Morning everyone, and welcome to the Cue Biopharma Conference Call on the CUE-221 CSU phase II top line results. After the speakers' presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one one on your telephone. You will then hear an automated message advising that your hand is raised. I would now like to turn the call over to Agnes Lee, Chief Investor Relations and Communications Officer at Cue Biopharma. Please go ahead, Agnes. Good morning, and thank you for joining us today. Before we begin our formal comments, let me remind you that during today's webcast, we will be making forward-looking statements that represent the company's intentions, expectations, or beliefs concerning future events. These statements represent our views as of this date, are subject to risks and uncertainties, and should not be relied upon as representing our views or of any subsequent date in the future. As a reminder, this call is being recorded, and a replay will be made available on the investor section of Cue Biopharma's website following the conclusion of the event. With me on the call today are Dr. Shao-Lee Lin, our President and Chief Executive Officer, and Dr. Dominic Borie, our Chief Medical Officer and Head of R&D. Dr. Lin will open the call and then hand off to Dr. Borie to walk through the study data. Dr. Lin will then close our prepared remarks, and we will take questions. With that, I will now turn the call over to Shao-Lee. Thank you, Agnes, and good morning, everyone. Thank you for joining us. Today, we are reporting results from the phase II study of CUE-221 in the chronic spontaneous urticaria, or CSU. We're pleased to share that the study results were positive and that we will be reviewing together those top-line clinical results with you today. The key takeaway is that CUE-221 met its primary and key secondary endpoints in a manner that reinforces our enthusiasm for the precision-engineered unique dual mechanism of action of CUE-221, and its potential to offer clinically meaningful and differentiated benefit in IgE-mediated disease. Slide three summarizes the salient findings from the study. The study demonstrated robust, durable, and dose-responsive clinical effects. The primary endpoint of complete resolution of hives, or HSS7=0 at week 12, was met with the treatment effect further increasing past the final dose at week 16 to its peak at week 22. The key secondary endpoint of complete response, or UAS7=0, was statistically significant in the high-dose group, further supporting the clinically meaningful impact of CUE-221. These results were achieved in a context of a favorable safety and tolerability profile. Of note, for the CUE-221 high-dose group, both the complete resolution of hives and the overall complete response persisted for 12 weeks or a full quarter, and on the order of five half-lives after the last dose. This was not seen for the lower doses or for omalizumab, despite a comparable dose level, highlighting a fundamental clinical difference consistent with the biological design differences between the two drugs and supporting the concept that CUE-221 has the potential to be a disease-modifying therapy. This marked difference observed off drug at week 28 relative to omalizumab provides our first clinical evidence supportive of the CUE-221 engineered dual mechanism of action that includes not only blocking of the IgE-mediated allergic cascade, like omalizumab, but also supports the clinical potential of downregulation of new IgE production unique to the design of CUE-221. Additional PK and IgE data are of interest, and while not available today, will be the subject of further modeling analyses and future presentations at upcoming medical meetings. Based on this demonstrated potential for differentiated clinical efficacy in CSU and the potential to develop a new tool to target disease modification and the concept of functional cure for IgE-mediated diseases, we are more than excited to now plan both a phase II-B/III next study in CSU as well as a phase II study for food allergy. I will now hand the call over to Dominic Borie, our Chief Medical Officer and Head of Research Development. Dominic? Thank you, Shao-Lee. Let me take a couple of minutes to quickly walk the audience through the science behind CUE-221. First, reminding ourselves that IgE drives allergic disease by engaging two receptors. The high-affinity receptor, shown here on the left, through which IgE and the allergen will trigger degranulation and allergic symptoms. And the low-affinity receptor, also known as CD23, shown on the right, which is expressed on the surface of B cells and has an important role too, as when bound by IgE, it triggers a natural negative feedback loop that results in reduced IgE synthesis. On slide five, CUE-221 was designed to block IgE binding to the high-affinity receptor, and in doing so, provides potent IgE neutralization or IgE blocking. CUE-221 high binding affinity for IgE, shown here on the left, supports a greater potency at preventing IgE-mediated cell degranulation over omalizumab, as shown on the graph on the right. On slide six, on the flip side, CUE-221 was also designed to preserve IgE binding to CD23. This was achieved through selecting binding sites on IgE that are distant from the IgE region that engages CD23, whereas the binding site on IgE for omalizumab and its analog, RPT904, is the same as shown on the