Cue Biopharma, Inc. Q2 FY2022 Earnings Call

Greetings and welcome to the Cue Biopharma Update Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the presentation. As a reminder, this conference is being recorded. I would now like to turn this conference over to Mr. Dan Passeri, Cue Biopharma's Chief Executive Officer. Thank you, sir. You may begin.

Thank you, and good afternoon everyone. Just to remind you, as we proceed through the presentation we'll convey which slide we're on and you can advance the slides directly. We appreciate your time and interest in our update call regarding our ongoing trials of CUE-101, as well as CUE-102. Our initial representative drug candidates of the IL-2-based CUE-100 series. Joining me on today's call is Dr. Anish Suri, our President and Chief Scientific Officer; Dr. Ken Pienta, our Acting Chief Medical Officer; Dr. Matteo Levisetti, our Senior Vice President of Clinical Development; and Kerri Millar, our Chief Financial Officer. This conference is being recorded and will be available on our website for the next 30 days. As a reminder, and as shown here on Slide #2 of this presentation. An overview may contain some forward-looking statements, and any forward-looking statements made during the call represent the company’s views only as of today, August 23, 2022. So our agenda for today's call is shown on the next slide. As an introduction, each will provide a synopsis of our progress to date, as well as describing our strategic and competitive positioning prior to turning the call over to Ken and Matteo who will each provide a summary and status update of the data associated with observations from our ongoing Phase 1 trials of CUE-101, as well as the recently initiated CUE-102 trial. Following Ken and Matteo, I'll provide an overview of our corporate strategy and additional pipeline expansions within the CUE-100 series. Kerri will then provide a brief update on our financials, after which I'll return for closing remarks and then open up the call for a Q&A session. With that, I'll now pass the call over to Anish.

