Compugen Ltd (CGEN) 2021 Q4 法說會逐字稿

Ladies and gentlemen, thank you for joining us today. Welcome to Compugen's Fourth Quarter and Full Year 2021 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 Yvonne Naughton, Head of Investor Relations and Corporate Communications. Yvonne, please go ahead.

Thank you, operator, and thank you all for joining us on the call today. Joining me to present the prepared remarks are Dr. Anat Cohen-Dayag, President and CEO; and Ari Krashin, Chief Financial and Operating Officer. For the Q&A session, we will also be joined by Dr. Henry Adewoye, Chief Medical Officer; and Dr. Eran Ophir, Vice President, Research and Drug Discovery.

Before we begin, we'd like to remind you that during this call, the company may make projections or forward-looking statements regarding future events, business outlook, development efforts and their outcome, the company's discovery platform, anticipated progress, results and time lines 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 beliefs, expectations and assumptions, but actual results, performance or achievements of the company may differ materially.

These statements are subject to known and unknown risks and uncertainties, and we refer you to the SEC filings for more details on these risks, including the company's most recent annual report and filed Form 20-F filed with the SEC on February 25, 2021. The company undertakes no obligation to update projections and forward-looking statements in the future.

With that, I now turn the call over to Anat.

Thank you, Yvonne. Good morning and good afternoon, everyone, and welcome to our fourth quarter and full year 2021 update. I'm proud to say that Compugen made excellent progress in 2021. Our fundamentals have improved and we're delivering on our promises. Compugen has done groundbreaking work on the biology of the key targets of the DNAM axis PVRIG and TIGIT. This is evidenced by our numerous publications and patent filings. We are pioneers in an uncharted territory. We're the first to test in the clinic 2 agents never combined before, primarily focused on PD-1 non-responsive patients.

Our differentiated clinical strategy with our potential first-in-class anti-PVRIG antibody COM701 is to lead the next wave of innovation by executing a unique combination approach to realize the full potential of TIGIT and PVRIG. Immune checkpoint inhibitors have become multi-billion dollar drugs and are having a major impact on cancer care. However, as most patients do not respond to immunotherapy, there is a need for new drugs for these cancer patients.

At Compugen, we believe that immune checkpoint inhibitors that target the DNAM axis have the potential to be a game changer in the treatment of cancer. As we continue as leaders in the DNAM axis by unlocking the potential of both PVRIG and TIGIT pathways with a vision to deliver the next transformational drugs, we're excited to see the growing interest in the space by major pharma companies providing further validation of our hypothesis and the possibility of opening additional opportunities for us in the future.

Data from our clinical studies presented in 2021 with COM701 and COM902 support our hypothesis, the treatments that target the DNAM axis could be effective in inflamed or even more exciting less inflamed tumors. Our studies show early signals of anti-tumor activity with immune activation across studies and a good safety profile in mono, dual and triple therapy settings. Today, we would like to update you on our clinical program, upcoming anticipated milestones and report on our financial results for the fourth quarter and full year 2021. I'll start by updating you on our key 2021 and 2022 anticipated milestones. Then I will review the clinical program with you. Ari will summarize our financial results, and then I will come back to make a few closing remarks.

2021 has been a year of progress for Compugen with a strong execution across our differentiated clinical strategy. I want to highlight 3 of our important accomplishments in 2021. First, in keeping with our goal to develop first-in-class or best-in-class immunotherapies for cancer patients who are not responding to currently available therapies, we delivered on our clinical milestones to complete dose escalation studies and begin expansion cohorts across all our programs. These encouraging results from our initial clinical studies reported at major medical and scientific meetings throughout the year paved the way for a comprehensive evaluation of Compugen's DNAM axis hypothesis in our ongoing expansion cohort studies.

Second, in keeping with our goal of maximizing value for patients, we expanded our collaboration with Bristol Myers Squibb and are happy to see AstraZeneca progressing their TIGIT/PD-1 bispecific derived from our COM902 into the clinic. In addition, we expanded our research collaboration with Johns Hopkins University. These partnerships support our focus on expediting our early and clinical stage programs and bringing them to the market.