right and overlaps with the CD23 binding site, and therefore does not allow the drug IgE complexes to bind CD23. On slide seven, as the result of the difference in engineering, increasing concentrations of IgE in complex with CUE-221 can bind to the CD23 receptor, as shown by the orange curve on the right, whereas no binding at all was measured with IgE in complex with omalizumab, as shown by the gray triangles. On slide eight, the biological impact of preserved binding to CD23 was demonstrated both at the mRNA and at the protein level, where addition of CUE-221 resulted in a significant reduction in IgE synthesis, shown by the orange bars, that was not observed for omalizumab, in gray bars, indicating that omalizumab in complex with IgE cannot block new IgE production. On slide nine, it was therefore very exciting to test the clinical impact of these fundamental biological differences in the context of a phase II randomized, double-blind, and placebo-controlled study. An omalizumab arm was included for comparative efficacy and safety, but no formal statistical testing was planned. The study enrolled participants with moderate to severe chronic spontaneous urticaria, or CSU, inadequately controlled with H1 antihistamines. Patients were randomized to either one of CUE-221 dose groups at 1 mg, 2 mg, or 4 mg/kg, administered subcutaneously, or to omalizumab at the registered dose or to placebo. All patients received subcutaneous injections every four weeks, and the primary endpoint was assessed at week 12 and measured the rate of complete resolution of hives, or HSS7 score of zero. This endpoint leverages an objective assessment of the number of hives, which is carried out by the physician, and achievement requires all clear skin or no hives. The final dose in the study was administered on week 16 for all groups, and after which patients were monitored off drug for 20 weeks through week 36. Slide 10 shows the subject's disposition for the trial. Two subjects were randomized but not dosed, one in the 4 mg/kg group and one in the omalizumab group. The dropout rates are in range with expectation for a clinical trial of that duration, further considering the five-month observation period of drugs. This study was analyzed using a modified intent-to-treat approach. The two subjects who were not dosed were not part of that analysis, but all other subjects were included in the modified intent-to-treat analysis. On slide 11, the baseline characteristics were overall well-balanced across groups. Disease duration ranged approximately for four-six years across groups, and mean baseline Urticaria Activity Score 7, or UAS7, were in the 28+ point range, indicative of severe disease activity. On slide 12, getting to the results, we are excited to report that the study primary endpoint was met. Complete resolution of hives, HSS7=0 at week 12, was significantly higher than placebo for all dose groups in a dose-responsive manner with a high P value of less than 0.005 for the high dose group. On slide 13, the key secondary endpoint of complete response for UAS7=0 was also met, and the difference versus placebo was statistically significant for the high dose group. On slide 14, another way to visualize the depth of response is to measure the change from baseline in UAS7 score at week 12, which was found to be profound and statistically significant across all dose groups. On slide 15, this slide captures the depth of response at week 12 by presenting the percent reduction from baseline in UAS7 across various mechanisms. Although we note that cross-trial comparisons are for illustrative purposes only and should not be interpreted as direct comparison of efficacy, across various modalities, CUE-221 seems to come closest to providing full control of disease activity. On slide 16, if you allow me to shift gears now, I want to focus on additional exciting findings arising after the week 12 primary endpoint. On the middle graph, across all CUE-221 dose groups complete resolution of hives continued to increase beyond week 12 and peaked at week 22, which is six weeks after the last injection, in a dose-responsive manner. More than 2/3 of subjects in the high-dose group responded and achieved complete resolution of hives. Now if we look at the week 28 results, this is a time point when patients have been off drugs for 12 weeks. This corresponds to approximately five half-lives after the last dose for both CUE-221 and omalizumab, given expected half-lives of two-three weeks for these IgE monoclonal antibodies. Let's also note that the 4 mg/kg dose is, for a 70 kg patient, the molar equivalent of a 300 mg XOLAIR dose. At that week 28 time point, where 60% of CUE-221 patients are still experiencing complete resolution of hives, only 24% of patients in the omalizumab group are. This stark contrast cannot be explained only by pharmacokinetics, as residual circulating drug concentrations are likely extremely low to nil for both groups. Rather, we think that this indicates a fundamental difference in biology and provides clinical data indicating that for the CUE-221 dose group, there is something different happening, which is more than just IgE neutralization. Note that a post hoc Fisher's exact test was run and found that the difference between CUE-221 and omalizumab was statistically significant. On slide 17, to provide further perspective, we are providing here this