Compugen Ltd (CGEN) 2020 Q3 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to Compugen's Third Quarter 2020 Results Conference Call. (Operator Instructions) An audio webcast of this call is available in the Investors section of Compugen's website, www.cgen.com. As a reminder, today's call is being recorded.

I would now like to introduce Elana Holzman, Compugen's Director of Investor Relations and Corporate Communications. Please go ahead.

Thank you, operator, and thank you for joining us today. With me from Compugen are Dr. Anat Cohen-Dayag, President and CEO; Dr. Henry Adewoye, Chief Medical Officer; Ari Krashin, CFO and COO; and Dr. Eran Ophir, VP, Research and Drug Discovery.

Before we begin, I would like to read the following regarding forward-looking statements. During the course of this conference call, the company may make projections and other forward-looking statements regarding future events or future business outlook, the development efforts and their outcome, our discovery platform, anticipated progress and time line of our programs, financial and accounting related matters as well as statements regarding our cash position. We wish to caution you that such statements reflect only the company's current expectations and that actual events or results may differ materially. You are kindly referred to the risk factors and cautionary language contained in the documents the company filed with the Securities and Exchange Commission, including the company's most recent annual report on Form 20-F filed on February 24, 2020. The company undertakes no obligation to update projections or forward-looking statements in the future.

I will now turn the call over to Anat. Anat?

Thank you, Elana. Good morning, and good afternoon, everyone. And welcome to our third quarter 2020 corporate and financial update. As Elana mentioned, with me today are Dr. Henry Adewoye, our Chief Medical Officer; Ari Krashin, our CFO and COO; and Dr. Eran Ophir, our VP of Research and Drug Discovery. After my corporate highlights, Henry will review the progress across our clinical programs, followed by Ari's review of our financial statements and position. We will all be available for the Q&A session.

Throughout the third quarter of 2020, we continue to advance our clinical programs and execute on our differentiated clinical development strategy with 2 ongoing clinical programs, COM701 and COM902. For this, we currently have 4 clinical studies. The COM701 monotherapy expansion study, the dose escalation study of COM701 with Bristol-Myers Squibb's Opdivo, for which, we have completed enrollment and continue to collect data from patients on study treatment. The triple combination study of COM701 with Opdivo and Bristol-Myers Squibb's anti-TIGIT antibody and the COM902 monotherapy study.

Our clinical strategy is designed to evaluate the role of the DNAM axis in immuno-oncology, along with a new PVRIG pathway biology that we have identified in order to develop new cancer immunotherapy treatment for patient populations unresponsive to existing drugs. I'm pleased with our progress, keeping these multiple studies on track, especially in these unusual times.

With encouraging data that we have shared to date and growing excitement and focus on the DNAM axis and specifically TIGIT among industry and academia in the immuno-oncology space, we are confident in our approach and in our candidates and strategic clinical path forward.

Before I turn the call over to Henry to discuss these trials, I would like to highlight some recent accomplishments that support our unique path and strategy. As a reminder, the foundation of our clinical strategy is our computational discovery of 3 immune checkpoints in the DNAM axis, PVRIG and TIGIT. Building on these discoveries and based on our extensive and pioneering research of the DNAM axis, we believe that these 2 checkpoint pathways are parallel and complementary inhibitory pathways in the DNAM axis. We have also identified, along with data from others, that there is an intersection between these 2 pathways and the PD-1 pathway. Further, our data suggest that these 3 inhibitory pathways have different dominance in different tumor types and patient populations. Accordingly, various patient populations may require the blockade of different combinations of the 3 pathways in order to induce antitumor immune responses.

This is the underlying rationale for our multiple ongoing clinical studies in various tumor types, all based on the translation of our considerable scientific knowledge of the DNAM axis, which we continue to expand in our company. In line with this, in our last call, I discussed the growing body of evidence that supports the distinct nature of PVRIG and TIGIT. Although these are 2 complementary pathways, the 2 targets bind different ligands have different levels of expression and dominance across tumor types and have differential expression across immune cell types. This further supports their nonredundant role and our overall drug combination hypothesis and strategy.

As we're continually working to drive a deeper understanding of the DNAM axis in cancer immunotherapy, in order to further support the strong scientific foundation that has been integral to our efforts and continuously feed our clinical strategy, we were pleased to present new research data at the 2020 TIGIT Therapies Digital Summit held at the end of October. This research further supports the distinct biology of PVRIG and TIGIT and the biological rationale of our combination strategy to maximize clinical responses.

