Cue Biopharma Inc (CUE) 2020 Q2 法說會逐字稿

Thank you for standing by. This is the conference operator. Welcome to the Cue Biopharma Second Quarter 2020 Earnings Call. (Operator Instructions)

The conference is being recorded. (Operator Instructions)

I would now like to turn the conference over to George Zavoico, Vice President, Investor Relations and Corporate Development. Please go ahead.

Thank you, and good afternoon, everyone. Thank you for joining us on today's investor and Analyst update call. Joining me on the call today are Dan Passeri, Cue Biopharma's CEO. Dr. Anish Suri, President and Chief Scientific Officer; Dr. Ken Pienta, acting Chief Medical Officer; and Kerri-Ann Millar, Chief Financial Officer.

Before we begin, I would like to remind you that during today's call, the company will be making forward-looking statements. Various remarks that the company makes during this call about the company's future expectations, plans and prospects constitute forward-looking statements for purposes of the private Securities Litigation Reform Act of 1995.

Actual results may differ materially from those indicated by the forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of the company's annual report on Form 10-K filed with the SEC on March 20, 2020, and the most recent quarterly report on Form 10-Q filed with the SEC on August 7. As well as other filings made by the company to the SEC from time to time, which can be accessed on the EDGAR database at www.sec.gov.

In addition, any forward-looking statement represents the company's views only as of today, August 31, and should not be relied upon as representing the company's views as of any subsequent date.

While the company may elect to update these forward-looking statements at some future point, the company specifically disclaims any obligation to do so even if the company's views to change. These forward-looking statements should not be relied upon as representing the company's views of any date subsequent to today.

Please be advised that today's call is being recorded and the webcast. The slides we're presenting today and a recording of our call will be available on our website for the next 90 days. We will also be available via the e-mail provided on our website for questions not addressed during the call. I'd now like to turn the call over to Cue's CEO, Dan.

Yes. Thanks, George. Good afternoon, everyone, and thanks for joining us today for a review of our ongoing progress and second quarter financial results, which are available in more detail in our Form 10-Q filed with the SEC on August 7. Also, I have to remind everyone on the call as, we proceed through the call, the slides may be advanced directly from your computer.

So the next slide, on Slide 3 shows our agenda for today's call. I'll provide a brief synopsis and overview of our pipeline, emphasizing the importance of data that's emerging from our lead program, CUE-101, representative of our breakthrough approach for the selective modulation of disease-relevant T cells directly in the patient's body. I emphasize breakthrough because we believe we're on the cusp of demonstrating that CUE-101 is -- which is representative of our CUE-100 series is capable of presenting a tumor-associated antigen directly to the targeted T cell receptor or TCR, together with a costimulatory cytokine, in this case, IL-2. Specifically and to selectively activate or to safely activate only disease-relevant T cells directly in a patient to elicit a clinically meaningful response without dose-limiting off-target adverse events.

I'll be followed by Dr. Ken Pienta, who will provide further details on our most recent observations. From our ongoing Phase I CUE-101 monotherapy dose escalation and expansion trial and HPV-positive head and neck cancer patients. Then Dr. Anish Suri will describe our continued innovation and additional progress that we've made in advancing our differentiated Immuno-STAT and associated Neo-SAT platforms. Anish will also highlight our expanding immuno-oncology pipeline, including the continuing progress with our Q3 hundred program in collaboration with Merck. The progress we've made with our ongoing Phase I trial with CUE-101 and additional programs, particularly throughout the challenges of the ongoing COVID-19 pandemic demonstrates focused execution towards platform validation.

To this point, I'd like to just take the time to thank our dedicated employees for their unwavering commitment and focus in diligently working under these difficult and stressful conditions. Following Anish's update, Kerri-Ann Millar, who has recently been promoted to Cue Biopharma's Chief Financial Officer, will review our current financial status. I'll then provide concluding remarks and followed by a question-and-answer session.

Okay. On the next slide, an overview of our core strategic objectives and progress in the second quarter, as shown here on Slide 4. Our primary objectives through focused deployment of resources continue to be: first, increasing shareholder value through validation and systematic risk reduction of our Immuno-STAT platform through continual generation of data from our Phase I CUE-101 dose escalation clinical trial, furthering confidence that our approach represents the potential to be a major disruptive breakthrough for safe and selective immunomodulation.

Our near-term goal is to de-risk CUE-101 by demonstrating safety and tolerability, thereby reducing the uncertainty and risk profile associated with the CUE-100 series, which is IL-2 based as well as our follow-on CUE-300 series and biologics from our Neo-STAT platform. In addition, we believe the clinical data generated with CUE-101 is likely to be predictive of the entire CUE-100 series as the underlying molecular framework is largely preserved in all biologics of this series. The primary difference is the tumor-associated peptide epitope presented by the molecule, which determines the cancer indication being targeted.

In this regard, in our ongoing CUE-101 Phase I trial, and so far, through the first 4 cohorts, we continue to observe dose proportional pharmacokinetics, or PK, early signals of relevant pharmacodynamics or PD and activity and encouraging evidence that the drug appears to be clinically active as a single agent. Moreover, since our last earnings call, we've advanced through cohorts 4 and 5. And following authorization from our safety review committee last week, we're now enrolling cohort 6, which is at 4 mg per kg.

Secondly, broaden our pipeline by initiating a CUE-101 trial in combination with anti PD-1 antibody, PEMBRO or KEYTRUDA, as is known, in October as well as the neoadjuvant trial towards the end of this year or early next year, both in the frontline setting. We're also expanding our protein engineering and platform applications for developing therapeutics to address other cancers, specifically 102 and Wilms Tumor 1, our WT1 expressing cancers as well as expanding into autoimmune and infectious diseases. Moreover, we are incorporating additional HLA-A into our biologics to further broaden patient coverage. And third, acceleration and enhancement of our productivity through further development of our Neo-STAT platform, which has already demonstrated significant promise in preclinical studies.

