CUE

Good day, and welcome to the Cue Biopharma Second Quarter 2024 Earnings Call. All participants will be in a listen-only mode. [Operator Instructions] After today's presentation, there will be an opportunity to ask questions. [Operator Instructions] Please note, this event is being recorded. I would now like to turn the conference over to our Chief Executive Officer, Mr. Dan Passeri. Please go ahead, sir.

Thank you, and good afternoon, everyone. As a reminder, this presentation and discussion is being recorded and will be available on our website for the next 30 days. Also, please be aware that the slides accompanying today's update may be advanced directly by those listening in and we will notify you on what slide we're on throughout the presentation. Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; and Dr. Matteo Levisetti, our Chief Medical Officer. Shown here on Slide 2, this presentation and overview may contain some forward-looking statements, and any forward-looking statements made during this call represents the company's views only as of today, August 19, 2024. I'd like to begin the call by providing you with some context pertaining to our recent announcement focused upon near-term developments with our autoimmune programs and associated corporate restructuring. I'll begin with a brief synopsis of the objectives underlying these measures. And just to underscore, we carefully assessed our strategic positioning and evaluated various options for optimizing probabilities of success within the challenges and constraints of the current capital market conditions. The measures recently implemented aim to reduce our capital requirements, while also achieving enhanced productivity through what we consider to be basically a balanced business model focusing upon accessing capital and additional resources through a series of anticipated strategic partnerships. Furthermore, we've taken measures for our clinical data to further mature to enhance competitive positioning, particularly relating to patient survival data, enabling near-term cost savings and delaying the launch of a capital-intensive trial towards registration. This path provides a higher probability of success as more mature data should bolster the veracity of our mechanistic advantages for establishing the potential of a new standard of care for cancer patients. As shown in Slide number 3, we believe we've developed a breakthrough proprietary therapeutic approach to establish a new standard of care for treating both cancer and autoimmune diseases by restoring immune balance to the patient's immune system. As Matteo will elaborate upon shortly, our data from the ongoing CUE-101 Phase 1(b) trial clearly demonstrates evidence of substantial prolongation of survival in patients treated with CUE-101, monotherapy in the second line plus setting, and emerging data from the combination trial in front line with KEYTRUDA, that's pembrolizumab, that also appears to be following a similar pattern as what we saw with the monotherapy trial. We believe this data to be quite remarkable underscoring what we believe to be the true competitive positioning of our approach. As such, it's our intention with the measures taken to enable clinical data to further develop and mature in support of our foundational platform that we believe can induce effective and long-lasting anti-tumor activity or can be harnessed to rebalance the aberrant immune responses to address autoimmune disease. We've also made significant progress with our lead autoimmune disease program, CUE-401, being developed in collaboration with our partner, Ono Pharmaceutical, to address multiple autoimmune and inflammatory diseases, such as rheumatoid arthritis, graft-versus-host disease, lupus, inflammatory bowel disease, psoriasis, multiple sclerosis, amongst others, representing large, multi-billion dollar market potential addressing significant unmet medical need. Through this partnership, we've made impressive progress to date in moving towards selection of a lead candidate, which we anticipate in the first quarter of the coming year. Our collaboration with Ono has been highly productive and supportive, resulting in a growing body of promising data demonstrating the ability of CUE-401 to generate and expand regulatory T cells or Tregs fostering disease control in several disease models tested to date. As a reminder, Cue Biopharma has retained an option to a 50% U.S. co-development co-marketing right to CUE-401. Turning to 501, this program continues to advance and progress forward with the potential of eliminating autoreactive B cells with a highly selective and well-tolerated biologic. This program has the promise of addressing multiple B cell mediated autoimmune diseases, such as lupus, myasthenia gravis, Sjogren's disease, and myositis, amongst others, representing significant unmet medical needs with large multi-billion dollar market potential. Furthermore, the same mechanism of action that we would be seeing in B cell ablation for autoimmune disease may be deployed to address B cell malignancies, such as B cell lymphoma. We're presently assessing strategic partnering alternatives for furthering the development of this promising program, and look forward to providing updates as they become available. We have positioned ourselves with a growing portfolio of highly promising drug candidates in both oncology and autoimmune disease, all of which represent significant market opportunities addressing major unmet medical needs. We believe we've de-risked and validated our therapeutics platform with the existing data sets from our CUE-101 and CUE-102 programs, and have established foundational preclinical data pertaining to our autoimmune programs with potential to rebalance the patient's immune system to restore health. We've implemented a cash-efficient business model enabling a reduction of capital requirements with an emphasis on validating near-term partnering structures. I'm going to now turn the call over to Anish, who will describe the core attributes and advantages of our approach for treating autoimmune disease, as well as provide some additional context on our underlying platform developments for both oncology and autoimmune disease. After Anish, Matteo will provide further updates on the CUE-101 and -CUE-102 clinical trials and highlight the importance of the maturing data sets with particular attention to the survival metrics that are emerging. I'll then return for a brief summary before opening the call up to questions. Anish?

Thanks, Dan, and good afternoon to all listening in on today's call. I'll start by briefly summarizing our platform and the significant potential of our approach for restoring immune balance for treating cancers and autoimmune diseases. As described previously, the Immuno-STAT platform enables selective modulation of disease relevant immune cells, while avoiding broad perturbations of the immune system. This approach allows us to maximize efficacy, while preserving patient safety. As Dan indicated previously, and as summarized on Slide 3, we have now clinically validated Immuno-STAT’s via the CUE-100 series that selectively and safely delivers the potent cytokine IL-2, along with a TCR-activating signal, to preferentially activate tumor-specific T-cells while sparing all other irrelevant T-cells. This selective stimulation allows for the generation of a therapeutic index for IL-2, which has eluded many others trying to develop IL-2-based cancer therapies. In over 120 patients dosed, we have demonstrated a remarkable increase in efficacy with favorable tolerability. Matteo will provide further details on the latest clinical data that continue to demonstrate impressive benefit for patients being treated with CUE-101 and CUE-102. On the autoimmune front, we are focused on two distinct and highly promising approaches to reset immune balance. CUE-401 is a novel bispecific that stimulates the generation and expansion of regulatory T cells. Regulatory T cells, or Tregs, possess the ability to dampen and control autoreactive lymphocytes, hence are an important cell type to maintain immune homeostasis and health. CUE-401 has been partnered with Ono Pharmaceuticals and this collaboration continues to move forward strongly. In addition to CUE-401, we've also made significant progress developing CUE-501 from the CUE-500 series to enable T cell mediated depletion of B cells. This approach has the potential to deliver CAR-T like efficacy in a biologic while preserving patient safety, which offers significant differentiation from other competing approaches. Both CUE-401 and CUE-500 series are designed to address large patient populations across numerous autoimmune and inflammatory diseases with a multi-billion dollar market potential. We will expand on both programs in the next few slides. The next slide, Slide 4, exemplifies the unique attributes of CUE-401 in induction and expansion of Tregs. CUE-401 is a bispecific composed of the two key cytokines, IL-2 and TGF-beta that are known to convert peripheral CD4 T cells into Tregs, as well as expand pre-existing natural Tregs. This ability to induce new populations of Tregs provides CUE-401 with the prospects of significant superiority over other approaches deploying IL-2 variants to focus on only the pre-existing natural Tregs. As shown in Slide 4, we believe the mechanism of action of CUE-401 to enhance Tregs is qualitatively and quantitatively superior to IL-2 muteins targeting CD25, which is the high affinity subunit of the IL-2 receptor expressed on regulatory T cells. Slide 5 highlights data sets that show superiority of CUE-401 over an IL-2 mutein analog currently in clinical development for Treg generation. As shown on the left side of the slide, in an in-vitro human MLR assay, which is an in-vitro model for graft-versus-host disease, CUE-401 induces differentiation and expansion of Tregs. In contrast, a Treg directed IL-2 mutein is unable to achieve these effects. The bottom left panel confirms that both IL-2 and TGF-beta signals are needed for Treg generation, either alone is unable to achieve this effect. As shown on the right side and as previously discussed, short-term administration of CUE-401 results in long-term protection from autoimmunity, in this case, autoimmune gastritis. In our ongoing collaboration with Ono Pharmaceuticals, we have further extended the in-vivo efficacy with CUE-401 in several other disease models where we have noted a significant increase in Tregs accompanied by a notable decrease in pro-inflammatory cytokines. Let's now move to Slide 6 to provide an overview and update on the CUE-500 series for B cell depletion. The primary goal behind the design of the CUE-500 T cell engagers was to achieve T cell mediated depletion of B cells, while avoiding the adverse effects of systemic immune activation and broad engagement of all T cells. Our approach enables the potential to achieve CAR-T like efficacy, while avoiding the safety pitfalls of PAN-T-Cell Engagers. By design, the CUE-500 series Immuno-STAT’s bind to CD19 on B cells and effectively paint the B cells with a viral epitope, such as CMV. These B cells are then readily recognized and killed by the memory antiviral T cells as shown in the slide. Engaging virus-specific T cells, or VSTs, offers several advantages. These are trained killer T cells present in high frequency across the human population. They are localized in disease tissue and perform rapid killing of targets. And due to their specificity of virus antigens, the VSTs avoid the risk of potential reactivity against self-tissue or systemic immune activation as would be with PAN-T-Cell Engagers. Importantly, and as shown in Slide 7, VSTs, in this case CMV specific memory T cells, can achieve the same degree of killing of B cells as PAN-T-Cell Engagers, in this case an anti-CD19, anti-CD3 bispecific molecule. Note here, that the killing is specific to the engagement of CMV T cells since a CUE-500 molecule expressing an HIV epitope is unable to mediate B cell killing since HIV specific T cells are largely absent in most individuals. Slide 8 further exemplifies the difference in safety and cytokine production between CUE-501 and PAN-T-Cell Engagers. Due to their high selective engagement, the CUE-501 molecule does not result in copious production of inflammatory cytokines, such as interferon gamma and TNF as shown here. In contrast, a PAN-T-Cell Engagers molecule due to its anti-CD3 binding to all T cells results in significantly high levels of cytokine released, which ultimately compromises patient safety and drug tolerability. The following slide, Slide 9, highlights some of the notable points of differentiation between CUE-500 CAR-T approaches and PAN-T-Cell Engagers molecules. Note that all three approaches involve T cell mediated killing of target B cells, but it's only the CUE-500 series that can selectively engage trained memory killer T cells and redirect them to kill B cells. The selective engagement while avoiding systemic activation results in a significant reduction in cytokine release and related toxicities, which should favor patient safety while preserving efficacy. We believe the CUE-500 series of biologics are likely positioned as the best-in-class T cell engages for B cell depletion and could address a very large segment of autoimmune patients across many indications. In summary, there are three key takeaway messages. First, due to the shared core structural framework, the clinical de-risking and validation of Immuno-STAT’s in oncology via CUE-101 and CUE-102, including lack of clinically relevant immunogenicity, bolsters and supports the clinical application of CUE-500 series for B cell depletion in autoimmunity. Second, selective harnessing of antiviral memory T cells to kill B cells circumvents the safety risks associated with systemic T cell activation, as noted with PAN-T-Cell Engagers. And third, data demonstrating comparable killing while avoiding high levels of pro-inflammatory cytokine production positions the CUE-500 series to achieve desirable efficacy while not compromising patient safety, which is of highest clinical relevance when considering therapeutic applications in autoimmune diseases. With that background and update, I'll turn the call over to Matteo to describe the maturing clinical data from the ongoing oncology trials. Matteo?

Thanks, Anish. Good afternoon to everyone listening in on today's call. The maturing clinical data from the ongoing CUE-101 trial continues to demonstrate highly encouraging and robust metrics of clinical benefit for patients newly diagnosed with recurrent metastatic HPV+ positive head and neck cancer treated in combination with pembrolizumab, and for heavily pretreated recurrent metastatic HPV-positive head and neck cancer patients treated with monotherapy. The latest data continues to bolster prior observations, further enhancing our confidence in CUE-101 as a potential new standard of care therapeutic to improve outcomes for patients battling HPV+ head and neck cancer. As previously and consistently stated, we believe CUE-101's unique mechanism of action, as evidenced by the data generated to date, enables effective and tolerated dosing and selective expansion of the targeted tumor-specific T cells. Pembrolizumab is approved as the current standard of care treatment of first-line patients with recurrent metastatic head and neck cancer that have tumors with a combined positive score or CPS score of greater than or equal to 1%, which is a measure of PDL expression. The approval of pembrolizumab in this setting was based on immediate overall survival of 12.3 months and with an objective response rate of 19%, as observed in the KEYNOTE-048 study. As presented at ASCO in June, following combination treatment with CUE-101, the objective response rate of 46%, as shown on Slide 10, observed in patients with CPS greater than or equal to one represents a greater than doubling compared to the historical ORR of 19% observed with pembrolizumab monotherapy. As shown on the waterfall plot, out of 24 valuable patients, we have observed significant tumor reductions across many of these patients, including confirmed partial responses in 10 patients and a confirmed complete response in one patient. Importantly, four patients remain on treatment, including one with stable disease that exhibits a reduction in their target lesions of minus 28%. Notably for patients with low CPS scores, or scores of one to 19, an ORR of 50% was observed with CUE-101 and pembrolizumab, which represents a greater than tripling of the historical ORR of approximately 15% observed with pembrolizumab alone. In totality, our data suggests that not only does CUE-101 appear to demonstrably enhance the response rate of PD-1 inhibitions, but also does so by substantially enhancing responses in patients that are traditionally less likely to respond. This is particularly important since patients with low CPS scores represent approximately 50% of all patients that are CPS positive and eligible for treatment with pembrolizumab in the frontline setting. The responses observed in these patients have been durable as reflected in the 12-month OS and median OS, which is shown on the next slide, Slide 11. For patients treated with CUE-101 and pembrolizumab as first-line treatment, the median PFS of 5.8 months compares favorably to the median PFS of 3.2 months that was observed in the pembrolizumab arm of the KEYNOTE-048 trial. Importantly, the 12-month OS of 90% and the median OS of 21.8 months observed in patients with CPS greater than or equal to one, treated with combination treatment, is notable and substantially better than the historical data with pembrolizumab monotherapy, where 12-month OS and median OS were 51% and 12.3 months, respectively. These enhanced survival metrics, which continue to be followed, are particularly evident when looking at the patients with both low and high PD-L1 expression, as shown on Slide 12. Consistent with the enhanced ORR observed in patients with low PD-L1 expression, treated with CUE-101 and pembrolizumab, these patients are demonstrating favorable metrics of survival. In CPS-low patients treated with CUE-101 and pembrolizumab, the 12-month OS of 82% and the median OS of 21.8 months is importantly notable given the historical values of 44% in 10.8 months observed for pembrolizumab in the KEYNOTE-048. The benefit to CPS-high patients is also noteworthy with 12-month OS of 100% and a median OS that has not yet been reached in patients with CPS greater than or equal to 20, treated with CUE-101 and pembrolizumab compared to the historical values of 56% in 14.8 months, respectively. As a reminder, these maturing data from the combination trial appear to be following what we observed in the monotherapy second line plus setting, where CUE-101 demonstrated significant prolongation of survival, as shown in the following slide, Slide 13. As shown on the left, the median OS observed in patients treated with CUE-101 monotherapy at 2 mgs per kg was 24.8 months, and 20.8 months for those treated with CUE-101 at a dose of 4 mgs per kg. The survival observed in these patients is remarkable when compared to the median OS observed in the second line with checkpoint inhibitors, where median OS of 7.5 and 8.4 months were observed for nivolumab and pembrolizumab, respectively. We believe this enhancement of survival to be mediated by the durable and selective expansion of targeted tumor-specific T cells by CUE-101. In totality, our data suggests that CUE-101 increases the number of patients benefiting from checkpoint inhibition and appears to substantially improve survival in these patients. We continue to monitor and carefully follow the patients remaining on treatment, as well as in survival follow-up, and look forward to providing an update at [CITC] (ph) in November. The data continues to mature over time, and we believe the observations to date, particularly pertaining to what appears to be a substantial enhancement of survival, will place CUE-101 and by implication the CUE-100 series in a favorable and competitive position to potentially become a new standard of care. Moving onto the CUE-102 program, which is being explored in patients with WT1 expressing tumors, including colon, pancreatic, gastric, and ovarian cancers, CUE-102 has been well tolerated to date and no DLTs have been observed. Preliminary and emerging data shows dose-dependent increases in exposure and activation and expansion of WT1-specific T cells. Patients in all four indications have been treated at the expansion dose of 4 mgs per kg and remain on treatment or an active follow-up. As previously reported, we've observed anti-tumor activity in gastric and ovarian patients, as well as durable disease control in several tumor types, including pancreatic cancer. These data continue to mature, and we look forward to presenting updated data at CITC in November. With that, I will now turn the call back over to Dan. Dan?