line graph showing the rate over time of HSS7 for the 4 mg/kg CUE-221 dose group, shown in orange, versus omalizumab and placebo. After the initial injections, there is a rapid clinical impact, and we can then clearly see the curve diverging after the last injection, reaching the maximal difference at week 28 as we previously discussed. This graph clearly shows the sustained high rate of complete hives resolution throughout the 12 weeks that follow the last injection of CUE-221. After week 22, both curves are converging again, trending towards the placebo response in the absence of further administration of drug beyond the week 16 dose. On slide 18, similar to the results seen for HSS7 of zero, a similar pattern of efficacy was seen with the complete response rates for UAS7=0, which was also sustained for over 12 weeks of drug for the high-dose group. Again, with the same pattern of marked clinical impact over omalizumab and supportive of fundamental difference in biology that is consistent with a differentiated mechanism of action. On slide 19, building on the prior slides, we can start contrasting the features of IgE-targeted therapies. What we think stands out from the week 12 data is that IgE neutralizer, like omalizumab or RPT904, which share the same binding epitopes and therefore the same biology of IgE neutralization. They appear to perform closer to CUE-221 low doses rather than CUE-221 high dose. Later time point data has not been made publicly available for RAPT. Again, we are extremely pleased with the different efficacy profiles seen with CUE-221 over omalizumab at week 28 off drug as it supports fundamental biological differences, which may be directly deriving from CUE-221 engineering. On slide 20, from a safety standpoint, CUE-221 was well-tolerated. There was no treatment-related serious adverse event, or SAE, and no adverse events of anaphylaxis. Treatment-related adverse event of special interest was limited to one case of Grade 2 injection site reaction. There were two instances of treatment-related adverse events leading to study discontinuation. Namely, one case of worsening urticaria and one incident of insomnia. As expected, there were no deaths in the study. On slide 21, to help place these safety findings in context, and because safety considerations will be part of the benefit/risk analysis when comparing across different mechanism of action, this slide provides a summary of anticipated side effect profile for different mechanisms investigated currently in CSU. We believe that CUE-221 dual MOA should not introduce specific mechanism-related safety that will be different from sole IgE neutralizer, even in the presence of possibly more potent IgE control, and this will be contrasting with the recognized mechanism-related safety findings of other MOAs. We do recognize that broad interest for the field of allergy and IgE-mediated disease results in additional MOAs currently tested at earlier stages of clinical development. We believe that although still emerging, CUE-221's potential is already more developed, and we look forward to further characterizing CUE-221 safety and efficacy profile for IgE-mediated disease. On slide 22, altogether, we are extremely excited to have clinical results in hand that indicate the potential to reach a functional cure for IgE-mediated disease. This did not happen by chance, but may result from the fact that from the very beginning, CUE-221 was engineered to be different from omalizumab and to not only block the high-affinity receptor, but do so while preserving the binding to CD23. The preserved capacity of CUE-221 IgE complexes to bind CD23 results in reduced IgE synthesis at the mRNA and protein level, something that was not seen with omalizumab. Here, we now have clinical data strongly supportive of fundamental biological differences between CUE-221 and omalizumab. We are eager to characterize the PK/PD relationship, and will be presenting these additional results at an upcoming scientific conference. On slide 23, I will not read this final slide, but it may be helpful to keep it staying up during the Q&A session. Thank you for your attention, and now I will hand it back to Shao-Lee. Thank you, Dominic, and thanks to those who have dialed in to be with us today. As you can see, we are very pleased with the potential that CUE-221 has now demonstrated clinically, and which is consistent with its novel precision engineered dual mechanism of action. Based on these exciting positive results, we are working towards the initiation of a phase II-B/III study in CSU, in addition to our planned phase II study in food allergy. I would like to thank the Genesis Life Sciences team for designing and executing a robust phase II trial. I would also like to extend our gratitude to all the patients, investigators, and study staff who participated in this trial and supported the advancement of CUE-221 for allergic disease. It has been a privilege to be at Cue over the past five months and witness all the hard work and progress across our portfolio, and I want to thank the entire Cue team for their commitment to our mission to identify and advance transformative therapies designed to enable functional cures across immunologic diseases. We could not do what we love to do without the support of our board, investors, and the patients we strive to serve. With that, I will open the call for