Good morning. I am Matthew Rothman, counsel for Aclaris. Before we begin our prepared remarks, I would like to remind you that certain statements we make during this call about the company's future results of operations and financial position, business strategy and plans and objectives of Aclaris' future operations are considered forward-looking statements within the meaning of the federal securities laws. Our forward-looking statements are based on current expectations that involve risks, changes in circumstances, assumptions, and uncertainties that could cause actual results to differ materially from those reflected in such statements. These risks are described in the Risk Factor section of Aclaris' Form 10-K for the year ended December 31st, 2020, and other filings Aclaris makes with the SEC from time to time. These documents are available under the SEC Filings page of the Investors section of Aclaris' website at www.aclarisrx.com. All of the information we provide on this call is provided as of today, and we undertake no obligation to update any forward-looking statements we make on this call on account of new information, future events or otherwise. Please be advised that today's call is being recorded and webcast. A link to the webcast can be accessed under the Events page of the Investors section of our website. I'll now turn the call to Dr. Neal Walker, President and Chief Executive Officer of Aclaris. Neal. Good morning, everybody, and thank you for attending Aclaris Therapeutics virtual R&D Day. Today we'll be discussing the productivity of our platform. A little bit about our agenda and the presenters. I will be presenting along with our Chief Scientific Officer, Joe Monahan, and our Vice President of Biology, Paul Changelian. I'll start out with an introduction of the company and an overview of our portfolio. I will then move to some specifics on our MK2 inhibitor program, talking first about a clinical update on zunsemetinib, ATI-450, which is our investigational MK2 inhibitor. We'll then talk a little bit about our role of MK2 in IL-17 biology. Then finally in this section we'll talk about ATI-2231, which is our second MK2 inhibitor that we're looking at for indications in oncology. Next, we'll talk about ATI-2138, which is our oral small molecule. It's a covalent binder of ITK, TXK, and JAK3. Recently we announced that the IND was allowed. We'll be talking about our clinical plans moving forward. Then next we'll be talking about some of the work we've been doing on gut bias, JAK inhibitors for inflammatory bowel disease. Then finally, I'll have some closing remarks, and then we'll allow Q&A. First, a little bit about the company. Aclaris is a development stage biopharmaceutical company focused on developing small molecule therapeutics for immunoinflammatory diseases. There are three important components to help drive success. First, the people. We have world-class experts that are from companies such as Pfizer and GSK, with years of experience at developing kinome-targeted medicines. Second is the platform. We have a proprietary drug discovery engine that's composed of a proprietary chemical library combined with a fully integrated multidisciplinary discovery team. This allows us to advance our small molecule drug candidates from concept to development candidate, in some cases in less than half the time of larger organizations. Third is our innovative pipeline. We have three clinical-stage assets, which we'll talk more about, in addition to an early preclinical pipeline that is currently building. Next is our drug development pipeline. Zunsemetinib, ATI-450, is our MK2 inhibitor. This is an oral small molecule, and we're looking at three indications: rheumatoid arthritis, hidradenitis, and psoriatic arthritis. These are all phase II clinical-stage assets. Next is ATI-1777. This is our soft topical JAK1/3 inhibitor, and this is for the indication of moderate to severe atopic dermatitis, and we'll be embarking on a phase II-B starting next year for that program. ATI-2138 is our oral small molecule covalent inhibitor of ITK, TXK, and JAK3. This asset is geared to get into psoriasis next year, and the IND has recently been allowed. Next are two earlier stage programs, our gut-biased program and ATI-2231, which is an MK2 inhibitor. The gut-biased program is an oral small molecule, and we're looking at inflammatory bowel disease, and that is at dev candidate stage. ATI-2231, our MK2 inhibitor, is in IND-enabling tox work at the moment, and we're looking at an IND towards the back part of 2022. Here we're looking at potential indications in oncology. First, a little bit of an update on ATI-450. Obviously, we have messaged that we will be starting three phase II clinical studies, and I'll be going through a little bit of a high-level design on each of those in the next two slides. ATI-450 in rheumatoid arthritis. This study is designed as a three-arm study, placebo, 20 mg BID, and 50 mg BID. This is on a backbone of methotrexate. This study will span over 12 weeks with a four-week off-drug safety follow-up period. The primary endpoint will be ACR20 responders, and you can see there's a variety of secondary endpoints that we'll also be studying. We'll also be looking at a variety of pharmacodynamic parameters as well. We anticipate enrolling both treatment naive and also treatment-experienced patients, and we opted to test the 12 mg and 50 mg BID as the top dose in this study since we are already achieving multiples of the IC80 in terms of the relevant cytokine suppression, with only a small increment of additional cytokine suppression noted at 80 mg and 120 mg. Similarly, in HS, we're looking at two dose groups, a placebo and 50 mg BID. In this study, we'll be looking at a variety of the traditional secondary endpoints and with one exception as the primary endpoint, we'll be looking at a mean change from baseline in the change of inflammatory nodules or abscess count. We're looking at this study as more of a proof of concept study versus RA and psoriatic arthritis, which we believe will be key value generating. Finally, the third study that we'll be studying ATI-450 in is psoriatic arthritis, and this will be in adult patients with moderate to severe psoriatic arthritis. Again, a placebo and 50 mg BID will be the two dose groups. We'll look at 12-week primary endpoint, again, with a four-week safety off-drug follow-up period. The primary endpoint will be ACR20 responders with a variety of the traditional secondary endpoints as you see here. Once again, this will be a key value generating study. Next, I'm going to have Dr. Joe Monahan walk through the KINect drug discovery platform in a little bit more detail before he gets into his next section. Joe. Thanks, Neal. The approach that we take to drug discovery is to focus on disease-relevant biologically interesting kinase targets that have proven difficult to drug. The platform strategy is to tailor the drug discovery approach to the specific kinase of interest. We start off with a team of experienced drug hunters with proven success driving compounds through discovery into clinical development. We develop custom translatable assays and use structure-based drug design in this process. The unique feature of the KINect platform is the trusted compound library that we built using structure-based approach to globally target the more than 300 kinases in the human kinome that has cysteines in and around the active site, and that's called the human cysteinome. At Aclaris, we've advanced several compounds through discovery and into development and the clinic for autoimmune inflammatory diseases and cancer using this approach. We're also in the process of reloading the portfolio with discovery projects that include undrugged kinases and neurodegenerative targets. Next slide. We're gonna give you first an update on the discovery work that expanded our evaluation of inflammatory cytokines to investigate the role of MK2 and IL-17 biology and the impact that zunsemetinib or ATI-450 has on that biology. Next slide. This slide is just to remind you of the role of the MK2 pathway in regulating inflammatory cytokines, which is TNF-α, IL-1β, IL-6, and IL-8, and the ability of zunsemetinib or ATI-450 to block this. What we have here is three different graphs showing human whole blood and cytokine production stimulated on the left by engagement of the IL-1 receptor, in the middle, engagement of the TLR4 receptor, and on the right, engagement of the TLR7/8 receptor. We're looking at the inhibition of these cytokines with ATI-450 in a dose-responsive manner. From what you can see across all three of these stimuli, we get a dose-dependent inhibition of TNF-α IL-1, IL-6 and IL-8, with potencies in a low nanomolar range and comparable potency across cytokines and across stimuli. We wanted to then extend these studies to look at another key inflammatory cytokine, IL-17. Next slide. Given the importance of IL-17 in a number of autoimmune diseases, as evidenced by the efficacy of the biologic targeted cytokine and Th17 cells in general, we investigated whether the MK2 pathway is involved in the production of IL-17 or its receptor-mediated function. If MK2 is involved in IL-17 biology, then the axis modulated by zunsemetinib will provide additional mechanistic rationale for the potential utility of this compound in diseases for which we are currently planning phase II studies, particularly hidradenitis as well as psoriatic arthritis. Additionally, could potentially open this drug to additional diseases that have an IL-17 signature such as ankylosing spondylitis. The experimental approaches that we're taking with zunsemetinib is to look at IL-17 production in CD4 positive T-cells and also IL-17 stimulated protein phosphorylation and cytokine production in a number of cells. Next slide. This slide demonstrates the data from looking at IL-17 production. We're evaluating IL-17 production in human PBMCs stimulated with anti-CD3 and CD28, and we're looking at four different donors. What you can see on the left-hand panel is you see a dose-dependent inhibition of IL-17 production, and this is IL-17A. Qualitatively similar results were obtained with IL-17F. You see a dose-dependent inhibition with zunsemetinib, and similar curves are obtained with all four donors, looking at about 60%-70% maximal inhibition. IC50 is in the low nanomolar range, which corresponds well with the inhibition potency of zunsemetinib with the other cytokines I mentioned, including IL-1 and TNF-α. As a control on the right-hand side, IL-2 production was also evaluated, and as expected, zunsemetinib had no impact. Next slide. Now we looked at the impact of ATI-450 on IL-17 signaling. This is a schematic of the IL-17 signaling pathway. The binding of IL-17RA to its receptor initiates the formation of this complex multi-component signalosome, which engages deubiquitinases, DUB ubiquitinases, RNA binding proteins, chaperones, and kinases. The signalosome drives deactivation of several pathways. It activates three MAP kinase pathways, that's the JNK, ERK, and p38. It activates the NF-κB pathway as well as the ERK5 pathway. It also regulates the activation of a set of RNA binding proteins. The IL-17 pathway regulates these inflammatory gene production at both the transcriptional level by modulating transcription factors, as well as a post-transcriptional level, looking at message stability by activating RNA binding proteins. The question we wanted to ask is, number one, is MK2 activated by IL-17 engagement with this receptor? If the answer to that is yes, we then wanted to ask the question, what is the functional consequence of that activation? That's shown on the next slide. On the left-hand panel, IL-17-induced phosphorylation of the MK2 substrate HSP27 in human dermal fibroblasts is evaluated. We have three curves here. We have IL-17 activation of HSP27, or phosphorylation of HSP27, TNF-α stimulation of HSP27 phosphorylation, and then the combination of IL-17A and TNF-α. We use this combination in that it's been previously