Thanks, Dan. I'd like to start today's presentation by reminding folks of the genesis of our company's quest and the mission we seek to accomplish. Our mission is to address a very fundamental and consequential question for immunotherapy, which is, can we selectively and specifically activate anti-tumor T-cells, while avoiding the carpet bombing of the immune system to maximize efficacy and minimize toxicities. This is a very basic yet fundamental distinction from how others may be approaching the challenge of turning the immune system against cancers. To accomplish our objective, as shown in Slide 4, we envisioned exploiting the one unique marker of an anti-tumor T-cell, which is the tumor-specific T-cell receptor or TCR. We have engineered an innovative biologics platform termed Immuno-STAT, that generates TCR selective engages to deliver immune activating signals to tumor-specific T-cells. The figure on the left in Slide 4 depicts the core structure of an Immuno-STAT, which is essentially an antibody FC-based biologic containing stabilized tumor peptide HLA molecules to selectively target tumor-specific T-cells, along with desirable activation signals that are consumed by those T-cells. This framework provides a molecular basis for improved specificity for anti-tumor T-cell activation, while minimizing off-target toxicities due to systemic immune activation, which by the way, it continues to be a key impediment for many other broadly targeted immunotherapeutic approaches. On the right side of this slide, you can see a figure depicting the CUE-100 series, which is designed to selectively deliver IL-2 to tumor-specific T-cells over a relevant T-cell, hence generating a therapeutic index for IL-2 which has been a challenge. We believe this is a superior approach for harnessing the fullest potential of IL-2, especially since the tumor-specific T-cells are present in a very low frequency. Our current clinical candidates, namely CUE-101 and CUE-102 are derived from the CUE-100 series and share the core IL-2 framework as depicted here. The next slide, Slide 5 summarizes the key and impactful takeaways that highlight the progress and clinical validation of our approach. Ken and Matteo will provide detailed insights into the clinical data and patient benefit that support the conclusions noted here. To summarize, we have engineered a novel biologics platform Immuno-STAT for selective targeting of anti-tumor T-cell activation. As an initial drug construct, we chose to deploy IL-2 as the targeted activation signal. IL-2 is a well-characterized and validated therapeutic target but has suffered from significant safety liabilities due to lack of a therapeutic index. We have successfully generated a therapeutic index for IL-2 as evidenced by the fact that we have observed clinical activity between 1 mg per kg and 4 mgs per kg and have dosed up to 8 mgs per kg with no maximum tolerated dose. Most other IL-2 variants that are in the clinic have been dosed in the low-microgram per kilogram range due to unwanted adverse side effects. Our first clinical candidate, CUE-101, targets IL-2 to HPV-specific T-cells to attack HPV-driven cancers, such as head and neck cancer. Our clinical experience with CUE-101 highlights several important findings for our technology platform. Our molecules are well-tolerated with no evidence of systemic IL-2 toxicities, such as vascular leak syndrome or cytokine storms. They exhibit drug-like properties, including favorable pharmacokinetics, on-target pharmacodynamic signals and monoclonal antibody-like manufacturability to support desirable costs of goods. We have demonstrated clinical efficacy as monotherapy in late-stage cancer patients that have failed numerous prior therapies, including checkpoint inhibitors. Ken and Matteo will describe these signals in detail, including an emerging benefit in overall survival. The observed clinical benefit is supported by mechanistic signals demonstrating T-cell infiltration, which catalyzed our ongoing neoadjuvant trial in head and neck cancer. We have evidence of prolonged benefit and anti-tumor activity in patients remaining on therapy for long periods, which underscores the extended kinetics for the evolution of a beneficial immunotherapy response, as also noted previously by others. Lastly, early data from our first clinical experience in combination with the checkpoint inhibitor supports the potential for significant expansion of patient benefit. All these metrics will be described in greater detail in the ensuing clinical discussion. Importantly, since the core IL-2 framework is conserved across the CUE-100 series, we believe the clinical de-risking obtained by CUE-101 has essentially de-risked our entire platform. The recent IND acceptance for our next clinical candidate CUE-102 targeting Wilms’ Tumor 1 or WT1 underscores the strategic advantages of platform de-risking accomplished by CUE-101. The FDA accepted the CUE-102 IND with no requirement for preclinical talks and has authorized us to initiate the trial at 1 milligram per kilogram, a dose that has demonstrated clinical activity in the CUE-101 trial and is a significantly higher starting dose than the 0.06 mg per kg starting dose for CUE-101. These metrics highlight the resource, time, and operational efficiencies gained by the platform de-risking by CUE-101. To end, we believe the modularity of our platform, coupled with the clinical validation, positions us to generate a rich repository of therapeutic molecules targeting many cancers. As one evaluates the potential of IL-2 per cancer immunotherapy, we believe our platform has cracked the code for selective targeting of the cytokine to the tumor-specific T-cell repertoire. Dan will address this in the context of our corporate growth strategy towards the end of today's presentation. With that backdrop, I'll now pass the call to Ken for the clinical update.

Thanks, Anish, and good afternoon to everyone on the call. We are pleased to share our updated data from the ongoing CUE-101 Phase 1 trial as both a single-agent treatment and for use in third-line therapy and beyond for head and neck cancer. We also have encouraging early data from the combination study with pembrolizumab in first-line patients. As we have consistently mentioned, we believe the mechanism of action for CUE-101 is supported by the ongoing data we’ve generated, showing effective and well-tolerated dose levels that enable selective stimulation of tumor-specific T-cells. Recurrent head and neck cancer is a challenging and incurable disease. The findings we've observed in the monotherapy trial enhance our confidence that CUE-101 is stimulating cancer-specific T-cells in some of these patients, leading to an anti-tumor effect. Moreover, we continue to see a promising trend indicating improved survival rates. While this data is still developing, we are encouraged by the results so far. Observations beyond overall response rate and median overall survival further strengthen our confidence in the anti-tumor effect of CUE-101. For instance, we have seen patients experience tumor reductions after extended periods on the drug, even when initial imaging did not reveal any resistance-based objective response. This observation, consistent with others, showcases the dynamics of T-cell anti-tumor activity that can emerge over time. This pattern is illustrated in the tumor measurements presented on Slide 6 for a patient receiving CUE-101 at a dosage of 2 mg per kg, where the initial months show tumor growth exceeding the 20% threshold set by resist criteria. However, based on the overall clinical status, the patient continued treatment after we modified the protocol to permit this. After about six months, the tumor started to shrink, and the patient has been on therapy for 14 months since starting CUE-101. The data shown on Slide 7 for a patient treated at the recommended Phase 2 dose of 4 mg per kg indicates stable disease persisting for nearly 12 months, along with ongoing reductions of cell-free HPV-DNA, which may indicate disease activity in patients with HPV-positive cancers. This test is increasingly utilized by experts to inform treatment decisions for these patients, and it may suggest a pattern indicative of a complete pathological response. Collectively, this data enhances our confidence in the therapeutic potential of CUE-101 and its prospects for a registration study as a monotherapy in patients who have previously failed chemotherapy and checkpoint inhibitor therapy. We plan to present more data at an upcoming medical meeting. I will now hand over the call to Matteo for further discussion on this and our additional data.