Q&A. Thank you. To ask a question at this time, you will need to press star one one on your telephone and wait for your name to be announced. Please stand by while we compile the Q&A roster. Now first question coming from the line of Maury Raycroft with Jefferies. You may ask now. Hi, good morning. Congrats on the data update, and thanks for taking my questions. For the phase II-B/III CSU study, should we expect a longer dosing interval than the every-four-weeks schedule using the current study? Will you also evaluate additional dose levels? Is there anything additional on timing for when the CSU and food allergy studies could start? Yeah. Hey, good morning, Maury, and thanks so much for joining us, and thanks for the question. Yeah, I think we wanted to indicate with the II-B part of the phase II-B/III that we're interested in understanding a little bit more about the PK IgE and response. We feel like we have a fantastic dose at this point with monthly dosing that's differentiated. We'll likely utilize that as an anchor, but nothing's definitive yet. We're going to also explore, given the biology that we're seeing, how best to optimize dosing for each indication. For CSU, or actually for any indication, for instance, we think that we have something where we can think about fixed dosing. We think based on the profile that we're seeing, there's the potential to think about things like an induction and a maintenance regimen where we're fundamentally modifying some disease biology in the background. We think about this bathtub analogy and sort of not just emptying the bathtub from blocking or neutralizing IgE, but also turning off the spigot relative to the formation of new IgE. One can imagine if you can continue to turn that off better and better over time, that you might reach a point where the interval of dosing now, instead of induction to achieve that time point, becomes a lower dose and less frequent, in terms of a maintenance. All of these things, I think we're going to explore, interrogate the data carefully, and determine what the best sort of approach is to continuing to collect information about this new tool that we have to help patients with IgE-mediated disease. That's how we're thinking about it for CSU. From a timing perspective, obviously, we think we have something important for patients, and we'll move as quickly as we can relative to that. I'd say for food allergy, something completely different. We think of food allergy as a life-threatening disease. In the context of thinking about that in that way, we think that this new tool gives us, as Dominic was saying, the potential to approach this from a functional cure perspective, meaning that we don't want just 2/3 of patients having protection against three peanuts some of the time. We want to get as close as possible to 100% of people having 100% protection all of the time. As close to that as one can imagine getting. We'll approach at this sort of new tool, new mechanism, new potential to modify disease in a way that will aggressively pursue that ideal. We don't think about this from a convenience perspective. I care less in that instance if it's achievable, whether this is dosed every six months, three months, or even weekly. But really about whether or not I can create an entirely different paradigm for ourselves and our kids and our families who have this life-threatening condition. So, hope that helps, and thank you for your question. Yeah. All makes sense. Great perspective there. One other specific question on the data. You reported change from baseline in UAS7, which appeared fairly similar across the CUE-221 dose groups and omalizumab. How did HSS7 change from baseline compare across the treatment arms, and are you seeing a similar pattern there as well? Yeah, the patterns that we've seen across the endpoints have been very similar, which has been comforting to us from a robustness of the signal that we're seeing. We chose the change from baseline percent to compare with others because there are some studies that have placebo and some don't, and some have active comparators and others don't. This was the best way to have an internal sort of a given arm to itself comparison within the context of its own study. Got it. Makes sense. Thanks for taking my questions. Thank you so much, Maury. Thank you. Our next question in queue coming from the line of Mayank Mamtani with B. Riley Securities. Your line is now open. Yes. Good morning, team. Thanks for taking our questions, and congrats on the spectacular data here. On the response building for six weeks after the last dose, which was not a phenomena for omalizumab, is there anything in the diary data that separates continued deepening in existing responders from maybe new responders converting late? I was obviously interested in that because a neutralizer with long half-life can only hold an effect, whereas your mechanism maybe can have that depth of response coming in late. If you could talk to that. Yeah, Mayank. Thank you for that. I think maybe the best place to see that is in the line graph or in the bar chart before that. I know we're not synchronized in terms of projecting, so I'll have to ask you, the audience, to go to those slides yourselves. The bottom line is all of these representations are actually for complete resolution of. So resolution of hives is what we've shown the line graph for. There's no