shown that both IL-1 and TNF can augment the responses of IL-17. The important point here is looking at each of these curves, IL-17 does activate MK2, as evidenced by the phosphorylation of HSP27, as does TNF, and the combination has a greater response. We are seeing a IL-17-dependent phosphorylation of HSP. Zunsemetinib in a dose-response manner can block this HSP27 phosphorylation across all three stimuli. The consequence of this is shown on the right, looking at human PBMCs and looking at the chemokine GRO-α production. Looking at IL-17A, TNF-α, and then the combination. IL-17A can induce GRO-α production, as can TNF-α, and the combination looks like it's more synergistic than additive in this case. Zunsemetinib or ATI-450 can dose-dependently block this. The blockade of the phosphorylation of HSP27 and the blockade of the GRO-α production all have IC50s again in the low nanomolar range. We extended these studies on the next slide to look at IL-8, and we looked at human PBMC production of IL-8. We looked at human rheumatoid arthritis synovial fibroblast cells and IL-8 production. We also looked at human dermal fibroblasts IL-8 production. That data is not shown, but it corresponds with the other sets of data. We have three sets of bars in each panel. The first set of bars is IL-17A stimulation, the second set TNF, and the third set the combination. We're looking at stimulation in the absence of zunsemetinib, and then at two different concentrations. If you focus on the first set of bars in the left-hand panel, we do get elevation in IL-8 production in PBMCs stimulated by IL-17A and a dose-dependent inhibition by zunsemetinib. Similarly with TNF and then the combination. On the right-hand panel, you're looking at human RA synovial fibroblasts again. While you see the stimulation with IL-17A by itself of IL-8 is somewhat low, it is meaningful, and it is inhibited, as is the combination of 17A plus TNF. The level of inhibition seen in RA SF is lower than what we see in PBMCs, but still it's significant. Overall, these signaling data provide evidence that IL-17 activates the MK2 pathway, and that results in both chemokine and cytokine production that's differentially inhibited by zunsemetinib across disease-relevant cells. Next slide. Now we're going to transition to a second MK2 inhibitor. This is a 5th-generation inhibitor, ATI-2231, which is a compound that we're moving forward for oncology. Next slide. I'm gonna first go over some details about the biology around ATI-2231. It's an oral drug that was designed to decrease metabolism and clearance relative to zunsemetinib, and potentially result in lower dose levels. Potency selectivity is similar, and I'll show you some of that data on the next slide. We are advancing this compound through IND-enabling preclinical studies with the anticipation of an IND submission for oncology by the end of 2022. Next slide. Now to some of the data. This is looking at the PK of ATI-2231 in comparison with ATI-450 in the rat following oral dosing. Just as a reminder, ATI-450 in humans had a half-life of about nine hours to 14 hours. What you can see from this curve is that ATI-2231 has a longer half-life, has a higher AUC compared to zunsemetinib as a result of low clearance. This property should result in extended exposures at or above the targeted pharmacologic level for ATI-2231 at doses comparable to ATI-450. The next slide shows you the potency and selectivity against the target for ATI-2231. As a reminder, these drugs target the p38/MK2 complex, and the goal is to target that complex with a higher affinity relative to p38 in the complex with MK2 substrates or p38 or MK2 by themselves. In the top table shows the potency against this p38/MK2 complex target for ATI-2231 in comparison with zunsemetinib, and again, both are inhibiting this in a low nanomolar range. Selectivity ratios are shown on the bottom table where zunsemetinib and ATI-2231 are very selective against the p38/MK2 complex as well as p38 by itself and MK2 by itself. The properties of ATI-2231 against the enzyme complex and selectivity are comparable overall to zunsemetinib. On the next slide, we advanced this into cellular studies. Here we're looking at the ability of ATI-2231 to block the production of the inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 in human whole blood stimulated by either LPS, which is the top row, or IL-1β, which is the bottom row. As you can see, the potency is comparable for most cytokines and across stimuli with potency in the low nanomolar range. The only exception is IL-6 stimulated by LPS, which we had seen previously with zunsemetinib, where it's right shifted relative to IL-6 induced by other stimuli such as IL-1β. All the other cytokines and stimuli are in the same low nanomolar range. Additionally, in the bottom left, looking at the curve of phosphorylation of HSP27, ATI-2231 in human whole blood will inhibit the phosphorylation of HSP27 in a dose-dependent manner, again, with potency in the low nanomolar range. We then move this into in vivo studies shown on the next slide. Here we're looking at the mouse collagen-induced arthritis model, where it had collagen injections on day one and day 21 of the model and therapeutic dosing beginning on day 18. We looked at four admixed chow doses of ATI-2231 from 30 ppm - 1,000 ppm. On the left-hand side, we're looking at clinical score measurements. What we can see is a dose-responsive reduction in clinical score induced by ATI-2231, with the two highest doses giving very high level of efficacy. The activity of ATI-2231 in this model is compared to that of Enbrel in the orange circles. Again, the two highest concentrations or the two highest doses of ATI-2231 have efficacy or activity higher than what we see with Enbrel. On the right-hand side, we're looking at the PK from this model, looking at dose versus exposure, and we see a dose-dependent increase in exposure and activity is observed at exposures of 20 ng/mL or greater. With all this data that we have just around the general properties of ATI-2231, the next slide shows us the initial foraying into this mechanism and this drug in cancer. Most of the cancer-related non-clinical studies that we will describe, however, was carried out in zunsemetinib, and we're currently bridging these studies to include ATI-2231. That's the indication that I mentioned earlier that will be moved forward in oncology. These are collaborative studies with research scientists and physicians at Washington University, and the focus is on two different types of cancer, metastatic breast cancer and pancreatic cancer. The mechanisms are related but distinct. As far as metastatic breast cancer, MK2 impacts the tumor microenvironment by activating tumor-associated fibroblasts to secrete factors that promote tumor survival. Inhibiting MK2 can block tumor growth and metastasis, as well as protect bone against cancer and chemotherapy-induced bone loss. As far as pancreatic cancer, one of the current standard of care is FOLFIRINOX, which is an efficacious combo chemotherapy that's widely used now in pancreatic cancer, but it has a high level of toxicity. One of the components of FOLFIRINOX is irinotecan, and that's the main driver of the cellular stress induced tumor apoptosis, but it also activates a resistance mechanism. That resistance mechanism involves MK2, and MK2 blockade should amplify the tumor killing of irinotecan. The next slide we'll start talking a little bit about the breast cancer work. This breast cancer work was done as a collaboration in the labs of Sheila Stewart and Cynthia Ma at Washington University School of Medicine. The next slide just shows you a schematic of the observation that tumors rely on their associated microenvironment for both growth and survival. Stromal cells and cancer-associated fibroblasts express and secrete factors that promote tumorigenesis through the regulation of a number of biological processes such as proliferation, migration, invasion, angiogenesis and immune suppression. Importantly, a key subset of these tumor-promoting secreted factors are dependent on the MK2 pathway. The next slide shows that in addition to these being dependent on MK2, a phosphorylated and activated MK2 is expressed in tissues associated with both primary breast tumors and in bone metastasis from the same patients. As pro-tumor factors are MK2 dependent and activated, MK2 is present in this tumor tissue, it would follow that blocking the MK2 pathway could have anti-tumor activity. The next slide shows the model that we're currently using to investigate this. This is done in Sheila Stewart's lab at Washington University, and we're looking at a mouse breast cancer metastasis model. Approximately 70% of the metastatic breast cancer patients have bone metastasis, resulting in a number of comorbidities, including fracture risk. We wanted to investigate the impact of MK2 inhibition on breast cancer metastasis. There's no spontaneous mouse model that exists for this. Instead, a tumor cell intracardiac injection model is used where a murine metastatic luciferase transfected breast cancer cell line, 4-1 QIMT, is used, injected into the left cardiac ventricle and allowed to synchronously deliver tumor cells to the bone and to the visceral organs. The MK2 inhibitor zunsemetinib or ATI-2231 were administered in chow starting 1 day after the tumor cell injection. The data is shown on the next slide. Here we're looking at whole body bioluminescent imaging carried out two weeks after the study start. On the left-hand panel, metastasis observed in both the bone and visceral organs, but treatment with ATI-450 on the right-hand side reduced both the bone and visceral metastasis dramatically. Histological evaluation of these bone metastasis confirmed these bioluminescent imaging results. On the next slide, we extended this to look at the bone integrity in these animals. In addition to limiting metastasis as shown on the previous slide and graphically shown on the left, the impact of zunsemetinib on bone integrity is shown on the right. The bone loss is a result of bone metastasis driving increased osteoclastogenesis, as well as chemotherapy which exacerbates bone loss in metastatic patients. The p38 MK2 pathway plays an important role in bone homeostasis through its regulation of ligand-induced osteoclast differentiation. Here what we're looking at the right-hand side is protect the bone volume in tumor-bearing mice using micro-CT scanning. The animals that are tumor-bearing but don't have any therapy, bone integrity is almost completely lost. That would be. It's not shown here, but it would basically be on the X-axis, where the non-tumor-bearing mice bone volume is shown in the first set of circles. The next set is looking at paclitaxel, which is a chemotherapy which is used in breast cancer patients, and that does protect somewhat the bone volume. The last set of bars is zoledronic acid, which is standard of care, bisphosphonate standard of care to protect bone. Interestingly, looking at zunsemetinib, which is second to last set of symbols, you get protection that's at least as good as the standard of care of zoledronic acid. The important concept here is that with treatment with zunsemetinib in this model, you get a dual level of protection. You can protect against bone metastasis, and you can also protect against bone deterioration. The next slide shows the data that we've generated. All the data shown up to now is data that uses zunsemetinib. As I said, we're doing some bridging data to 2231. This shows the bridging data of this breast cancer metastasis model with 2231. On the left-hand side, we're looking at a comparison of ATI-2231 and ATI-450 in this model, looking at whole body tumor burden, at a single dose of 1000 ppm orally. You can see ATI-2231 is as good as ATI-450. On the right-hand side, we're looking at a dose response of ATI-2231 in chow, looking at 100 cells, 300 cells and 1000 cells per million. We get clear effects at 200 cells and 1000 cells per million. This just demonstrates that