Thanks, Ken. The goal in our CUE-101 monotherapy study was to first prove safety for this first in man biologic, and second to prove that we could demonstrate activity. In addition to the data just described by Ken, we have observed in our 20 treated patients at the recommended Phase 2 dose in our monotherapy trial, one partial response and seven patients with durable stable disease for an overall clinical benefit rate of approximately 40%. The next slide, Slide 8 shows the patient with a partial response and their supporting pharmacodynamic metrics. This heavily pre-treated patient has completed 17 cycles of CUE-101. You can see in the two upper right panel that the patient demonstrated a nine-fold increase in cancer-specific T-cells but did not demonstrate an increase in the general CD8 positive T-cell population, which might cause unwanted side effects, including immune related adverse events. The patient also demonstrated a transient and modest increase in Tregs that returned to baseline by day 15. The patient demonstrated a sustained increase in NK cells, a positive attribute for an anti-tumor response as the NK cells may assist in tumor killing. We observed similar pharmacodynamic effects across many patients. On the lower right portion of the slide is a graph showing a rapid decrease in circulating cell-free HPV DNA, corresponding with the decrease in tumor burden observed by imaging. We had made the same observation with several other patients who have demonstrated antitumor activity and continue to monitor cell-free HPV DNA as a possible predictive biomarker. The next slide, Slide 9 conveys our ongoing survival swimmer plot for the 20 patients dosed with the recommended Phase 2 dose of 4 milligrams per kilogram. We have taken the liberty to draw a median overall survival line at eight months, which is reflective of the median overall survival observed in both the KEYNOTE-40 and CheckMate 143 trials of pembrolizumab and nivolumab in second line patients. As any experienced oncologist understands, 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 is clearly trending to increased survival in the third-line setting for patients with head and neck cancer. This data has encouraged our principal investigators and they are aligned with our position that this potentially provides us with a promising path forward to a registrational trial. The demonstration of monotherapy activity bolsters our belief that we should see complementary mechanistic effects in combination with pembrolizumab. As a reminder, the data from patients treated in monotherapy clearly supports that CUE-101 increases the number of antigen-specific T-cells. It is likely that these T-cells will have greater freedom to kill with inhibition of the PD-1 pathway, a major mechanism used by cancer cells to prevent immune-mediated killing. Slide 10 demonstrates the spider plot. As shown at ASCO this past June of first-line patients treated in the dose escalation cohorts of the ongoing study. Early data and signs of activity of CUE-101 in combination with pembrolizumab are encouraging. With one patient each in cohorts 2 and 3 experiencing a confirmed partial response and an additional two patients experiencing durable stable disease. We are continuing to expand patient enrollment at the recommended combination Phase 2 dose and look forward to presenting additional data at an upcoming meeting. Slide 11 shows the patient from cohort 2 demonstrating a decrease in all four of their target lesions, including two liver lesions. I want to emphasize that this is not just shrinkage in lymph nodes, but shrinkage of visceral tumor disease. To any oncologist, this is a significant and meaningful response. This patient has also demonstrated a clearing of the circulating cell-free HPV DNA, which is ongoing. As mentioned before, circulating tumor DNA continues to be developed and used by our principal investigators as a potential surrogate for response. As shown in Slide 12, the patient with a confirmed partial response from cohort 3 also demonstrated reductions in all four target lesions, including two lung lesions and clearing of their circulating cell-free HPV DNA. We are excited by the preliminary data in this ongoing combination study, along with maturing data from our monotherapy and neoadjuvant studies, and look forward to presenting additional data at upcoming meetings. I'm also happy to report that we have treated our first patient with CUE-102, which targets Wilms’ Tumor 1 positive tumors in a trial that is enrolling patients with advanced colorectal, gastric, pancreatic, and ovarian cancers. As shown on Slide 13, CUE-102 and CUE-101 share 99% amino acid sequence identity. This enabled us to significantly increase the development time and cost of CUE-102 as we were not required by FDA to repeat IND enabling toxicology studies for CUE-102 and we are also able to initiate the Phase 1 dose escalation study at 1 milligram per kilogram, the dose at which we observed clear signs of biologic activity with CUE-101. As Slide 14 shows, and as mentioned just a moment ago, we are performing the CUE-102 dose escalation study in colorectal, gastric, pancreatic and ovarian cancer patients. This design offers us the ability to do monotherapy expansion studies in all or any of the indications being evaluated in the dose escalation phase of the trial. This trial is actively accruing and will be opened at 15 sites around the U.S. I will now turn the call over to Dan to talk more about our pipeline.