This data show that PVRIG is expressed on stem-like memory T Cells, or TSCM cells, that can differentiate into effector T cells, which can directly eliminate tumor cells. Notably, these results indicating PVRIG expression on these cell add to the prior belief that TIGIT and PD-1 were the main checkpoints expressed on these calls. TSCM are of growing interest in the field for their possible role in response to immune checkpoint blockade.

To complement this finding, we also reported that PVRL2, the ligand of PVRIG, is expressed on specialized cells involved in T cell proliferation, activation and infiltration into tumors and is also expressed in PD-L1 low less inflamed tumors. Specifically, PVRL2 is abundantly expressed across dendritic cell types, which are associated with efficient T cell activation as well as tertiary lymphoid structures in tumor beds where local T cell priming occur and which have been previously shown to be associated with response to cancer immunotherapy.

This data demonstrate for the first time that in addition to TIGIT and PD-1, PVRIG and its ligand PVRL2 are also expressed in and likely play a roll in the activity of these increasingly important sales involved in driving an anticancer immune response. In addition, these results suggest that PVRIG inhibition may enhance T cell priming and infiltration into inflamed as well as into less inflamed tumors, potentially rendering these tumors more prone to checkpoint blockade.

Importantly, our results provide additional evidence that PVRIG and TIGIT have distinct expression patterns and levels of dominance in different tumor types, reinforcing our hypothesis that different cancers or patient populations may require different drug combinations to address these 3 pathways. You can find the complete presentation given at the TIGIT Therapies Digital Summit in the Publication section on our website. So how does all these signs translate to the clinic?

This quarter, we were incredibly proud to announce the first patient dosed in our biomarker-driven triple combination study, a Phase I/II study which is evaluating COM701 in combination with Bristol-Myers Squibb's Opdivo and their anti-TIGIT antibody. The initiation of this trial was a particularly meaningful milestone for Compugen, as it marks the clinical evaluation of our underlying signs.

While combinations of TIGIT and PD-1 inhibitors are being evaluated by others, we're uniquely addressing what we believe is a key component in the DNAM axis. We believe that the simultaneous blockade of PVRIG, TIGIT and PD-1 may be required to provide the antitumor immune response needed to address nonresponsive patient populations in cancers where the 3 pathways are dominant.

Importantly, to the best of our knowledge as the only company with a clinical asset-targeting PVRIG and as a leader in the PVRIG space, we're currently the only company capable of applying this approach and testing this hypothesis. We're incredibly excited to get started and look forward to providing guidance on our first anticipated data readout from this study in our year-end earnings call.

As we shared last quarter, we completed enrollment in the 5th and last cohort of the combination dose escalation study of COM701 with Opdivo, and we continue to collect data from patients still on study treatment. We are also on track with patient enrollment in our COM701 monotherapy expansion cohort, and we look forward to providing data from these studies in the first half of 2021.

Moving next to COM902, our anti-TIGIT therapeutic antibody. Our dose escalation study of COM902 is ongoing, and we expect to present initial data from the study next year. We also intend to share further information about our development plan for COM902 beyond the dose escalation stage in our year-end earnings call. We have been watching the excitement around TIGIT grow over the past months, and we're pleased to see the clinical validation of this new checkpoint pathway. We believe this data provide important validation of our discovery platform as we were among the first groups to discover TIGIT. It also increases our confidence in our overall hypothesis and triple pathway blockade study.

In summary, we're highly encouraged by our clinical and preclinical data which together support our clinical combination strategy and which we believe has the potential to broaden the therapeutic benefit of checkpoint inhibitors to tumor types where they have previously not been successful. Our 2 clinical-stage assets targeting both PVRIG and TIGIT allow us to fully exploit the potential of blocking these pathways, which we believe may ultimately be required to drive robust immune responses in certain tumor types. We look forward to continued progress in leveraging our position in the field.

The third Compugen-discover target being evaluated in the clinic is ILDR2. This program is being developed by Bayer and their research and collaboration agreement. The Phase I study is designed to evaluate BAY 1905254, a first-in-class anti ILDR2 antibody as monotherapy and in combination with Keytruda in patients with advanced solid tumors. Bayer recently updated that the expansion will fully focus on head and neck squamous cell carcinoma.