ATI-2231 in this metastatic breast cancer model has activity comparable to that of zunsemetinib. With this preclinical data, the next slide, we have a plan that's being put in place to investigate ATI-2231 in combination with the chemotherapy standard of care in hormone receptor-positive HER2-negative metastatic breast cancer. The next slide just shows the plan that we have in place. We plan to have an investigator-initiated study, triggered by the scientists at Washington University led by Cynthia Ma. This is gonna be supported by Department of Defense grant award to the investigator. It will be a phase I/phase II study to investigate ATI-2231 in metastatic breast cancer patients. PK will be evaluated, safety will be evaluated as will impact on bone turnover and metastases. The study protocol is currently being worked out. If the IND submitted by the end of 2022 is allowed, this study should start sometime in 2023. We'll now transition to some of the data that's been generated in pancreatic cancer from the lab of Kian-Huat Lim at Washington University. Next slide. Pancreatic cancer is a major cause of cancer deaths in the world with an overall five-year survival rate of only about 10%. The standard of care in pancreatic cancer is changing from the chemotherapeutic drug gemcitabine to a combination drug FOLFIRINOX, which is a four-drug cocktail, has demonstrated superior efficacy post-resection, as shown in this graph. Along with this higher level of efficacy, FOLFIRINOX also has greater toxicity, and it induces resistance mechanisms. Based on this profile, any additional agents to overcome this resistance must be well tolerated. One of the FOLFIRINOX components, irinotecan, is the main driver of this stress-induced apoptosis in tumors, but also is the driver of resistance. This effect, resistance effect is thought to involve MK2. Therefore, our working hypothesis is that if you add an MK2 inhibitor to the FOLFIRINOX regimen, it will improve its activity and reduce toxicity. The next slide shows the value proposition for an MK2 inhibitor. As I mentioned, as FOLFIRINOX is the emerging standard of care in pancreatic cancer, the response rate is only about 30%-40%, and the duration of the effect is limited due to this resistance induction. An MK2 inhibitor will target the defense mechanism in pancreatic cancer that's induced by FOLFIRINOX to enhance its anti-tumor activity as a combination therapy. If successful, this combo has potential to be utilized in a number of different settings in pancreatic cancer, the operative setting, post-operative setting, as well as metastatic setting. Data generated in this collaboration in Kian-Huat Lim's lab that supports this hypothesis has just been published in the current issue of Science Translational Medicine. The next slide summarizes where we stand with these studies. Irinotecan's active metabolite, SN-38, is shown to drive the chemotherapy stress-induced apoptosis in tumors. Inhibiting MK2 alters the balance between the cell survival and cell death mechanism and skews it towards the apoptotic cell death pathway, thereby increasing the anti-tumor activity. We use the MK2 inhibitor zunsemetinib to test this hypothesis in the gold standard mouse model in pancreatic cancer, the KPPC model. The KPPC model is an autogenous genetically engineered mouse pancreatic cancer model where mice are genetically changed to include the oncogenic G12D mutation in KRAS, as well as having mutations in both alleles of P53. These mutations mimic the human disease and drive the cancer. Autogenous KPPC model is thought to be the best model of human disease progression and also mimics the pancreatic cancer microenvironment. The next slide is really the key study. The figure on the left is a Kaplan-Meier survival plot in the KPPC mice that were administered vehicle alone, the MK2 inhibitor ATI-450 or zunsemetinib, the modified FOLFIRINOX called mFOLFIRINOX. And this just doesn't contain the leucovorin component as that doesn't impact efficacy much and leads to increased rates of cytopenia. Finally, the combination of ATI-450 or zunsemetinib and FOLFIRINOX. Both ATI-450 and FOLFIRINOX had a positive impact on survival in this challenging model. The combination significantly enhanced survival over either treatment alone or the vehicle-treated mice. With this combination, you get almost a doubling in their survival. This doubling of survival is very unusual in this model. In addition to increasing survival, the evaluation of the pancreas weight in these mice following treatment is shown on the right. What you can see is you get a decrease in the pancreas weight with either treatment alone. The combination treatment can take the pancreas weight down to normal levels. These exciting preclinical results, along with the safety profile of MK2 inhibitors, provide a foundation on which a clinical study could be planned with the cancer-focused MK2 inhibitor, ATI-2231, for treating pancreatic cancer in combination with FOLFIRINOX. With that, we're gonna transition to another asset that's been pulled from the KINect platform, and I'm gonna hand it over to Paul Changelian, the head of biology. Thank you, Joe. I want to start by describing a very brief update on our ATI-2138 clinical candidate. This is a dual inhibitor of, it's an inhibitor of JAK3, ITK, and PXK, and that's described on the next slide. Which schematically indicates that this single compound inhibits both the T cell receptor pathway by virtue of inhibiting ITK and TXK and the cytokine pathway by virtue of inhibiting JAK3, which is required for all of the common gamma chain cytokines. What's unique about this approach is that in this single drug, we are inhibiting two key pathways required for T cell activation. What's particularly important is that the targets for this kinase inhibitor are fairly unique to lymphocytes. Unlike other drugs that are used for autoimmune disease like calcineurin, which targets a very widely expressed, protein, calcineurin. Our hope is that by inhibiting T cells in this way, we will have a potent effect on activated T cells in autoimmune disease, but very minimal, side effects as a result of its restricted tissue expression. I wanna show you just some of the, preclinical data that we generated to convince ourselves that we should be looking seriously at this compound in autoimmune disease. The first slide I'm showing you here is the, gold standard, arthritis model, the so-called collagen-induced arthritis model or CIA. This study was run at Bolder BioPATH, one of the world leaders in this, in this area. The model is run similarly in most labs. Animals are immunized against collagen. This induces inflammation in the paws. After about 21 days, they're re-immunized to speed up the inflammation further. We begin dosing at about that time point on day 18, just prior to the second immunization. The animals are continually dosed up to day 35 when the animals are taken down. What we do during the course of the study is follow their clinical arthritis score, essentially looking at the swelling and redness and inflammation of the paws. That's shown in the graph on the left. What you can see in the gray line, which are the vehicle-treated animals, at around day 23 or day 24, you see a very rapid increase in the clinical arthritis score. The positive control for this model, run in most labs is Enbrel, anti-TNF biologic that's used in patients. You can see a significant inhibition of the clinical arthritis score in these mice, that's significant from the vehicle. What's interesting is that, we use three different doses of our compound, ATI-2138. In the case of dosing with our compound, the compound is admixed into chow, and it was dosed at three different levels, 100 ppm, 300 ppm, and 1,000 ppm. You can see all three dose levels of this drug dramatically inhibit the clinical arthritis score relative to vehicle and also relative to Enbrel. On the right, you're looking at histology of those joints. This is really the gold standard readout for this model, actually showing that your drug has prevented damage to the joint. You can see in that first bar there for the vehicle, quite a bit of damage is measured histologically. In addition, Enbrel shows a significant inhibition of about 60%. For ATI-2138 at all three doses, you have a dramatic inhibition of histological damage at over 90%. The other model that we recently explored with this compound to sort of expand our understanding of how it works in autoimmune disease is the classical T cell adoptive transfer model of colitis. This is briefly depicted or schematized at the top of the slide, and I'll talk quite a bit more about this in the next section. Essentially, SCID mice, animals that do not have their own CD4 cells, are adoptively transferred with naive T cells. These animals then travel throughout the animal, or these cells travel throughout the animal, causing inflammation at all of the barrier surfaces, both the colon, the gut, the skin, the lungs. What we follow most closely is inflammation in the colon. What happens as these animals develop colitis is that they begin to have diarrhea and they have body weight loss because of that. As you can see on the left are the in-life measurements we make. Couple times a week, we weigh these animals and follow disease progression. Shortly after about two weeks post-transfer of these T cells, you start to see all the animals lose body weight. At four weeks post-transfer, day 28, the animals have lost most of the weight, and at that point, the animals are randomized and placed into different groups. What you can see in the right side of this graph is that animals dosed with 300 ppm of ATI-2138 in the chow, that's the green line, will rapidly increase their body weight up towards the black line, which are naive animals that are not sick at all. That's the normal body weight gain that's observed in these mice. In addition, at the lower dose of ATI-2138 in the red line, the animals stop losing weight and there's a significant increase in body weight as a result. In the vehicle, of course, in the blue line, you can see continued weight loss. The positive control that we ran in this study is shown in the purple line. That's an antibody to IL-12, IL-23. It's analogous to a drug that's used clinically in IBD patients. The most important readout for this study, and again, I'll talk about this in greater detail in the coming slides, is the histological readout. That is by taking different portions of the intestines, and here on the right side of the slide, I'm showing you the histological scoring of the ileum. You can see the dramatic damage done in the vehicle-treated animals. Some protection in the animals that received the anti-p40 or anti-IL-12/23. Very significant and dramatic inhibition of damage histologically at both doses of ATI-2138. Based on these data, we're very excited to submit, and we have submitted an IND to the FDA, and it's been accepted. In a matter of days, actually, we will begin dosing in our SAD study, our single ascending dose in humans. That will begin in December. We will explore basic parameters such as safety and tolerability, pharmacokinetics. We'll also study pharmacodynamics in the blood at both the T cell receptor level and the JAK3 level. We'll look at food effects. Interestingly, once we've completed our SHAD study over the course of the next several weeks, we will move to a multiple ascending dose study or a MAD study, and we're actually going to do this in patients. In addition to looking at safety and tolerability and PK and PD, we know from previous studies, in particular, the first study that was done with tofacitinib, the original JAK inhibitor, was done in a MAD study for two weeks in psoriatic patients. This is enough time to actually potentially see some efficacy or signs of efficacy. We're excited about that. But primarily it's the goal of the study is to look at multiple doses over the course of two weeks. As I say, that will start, and the single dose version of this will start next week. I'm gonna move on now