Yes. Thanks, Matteo. As conveyed throughout this update call and shown on the next slide, Slide 14, we continue to make significant progress across our platform with programs in both oncology and autoimmune disease. We've demonstrated the ability to selectively modulate targeted T cells, providing what we believe to be a superior therapeutic approach in both oncology and autoimmune disease treatment. We continue to generate data from our two lead oncology programs, CUE-101 and CUE-102, and believe the data will continue to strengthen and bolster our position as a potential new standard of care, particularly supported by ongoing data generation pertaining to what appears to be highly meaningful and remarkable survival enhancement. We believe these observations support the premise that our approach is selectively activating and expanding tumor-specific T cells, providing a durable anti-cancer effect resulting in the enhanced survival. We believe we have the potential of establishing a new standard of care in the battle against cancer, as well as autoimmune disease. Importantly, as oncology data continue to mature, we have recently taken measures to prioritize our near-term focus and resource deployment upon near-term development milestones in our autoimmune programs, including lead selection and advancement towards the clinic in our partnership with Ono for CUE-401, as well as positioning CUE-501 for strategic partnering to further extend our capital runway and to enhance our capacity. As a reminder, we've retained a 50% co-development and co-marketing right to CUE-401, which has the potential application to multiple autoimmune diseases with multi-billion dollar market potential. Through various proactive measures taken, we've extended our runway to mid-2025, reduced our going forward cash burn from approximately $40 million per year to approximately $30 million per year. And importantly, additional partnering will further enhance our cash position with upfront milestone payments, as well as reduce our operational cash burn requirements through sponsored full-time equivalent supports. Through these measures, we believe we'll be increasingly capable of sustaining operational continuity through partnerships and other means of support. As a result of these measures combined with the ongoing progress with our maturing data across our programs, we believe we're very well positioned to realize a series of upcoming risk reducing and value driving milestones as we continue towards the goal of establishing a new standard of care for treating both cancer and autoimmune disease with our approach to restore health by restoring immune balance. With that, I'd now like to open the call up to questions. Operator?

Thank you. We will now begin the question-and-answer session. [Operator Instructions] And the first question will come from Stephen Willey with Stifel. Please go ahead.

Yes, good afternoon. Thanks for taking the questions. Anish or Dan, I was just wondering if you could speak to maybe what you know at this point about the trafficking capacity of CUE-501? And then also just what's your estimate of [CMV 0] (ph) positivity in the general population? I know it's correlated to age. I think it tends to be lower in males versus females, but just wondering kind of what your general estimate of this would be and whether you would need to screen for CMV positivity in the context of a Phase 1 dose escalation trial.

Yes, so both very good questions, Steve. CMV is an example we presented, but just to make the point, Steve, we have made CUE-500 molecules with SARS-CoV-2 and EBV and other viral epitopes as well. So we presented the case with CMV. In the particular case of CMV zero positivity anywhere around 65% to 70%. In our experience when we've screened donors for SARS-CoV-2 at this point in time in the history of mankind. Virtually 100% have been SARS-positive for obvious reasons. From the trafficking, we are now doing in-vivo studies, but with Immuno-STAT’s in general, Steve, we had published a paper in Nature Methods with [indiscernible] several years back where we used ImmunoPET imaging to make the point that Immuno-STAT’s could penetrate solid tumor tissue as well as an infectious model and directly engage the relevant antigen-specific T cells. And we believe the same should hold true for the 500 series, where you can have extravasation and local engagement to essentially be able to recognize the T cells that are bound by these molecules.

Okay, that's helpful. And then maybe just a key one on one question. So, I understand that you guys are obviously kind of pausing things for now and allowing the survival data to mature. But I guess in the context of frontline head and neck right now and what is capable with pembro monotherapy, I think that appears to be the subject of some increasing debate as a function of primarily, I guess, the LEAP-10 data. So just curious, if you think a more mature survival statistic could help attract strategic interest, and just curious if you can share anything in terms of the conversations that you've had thus far with potentially interested parties in terms of how they're thinking about what pembro monotherapy historically is capable of? Thanks.

Sure. Thanks, Steve. This is Dan. So it's an important question. We've had dialogue with multiple potential partners on the data sets that we've had historically. When we look at the monotherapy data, we've actually had the comment of the data looks so promising that how do they know that we haven't biased by selecting healthy patients? That's one of the reasons we emphasize the randomized strategy for the Phase 2. I think what's really important here when you look at the landscape of competing molecules, different kinase inhibitors, et cetera, in this space, we think the survival data is going to really differentiate and truly position Cue with an advantage and a competitive advantage in terms of the durability of triggering an immune response. So that survival data as it continues to mature, I think what we've seen in monotherapy is very impressive. What we're seeing emerge with the combination appears to be following suit. And I think that's going to be dispositive in the long run. I think ultimately a randomized study is basically far more convincing because you're going directly against pembro as a single agent. But it is an important topic and it is being watched. And we do have ongoing dialogue with companies on 101.

All right. Thanks for taking the questions.

The next question will come from Ren Benjamin with Citizens JMP. Please go ahead.

Hey, good afternoon, guys. Thanks for taking the questions. So, thanks for the update on 101 in combination with KEYTRUDA and as in the monotherapy. I guess my first question would be, how to think about these results given the current landscape. And in particular, kind of the developing landscape given the provocative data we saw at ASCO from Merus and some of the others, that are also in the space. And just as a follow-up to that, I'm kind of curious -- I don't think it was mentioned in the earlier comments, can you provide any sort of an update on the neoadjuvant study?

Sure. Matteo, why don't you take that question?

Yes. No, I will. And again, just to follow up on the prior question, again, I think this really -- the data from the LEAP-10 trial underscores the importance of looking at early survival metrics, specifically like a 12-month survival and also median OS as it matures. And so, if you actually look at the pembro mono data set from LEAP-10, the 12-month survival is 59%, okay? If we look at the CUE-101 combination data, our current 12-month survival is 90%, okay? And if you look at CPS high, it's 100% of patients are alive at 12 months. Okay? And so with regards to the question now of the evolving landscape and with, I guess, in particular, Merus's compound PetoSemtamab, again, it's really important to look at the data that they've shared with regards to their survival, okay? And so, in the second line setting and beyond, they reported a survival of 11.5 months. With CUE-101 mono, we're currently at 20.8 months, and even 20 -- almost 5 months in the 2 mg/per kg cohort. So although in the second line plus they reported a response rate of 37%, their survival is about half as long, okay, as CUE monotherapy where we observed a response rate of 5%. And again, this is fully consistent with patterns of clinical benefit that have been now well defined in immunotherapy. So if we look at KIMMTRAK, recently approved for uveal melanoma, really modest response rate but a clear survival benefit led to its approval. And so back to pertuzumab now in the frontline setting, they -- at ASCO reported some very preliminary data. They actually only reported data on about half of the patients that were treated with very minimal follow-up. So with the follow-up -- a median follow-up, if you looked at the swimmer plot about four months. So again, I would just use caution and clearly hear the data needs to mature. And as I mentioned before, we have maturing metrics both at 12-month OS and median OS that are established. So that's real data and we'll have to see what happens going forward with pertuzumab and perhaps one could hypothesize it'll be similar to different inhibitors of these pathways for which they're inevitably pop-up bypass pathways and hence the advantages of engaging the immune system and inducing expansion of a durable anti-tumor T cell population.

Got it. And just…

I'm sorry, Ren. I think there was one other question about the new adjuvant, if I recall. And so, that study is progressing well. The investigators at Washington University are very close to completing enrollment in schedule B, where patients are getting two doses of 101 and we're getting tissue pre and post-treatment. Again, this is the preliminary data that we've seen looks very encouraging. The investigators really, I think, have -- I know, have the intent of submitting this for publication in a very high-level journal. And so, when this will become public and shared really depends on how they choose to proceed.

Got it. And then just maybe a final question on kind of funding and your current cash position and the like. Can you maybe help us understand how you plan on bridging the gap between now and kind of initial milestone payments expected from the Ono opt-in versus selection of lead candidates and the like, how do you see that kind of unfolding? Thanks.

Yes. Thanks, Ren. This is Dan. It's an important question. One thing I want to emphasize, we were very prudent and deliberate in basically looking at that question in a very dynamic way. The one thing we have not chosen to do historically is with the cost of capital as the small cap biotech sector has basically been compressed in terms of valuations. We have not chosen to go out and do a massively dilutive financing. So we've taken a look at a business model where we have programs that are all kind of moving over time. We have a partnered program right now, 401 with Ono. And if one looks back at that, it was actually a really nice design. They're helping, they're subsidizing basically the preclinical development, working very closely with us. They're supporting scientists. And that has resulted in a really good, high-quality body of data going forward to select a lead candidate that then with the objective of getting into the clinic, we have a 50% opt-in there. Even with the 50% opt-in, we'll receive milestones. So if those milestones get triggered, they help subsidize the development of that program. We have 501 in late stage discussions with several companies. The objective there is to consummate a transaction where we have an upfront. We have additional support of our scientists that are going to be committed to that program. That reduces our burn rate. And then a series of milestones beginning, obviously, with lead candidate selection, IND filing. Those milestones overlapped with the Ono milestones, are really important to basically give us continuity. So the measures we've taken for reducing our burn, basically enabling 101 data to mature without going into a very costly Phase 2 and just being prudent about what we're focusing on in the near term, focusing on partnering 501 to supplement. So these milestones help extend the runway in a sort of tiered manner. So if we do need to raise any capital, and not sure right now where we're going to need to, but if we do, it's going to be a modest amount, we're really trying to keep dilution down to a minimum because cost of capital is key. And ultimately what we want to do is, hit these milestones, further develop the pipeline, demonstrate further robustness of our clinical competitive positioning, and ultimately at some point in the future when the stock is a healthy evaluation, cost of capital isn't as onerous. So I hope that's a clear answer, but it's basically a dynamic analysis and we have a lot of moving parts here, but it's basically building up. That's why I meant by a balanced business model, having a stream of capital options coming in with these milestones being triggered and looking at raising capital in a very prudent, pragmatic manner based on cost of capital.

Great. Thanks, and good luck going forward.

All right. Appreciate it, Ren. Thank you.

The next question will come from Maury Raycroft with Jefferies. Please go ahead.

Hi, congrats on the data update, and thanks for taking my questions. I'll ask one on the CUE-500 series. For CUE-501, can you talk more about plans or options for next steps to position this program for partnering? Would it enhance potential for BD if you got regulator feedback or even key investigator buy-in to help define what the clinical development path could look like?

Yes, very important question. I think obviously the Ono partnership has enhanced our sort of insight on the autoimmune space. We have a very attractive sort of preclinical data set right now. We've been in discussions with several potential pharma partners on 501, various stages of diligence and progression. We're just highly confident that based on the feedback we have, it's a differentiated asset. It's very attractive based on basically being a biologic that mirrors what CAR-T was able to do with lupus. That's what the intent is. Compares favorably with bispecifics, the CD3, CD19 molecules. So we think the data set presents an opportunity for us to partner in the near term. And in terms of indications with that molecule, we're obviously going to hold off until the asset's partnered and we're able to engage in strategic dialogue with the partner on what to focus on in a sort of a series of indications. But I think for that program, we look at partnering as an important means of subsidizing development. We'd also aim to preserve a cell type, for instance, eosinophils or mast cells, something like that, where we retain control and upside of sort of a number of indications from those cell types. So I hope that answers your question, Maury.

Yes, really helpful. And maybe just to follow-up on the financial side as well, I guess for the Ono opt-in, is there any room to negotiate and potentially accelerate milestones or opt-in potential based on the data that you've generated so far, or would it not make sense to try to do that at this point?

Yes, I don't think it would make sense to try to modify it right now. We've been making really good progress. The partnership's actually been extremely productive. They've really been an outstandingly supportive partner. And we're aligned on what the next steps are, so I think we're very much seeing things from a similar perspective.