sort of deepening of response beyond the zero, right? The percentage just tells you the percentage of individuals that achieve that complete resolution of, in this case, hives response. We are definitely getting that. If you look at what we think is particularly amazing about the line graph is what I'm looking at currently, you start to see the separation by week eight. You see the space between the gray line and the orange line, which is XOLAIR versus the 4 mg group. That area under the curve is really quite striking. If you follow the gray line, which is omalizumab from the last dose, which is week 16, and follow your eye down to the week 30 time point and extend that line, you can really see how that continues to degrade towards the placebo line. There was maybe one subject that sort of even off drug at that period of time spontaneously improved, which happens in this disease state and certainly happens with small numbers. You can see how that's degrading towards placebo, which you expect five months off of drug. What was surprising was the durability of the 4 mg group off of drug. Again, as Dominic pointed out, sort of same milligram dose level, therefore same molarity because they're both monoclonal antibodies, same sort of number of half-lives off of drug, which is like four-five, so the drug itself should really be gone, and yet the effect is still there. It tells us that there's something fundamentally different in terms of the biological effect that's happening in those outer weeks between omalizumab and CUE-221. For us, given that CUE-221 was engineered specifically with a second mechanism, our assumption at this point is that that's that second mechanism in terms of synthesis of new IgE that's kicking in. One can imagine then, for instance, that over time, if you are in fact effective against, again, turning that spigot off and decreasing free IgE over time, that that may actually cross zero at some juncture and modify the way that you approach the dosing of the disease itself as well. You can think about mechanistically things like total IgE and receptor engagement on the effector cells or the high affinity receptor really downregulating those receptors and making those effector cells more quiescent over time. Then you can think about also turning off the synthesis of new IgE and reaching some sort of steady state that fundamentally is disease-modifying for these patients. That's what we're going to explore at a bare minimum. Purely clinically, all of the scientific hypothesizing aside, the bottom line is that we have a remarkable clinical difference here that we think is meaningful for patients. Pointing to the fact that this molecule is providing a new tool by which we can approach getting more for each of these patient types. Thank you. That was very thorough. I think the IgE data also will help as that becomes available. Maybe my follow-up was, do you have baseline IgE data? I did not see that in the table. I was also asking that in context of CSU, the range is very narrow in the 100 sort of range. With food allergy, the baseline IgEs can be much higher. If you could maybe comment on how you are thinking of what the induction maintenance paradigm, some of it I know you commented, but what high dose levels you could go there, just because of where you are starting with your IgE levels. How does the data here inform how you progress in CSU versus food allergy? Yes. Thank you for that, Mayank. I think we are very excited to be able to provide specific IgE, PK response data, and modeling associated with that. How we are thinking about that relative to each of these disease states, as we said, at a future scientific meeting. That is not us being coy, to be clear. We have the clinical data at this juncture. We definitely wanted to make good with our promise to provide data by the end of the third quarter, which is what we are delighted to be able to do at this time. Those data otherwise are just not available at this juncture. The way I think about this, it would be a tremendous grand slam to have both of those pieces together today, and tell you the other piece of the story. The way I think about this, certainly as a clinician and a drug developer is, if I had the bioassay data today, I would be asking myself, yes, but is it clinically relevant? What does it really mean clinically? That is really ultimately the takeaway. I think that we are incredibly fortunate to have very clear clinical data, despite the relatively small numbers. It is a phase II trial. It is not tiny, but it is also not massive. To get the kind of clarity across endpoints, the kind of statistical significance that we are seeing with these numbers, we are very pleased by. We think it is very clean and very consistent. It is telling us that there is something different, and we can argue about what that thing might be, but we think the most likely, Occam's razor and all, we think it is most likely the thing that it was engineered to do. More to come there. Makes a lot of sense. If I could, final question. On ADA formation, anything on tolerability, on immunogenicity, if you could comment, because that obviously is relevant as you develop this in sub-Q format. I know there was one patient in your phase I that had nausea, headache. Just clarify if you've not seen any of that. Thanks again for the new question. Yeah. Apologize, Mayank, I didn't quite