to a program we've been working on for several years, and we've arrived at a very exciting point in the history of the program, and that is to generate an oral gut-biased JAK inhibitor for inflammatory bowel disease. I'm gonna tell you about our two development candidates, CDD-2603 and CDD-2676. As I'm sure this audience knows, most autoimmune diseases are treated with broadly immunosuppressive drugs, whether that's steroids, JAK inhibitors or anti-TNF biologics. When you do this, you have systemic effects with these drugs, and that leads to things like infections, as well as malignancy. As a result of that, people have thought that one of the ways to get around this issue of the systemic side effects of these drugs is to try very hard to deliver these drugs to the site of inflammation. That's been done in a couple of disease areas, in particular, with inhaled corticosteroids for asthma, and of course, with steroids like budesonide in an enema format for ulcerative colitis. Not as common as the inhaled steroids, but certainly is done, and it can generate some efficacy for the patients. As a result of this type of thinking, our approach here is to develop an orally administered molecule that will stay in the gut, minimize systemic exposure, but provide patients with the benefit or the convenience of oral dosing as opposed to intravenous dosing, which is required for many of the biologics that are on the market today. When you think about JAK inhibitors for IBD, there's only one out there. It's XELJANZ or tofacitinib. It was approved for ulcerative colitis. It failed in its trials for Crohn's disease. It works quite well in these patients who have become refractory to other biological therapies. Of course, it comes with a number of systemic side effects, as I mentioned earlier, infections and malignancy, et cetera. More importantly, just in the last couple of months, the FDA has issued a warning for all JAK inhibitors on the market, related to the heart-related events that are seen in these patients. Things like heart attacks and stroke, effects on, and cancer, effects on blood clots. As a result of this, heightened awareness of the danger of these systemic JAK inhibitors, a company by the name of Theravance Biopharma recently proposed the idea of creating another pan-JAK inhibitor similar to tofacitinib, that would in fact stay in the gut, and therefore not have systemic side effects, but could in fact be active in patients who have gut inflammation. One thing I'll point out about their data that we're familiar with so far that's been published, their in vivo activity with their compound TD-1473 was evaluated in a mouse model, the murine model of VAMID, the oxazolone model. This was done with prophylactic dosing, and that's important, and I'll speak to that later when I describe for you how we've decided to test our compounds. To give you a sense of the potency here, what's shown in the table below is the potency of TD-1473 versus tofacitinib across the family of cytokines and JAKs that are used for these cytokines. What you can see is that these two compounds are broadly equivalent in their potency. The question became, would they be broadly equivalent in the actual disease setting? Based on the history of tofacitinib and the information that we had gleaned from various documents that have been published by Theravance Biopharma, we designed the following essentially screening strategy to try to make our own gut-biased compound. Our chemists are wizards. They created some compounds that are very potent against the JAK kinases. They have low to moderate permeability, so they're not getting out of the gut very easily. They're lipophilic with high rates of efflux, and they have moderate metabolic stability, so much that if they do get out, they're not gonna hang around for too long. An important decision we made, a couple years ago was to insist on using what's considered the gold standard model of inflammatory bowel disease in mice. This is the T cell transfer model, or TCT is how I'll refer to it throughout the next few slides. This is the model of colitis. In order to claim or believe that we have compounds worth following, in addition to the in-life measurements that we made in this model, we demanded that the compound produced histological protection of the gut tissue at the end of the study. What we did is also, in all our studies, compare our compounds to tofacitinib, and we used tofacitinib at relevant exposures, and I'll show you why we think that's true. We looked at multiple doses of TD-1473 since we really didn't know what dose or exposure was going to be effective for that compound. In addition to demonstrating efficacy, and again, the efficacy at the histological level, we also needed to figure out ways to demonstrate effects on systemic immune activity. This is what we wanted to minimize because we're quite confident that that's what causes the systemic side effects seen with tofacitinib. What we did within the models that we actually looked at the efficacy or the activity in, we looked at ex vivo stimulation of the blood cells to look at signaling of the JAK kinases. We looked at the activation marker status of cells that were transferred in, the CD4 cells that drive the disease. Of course, we looked at gut and plasma drug exposures. I wanna just talk a little bit on a little more detail about the model and how we settled on running this within the course of the study of all these compounds. As I said, on day zero, in these SCID mice, naive T cells are purified from a normal mouse adopted to be transferred into these animals. In the absence of regulatory T cells, and that's what you find in these SCID mice. They have no regulatory T cells. The transferred mice react to the microbiome at various barrier surfaces, in particular the gut, and this induces colitis and weight loss. After three weeks, when the animals start losing weight, the animals are treated with compound, randomized and fed compound. Again, drug is administered admixed in the chow. One of the things that this does is it allows us to minimize the handling of the mice. We know from both mouse studies as well as from patients that this type of stress exacerbates the disease. What we're looking at here is really the disease caused by the transferred cells and the effect of the drug. On day 49, after four weeks of dosing, the study's terminated. Tissues are analyzed for the local as well as systemic effects. We look at plasma levels and we perform histological scoring of both the colon and the ileum, and I'll describe that for you in a moment. For those of you who are not familiar with what a mouse intestine looks like, this is it here. It's adorable, as you can see. Just north of the cecum is the ileum, shown at the top. Just south of the cecum is the proximal colon, and all the way down towards the rectum is the distal colon. At the end of every one of these studies, we cut out a piece of the ileum, a piece of the proximal colon, and a piece of the distal colon, and that is handed off to the histologist who then scored the tissue. For every study that I'm gonna show you, we have histological scoring at three different locations throughout the intestines of these animals. I want to go through a little more detail in terms of how we are gauging systemic effects in these animals. What we do is we transfer in these naive T cells on day zero. Now, naive T cells once they enter the animal, travel throughout the animal, and as I mentioned, they become activated at various barrier surfaces. After seven weeks in the animal, a number of these cells have become activated. We know that by looking using fluorescence activated cell sorting at the level of CD25 or the IL-2 receptor on the surface of these CD4 cells. What you're looking at in the left panel, in the left graphic here, is the level of CD25 expression on CD4 cells in the spleen, one of the tissues the CD4 cells travel to, and they travel to all the tissues. You can see that in this, in this particular tissue, the CD4 cells are expressing high levels of CD25, indicative of activation at about 11%. In contrast, on the right, in the same study from animals that were dosed with tofacitinib, which we know is a systemic JAK inhibitor, the levels of CD25 are much lower, around 1%. This is something we looked at with our compounds as well as a way to assess whether or not systemic activity is being seen. The other thing we did, which gave us a much more robust signal to me, is look at activation of the blood. At the end of these studies, after four weeks of dosing, seven weeks after transfer of CD4 cells, we bleed the animals and stimulate the blood with either IL-2 and IL-12. If you look at the top of this figure, the top two panels on the left and the right, what you're looking at is unstimulated blood, which shows very low levels of phospho-STAT5 in that box. In contrast, after you add IL-2 or IL-12, you see very high levels of phospho-STAT5 in response to IL-2, up to close to 60%. This is a measure of the ability of the cytokine to activate the JAK kinases in the blood. These are from the vehicle-treated animals. The lower two panels, you're looking at the same thing for IL-12-induced signaling and activation of phospho-STAT4. Again, closing in on 60% of the cells have phosphorylated STAT4 in that box that you can see. What you're looking for as a measure of systemic activity or in particular as a measure of systemic drug levels is a decrease in that level of phospho-STAT5 or phospho-STAT4. That will be another measure of how we discern whether or not our drug is systemic. In all of our studies, we looked at our compounds versus the positive controls, tofacitinib. Again, optimized to be commensurate with that dose which we use clinically. We looked at the Theravance drug candidate, TD-1473. We looked at our two drugs, CDD-2603 and CDD-2676. We ran each compound twice in the TCT model. This is a 7-week model which requires an additional four weeks for histological analysis. In every study we ran, each group has 10 animals, and every compound was run at multiple doses. Now what I'm showing you here are clinical data of tofacitinib from their phase III trial in ulcerative colitis. On the left, you're looking at the histological scoring or basically mucosal healing of the patients who were dosed either with placebo on the left or the two doses of tofacitinib, 5 mg BID and 10 mg BID. Both of those doses are significantly different from placebo in terms of the effect on mucosal healing. The doses themselves were not significantly different. What's important for purposes of our studies was understanding what the exposure of tofacitinib was in these studies. If you look at the right, this shows the drug levels of tofacitinib at these doses at the 10 mg BID and the 5 mg BID. What we did is we looked at these exposures in the blood, the concentrations of tofacitinib in the blood in nanograms per mL, and it turns out the potency in mouse and human blood is analogous. They're very similar. We were able to then say, "Okay, let's use a similar exposure of tofacitinib in the mouse, compare that to our drugs, and that will therefore make the comparison relevant." What you're looking at here are on the left, the plasma PK from the TCT studies, all the TCT studies in which we studied tofacitinib. We studied it at two different doses in the chow at 180 ppm or 600 ppm. What you're looking at, each symbol on the left is an individual mouse, and that shows the drug level from that mouse at the end of the study. The dotted lines represent the corresponding dose levels that were used clinically in that phase III study with tofacitinib. What you can see is that our lower dose of tofacitinib at 180 ppm, we are right in the range that was used clinically. If you go over to the right side of this slide now, what I'm showing you is the histological protection seen across the intestinal tract. I for ileum, P for proximal colon, and D for distal colon. In all cases, the 180 ppm tofa dose is superior to the vehicle dose. Essentially, what