Got it. Okay, thanks for taking my questions.

The next question will come from Leland Gershell with Oppenheimer. Please go ahead.

Hey, good afternoon. Thanks for the update and taking my questions. May be just a few for you, Dan or Anish. It looks like you have a good base of preclinical data here for 401, 501. I wanted to know what might be the next set of non-clinical data that we might be looking for that you might have to present to us. And in that, are there any particular studies you're doing that may guide your thought process with respect to the indications that you prioritize for both those assets? Thank you.

Yes. Thanks, Leland. This is Anish. So we continue to generate pretty exciting data for both programs in autoimmunity with 401, obviously in collaboration with Ono, where we have seen efficacy in activity in several disease models and in due time collectively and collaboratively we'll release that in the public domain. In total, the data does seem to reflect what I've mentioned, which is a molecule that generates copious amounts of regulatory T cells along with signatures for halting autoimmune processes, seizing and reversing or minimizing pro-inflammatory cytokine production and related pathologies. For 500, we are in the process of in-vivo experiments, and again, we hope to release that as we start further understanding the relationship between dosing, B cell depletion, and some of the models that we're characterizing now. So both programs, the intentions are -- as we continue to go through this year to be able to talk about these datasets as they emerge.

Very thanks for taking my questions.

[Operator Instructions] Our next question will come from Ted Tenthoff with Piper Sandler. Please go ahead.

Great. Thank you very much. Just to sort of the evolving world of targeting CD19 [indiscernible] B cells for autoimmune disease. How much is the safety, the potential safety profile that you generated on the Immuno-STAT platform from 101 and 102 differentiating from the cell therapies? And is that something that investors are focused on? Thanks so much.

Yes. Ted, again, very good question. And I think I try to stress that, but the clinical de-risking and vulnerability of Immuno-STAT’s in man, in general, what we've shown with 101 and 102, we believe has an almost positive implication on the 500 series of B cell depletion. Simply, even if you look at the metrics of tolerability from immunogenicity, as you will know, we have not seen any clinically relevant immunogenicity in our 100 series trials with 101, 102. We've had patients receiving drugs up to two years. So again, that speaks to the nature of selective TCR engagement via this framework. The second is the fact that by virtue of the fact that you're only co-opting a very small percentage of your peripheral T cell repertoire in an individual and not carpet bombing all T cells with anti-CD3 based approaches, which we refer to as the PAN-T-Cell Engagers, we believe should also offer superior safety and tolerability metrics. And some of that is evident from this in-vitro assessments of cytokine release that we did, where you saw this profound production of cytokines by PAN-T-Cell Engagers molecules as opposed to CUE-500, where it was significantly reduced, despite the fact that CUE-500 shows very comparable metrics of killing efficacy of B cells. So that's also quite important. Thirdly, I think we should sort of reemphasize the fact that through nature, your memory antiviral T cells is something that all of us have harbored from the time we're born through our life to provide us protective immunity. So there's no other better long-lasting killer T cell population that one harbors, as compared to what these cells offer. So we do think being able to redirect them to kill targets such as B cells provides a very exciting avenue for really harnessing a potential of what nature has already given the individual.

Yes, I agree and obviously a very different manufacturing approach than what we're seeing with the [indiscernible]

That's exactly right. So just to add to that, the manufacturability is exactly what we've seen with 101, 102, antibody-based biologics. The yields are in line with what we've seen at similar stages for Immuno-STAT’s, which are clinically great products have yielded in grams per liter with very good shelf stability of the GMP product. That's a very important point. Thank you.

Great. Well, thanks, [indiscernible] progress.

Thank you, Ted.

This concludes our question-and-answer session. I would like to turn the conference back over to Mr. Dan Passeri for any closing remarks. Please go ahead, sir.

Thank you. We just want to thank everyone for listening and your continued interest in our progress. And we look forward to keeping you updated with the progress we make going forward. So thank you very much and take care.

The conference is now concluded. Thank you for attending today's presentation, you may now disconnect.

Greetings and welcome to the Cue Biopharma Investor Update call. At this time, all participants are in listen-only mode. A question-and-answer session will follow the presentation. [Operator Instructions] As a reminder, this call is being recorded. I would now like to turn over the conference to Dan Passeri, Cue Biopharma’s Chief Executive Officer. You may begin now.

All right, thank you, and good afternoon, everyone. As a reminder, this presentation and discussion is being recorded and will be available on our website for the next 30 days. Also, please be aware that the slides accompanying today's update may be advanced directly by those listening in on the call, and we'll notify you on what slide we're on throughout this presentation. Joining me on today's call are Dr. Anish Suri, our President and Chief Scientific Officer, Dr. Matteo Levisetti, our Chief Medical Officer, and Kerri-Ann Millar, our Chief Financial Officer. As shown on slide two, this presentation and overview may contain some forward-looking statements, and any forward-looking statement made during this call represents the company's views only as of today, April 8th, 2024. As shown on slide three, I'm going to begin with a summary overview of the broad reach of our therapeutic platform and review our competitive positioning and key corporate objectives going forward. Anish will then provide an overarching summary of our platform approach in support of developments, reinforcing our positioning as a leading solution provider, and the development of selective immunotherapeutic biologics to address pressing unmet medical needs in both oncology and autoimmune disease. Matteo is then going to review and update of our promising and evolving oncology clinical datasets, as well as provide a summary synopsis of our recent and productive type B meeting with the FDA to align on registration paths forward for CUE-101. Anish will then return to provide an overview of highly promising data from our preclinical autoimmune programs with the potential of having a profound impact on the treatment of autoimmune disease. Kerry will then join the call and provide a brief update on our financials, and I'll return for closing remarks prior to opening the call to questions. Okay, so to summarize, the data generated to date from our ongoing clinical trials with CUE-101and CUE-102, as well as our preclinical programs, continue to move us closer to achieving our core mission and vision of becoming a leading solution provider for realizing the tremendous therapeutic potential of selective modulation of the patient's immune system in the treatment of cancer and autoimmune disease. As shown here on slide number four, we aim to achieve this by engineering biologics that translate nature's CUE’s, that is signals from nature that are built into our biology, and to break through immunotherapies. We have continued to progress forward with positive and evident results in our on-going clinical trials, demonstrating and further bolstering the therapeutic potential of our Immuno-STAT platform for treating cancer. To date, the strengthening data from our ongoing clinical Phase I A and B trial with CUE-101 for HPV-positive head and neck cancer, and CUE-102 for treating the numerous types of WT1, Wilms’ Tumor 1 overexpressing cancers, strengthens our belief that we've developed a therapeutically effective and well-tolerated approach for the selective modulation of cancer-relevant T cells. Importantly, we recently received guidance in alignment with the FDA through an end of Phase 1 Type B meeting for the continued development of CUE-101 towards registrational trial. Mateo will provide further details on this prospect momentarily. We've also made significant prospect with our preclinical autoimmune programs, principally CUE-401 in collaboration with our partner Ono Pharmaceutical, and the CUE-500 series, with both programs demonstrating clear evidence of the desired mechanistic effect of these novel approaches. Anish is going to cover these in more detail momentarily. Through these ongoing developments, both in oncology as well as autoimmune disease, we're well-positioned for strategic alignment with third parties for further increasing and enhancing our capacity to develop our highly promising and potentially transformative therapeutics. We've made significant progress towards our goal of consummating a transformational transaction that would enable greater capacity and enhance productivity. I'm going to come back at the end of this call and further elaborate on this topic in the closing remarks. I'll now turn the call over to Anish, who will describe our core competitive positioning and the strategic implications of our approach for treating both oncology as well as autoimmune disease. Anish?

Thanks, Dan. Good afternoon to all listening in on today's call. I'll provide a brief summary of our platform and the significant potential of our therapeutics for treating cancers and autoimmune diseases. As shown on slide five, immune balance is a key central pillar of human health, and deviation from this state underscores diseases such as cancer and autoimmunity. Hence, an effective therapeutic strategy for resetting immune balance should focus on selective modulation of disease-relevant immune cells while avoiding broad perturbations of the immune system. Most importantly, this approach allows us to maximize efficacy while preserving patient safety. Slide six provides an introduction to our Immuno-STAT platform for resetting immune balance via selective modulation of disease-relevant immune cells. The core framework of an Immuno-STAT builds upon nature's selectivity for T-cell engagement and activation. Disease-specific T-cells express singular T-cell receptors, or TCRs, that engage the stabilized Peptide-HLA, or PHLAs, in an Immuno-STAT. Only those engaged T-cells can then receive a disease-modifying secondary signal. This approach enables selective targeting and modification of disease-specific T-cells while sparing broad effects on other T-cells that are not relevant to the disease of interest. Importantly, the Immuno-STAT framework was engineered to be highly flexible and modular, enabling us to deploy the same or similar core functional elements for diverse therapeutic approaches. For example, in the case of oncology, Immuno-STATs can selectively engage and activate tumor-specific T-cells while avoiding systemic immune activation. In contrast, for autoimmune diseases, Immuno-STATs can selectively down modulate autoreactive T-cells while avoiding broad immunosuppression. The next slide, slide seven, highlights the pipeline of assets that we have developed for restoration of immune balance. In oncology, we have clinically validated the CUE-100 series that selectively delivers the potent cytokine IL-2, along with a TCR-activating signal, to preferentially activate tumor-specific T-cells while sparing all other irrelevant T-cells. This selective stimulation allows for the generation of a therapeutic index for IL-2, which has eluded many others trying to develop IL-2-based cancer therapies. In over 100 patients dosed, we have demonstrated a substantial increase in efficacy with favorable tolerability. For our lead clinical candidate, CUE-101, in recurrent metastatic head and neck cancer, we have recently concluded a meeting with the FDA aligning on a registration path, which will be further elaborated upon momentarily by Mateo. With our next clinical candidate, CUE-102, that targets Wilms Tumor 1, or WT1, we have completed the Phase 1 monotherapy dose escalation in patients with gastric, ovarian, colorectal, and pancreatic cancers, and have noted evidence of anti-tumor activity and disease control in multiple patients. Mateo will describe this efficacy data in detail, along with the plans for our registrational path forward with CUE-101. On the autoimmune front, as shown here, we have developed two novel and highly promising approaches for restoring immune balance. CUE-401 is a novel bispecific composed of an attenuated IL-2 and TGF-beta that together can stimulate the generation and expansion of regulatory T-cells. Regulatory T-cells, or Tregs, possess the ability to dampen and control autoreactive lymphocytes, which are responsible for inducing tissue damage in autoimmune disease. Hence, in this regard, Tregs are the master regulators of maintaining immune homeostasis in health. CUE-401 is currently partnered with Ono Pharmaceuticals, and this collaboration is moving forward at a strong pace with much productivity. In addition to CUE-401, we've also developed the CUE-500 series to enable T-cell mediated depletion of B-cells. We believe this biologic holds the promise for achieving CAR-T-like efficacy in autoimmune patients and is significantly differentiated from other competing approaches, such as ADCC, PAN-T-Cell Engagers, or CAR-T-cell therapies. We will expand on both autoimmune programs in the later part of this presentation. With that background, I'll now turn the call over to Matteo to provide a detailed clinical update on the data and future plans. Matteo?

