Cue Biopharma, Inc.

Greetings and welcome to the Cube Biopharma update call. At this time, all participants are in listen-only mode. The question and answer session will follow the presentation. If anyone should require operator assistance during the conference, please press start and zero on your telephone keypad. As a reminder, this conference is being recorded. I would now like to turn the conference over to Dan Passeri, Cube Biopharma's Chief Executive Officer. Thank you, Sal. Please begin.

Thank you, and good afternoon, everyone. Before I begin, I'd like to remind everyone that you have the slides in front of you that you need to operate manually, and we will notify you what slide we are on. Joining me on today's call is Dr. Anish Suri, our President and CSO, Dr. Ken Pienta, our Acting Chief Medical Officer and Dr. Matteo Levassetti, our Senior Vice President of Clinical Development, as well as Kerry 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 number two, this presentation An 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, November 14, 2022. Our agenda for today's call is shown on the next slide, slide three. I'll begin by providing an overview of our competitive and strategic positioning based upon data from both our monotherapy trial of Q101, as well as the data just recently reported at CITSE from our Q101 and Keytruda combination trial. Matteo and Ken will provide a review of this data in further detail momentarily, but first I want to provide context pertaining to the underlying implications and importance of the datasets observed to date. As you are aware, the ultimate promise of immunotherapy is to enable the intrinsic potential of a patient's immune system to recognize and kill cancer. We believe through our representative data generated from both our monotherapy trial and combination trials of Q101, our IL-2-based Q100 series is now well-positioned to become a first-in-class selective T-cell engager and best-in-class IL-2 for cancer immunotherapy, as shown here on slide number four. The data bolsters our belief that the demonstrated mechanism of action and resulting activation and amplification of cancer-specific T cells will mechanistically complement and enhance therapeutic benefit derived from checkpoint inhibition, such as PD-L1 inhibitor Keytruda. We believe the compilation of data from both the monotherapy and combination trials supports Our central thesis of selective activation of cancer-specific T cells while avoiding systemic immune activation will enhance the desired anti-tumor efficacy. The recent data presented at CITSE positions us well to push forward and potentially transform cancer therapy where patients' own immune systems can be harnessed to the fullest extent to eradicate cancer. I'm now going to turn the call over to Anish, who will provide a brief synopsis and overview of the key mechanistic features of our selective T-cell engager, the IL-2 base Q100 series, and he'll then turn the call over to Ken and Matteo to review the supporting efficacy data that has emerged from the monotherapy trial and provide an update from our recent CITSE presentation pertaining to to the current efficacy data from our combination of Q101 with Keytruda and frontline HPV-positive head and neck squamous cell carcinoma patients. Manish?