we've created now is an ability to look at tofacitinib at doses relevant to the clinic and compare those to our compounds. Let me move on to TD-1473, the Theravance compound. Consistent with what Theravance reported, we took this compound and dosed it orally in mice to look at its exposure. The blood levels were explored in the ileum, which is shown in the red line, in the colon, which is shown in the green line, and in the plasma, which is in the blue line. What you can clearly see, as Theravance reported, is that this is very much a gut restricted compound. Very high levels in the tissues, very low levels in the plasma. What's really unknown here is if the exposures in the gut by themselves are gonna be sufficient to treat disease, or does one need some level of drug in the periphery? That's really, to date, an unknown question. Now, I'm not gonna show you all the data, but basically, all of the parameters that I looked at, that I described for you in terms of what we were gonna look at for these models, TD-1473 did not have an effect. Unlike tofacitinib, which prevented weight loss in the TCT model, this did not happen with TD-1473. When we looked in the splenic CD4 cells, which had significantly reduced levels of CD25 with tofacitinib, that was not seen with the Theravance compound. When we looked in ex vivo blood assays, dramatic inhibition by tofacitinib, no effect of TD-1473, and all the PK data from these studies were consistent with those findings. The gold standard really or the key data that show you to convince you this compound is not active is, of course, histology. What you're looking at here is the histology in the ileum, distal colon and proximal colon from one of the two studies we ran with TD-1473. Again, our positive control was tofacitinib with both 180 ppm and 600 ppm. It's really the 180 that's most relevant because that's the equivalent to the clinically used dose. You can see that the three doses that we studied, or I guess in this slide, it's just the two doses of TD-1473 that we used, 300 and 1,000, there was no significant effect on histological protection. To summarize then, what we found, and consistent with Theravance's findings, this TD-1473 is primarily a compound after oral dosing resides in the ileum and the colon, with low levels in the plasma. In-life systemic measures of activity were consistent with low levels in plasma. No drug was available. Importantly and most critical to the furtherance of this compound, there was no evidence of histological activity in the GI tract of these animals across two TCT studies. The question that we are asking, and we hope to find out is, if this TCT model is a better predictor of clinical efficacy as opposed to the short-term oxazolone model used by Theravance, these data may have predicted the failure of TD-1473 in the phase II-B ulcerative colitis trial that was just released. Importantly, in the last few weeks, Theravance has also announced they've discontinued their phase II study of this compound in Crohn's disease. I want to move now to our clinical candidates that we are excited to develop in terms of bowel disease, and the first one is 2603. Similar to what I showed you before for the Theravance compound, I'm showing you here on the left, after oral dosing of a mouse with this compound, looking at the ileum in the green, and what color is that? Purple for the colon, and the black dotted line for the plasma. This drug primarily resides in the intestinal tissue, the ileum and the colon. There's very low levels in the plasma. That's what the compound was designed to do, and it's doing it very nicely. On the right, just to give you a sense of the potency of this compound, again, this is using the human PBMC assay, where we're looking at the two cytokines, IL-2, which signals through JAK1 and JAK3, and IL-12, which signals through JAK2. The potency of tofacitinib compared to 2603, you can see the IL-2 potency is equivalent, and you can see that our potency against IL-12 is quite significantly more potent, and we'll see if that makes a difference. In life parameters, as I mentioned, is looking at body weight over time. If you look at the graph on the left, all the way to the left in the left graph is the vehicle group. In the blue, that shows the animals are losing weight over the course of seven weeks. In contrast, naive mice all the way to the right in the brown, those are animals that are not given disease. They kept gaining weight. That's the range of weight gain you expect to see in this model. What you can see, with the dosing of 2603, across a very large dose range from 30 ppm-1000 ppm, we see a very nice dose-dependent protection of weight loss with this compound. We repeated this using the 200 doses, 100 ppm and 300 ppm. You can see that, equivalent to 180 ppm of tofacitinib, we are protecting the animals from weight loss at 300 ppm. This has been predictive of histological benefit, but I haven't shown you that yet, but this was an exciting finding. Here's that exciting finding, which is what we demanded of all our compounds, and that is to show histological benefit. The first study we ran is shown on the left. Again, I'm showing you data across the intestinal tract, ileum, proximal colon, distal colon. The bars represent vehicle in blue, and then red is CDD-2603 at 300 ppm and so forth across that first graph. A very nice and significant inhibition of histological damage. In the second study, shown on the right side of this slide, again, here we actually ran tofacitinib at a relevant dose, 180 ppm. And you can see that the CDD-2603 was equivalent to or better than tofacitinib, again, across the intestinal tract, ileum, proximal, and distal colon. Finally, we wanted to understand if in fact during these studies at which we've shown histological benefit, was the drug systemically active? If you look on the left, we're looking at the levels of CD25 on the CD4 cells that were transferred into these mice in the spleen. Looking at the levels of CD25, a measure of activation. That level of CD25 is inhibited in a dose-dependent manner by tofacitinib on the left, both at 180 ppm and 600 ppm. Minimal effect with 2603. Similarly in the study, when we looked at the blood taken from these animals at the end of the study and stimulated those cells with IL-2 and looked at phospho-STAT5 in the NK cells in the blood, you can see there's no effect at 300 ppm in 2603. Tofacitinib, of course, crushes the ability of IL-2 to signal. The combination of these two sets of data gives us great excitement about the compound histologically protecting damage but not having significant effects in the periphery. I'll move on to our second compound, 2676. As I showed you before, this is the oral dosing in a mouse. The green line is the ileum, proximal colon, dotted line is plasma. Same sort of thing. The chemist did a marvelous job of creating a compound that shows selective exposure. Similarly, if you look at the potency of this compound in these two key cytokine pathways, IL-2 and IL-12, we are either equally potent or more potent than tofacitinib for both of these parameters. Again, looking in vivo at weight loss, you can see a dose-dependent prevention of weight loss by CDD-2676 in two studies here of both number one and number two. Importantly, the gold standard here of our histological protection, this is again just showing you the ileum in this case. We saw this in the colon as well. Basically you can see dose-dependent protection of histological damage on the left, in the ileum on the right. You can see protection equivalent to tofacitinib at the 180 ppm dose. Finally, again, looking at the activation of CD4 cells as measured by CD25. CDD-2676 shows less of an effect than tofacitinib. On the right where we're looking at IL-2-induced phospho-STAT5, the effect is more pronounced. There's really very little happening in the blood at the end of this study, even though histologically we showed protection. Both of these compounds have been through seven-day rat dose ranging, dose range finding studies in rats at very high doses, 30 ppm, 100 ppm and 300 ppm. These doses are all way above the levels that we would expect to need for efficacy. We looked at the drug levels in the gut and the plasma in all these rats. It confirmed what we saw in the mouse. The drug is gut-biased. The only thing we saw at the highest levels of dosing was consistent with the mechanism of inhibiting JAK3 and JAK1 is lymphoid organs, which were showing decreased weight. We'll find this in spleen. The second test species for this compound will be cynomolgus monkeys. We'll be able to look at a number of immunological parameters there because of how close we are to human. Once we have the 7-day study complete, we'll move on to 28-day studies in both of these species. Okay, I'd like to summarize the section I just spoke to you about on our gut-biased compound, which we hope to move into clinical development for inflammatory bowel disease. This single slide summarizes essentially everything I've told you in a very compact way, which I believe really captures the dichotomy of what we're trying to accomplish. On the left, we're looking at the histological data for all compounds that we studied. Our two clinical candidates are 2603 and 2676. We compared that to tofacitinib, and we compared it to 1473. In the blue, I'm showing you the histological data for the ileum, in the red, the proximal colon, and in the green, sorry, for the distal colon. This is all relative to placebo or vehicle. Essentially what we're trying to do here with any of these compounds is minimize the histological damage or essentially make those bars go down. What you can see from moving from left to right is that CDD-2603, CDD-2676 and tofacitinib are essentially equivalent in terms of their ability to inhibit histological damage in the ileum, proximal and distal colon. That's really what we set out to do. What's notable is the data for TD-1473, much less benefit at the histological level, running around 80% of no drug whatsoever or the vehicle level. If you look at the right side, this was really the goal of this entire program. We knew, of course, from tofacitinib that you could make a JAK inhibitor that would be orally available and effective in inflammatory bowel disease. What we didn't know is could you make a drug that was going to stay largely in the gut, and when you look in the periphery, as we've done in a couple of ways, and not have much of an effect. What I'm sort of showing you on the right is specifically the based on the blood taken from the end of these seven-week studies, where the blood is pre-loaded with IL-2, and we look by fluorescence activated cell sorting at the levels of phospho-STAT5 in natural killer cells in the blood for those very same animals that were used to generate the efficacy. Again, same idea here. The percent relative to the vehicle is shown. The amount of inhibition that you find in a vehicle animal is none because there's no compound there. Similarly in animals that were dosed in CDD-2603 and CDD-2676, which had histological benefit in the gut also were not showing any evidence of systemic inhibition of cytokine signaling. In contrast to tofacitinib at 180 ppm, equivalent to what they use clinically, you see a very significant, essentially a crushing of the ability of IL-2 to signal in the whole blood of those animals. Not surprisingly, with TD-1473, no effect in the blood. Of course, this compound had no effect anywhere. It's really the dichotomy between these two images, the histological benefit on the left, and the lack of obvious systemic effect in the blood, which gives us great excitement and gives us hope that we should further develop these compounds in the clinic. If this model has any predictive value whatsoever, we hope we will see something in patients as well. What I hope I convinced you is that we have a couple of gut-biased development candidates that are worthy of moving forward. I've shown you their histological benefit, and I've shown you that within the