Thanks, Anish. Good afternoon to everyone listening in on today's call. I'm particularly pleased to provide you with this summary update, as we have achieved important developmental milestones with the recent clinical data and believe we have not only defined the registration path forward, but also demonstrated the opportunity of the CUE-100 series as a potential breakthrough for improving patient outcomes across multiple cancers. The clinical data from the ongoing CUE-101 trial continues to demonstrate highly encouraging and robust metrics of clinical benefit for patients with newly diagnosed recurrent metastatic HPV positive head and neck cancer treated in combination with pembrolizumab and for heavily pretreated recurrent metastatic head and neck cancer patients treated with monotherapy. We recently had an end of Phase 1 type B meeting with the FDA where we received guidance and aligned on a path forward to a registration of trial for CUE-101. To that end, we plan to conduct a randomized Phase 2 study of CUE-101 in combination with pembrolizumab compared with pembrolizumab alone as first line treatment of patients with recurrent metastatic HPV positive head and neck cancer. This trial design and the resulting data will provide a clear assessment of treatment effect along with confirmation of optimal dose for the Phase 3 registrational trial will increase overall confidence and probability of succeeding with the registrational trial. We believe this approach is the optimal means of generating the highest probability of success in the most cost effective and direct manner. We intend to pursue this registrational approach with CUE-101 in the first line setting in combination with KEYTRUDA as this setting represents a significantly larger market and we believe due to the complementary mechanism of action between CUE-101 and KEYTRUDA the patient impact and durability would likely also further reduce the patient population available in the second line setting over time. It also represents a straight path forward to move upstream in the treatment paradigm extending market reach potential into the adjuvant setting which represents the largest market opportunity. As shown on slide 9, data from the ongoing clinical trials with CUE-101 as monotherapy and in combination with pembrolizumab have provided clinical proof-of-concept to validation and de-risking of our Immuno-STAT platform. The latest data generated to date in 2024 continues to bolster prior observations further enhancing our confidence in CUE-101 as a potential therapeutic to improve outcomes for patients battling HPV positive head and neck cancer. As previously and consistently stated we believe CUE-101's unique mechanism of action as evidenced by the data generated to date enables effective and tolerated dosing and selective expansion of the targeted tumor specific T cells. We continue to observe prolonged survival in patients with advanced recurrent metastatic head and neck cancer treated with CUE-101 monotherapy. Notably as previously presented the median overall survival of patients treated in the second line and beyond at the 4 milligram per kilogram monotherapy expansion dose is currently greater than 20 months which compares favorably to the historical median overall survival of approximately 8 months observed in the second line trials of nivolumab and pembrolizumab. We believe this enhanced survival is due to the repeated stimulation and expansion of tumor specific T cells given CUE-101's mechanism of action especially in the tumor microenvironment. As shown momentarily the overall response rate in median progression free survival observed in first line patients treated with CUE-101 in combination with pembrolizumab represents a greater than doubling of the overall response rate in progression free survival compared to historical rates with pembrolizumab monotherapy. Enrollment in the neoadjuvant trial is progressing well and preliminary observation support expansion of E7 specific anti-tumor T cells and increases in NK cells within the tumor microenvironment. These findings are consistent with the pharmacodynamic changes observed in the peripheral blood of patients treated with CUE-101 as previously reported. We believe these observations in addition to the clinical efficacy observed in the recurrent metastatic setting support a development strategy of moving further upstream into earlier lines of therapy such as the adjuvant setting where a larger number of patients may benefit. Pembrolizumab is approved as the standard of care treatment of first line patients with recurrent metastatic head and neck cancer that have tumors with CPS scores of greater than or equal to 1%. CPS is a measure of PD-L1 expression based on a response rate of 19% observed in the KEYNOTE-048 study. Following combination treatment with CUE-101, the overall response rate of 46% as shown on slide 10 observed in patients with CPS greater than or equal to 1 treated to date represents a greater than doubling compared to the historical overall response rate of 19% observed with Pembrolizumab monotherapy. As shown on the waterfall plot, we have observed significant tumor reductions across many patients including confirmed partial responses in 10 patients and a confirmed response in one patient. Importantly 11 patients remain on treatment including three with stable disease that exhibit reductions in their target lesions. Notably for patients with low CPS scores and overall response rate of 50% was observed with CUE-101 and pembrolizumab which represents a greater than tripling of the historical overall response rate of approximately 15% observed with pembrolizumab alone. In totality our data suggests that not only does CUE-101 appear to demonstrably enhance the response rate of PD-1 inhibition but also does so by substantially enhancing responses in patients that are traditionally less likely to respond. This is particularly important since patients with low CPS scores i.e. values of 1 to 19 represent approximately 50% of all patients that are CPS positive and eligible for treatment with checkpoint inhibitor in the frontline setting. The responses observed in these patients have been durable and observation that is reflected in the improved progression-free survival which is shown on the next slide, slide 11. Of note, the Kaplan-Meier estimate of median progression-free survival for patients treated with CUE-101 in combination with pembrolizumab as shown on the left is currently 8.3 months which compares very favorably to the historical median progression-free survival of 3.2 months observed with pembrolizumab monotherapy in the KEYNOTE 048 trial as shown on the right. Furthermore, 20 of the 25 patients treated to date, the 4 mg/per kg expansion dose in the ongoing CUE-101 combination trial remain alive as of the last follow-up for each patient. This portends well for the median overall survival as it matures throughout the year. As shown in the panel on the left of slide 12, we have observed robust expansion of tumor-specific HPV E7-specific T cells in the peripheral blood of patients treated with CUE-101. As shown on the graph on the right, we have observed an approximate 100% decrease in cell-free HPV DNA which is an increasingly recognized biomarker of disease burden in all patients that have experienced objective responses that were tested to date, further supporting the magnitude of their responses. Reductions in cell-free HPV DNA of this magnitude have also been observed in multiple patients with durable stable disease as defined by RECIST. The data from the CUE-101-01 trial provided the substrate for a productive Type B meeting with FDA which occurred earlier this year. In the course of this meeting, we aligned with FDA on a path to support a future CUE-101 plus pembrolizumab registrational trial, including guidance on the design of a small Phase 2 trial to confirm the CUE-101 dose used for a subsequent registrational trial consistent with a project optimist directive. An overview of the plan Phase 2 trial is displayed on slide 13. Treatment-naive first-line patients with recurrent metastatic HPV-positive head and neck cancer will be randomized to one of two CUE-101 doses in combination with pembrolizumab or pembrolizumab alone. Overall response rate will be the primary endpoint with others, including PFS and OS as secondary endpoints. The primary analysis of overall response is anticipated to occur approximately 24 months after the first patient is rolled. As outlined on slide 14, the clinical benefit observed with QUE-101 combination treatment in first-line patients with HPV-positive head and neck squamous cell carcinoma is compelling compared to historical published data. We believe this Phase 2 trial design and the resulting data will provide a clear estimation of treatment effect, confirmation of the dose to be tested in Phase 3, and increase the overall probability of success for the registrational trial. As demonstrated with the CUE-102 program, which I will now discuss, we believe the data from CUE-101 has provided a de-risking and mechanistic validation for additional biologics from the IL-2-based CUE-100 series. As a reminder, shown on slide 16, CUE-102 and CUE-101 share 99% amino acid sequence identity. This enabled us to significantly decrease the development time and cost of CUE-102 as we were not required by the FDA to repeat IMD-enabling toxicology studies for CUE-102, and we were also able to initiate the Phase 1 dose escalation study at 1 milligram per kilogram, a dose at which we observe clear signs of biologic activity with CUE-101 We have now completed the dose escalation portion of the 1-2 study without observing any dose-limiting toxicities and are currently enrolling patients in all four indications in the expansion phase of the trial. As shown on slide 17, gastric, ovarian, pancreatic, and colon cancer represent areas of high unmet need. Note that these numbers are greater than a collective of 200,000 patients with recurrent metastatic disease in need of therapeutic options. In addition, an almost equal number of patients with other WT1-positive cancers are eligible to benefit from CUE-102 therapy in the future. Emerging pharmacodynamic data from blood samples of patients treated with CUE-102 is shown on slide 18. As seen here on the left, and consistent with our preclinical data sets and our experience with CUE-101, selective and robust expansion of WT1-specific T cells has been noted among the patients treated with CUE-102, with two representative examples shown here. Expansion of these tumor-specific T cells is expected to enhance anti-tumor immunity with the potential to drive tumor reductions, as shown on the right. A patient with gastric cancer that progressed on three prior lines of therapy, including a checkpoint inhibitor, has experienced a decrease in the sum of three target lesions of minus 34% at week 36. Another example of reduction in tumor burden, this time in a patient with recurrent metastatic ovarian cancer, is shown on the right. Unfortunately, these two patients were found to have new lesions on subsequent scans and have now come off treatment. Also of note, a pancreatic cancer patient treated on the study has benefited through maintaining stable disease for greater than eight months, which is remarkable in the setting of this devastatingly aggressive tumor type. Given the encouraging signals of clinical activity, including multiple patients with stable disease observed across all four indications, and the enthusiasm of the investigators, the protocol was amended to expand into all four indications. The study is actively enrolling patients in all four of these indications. Patient screening and enrollment rate continue to go exceedingly well, underscoring investigator enthusiasm and the need for effective therapies in WT1-expressing cancers. As demonstrated on slide 19, it's important to note that while checkpoint inhibitors have had a major positive impact on changing the therapeutic options for patients, there remains a substantial need for improvement. There have been significant persistent challenges in realizing the fullest potential of immunotherapies. While many therapeutic modalities and combination approaches for immune modulation are being pursued, significant challenges exist with regards to suboptimal safety, tolerability, and efficacy to enable broad patient reach. We believe solution providers to these challenge will emerge as best-in-class market leaders defining the paths forward for more effective therapies, both as standalone treatment options as well as combination approaches, for example, with checkpoint inhibitors. As just conveyed, the ability of CUE-101 to selectively expand and activate targeted tumor-specific T cells complements the mechanism of checkpoint inhibition, thus expanding patient reach and enhancing therapeutic benefit, as demonstrated in this chart. We believe our platform has the potential to significantly expand patient reach by increasing the number of patients that benefit and enhancing the magnitude of that therapeutic benefit. In short, we believe our platform represents a major breakthrough towards realizing the full potential of immunotherapy. We're further encouraged by the early observations of CUE-102 monotherapy, anti-tumor activity across multiple indications where checkpoint inhibitors have been largely ineffective. We look forward to presenting additional data on both programs at ASCO in June. I will now turn the call over to Anish. Anish?

Thanks, Matteo. Let me take a few minutes to update on the notable progress with our platform for autoimmune diseases, starting with CUE-401 and regulatory T cells as indicated on slide 20. Slide 21 describes the design and rationale for CUE-401 as an attractive approach to generate a new and differentiated class of regulatory T cells, or Tregs. As mentioned previously, CUE-401 is a bispecific molecule containing attenuated forms of IL-2 and TGF-beta, which are the two known signals that can convert peripheral T cells into regulatory T cells, also known as induced Tregs or ITregs. In addition, CUE-401 also strongly expands existing natural Tregs. This program has been a very productive collaboration with Ono Pharmaceuticals, wherein Ono is supporting all of our ongoing preclinical work to identify an optimized clinical lead compound, which we are on track to accomplish in the second half of 2024. The next slide, slide 22, highlights the unique and differentiated mechanism of action of CUE-401 over other CD25-biased IL-2 muteins for expansion of existing Tregs. As shown here, CUE-401 can expand pre-existing regulatory T cells and convert naive CD4-positive T cells into new Tregs, thereby enhancing the quantitative population and the qualitative features of Tregs to control the pathogenic cellular reactions in autoimmune patients. Slide 23 provides examples of the potent activity of CUE-401 in the conversion and generation of stable Treg cells. As shown on the left panel, conversion and expansion of human CD4 T cells to Tregs only occurs when the IL-2 and TGF-beta signals are delivered via CUE-401. Either signal alone does not result in Treg conversion, and CUE-401 represents the first singular biologic capable of delivering both signals simultaneously. In the right panel is an in-vivo study demonstrating efficacy of CUE-401 in an animal model of autoimmune gastritis. This is a model developed by Dr. Rich DiPaolo at Saint Louis University, wherein a short treatment with CUE-401 results in a long-lasting protection from gastritis, as shown by the histopathological analysis and disease scores. We believe this mechanism of action of CUE-401, including the demonstration of long-lasting efficacy after just a short duration of treatment, will apply to many other autoimmune diseases. Let's move on to slide 24 that introduces a new series of Immuno-STATs, termed the CUE-500 series that we have developed with the goal of achieving deep B cell depletion via T cell mediated approach. As shown in the next slide, slide 25, recent data sets from small clinical studies have demonstrated remarkable efficacy in autoimmune patients treated with CAR-T cell directed against CE-19 to deplete B cells. In many cases, long-term ongoing clinical remissions have been noted in patients with lupus and myositis with no concurrent immunosuppressive regimens, which could be early signals of functional cures. This curative potential via immune reset is what propelled us to start working on the CUE-500 series, which enables T cell mediated B cell killing, akin to what CAR-Ts do, except with an off-the-shelf biologic. This concept is best shown on the next slide, slide 26. The CUE-500 series builds upon the clinical de-risking accomplished with the CUE-100 series. The constant is the presence of a bivalent peptide HLA molecule that selectively engages TCRs of selected T cells. In the case of the CUE-500 series, the peptide presented by the HLA is a well-characterized virus epitope recognized by virus-specific memory T cells present in high frequencies in all of us. Examples of such virus epitopes, which include CMV, EVV, SARS-CoV-2, etcetera. In addition, the CUE-500 molecule also contains SCFEs directed against B cell cell surface molecules such as CD-19. This configuration allows for CUE-500 molecules to bind target B cells and make them appear as virally infected cells that can be recognized and destroyed by a protective antiviral memory T cell repertoire. This novel mechanism of action is depicted in the left panel on the next slide, slide 27. This mechanism of natural target recognition via TCRs is of similar sensitivity, if not higher compared to how a CAR-T cell recognizes its target via the CAR domain. On the right side of the slide is an example of a CUE-500 molecule enabling cytomegalovirus-specific T cells CMV T cells, to kill primary human B cells. It is well known that CMV-specific T cells are a significant composition of the protective antiviral T cell repertoire and are present in large fraction of the population. As shown here, B cell killing is specific to the engagement of CMV-specific T cells. In other words, a CUE-500 molecule harboring an HIV peptide does not mediate B cell killing since the HIV-specific T cells are not present in circulation. The selective harnessing and redirection of the protective antiviral T cells to kill targets creates a very attractive opportunity for CUE-500 series Immuno-STATs. This is particularly exemplified in the next slide, slide 28, which highlights the market opportunity for a broad therapeutic pipeline with a single product. The therapeutic applications span from multiple autoimmune diseases where pathogenic B cells play a role to additional applications in transplantation and allergic inflammation. The CUE-500 series could also be effectively applied for the treatment of B cell malignancies in the oncology therapeutic area. The next slide, slide 29, briefly summarizes the superior differentiation of the mechanism of action of CUE-500 over other competing modalities for B cell depletion, including ADCC, CAR-T, cellular therapy, and Pan-T cell engagers. We now recognize that ADCC mechanisms result in incomplete depletion of B cells, primarily due to variable expression of the target antigen, such as CD-19. Low target expression allows for escape of B cells from ADCC, primarily mediated by NK cells. Furthermore, FC receptor polymorphisms dictate high versus low ADCC effector genotypes. In the case of CAR-T approaches, complex manufacturing and supply chains remain a challenge for broad access. In addition, patient conditioning regimens, inpatient administration, and safety risks, including CRS and neurotoxicity, continue to pose challenges for CAR-T therapies. Pan-T cell engages that activate T cells via anti-CD3 or anti-CD28 cross-linking are also not favorable for autoimmune applications. These modalities activate all T cells indiscriminately, resulting in CRS and other toxicities, hence are unsuitable for autoimmune patients. In addition, they pose the very real threat of further activating and propagating autoreactive T cells that may exacerbate the underlying autoimmune disease. In contrast to these modalities, the CUE-500 series offers an elegant potential solution for selectively exploiting the long-lasting antiviral memory T cells to drive B cell depletion. This off-the-shelf approach, therefore, offers the potential to achieve CAR-T-like efficacy while avoiding the pitfalls associated with cell therapy modalities. With that overview of both CUE-401 and CUE-500 and their applications in autoimmune disorders, I'll turn the call to Kerri to review the financial details. Kerri?

Thanks, Anish. Turning to slide 30, I'd like to provide a brief update on our financial results for the three months and full year ended December 31, 2023. For the three months ended December 31, 2023, the company reported collaboration revenue of approximately $1.8 million as compared to $150,000 for the same period in 2022. Revenue in the fourth quarter was primarily due to work related to the collaboration and option agreement with Ono Pharmaceuticals for CUE-401, which was executed in the first quarter of 2023. Research and development expenses were $10.9 million and $11.3 million for the three months ended December 31, 2023 and 2022, respectively. The decrease was primarily due to drug substance manufacturing projects for CUE-101 and CUE-102 that were completed in 2022. General administrative expenses were $4.6 million and $3.7 million for the three months ended December 31, 2023 and 2022, respectively. The increase was primarily due to an increase in professional and consulting fees during this time. For the years ended December 31, 2023 and 2022, the company reported collaboration revenue of approximately $5.5 million and $1.2 million, respectively. The increase was due to the revenue earned from our strategic collaboration agreement with Ono Pharmaceuticals. Research and development expenses were $40.8 million and $38.6 million for the years ended December 31, 2023 and 2022, respectively. The increase was due primarily to clinical development costs and research and laboratory expenses, which were partially offset by decreases in employee costs and rent expense. General administrative expenses remain relatively flat at $16.7 million and $16.2 million for the years ended December 31, 2023 and 2022, respectively. And as of December 31, 2023, the company had approximately $48.5 million in cash and cash equivalents, $34.4 million in working capital, and $47.2 million in common shares outstanding. We expect our current cash and cash equivalents to fund operations into the first quarter of 2025. I'll now turn the call back over to Dan for closing remarks. Dan?