In addition to cancer immunotherapy, we're also assessing the potential applications of Neo-STAT in infectious diseases, particularly against noval pathogens such as SARS-CoV-2, where immediate T cell responses could provide protective immunity to those infected with SARS-CoV-2. Anish will elaborate upon this in his update on Neo-STAT. I'm now going to turn the call over to Ken, who will provide further details regarding the progress of clinical development for CUE-101, which is our first clinical drug candidate, representing the CUE-100 series. Ken?

Thanks, Dan, and I'm excited to be talking to everyone this afternoon. I thought to remind everyone about the tremendous commitment we have from the participating clinical centers and associated oncologists shown here on Slide 5. Throughout the COVID-19 pandemics, this group of highly respected and dedicated oncologists have remained focused upon screening and enrolling HPV-16 positive head and neck cancer patients to participate in our trial, as evidenced by the full enrollments of cohort 5 -- in cohort 4 and cohort 5 since our last earnings call in May of this year. Through our prescreening process, we continue to identify patients for our trial for future cohorts.

Slide 6 shows a high-level summary of the design for our ongoing Phase I trial of CUE-101. As a reminder, we are enrolling second line and beyond patients with recurrent or metastatic head and neck squamous cell carcinoma driven by HPV, specifically HPV-16. This represents approximately 70% of all head and neck cancers occurring in the oral fair and GEO region, accounting for an estimated 13,500 patients annually in the U.S. alone. With our precision medicine approach, this Phase I trial defined molecular inclusion criteria to include head and neck cancer patients that are HLA-0201 positive and whose tumors are confirmed to be driven by HPV-16. Through these specific inclusion criteria, we are ensuring that only patients with the potential for clinical benefit are enrolled and treated. This trial is designed with the primary endpoints of safety and tolerability, while concurrently defining the PK parameters of CUE-101 with secondary endpoints of TV evidencing the drug's mechanistic activity on T cell activation and proliferation as well as assessing signs of clinical activity via periodic patient scans. The trial is a standard 2-part trial with the first part a designed as a typical 3 plus 3 monotherapy dose escalation. Patients received CUE-101 once every 3 weeks via IV infusion.

However, the trial protocol also provides the opportunity to dose up to 9 patients in any given cohort where we see evidence of clinical activity or PD effect. This strategy allows us to further explore PK/PD effects as well as build supporting data for determining the most appropriate dose for the Part B expansion. After the...

Ken's breaking up.

And have enrolled a seventh patient at this time. Based on the drug and safety, PK/PD and efficacy data from the dose escalation part a we will accrue additional patients at the appropriate dose level during the Part B expansion phase to confirm the recommended Phase II dose for 20 patients.

Therefore, in summary, both parts A and B of the trial will wait the safety -- we'll evaluate the safety and tolerability of CUE-101, the expansion cohort is designed to confirm the safety, biologic activity and antitumor activity at the effective dose in additional patients to provide further support and confidence as we move into later phases with more patients.

As we show on Slide 7, we initiated dosing of cohort 1 in late September last year and then moved forward to cohort 2 in December, cohort 3 in March in cohort 4 in May. One of the first 3 patients in cohort 4 experienced a Grade 3 anemia that was designated as a dose-limiting toxicity or DLT that was possibly drug-related. We, therefore, enrolled 3 more patients in cohort 4 in July for protocol design. After these 3 patients were observed through a 21-day safety period without any additional DLTs, we were authorized by our safety review committee to proceed with enrolling 3 patients in cohort 5 at 2 milligrams per kilogram during the month of August. We have completed the enrollment and safety period for all 3 patients at this dose level, and the data from these 3 cohort 5 patients was reviewed by our SRC last week. And I'm pleased to report that we've been authorized to commence treating patients in cohort 6 at 4 mg per kg over the coming weeks.

To date, 19 patients in cohorts 1 through 5 have received a total of 54 doses of CUE-101, 3 weeks apart with what appears to be an attractive safety profile with limited toxicity. We've been able to administer doses of CUE-101 in cohort 5 that deliver about 16 fold higher amounts of an IL-2 variant on a molar basis than IL-2 delivered by the approved dose of Proleukin. With this data, we are confident that we can deliver high doses of an IL-2 variant on target safely. We continue to be highly encouraged by our early progress and observations.

We continue to observe encouraging early signs of biologic and clinical activity in this heavily pretreated patient population. It's worth pointing out that the average patient in this trial has received 4 prior lines of therapy and have been exposed to at least 6 different anticancer agents while getting those therapies.

As previously reported in cohort 1, a patient inadvertently received 5x the prescribed dose of CUE-101 or a dose between the doses intended for cohorts 2 and 3. This patient demonstrated tumor regression on scan after receiving this dose, but also developed worsening of a pre-existing bullous pemphigoid rash. As a result of the bullous pemphigoid rash, CUE-101 was discontinued, but the patient remained with stable disease off therapy for 9 weeks before eventually progressing. A heavily pretreated patient from cohort 2 who had previously progressed well on therapy with a checkpoint inhibitor had confirmed stable disease with tumor reduction of the target lesion. This patient was on trial for 19 weeks.

A patient in cohort 3 and a patient in cohort 4 demonstrated stable disease after 2 cycles of therapy that manifested disease progression at 3 months. Three patients in cohort 4 and 3 patients in cohort 5 remain on trial with the first patient in cohort 5 having received their third dose already. The latest PK data with patients in cohort 4, as shown in Slide 8, continues to demonstrate dose-dependent increase in exposure in patients that receive multiple cycles of CUE-101.

We see no evidence of a decrease in exposure of CUE-101, which suggests lack of immunogenicity of drug clearing antidrug antibodies or ADA. And as I just mentioned, we continue to see a highly favorable safety and tolerability profile, even with about 16x the molar content of our IL-2 variant in cohort 5 at 2 milligrams per kilogram compared to the approved dose of Proleukin. Therefore, I mean, really want to emphasize this. We've already established that we have a safe vehicle for delivering unprecedented doses of IL-2 to patients.