Thanks, Dan, and welcome to all listening to this update. As noted in the next slide, we all appreciate the fact that selective activation of tumor-specific T cells is central to successful outcomes from cancer immunotherapy. However, there are biological constants that nature has imposed that must be considered when thinking about tumor-specific T cells. One, the frequency of tumor-specific T cells in a patient is extremely low. Greater than 99.9% of T cells in a patient have no relevance to cancers. So how does one go about selectively activating tumor-specific T cells while sparing the broad activation of all other T cells? Another biological constant is the fact that the only unique marker on an anti-tumor T cell is the tumor-specific T cell receptor, or TCR. There are no cell surface markers that exhibit an absolute fidelity to the anti-tumor T cell repertoire as the tumor-specific TCR. For example, PD-1 expression is a shared phenotypic marker, or CD8 expression is a shared lineage marker, but neither are unique to an anti-tumor T cell. Hence, to exploit this unique selectivity, we've developed the Immunostat platform to harness the TCR specificity to activate tumor-specific T cells. We believe, as supported by our clinical data, that this approach is differentiated in terms of both safety and efficacy outcomes over other modalities that attempt to activate the immune system in a non-selective manner. The next slide, slide six, depicts the core structure of an Immunostat molecule derived from our IL-2-based Q100 series, which is the major focus of today's presentation. As shown here, the Q100 series immunostats harness the TCR selectivity via the stabilized peptide HLA molecule to target an affinity-attenuated IL-2 variant selectively to tumor-specific T cells. The co-signaling via the TCR and IL-2 receptors on the right anti-tumor T cell results in T cell activation and expansion. In contrast, if this molecule encounters the vast majority of irrelevant T cells in the patient, that is greater than 99.9% of irrelevant T non-tumor-specific T cells, the attenuated IL-2 on its own is very weak. Hence, with this unique bias, we have created a therapeutic index for IL-2 via selective focusing on tumor-specific T cells over all other cells. This strategy also forms the mechanistic basis for targeting numerous other activation signals, including other cytokines such as IL-12, IL-15, IL-21, et cetera. Two additional aspects. of the Q100 series are important to appreciate. One, the primary core IL-2 framework is largely conserved between different therapeutic candidates. The primary difference from one therapeutic candidate to the next is the 9 to 10 amino acid T cell epitope depicted by the yellow circle in the diagram in the slide. Due to this conserved structure, we believe the clinical proof of concept with our first clinical candidate, Q101, has dearest the entire platform. This conclusion is supported by the IND approval by the FDA earlier this year for our second clinical candidate, Q102, wherein based on the clinical safety data from Q101, we did not need to perform any additional IND-enabling toxicology studies and were allowed to start the Q102 trial at a MIG per gig dose, which is a clinically active dose from our experience with Q101. Both Q101 and Q102 are 99% sequence identical, except for the 9 to 10 amino acid T-cell epitope. Q101 targets a T-cell epitope from human papillomavirus for HPV-driven cancer, such as head and neck cancer, while Q102 targets a T-cell epitope from Wilms tumor 1, or WT1, an oncofetal antigen widely expressed by many solid and hematological cancers. The other key aspect of the Q100 series immunostats pertains to their favorable stability and manufacturability metrics as a biologic platform. These are antibody FC fusion proteins that follow established manufacturability and CMC protocols for many decades of commercial monoclonal antibody production. The shelf stability for the Q101 GMP drug product, our first clinical candidate, is greater than 36 months, which underscores the robustness of rational protein engineering. Let's move to the next slide, slide seven. Based on the generation of a therapeutic index for IL-2 by selective targeting of tumor-specific T cells, we believe that the Q100 series has the potential to be the best-in-class IL-2 modality for cancer immunotherapy. As shown here, the improved safety and tolerability coupled with the anti-tumor T cell selectivity possessions the Q100 series in a significantly different bracket when compared to all other IL-2 variants that are being pursued none of which are selective for the tumor-specific T cells. In fact, most of the focus of other IL-2 variants has been on modulating IL-2 receptor interactions, but little thought towards anti-tumor T cell selectivity. This lack of biological relevance will continue to generate suboptimal clinical outcomes, as recently evidenced with the clinical data sets from the recent trials from the pegylated IL-2 and the non-alpha IL-2 modalities. Finally, let's move to slide eight that highlights supportive data for biological selectivity and activity of the IL-2-based Q100 series. The panel on the left shows selective engagement of the Q100 series immunostat with an antigen-specific T cell. These data were generated by the lab of Dr. Michael Dustin at University of Oxford. Dr. Dustin has been a pioneer in describing the T cell immune synapse that leads to downstream activation and effective function. As shown here, the Q100 series immunostat only forms an immunological synapse shown in green with the antigen-specific T cells wherein both the TCR and IL-2 signals are operational. The same molecule with an irrelevant T cell as shown in the bottom left panel demonstrates no immune synapse in absence of TCR engagement. The middle panel shows selective expansion of tumor-specific T cells from primary human blood samples while no off-target effects are noted with irrelevant T cell specificities. This is exactly in line with the molecular design of the drug, that is selective expansion of tumor-specific T cells while sparing all other non-specific T cells. The panel on the right shows intratumoral infiltration and expansion of tumor-specific T cells in an HPV-driven cancer model in mice. Note that in this study, not many T cells are evident in the vehicle treated mice or in mice treated with the anti-PD-1 antibody alone. In contrast, a significant number of T cells are present after monotherapy with Q100 series immunostats, and this population is further enhanced in combination with anti-PD-1 antibody treatment. We believe this ability of the Q100 series molecules to turn a cold tumor hot by selectively activating the right T cells is a key differentiating feature of our drug design. Similar observations are also evident from the early emerging data from the ongoing mechanistic clinical trial with Q101 in a neoadjuvant setting in locally advanced head and neck cancer patients. With that background on our differentiated mechanism for IL-2 targeting, I'd like to now pass the call to Ken Pienta and Matteo Levesetti to share the exciting clinical data from the ongoing trials with head and neck cancer patients with our lead clinical candidate, Q101. Ken?