Yes, thanks, Keri. As you have just heard, our growing body of data in both clinical oncology and with preclinical autoimmune disease continues to support and reinforce our central premise and firm belief that CUE's platform holds tremendous potential to transform immunotherapy for both cancer and autoimmune disease by selectively modulating the patient's immune system in a highly targeted and tolerated manner. We believe the data we've generated to date in oncology with CUE-101 and CUE-102 have clearly demonstrated the selective and targeted activation and expansion of cancer-relevant CD8 positive T cells in a qualitatively distinctive manner. Furthermore, these data demonstrate clear signs of durable anti-tumor activity and mechanistic complementarity with checkpoint inhibitors. Let me remind everyone listening in that the patients we're treating are refractory, that is, resistant to prior therapy, and metastatic, that is, their cancer has not only recurred but has also spread to multiple locations after primary treatment. As a result, these patients have a very poor overall prognosis. And importantly, both CUE-101 and CUE-102 have demonstrated the potential of stimulating the patient's immune system to recognize the tumors growing in their bodies as foreign, marshalling an attack. Furthermore, the clinical observations to date support the putative mechanism of action for CUE-101 and by implication, CUE-102, as well as the entire IL-2-based CUE-100 series, mechanistically complementing immune checkpoint inhibitors such as KEYTRUDA. We see this compilation of data as a key strategic advantage for expanding patient reach and therapeutic benefit of checkpoint inhibitors, positioning us well for strategic alignment with potential partners to enhance their competitive positioning. As conveyed in slide number 31, we are well-positioned for value inflection milestones over the coming year, namely with CUE-101 moving into a randomized Phase 2 study with the intention of providing confirmation of enhanced efficacy that we've seen in the prior studies that we've presented on in the 1A and 1B, which is our CUE-101 plus checkpoint inhibitor versus the checkpoint inhibitor standard of care alone. We expect interim analysis at 14 months and the overall response rate and medium progression free survival analysis between 22 and 24 months, both of which underscore breakthrough potential with CUE-101 plus checkpoint inhibitor to establish a new standard-of-care for these frontline refractory metastatic head and neck squamous cell carcinoma patients, but also has far reaching implications for our Immuno-STAT platform application in solid tumors per se by expanding patient reach and enhancing clinical benefits of checkpoint inhibitors and to a broad range of cancers. Successful readout in the randomized Phase 2 would place CUE in a position of leverage and strength as a partner of choice for checkpoint inhibitor franchises. Furthermore, CUE-102 patient expansion positions combinations with checkpoint inhibitors in large indication segments where checkpoint inhibitors have historically failed to achieve approval. We have also generated a body of data highly supportive of the mechanistic advantages and disruptive potential of our autoimmune programs, namely CUE-401 for Treg induction currently partnered with Ono of which we have retained an option for a 50% interest in the U.S. market with two near-term milestones potentially being realized and CUE-501 for B-cell ablation with the potential to displace CAR-T with a biologic for B-cell driven autoimmune disease such as lupus. As conveyed in the next slide, number 32, we have positioned CUE well for strategic and competitive positioning with the establishment of clinical proof-of-concept with our two lead oncology programs whereby our clinical data generated to date have the potential to shift the treatment paradigm and that we have demonstrated significant and meaningful increase in the overall response rate, median progression-free survival, and overall survival resulting in the promise that we have the potential to revitalize the checkpoint inhibitor sector and enhance market reach and have also demonstrated platform modularity and scalability. Through this modularity and scalability, we have multiple applications of our novel platform having the potential to address some of the largest pharmaceutical markets in the U.S. and global application for solid tumors and autoimmune disease indications. Through these ongoing developments, we have made significant progress over the past quarter with our corporate development and business development initiatives. We are presently engaging in ongoing strategic discourse with multiple prospective strategic partners. Based on continued development through these ongoing discussions, we are highly confident we will be successful consummating one or more of these transactions in a timely manner enabling strategic alignment, enhancing our capacity, and enabling access to requisite capital towards the realization of our corporate mission. On that, we would like to extend our sincere thanks and appreciation to our committed shareholders, passionate employees, board of directors, scientific advisory board, clinical investigators, and our collaboration partners for their continued support, guidance, and trust. Most importantly, we extend our profound appreciation and respect to the patients and their families who have participated in our clinical trials enabling us to gain insights and knowledge essential for continued progress in the fight against cancer and other debilitating diseases. With that, I would like to now turn the call back over to the operator to open up for questions. Operator?

Thank you, ladies and gentlemen. [Operator Instructions] Your first question comes from Marvin Rakaroff [ph] from Jefferies. Your line is now open.

Hi. Congrats on the progress, and thanks for taking my questions. I was going to ask about the randomized phase 2 combo study. Can you talk about how many patients you anticipate you'll need in each arm? And if you're successful on that first interim, on overall response rate, would that allow you to advance into a registrational phase 3?

Sure. Matteo, do you want to take that question? And thanks, Mark.

Yes, certainly. So the patient sample size for the entire trial is planned to be less than 100 patients, so approximately 25 patients per arm. And then regarding the first interim analysis, given that this is a randomized trial, we'll have a data safety monitoring board that will look at the results of that first interim and provide a recommendation to continue the trial per protocol if everything looks good. And it's really the final analysis at 24 months, 22 to 24 months that would serve as the substrate to proceed into a registrational trial, although a fair bit of trial startup could be done once the interim analysis, the first one, provides a positive recommendation to move forward.

Got it. That's helpful. And Dan, you talked about potential partnering. Can you clarify what stage you would look to potentially partner? Would it be as you're running the Phase 2 or before the Phase 3? And then what could potential partnership look like from a development and economic standpoint?

Sure. Very important question, and, Maureen [ph] it's a dynamic question, and there's no one answer to that. It's really looking at a number of factors that we will consider. So we're presently in discussions, let's just say, with multiple parties across the various asset classes we have. So pertaining to CUE-101, CUE-102, I think the key there is identifying an appropriate party with the sort of requisite insight on the disease indication that can sort of enhance our own capacity and provide the requisite support. We certainly don't want to be giving up on the economics too much of the promise of those assets. So it's really going to be based on our continued involvement, particularly in the randomized Phase 2, the type of support we would have in the economics downstream. So we're in discussions with various parties, and we'll be looking at different economic structures to make that decision. And ultimately, it's a board decision. So, we've been in dialogue with the board on an ongoing basis, and ultimately we will present various scenarios and make the decision accordingly. And regarding autoimmune, same type of sort of dynamic analysis. I would just use Ono as an example. The structure of that partnership was very favorable. They've actually been an outstanding partner with an early asset. They're basically subsidizing the development. We have a very interactive partnership, but we've retained a 50% upside option upon selection of the clinical candidate when we begin IND-enabling studies. And that allows us to preserve sort of optimal upside for our shareholders while the sort of risk capital, particularly in the early stages, is being subsidized. So I hope that answers your question, but we'll be looking at it, in a dynamic manner based on the various options we have in front of us.

Got it. That's, yes, that's helpful. And for the 501 program, just wondering if you'd talk more about where you're at with preclinical development for that program. And you talked a little bit about potentially partnering this one, too. Would this be from the 500 series, would it be one asset or would it be part of this 500 series platform? How would you think about that?

Yes, Maury, so this is Anish. What we have so far is clear evidence that we've been able to make the scaffold and it's biologically active, as you can see. We've tested this across a number of different memory T cell specificities, so CMV being one which is highly present in a majority of us, but also SARS-CoV-2. At this point in time, there's a very conserved epitope from the spike protein that virtually all of us today in the world should have SARS-specific T cells, whether it's by vaccination or natural infection. So that provides a great substrate to essentially use this nature's pandemic to redirect it to something good, which is destroying these pathogenic B cells down the road. We started initially with CD-19, Maury, but you can think about the concept actually extending beyond just B cells to other pathogenic cell types. I also think, and we think very strongly, that this can also extend into very nicely into the oncology setting, particularly solid tumors where you just swap out the SCFE of the B cells to a cell surface tumor antigen. I mean, think about PSMA, think about TROP2, think about HER2, etcetera. So I think there's a vast potential for this. As we started talking, the additional interest has actually been an extraordinary amount of inbound interest from companies and parties that have been interested in really getting CAR-T-like efficacy in what was recently demonstrated in these small studies in autoimmunity. So that is the starting position and we've made good progress. The scaffold actually is de-risked very much by the 100 series, that's why I sort of stressed that. The core component remains the same, it's a bivalent peptide HLA and obviously has no IL-2. Instead of that, the mod is an anchoring SCFE. So again, there's a lot of good learnings from the 100 series, 101, 102, that sort of beneficially impact the 500 series.

Got it. That's really helpful. Thanks for taking my questions.

Thank you, Maury.

Your next question comes from Stephen Willey from Stifel. Your line is now open.

Yes, good afternoon. Thanks for taking the questions and I apologize for the background noise. But maybe just a couple more Phase 2 questions. Can you just maybe speak to the second key one-on-one dose that you're contemplating including into the randomized Phase 2? And then can you also speak as to kind of what triggers the interim analysis? Is that just having a given number of patients beyond some specific duration of follow-up? And then I just have another question.

Okay. Thank you, very good questions. And so the doses that we anticipate examining are certainly the four milligram per kilogram dose that we've really studied in 25 patients with now an objective response rate of close to 50%. We haven't finalized the selection of the other dose. However, we have quite a bit of experience with two milligrams per kilogram as monotherapy, where in that set of patients, of nine patients, we actually see a very pronounced extended survival. And then in the dose escalation at 2 mgs per kg with pembrolizumab, we also observed a very profound durable objective response. So I think the answer there will be two doses. Certainly, we believe at this point 4 mgs per kg and then very likely a 2 mg per kg dose where we've seen really very strong activity as well. With regards to the triggering of the first interim analysis, it really will be determined when approximately 70% to 80% of patients have gotten through the cycle five scan. Okay. So it's really a look to be sure that what we anticipate to observe or the DSMB would observe can make that assessment once, as I mentioned, 70% to 80% of patients have gotten to their cycle five scan. And we'd anticipate that, based on what we've observed to date in the 101-01 trial and the historical monotherapy rate, that that would progress then to ultimately the final analysis, which, again, that will be a complete analysis of the data set with all patients now having follow-up through cycle five to get to your primary overall response rate. That final analysis is very valuable because that yields data then that can be brought forward to start your Phase 3. And the way it's designed then allows also for follow-up with the supplemental analysis for PFS and OS, but we don't have to wait for that to hold up the initiation of the Phase 3 trial.

Okay. I guess that's helpful. And can you maybe just talk a little bit about kind of the pushes and pulls that were under consideration as you thought about carving out kind of an independent randomized Phase 2 versus trying to do something more Phase 2, 3, adaptive, seamless. And maybe in answering that, you can speak to, I guess, to what extent, if any, was this path forward kind of informed by some of these ongoing strategic discussions?

So, very good question. And certainly an option to further develop the combination is to go with a Phase 2, 3 sort of seamless design. The first component of that, and this has become, I think, quite common since Project Optimus has sort of gone into effect as a directive or mandate, is to have a lead-in with the two doses to select your dose and then to go into the Phase 3 randomized portion. So, I think, there's multiple components to considerations. The initiation of that phase two, three is a larger endeavor and investment, I think, clearly. And the Phase 2, really offers the opportunity to generate data that confirms the dose to go into Phase 3. And therefore, the Phase 3 is simpler in design where there's no lead-in, which is actually takes quite a bit of time, at least a year to do. And then also gives the opportunity to have, if you will, a confirmatory analysis that would increase one's confidence in being successful in ultimately the Phase 3 trial.

Okay. And then maybe just one quick follow-up. Matteo, I was just wondering if you had any thoughts around the Pembro survival number that was recently presented from the LEAP-10 trial. And just, I know we're still a couple of years away from a registrational study, but even in the context of a Phase 2, how do you think that influences your expectation as to what that survival number might look like? Thanks.

Yes. So, I think, well, it's a bit of a mystery to me. I don't know that I've heard or that I'm aware of a clear, explanation. Also a surprise that the objective response rate was 27% as opposed to the historical rate of 19%. So, that arm in the trial did appear to do better than anticipated. I think, again, it then supports the value of doing a phase two trial before, you know, engaging into a registrational Phase 3 with, almost, 5 to 10 times the investment to really just gain confidence that we're on track with regards to what we believe the combination treatment effect is to the current monotherapy effect. So, I think, I hope that addresses the question. I don't, and again, when this was presented at the Head and Neck conference in Arizona, there was quite a bit of a discussion with the head and neck experts, and no one really seemed to have an explanation. But, again, with regards to lenvatinib, I think there's ideas or conceptions that the sort of broad array of kinase coverage may have some negative effects on the whole immunotherapy response to the checkpoint inhibitor. But that's conjecture on my part, but, again, I hope that addresses your question.

It does. Thanks for taking the questions.

Your next question comes from Ren Benjamin from JMP. Your line is now open.

Hey, good afternoon, guys. Thanks for taking the questions, and congrats on the progress.

Thanks, Ren.

Matteo, I think you mentioned that there was some data coming out at ASCO for both 101 and 102. Can you just give us a sense as to, I mean, I think the 101 studies, it's largely just longer term follow-up. Correct me if I'm wrong there. And then for 102, about how many patients' worth of data and what kind of follow-up should we be expecting?

Yes, certainly. So I can share here that we're actually delighted to have been selected for an oral presentation on our CUE101-01 dataset at ASCO in June. It will be, as you alluded to a comprehensive, analysis of all the data with longer follow-up. With regards to the CUE-102, which was also selected for presentation as a poster at ASCO, we anticipate now having data on approximately 35 patients or more with some follow-up as long as, out to eight months.