Based on observations during dose escalation, the evolving treatment landscape in immuno-sensitive solid tumors and their supportive preclinical data, Bayer decided to focus on treating I-O naive first-line head and neck squamous cell carcinoma patients with a combination of BAY 1905254 and KEYTRUDA. We continue to guard by Bayer's commitment to this program and we look forward to Bayer providing additional data on their progress.

Moving next to touch upon some corporate highlights from the quarter. We were very pleased to announce the expansion of our patent portfolio for COM902 with new U.S. and Chinese composition of matter patents. These patents relate to the composition of matter of COM902, alone or in combination with a second antibody, targeting an immune checkpoint, including PD-1 and PVRIG, specifically COM701. This patent further strengthens our IP portfolio for COM902, which is now covered by composition of matter and use patents in both U.S. and Europe.

We were also thrilled to strengthen our incredible Scientific Advisory Board with the appointment of immuno-oncology pioneer Dr. Nils Lonberg. Dr. Lonberg has over 30 years of experience in the biopharmaceutical industry and his career laid the early foundation for cancer immunotherapy translating checkpoint inhibition to new therapeutics that have transformed the cancer treatment landscape for millions of patients. We are honored to have him with us and grateful he will be sharing his expertise as we work to advance our programs and vision of expanding the reach of immunotherapies.

We look forward to 2021 as we continue to gather more data on patients from our ongoing clinical trials, which we believe will provide additional insights into the role of PVRIG within the DNAM axis pathway. We are grateful to our team, partners, investigators and shareholders and look forward to continued progress.

With that, I will turn the call over to Henry to review our clinical programs.

Thank you, Anat, and good day to everyone. As Anat mentioned, we'll continue to expand and are currently executing multiple studies in our clinical programs. On our COM701 program being conducted in collaboration with BMS, we are evaluating the safety and tolerability of COM701 in the therapy and in combination with nivolumab in patients with advanced solid tumors.

In addition, we have a Phase I/II triple combination study evaluating the safety and tolerability of COM701 in combination with BMS-986207, BMS's anti-TIGIT antibody and nivolumab. And our anti-TIGIT antibody program, COM902 is being evaluated in a Phase I dose escalation study in patients with advanced solid malignancies. As a reminder, in April, at the oral virtual AACR conference, we reported data from the ongoing Phase I COM701 monotherapy and combination arm with nivolumab. This data included all monotherapy dose escalation cohorts and 4 or 5 cohorts from the dual combination arm. We and the investigators were highly encouraged with both safety and tolerability and preliminary anti-tumor activity of COM701 as monotherapy and in combination with nivolumab.

We reported 2 confirmed partial responses on the study. In one patient with microsatellite stable platinum-resistant primary peritoneal cancer on the COM701 monotherapy arm, ongoing for 25 weeks at the time of the presentation. And in a patient with microsatellite stable colorectal cancer on the COM701 plus nivolumab arm, ongoing for 44 weeks at the time of the data presentation.

These confirmed partial responses with durability in tumor types typically unresponsive to immune checkpoint inhibitors were encouraging and demonstrated the potential preliminary activity of COM701 as monotherapy and in combination with nivolumab. We also have been encouraged by the durability of responses across all cohorts at the time of the presentation. We reported durable responses of at least stable disease or partial response for over 6 months in 6 out of 28 patients with 4 of 12 patients in the combination arm remaining on study for over 200 days.

We have completed enrollment in the 5th and final cohort of the dose escalation combination arm of COM701 with nivolumab and continue to accrue clinical and laboratory data on the patients. We anticipate presenting data at a scientific conference in the first half of 2021.

Enrollment is ongoing on the COM701 monotherapy expansion cohort. We anticipate enrollment of 20 patients that is 4 patients per tumor type in this cohort. They will consist of patients with advanced non-small cell lung, ovarian, breast, endometrial and colorectal cancer. It is important for us to evaluate the safety and tolerability of COM701 monotherapy at the recommended dose for expansion, 20 milligrams per kilogram IV Q4 weeks in keeping with the primary objective of the study.

For the expansion of this monotherapy study in specific indications will be considered as part of the contribution of components based on data gathered in the ongoing COM701 combination studies. We aim to present our monotherapy dose expansion data at a scientific conference in the first half of 2021.

