 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 esophagitis patients, and we have this desirable selective pathway potency. We also do not see any signs of pro-apoptotic BAD activation, which we think could be an important favorable safety feature. So EoE is targeted as a first indication for ACR-525.
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 Lingbo Chang at Jefferies. Liang asks a two-part question. "Based on the phase I PK/PD data, how many doses would you evaluate in phase II, and what exposure or target engagement threshold do you believe is necessary to maximize JAK1-mediated efficacy while preserving the intended safety advantage?
I can answer based on some of the existing data. Also, if needed, I will let Evan and Arjan maybe supplement. Based on the data we have so far, I think it would be reasonable. There have been two different short phase I studies conducted. Based on those, I think it would be reasonable to approach this with potentially two doses in the phase II study. In terms of required drug target engagement, we know the plasma concentrations reach several micromolar for several hours. Many of the studies we showed you are down around one micromolar for maximal effects. We think a drug target engagement that is maybe 60% plus, 50%-60% plus, will be quite beneficial based on all the studies done so far.
That is, of course, primarily based on the preclinical studies, but also very importantly on the PD studies conducted in the phase I. You saw the 60 milligram CXCL10 reduction that Mansoor shared, the dose-dependent reduction of that. The levels in that obviously show that we have a very, very potent downregulation of CXCL10. That is kind of how I would answer that. I do not know if either Arjan or Evan has anything to add.
I can add that in EoE, the endpoints are rather well-established. There is hardly a placebo effect seen here on the objective endpoints. Typically, a study with a small sample size could give us good information on efficacy.
Great. Maybe it is Arjan and Evan. Of course, we are excited about I&I because of our AP3 platform and biomarker expertise. I know that peak eosinophilic counts are one of the measures in biopsies from these patients and histology and symptom scores. We also hopefully can use our We have single-cell phosphoproteomics and very sensitive technologies developed, as well as our multiplex biomarker platform we are using in our registrational intent trials, in patient trials, phase II-B, that we can use some of those perhaps for also additional early endpoints in such a study. I do not know if you want to comment on that. I think it is
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 a unique aspect of EoE, and it is quite routine to do this. 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.
Finally, too, I think with Lingbo Chang from Jefferies, we also, if you recall, have developed already for our ACR-2316, that is in phase II expansion right now, we developed a mass spec-based AP3 PD assay, a global PD assay, which we used to support our phase I, and we could see drug target engagement already at dose level one with hundreds of PD markers statistically significantly regulated. PBMC access is also readily available for all I&I patients, obviously. So we have also potentially meaningful readout there. I think that is why we are so excited about I&I, is the good fit with our capabilities.
Great. Our next question is from Li Watsek 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 II 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 Mirza and Erick Gamelin 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. Alternatively, and that could be a small study, I think, phase II 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. 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 is all I can share at this point. Regarding trial design, Arjan and Evan, you have done a lot of that. Any comments?
Yeah, the typical duration of such a phase II trial would be between 12 and 20 weeks. With a small sample size, this would not be a study that would take for a very long time.
Yeah, and as Arjan, you had 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. You can certainly see many changes and even great improvements or normalization by 16 weeks.
Thank you.
Our next question is from Mark Tepper. Congratulations, Acrivon. 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 reading and from Arjan and Evan is that if indeed we compare favorably with dupilumab or equally good, this would be an interesting opportunity given its oral availability versus the injectable dupilumab. I will let the expert answer that. I think Evan alluded that on his slide that there is opportunity in second and potentially eventually, of course, depending activity going towards frontline.
Yes. I would see a treatment like this being prescribed to patients before any second-line or injectable therapies. That would be either immediately after first-line or perhaps even as a first-line therapy. Most EoE patients typically would have a PPI first, but it could follow after that.
Yeah, Evan?
Yeah. I have the exact same opinion. I think it is much easier, especially with the pharmacokinetics. A 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. The current steroids, which are sometimes rather complex in administration, taken twice a day, then a drug that is 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 ACR-525 and how this is aligned with the dysphagia challenges seen in these patients?
Yeah, I can briefly do that, and Erick Gamelin or Mansoor Mirza can also. Basically, there is both a capsule and a tablet formulation, and a bridge study has been done that has shown very, very good comparability. One of the phase I studies actually was part of that bridge study. There is an easily, call it, absorbable formulation where the drug simply can be kind of taken as part of a drink, where you let it just slowly flow down, and you get a high local concentration in the esophageal diseased lining. Yeah, that is really what there is to that.
Erick, 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 or swallowed by the patients. We don't see any problem in our formulation.
Yeah, I would add a question to Evan and Arjan. 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. The first-line therapy for EoE that's most often prescribed is a PPI, is a tablet or a capsule.
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 TOP1 and ICI combination opportunities?
Thank you. I think I will take that. Absolutely, yes. I already mentioned the PKCθ 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 is an area of great interest right now, as you know, as well as TNF antagonists. The IL-23s now, the hunt there is for long-lasting injectables, and I think there is also an oral on the way. Still, the combination desire, I think, is high amongst pharmaceutical leading I&I companies, for example, for the simple reason that we are aiming for improved efficacy, lifelong therapies often in big indications. Absolutely. 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 ACR-525 and get full pathway insights, so we directly unbiased can see the combination benefit or lack thereof.
Very good. Our next question is from Michael Okunewitch at Maxim. Two-part question. JAK1 selectivity. Aqilion and Acrivon have both profiled ACR-525 and found superior selectivity for JAK1 versus other kinases, i.e., JAK2. What quantitative comparisons can be provided in particular compared to other JAK1 selective molecules such as filgotinib? 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?
Yeah. I showed it on one of the slides. We actually do not, 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, filgotinib?
Yes.
And-
Yes
maybe more like in biochemical, actually more one-to-one and 20x or so in our cell-based assays. Much less than the 120x we have seen so far with ACR-525. 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 TYK2, and I should add there is also a kinome 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 they 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, the studies what we have done and seen until now, there are absolutely no serious adverse events.
Yeah. There were no SAEs, as you mentioned also, and you observed that also. No effect on reticulocytes that is significant. A lot of things that already are differentiator from the initial phase I. Evan, Arjan, any comments on maybe black box or other things? I mean, that is 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. We could take a question more if there is, but otherwise, I'll be happy to.
There's a Lingbo Chang from Jefferies just submitted a follow-up question that we can
Okay
probably quickly turn to. Follow-up, if 50%-60% target engagement is expected to be sufficient and 60 mgs already produces robust CXCL10 suppression, what would you expect the second phase II 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 II readiness implies longer, not only clinical activity, but also more safety. 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. I think that would be our goal with that, such a trial design. I want to thank you, everyone, for joining this meeting. We are super excited about this, as Adam Levy pointed out in the beginning, long planned entry into the I&I area, an area we think we are particularly well-suited for with our AP3 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.
We are really excited about this. Thank you to everyone, and have a great rest of your day. Thank you, Arjan Bredenoord. Thank you, Evan Dellon.