Terrific. And then, just going back to the strategic sort of partnerships and things that you're evaluating, as you think about, I guess, the way to move forward, how are you thinking about potentially just wrapping up 101 and 102 kind of in a nice typo and presenting that as a potential acquisition that provides a significant upfront that allows you to fund, let's say, the autoimmune, programs, which investors are paying a lot more attention to. You're clearly seeing that in the cell therapy space as well. They seem to be, very enamored by the autoimmune data. How do you take that kind of decision-making versus trying to find a strategic that can move with you, both 101 and 102 while spending your own money moving that forward?

Yes, Ren, this is Dan. Probing question and a really important one, particularly, I think, in the headwinds in the current capital markets in oncology. I think it's clearly a prudent question with, I think, strategic insight into the challenges in the oncology sector. So, we are looking at sort of that dynamic. It hasn't evaded our thinking that the time frame and the capital requirement for increasing value for shareholders would probably be more in favor of autoimmune in the current capital markets, but we have much deeper, more mature data. So, I think the key for oncology is to align with a company that has the capacity and competencies to get through a registrational path, and the objective for us would be to be able to retain as much upside for our shareholders. So, the calculus that we're ultimately going to decide upon is how we address capital requirements, which are pretty deep in oncology for a registration path. By the way, it's part of the rationale that Matteo articulated as to the decision to do a randomized Phase 2 with a very defined, discrete number of patients. We can add a substantial amount of confidence and value, and I think that's also part of our analysis having to do with strategic alignment with parties. I think pharma companies are finding that structure to be very attractive, where the degree of confidence goes up dramatically if the randomized data repeats what we've seen in our Phase 1 A and B. So, it's a very important question, and it is part of our overall analysis, and ultimately the calculus that determines what path we choose.

Got it. I guess one final question for me on the autoimmune side. I'm -- on the one hand, I'm a little bit confused as to how T-cells that are targeting, that are targeting CMV can, completely deplete kind of all the B-cells over there. I can imagine some proportion, but all of it. Maybe, Anish can help me understand this a little bit better, and when might we see some, preclinical data at any upcoming conferences this year?

Yes, Ren. So, the T-cell mediated depletion is essentially Pan-B-cell depletion simply because of the CD-19 anchoring that's on every B-cell out at least in circulation. So, when the Immuno-STAT binds to the B-cell displaying the CMV peptide HLA, for the CMV T-cell that's simply presenting it as a surrogate for a virally infected cell, and the cell goes into the effector mechanism. One of the reasons we focus on the virus specific for this application, Ren, is because of the ability to rapidly respond the effector memory compartment, and one that is not dependent much on co-stimulation. So, you can actually rapidly recall these. They're present in high frequencies in a large majority of the population, and importantly, they're not exhausted. We know that from a body of literature that we've now had for decades in terms of the longer-lasting memory repertoire. So, that, those things together make for a really strong case for selective harnessing of what nature gave you as the nature's sort of long-lasting killer population. You could make it specific to a discrete B-cell subset if one chooses to, and achieve selective B-cell depletion, and that would just mean that you would swap the marker from a CD-19 targeting to something else, and so that optionality remains with us. But I think as a central early mechanistic proof-of-concept, CD-19 was attractive enough, particularly also since the CAR-T data is with CD-19 targeting, and that looks pretty robust, at least with the early metrics we've seen. So, we are in the midst of generating, actually, a body of data. There's a large part of the organization is looking at this with a significant amount of intensity, likely thinking to aim for either an autoimmune meeting or some translational autoimmunity meeting to be able to sort of bring out these concepts a bit more. So, hopefully, maybe try to find something either in the second half of the year or early next year to be able to talk more about this.

Excellent. Thanks for taking the questions.

Hello Operator?

This is Dan. I think we have lost the operator. Yes. I think we're having a technical difficulty. We're having a technical difficulty with the operator, so…

There's one more person waiting in the question queue that we'll try to get on.

Okay. We seem to not be able to resolve the technical issue with the operator, so, Dan, with that, I think we will end the call. I want to thank everyone for listening in, and we look forward to providing everyone with substantive updates as they become available over the coming quarter. And as Mateo stated, we have two presentations at ASCO. Looking forward to presenting that data and autoimmune data at the appropriate conferences coming up over the coming year. I want to thank everyone for your attention, and have a pleasant afternoon and evening. Thank you very much. Take care.

Good afternoon, ladies and gentlemen, and welcome to the Cue Biopharma Third Quarter 2023 Earnings Call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. [Operator Instructions] As a reminder, this call is being recorded today, Thursday, November 9, 2023. I would now like to turn over the conference to Dan Passeri, Chief Executive Officer. Please go ahead.

Yeah. Thank you and good afternoon, everyone. As a reminder, this presentation and discussion is being recorded and will be available on our website for the next 30 days. Also be aware that the slides accompanying today's update may be advanced directly by those listening in on the call, and we'll notify you of what slide we're on throughout the presentation. Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; Dr. Matteo Levisetti, our Chief Medical Officer; and Kerri-Ann Millar, our Chief Financial Officer. As shown on Slide number 2, the presentation and overview may contain some forward-looking statements, and any forward-looking statement made during this call represents the company's views only as of today, November 9, 2023. The next Slide, Slide number 3, outlines the agenda for today's call, and I'll begin with a brief summary overview of our therapeutic platform and core competitive positioning, which is bolstered and further validated by the recent data update presented this past weekend at SITC. I'll then turn the call over to Matteo, who will provide a detailed synopsis of our clinical data from both the monotherapy and combination portions of the ongoing CUE-101 trial, as well as the highly encouraging early signs of clinical activity from the dose escalation portion of the CUE-102 monotherapy trial. As a reminder, these data are representative of our modular Immuno-STAT platform, which we believe has significant potential for broad market applications in cancer immunotherapy, autoimmune and inflammatory diseases, as well as chronic infectious diseases. After Matteo, Anish will provide a further details of our platform developments, underscoring the far-reaching potential of our approach for selective modulation of disease-specific T-cells and the potential for superior differentiation. Following Anish, Kerri will provide an overview of our financials for Q3 and guidance going forward. I'll then return for some concluding remarks and open the call for questions. All right. Let me first begin by emphasizing our strategic positioning and core competitive advantages. It's self-evident that within the immuno-oncology sector, there have been significant and persistent challenges in realizing the fullest potential of immunotherapies. While many therapeutic modalities and combination approaches for immune modulation are being pursued, significant challenges exist with respect to suboptimal efficacy, the safety and tolerability experienced by patients, scalability and cost of goods to enable broad patient reach. It's important to note that despite the significant promise of checkpoint inhibition, such as anti-PD-1, PD-L1 antibodies, there remains a pressing unmet medical need within oncology for an effective and well-tolerated means of stimulating and activating relevant anti-cancer T-cells while sparing the vast majority of cancer-irrelevant T-cells. Solution providers to these challenges will likely emerge as best-in-class market leaders defining the paths forward for more effective therapeutics, both as standalone treatment options as well as combination approaches, for example, with checkpoint inhibitors. To that end, as shown in Slide 4, we believe our Immuno-STAT platform offers a potential breakthrough path forward for cancer immunotherapy. With data from over 100 cancer patients dosed with Immuno-STAT from our IL-2-based CUE-100 series, and namely that's the experience with CUE-101 targeting HPV E7 and CUE-102 targeting Wilms Tumor 1. We can summarize some key distinguishing features bolstering our competitive positioning in this crowded space. There are four predominant and core features to highlight. First, as noted in this slide, we have created a therapeutic index for IL-2 by selectively targeting tumor-specific T-cells through the T-cell receptor, or TCR, that provides the highest degree of specificity for the desired T-cells relevant to antitumor immunity. When we refer to a therapeutic index, this basically refers to the ability to dose patients at a range of doses whereby they experience demonstrable clinical benefit, example, an increase in overall response rate, and/or an increase in median overall survival, while also having an accepted tolerability profile for maintaining quality of life. There have been high-profile field approaches attempting to develop IL-2 therapies for cancers. Notable among these recent failures are pegylated versions of IL-2 and non-alpha variants of IL-2. There have also been failures in combinations with pembrolizumab with, for instance, kinase inhibitors where they may have an ORR but a very poor tolerability profile. Our success with IL-2 may also be replicated for many other cytokines and immune-activating receptors where the generation of a therapeutic index would be of paramount importance to maximize efficacy, while preserving patient safety and tolerability. Second, our clinical candidates demonstrate antitumor efficacy in late-stage poor-prognosis refractory metastatic cancer patients, both as monotherapy and in combination with checkpoint inhibitors, namely pembrolizumab anti-PD-1 antibody. While much of the maturing efficacy data is from our CUE-101 trial in HPV+ refractory and metastatic head and neck squamous cell carcinoma patients. We have also begun to observe antitumor activity with our second clinical candidate, CUE-102, that is currently in the dose escalation portion of a monotherapy trial in patients suffering from metastatic solid cancers, namely colorectal cancer, ovarian, pancreatic, and gastric cancer. These WT1 overexpressing cancers have historically not been responsive to checkpoint inhibitor therapy and have a poor prognosis. Hence, demonstrating disease control and antitumor activity may represent a breakthrough that can be further expanded with checkpoint inhibition and our other combinations to benefit these patients in need of new therapeutic options. Matteo will present and discuss these clinical data in greater detail in a moment. Third point, we believe that maturing clinical data from the CUE-101 trial offers opportunities to pursue multiple registrational paths in HPV+ refractory metastatic head and neck patients. The prolonged survival signal we've seen in the CUE-101 monotherapy treatment arm and second line and beyond patients, in fact, the majority of the patients are beyond third line, and the enhanced overall response rate with maturing progression-free survival and overall survival in frontline patients treated with CUE-101 and standard-of-care pembrolizumab offer attractive development opportunities in these respective lines of treatment. To that end, we have submitted a request for discussions and feedback from the FDA to gain alignment and clarity on the next steps towards a registrational trial. Importantly, CUE-101 serves as a clinical validation beachhead from which we can expand the application of the CUE-100 Series across many different cancers. A key strength of our platform is the modularity, wherein any given tumor antigen can be incorporated to selectively activate the relevant cancer-specific T-cells. This strategy has also significant regulatory advantages since the core IL-2 framework, which has been de-risked by CUE-101, remains essentially the same across therapeutic molecules of the CUE-100 Series, and this was clearly demonstrated with the IND approval of our second clinical candidate, CUE-102. In essence, the IND application for 102 was supported by the clinical data from CUE-101 as an analog molecule, where the FDA did not require us to perform additional IND-enabling preclinical toxicology studies, and we were allowed to initiate the CUE-102 clinical trial at an active dose of 1 mg per kg, which is essentially a situation that saved us about a year in dose escalation timelines and the associated costs. Anish will provide additional details on our focus strategy of expanding our preclinical pipeline with validated Immuno-STAT targeting attractive tumor antigens, such as KRAS involving the G12 hotspot mutations and other tumor antigens. As conveyed in this slide, we believe we are positioned as a potential leading solution provider, realizing the promise of precision immune modulation for superior patient outcomes. As such, we believe our data places us in a potential position as not only first in class for selective modulation of disease-relevant T cells, but also best-in-class therapeutic platform for immunotherapy. With that background on the progress in differentiation and competitive positioning, I'm going to turn the call over to Matteo to review the clinical data, particularly what we just presented at SITC. Matteo?