Yeah. Thanks, Matteo. As just described by Anish, Ken, and Matteo, we've made significant progress towards the establishment of CUE-101 and by implication, the entire CUE-100 series as a breakthrough therapy for stimulating patients’ immune systems against cancer. And remind you that we are stimulating the immune system directly in the patient’s body. As we continue to progress forward with CUE-101 and CUE-102 as our lead programs, we also have the potential to rapidly expand our pipeline and productivities as conveyed in the schematic shown on Slide 15. However, under the current market conditions where capital is constrained and resource prioritization is paramount, we've streamlined our operational footprint and taken prudent measures to foster a focused and strategic prioritization of clinical development and those activities associated with pipeline development, fostering strategic partnerships. Our core approach is to validate and de-risk the IL-2 based CUE-100 series through the emerging data and associated metrics from our ongoing 101 and now 102 clinical trials and position ourselves with greater leverage for retained value creation for our shareholders. We have promising preclinical data from our KRAS program, which is an extremely important target covering a broad set of cancers with expanded allele coverage into HLA-A03 and HLA-A11 and have preserved this clinically important program for potential strategic partnering to be catalyzed by our emerging data from our 101 and our 102 trials, as well as a possible registration submission in 101. We have also positioned ourselves for enhanced productivity and efficiencies with the development of CUE-100 series derivative, referred to as Neo-STAT entailing a stabilized molecule as the MHC HLA binding pocket with the epitope fits in, that's been stabilized for covalent chemical attachment of an identified cancer epitope. This will allow for the manufacturing of each allele framework, for example, HLA-A02, A03, A11, et cetera, with an empty binding pocket, whereby the epitope may be subsequently attached chemically rather than made as a single fusion protein. This will provide us with cost savings, production efficiencies, and greater flexibility for epitope selection in combination, such as in the case with tumor instability and heterogeneity. Furthermore, we envisage that Neo-STAT may be an enabling innovation to realize the potential of personalized cancer immunotherapy where one could sequence the tumor and identify particular epitopes and chemically attach those to a Neo-STAT. While we are currently prioritizing and strategically focusing internal efforts on the development of our CUE-100 series drug candidates for treating cancer, we're also actively engaged in strategic discussions with third parties to further develop CUE programs outside of oncology, including the CUE-400 series for treating autoimmune disease. These activities aim at ensuring optimal use of our internal resources on our most advanced programs while augmenting and enhancing our capacities with third-party relationships to further develop promising assets beyond our core focus. I'm now going to turn the call over to Kerri, who will provide a brief overview of our current financials and I'll then return to provide some closing summary remarks prior to opening the call up to questions.