Thanks, Aneesh. As shown on the next slide, data from the ongoing clinical trials with Q101 as monotherapy and in combination with pembrolizumab have provided clinical proof of concept, or POC, and de-risking of the immunostat platform. We're pleased to be presenting our updated data from the ongoing Q101 Phase 1 trial as both a single agent monotherapy and third line and beyond patients. as well as the encouraging emerging data from the combination study with pembrolizumab in first-line patients. As previously and consistently stated by us, we believe Q101's mechanism of action, as evidenced by the ongoing data generated to date, provides effective and tolerated dose levels enabling selective stimulation of tumor-specific T cells. Recurrent head and neck cancer is a tough and curable disease. The data we have observed throughout the MONS therapy trial enhances our confidence that Q101 is stimulating cancer-specific T cells in a subset of these patients with resulting anti-tumor effect. Furthermore, and more importantly, we continue to observe an evolving trend of enhanced survival. Key observations in patients treated with Q101 monotherapy in third line and beyond include, as detailed on slide 10, demonstration of single-agent anti-tumor efficacy, evidenced by resist-based PR and durable stable disease in third line and recurrent metastatic head and neck squamous cell carcinoma. and a median overall survival benefit emerging from the survival follow-up in the RP2D cohort. The robust data on Q101's activity in monotherapy and in combination with pembrolizumab has triggered the granting of fast-track designation status for the treatment of patients in both first and third line settings. As shown on slide 11, Q101 demonstrates well-behaved pharmacokinetics with low interpatient variability at the recommended phase 2 dose of 4 mg per kg. Exposure is maintained throughout multiple cycles of treatment without any attenuation of PK parameters consistent with the lack of clinically relevant immunogenicity. Q101 treatment results in sustained increase in NK cells, a positive attribute of an anti-tumor response, as the NK cells may assist in tumor killing, and as you can see in the lower left panel, with only a modest and transient increase in Tregs. As shown in the middle panel, we observed robust expansion of tumor-specific E7 reactive T cells in the peripheral blood of patients as early as one week after administration of Q101. In the right panel, paired and post-treatment biopsies demonstrate an increase in tumor-infiltrating T cells and tumor necrosis. In addition to the favorable PK and PD just described, patients with advanced HPV-positive head and neck squamous cell cancer, we are experiencing intriguing patterns of clinical benefit. Three examples are shown in the next slide, slide 12. Patient A experienced a durable partial response with an approximately 60% reduction in tumor burden that was evident starting at six weeks after two cycles of Q101 and lasted close to one year. Patient B, who remains on treatment at the present time, has had stable disease with tumor burden reduction of approximately 20% observed at week 48 and notably complete disappearance of HPV cell-free circulating tumor DNA in the blood observed at week six and maintained. The undetectable HPV CFDNA is an increasingly recognized biomarker of disease activity and suggests the possibility of a pathologic complete response and cure in this patient who will likely have a surgical resection of their solitary cancer lesion early next year. Patient C has experienced tumor reduction after a prolonged period on the drug where no resist-based objective response was initially observed by imaging. In this patient treated with Q101 at 2 mg per kg, we can see that the first several months appear to demonstrate tumor growth even beyond the 20% threshold used by resist criteria. However, based upon the overall clinical status, the patient continued on treatment. After approximately six months, the tumor began to shrink and the patient remains on therapy 14 months after starting treatment with Q101. This observation, consistent with observations made by others, demonstrates that the kinetics of T-cell anti-tumor activity may manifest over a long period of time. The next slide, slide 13, conveys our ongoing survival swimmer plot for the 20 patients dosed at the RP2D of four mgs per kid. The emerging Kaplan-Meier estimate of a median overall survival of greater than 13 months compares favorably to the survival of approximately eight months observed in patients treated in the second line in the Keynote 40 trial of pembrolizumab. As any experienced oncologist understands, the survival in third line treatment is expected to be less as the disease is further developed and become more unstable. Our continued evolving data supports the premise that treatment with Q101 is clearly trending to increase survival in the third line setting for patients with head and neck cancer. This data has encouraged our principal investigators and they are certainly aligned with our position that this 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 PEMBRO. As a reminder, the data from treatments treated in monotherapy clearly supports that Q101 increases the number of antigen-specific T cells. It is likely that these T cells will have greater freedom to kill with concurrent inhibition of the PD-1 pathway. a major mechanism used by cancer cells to prevent immune-mediated killing. I will now pass the call to Mateo to provide an overview of the exciting emerging data and clinical efficacy of Q101 in combination with PEMBRO. Mateo?