Regarding the triple combination study that is also being conducted in collaboration with BMS, as Anat mentioned, during the third quarter of 2020, study treatment was initiated in the first patient on the dose escalation arm of the study. This Phase I/II study will evaluate the safety, tolerability and preliminary antitumor activity of COM701 in combination with nivolumab and BMS-986207. The study consists of 2 parts, namely dose escalation part 1, and dose expansion part 2.

In part 1, COM701 will be administered in ascending doses in combination with fixed doses of BMS-986207 and nivolumab. All patients enrolled during this escalation will have advanced solid tumors and have exhausted all available standard therapies. At the completion of the dose escalation study, a recommended dose for expansion of COM701 with BMS-986207 and nivolumab will be determined.

In part 2, patients will be administered the recommended dose of COM701 in combination with BMS-986207 and nivolumab. Patients will be enrolled into 1 of 3 cohorts based on their cancer type. Cohort 1 will enroll patients with platinum-resistant/refractory ovarian cancer, primary peritoneal or fallopian tube cancer. Patients will be randomized 1:1 to receive study treatment with either the 3 drug combination or nivolumab monotherapy. Cohort 2 will enroll patients with microsatellite stable endometrial cancer and receive study treatment with a 3 drug combination.

Cohort 3, which is a basket cohort will enroll patients with tumors that have high expression of a biomarker, PVRL2 and receive study treatment with a 3 drug combination. Subjects with tumor types in cohorts 1 and 2 will not be enrolled into this cohort. Additional key objectives of the study, including evaluation of pharmacokinetic parameters and the preliminary antitumor activity of the study drugs. Regarding our biomarker strategy for the ongoing clinical studies, we will evaluate PVRL2 and PVRIG expression retroactively in tumor samples obtained in patients enrolled in the COM701 monotherapy and triple combination expansion cohorts.

In addition, specifically in patients enrolled in the basket cohort of the triple combination study, patients will be required to have tumors that have high expression of PVRL2 prior to enrollment into the cohort. The COM902 monotherapy dose escalation study, evaluating our anti-TIGIT antibody is currently on track and enrolling patients. As you know, we made a strategic decision to develop our own anti-TIGIT antibody following our understanding of the biology of the DNAM axis. We ultimately will evaluate the combination of COM902 with COM701 as part of a PD-1 PD-L1 free regimen.

In our year-end earnings call, we intend to share our development plan for COM902 beyond induced escalation stage. I would like to very briefly address the ongoing COVID-19 pandemic. Patient enrollment in our studies has not been significantly adversely impacted by the pandemic, and as indicated by Anat and myself, we expect to meet our previously provided guidance on data readouts in 2021. We and the investigators are committed first and foremost to the safety of patients on our clinical trials.

And finally, before turning the call over to Ari, I would like to express my gratitude to the patients in our clinical trials and their families. The investigators and clinical trial sites and the excellent work of our hard-working competent team advancing our clinical programs. Ari?

Thank you, Henry. Good morning, and good afternoon to everyone. Our financial results for the third quarter of 2020 release this morning continue to reflect the solid financial position and expense structure aimed to support our clinical programs in their various stages. R&D expenses for the third quarter of 2020 were $5.5 million compared with $4.3 million for the same period in 2019. Our R&D expenses reflect cost associated with our multiple ongoing clinical programs, which now include the dose escalation of COM701 in combination with Opdivo, the expansion cohort of COM701 monotherapy, the dose escalation study for COM902 and the dose escalation study of the triple combination.

Net loss for the third quarter of 2020 was $7.8 million or $0.09 per basic and diluted share compared with a net loss of $6.5 million or $0.10 per basic and diluted share for the same period in 2019. As of September 30, 2020, we had approximately $133 million in cash and cash-related accounts compared with approximately $136 million as of June 30, 2020. The slight decrease in our cash balances during the third quarter is mostly attributed to approximately $8 million of operating expenses and working capital, offset by approximately $5 million of net proceeds received from exercise of warrants and exercise of employee options.

Going into the fourth quarter of 2020 and beyond, we expect our ongoing R&D expenses to increase slightly as our clinical trials continue to expand and progress. Cash balance at the end of the year is expected to be approximately $124 million. In our next earnings call, we will provide a financial outlook for 2021.

Thank you for joining today. And on behalf of all of us at Compugen, we hope you stay safe and healthy. And with that, we will now open the call for questions.

(Operator Instructions) The first question is from Stephen Willey of Stifel.