Thanks, Dan. Good afternoon to everyone listening in on today's call. I am particularly pleased to provide you with this summary update as the clinical data from the ongoing CUE-101 trial continues to demonstrate highly encouraging and robust metrics of clinical benefit for heavily pretreated recurrent metastatic HPV+ head and neck cancer patients treated with monotherapy and for newly diagnosed patients with recurrent HPV+ head and neck squamous cell carcinoma treated in combination with pembrolizumab. As shown on Slide 5, data from the ongoing clinical trials with CUE-101 as monotherapy and in combination with pembrolizumab have provided clinical proof-of-concept and de-risking of our Immuno-STAT platform. The latest data generated to date in 2023 continues to support prior observations and further enhances our confidence in CUE-101 as a potential therapeutic for patients battling HPV+ head and neck cancer. As previously and consistently stated, we believe CUE-101's mechanism of action as evidenced by the ongoing data generated to date provides effective and tolerated dose levels enabling selective expansion of targeted tumor-specific T cells. Recurrent metastatic HPV+ head and neck cancer is a tough and curable disease. The data we have observed throughout the monotherapy trial bolsters our position and enhances our confidence that CUE-101 is in fact stimulating the targeted cancer-specific T cells within these patients, resulting in demonstrable anti-tumor effect. Furthermore and importantly, we continue to observe an evolving pattern of disease control and enhanced survival in the monotherapy trial. We believe this enhanced survival is due to the superior qualitative features of tumor-specific T cells given CUE-101's mechanism of action, especially in the tumor microenvironment and the recent description of the role of IL-2 in generating potent effectors CD8+ T cells. On this note, enrollment in the neoadjuvant trial is progressing well and preliminary observations demonstrate expansion of T cell clonality and increases in natural killer cells within the tumor microenvironment. These findings are consistent with the pharmacodynamic changes observed in the peripheral blood of patients treated with CUE-101 as previously reported. We believe these observations in addition to the clinical efficacy observed in the second and first line recurrent metastatic setting support a development strategy of moving further upstream into earlier lines of therapy where a larger number of patients may benefit. We believe the selective perturbation of the relevant immune cells results in durable clinical benefit as seen in CUE-101 treated patients that have failed prior checkpoint inhibitor treatment. As shown on Slide 6, durable clinical responses are observed with CUE-101 monotherapy. Now, with new data demonstrating an unconfirmed partial response in a patient at 24 months after starting therapy. As shown before, patient A, experienced a durable partial response with an approximate 60% reduction in tumor burden evident at six weeks after the first two cycles of CUE-101, which lasted close to one year on therapy. Importantly, this patient also demonstrated a significant reduction in HPV cell-free DNA that coincided with the initiation of the partial response and HPV cell-free DNA remained undetectable for the majority of time on treatment. Patient B, who just completed 24 months of treatment, has demonstrated an unconfirmed partial response on their cycle 35 scan. Notably, this patient has also had complete disappearance of HPV cell-free DNA in the blood since week six. The undetectable HPV cell-free DNA, which is an increasingly recognized biomarker of disease activity is suggestive of a pathologic complete response or cure in this patient who we expect may have surgical resection of the lesion for histopathological analysis. As shown on Slide 7, the current Kaplan-Meier estimate of median overall survival observed in the 20 patients treated that the recommended Phase II dose of 4 milligrams per kilogram is 20.8 months. The observed median overall survival of greater than 20 months in patients treated in the third line and beyond is notable when compared to the historical median overall survival of approximately eight months observed in patients treated in the second line. In the CheckMate 141 in KEYNOTE-040 trials of nivolumab and pembrolizumab respectively. As any experienced oncologist understands that the survival with third line treatment is expected to be less as the disease has further developed and become more unstable. Our evolving data continues to support the premise that treatment with CUE-101 demonstrates single agent activity by durably expanding tumor specific T cells with anti-tumor activity, resulting in what appears to be a meaningful increase in survival for patients with advanced recurrent metastatic HPV+ head and neck cancer. Based upon the strength of this data, we plan to meet with FDA to define a registration path for CUE-101. The demonstration of monotherapy activity in these patients bolsters our belief that we should observe complimentary mechanistic effects in combination with Pembrolizumab. As indicated on Slide 8, I will now provide an update on the ongoing trial of CUE-101 in combination with pembrolizumab in first line recurrent metastatic HPV+ head and neck cancer patients. Pembrolizumab is approved for the treatment of first line patients with recurrent metastatic head and neck cancer that have tumors with complete positivity scores greater than or equal to 1%, which is a measure of PDL-1 expression. The next slide, Slide 9, shows the current overall response rate of 47% observed in first line patients treated with CUE101 and pembrolizumab as presented at the SITC meeting earlier this month. The overall response rate of 47% observed in patients with CPS scores greater than or equal to 1 treated with CUE-101 in combination with pembrolizumab to date represents a greater than doubling compared to the historical overall response rate of 19% observed with pembrolizumab monotherapy in the KEYNOTE-048 study. Notably, for patients with CPS scores of 1 to 19, an overall response rate of 56% was observed with CUE-101 and pembrolizumab, which represents a greater than tripling of the historical overall response rate of approximately 15% observed with pembrolizumab alone. Furthermore, CUE-101 also appears to increase the overall response rate in patients with CPS scores greater than 20 with an overall response rate of 38% for CUE-101 and Pembrolizumab and an overall response rate of 23% for Pembrolizumab alone. In totality, our data suggests that not only does Q-101 appear to demonstrably enhance the response rate of anti-PD1 inhibition, but also does so by substantially expanding responses in patients that are traditionally less likely to respond. This is particularly important since patients with low CPS scores, range of 1 to 19, represent approximately 50% of all patients that are CPS+ and eligible for treatment with checkpoint inhibitor in the frontline setting. The swimmer plot shown on Slide 10 shows that 21 of the 22 patients treated to date at the RP2D and the ongoing combination trial of CUE-101 remain alive as of the last follow-up for each patient. Of note, the median progression pre-survival is still maturing and is currently at 5.8 months, which compares favorably to the historical median progression pre-survival of 3.2 months observed with pembrolizumab, monotherapy in the KEYNOTE-048 trial. Eight patients have lived beyond 12 months, which was the median overall survival observed in patients treated with pembrolizumab alone in the KEYNOTE-048 study. A summary of the clinical validation and platform de-risking of Immuno-STATs via the CUE-101 clinical experience is shown on Slide 11. Key observations in patients treated with CUE-101 monotherapy in the third-line and beyond include demonstration of single-agent antitumor efficacy evidenced by resist-based partial response in durable stable disease in third line and beyond recurrent metastatic cancer patients and a median overall survival of greater than 20 months in the recommended Phase II dose cohort. In the first line setting, CUE-101 and pembrolizumab demonstrate an objective response rate of 47% and a current median PFS of close to six months, which is continuing to mature. As previously announced, the robust data on CUE-101's activity in monotherapy and in combination with pembrolizumab enabled the granting of Fast Track designation for the treatment of patients in both the first and third line setting. The Fast Track designation will facilitate planned interactions with the FDA to define a monotherapy registration path. The cumulative data from these ongoing trials with CUE-101 have provided us with clear evidence of targeted expansion of HPV-E7 specific T cells with antitumor activity as a single agent and as a complementary mechanism with checkpoint inhibition for what we believe will broaden patient reach and enhance efficacy of checkpoint blockade therapy. Furthermore, we believe the preliminary observations from the neoadjuvant study, in addition to the clinical efficacy observed in the second and first line recurrent metastatic setting, support a development strategy of moving further upstream to earlier lines of therapy where a larger number of patients may benefit. As such, we believe CUE-101, our first biologic therapeutic from our CUE-100 series, represents a potential therapeutic breakthrough for patients. Moreover, we believe the data from CUE-101 has provided a de-risking and mechanistic validation for additional biologics from the IL-2-based CUE-100 series, beginning with CUE-102. As a reminder, shown on Slide 12, CUE-102 and CUE-101 share 99% amino acid sequence identity. This enabled us to significantly decrease the development time and cost of CUE-102, as we're not required by the FDA to repeat IND-enabled toxicology studies for CUE-102, and we are also able to initiate the Phase I dose escalation study at 1 milligram per kilogram, a dose at which we observe clear signs of biologic activity with CUE-101. As shown on Slide 13, we are conducting the CUE-102 dose escalation study in colon, gastric, pancreatic, and ovarian cancers. This design offers us the ability to perform monotherapy expansion studies in any or all of the indications being evaluated in the dose escalation phase of the trial. The study is actively enrolling patients in all four indications. The patient screening enrollment rate continue to go exceedingly well, underscoring investigator enthusiasm and the need for effective therapies in WT1 positive cancers. We have observed substantial WT1 expression across the target indications, with 60% of colorectal, 53% of gastric, 100% of ovarian, and 60% of pancreatic cancers testing positive. We have completed enrollment of patients in cohort 4 at a dose of 8 milligrams per kilogram and are expanding the 2 and 4 milligram cohorts. CUE-102 has been well tolerated to-date with no dose-limiting toxicity observed. The expansion of cohorts 2 and 3 will provide additional pharmacokinetic, pharmacodynamic, and antitumor activity data to help inform the selection of the recommended Phase II dose for the expansion cohorts. Data on the first 18 dose escalation patients treated with CUE-102 shown on Slide 14, demonstrates encouraging disease control with rates of 80% and 75% observed in cohorts 2 and 3 respectively in this heavily pretreated patient population. Seven of the 11 patients treated in cohorts 2 and 3 remained on treatment at the time of data cutoff. Reductions in tumor burden have been observed in patients treated in the dose escalation portion of the study. As shown on Slide 15, a patient with gastric cancer that progressed on three prior lines of therapy, including a checkpoint inhibitor, has experienced a decrease in the sum of three target lesions of minus 29% at week 24 and continues on treatment. Reductions of approximately minus 50% in the tumor markers CEA and CA 19-9 coincide with the shrinkage of the patient's cancer. Another example of reduction in tumor burden observed in the 2 milligram per kilogram dose escalation cohort, this time in a patient with ovarian cancer is shown on Slide 16. This 52-year-old patient that progressed on four prior lines of therapy has experienced an unconfirmed partial response with a reduction of minus 30% in their tumor burden. We are encouraged by these early observations of monotherapy antitumor activity and these indications where checkpoint inhibitors have been largely ineffective. We look forward to presenting additional data at an upcoming scientific meeting. I will now turn the call over to Anish. Anish?

Thanks, Matteo, and thank you all for joining this call today. As Matteo highlighted, the maturing clinical data with CUE-101 and 102 bolstered the validation for Immuno-STATs as a differentiated class of T cell engager therapeutics that can be deployed widely for immunotherapy of cancers. To that end, Slide 17 depicts the opportunity for expansion of the CUE-100 series to generate therapeutic molecules targeting numerous cancers. Note that the core IL-2 components remain the same among all therapeutic candidates, with the primary difference being the tumor antigen HLA complex that provides selectivity for the cancers being targeted. Following the success with our clinical assets, CUE-101 and CUE-102, we have designed and manufactured a rich pipeline of preclinical Immuno-STAT candidates that can be readily progressed towards the clinic. Examples of some of these preclinical candidates include Immuno-STATs targeting mutated KRAS isoforms, especially the hotspot mutational variants at the G12 possession, including G12V and G12D, and additional Immuno-STATs targeting well-characterized tumor antigens such as MAGE A4, PRAME, and COL6A3, which is derived from a tumor-specific splicing variant of collagen type VI alpha-3 protein and appears to be shared across many solid cancers. Many of these preclinical Immuno-STATs have also been validated in functional T cell assays. It is important to highlight that the evolving Immuno-STAT pipeline encompasses multiple cancer targets and multiple HLA alleles, which together provide broad patient coverage for many cancers. In addition, we've also evolved the platform to accommodate multiple tumor antigens and personalized neoantigens. This extension of our platform is known as Neo-STAT, as shown on the right side of this slide. In the Neo-STAT framework, the peptide binding pocket of the HLA is empty, which allows us to readily conjugate different tumor epitopes to generate off-the-shelf, therapeutic molecules. Neo-STATs are a potential solution for tumor heterogeneity and often an attractive opportunity for personalized cancer immunotherapy. Taken together, we believe the IL-2 based CUE-100 series can generate an infinite number of therapeutic molecules to address solid and hematological cancers. The next slide, Slide 18, highlights the important feature of TCR-selective targeting in generation of a therapeutic index for IL-2. The core structure of an Immuno-STAT, as shown in the example on the left, allows for selective engagement and activation of the tumor-specific T cells while avoiding the systemic activation of all T cells. This principle of generation of a therapeutic index via focusing on disease-specific T cells can be applied to many other relevant immune signals. And as noted here, our platform is well-positioned to exploit the full breadth of the therapeutic potential of other cytokines, such as IL-7, IL-12, IL-15, et cetera, and cell surface receptors, like CD28, 41BB, among others, for immunotherapy of cancers. I will point out that numerous other approaches have tried to harness the signals I just mentioned for cancer immunotherapy. However, these attempts have been largely unsuccessful due to the lack of a therapeutic index, resulting in poor drug tolerability and suboptimal efficacy. We believe our approach with Immuno-STATs should circumvent many of these challenges as already demonstrated with the IL-2-based CUE-100 series. Let's move on to Slide 19 that describes notable features of superior differentiation that Immuno-STATs offer over the current categories of Pan T cell engager molecules. As mentioned earlier, by design Immuno-STATs are TCR-selective engagers of only the tumor-specific T cells. In contrast, other T cell engagers are promiscuous and engage every T cell via broadly expressed molecules, like CD3 or CD28. Due to their selectivity, Immuno-STATs avoid the broad systemic activation of the immune system to minimize toxicities. On the other hand, the Pan T cell engager molecules have had notable challenges with systemic immune activation and related toxicities, which have been significant hurdles in furthering clinical development. The tolerability and toxicity challenges of Pan T cell engagers have also hampered combination approaches with other agents, including standard-of-care therapies, such as checkpoint inhibitors. Such combinations in patients have often resulted in a significant increase in toxicities, including fatalities. In contrast, the favorable tolerability profile of Immuno-STATs has enabled us to pursue combination therapies in our clinical trials with little to no evidence for synergistic toxicities. As Matteo shared, our clinical data with CUE-101 and pembrolizumab in frontline recurrent metastatic head and neck cancer patients demonstrates significantly greater efficacy while not compromising patient safety. CUE-102 seems to have a similar tolerability profile to CUE-101, wherein currently in the monotherapy dose escalation trial, we have completed dosing the highest cohort at 8 mgs per kg, with no evidence of dose-limiting toxicities. And finally, and very importantly, in contrast to the generic classes of Pan T cell engagers, the clinical de-risking of the Immuno-STAT platform offers significant regulatory advantages and clinical development efficiencies, as previously described by Matteo. We believe these are significant wins for a first-in-class therapeutics platform that has convincingly demonstrated clinical efficacy and tolerability. I'll now change gears slightly and give you a brief update on our platform applications in autoimmune and inflammatory diseases. As shown on Slide 20, we have developed two broad classes of therapeutics for addressing autoimmune disorders. For diseases with well-described and dominant antigens, we can deploy the CUE-300 series of Immuno-STATs for selective targeting and down-modulation of autoreactive T cells. In this case, we've used the natural signal of PD ligand, which we know is involved in maintaining peripheral tolerance. We have demonstrated feasibility and proof-of-concept in type 1 diabetes via selective dampening of proinsulin-specific T cells. Another extension of this approach can be used for selective depletion of autoreactive pathogenic T cells, while sparing protective immunity. We are currently engaged in discussions with prospective partners to progress our work in antigen-specific targeting of autoreactive T cells. Our other program in autoimmunity is CUE-401, which is novel TGF-beta IL-2 bi-specific for selective induction and expansion of regulatory T cells, or Tregs, which are a key cellular component of maintaining immune balance by controlling and suppressing pathogenic inflammatory responses. This program has been a very productive collaboration with ONO Pharmaceuticals, wherein ONO is supporting all of our ongoing preclinical work to identify an optimized clinical lead compound. CUE-401 offers a unique opportunity to not only expand preexisting regulatory T cells, but also possesses the ability to convert naive CD4 T cells into Tregs, thereby enhancing the quantitative and qualitative fraction of Tregs. Early data from this program has demonstrated potent activity in in-vitro assays, as well as generation of stable Treg cells, and early in-vivo studies have demonstrated efficacy in an animal model of gastritis, as shown on the right side of the slide. This is a disease model developed by Dr. Richard DiPaolo at Saint Louis University, wherein a short treatment with CUE-401 results in a long-lasting protection from gastritis, as demonstrated by the pathology scores shown here. Our teams are working diligently with our ONO colleagues to aggressively advance the CUE-401 program in order to enable the next stages towards IND filing. We will provide more updates in the future as the current ongoing studies generate mature data sets. With that background on the platform applications in oncology and autoimmunity, I will now pass the call to Kerri to review the financial details. Following Kerri's remarks, Dan will provide some additional context on our strategic positioning and continuing next steps of our corporate development. Kerri?