As shown in Slide 9, we continue to generate and evaluate PD biomarker data, including detectable expansion of targeted HPV E7 specific T cells from peripheral blood of early cohorts with an emerging trend that appears to support a correlation of T cell expansion and duration on trial. The veracity of this correlation will be further studied in the ongoing analysis of patient samples from higher dose cohorts that is cohort 4 and higher. An example of early PD analysis from cohort 4 is shown here where in HBV specific T cells were not evident in the predose sample or at the first sampling at day 21 after the first cycle. However, at day 42 after the second treatment cycle, an emergent population of HPV specific T cells as detected by peptide HLA tetramers was noted.

We continue to be encouraged and remain highly optimistic in our ongoing data generation and analysis and look forward to providing further details as they become available. The totality of the current metrics are strongly supportive of an emerging synopsis of safety, tolerability as well as biologic and clinical activity. I also want to emphasize and point out that the totality of our data already in the early -- with our early monotherapy study has given us the confidence to move forward with our combination trial with KEYTRUDA.

Slide 10 shows our collaboration with MART to initiate this parallel trial in frontline therapy to evaluate CUE-101 in combination with pembrolizumab or KEYTRUDA for patients with HPV-positive head neck cancer who are also HLA-0201 positive. Our intention is to continue to advance the monotherapy trial for second-line and later HPV-positive tumors and patients and enhance our patient reach by expanding into frontline patients in combination with KEYTRUDA, which is the current standard of care. In this trial, referred to as key note A78, we intend to translate our preclinical findings, demonstrating highly significant synergistic antitumor activity with CUE-101, combined with an anti PD-1 antibody.

In addition, the safety and tolerability data from our current ongoing monotherapy trial enables us to start the combination trial at a higher starting dose of CUE-101, which is a significant step forward in terms of timelines for generation of clinical data. As we noted, we've already been approved at multiple sites, and this trial will commence in October of this year at our monotherapy sites. We're using the same sites.

We also plan on initiating a neoadjuvant trial in patients newly diagnosed with resectable and localized head and neck cancer patients in the coming months. The trial is designed to provide us with further evidence and insights into CUE-101's mechanism of action by directly studying the tumor tissue post resection to assess infiltration and proliferation of HPV-specific tumor-infiltrating lymphocytes or TILS. This latter point is an important one with respect to the mechanism of action of CUE-101 and Anish will further elaborate upon this with some recent data that underscores our excitement for the neoadjuvant trial. And finally, once we've established clinical proof of concept, for CUE-101 in head and neck squamous cell carcinoma, we may expand opportunistically into other HPV-driven cancers for example, cervical cancer.

I will now hand the call over to Anish to discuss other advances in our pipeline and platform. Anish?

Thanks, Ken, and thank you to everyone listening in, and I hope all of you and your families continue to be safe and well. I'd like to underscore on Slide 11, our scientific vision to fully exploit the exquisite selectivity and specificity of the immune system, while not compromising patient safety. We believe this approach for selective modulation of T cells directly in the patient is distinct and differentiated from other approaches where in broad immune modulation or global systemic activation often present with significant challenges associated with compromise safety, compromised efficacy and tolerability.

The Immuno-STAT framework as exemplified by the CUE-100 series, as shown in Slide 11, contains the 2 key signals: signal 1 and signal 2 for tumor-specific T cell activation. CUE-101, our lead clinical candidate is our first drug from the CUE-100 series. Signal 1 here on the CUE-100 series consists of stabilized peptide MHC molecules to engage tumor-specific T cells via the T cell receptor or TCR, thereby locking in the specificity, combined with rationally engineered IL-2 molecules serving as a co-stimulatory signal to that selectively act upon those T cells to control their activation directly in the patient.

There are 2 modifications to our IL-2 variant molecule that are important for its specificity and selectivity. The first is application of binding to IL-2 receptor alpha subunit in order to avoid Treg engagement which labels it as a non-alpha IL-2 variant. The second is attenuated binding to the IL-2 receptor beta subunit, such that the IL-2 activity is biased to those T cells that are docked to the specific peptide HLA complex via their T cell receptor, as perhaps best shown in the top-down view of the CUE-100 series framework here.

Now we've invested considerable time and effort to define this molecular framework and spatial organization, thereby enabling selective activation of tumor-specific T cells, while mitigating or eliminating effects on the vast majority of the irrelevant non-tumor-specific T cell repertoire and thereby minimizing safety liabilities such as vascular leak syndrome. These features of the CUE-100 series is what distinguishes it from other IL-2 modalities, either wild type IL-2 or the not alpha IL-2 variants, wherein the IL-2 broadly acts upon many T cells without preferential bias or specificities towards the desired tumor-specific T cell repertoire.

We're highly encouraged with the emerging metrics and clinical data associated with CUE-101, and by implication, the IL-2 based CUE-100 series. In addition, the initial PD data continue to demonstrate early evidence of T cell expansion in blood, which will be further bolstered with continued sampling analysis from cohorts 4 and 5 and beyond. The measure of T cells in the periphery, as you can appreciate, is a surrogate for mechanism of action. With the understanding that the ultimate gold standard for successful immunotherapy is the measure of T cell activity and function. Within the tumor lesion. To that end, it is important to highlight key observations with respect to the Immuno-STAT framework and its potential for direct activity within the tumor tissue. I'll address this more in detail in the following slides.

So the next slide, Slide 12 shows the data from our recent paper in clinical cancer research wherein we made the observation that the murine CUE-101 treatment resulted in a highly enriched presence of tumor antigen-specific T cells in the tumor tissue when compared to the presence of the same T cells in the peripheral compartments like blood or spleen. As we show here, post-treatment with mouse CUE-101, approximately about 0.5% of CD8 T cells measured in blood or spleens were specific to the tumor antigen. In contrast, in the tumor tissue, the same T cells were enriched by almost 2 orders of magnitude.

Nearly 50% of all CD8 were specific to the tumor, complementing our published data in clinical cancer research and the data emerging from the current clinical trial I want to share with you an equally important data center observation, which is presently impressed, and as such, details are embargoed. But what I can't share is that this preclinical work highlights that the targeting peptide MHC moiety of the CUE-100 scaffold penetrates and localizes to solar tumor tissue and directly engage antitumor T cells in the tumor tissue. This observation could have very important implications for the differentiated mechanism of action of the CUE-100 series.