Thanks, Ken. As shown on slide 14, even at our starting dose of 1 mg per kg, we observed a patient with durable stable disease. At two milligrams per kilogram, we observed a patient with durable stable disease and a patient with a deep partial response who continues on therapy today. At the presumed recommended phase two combination dose, we have not only not observed any DLTs, we have observed a 40% objective response rate with four now confirmed partial responses and another four patients with stable disease that are currently being monitored on the trial. This compares favorably with the reported overall response rate of single-agent pembrolizumab of 19% in the first-line treatment setting as observed in the Keynote 48 trial. Let me show you two examples of these partial responses. Slide 15 shows the patient from Cohort 2 demonstrating a decrease in all four of their target lesions, including two liver lesions, as seen on the two scans on the left. I want to emphasize that this is not just shrinkage in lymph nodes, but shrinkage of visceral metastatic tumor disease in the liver. On the upper right side, the graph depicts the absolute measurements of the four target lesions with the best overall response of approximately 70%. 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 cell-free HPV DNA continues to be developed and used by our principal investigators as a potential surrogate for response. As shown in slide 16, one of the patients with a confirmed partial response from cohort 3 also demonstrated reductions in all four target lesions, including two parenchymal lung lesions, as well as a clearing of their circulating cell-free HPV. As you can see on the scans on the left, target lesions 3 and 4, both are very substantial parenchymal metastatic disease lesions in the lung decrease in size by greater than 60%. The absolute measurements of the four target lesions are depicted in the right upper panel. And as we have seen in the last patient, this patient completely cleared their tumor DNA from the blood at a time concurrent with the observed resist response. In the next slide, slide 17, we see that all of the patients treated in the combination trial are still alive, five of whom have already passed the median overall survival observed in the Keynote 48 trial, which was 12.3 months. We also anticipate an increase in progression-free survival as the data from the 4 mg per kg plus pambrolizumab cohort matures. Taken together, the observed doubling of overall response rate 40% compared to the historical 19% observed in Keynote 48 with pembrolizumab monotherapy, along with an increase in median PFS, will expand patient reach and may provide an attractive therapeutic option for patients with the recurrent metastatic head and neck squamous cell carcinoma in the first-line settings. A high-level perspective of study designs to support approval of both monotherapy and combination with pembrolizumab is presented on slide 18. We are excited by the preliminary data in the ongoing monotherapy and combination trial and plan to get clarity on the registrational path to approval for both lines of therapy. The recent granting of FAST-TRACK designation further underscores our confidence in realizing successful regulatory interactions. I am also happy to report that we have treated our first patient with Q102, 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 19, Q102 and Q101 share 99% amino acid sequence identity. This enabled us to significantly decrease the development time and cost of Q102 as we were not required by the FDA to repeat IND-enabling toxicology studies for Q102, and we were also able to initiate the Phase I dose escalation study at 1 mg per kg. the dose at which we observed clear signs of biologic activity with Q101. As slide 20 shows, we are performing the Q102 dose escalation study in colon, gastric, pancreatic, and ovarian cancers. This design offers us the ability to do monotherapy expansion studies in any or all of the indications being evaluated in the dose escalation phase of the trial. The trial is actively accruing. and will be open at 15 sites around the United States. We plan to present additional data at an upcoming medical meeting. I will now turn the call over to Anish to talk more about our pipeline. Anish?