Thanks, Dan. Turning now to Slide 16, I'd like to provide a brief update on our financial results for the three months ended June 30, 2022. The Company reported collaboration revenue of approximately $26,000 and $2.7 million for the three months ended June 30, 2022 and 2021, respectively. Research and development expenses were $9.6 million and $8.8 million for the three months ended June 30, 2022 and 2021, respectively. The increase was primarily due to an increase in laboratory and drug substance manufacturing costs, as well as clinical expenses related to our CUE-102 Phase 1 dose escalation clinical trial that was initiated during the second quarter of 2022. General and administrative expenses were $3.8 million and $4.3 million for the three months ended June 30, 2022 and 2021, respectively. The decrease was due primarily to a decrease in stock-based compensation and professional and consulting fees incurred during the second quarter of 2022 as compared to the same period in 2021. We ended the quarter with approximately $66.1 million in cash and cash equivalents and working capital of approximately $60.7 million. Importantly, we took proactive steps to decrease the company's office and lab footprint and restructure specific functions, which will afford us significant cost savings that can be allocated to our clinical programs. We believe our cash and cash equivalents as of June 30, 2022 will allow us to support the development of our Immuno-STAT platform, including the clinical development of CUE-101 and CUE-102 through the third quarter of 2023. I'll now turn the call back over to Dan for closing remarks.

Yeah. Thanks, Kerri. As you've heard on this call, we continue to execute and make significant progress towards further advancing our lead and representative candidate CUE-101 towards a potential path for registration. Through the clinical development of 101, we've clearly demonstrated the ability to selectively target and activate defined anti-tumor T-cells, while not compromising patient safety. As seen on Slide 17, we have successfully executed and continue to execute on defined strategies providing risk reduction and validation of the CUE-100 series and its derivatives. As such, CUE-101, which is targeting the HLA-A02 allele has clearly demonstrated tolerability and single-agent activity. And remind you, with no maximum tolerated dose emerging from the dose range of 0.06 mgs per kg, all the way up to 8 mgs per kg. We've seen clear evidence of pharmacodynamic effect on targeted tumor-specific immune cells, namely T-cells as well as natural killer cells. Clinical activity demonstrated from 1 mg per kg to 4 mgs per kg with 4 mgs per kg being our recommended Phase 2 dose. And clear evidence of anti-tumor activity, which we've gone through some of these data being a prolonged effect having to do with the kinetics of stimulating the immune system, where the immune system then dynamically interfaces with the cancer. So clear evidence of that anti-tumor activity manifested as a confirmed partial response, seven durable longstanding stable diseases with one potential pathological complete responder that Ken reviewed. We appear to be providing a survival benefit, this obviously needs to be determined as to what the median overall survival is, but it is clearly trending in a positive direction, and we believe it will provide us with a potential path forward for registration. 101 in combination with pembrolizumab is showing encouraging early signs of activity, which we look forward to presenting further details at an upcoming medical meeting later this year. CUE-102, the IND was accepted at 1 mg per kg starting dose and we consider this to be a major achievement, underscoring the quality of the supportive data, but also underscoring the risk reduction and validation that we believe we've achieved with the data emerging from the 101 trial. Any evidence that emerges in the 102 trial of clinical activity will be a further catalyst for validation and value creation regarding the platform's analog nature and modularity. Wilms’ Tumor 1 is expressed in a significant range of tumors representing a very significant market potential and multiple tumor types. We believe those two programs add significant validation and value for our shareholders, and then coupled with Neo-STAT representing a derivative of the 100 series as a next-generation construct, providing scale and flexibility, that allows us to address tumor heterogeneity and, just as importantly, it should substantially decrease our cost of goods and provide us with flexibility that will enable us to potentially go into personalized medicine. The attachment of the peptide is in the HLA pocket, that's a covalent attachment. We have attractive preclinical proof of concept data supporting that premise and look forward to providing you with updates as we continue to progress. We are positioned very well strategically and anticipate several important milestones throughout the coming year, including the potential of a registration path for CUE-101 as a monotherapy. This includes CUE-101 monotherapy with a median overall survival date by the end of the year, clarifying this is a potential start of a registrational trial in the second half of 2023. CUE-101 plus pembrolizumab combination, the preliminary overall response rate data reading out in the second quarter of next year, and the 102 monotherapy data, which we've just recently initiated, data from the dose escalation will be reading out mid-2023. This is a major significant market opportunity, so any evidence of clinical activity will represent a significant perspective value increment. As we focus our efforts and resources on the clinical development of 101 and 102, we believe that further clinical datasets will catalyze significant business development and corporate development opportunities for pipeline expansion. We look forward to providing further details on these trials at an upcoming medical conference later this year. We'd like to thank our employees and clinical principal investigators whose dedication to our mission through their commitment and professionalism allows us to continue progressing our goal of helping patients in need. We also want to thank our Board of Directors for their support and guidance. We want to thank our shareholders who provide us with the essential resources to continue this important work developing promising immunotherapies for patients. Most importantly, we want to thank the patients who are participating in our trial and their families for their courage and willingness to be part of clinical studies, allowing us the opportunity to assess and determine the potential therapeutic benefit of our promising drug candidates. I'd like to thank you very much for your attention and interest. I'd now like to turn the call back over to the operator for questions.