In other words, the ability to localize and directly engage tails within the tumor tissue to activate the effector killing response may be a unique and highly promising property of the Immuno-STAT platform. In light of these important data sets, we believe that expediting a neoadjuvant clinical trial in resectable localized head and neck cancer, will provide convincing translational and biomarker clinical data that further strengthens the case of CUE-101's mechanism of action.

Slide 13 here provides an update on CUE-102, our second asset in the CUE-100 series, which targets a unique epitope from Wilm's Tumor 1 or WT1, a well-characterized and attractive oncofetal antigen for many hematological and solid cancers. We've continued to make significant progress with this program, which is being prosecuted with both HLA-A2 and HLA-A24 alleles. We're pleased to inform you that an IND filing for the A02 CUE-102 program is projected for late in the second half of 2021. Data recently presented at the AACR and the New York Academy of Sciences Virtual meetings show that CUE-102 selectively expands primary human T cells from blood. These expanded T cells are polyfunctional as measured by cytokine production and the mediate killing of targets expressing the WT1 antigen. An example of each of these functional attributes is shown in this slide.

As predicted by the platform similarity across the CUE-100 series of compounds, the preclinical safety assessment of CUE-102 has mirrored what was noted with CUE-101. That is the rational engineering of IL-2 prevented and minimized or eliminated effects on Tregs and irrelevant T cells. This observation underscores my previous point that the current clinical experience with CUE-101 has an enormous net positive effect in derisking the platform and the CUE-100-based pipeline. Let me briefly comment on the recent developments and exciting prospects with our next-generation Neo-STAT platform, which is expected to greatly accelerate our scalability and enhance our productivities and efficiencies, both from a time and cost perspective.

So the next slide, Slide 14 is a schematic of the Neo-STAT platform. A key step forward in platform enhancement was to reproduce the key components of the CUE-100 Series Safford, but without any specific peptide attached to the HLA molecule. To remind you that peptide epitope is an integral part of the Immuno-STAT, meaning it's incorporated into the molecule as a fusion protein at the time of synthesis. In contrast, Neo-STATs are synthesized without a peptide epitope, that is with an MT MHC pocket. Instead, the peptide epitope is attached subsequently using an advanced attachment chemistry as shown in the current figure via the examples of 3 different peptides bound to the Neo-STAT scaffold. The versatility afforded by this approach is expected to significantly expand our reach into diverse antigens for applications in cancer immunotherapy and more recent interest in emerging infectious diseases, including the SARS coronavirus. From an efficiency perspective, the Neo-STAT platform allows us to generate a core generic scaffold for any HLA allele via a single cell line and then use the scaffold to conjugate various peptides of interest based on the disease to generate therapeutic candidate molecules. The fact that only a single scaffold needs to be generated will save a significant resources in both time and cost for generation of clinical-grade material. In our prior presentation, we shared proof-of-concept data, supporting the biological activity of molecules generated via the Neo-STAT platform. Shown in Slide 15, are representative examples of T cell expansion to a viral epitope namely from the cytomegalovirus or CMV or T cell expansion against a tumor antigen, namely from an epitope from MART-1. As shown here, the Neo-STAT platform could be effectively deployed using the Core IL-2 based CUE-100 series to generate molecules that enhanced pathogen specific T cells or tumor-specific T cells. The anti CMV T cell response as shown in the left panel wherein the CMV Neo-STAT shown in dotted red lines expand T cells with the same efficiency as conventional CMV immuno-STAT shown in solid red lines. The MART-1 Neo-STAT here is a negative control. Similarly, the anti MART-1 T cell expansions from primary human blood are shown in the right panel. Here again, MART-1 Neo-STAT in dotted blue lines demonstrate T cell expansion that is very comparable to what was seen with MART-1 Immuno-STAT shown in solid blue lines.

As shown on Slide 16, based on these promising proof-of-concept studies, we've now initiated preliminary studies to determine the application of the Neo-STAT platform to generate robust T cells against SARS-CoV-2. We believe that the Neo-STAT platform may be uniquely positioned to selectively induce and expand antiviral T cells, especially in instances where preexisting immunity is nonexistent or inadequate. Numerous recent studies have highlighted a key role for T cells and beneficial outcomes in SARS-CoV-2 infections. Furthermore, while most vaccines are focused on generation of protective neutralizing antibodies as a prophylactic measure induction and expansion of anti SARS-CoV-2 T cells may be a unique determinant of therapeutic immunity, especially in circumstances where the virus is present in the intracellular compartment in infected host cells and is largely invisible to antibodies in the extracellular milieu. We are very excited about the prospect of deploying our science and innovation to help with the SARS coronavirus global pandemic and look forward to providing updates on our progress in this new direction in the near future. Lastly, additional data underscoring the protein engineering, design and manufacturability of Neo-STAT were disclosed at a recent presentation at the Pegs virtual meeting this past week. More details with regard to this presentation are available on our website.

Let me move on to Slide 17 that highlights our pipeline progress. We've made significant progress with CUE-101 in the Phase I dose escalation monotherapy trial, as you heard, and are well positioned for the combination trial with pembrolizumab scheduled to start next month. CUE-102 with WT1 and 2 different HLA alleles, A2 and A24 continues to make strong progress with the planned IND submission for late 2021, as mentioned before. We've also made promising progress with our KRAS program within the CUE-100 series and are planning to share those data at an appropriate forum in the near future. We continue to extend the application of our platform with the CUE-200 series, where we have early data sets with cell surface receptors, such as CD80 and 4-1BB ligand. To that end, we recently coated a paper published in Plos in June 2020 with Dr. Steve Almo, the co-founder of biopharma this study deployed structure based rational protein engineering to dissect the molecular interface between PD ligand CD8 and CD28 CTLF-4 interactions to enable the choice of modules for future Immuno-STAT such as the CUE-200 series. And finally, as disclosed recently, we continue to make progress in autoimmunity with CUE-300 series when we've successfully generated Immuno-STAT incorporating Class II HLA lies to selectively target and modulate or reactive CD4 T cells.

As we've underscored in prior presentations that immunostatus and by extension the Neo-STAT platform address a fundamental immunological challenge which is how does one maintain selectivity and specificity of a desirable immune response without reaching patient safety or creating toxicities.