same models, these compounds do not have a significant effects on ex vivo blood assays or in measurements of splenic CD4 cell activation. We've done toxicology, nothing dramatic was noted. We're waiting on histopathology, and that will be forthcoming. What we're also gonna do, just to remind people, if it wasn't clear from the beginning, we will compare these compounds in a series of studies in normal mice to look at the full complement of immune cells that are found in normal animals. Of course, in the SCID mice which are used in the IBD model, they do not have CD4 cells, and we want to be able to look at normal animals as well. I'll stop there, and I'll hand it off to Dr. Neal Walker. Thank you, Paul. Now for a few closing remarks before we head to Q&A. A number of takeaways here today. Hopefully everybody got a really nice flavor of some of the great science that the team has been working on over the past several months. First with tofacitinib, ATI-450. These two programs are on track. We have three phase II studies planned, again, in rheumatoid arthritis and psoriatic arthritis, which will be key value generating. Then in hidradenitis, where we're looking more at a proof of concept study design. We are potentially planning to add two additional programs to the ATI-450 larger program. More on that to follow in the coming months. We do have available capital to add additional programs to that asset. We also have clearly shown through some recent preclinical work a nice dose-dependent inhibition of IL-17 production. I think this opens up to more opportunities, perhaps, ankylosing spondylitis as an indication. I think it just reinforces the importance of the MK-2 pathway on a number of these cytokines, and the team worked hard to produce some of that additional data over the last two quarters. In addition, as you probably saw, recent publication in Science Translational Medicine, we're pretty excited about the potential to use MK-2 inhibitors in oncology. We think there's obviously potential in metastatic breast cancer and also pancreatic cancer. In particular, one of the novel features of our MK-2 inhibitors, that it also is quite a potent bone preservation asset. I think that's obviously important in metastatic breast cancer, where patients often suffer from metastasis to bone. More on that, you know, as we evolve, but we are looking at different routes to start studying these different disorders and we'll update you accordingly. Certainly ATI-2231 is exciting. It's an additional MK2 that we developed. As Joe went through, it's got some really interesting properties, and we are currently looking at that particular asset for oncology indications and potentially down the road some orphan I and I indications. Next, ATI-2138 is our oral covalent inhibitor of ITK. IND is allowed. This is our third asset now that's been produced from the platform, so we've been quite productive over the last couple years. We're heading into SAD studies, which will start this year. The MAD work will begin and read out in 2022. Hopefully we are able to show that what we're calling our gut-biased development candidate program for IBD is differentiated from, you know, the existing therapy tofacitinib, which is on the market. At least from a preclinical perspective and also perhaps paint a picture of why others may not have been successful in the space. We are gaining some excitement about that program and we'll be talking about that more in the future. A little bit on our key milestones. Obviously, we've got three phase II studies starting with ATI-450, and those are starting imminently, with rheumatoid arthritis starting first, followed by hidradenitis and then psoriatic arthritis in the very beginning portion of next year. We do expect those readouts, at least, where we currently sit here today, we expect those readouts to occur on a top-line basis in the first half of 2023. There might be a possibility to pull forward HS as a proof of concept study. We're also starting to think a little bit about perhaps an interim look on that study since we aren't really looking at key values there, that it might be possible and more on that to come, you know, as our thinking evolves on that. ATI-1777, that study will start in the early part of 2022, and we would expect top-line data on that, at least right now we're planning for the first half of 2023. With ATI-2138, as I mentioned before, we just got through the IND process. We'll be starting SAD work in healthy volunteers this month. Should that be successful, we'll be rolling into a MAD cohort in patients with psoriasis. That will be a two-week study, and we'll be looking to report that data out in 2022. ATI-2231, which is our MK2 inhibitor that we're looking at potentially for oncology indications. We're right now in the throes of IND-enabling tox work, and we would look to have that into an IND in Q4 2022. That's what our catalyst calendar looks like over the coming months. As a reminder, as of our last reporting date, our cash balance takes us to the end of 2024. Thank you for your attention today. I hope we were able to answer a lot of questions in terms of the science that we've been working on over the last several months, and I'll now open it up to Q&A. Thank you. Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. To withdraw your question, press the pound key. Please stand by. We will start with Q&A after. Our first question comes from Leland Gershell with Canaccord. You may proceed with your question. Hi, good morning, everyone. This is Harvey in for Leland Gershell with two questions, kind of, over a little bit of everything. First of all, in molecular level for your MK2 inhibitors, how does ATI-2231 differ from ATI-450 in addition to the longer half-life, which would lead to longer exposure? Would side effects or toxicity be greater than ATI-450 as a result? Secondly, this is on ATI-2138. Given that this is animal model data, which type of severity for psoriasis patient would it get most benefit? Are we talking about moderate, mild, severe? What are your thoughts on how it would fit into treatment paradigm? Lastly, on your gut bias checks, just curious to know when you might move CDD-2603 and/or CDD-2676 if you keep going. Thank you so much. Thank you for the questions. Hi. Hi, everyone. This is Neal. I'll start with your second question relative to 2138. You know, I think for something like psoriasis, I think you wanna be in the, you know, moderate to severe end of the spectrum. That's where we would be targeting. We're also looking at a variety of other indications there, things like inflammatory bowel disease and some others. We haven't fully completed down selecting to indications. It's a pretty potent molecule. It's, you know, we liken it to cyclosporin, but a little bit more specific. That's our current thinking on that molecule. You know, that would be updated as we get through our kinda SAD and AD work, and the SAD work starts this month. For your first question on the 2231, let me hand that off to Joe to answer that. Yeah. Thanks, Neal. Yeah. The molecular differentiation of 2231 versus zunsemetinib from a structural standpoint, the two compounds are very close to one another. From a chemistry standpoint, we don't see much differentiation. As you mentioned, from a PK standpoint, we do have a long half-life and low clearance. From a pharmacology standpoint, they're very similar as far as their potency goes on various enzyme cellular in vivo studies. The concern about a longer half-life and increased exposure resulting in higher potential toxicities. The way we approach clinical studies will be to look at doses, exposures, and pharmacodynamic measurements and to sort of have the pharmacodynamic analysis guide the doses that we will go forward with ATI-2231, both from a dosing level as well as dosing interval. We don't anticipate having any issues there. Zunsemetinib is proven to be, in the studies we've done thus far, very safe, and we take the same approach with ATI-2231. Yeah. I think I'll take the last question. You know, the gut bias work that we've done thus far, as you can tell, you know, Paul and team have been working really hard on taking the ground out of some of the controversies out there, whether you know there seems to be a camp that thinks that perhaps you can go quite selective and drive meaningful efficacy. You know, I think maybe we've seen some of the shortcomings of that approach. There's the other camp that feels you have to be systemic. I think we kind of believe you have to be somewhere in the middle, and I think we've started to make that case through at least some of the preclinical models. In terms of, you know, moving forward with it, certainly the next step is to down select. We've got two path candidates, and as Paul mentioned, we're doing a little bit of additional work just to choose kind of a lead molecule. They're very similar in a lot of ways. Then, you know, it's just doing IND enabling tox work. I think, you know, one of the things we're cognizant of is just kind of the evolving landscape with JAK inhibitors in general. You know, we'll certainly continue to give that some thought. We just recently saw the new updates for RINVOQ label. You know, as we've stated a number of times for assets like this, you know, we certainly have a lot to work on in the portfolio and certainly would look to potentially look at partnerships as well, you know, for something in the IBD space. You know, a little bit of extra work to do there and also a little bit of triangulating with how the market continues to evolve relative to JAK inhibitors. Got it. Thank you for the update. Thank you both for taking our questions. Keep us in the progress. Thank you. Thank you. Thank you. Our next question comes from Tim Lugo with William Blair. You may proceed with your question. Hey, guys. This is Lachlan on Tim. Thanks for taking the questions. I guess first on ATI-2231. You know, I understand the MK advantage there over ATI-450. But are there other important advantages that make you prefer it over ATI-450 in oncology, or is that more of a kind of portfolio planning decision? Then second, on the gut bias molecules, sorry if I missed it or just haven't connected the dots yet, but do you understand why your compounds are showing activity when, you know, Theravance's weren't, despite having a sort of relatively similar tissue to plasma PK profile? Is it just slight differences there, or is there some other factor that I'm missing? Let me start out with your question on 2231. I think there is a component of kind of lifecycle management there. We have a, you know, an IP window on that that extends seven years past. You know, we're looking at ATI-450 as, you know, a good asset for a variety of immuno-inflammatory indications. Then, you know, perhaps looking at 2231 for some oncology indications. It's a little bit different landscape. We don't rule out looking at 2231 for also some immuno-inflammatory indications. It's just as we were kind of looking at this whole landscape and some of the data was evolving. You know, you saw the recent publication of pancreatic cancer. You know, we just thought it might be good to differentiate the assets according to indication. You know, I'll hand off the molecular question to Joe again, if he has any additional comments. Then maybe Paul, or you can hand to Paul and answer the question on the gut bias front. Yeah, I think you covered it, Joe. I think from a molecular standpoint, when we look across all the different analysis that we've done, the two compounds are interchangeable, the zunsemetinib and the 2231. So it's more of a strategic decision on putting the assets into the various therapeutic areas. Paul with the gut bias. We don't mute you, Paul. Oh, sorry. There you go, Paul. You can hear me? Yep. Great question, on Theravance. A couple things. The TD-1473 is actually, when you look at those initial gut PK studies, it indeed is gut selective. It's metabolically less stable than our compounds, number one, so it doesn't survive as long. Moreover, to