hear the first part of your question, but I'll go ahead and address the second part, which is, from a safety perspective, we feel very, very good about the profile. You saw the table with all the zeros all over it. There hasn't been anything. That subject in the phase I think it's stated clearly in the supplemental as well, it was not deemed to be related to study drug, if I recall correctly. Yeah. Sorry, the first part was about ADA or any immunogenicity comments. Oh, yeah. Like PK, like IgE, ADAs, these are things that require assays to be run. Yeah. And with typical studies, this is not specific for this particular study, we will batch them at the end so that they are all run at the same time, which eliminates some variability associated with them and some noise. They typically come after the clinical data. That is what you are seeing here. Thank you. Our next question in the Q&A queue coming from the line of Dev Prasad with Lucid Capital Markets. Your line is now open. Hi. Congrats on the update and the data, and thank you for taking our question. I have a couple of questions. One is, if we look at week 12, the 4 mg/kg and 2 mg/kg dose are nearly identical at 54% and 53% for HSS7. But they are substantially different at week 28 at 60% and 31%. How do you interpret that item pharmacologically? Does it suggest a 4 mg/ kg crosses an exposure threshold required for durable expression, or is it just accumulation? One question on planned phase II-B/III design. Are you aiming to demonstrate superiority over placebo or omalizumab or both? Thank you. Yeah, no, great question. Maybe I will take the second question first, which is, are we planning to design a head-to-head trial, I think is what you are asking us. I think that is to be determined. I think we had shared previously that based on the phase I data and what we were seeing relative to a single IV dose really having a very prolonged effect on suppressing IgE below limit of quantification, that we were especially interested in this molecule and its potential in food allergy, because it is such a strictly IgE-mediated disease, so it seemed like the perfect place for something like this. We now feel doubly excited about food allergy as a result of that. We had also always stated that CSU is a more complex disease, has lots of potential mechanistic aspects that are involved in the disease state. How much more we would get with better IgE coverage was an unknown, and we would commit to CSU if it had the potential to be differentiated. I think what we're seeing with these data, we feel, again, very clean, very consistent, dose response is statistically significant, and the line graph really says it all in terms of the difference between those curves, not just at one point, but across the experience of what these patients are achieving, and then a durability 12 weeks thereafter. With these data, we're committed to the phase II-B/III for CSU. Some of the things, as I shared with Maury earlier as well, is in terms of exactly what those dose levels will be, and whether we'll run an active comparator in a head-to-head fashion, I think is TBD as well. Yeah, maybe to the first start of your question about the differences or potential differences between the 2 mg/ kg and the 4 mg/ kg dose. You're correct that there is a slight difference at week 22, but that may not be where it's the most relevant to look at it. I think we agree, for example, when we looked at slide 16, that these two dose levels seem to behave somehow similarly at week 12, but maybe with some slight separation at week 22. What we think is really relevant is to look at week 28, after dose, and that's where maybe we start unmasking this second mechanism by the fact that the 4 mg/ kg dose really seem to have done something in excess of the 2 mg/ kg, so. Maybe to add on to that, just to reiterate that that isn't an exposure issue. Because again, these are antibodies that have a regular monoclonal antibody half-life of two to three weeks, and so we're four to five half-lives out at week 28. We don't expect a lot of drug around. It's less about an exposure issue in our minds and more likely a biological threshold effect. We obviously are biased given, again, the design of the molecule to have one explanation for all of this, which is, we know we were designed to have the potential to continue to utilize the natural mechanism to dampen new IgE synthesis. We think as the total IgE complexes are formed, as they stabilize as a total IgE complex, we have the benefit not only of sopping up the IgE, preventing it from binding to the high affinity receptor, but also utilizing that complex to be a high IgE state, if you will, and dampen new IgE production. It's not unreasonable to think that that has a threshold associated with it. Very excited for CSU patients, we think for food allergy patients, and then frankly, the CSU study being a complex disease and having this kind of effect gives us enthusiasm for other disease states like atopic dermatitis, allergic asthma, et cetera. More to come as we continue to explore the biology and think about our study designs moving forward. Great. Thank you. Thank you, Dev. Really appreciate it. Thank you. There appears to be no more questions in the Q&A queue at this time. Ladies and gentlemen, this does conclude today's conference call. Thank you all for your participation, and you may now disconnect.