We believe our approach built upon rational protein engineering which is now bolstered by the supporting data sets, offers a highly promising solution to patients suffering from cancer, autoimmune diseases and threats from pathogenic infections. With that, I'll now turn the call over to Kerri to review our financial results. Kerri?

Okay. Thank you, Anish. Turning now to Slide 18. I'd like to provide a brief update on our financial results for the second quarter ending June 30, 2020. We finished the quarter with approximately $84.9 million in cash and cash equivalents and working capital of approximately $73.5 million. During the second quarter of 2020, we extended our cash runway with $42.4 million from our at-the-market equity offering through Stifel, Nicolaus & Company who acted as sales agents.

Cash received from the ATM equity offerings with Stifel puts us in a solid financial position to support the development of our immuno-STAT platform, including the clinical development of CUE-101 into 2022.

We recorded collaboration revenue of $1.1 million from a collaboration with Merck and LG Chem during the second quarter of 2020, which is consistent with the $1.1 million we recorded in the same period in 2019. Research and development expenses were $8.1 million for the quarter ended June 30, 2020, as compared to $6.9 million for the same period in 2019. This increase in R&D expenses was due primarily to an increase in laboratory and drug manufacturing costs, stock-based compensation and clinical expenses. These increases were offset in part by a decrease in travel expenses due to the COVID-19 pandemic, which hampered travel throughout the second quarter.

General and administrative expenses were $3.9 million for the quarter ended June 30, 2020, as compared to $3.4 million for the same period in 2019. This increase in general and administrative expenses was primarily due to the increase in stock-based transportation expenses and legal and accounting fees incurred during the second quarter of 2020.

I'm pleased to say that despite the challenges presented from the COVID-19 pandemic, we've been able to maintain momentum in the clinic and development of our pipeline while strengthening our financial position through a combination of at-the-market equity offerings and disciplined spending. We continue to be well positioned to execute against our 2020 objectives. I'll now turn the call back over to Dan for closing remarks. Dan?

Thanks, Kerri. Yes, since our last update call, and despite these ongoing challenges that we're all confronting due to the COVID-19 pandemic, we've continued to make significant progress across our platform and associated programs, as I'm showing here on Slide 19. Our key accomplishments include the ongoing timely enrollment through cohorts 1 to 5 and now into cohort 6, which is at 4 milligrams per kilogram and our CUE-101 monotherapy trial, and a demonstration of favorable safety and tolerability through cohort 5 at 2 milligrams per kilogram. Dose proportional exposure, which is -- has been in line with our preclinical projections. And emerging evidence of PD activity and early signs of monotherapy clinical activity having raised additional capital this past quarter and having enrolled and treated patients into cohort 5 in our Phase I trial of 101, our lead program, we're very well positioned to continue building a meaningful body of data, including safety, tolerability, PK and PD biomarker activity as well as ongoing scans from patients to assess clinical activity. We're also advancing closer to determining a recommended Phase II dose for CUE-101 as a monotherapy and to initiate a combination trial with KEYTRUDA in October. And a neoadjuvant trial beginning end of year or Q1 of 2021, both and newly diagnosed and previously untreated patients in head and neck cancer. These data would significantly derisk and validate our approach, allowing us to then further build our pipeline based on the same foundational principles upon which we've brought CUE-101 forward and to establish Cue Biopharma as a differentiated leader in the immunotherapy space with a potentially transformative and disruptive breakthrough therapeutic platform.

Our guidance for the second half of 2020 milestones, as shown in Slide 19 and they are largely unchanged from our last call, are reporting PK/PD results from cohorts 4, 5 and perhaps cohort 6 from our Phase I 101 clinical trial by year-end. The potential for reporting clinical responses in Phase I, CUE-101 via resist criteria by year-end, initiating a CUE-101 combination trial with KEYTRUDA in frontline HPV-positive head and neck cancer in October. And by year-end, we also expect to initiate and extend IND-enabling activities for CUE-102, select the target for CUE-103, and demonstrate Neo-STAT manufacturability and further efficiencies, identify potential clinical candidates in autoimmune disease. And finally, to perform initial feasibility assessments of the Neo-STAT platform for activating and enhancing T cells against COVID-19.

With that, I'd like to once again thank our employees for their hard work and commitment to advancing our science forward during these challenging times. And finally, I'd also like to thank our shareholders and our Board of Directors for continued support enabling us to advance Cue Biopharma's platform towards validation in the clinic, while also moving our preclinical assets closer to IND-enabling studies. We look forward to providing further updates on the validation, growth and expansion of our pipeline, including, obviously, our CUE-101 Phase I trial. Most importantly, we're grateful to all who have enabled us to pursue our noble vision to serve patients in need. And with that, I'd like to open the line for questions.

Operator?

(Operator Instructions)

The first question comes from Stephen Willey from Stifel.

Congratulations on the progress. Of the 6 patients that you talked about remaining on therapy, I think, 3 cycle 4, 3 cycle 5. Are you able to say, I guess, how many cycles on average, those patients have seen? Are they beyond cycle two? Are they in cycle 3? I guess any color on that front with respect to just kind of treatment intensity would be helpful.

Yes. Ken, do you understand?

Yes. So those patients are still relatively early there past the cycle cohort 4 folks are beyond cycle 2 and just -- and just -- and one of our cohort 5 patients is beyond cycle 2 at this point. So it's still relatively early in the process for these guys -- for these patients.

Got it. Got it. And then just with respect on -- or with respect to the expansion of the peripheral T cells that you're seeing, I know it's maybe not the best of surrogates, and it sounds like you may have some data coming out to suggest that perhaps the real impact is happening within the tumor microenvironment itself with respect to direct engagement of TILS. But is that day 42 metric of T cell expansion that is being shown. Is that a pre dose or is that a post-dose level? And I guess, if it's the latter, is there any interest in trying to do a little bit more refined peripheral blood draws between doses, just in an effort to maybe better understand what the persistency of that expansion in the periphery might look like?

Yes. That’s great. Go ahead, go ahead.