This is Bonnie on for Steve Willey. I wanted to add about your Q1 trial evaluating COM701 monotherapy. Since your (inaudible) 5 different tumor types of 4 patients with tumor type. Is there any color that you can provide in terms of the strategy or what evidence there will be that will be compelling to you when you choose which cohorts to upsize later down the line?

Yes. Thank you very much for your questions. The primary objective of the study, as you realize, is the safety and tolerability of COM701 at the recommended dose for expansion, 20 milligrams per kilogram per week IV Q4 weeks. Therefore, we are focused primarily on ensuring that we follow up on this. The tumor types that we have specified in the expansion cohort, a combination of preclinical data and emerging clinical data that we previously presented first at SITC in 2019 and more recently at the AACR conference by Dr. Ryan Sullivan. So the preclinical data were guided by tumor type specified as non-small cell lung cancer, ovarian, breast and endometrial, which we observed have high expression of issue of PVRL2. And we added microsatellite tumor colorectal cancer as a result of the emerging data we saw first at SITC, and more recently AACR, where we disclosed we had a patient with the partial response that have been ongoing at the time of the presentation for 25 weeks.

Going forward, we will continue to monitor this data. And, as Anat mentioned and I mentioned in my prepared comments also, additional data disclosures are scheduled for the first half of 2021.

Okay. And for your biomarker analysis from patient biopsies. At what point will you be taking these patient samples? I think it'd be interesting to see, not just for patient selection in your other trials, but with all the preclinical biomarker data that you've shown, it'd be interesting to see a change of an expression of different DNAM axis members and if that correlates with response.

Yes, you're correct. So for the expansion cohort, specifically I'm referring now to COM701 monotherapy expansion cohorts. One of the requirements for enrollment in the study is the collection of a biopsy prior to treatment and an on study biopsy also during the course of treatment. We will examine those results retrospectively and then find out if there's a correlation between expression of PVRL2 and treatment outcomes. And the treatment outcomes I'm referring to are measures such as response rates and also looking at safety parameters, duration of response and the correlation with the expression itself of PVRL2, whether it's 1 plus, 2 plus or higher.

For the expansion cohort for the basket study, like I mentioned in my prepared comments, that will actually be a prospective collection. We will look at PVRL2 expression in the third cohort, which is the basket cohort, and early patients that have high expression of PVRL2 as we determine centrally will be permitted on to this study. So those are our plans. I also mentioned in my prepared comments that we will also look at PVRIG expression in addition to PVRL2 for the ongoing COM701 study.

All right. Is there any color that you would be able to provide in terms of like when you will be taking these patient samples?

Yes. The patient samples will be taken for the basket cohorts before patients get enrolled into this study. And for the COM701 monotherapy expansion cohort also before they start study treatment and during the course of study treatment.

The next question is from Daina Graybosch of SVB Leerink.

I have 2 questions. One, I'm wondering if you can talk about the profile of COM701 and COM902 for Fc gamma receptor binding and engagement. And how it compares perhaps to other version we see out there in the clinic with IgG1 that are mutated to make them Fc functionally incompetent? And I'm asking because given some of the updated data we saw at the TIGIT Summit and in recent publications, specifically from Merck and some from Agenus that the Fc gamma receptor engagement could be through myeloid or dendritic cell binding and not through the traditional recruitment of NK cells and macrophages. I'm just wondering whether the IGg4 backbone in your programs actually would engage that Fc gamma receptor on the myeloid population? And if you could expect IGg4 look different than these mutated IGg1 programs?

And then the second question on the new PVRIG data in the T stem cell memory population. I know there's a recent publication that split the T memory populations into dysfunctional and functional and showed that the dysfunctional population had really high TIGIT and PD-1 expression, and I wonder if you've had a chance to look at PVRIG expression or replicate any of the work in that paper.

Yes. Thank you, Daina. So for the first question, so IgG4 has some binding to Fc receptors, probably a bit higher than the IgG1 mutated. But overall, we expect to have similar patterns. Mainly, they're probably going to look similarly. And yes, all these very interesting publications of Agenus and Merck that were shown in the posters in the recent years and then now in publications, indeed shown the ability or maybe even the requirement in preclinical models of TIGIT to engage Fc receptors in order to mediate activity.