Thanks, Matteo, and moving on to the next slide. As you heard from the clinical update, and as shown in this slide, we believe the clinical de-risking by Q101 has essentially de-risked our entire platform. As noted by Matteo, the recent IND acceptance for Q102 targeting Wilms Tumor 1 underscores the strategic advantages of platform de-risking accomplished by Q101, which also highlights the resource time and operational efficiencies. Furthermore, 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. Some examples of additional tumor antigens that can be effectively targeted such as mutated KRAS or MAGE A4 or PRAME are shown here. Furthermore, to extend the application of a platform to incorporate multiple T-cell epitopes or even personalized neoantigens, we have created the NEOSTAT framework with an empty HLA molecule to which we can chemically conjugate any given tumor epitope. Here again, the core IL-2 variant and valency is conserved. The NEOSTAT platform expansion realizes significant time and cost efficiencies by having an off-the-shelf approach to selectively target multiple tumor antigens across many cancers. As one evaluates the potential of IL-2 for cancer immunotherapy, we believe our platform has cracked the code for selective targeting of this important cytokine to the tumor-specific T cell repertoire. With that, I'll now turn the call over to Kerry to give a brief financial update. Kerry?

Thanks, Anish. Turning now to slide 22, I'd like to provide a brief update on our financial results for the three months ended September 30, 2022. The company reported collaboration revenue of approximately $68,000 and $2.4 million for the three months ended September 30, 2022 and 2021 respectively. Research and development expenses were $7.6 million and $11.3 million for the three months ended September 30, 2022 and 2021 respectively. The decrease was primarily due to degree cases in laboratory and drug substance manufacturing costs, employee compensation, licensing fees, and rent. General administrative expenses were $3.5 million and $4.1 million for the three months ended September 30, 2022 and 2021, respectively. This decrease was due primarily to a decrease in stock-based compensation and professional and consulting fees incurred during the third quarter of 2022 as compared to the same period in 2021. We ended the quarter with approximately 59.1 million in cash, cash equivalents, and marketable securities, and working capital of approximately 51.5 million. Earlier today, we announced that we had entered into a securities purchase agreement with certain accredited investors for $30 million private investment in public equity, or a PIPE financing. We believe our cash and cash equivalents and marketable securities as of September 30th, 2022, along with the $30 million that we will receive from the PIPE financing, will allow us to support the development of our Immunostat platform, including the clinical development of Q101 and Q102 into 2024. I'll now turn the call back over to Dan for closing remarks. Dan?

Yeah, thanks, Carrie. With the recent financing extending our runway upon closing, combined with the supportive and promising data from our ongoing clinical trial, we're now able to focus on core strategic initiatives to further enhance our competitive positioning to optimize shareholder value. The clinical data recently reported at CITSE enhances our confidence in the breakthrough potential of our platform and the transformative nature of our approach to selectively modulate disease-relevant T cells directly in the patient's body. We believe we're now very well positioned to take the company to the next level and emerge as a leading provider of effective and well-tolerated T-cell engages with the potential of transforming cancer therapy. In the near term, we're focused on several core corporate development catalysts and strategic initiatives to further enhance our competitive positioning. Primary among these core initiatives are the following milestones to enhance shareholder value, as shown on the next slide. With Q101 monotherapy expansion cohort and third-line and beyond refractory and metastatic HPV-positive head and neck cancer patients, we'll have mature median overall survival data by the end of this year, with a potential registration trial being defined mid-next year. With Q101 plus pembrolizumab combination expansion cohort, we anticipate reporting on preliminary overall response rate in the second quarter of next year on the full 20 patients with a potential registration trial being defined in the second half of the year. We are highly encouraged by the data reported at CITSE on the first 10 patients and look forward to reporting on the full 20 of the four-mig per kid cohort. Again, to remind you, we believe the data reported to date supports the premise that Q101 as representative of the Immunostat platform Q100 series, demonstrates the potential of expanding patient reach and therapeutic benefit of checkpoint inhibition, placing us in a strategic position for corporate partnering. The Q102 monotherapy dose escalation trial is ongoing, with Q102 targeting Wilms Tumor 1 expressing cancers The evidence of clinical activity should be a catalyst for further validation and value enhancement of our platform. Data from this dose escalation should be reported by mid-2023 with significant potential market opportunities and WT1 positive cancer indications. We believe the differentiated therapeutic potential of the IL-2 base Q100 series, as evidenced by our current data sets, will further catalyze significant business development and corporate development opportunities for pipeline expansion addressing hematologic and solid cancers. We look forward to providing ongoing updates in the coming months and want to thank our shareholders for their support and shared vision and the potential of QBioPharma to transform the treatments of cancer. And we want to extend our gratitude to our employees the Board of Directors, and most importantly, we want to thank the patients and their families for participating in our trials. Thank you all very much for your attention and interest, and I'd like to now turn the call back to the operator for questions. Operator?