No, I was just going to -- I was just going to jump in here.

Go ahead, Anish.

Sorry, just -- Steve, just to clarify, that was post-dose analysis and rightfully, and I think this is what Ken was getting to as well that one of the sample time points is the challenge here because these are all 21 days apart. So what happens after you give the drug in the interim time and if there is extravasation to the peripheral lesion tumor tissues is exactly what's not measurable here and to what Ken alluded to, the neoadjuvant study becomes very important to study that mechanistically.

So one of the limitations, of course, here is the limited availability of tumor tissue to be able to quantitate that. I think the paper that we presented from our clinical cancer research and this publication that's in press are making a very important point, which is that what ultimately matters in immunotherapies, what happens locally. The peripheral is a good surrogate for the mechanism, as you well alluded to, Steve. But ultimately, what we're missing here is that final piece in the puzzle, which I think the neoadjuvant gets us there. I'll let Ken comment on the sampling frequency and again in the current times to how best we've navigated that.

Yes. I was just going to add that. We will -- as we learn more and more about the PD and sampling, we have thought about expanding out quite -- to be quite honest, we're -- right now, we're limited by COVID and that most of the sites in the hospitals don't even want the patients coming in for any extra blood draws. But we're constantly monitoring how to potentially get more data. For example, we're exploring using mobile phlebotomy to try and fill in some of those future data points. Especially, we're thinking hard about that in -- as we start the combo trial in October that if COVID is still going to be a problem, which is likely that it is going to be, we really feel that we need to be able to be as nimble as possible in collecting samples.

I think you all have noticed that we have done -- what I continue to be, as a medical oncologist amazed by is our ability to accrue patients on time through this COVID crisis. And I'm humbled by the fact that my medical oncology colleagues have considered it's so important that to administer CUE-101 to these patients that they've managed to keep our trial open and accruing. It is a challenge, though. Once we get them in, to get those extra blood draws that we'd all like to see, again, to decrease exposure of the patients to the risk of COVID. And that's why we're exploring other options to help us fill in those data points in the future. So that was a bit of a long-winded answer, but I hope that helped.

Yes. No, that was very helpful commentary. And I guess just lastly for me. You talked about now being able to start at a higher dose of CUE-101 in the KEYTRUDA combo study. Are you able to say what that target starting dose will be?

Well, what I can say is it's -- we're ongoing to -- and analyze where we'd actually like to start. Initially, for example, we were thinking we'd have to start a cohort 3 at 0.54 mg per kg. But really, what we're planning on doing is starting at safe dose minus 1. So currently that is -- we'll start at a mig per kig, and we may or may not go to 2 mg per kg, depending on where we are with accrual in cohort 6 at that time. So right now, we're at a mg per kg.

Our next question comes from Madhu Kumar from Baird.

So first question is on...

Madhu, you're breaking up a bit difficult to understand. Operator, maybe we could take.

Getting worse.

Yes, we're not able to catch you. Operator, maybe we can take another question in sequence and then put menu back in.

Our next question comes from Tom Shrader from BTIG.

Not surprisingly, I think I have almost the same questions as Steve. Can you let us know your longest stable diseases so far? I guess these are from cohort 3. What are the longest couple you've seen?

Ken, do you want to take that?

Yes. So our longest couple have been 19 weeks, and we had 1 patient that had a break in therapy with the BP and that was about a total of 12 weeks.

And are they both still on therapy?

No.

Okay. And then kind of a question for a niche. This patient 10, I assume that's a pretty good response. Is that consistent with the memory response to you, the time course? Can you dig any quantitative data out of there between what happens between day 21 and day 42? Or is this somebody building kind of a response from naive T cells? Is that something you can dig out of data like this?

Yes. I think, Tom, look, firstly, these are early metrics. So the data looks promising. We need to build this out a bit more. If you were to compare this to an established chronic sort of a memory repertoire against viral determinants like CMV or EPV this would not be as robust as that. And the fact is even with -- if you look at the staining pre dose, you don't really see much of a population. So you could say maybe there was something there, but a really rare frequency, and it took a couple of cycles of treatment for it to present itself or the likelihood is that it's being primed from a naive baseline repertoire, hence, you need the additional sort of time on therapy for it to manifest and present itself. I think that's how we interpret it as this being either a rare or from an unprimed simply because of the fact that at baseline, you don't see that population. If you -- in contracts, if you look at for example, the data with CUE-102 in that example that we presented, Tom, I mean, there, you could see a little bit of a pre dose, pre population that's present at baseline and blood which then further expanded out. So this is -- these are rare T cell frequencies. We know that. They are usually not easily detectable in patients and the fact that we start to see them is what's very encouraging and promising and that's exactly then building out on -- going up in the dose and escalation and exposure to see if we can further solidify these metrics.

And then maybe if Ken could just comment on, does that change the way you think about a trial like this, if you are really going to need 8 weeks to see a response?

Yes. So I think we're -- we all recognize that these patients are sick, right? I mean they've got rapidly progressive disease. They've had multiple lines of therapy. And ideally, we will move to earlier treatments. I think that's what makes the combo study so important because those patients will have -- be first-line therapy patients and that gives -- makes me optimistic that we'll see even better responses and they have more time to see those responses. That also makes me think about whether in the future, as we think about other diseases, certainly, again, the less heavily pretreated patients, the better. And so I really am optimistic and continue to be optimistic about the first-line therapy patients and as well as even the neoadjuvant. So as you well know, in these Phase I studies, first-in-human studies, first and foremost, it's safety, safety and anything we can see clinically is a huge win.

Tom, just to clarify, just an add-on, again, I wouldn't look at it that it takes 8 weeks of response because one of the things coming back to the point we discussed when -- with Steve was the fact that in the tumor lesion, is something that is not being quantitative. So while these are peripheral signals, if you've got a presence that is extravasate localized to the tumor, the drug is getting there, which is why this important paper coming out is very important. Then that effect may well be very central to the response, but not being appreciated by just a blood analysis. I always want to put that caveat, which is why I come back and what can articulate very nicely is the importance of the neoadjuvant study to get this to really delve deep into that mechanistically.