And then this comes to this highly debated question how this will translate. And for example, for PDL-1, it was published as well. The PD-L1 requires Fc binding to modulate (inaudible), it's very similar MOA I would say, maybe not to the fine details but roughly the same MOA. PD-L1 was shown to require PD-L1 to modulate (inaudible) in preclinical model and now they the clinic, nobody thinks that the PD-L1-mutated Fc bindng or the Fc competent PD-1s are -- that are inferior. So basically, this is for the Fc binding question.

So probably IgG4 similar to the mutated one. But definitely, we are not sure that this is going to be translated into clinical efficacy, again, similar MOA one for PD-L1 that did not translate well.

And then for the second question, yes, this one publication did split the TSCM into population, one which have PD-1 and TIGIT and might be developing to more exhausted, and this is actually a very nice publication. But actually, there are multiple publications now that shows that the PD-1 responding TSCM are key for checkpoint activity, they respond to checkpoint blockade. They require to checkpoint blockade. This was shown in new and preclinical model. This was shown by correlation to clinical efficacy of checkpoint. So definitely, the field is evolving and is any new vertical field, you can have researchers going into different direction. Overall, I still think that most of publications shown that the PD-1 TIGIT and what we now see also PVRIG expressing positive TSCM are required for checkpoint activity.

Now the data that we have currently for PVRIG is correlative. We know that PVRIG has very nice expression by TSCM as TIGIT and PD-1. We know that PVRL2 has very nice expression, actually broader than PD-L1 and PVR on dendritic cells and industrial infrastructures. And indeed, we need to translate either in patient samples or a preclinical model to transit all these interesting observation also into direct mechanistic studies, but we haven't done so yet.

The next question is from Mark Breidenbach of Oppenheimer.

Congrats on the continuing progress. Just a few from me. First of all, do you think the relative dominance of the PVRIG/PVRL2 checkpoint can be directly inferred from PVRL2 and PVRIG expression profiling? I guess I'm just wondering if there are any downstream signals that we should be looking at to confirm that the inhibitory checkpoint is engaged as you analyze the tumor biopsies?

Yes. So in terms of signaling, the PVRIG signals through an ITIM domain, the recruitment of phosphatase and et cetera, critical to other checkpoints. It's a new checkpoint. So there's not a lot of studies. So we do not a lot about unique signaling. We would expect to have generally, again, increased [filtration], increased T cell refer to our in the patient samples following treatment, et cetera, due to all these recent observations and biology of PVRIG/PVRL2. I don't think it's the expression level necessarily, but definitely, the expression pattern is going to be interesting, and we're also going to try to look at it. Maybe responding patients have not only the level of PVRL2, but maybe specific cell population, which express PVRL2, like dendritic cells, et cetera, are the ones important for response. So we are going to look at all of it and correlate to clinical response eventually.

Got it. And if the expression is concentrated into these tertiary lymphoid structures, does that potentially complicate the expression profiling just due to sampling error and factors like that? Or do you don't anticipate that wouldn't be a problem?

Well, the expression is not only the tertiary lymphoid structures. We do see a very nice expression tertiary lymphoid structures but the expression is also on the tumor cell themselves. The expression is also in dendritic cells, which are not specifically in the tertiary lymphoid structures. So basically, we don't -- I don't think this is any complexity. We're going to look at expression across all the different subtypes. Again, it's going to be that the tumor cells level of expression is going to matter. It's going can be tertiary lymphoid structures, dendritic cells, different subtypes and eventually at the end the day also PVRIG expression or T cell, NK cells, et cetera.

Okay. Got it. And just one last one for me. I'm wondering if you can talk about any of the the data that led Bayer to focus on I-O naive front line head and neck cancer with the ILDR2 antibody? And are you anticipating any milestones from Bayer in the next 12 months with respect to this program?

So Mark, there's not a lot that we can say about it, except, of course, it's being in the public and what we align with Bayer that we cannot share with the shareholders. But basically, this is based on observations that they have in the dose escalation and -- of their clinical study, their analysis of then involving the last type of I-O treatment and supporting preclinical data, and that was the decision to refocus on I-O naive, first-line head and neck. And this is -- that's the only information that we can share. Obviously, this is a program that is being controlled headed by Bayer and it's their decision-making. With respect to milestones, as always, we cannot comment on timing, when we're going to pre-randomized trial, the size, but we would share and we'll share then (inaudible) obtain them.

The next question is from Asthika Goonewardene of Truist.