Thank you, sir. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, please press star and then one. If you're using a speakerphone, please pick up your handset before pressing the star keys. If at any time your question has been addressed and you would like to withdraw your question, please press star and then two. Again, if you would like to ask a question, please press star and then one now. The first question we have is from Ren Benjamin from JMP Securities.

Hey, good afternoon, guys. Thanks for taking the questions and congratulations on the data update at CITSEE. Maybe just to start off, can we talk a little bit, especially in the combination study, what are the typical treatments that you're seeing kind of post-progression, and are you seeing in these first 10 patients any sort of recycling of checkpoint inhibitors, you know, and potentially getting a subsequent response in patients who maybe didn't have that before?

So, Ren, this is Ken. Thanks for the question. So, the reality is we don't know what's going on with those folks. That's data we're collecting, but we really can't give you an update on what other therapies they might be getting afterwards. It's, you know, across multiple sites, and there's no specific regimen that these folks are going to. Got it.

And then either for the monotherapy or the combination study, I don't think I saw this number, but I'll just ask it anyway. Do you have a median duration of response for either of those two?

No, we haven't calculated that because we won't calculate that until we get the final survival data in the monotherapy, and it's just too early to do that in the combo.

Got it. And then just switching gears real quick to the neoadjuvant study, can you talk a little bit about maybe how many patients have been enrolled And have you been, you know, successful in obtaining biopsy samples? And is there any color that you might be able to provide from sort of the initial or any initial takeaways?

Yeah, so the neoadjuvant study is really a spectacular opportunity for us to really examine in the tissue itself the effects of Q101 therapy. So we're obtaining in the neoadjuvant setting pre- and post-treatment biopsies. We've treated close to 10 patients to date. The preliminary data that we have in these paired biopsies demonstrates some of the findings that we've observed in patients, i.e., we have observed increases in NK cells pre- and post-treatment, We also observed findings consistent with the increase in TILs, or tumor infiltrating lymphocytes, that we've observed in the paired biopsies obtained in the patients in the Q101-01 trial.

Terrific. Thanks very much for taking the questions. I'll jump back in the queue.

Thank you, Ray.

Thank you. The next question we have is from Stephen Wiley from Stifel. Please go ahead.

Yeah, thanks for taking the question. Maybe just to follow up on Rand's question, I know you don't have median duration of response for the combo just yet, but do you have the duration of response from the best responding combo patient who I believe is no longer ongoing therapy?

If I can mention here, really the duration of response in monotherapy is 42 weeks. So the confirmed PR that we observed in monotherapy at 4 mg per kg is really a very durable response. I think if we look at the spider plot, so slide 17 from the, I'm sorry, swimmer from slide 17 in the combination therapy, what clearly is evolving is an increase in progression-free survival. And so if you look at the length of time that patients remain on therapy, and if you had the sort of eyeball, the median PFS, it really appears to be perhaps somewhere between six months and seven months. And so, in contrast to the PFS that was observed in Keynote 48 of three months, it really appears that there's a differentiated signal with regards to progression-free survival. and one can infer to come back to your question regarding the median time on treatment. I think PFS is a very good surrogate for that because our patients tend to stay on treatment without progression because the combination of Q101 and pembrolizumab is being so well tolerated.

Okay. And then

What can you say about where you are on the development side with Neostat? And to the extent that you've de-risked the Q100 series, how do you think about advancing Neostat versus maybe just swapping in a different allelic variant of the Q100 series and and trying to leverage some of the progress and the de-risking that you've made to date on the platform.

Yeah. Hi, Steve. This is Anish. Very, very good question. So there's two ways how we are thinking about this, Steve. Obviously, for antigens where we have very strong confidence of other alleles coming in that select for the tumor epitopes, and KRAS is a very good example of that where HLA-A11-A03 For example, there's very good data that's emerged, including some of the TCRT-based approaches that are being pursued for the mutated G12V, G12D variants. So in that case, it makes very good sense, and that's what we've done, but it makes sense to go forward with a different allelic variant that gives us confidence of targeting that particular epitope from a primary tumor driver. The NEOSTAT framework, on the other hand, has been created on AO2, which essentially just gives us excellent continuity for the pipeline because of the de-risking and the nature of sort of impression we already have from 102, for example. So this is another analog. That's how we look at it, except that the time to generation of the active drug product is going to be substantially lesser than making a separate antibody molecule as we have to do where the peptide is linked in like 101, 102, 103, et cetera. So both prongs are being pursued. The Neostat, we've Obviously, you've seen some of the data where we've had early proof of concept experiments and validation. We're now in the midst of optimizing our processes for conjugation and scale-up, hoping with the intention of sort of really moving this towards a clinical application in the future.