Thank you, Anish. Turning to Slide 21, I'd like to provide a brief update on our financial results for the three months ended September 30, 2023. During the third quarter, the company reported collaboration revenue of approximately $2.1 million, as compared to $68,000 for the same period in 2022. Revenue in the third quarter was primarily due to work related to our collaboration with ONO Pharmaceuticals for CUE-401, which Anish just described. Research and development expenses were $9.9 million and $7.6 million for the three months ended September 30, 2023 and 2022, respectively. The increase is due to higher clinical expenses, stock-based compensation, and research and laboratory expenses in the third quarter. General and administrative expenses remained steady at $3.6 million and $3.5 million for the three months ended September 30, 2023 and 2022, respectively. As of September 30, 2023, the company had approximately $54.7 million in cash and cash equivalents, $40.3 million in working capital, and $45.1 million common shares outstanding. We expect our current cash and cash equivalents to fund operations through 2024. I'll now turn the call back over to Dan for closing remarks. Dan?

Yeah. Thanks, Kerri. As conveyed at SITC last weekend and now summarized on this call, the design of our Immuno-STAT molecules achieves selective modulation of disease-relevant T cells, while sparing the detrimental effects of the stimulation of the vast majority of irrelevant T cells. In essence, we believe we have achieved the biologic equivalence of precision targeting, thereby creating a therapeutic window for potent cytokines such as IL-2. This desired profile enables combinations with, for instance, checkpoint inhibitors, wherein the complementary mechanism of actions should provide enhanced efficacy while not compromising tolerability and patient safety, as shown on Slide 22 with our clinical data from CUE-101 plus pembrolizumab in frontline HPV-positive refractory and metastatic head and neck cancer patients. Turning now to Slide 23, let's review the modest overall response rates reported on checkpoint inhibitor monotherapy in various solid tumor cancer types. It's important to note that while checkpoint inhibitors opened up the potential promise of immuno-oncology, their impact on antitumor efficacy is primarily dependent upon the presence of a robust anti-tumor T cell repertoire. As such, the rational combination of checkpoint inhibitors and Immuno-STATs increases the probability for patients to derive enhanced therapeutic benefit from immunotherapy. And that's actually shown if you look at the head and neck cancer patient. We increased the overall response rate from 19% with pembrolizumab alone in frontline to 47% in the combination. Okay, finally, let's move to Slide 24. This shows the anticipated milestones and accomplishments we anticipated achieving over the next year, including the defined prospective registration path for CUE-101, as well as multiple clinical milestones with our two clinical candidates and several solid tumor types. It's important to note that we're very well positioned for strategic alignment with prospective partners, recognizing the potentially disruptive implications of our emerging data. We look forward to continuing our progress forward into a highly productive and transformative 2024. With that, I'm going to turn the call back over to the operator, and we'll now open the call, open the questions. Operator?

Thank you. Ladies and gentlemen, we will now conduct a question-and-answer session. [Operator Instructions] Your first question comes from Stephen Willey from Stifel. Your line is now open.

Hi, guys. This is Torian (ph) for Steve. Can you guys hear me, okay?

Yes. Thank you.

Thank you. Thank you for taking my questions and congrats on the data update. I have just two quick ones on my end. So the first one is starting with CUE-101. I understand that you guys submitted a request to FDA, and it looks like you guys are now planning on defining a registration path in the beginning of 2024. And I'm wondering what the format of that communication be. Would it be just a press release or do you think you will likely disclose that information during earnings call, et cetera.? And second is related to CUE-102, and very interesting data. And I guess my question would be, what gives you guys the confidence in pursuing colorectal and pancreatic cancers in expansion cohorts besides, high prevalence of WT1 expression in these tumor types? That would be it. Thank you very much.

Okay. First question, I want to emphasize that these -- and the request for discussions with the FDA are basically our initial discussions regarding registrational trial design. And the first foray is in the second line and beyond monotherapy. But we view this as a really important sort of foundational discussion to build support for our subsequent dialogue with the FDA for defining future registrational paths, et cetera. I also want to emphasize we're in the -- we are engaged in some partnerships and partnering discussions, and we want to be cognizant of the fact that defining registrational trials need to correspond with those partnering objectives as well. So this is an important initial interaction with the FDA to establish kind of foundational support for the mechanism of 101 as a monotherapy, which then builds on our subsequent discussions. So that's really the strategy there. With 102, again, we have done a basket study in the dose escalation. Initially, we were looking at focusing on colorectal, but based on the observations we're seeing, we're looking at several tumor types that we would likely do a patient expansion in. And I'm going to turn this over to Matteo, if he wants to elaborate on that.

Yeah. Thanks, Dan. Just to add at a couple points. We're very happy with the tolerability profile that we've observed to-date. In addition to the signs of antitumor activity in multiple indications. And so just to sort of set the context for this late line of colorectal cancer, these patients are very advanced, very refractory. And if you actually look back to the approval of stivarga, regorafenib, in colorectal patients, there was about a 30% disease control rate at six weeks that ultimately was then associated with a 1.4 month increase in survival. And that led to the approval of that drug in late line colorectal cancers. So observing stable disease in a high proportion of patients, even at six weeks is significant. And then furthermore, we have patients now across several indications with stable disease beyond 18 weeks, and that includes patients with pancreatic cancer. And then as we've shown, the patient with gastric cancer that has a very close to threshold partial response at 24 weeks continues on therapy. So we're very encouraged, as are our investigators, by our observations. And in fact, our investigators are really keenly interested in pursuing all the indications. And we, going forward, will consider how doing so and the timing of that fits in our overall development strategy for CUE-102.

Very helpful. Thank you.

Your next question comes from Reni Benjamin from JMP Securities. Your line is now open.

Hey, guys. Thanks for taking the questions and congratulations on all the data that was released. It's nice to see the continued improvement in overall survival. Several questions from us. Maybe just starting off with the CUE-101 series. When we talked about that patient who got a PR, quite late in the whole process, can you talk a little bit about how many doses that patient actually received? Do they continue to receive doses or has the dosing schedule been modified at all? And then sticking with CUE-101, the combination study, if we focus just on the low CPS patients, can you talk a little bit about the duration of response and maybe the PFS as well for those patients?

Yes, Matteo, you want to take that?

Sure. So thank you for the question. Regarding the patient that had stable disease for 24 months, this is, again, the patient that at six weeks had undetectable cell-free DNA. So you asked regarding the length of their treatment. It was a complete 24 months. This patient did have their regimen reduced from Q3 to Q6 weeks. After approximately 12 months or 14 months of treatment, but they completed the whole two years of therapy. I'm sorry. Now, the second question was in terms of how…¦

Durability, low CPS patients, and the duration, progression-free survival, like -- is that durable?

Yeah. So the durability, really is, it's evolving. So it's maturing. So we have several patients with ongoing objective responses. So it's really a bit premature, I think, to define the duration of response. It's approximately 30 weeks now, but really maturing with several patients remaining on treatment. The median PFS is close to six months. And again, that compares favorably to the monotherapy data where it was approximately three months from KEYNOTE-048. But again, as the duration of response needs time to further mature, the PFS will be maturing as well in parallel.

Got it. And then just you had mentioned -- you had made some comments, Matteo, in the call regarding the neoadjuvant trial. I was wondering if you could provide a little bit additional color on those observations, maybe -- I mean, anything you can provide. Is it just CD8 and CD4 cells that are moving up or are there NK cells involved as well? And kind of what are next steps and when might we see that data?

Certainly. So this is really an exciting trial and a wonderful opportunity to look at the effects of CUE-101 on the tumor microenvironment in a setting where one can obtain substantial amounts of tissue from biopsy. And so, again, just to point out that this is an investigator-sponsored trial at Washington University. However, we have been able to see some preliminary data, which is really very, very encouraging. And what we've seen is expansion of T cell clonality in the tumor microenvironment. And increases in natural killer cells in the tumor microenvironment after two doses of CUE-101. So this study continues to enroll. I think we anticipate enrollment may be complete by the end of next year. And we are respectful of the investigator's desire to publish this work when the time is right. But it really, certainly, is very supportive of everything we've observed to-date in our clinical study.

Got it. I'll ask one more and then just hop back in the queue. As we think about WT1, and that program and the advancement of that program, I kind of look at CUE-101 as kind of the poster child. And so it begs the question, what potential combinations might you ultimately want to be exploring, as you move that program forward?

Yeah. So great question. Thank you. I think, clearly, as we learn more about the activity of CUE-102 and the different tumor types that the rational next step with regards to development would be to look at combinations. And potential combinations, I think, will likely depend on which tumor Type 1 is talking about. And so, we looked, for example, at gastric cancer, where we've seen this tumor reduction of 24 weeks duration. Considering a combination with anti-PD1 or checkpoint inhibitor, given the history of some, although limited activity in some subsets of gastric cancer, I think in other indications, like colorectal cancer, it would be very interesting to move up one or two lines of therapy and think of combinations, perhaps, even with chemotherapy or anti-VEGF therapy, for example. But this is certainly an area of very active deliberation for us. And it, of course, dovetails, importantly, with our strategic ongoing activities with potential partners.

That’s great.. Thanks for taking the questions. I’ll hop back in the queue.

Thanks, Reni.

Your next question comes from Ted Tenthoff from Piper Sandler. Your line is now open.

Great. Thank you very much. And, again, I appreciated all of the SITC and the update. Just kind of looking at now that you've really got Immuno-STAT proof-of-concept, what other are some of the antigens? I know that you've talked about KRAS in the past. Would potential partners be interested in looking at their own antigens on this active construct or are they more looking at kind of the existing products or maybe even kind of a mixture of both?

Yeah. I'll turn that over to Anish. Thanks, Ted.

Yeah. Hi, Ted and thanks for the questions. So, Ted, as you well saw with some of what we've said in the expansion, going after primary cancer drivers is obviously a low-hanging fruit. So, mutated KRAS, you're aware of the G12C small molecule covalent inhibitor from Mirati being approved and the Amgen compounds. We believe the valine and the aspartic acid, well appreciated, are much larger patient populations, particularly in the three major cancers of colorectal, lung, and pancreatic. And they do donate T cell epitopes. So, just in that space, for example, Ted, we've got four different KRAS molecules addressing G12B and G12D on a couple of different HLA alleles. We've also got strategies looking at other primary mutated cancer drivers. And that is still early in the pipeline, but we have confidence they'll be validated. We've got primary tumor drivers like MAGE-A4 and Cancer-Testes Antigens that offer very attractive opportunities and perhaps some level of validation through the ongoing work of others looking at TCR T cell therapy approaches. Of course, ours is with the biologic, so a very different application and perhaps a bit more easy to sort of think about from the commercial and patient accessibility viewpoint. We've got interest on these sets of antigens from certain sort of parties to what you referred to going after some of these primary drivers. But then, as you well know, there is a significant community out there that has been focused on discovering and doing their own work on bespoke antigens, which the platform can easily be deployed to drug those moieties. To that end, Neo-STAT becomes a fantastic opportunity, and that's one of the reasons we sort of highlighted that modality, even though that is an extension of the Immuno-STAT. The opportunity there is the fact that you can go after multiple antigens, Ted, and it's the same core IL-2 framework. So, we do believe the efficiencies and the advantages that we've demonstrated, the CUE-101 and CUE-102, should apply to Neo-STAT as well. So, there's, again, we look at this in three sort of broad buckets. We look at driver antigens, where single dominant antigens should have benefit. And CUE-101 is a great example because E7 is a viral proto-oncogene in the case of HPV-driven cancers. And by the way, that data is in head and neck cancer. That same molecule can go to other indications like cervical, penile, anal, vulva cancers as well. CUE-102, with what Matteo just described, follows up a beautiful example of a onco-fetal antigen that is selectively expressed and has activity. And then KRAS, for obvious reasons, including the MAGE A4, PRAME follows suit. And then we've got this opportunity to go after multiple different antigens, where one can simply deploy the platform. And that's the reason I highlighted the plug-and-play approach virtually has a potential to generate therapeutics.

Thanks. Super helpful. Really exciting time for the company. Thanks, guys.

Thank you, Ted.

Your next question comes from Reni Benjamin from JMP Securities. Your line is now open.

Hey, guys. Thanks for taking the follow-up. Yeah. You mentioned on the call partners and partnerships. And I guess, I'd like to just, if you can, provide a little bit additional color as to maybe how those discussions are going. Should we be thinking about, I don't know, sort of the who's who of checkpoint inhibitors are who you're kind of talking to or are there other types of potential partners for one-on-one that you're talking with? And I guess just as a follow-up to that does a partnership -- is that necessary to move into a pivotal study or is that something that you believe after the FDA discussion is complete you might need to and want to take on your own? Thanks very much.

You're welcome. So, important question, Ren, and it's a complex question, right? It doesn't have a simple answer. So, let's start-off with the last part of the question. It's not necessary for going forward with a pivotal study, but I would say with the current market dynamics that the biotech sector, particularly oncology, is confronting with the headwinds in the capital markets, we have limited resources. And we're trying to look at dynamically how do we continue to evolve the platform for maximizing patient reach and demonstrating the value of our platform for addressing serious disease, cancer, autoimmune, et cetera. So, we're looking at partnering strategies that give us flexibility but still engaged in involvement in the drugs development. We don't want to become a licensing company. We want to become a strategic collaboration partner. And I would say Ono was a great example. We have a co-development option with them in that collaboration. In terms of the characterization of the companies we're talking to, it's the full spectrum. We're certainly talking to the who's who. I'd say what's intriguing is, first of all, we very deliberately did not go out with a BD emphasis early on in our development. We wanted to build a sound, substantive data package based on rigor and solid data that we could stand on. We're also getting sort of inbound inquiries, and that's actually very encouraging. So, we're talking to a spectrum of potential partners, and I would say a sort of spectrum of opportunities and different sort of structures that we're assessing. So, I appreciate the question. I can't answer it with any more detail for obvious reasons, but I'm doing the best I can to address your question.

Yeah, enough. Thanks. I appreciate that. Good luck going forward.

Thank you.

[Operator Instructions] There are no further questions at this time. Daniel Passeri, please proceed with your closing remarks.

Yeah, great. Thank you. First, we want to thank those of you listening in to this call and recognizing the importance of our mission towards developing these important novel therapeutics for enhancing patient treatment outcomes for debilitating disease. We want to thank our employees for their consummate dedication and professionalism helping us achieve our mission. And obviously, we want to thank our shareholders and Board of Directors for their support. Most importantly, we want to thank the patients and their families participating in these ongoing and important trials. So, thank you again for listening in and take care. Thank you.

Ladies and gentlemen, this concludes today's conference call. Thank you for joining. You may now disconnect.