At this time, we'll be conducting a question-and-answer session. Our first question comes from the line of Stephen Willey with Stifel. You may proceed with your question.

Yeah. Good afternoon. Thanks for taking the question and thanks for the update here. With respect to the updated CUE-101 data, do you have a median duration of treatment at this point? I think it looks to be about two months just in terms of eyeballing it, but just wanted to know if that's correct? And then also, can you just broadly speak to post-study therapy that these patients may or may not be receiving following discontinuation of CUE-101 and I guess your confidence that post-study therapy is not impacting extended OS time that you're seeing off treatment? And then I just have a quick follow-up on CUE-102.

Okay. Thanks, Steve. Ken, you want to take those questions?

Hi, Steve. The median therapy duration is two cycles, which means half of the patients received two cycles before stopping. This is quite similar to what we observe with second-line checkpoint inhibitors. The main factor to consider is how these patients performed in terms of overall survival, since progression-free survival doesn't correlate as one might expect. We are still in the process of gathering data on follow-up therapies and do not have anything concrete to share at this time. We do know that some patients are doing quite well off all therapies, but we don’t have complete data yet. Thank you.

Okay. And then just on CUE-102, I know that dose escalation portion and presumably expansion is requiring WT1 antigen positivity. Is this just kind of like a binary yes/no type of assay that's, I'm guessing, IHC-based or is there some kind of graded expression that a clinic needs to have in order to be eligible?

Yeah. It is IHC-based and it is graded, but our sort of minimal requirement is that 1% of the tumor cells are expressing WT1.

Our next question comes from the line of Reni Benjamin with JMP Securities. You may proceed with your question.

Good afternoon, everyone. Thank you for answering the questions and congratulations on your progress. To start, could you elaborate on the biomarker data you've generated? I've noticed a significant decrease in HPV-DNA levels, but while there is tumor shrinkage, it doesn't seem as pronounced. You mentioned a pathological complete response, but I'm uncertain about its correlation. Could you clarify that for us? Will you utilize this in the future? Additionally, what other biomarker activities do you have planned for studies 101 and 102?

Okay. Ken, you want to take the first part of that and then have Matteo cover the second half.