Our next question comes from Reni Benjamin from GMP Security.

Congrats on all the progress. I guess, maybe just to start off with a question for Anish. Hopefully, you can hear me okay?

Yes.

Selective -- we keep focusing on the selective population of T cells expanding out. And I'm kind of curious, what other metrics outside of the selective T cells should we be looking at or be measuring? For example, maybe cytokine levels or CD8 and CD4 T cell ratios. What all are you gathering that might be able to help kind of complete the picture of what's happening here?

Yes. Ren, the intentions are in parallel to look at immunophenotyping for other subsets like you pointed to. One of the cell types from our preclinical models is the activation and possible effects on NKS, which could be something that could be favorable. They are highly sensitive to IL-2, even attenuated versions. We've not seen any consistent movement on Tregs with sort of consistent data, and that's in line. Other mobile upregulation of T cell subsets should not really happen by the molecular design.

So -- and that is at least in these early data sets that seems to be consistent. But I think overall immunophenotyping and understanding other IL-2 from the periphery, it's something we will continue to look at, and that data will continue to be strengthened. We haven't looked at cytokines. We've, of course, bang those samples. So we'll come back to that as we sort of accumulate enough sampling and decide on time points. The other than from a metrics of just immune recognition and effector mechanism, again, coming back, the tumor tissue becomes a very important composite of really what I referred to as earlier as sort of the gold standard metrics. And that in the monotherapy where the biopsies have been optional is going to be limited. And again, we can garner some of that through the neoadjuvant study that Ken described, I think that will further add on. And in that modality, one could focus not only on the antigen specific, localized, but also the repertoire diversity, including effects and other immune subsets, which would be very telling to the mechanism of action.

Got it. And then when we think about the kind of cohort 6 that they're going to be starting to enroll or have started to enroll. There's a significant amount of dose kind of relative to the Proleukin dose, right? And of course, you continue to have a really good side effect profile. And I'm trying to -- maybe you can help me reconcile is this a true reflection of the side effect profile of the drug? Or are the patients' immune status and that weaken immune status since they've, I think Ken mentioned, had 4 prior lines of therapy. Does that potentially impact what the side effect profile is actually looking like? In effect, are we masking the side effect profile, the true side effect profile, given the patient's immune system status?

Yes. Ken, do you want to take that one?

Yes. Thanks. So that's a really interesting question. I think the best way to think about answering that and thinking it through is that if you look at the IL-2 data for the Proleukin data in -- similarly, ill groups of patients you saw -- you didn't see an attenuation of the side effect profile of the toxicities at all of Proleukin. I mean even in heavily pretreated sick patients like we're dealing with -- the toxicity profile of Proleukin was very, very evident. So I don't personally believe that, that's the reason why we're not seeing a lot of grade 3 and grade 4 toxicities. I think it's because we really do have selective on target -- we have a selective on-target treatment and so I would have -- again, the Proleukin patients really did have a lot of side effects. You also saw that in the checkpoint inhibitors. When they -- in the early trials, again, in very advanced patients, you saw them have tremendous toxicities so I don't think that idea holds up.

Got it. All right. And I guess one final one for me. All this data that is being accumulated, when do you think we might be able to see this in a scientific or publication form?

So Ren, we have the clinical...

Well...

Go ahead. Go ahead, Ken. If you want to comment on the clinical data presentations later in the year?

Yes. Well, I think we would typically not publish certainly a manuscript on this until we got through the Phase IA and IB where we had total data clinical PK/PD data on all the patients that went forward to establishing the RP2D. I think we'll start putting out some abstracts and things, for example, at SITC and ASCO next year in between. But that -- but the totality of the data we'll wait until the trial is complete. But -- and we do have an abstract will be presenting at SITC.

Our next question comes from Mark Breidenbach from Oppenheimer.

Congrats on all the progress with dose escalation and also carry, congrats on the promotion. Two quick ones from me. Maybe revisiting one of the questions from Tom on the kinetics of T cell expansion you're seeing in patient 10 obviously, 42 days seems maybe a bit longer than I would have expected based on what we saw in some of the preclinical models. And I just want to be absolutely clear, Anish or Kenneth, if you're attributing the discrepancy in kinetics between preclinical and clinical data to the fact that we're looking at peripheral T cells only and maybe in the preclinical models, you were looking at tumor biopsies. Is that the right way of thinking about it?

Yes. I think, Mark, there's a couple of things. In the preclinical models, you're not facing the headwinds of a compromised immune performance status. So these are extremely sick patients as you realize. And so you're starting baseline as a healthy diverse reparatory you can tap into. Whereas here, you obviously have the spectrum of patients that have been through multiple lines, and that's hard to decipher.

I think in our own instances, there have been cases where we've seen it after the first cycle and in cases like this where it needs a bit more. And that comes back to the question, well, does the patient really didn't have enough that you had to prime and boost, and that's what you're seeing here, that's what it's indicative. Or did they have something in a peripheral lesional side that you're not able to quantify. And I just put that out there as a variable because we -- through much of the work in cancer immunotherapy, reading things out of the blood, that's the one variable that is very hard to pin point to.

And again, coming back to the preclinical model. The reason I showed you the data is if you look at it in blood in the preclinical motors is again a fraction of a percent in the same animals where you had the response. And when you look at the tumor lesions that relative presence of at cell repertoire that was enriched enormously. That we are obviously applying to here in this scenario. We're always -- we've got a peripheral presence that we're easing out again in fractions of a percent without knowing what's happening centrally. And that, again, comes back to the importance of a study like a neoadjuvant where you have the pre and post mass with you to be able to really quantify and establish that relationship once for all.

Okay. Fair enough. And I guess my second question is in relation to how you'll know when to stop to discuss escalation so you go through cohort 7, 8 mg per kg, and you still are not seeing DLTs. How do you really decide when to declare a recommended Phase II dose? Why not consider going higher than 8 mg per kg?

Yes. Ken, do you want to take that one?