sort of make a direct comparison within the context of our mouse models, we looked at activity of these compounds in mouse whole blood. The Theravance compound is anywhere from 5x-10x less potent than our two compounds in the colitis. In particular, when you look at its potency against IL-12 in a whole blood setting, which of course encapsulates protein binding, which is important for an in vivo analysis. Those are the two things that we think are most unique about it and that led to its problems. The third thing, of course, I think is the model that they chose to base this on, the short-term oxazolone model, is not particularly predictive based on what we've seen in the literature and what we see in our own studies. Thanks for clarity. Okay. Your next question comes from Tom Shrader with BTIG. You may proceed with your question. Hi, guys. Thanks for putting together this R&D event, and thanks for taking the questions. I had a couple on zunsemetinib and the phase II plans. Can you talk a little bit more about how you're thinking about dosing here? I know you mentioned hitting the IC80 with a 50 mg QID dose. We've also looked at doses up to 120 mg QID and just wondering whether there's any additional dose ranging plans either in these studies or perhaps in some of the additional programs you're contemplating any potential for once daily dosing. Yeah. Thanks, Tom. Certainly on the once daily dosing, we've been pretty clear on that and, you know, that'll become part of the program as, you know, we talk about more studies. You know, as we look at the 50 mg QID, you know, clearly we talk a lot about the fact that we're hitting multiples of the IC80 and, you know, we're hitting the target pretty hard. I think when you look at the IL-17 work that Joe just went over, it's a very similar pattern as we saw with TNF IL-1. We're hitting multiple cytokines at multiples of the IC80. It's really knocking the target down. I think that's kind of the main consideration. I think some of the other minor considerations are, you know, just seeing if you remember our SAD/MAD data, you know, although they're mild to moderate. You know, we saw an increase in some of the mild AEs as we dose escalated at 80 mg and 120 mg in the MAD cohort extension. We recently conducted some DDI studies where we saw kind of a similar pattern to what we saw in the MAD study with 80 mg. You know, transient dizziness, some skin findings, some transient headache, and some upper respiratory infection findings, things like that. No SEs or serious AEs, but you know, as we thought more about it, you know, we feel that 50 mg is hitting it hard enough. Certainly doesn't preclude us from going, increasing the dose, you know, on an indication specific basis, and we're still contemplating that. As I mentioned in my prepared remarks, we are looking at adding in a couple of indications. At the end of the day, our job is to find the minimally effective dose. We actually made all of Joe's comments on this. We've actually found, you know, when we look back at the data at 20 mg and 30 mg, some pretty potent cytokine suppression. Maybe, Joe, you should make a comment on that. Yeah. In the fed MAD studies, we did 10 mg, 30 mg, 50 mg, 80 mg, and 120 mg. You know, we're going forward with the 20 mg dose in the RA 2B study. Even in 20 mg, as Neal said, we're projected to inhibit TNF and IL-1β by 70%-80% at peak and 50%-65% at trough. This suggests to us that, you know, a 20 mg BID dose is probably gonna be a pharmacologically active dose in addition to what we see at the 50 mg, which, as you mentioned, we're seeing multiple of the IC80 at trough, knocking down TNF by 92%-93%. Okay. Thanks for the color. I thought really interesting data for zunsemetinib looking at the impact on IL-17. We know a competitor just recently presented some data at ACR, and they've seemed particularly focused on the IL-17 impact. Can you just help put your data in context with the Bristol data and your thoughts on how zunsemetinib and ATI-2231 compare? Joe, why don't you handle that one? Yes. The Bristol compound describes inhibition of IL-17 production with a maximal inhibition in the neighborhood of about 70%, and 60%-70%. We're seeing similar inhibition with zunsemetinib on IL-17 production, albeit our compound is more potent in regulating that. Secondly, we also, as I mentioned, saw impact on IL-17 signaling through its receptor with zunsemetinib, again, talking in the low nanomolar level, reduction of cytokines driven by IL-17. We don't believe that we haven't seen any data where the BMS compound looked at IL-17 signaling. Just putting it in perspective, we just feel like this adds another key inflammatory cytokine that is regulated by MK2 and dependent on MK2 for activity in addition to the TNF, IL-1, IL-6, etc. Just adds to the possibilities both around the indications that we're interested in as far as mechanism validation as well as additional indications as Neal mentioned earlier. Okay, great. Yeah, that's helpful. Thanks, Joe. Just a clarifying question on the ITK/JAK3 inhibitor, ATI-2138. Can you clarify how you're thinking about the cadence of the updates here? Can we expect an announcement with the healthy volunteer SAD data, or are you planning to move this directly into a trial with patients and generate a potential proof-of-concept before, I guess, releasing the top-line results? I think at this point we're likely to announce some top line on the SAD portion, just so we indicate, you know, some clarity around the pharmacodynamics and the dose. I think that would be valuable information. Then the MAD, obviously we'll be doing that in patients. I think the remit there would switch a little bit in terms of just showing potentially some efficacy or some early efficacy in addition to some pharmacodynamics. We kind of look at those as just kind of SAD in healthy volunteers and MAD in patients is a little separate. I think, you know, I would expect at this time, you know, at least an announcement on the SAD to show that we're making some progress and then move on to the MAD. Okay. Makes sense. Thanks, Neal. Thanks, guys, for taking the questions. Sure. Thank you. Your next question comes from Chris Raymond with Piper Sandler. You may proceed with your question. Thanks. Thanks from me. Just on the three phase II studies for ATI-450. I think, Neal, I heard you say success might be the earlier of the three. I think I heard you say there's an interim look in maybe next year. Can you just clarify timing and then, you know, for the other two studies, is there a timeframe for an interim look in 2H 2022? You know, just a question that's come you didn't really talk much about is ATI-1777. Just noticing you guys didn't really provide any update on the clinical trial design for the next clinical work. Maybe when should we get more granularity on that design? Let me answer those for you. You're right. I mean, that's. There's only so much we could put into this deck, but I can provide an update now. A couple things. The study starts very imminent. RA is gonna happen first. HS will happen within, you know, like a week or two after. RA, by the way, I didn't provide this color either. RA is in 51 sites. Twelve of those are in the U.S. And then HS is 20 sites. That will be all U.S.-based. Psoriatic arthritis will be a study start in the early part of 2022, and that's 20 sites, and that's U.S. and Poland, where those sites will be located. That's kind of the cadence. We're not going to be doing any interim looks on either RA or psoriatic arthritis. You know, those are P-value generating studies. You know, it's tough to take a hit on that, you know, when you do an interim look. You know, I think it makes sense just to run those to ground and report the top-line data. HS, you know, we're looking at that as proof of concept. You know, I mentioned a little bit different primary endpoint. You know, we feel it's important to prove out the acute inflammatory aspect. We'll certainly look at the regular regulatory endpoint too. As many on this phone call know, HS studies can be a little difficult, and I think it would be important to perhaps, you know, look at, you know, an interim look as a way to pull some data forward and also make sure you're on the right track. We haven't finalized plans on that. That's something we're contemplating. We do think HS probably has the best shot, you know, just given that it's more POC in nature of reading out first. On ATI-1777, some thoughts on the trial design there. We're looking at, I think it's about a five-arm study. We're doing the top dose, which is 2%. That's the highest we could get in that formulation. That's BID, and we're also gonna look at 2% TD. You know, because we do believe that there's a chance for TD dosing. We also will look at a lower concentration. 0.5% is I think what we'll be looking at. That will be BID, and then, of course, the two-arm. You know, we're trying to check a number of boxes here, looking at both TD and BID dosing. Obviously, TD you know has a better, more advantageous profile than BID. It's always important in atopic derm topical studies to look at a lower dose, particularly when you start treating younger patients and also you know treating potentially more sensitive areas like the face. That's our thinking, and that'll kick off early next year in 2022, first half. We anticipate that data as well in first half of 2023. Got it. it. Great. That's great, Color. Thank you. Thank you. Our next question comes from Roger Song with Jefferies. You may proceed with your question. Great. Thank you for the presentation. A couple questions. First one is, you know, here the ATI-450, you have three phase II, and the two of them are p-value generating. I don't know. Can you just provide some high-level powering assumption for those trials? That'll be helpful. Given the hidradenitis is not p-value generating, how do you think about the go/no-go decision criteria for the phase II readout? The psoriatic arthritis study is powered at north of 83%, I think, is where we had that. RA is also in the 85%+ range. Similar powering assumptions there, and possibly just use some other comps to look at that. With HS, can you just repeat that question? I missed that last part. Yeah. It's not p-value generating. It's not powered, but just how do you make the go/no-go decision for that indication? Yeah. I think what we really wanna see there is, number one, quite frankly, we wanna make sure that the way we've designed it, that we've learned from others who perhaps can drive responses given clinical study design. I think that's kinda one piece. I think from my perspective, what I really wanna see is, you know, this is a disease that is certainly in its acute form, is characterized by a lot of inflammation. That's why we're measuring a mean change from baseline and acute inflammatory nodule and abscess reduction. If you drive positive effects there, then, the tunnel formation and fibrotic changes that are more long term. You know, you can imagine if you get a lot of pus in this area, you're gonna start getting fibrotic changes eventually because it's a constant inflammatory cycling on and off process. If we can show that we're driving a strong result on that primary, and if we're right about the mechanism, we should then that to me is the go decision. Because it in my mind, if we can get rid of the inflammation, certainly characteristic of the molecule of ATI-450 in general, the anti-fibrotic nature of it, the IL-1 data nature, which really is becomes more important in the later stages of hidradenitis. You know, I I'm very confident in that working, and then it's just powering it appropriately enough to check the boxes on the regulatory end points. You know, it's something I talk with investors about and also you guys on the sell side. I really like HS for an indication. The one part that just worries me sometimes is just thinking about the vagaries of the clinical study. I think our effort here is to show that we're right about the mechanism, and I think if we can show total