We are observing that several patients have achieved durable stable disease. With immunotherapy treatments, it is common to see some stabilization, which could manifest as scar tissue, fibrosis, or inflammation. For instance, we had a patient who received 1 mg per kg of treatment and demonstrated stable disease. We later examined this patient in the operating room, and they have now been off therapy for 14 to 19 months. The ongoing cell-free DNA assays, which were not available when we initiated the trial, have allowed many of our investigators to monitor nearly all patients for insights into their condition. This is particularly useful when determining whether a tumor increase is due to response evaluation criteria or if it represents inflammatory changes that we should monitor, either through rising or falling cell-free DNA levels. With patients exhibiting stable disease, it is crucial to ascertain whether any active tumor remains. We discussed one patient who shows stable disease where the tumor appears non-viable, resembling scar tissue, and their cell-free DNA levels are at zero. This may suggest a pathological complete response if the tumor were to be removed. This area, especially in head and neck cancer, is evolving, and our investigators are adapting to the use of cell-free DNA. Although it is not yet an accepted biomarker of response by the FDA, we are focused on further understanding its implications. We have not yet received all the results from the cell-free DNA analyses as these are processed in batches, but both we and our doctors are optimistic about its potential as a biomarker. Additionally, we are in discussions with an investigator about potentially conducting an adjuvant study based on cell-free DNA responses in patients. I will now let Matteo discuss our initiatives regarding WT1.

Thanks, Ken. I believe that the questions have been well addressed at this point. I did want to add one comment regarding the previous question on the WT1 assay. Although we do use a binary results for eligibility, I just would add that we are paying very close attention and tracking both the nuclear and cytoplasmic expression of WT1 by grade, so that we can correlate this data with potential patient outcomes.

And sorry, just kind of sticking with this thing for a second, are you seeing the converse accrue in that once patients are kind of progressing or off the study. Are you seeing HPV DNA – cell-free HPV DNA pick up in those patients as well or do they consistently stay low all the way through?

Good question. We do not have cell-free DNA data from patients after they leave the study. We are monitoring their survival and any therapies they have received. However, we have observed that in patients who experience progression, their cell-free DNA levels increase. This tends to correlate with tumor burden, so while it's dynamic, we are still learning about its role as a biomarker. Nevertheless, we have noticed that in patients who are truly progressing, their cell-free DNA levels do rise.

Yeah. I’d add as well, Ken, that this is an endpoint in the biomarker assessment that is gaining traction with FDA over the last 12 to 18 months. Whereas, it may be possible in the future to use it as a secondary endpoint and actually to use it to inform decisions and adaptive trial design, but it's really not there yet. So that would be an opportunity in the future to introduce that biomarker to sort of accelerate or possibly enhance decision-making in the next trial.

Got it. So my second question is, when I examine the overall survival curves you have presented, it is evident that there are patients with durable FD, and some who display partial responses. Then there are those who have clearly progressed. They are surviving, but I assume those who lack a durable FD marker have tumors that are growing. My question is, have you been able to explore the mechanisms of resistance that might be at play? Furthermore, as you consider this, what types of combination therapies are you contemplating that could enhance 101’s durability moving forward?

Well, that’s the $1 billion question. It's a great question. We honestly don't know of the myriad of resistance mechanisms, which ones are at play. What I think has caught us, certainly surprised early on and caught all of our docs by surprise early on is the durable overall survival in these patients that have even come off therapy fairly soon. I think obviously when we're increasing the number of cancer-specific T-cells in the periphery and then the tumor itself, we're allowing for checkpoint therapies to work better. Certainly, we've seen some early indications of potential antigen spread which would suggest that combinations with further cytotoxic types of therapies that are going to increase neo-antigens to be seen by T-cells is certainly something that we'll consider in the future. As far as other mechanisms like HLA down-regulation, et cetera, we just don't know yet, we don't have that data. Maybe Anish wants to comment on this, but clearly we think there are going to be synergies, the obvious ones with checkpoints as well as with chemo.

I would like to emphasize that this is an important question, and we need to analyze these factors. We've observed various operational resistance pathways, such as those arising from the tumor microenvironment, cell types, and changes in the tumor's immunogenicity profile, which may be due to the loss of HLA or changes in antigen processing. We need to improve our understanding of these aspects as part of our ongoing analysis. This will help us gather the necessary data to determine what additional combinations we can explore with CUE-101 to maximize the benefits we've begun to observe.