Great. Thanks for taking the questions. Sure.

Thank you.

Thank you. Ladies and gentlemen, just a reminder, if you would like to ask a question, please press star and then one now. The next question we have is from Mark Barenbach from Oppenheimer. Please go ahead.

Hey, good afternoon, guys, and congrats on the update. Maybe a couple of quick ones for me. First, maybe a clarification question for Dan. just around the language of defining potential registrational trials in 2023, both for the monotherapy and for COMBO. By defining the trial, do you mean finalizing the protocol or initiating the trial? Maybe you can just be a little more specific there. And then another question, maybe on the science side, I'm just wondering if you're continuing to see evidence of clonal T cell expansion in the peripheral blood in the ongoing combination study. We saw some of that in the monotherapy part of the study, but it's been a while since I've seen some of those data presented. Is that being superseded by the circulating tumor HPV DNA? Or, you know, can we look forward to more of that sort of analysis once you have the full 20-patient cohort? Thanks for taking questions.

Sure. Thanks, Mark. I'll give you a broad overview response to the first question, then I'm going to turn it over to Mateo, and maybe Mateo and Anish can take the second question. So, regarding the registration path, the reason we're putting it out is defining things. is we want to assess, you know, do we want to approach both third line and front line or determine whether we're just going to, you know, get a registration path defined, meet with the FDA to show confidence in the underlying supportive data set, and then continue on with the front line because what we have to assess is how rapidly would a registration path on the front line kind of cannibalize the market on the third line. So that's one of the factors we're looking at. But the key is for us to define, based on the strength of the data, meet with the FDA and define the protocol. But I'll turn it over to Matteo.

Yeah, no, thanks, Dan. So, Mark, it's really an important question. And what we really have is a harmonized regulatory strategy where we mutually leverage the data that's being acquired in monotherapy and the data that's being acquired in combination. and we have a planned interaction with FDA in the first quarter of next year, we will really use that as an opportunity to get as much clarity as possible with regards to registrational paths for both approval of monotherapy in the third line and beyond, as well as approval of the combination therapy in the first line. So in our experience and my experience in particular, Given the strength of our emerging combination data, the FDA will be very keen to partner with us to really explore ways that would bring the combination therapy to patients as fast as possible. If the objective response rate of 40% continues to be observed in the additional 20 patients, We will then have a very compelling data set to discuss with FDA the opportunity of pursuing an accelerated approval based on an overall response rate, which we're currently seeing is twice that of Pembro-Mono first line, in the setting of a trial where we have fully enrolled the cohort power to meet an overall survival co-primary. So that really is sort of the approach that we're taking. We'll have to decide from a business perspective whether to pursue both or one and in what order.

Yeah. And just to add on, Mark, to the question around PD for T cell analysis, that is very much planned for the combo. We just haven't executed on that and initiated. We would like to do a batch analysis with all these samples together as these patients are being recruited, just like we'd sort of started to do some of that for mono. But I anticipate, you know, similar outcomes, if not even possibly higher frequencies based on some of our preclinical observations. So, we'll share that when we generate the data. All right. Terrific. Thank you.

Thank you for taking the questions, and congrats on the progress. Thank you, Mark.

Thank you. The next question we have is from Brian Scorny from BOD.

Hey, guys. This is Charlie on for Brian. So, I just had a couple quick ones. I was curious how we should think about comparing data between the Q101 and some of the other therapies that are in the HSNCC space given that it's targeting the HPV plus slash T16 plus patients. Like, is that, do you think that's something that might come up with regulators given the literature tends to see it as having a better prognosis than HPV negative. And then secondly, if you could just give some color on how you're thinking about advancing 101 as a monotherapy and what kind of hurdle you think you're going to have to hit in terms of overall response rate, that'd be great. Thank you, guys.