Yes. Thanks. So I think that we've built this trial and, again, put on the basin approach over-the-top of the 3x3 design, specifically so that we could expand dose cohorts up to 9 patients so that we could explore clinical response as well as PD because if we don't hit a maximally tolerated dose, we have to choose what are biologically effective doses. There's no reason why we can't go to higher cohorts at all to higher doses. And we may consider that as we move forward. But again, that whole approach to really see if we can define a biologically effective dose by not just relying on 3 patients per dose level and actually going up to 9 will give us confidence that potentially that we cannot define a BED when we don't see an MTD. So we really -- I'm just so thrilled with this design because it gives us this opportunity to find that effective dose as we anticipated that we may be so safe that we can't find an MTD but that's the longer answer. The shorter answer is, we may decide to go to higher doses. We just -- we'll just see what happens.

Our next question comes from Madhu Kumar from Baird.

Yes. Hopefully, this is better in terms of being able to hear me?

Yes. I'm glad.

Very good. Okay. Great. So really kind of coming back to a lot of the questions that have been coming out during this call. If you put it all together and think about the absence so far of RECIST responses with 101 monotherapy. To what extent do you all believe that's due to intervention dose of the drug the kind of refractory nature of the patient population or the absence of PD-1, PD-L1 blockade or any kind of mixture of the three? How would you kind of rank those 3 in terms of and a likely reasons why you haven't seen RECIST responses so far?

Yes. So this is Dan. Probably the least qualified to answer that question. I'll give a -- put a broad overview and then going to turn it over to Ken and Anish. So Madhu, good question, great question, and it's probably all of the above in various aspects. This is a heterogeneous patient population, very poor health condition, compromised immune system. Immune system has been basically circumvented by the tumor in various ways. So I think all of the above is probably at play in various degrees with this patient population. So the objective with the monotherapy is obviously primarily to show that the drug is well tolerated and safe, showing the drug-like properties pertaining to its dose proportional exposure with PK, the PD effect. And as this conversation is obviously focusing on in a series of questions is tying all that into what's going on at the tumor level. We appear to be seeing metrics of clinical benefit. So the monotherapy, it's really dose escalating to the point where we see in a subset of patients, clinical activity. And just to remind everyone, in this patient population, if we see 1 patient out of 10 on average, with a RECIST criteria, partial response, that's extremely encouraging just based on historic performance with this patient population. So we're going to be following this data, clearly going into upstream into the front line with Pembro, I think bodes very well for the compilation of data we've already seen. But even with the monotherapy, we just continue to move forward with optimism based on the metrics that we've seen emerge to date. So on that, I'll turn it over to the clinician, who, obviously, on call just knows a lot more about this than I do. Ken, do you want to elaborate?

Well, you did a great job answering. I think I would turn it around and go. I'm amazed, we've seen the amount of activity we've already seen. In fact, I think we've already -- as I mentioned on the call, we've already seen enough data to be confident to move forward into the combo study because of the amount of activity we've seen and I think it's just too early to expect more. That -- it's just amazing to me that we've seen as much as we have already, and I'm so highly encouraged by that I said -- we've got to pull the trigger on the combo. And as well as the neoadjuvant to get us even more, more data. I mean, those are things we do, unless we're really confident we have an active drug. So I'm not at all discouraged or somehow surprise that we haven't seen more. I'm actually surprised we've seen as much as we have.

Okay. But following from that, if you see kind of better than PD-1 efficacy when you combine 101 with PD-1 in frontline HPV 16 positive head and neck cancer, would you revisit 101 monotherapy in a kind of more early line proximal kind of right after PD-1 line of therapy to kind of address this issue of these kind of super late-line patients not really being immunologically up for a new experimental agent, like? Would you be -- would we be possible to revisit kind of a second or second third line therapy post PD-1 rather than you kind of really late line patients?

So, absolutely. I would point out by the FDA that we were constrained that all the patients in the monotherapy trial had also had to see platinum-based chemo, and that's why we have an average of 4 lines of previous therapy on all of these patients. I also think we'll be seeing the -- we'll be seeing what effects we have as a single agent in the neoadjuvant study. So I think we'll get -- start to get more hints about that as we move forward. But again, short answer, absolutely, yes.

Our next question comes from Gil Blum from Needham & Company.

Congratulations on all the progress. So just a couple of questions. Just on CUE-101, the combo study, it was -- maybe you can clarify something from RECIST to think that Pembro combination with chemo had a higher response rate than just Pembro by itself. Is there a reason to go with just Pembro by itself, maybe due to the immunosuppressive effects of the chemo?

Ken, you want to take that?

So yes. So there is -- there is some data -- the data with chemo plus pembro. We wanted to -- again, as we move forward in trying to understand how our drug works best. We thought it would be better and cleaner to -- and we're expecting great activity. So we thought it would be cleaner. And as did Merck, together with us, I think it would be cleaner and made the most sense just to do the dual agent combo and that mix in with the chemo.

That make sense. And maybe a bit of a different question on the CUE-200 series. So these are some tumor necrosis factor, agonist. Is there any challenges associated with the structures and the trimerization that's required from these types of signals?

Yes. So we do a systematic sort of derivatization where we look at the sort of spatial relationship of the molecule, how it's all sort of tethered together. And then we do a systematic extension contraction of the various linker lengths, et cetera. And we try to optimize the valencies of where these receptors are on the T cell. So we're not just putting these molecules together and seeing what happens. It's a very systematic study, trying to sort of optimize the combination in terms of spatial relationship and how they engage with these -- this sort of collection of receptors so that we don't have steric hindrance, and we have sort of optimal sort of resonance of the valence so that the signals are able to sort of align with each other based on that combination of factors. And all of that obviously plays into our intellectual property.

Right. That makes sense. I mean, you definitely have the potential of using more than one vigan on each antibody cell. So that might be the possibility there?

Yes. That's right. Yes.

This concludes the question-and-answer session. I would like to turn the conference back over to Dan Passeri for any closing remarks.

Okay. Thank you, operator. Again, I want to thank everyone for your ongoing interest, listening in. We look forward to providing continual updates. We're obviously entering a very exciting period for the company going forward, and everyone stays safe and stay well. Thank you very much.

This concludes today's conference call. You may disconnect your lines. Thank you for participating, and have a pleasant day.