This is Allen on for Asthika. Congratulations on the progress reported. So my question is that given all the large pharma TIGIT presentations that we've seen throughout the year at medical conferences, those presentations haven't really showed very exciting monotherapy activities and realizing it's early and before your year-end update, I guess we're curious to know, what would you like to see in your COM902 Phase I that would give you the confidence to proceed with the program and maybe to eventually replace the first TIGIT in the triplet study?

Yes. Thank you, Allen. So as you know, this is the first time we're doing a clinical trial with anti-TIGIT antibody, COM902. So for this Phase I study, the focus primarily is on safety and tolerability of COM902. And as we do the ascending dose escalation cohorts, we will keep on accruing data on the patients that are enrolled. I -- and we are all familiar with the data presented by Roche, Genentech, the data that was previously presented by Mereo, OncoMed. And more recently, the data by Merck regarding the activity of anti-TIGIt antibodies, as monotherapy and in combination with the PD-1 or PD-L1 inhibitor.

We cannot -- I cannot comment at this time, since we are still accruing data, on the monotherapy activity of COM902 in terms of preliminary anti-tumor activity. But we are cognizant of the fact that in this space now that it appears that combination therapies are the way to go. And Compugen is uniquely positioned in that space. In my prepared comments, I mentioned we will eventually test a PD-1 PD-L1 free regimen. So we will keep accruing the data and then observe for preliminary anti-tumor activities of the (inaudible). You also mentioned something about swapping BMS-986207 into either the triplet combination also. There is no plan at the -- there's no plan to substitute our TIGIT antibody into the triplet combination as it's currently being perceived now.

Yes. I'll just add (inaudible) that we don't it as a competition between the 2 programs. And we've just expanded the study with BMS. We moved into a triplet study. And we'll continue to push this forward as much as possible. Our COM902, as Henry said, is really designed in order to test combinations that we can test alone, not as part of the collaboration and mainly COM701 plus COM902 in a PD-1 independent regimen. And COM902 in general allows us to keep the flexibility and really control the 2 arms of the DNAM axis. So this is the reason why we have it. It's not in order to compete with the (inaudible).

The next question is from Reni Benjamin of JMP Securities.

This is Justin Walsh on for Reni. It looks like your BMS and Bayer collaborations are moving forward nicely. I was just wondering when we could potentially see an update on your AstraZeneca bispecific program? And maybe just remind us about what parameters are public with respect to that partnership?

Sure. So basically, this partnership is -- it's a license agreement for AstraZeneca to develop bispecific antibodies to one of the programs in our pipeline. We kept the rights for monotherapy and combination therapy and also some bispecific rights, and AstraZeneca got the total rights for bispecifics other than what we have. As I said, it's a license agreement, and under the agreement, AstraZeneca is in charge of the -- of all the R&D and commercial activity. And in addition to the milestone that we got when we entered to this collaboration, we're eligible for packages of milestones and royalties for each and every product that is going to be developed based on this license that AstraZeneca obtained. So as such, it is really on AstraZeneca to report any advancements in this program. We'll obviously share when we will obtain a milestone payment, but we cannot say anything more than that.

Got it. And I guess just one more clarification on the biopsy data. So of course, you're going to look for the PVRL2 and PVRIG expression and correlate that to response. So I was just wondering if there is anything else specifically that you'll be looking for to identify responders or get some sort of a sense of the drug efficacy?

So basically, we're going to look at multiple parameters. When you look at the pathway expression, probably also other clinical molecules, we're also going to look at the [TME], general modulation, we're going to look at T cell sequencing, RNA. So to try to see -- look for drug MOA [hints] of activity, along with potential exploratory biomarkers as well.

The next question is from Tony Butler of ROTH Capital.

Just back to the biology a little bit, especially with the recent TIGIT Summit. So the question is, it's really one, but it has 4 parts. And the first is around -- when you look at over-expression of PVRL2, I'm curious if, in fact, that's in tumors, which have already seen, maybe they're second or third line tumors. In other words, they're not front line tumors. So the over-expression is present there.

And the question is, if one were to look at a naive patient that maybe even had breast, endometrial, ovarian cancer, would you also in those naive patients see over-expression of PVRL2 or is that a hypothesis? That's part A.

Part B is if you have over-expression of PVRL2 on DC, what's the level of expression of PVR, is it there at all?

And then Part C is, if you have over-expression of TIGIT in Treg, would you not think that always using an anti-TIGIT antibody would be useful because this gets into this dominant question yet again?