I'm happy to start there. So with regards to the prognosis of patients with HPV positive cancer in contrast to those that are HPV negative, I think you point out, you know, a very relevant observation. It's true that they appear to do a little bit better at each line of therapy, but not that much better. So, you know, we have a host of really experts in HPV-driven head and neck cancer as investigators. and there is a limited set of subgroup data available in the second line. If you do look at the four studies where that subgroup analysis is available, it appears that they may do better by a month or two, okay, not by six months or greater. And so the treatment effect and the benefit that's emerging in monotherapy is really is very differentiated, factoring in what you're saying, which is accurate, that HPV-positive patients may do a little bit better at each line of therapy. With regards to the registration path for monotherapy in the third line and beyond, we really have a consensus among experts that if we demonstrate in the monotherapy cohort a median overall survival of 12 months. And currently, as we showed at CITSE, the median OS Kaplan-Meier estimate is at 13.3 months, that that would really represent a very significant clinical benefit compared to the anticipated survivorship. So in the second-line setting, HPV-positive patients have a median OS of about eight months. And so if you do a meta-analysis of the subgroup data that's available, We're observing a treatment effect that goes now beyond 13 months, so again, a greater than 50% improvement. So with regards to a registrational trial in the third line and beyond, given that there's no standard of care, we would envision doing a very efficient trial of Q101 monotherapy versus investigators' choice of chemotherapy, and we would power it based on the numbers that I've just mentioned.

Fantastic. That's very helpful. Thank you very much.

Thank you.

Thank you. Our final question comes from Ted Tintoff from Piper Sandler. Please go ahead.

Great. Thank you very much, and thanks for squeezing in my question. All the questions on 101 have been answered, and I'm excited about the progress you're making there. When it comes to 102, can you kind of share with us sort of what you envision as the broader opportunity Now that you've de-risked the immunostat platform with 101 in HPV-positive head and neck, where could you go with 102? Thanks.

Yeah, thanks, Ken. So the importance of 102 is initially stated as an analog of 101. It's been de-risked from the standpoint of we're able to start at 1 mg per kg. Preclinical data on human blood samples and from cancer patients even, we were able to show significant amplification of targeted T cells. So we're actually going into this with a lot of confidence. The importance of Wilms tumor 1 is it's overexpressed in a significant number of solid and hematologic cancers, you know, including colorectal, pancreatic, ovarian, and glioblastoma, for instance. And we're looking at any activity we see And this dose escalation phase is going to be a real catalyst in terms of demonstrating the modularity and reaffirming and validating this analog nature. It's the exact same framework. All we're doing is swapping out the epitope. So it really will reinforce that sort of cassette form of being able to swap out an epitope and have the molecule active against a different subset of T cells to address various cancers. So I'm going to now hand it over to Matteo just to elaborate.

Yeah, so really, you know, very good question. And so clearly you recognize that WT1 is overexpressed in really a large number of cancers. And so we decided to initiate development in a small basket of solid tumors focusing on GI tumors, including colon, pancreatic, and gastric tumors. as well as ovarian, to really most efficiently achieve several objectives, including demonstrating the safety, tolerability, PKPD in a defined population in a trial where we can also expand and look for, in a very population of a huge unmet need, being colorectal cancer, whether the activity there is competitive and promising. However, we did write the protocol in such a fashion that we can very easily expand into any of the four indications if we see early signals of activity. And clearly, you know, other indications where this is quite de-risked as a target include glioblastoma. So as soon as there's some data in a small number of patients, it would be very easy to amend the protocol and include cohorts of patients, including glioblastoma. In terms of liquid tumors, there it's perhaps most greatly de-risked with TCRT experience with WT1 as a target. And so AML, myelodysplastic syndrome, you know, there's a whole family of liquid tumors. So we really decided to do sort of a stepwise you know, de-risk triggered by data investment and expansion into the multitude of addressable indications with WT1.

Super helpful. Appreciate the call. Thank you. Thank you, Sal.

Let's conclude our question and answer session. I would now like to turn the conference back over to Dan Passeri for closing remarks. Please go ahead, Sal.

Okay, again, we want to thank everyone for your time and interest in our ongoing progress, and we look forward to providing you with updates in the coming months. Thank you again, and take care, everyone.

Thank you, sir. Ladies and gentlemen, that then concludes today's conference. Thank you for joining us. You may now disconnect your lines.