reduction of the acute inflammation, that would be the go decision. All right. Thank you. Then for 2231. Since this MK2 HSP27 actually is the pathway for the resistance mechanism of the MK2 activation. If I remember correctly, ATI-450 actually has some kind of lower affinity for that complex versus the p38 alpha MK2. Maybe just can you provide some kind of a color around the 2231? What's the affinity for that particular complex with MK2 HSP27? Is that higher than ATI-450 and you potentially this is a better compound for the oncology versus ATI-450? Joe, do you wanna take that? I can take that. With respect to mechanism in the oncology setting, particularly pancreatic cancer setting, you're correct in that. The thought is that to try to skew the downstream effects to more of an apoptotic effect for the chemotherapeutic, you'd wanna block HSP27 phosphorylation, and that will just decrease the negative impact that would have on the apoptotic mechanism. You'd also wanna decrease the phosphorylation of another downstream substrate, Beclin-1, which would have an impact on the autophagy and the survival mechanism. Now as far as mechanistically or molecularly, what's happening with 2231 versus 415, the affinity of the complexes, both 2231 and enzalutamide bind tightly to the p38 and MK2 complex, lock MK2 into an inactive conformation, and prevent MK2 from phosphorylating HSP27 or Beclin-1. The affinity of either of these two, enzalutamide or 2231 for the MK2 HSP27 complex is low. But in our opinion, that's irrelevant in that the key is to block the phosphorylation of these downstream substrates that are involved in both inflammation as well as the resistance mechanisms in cancer. By blocking the p38 and MK2 complex and not allowing MK2 to be activated, that will just stop MK2 from performing its function of phosphorylating these downstream substrates. Got it. Okay. That's very helpful. All right, then maybe just one last one from us. For the gut-biased JAK inhibitor, maybe just tell us a little bit about what the targeted product profile is in terms of the efficacy case, given you have limited the systemic exposure, but high local and the potential kind of oncological impact. You know, because we know that tofa has the black box warning and the you know, so in terms of the clinical profile, how are you gonna differentiate with tofa? Yeah, I think, let me start out and then maybe hand it to Paul to fill in the blanks. I I mean, I think, you know, that the black box issue is certainly an overhang, right, in the space. I mean, we saw, like I said earlier, RINVOQ get some maybe a little bit watered down language. You know, maybe there's a lot more narratives to play out. I think, you know, the thrust of the data, at least preclinically, as Paul was trying to share, and look, we gotta do the work. We gotta see if that's validated within the clinic. I think what he was demonstrating there is that if one can design a drug that gets efficacy that starts or activity that starts to, you know, get right in the ballpark, if not better than tofa, yet not have nearly the same systemic exposure as tofa. Then it, you know, I think you have something there. In particular, a disease like IBD where there's a lot of unmet need. I think that's the way we think about it. I think the conclusion we've come to is that if you're too gut-selective, you're just not gonna drive an appropriate level of efficacy so that you need some systemic exposure. At the end of the day, it's kind of the same argument that we had for our topical soft JAK. That if you take a PK driven approach, and you say, "Hey, if I'm driving, you know, really nice efficacy or activity in the skin, then I can have a pretty minimal PK exposure." You know, if that actually matters in the grand scheme of things relative to just label considerations down the road, which is something that we don't know yet, then that's where you wanna be. I mean, any targeted approach, I think, is gonna be a better place to be than just, you know, more systemic. Paul, right, maybe you wanna fill in some blanks there. Sure. Thanks for the question. Fortuitously, just in the last few weeks, there was a very nice review in The Lancet Gastroenterology comparing all of the available IBD drugs, both small molecule and biologics. What they did essentially was sort of compare efficacy and AEs. The drug that comes out on top in their analysis, and I think we would agree, is Yes. RINVOQ. Efficacy is excellent, but it also comes out on top in terms of its side effect profile. I think that is the place we would like to position our compound. I think if there's biological efficacy in preclinical models, if our toxicology in cynomolgus monkeys, and if our early clinical data indicates we're having some activity, but we're not seeing the signs that would be consistent with systemic immune suppression, then we would be very excited, and I think we'll be hopeful. Clearly, when you look at this most recent review, the drugs that work the best have the worst AEs. It's just. That's just consistent across all these compounds and all these biologics. We're trying to provide, as Neal mentions, efficacy that approaches those compounds but minimizes the side effect profile, which is obviously a concern for these patients. Absolutely. Thanks. Great. Great. Thank you. Good luck. Yeah. Thank you. Thank you. As a reminder, to ask a question, you'll need to press star one on your telephone. Our next question comes from Ram Selvaraju with H.C. Wainwright. You may proceed with your question. Hi, this is Boobalan dialing in for Ram Selvaraju. Can you hear me okay? Yes. Yes. Okay. These are questions from Ram. Firstly, with respect to ATI-450 for RA, assuming your phase II data is positive data, do you intend to execute phase III study on your own or will it involve partnership? You know, I think if the data comes out how we hope and expect, I've been pretty consistent with this, and you always have the plan to go it alone. But I do think it's wise, you know, to look at partnership opportunities with an indication like this. It can be rather ambitious going after a large indication like RA. I think the clinical program, as I've mentioned in the past, is not just kind of single-threaded. I mean, the study we're talking about here is one study of a couple we're contemplating in the RA space. You know, we've talked in the past about potentially looking at monotherapy for earlier disease and trying to think about now what that broader programmatic approach is. I think as you start talking about breadth in clinical program, I think it obviously cost goes up, and complexity goes up. You know, I think if the data comes out how we hope and expect, we would be, you know, very interested in looking at a larger partner. Thanks for the clarity. With respect to HS trial, can you frame the market opportunity in HS for ATI-450? In your view, what would be the ideal attributes of an HS drug? Well, I think clearly we, you know, self-serving, I guess, but, you know, we think an oral approach makes sense. You know, we've seen some of the data with the biologics and, you know, I think as we often see in a lot of these markets, as the epidemiology and the pathophysiology of these diseases gets better understood, you see more and more interest in the space. We do think going after an oral approach makes a lot of sense. Patients prefer that. You know, something where if you're dosing either BID or TID, I think would be advantageous to an injectable. The other aspect is just like, you know, as we talked before, and I think hopefully we've highlighted here today, is that we have a molecule that takes out a number of legs of the stool. You know, we're not single-threaded at, you know, just going after TNF as an example. You know, we hit a number of the cytokines that are key to the disease. You know, one of the things that I like about, you know, this molecule is the potential to hopefully intervene earlier. Because like I alluded to before, often you don't catch these patients until they have quite a bit of fibrotic change, you know, quite a bit of tunnel formation. If you can catch them in the acute inflammatory stage a little earlier, you know, you don't get. You don't have to get a patient that suffers through all of that, all of that kind of recalcitrant disease. To me, the ideal compound would be, you know, something oral, something that addresses the spectrum of disease, which, you know, ATI-450 certainly does as it relates to HS. You know, I think there's also an opportunity to try to migrate a little bit earlier here as well. I mean, there's always reimbursement headwinds when you know, you make a statement like I just made where, you know, we have a desire to migrate earlier in the disease. You know, when we're talking about, you know, not getting on the market for a number of years, I think a lot of those things can change and good data can help change that. That's the way we think about it. Okay. Thanks for the color there. With respect to ATI-1777 for the atopic dermatitis, will your future phase IIb study involve pediatric patients roughly? Secondly, you used modified EASI score, peak score as your primary endpoint in your phase II-A. Do you anticipate studying the drug a little bit longer in your phase II-B study, say like week 16, given some competitors have used this time period for their investigational drugs? Right now we're in the throes of looking at the lower bound. We've sent some correspondence to the agency to see if we can get down to at least 12-year-olds. You know, I don't think we'll be looking at anything, you know, any ages lower than that. You know, relative to the. Sorry, I'm blanking on the second part of your question. Can you ask the second part? Yeah, yeah. Absolutely. You looked at EASI score at peak score as your primary endpoint in your phase II-A. Yes. Do you anticipate studying the drug a little longer in your phase II-B study? You know, I've been a firm believer that if you aren't, you know, just having lived in this space as a practicing physician, I'm kind of a firm believer that, you know, it's important in a disease where you're treating the flare, that you show something robust at four weeks. In the study, we're gonna do four weeks. I'm well aware of the other companies and assets that look at 16-week endpoints. They're a little bit different, you know, when you're talking about administering a biologic. Sometimes it takes a little bit longer for that to show the effect you'd like or the peak effect. You know, I think we're showing a nice effect and nice activity thus far at four weeks. We do have the ability to look longer, as in every AD trial you have to do an open label safety study. In that respect, we can pick up additional data that shows, you know, what that curve looks like as you treat longer. I'm a firm believer that four weeks is the key in this indication. Okay. That's all I have. Well- Thanks for taking my question. Thanks. I'm not showing any further questions at this time. I would now like to turn the call back over to Neal Walker for any further remarks. Well, I wanna thank everybody for joining us here today. Really appreciate the questions. You know, as you can see, I think the team's been working really hard. All credit to the folks in St. Louis and Wayne for driving hard all year through, you know, some pretty challenging times during this pandemic. I think hopefully what we've been able to convey is that we have a real platform here, and that platform consists of not only our kind of tangible asset and proprietary chemical library, but also the intangible asset or maybe more tangible than we believe, which is the people. You know, we have a great team that is able to work through looking at these molecules in interesting ways. You know, hopefully the data shown on IL-17 was yet another example of that. We're proud of the work that we've been able to generate thus far and, you know, we look forward to continuing to drive shareholder value over the coming years. Thanks everybody for attending.