Got it. And just one final one for me. I probably missed this in the prepared remarks. I remember we were talking about a neoadjuvant study for quite some time and primarily what gotten me most excited about was the ability to have biopsy samples kind of before and after. I just wanted to get an update as to what was happening with that study.

So I'll make a few comments, and then I'll turn it over to Dan to add on. The study is progressing well, and we've already recruited our first couple of patients. We've collected the biopsies and have plans to conduct a composite batch analysis as soon as we recruit a few more patients. This is in the context of locally advanced head and neck cancer. Matteo, feel free to share more from your perspective.

Thanks, Anish. That's really quite accurate. We've treated a bit more than a few, and we look forward to sharing the data in the future when it becomes available.

Okay. Thank you.

Thanks, Ren.

Our next question comes from Mark Breidenbach with Oppenheimer. You may proceed with your question.

Hey guys, good afternoon and thanks for taking questions. Just a couple from me. First, with respect to upcoming interactions with the FDA, is the plan right now to have the end of Phase 1 meeting in conjunction with the availability of median overall survival data from your Phase 1 trial? And when can we kind of expect to hear their perspective on the regulatory path forward? And then I guess I'm also just wondering why there looks to be kind of a gap between the availability of median OS data and the potential start of the registrational study? So that's one question for me. And the other one is just with respect to the CUE-102 trial. Does this protocol include paired biopsy collections? I know that wasn't something that was included in the head and neck study. I'm just wondering if any changes have been introduced so we have more translational data from the CUE-102 patients.

Okay. So Ken, you want to take that?

Yeah. Sure, I can start with the question regarding the interaction with the regulatory agency. As we've just covered here, we anticipate having mature median overall survival data by the end of the year in the 20 patients dosing at the recommended Phase 2 dose. We have designed a Phase 3 trial that we plan to present to the FDA in the context of a subsequent registrational trial. Again, we're beginning to do preparations for such a trial at risk and anticipate that we could begin open that trial, which would be a global multi-regional trial sometime later next year.

Biopsies as well in the WT1 trial.

Yes, you're right. We have made the paired biopsies optional. We’ve had many productive discussions with investigators, and we've recruited some who are very interested and capable of arranging those. In the tumor indications we are enrolling in the 102 trial, we hope to have the opportunity to obtain paired biopsies, potentially from anatomical locations that may be more suitable for biopsy. However, to answer your question, it is currently an optional procedure. In contrast, the neoadjuvant trial is designed in a way that allows us to examine pre and post-dose biopsies as part of the standard care for patients with locally advanced cancer undergoing resection with the intent to cure.

Okay. And just going back to the regulatory question. I just want to be absolutely clear, we wouldn’t hear until 2023 a regulatory feedback with respect to what a registrational trial might look like in head and neck cancer, is that correct?

I think that's correct. I would say early 2023, of course, some of the interactions will really depend upon the timelines granted by FDA. But in this setting, we're confident that requesting a Type B meeting request, but given where we are in the development that FDA would agree and be collaborative. So it's not to drive the potential of the development for this drug in this unmet medical need in third-line patients and beyond with head and neck cancer.

Yeah. This is Ken. We certainly, I think the end of ’23 is our conservative estimate. We know what that trial we want that trial to be, and as soon as we get the data, we will be ready to go and hopefully be able to launch sooner at this point.

Ladies and gentlemen, we have reached the end of today's question-and-answer session. I would like to turn this call back over to Mr. Daniel Passeri for closing remarks.

Okay. Thank you very much. I want to thank the research analysts for questions, very helpful and instructive. I just want to thank everyone for listening in and your ongoing interest and support of our activities and bringing these very promising therapies to patients. Thank you very much. Take care. We look forward to providing updates throughout the year. Take care.

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation. Enjoy the rest of your day.