And then finally, does -- and this is just straight biology, is there -- there is some question about PVRL2 binding the PVRIG, does you get any binding to TIGIT as opposed to PVRIG? In other words, there is some competition, and I just don't know the kinetics behind the differences in the binding.

Okay. So for the first question about the expression of PVRL2 on naive patients, well, actually, PVRL2 is expressed quite broadly. We expect it to be expressed on naive patients, on treated patients. We look at multiple patient samples, both by [IT], by flow. We don't expect to see any specific differences between I-O naive or heavily treated patients there, the expression is probably going to be there in all patient samples.

In terms of the expression of PVRL2 versus PVR on DCs. So there are few subtypes of DCs, one of them is activated DCs. These are the subtypes, which was highlighted to be the ones which actually capture the antigen, (inaudible) lymph nodes, activated T cells over there. So PVRL2 has a very dominant expression or activated DCs but PVR and PD-1 are also expressed in this specific, this is subtype. So there is co-expression of the 3 ligands on activated DCs while PVRL2, it is by RNA, it's more dominant on the activated DCs compared to PVR. But then there are also other subtypes of DCs, DC1, DC2, which also play different roles in T cell priming, different publications, about all of them very important in T cell priming. So PVRL2 is expressed also in these subtypes. And again, from what we know at this point, and it's mostly RNA data by now, but multiple data sets. It seems that PVRL2 has broader expression on the other DC subtypes compared to PVR and PD-L1.

Then for the third question about TIGIT on Tregs. So I'm not sure if I got it right, but basically, what is nice about TIGIT that it may be in contrast to some other checkpoints, a blocking antibody. On the one hand, we'll stimulate effector T cell activity, but it will also reduce Treg suppressive activity. So it's not a competition that whether you're going to have some checkpoints, if you block them, actually, the Tregs will be more suppressive. This is not the case for TIGIT as far as we know. So the same blocker antibody, we have a double benefit effect of enhancing T cell activity and reducing Treg suppressive activity.

And finally, for the question of PVRL2, PVRIG, PVR, so the binding affinity of PVR to TIGIT is in the nanomolar range. The binding affinity of TIGIT to PVRL2 is in the micromolar range. And actually, we hardly even saw it when we tried to look at binding, not to mention that when you try to look functionally, if there is a consequence of PVRL2 binding to TIGIT and we didn't see much.

On the contrary, PVRIG binding to TIGIT to PVRL2 is, again, nanomolar, in terms of nanomolar range. And of course, we saw in multiple assays that PVRL2 binding to PVR is functional so basically, there is some binding of PVRL2 to TIGIT. We believe this is not dominant, definitely not competing with the dominant binding of PVRIG to PVRL2.

We have a follow-up question from Daina Graybosch of SVB Leerink.

It's actually very related to the last question. I was just wondering if you had any thoughts on some of the recent report of Nectin-4 being another ligand for TIGIT? And if you think that's at all relevant and you're thinking about that in your development of your TIGIT combination?

So yes, it's an interesting report. I think it's one publication showing that Nectin-4 also bind TIGIT. According to that publication, actually, the affinity might be relevant. At this point, we didn't look much into this. And certainly, we didn't disclose anything, but we are not sure if it's very relevant. The binding site of the different Nectin is usually similar. So I would expect, but we didn't test that normal TIGIT antibodies will block also the binding to Nectin-4. But again, we didn't test it and we didn't look too much into this.

This concludes our Q&A session. I would now like to turn the call back to Compugen's President and CEO, Dr. Cohen-Dayag, would you like to make your concluding statement?

Thank you. We are very pleased with the steady progress and execution across our clinical program, ensuring all on track to our expected data readouts. In addition, starting our triple combination study in parallel to these other studies, was an incredibly important milestone, advancing our broader science-driven clinical approach to a direct evaluation of our underlying hypothesis. We're excited about what's to come. In 2021, we expect our data readouts to provide additional insights into the role of PVRIG in cancer immunology.

We also look forward to sharing additional guidance on the triple combination study and development plans for COM902 beyond the monotherapy dose escalation study. Thank you again for joining us today and your interest in Compugen, stay safe and healthy. Thank you.

This concludes Compugen Ltd.'s Third Quarter 2020 Financial Results Conference Call. Thank you for your participation. You may go ahead and disconnect.