Third, in keeping with our leadership position in the field and our goal to advance immuno-oncology research, throughout 2021, we presented new research and translational data at scientific conferences to support the unique biology of PVRIG and the potential of its blockade to target less inflamed tumor types. In addition, along with one of our trusted advisers and long-term collaborators, Professor Drew Pardoll, we co-offered a review on the biology and potential therapeutic relevance of the DNAM axis in cancer immunotherapy in the prestigious high-impact journal, Cancer Discovery.

Looking ahead to 2022, we're conducting 3 very important Phase I/II combination studies. As you know, our clinical strategy has been designed to allow us to systematically evaluate our hypothesis that simultaneously blocking 3 pathways, PVRIG, TIGIT and PD-1 in selected biomarker informed tumor types may produce game-changing results for cancer patients with inflamed or less inflamed tumors. PVRIG, which is differentiated from TIGIT and PD-1 may be the missing piece when current immunotherapies have failed by potentially generating new waves of T cells to infiltrate the tumor microenvironment turning it to a more inflamed environment.

Our ongoing combination studies are significant studies evaluating preliminary anti-tumor activity of COM701 in addition to safety and tolerability in multiple indications. These studies also include a parallel comprehensive translational analysis assessing immune activation to further evaluate our unique drug mechanism of action and potential biomarker identification that may be of relevance for future patient selection. Based on establishing proof of concept in specific indications, we will share our path forward in such indications, targeting the fastest path for registration to maintain our first-mover advantage.

Our studies have been designed to efficiently identify the optimal inhibitor combinations and tumor types. Although these are significant studies, this approach which includes some overlapping indications across studies is intended to help us understand the contribution of each study drug. Enrollment is underway in our ongoing clinical studies. The first study initiated at the end of June 2021 is designed to evaluate an anti-PVRIG PD-1 combination with COM701/nivolumab in patients with ovarian, endometrial, breast and microsatellite stable colorectal cancer. The second study initiated in July 2021 is designed to evaluate the anti-TIGIT PVRIG PD-1 triple combination with COM701/nivolumab and Bristol Myers Squibb's anti-TIGIT in patients with ovarian, endometrial and head and neck squamous cell carcinoma plus a cohort of subjects who have high expression of PVRL2, which we'll start enrolling following the assessment of correlation between PVRL2 level of expression and response.

The third study most recently initiated in November 2021 is evaluating an anti-TIGIT PVRIG combination with our wholly-owned COM902, COM701 drug candidates in patients with head and neck squamous cell carcinoma, non-small cell lung cancer and microsatellite stable colorectal cancer. Our intention is to report data from fully enrolled cohorts of each of these studies, taking into considerations that certain cohorts, indications enroll faster than others, and use the results to define our regulatory strategy on a cohort by cohort basis.

Based on the current enrollment rate, first data from combination studies are expected to be reported in Q4 2022, starting with the microsatellite stable colorectal cancer cohort from the COM701/nivolumab study. And we expect to complete enrollment in all cohorts by end of 2023. As enrollment progresses, we plan to share further guidance with respect to the other cohorts.

Microsatellite stable colorectal cancer is a tumor type that has so far been immunologically unresponsive. There is no approved therapy specifically for this MSS/CRC patients, and immune checkpoint inhibitors have demonstrated limited or no activity in this patient population. Treatment in this setting is typically regorafenib or Lonsurf, which show ORR of 1%, median PFS of 2 months and median OS of 6 to 7 months. As of today, we have presented data from 12 patients using various doses of COM701 with or without nivolumab across studies and have shown encouraging preliminary anti-tumor activity with a disease control rate of 58%, including 1 partial response of 44 weeks. Our current COM701/nivolumab study consists of additional 20 MSS/CRC patients, which will help us further assess the potential of this drug combination in this setting.

Looking back over 2021, I've been very pleased with encouraging data in our Phase I studies across mono, dual and triple therapy in multiple tumor types as presented at ASCO and SITC, as well as the expansion of our collaboration with Bristol Myers Squibb based on the data we've presented to-date. 3 observations from our overall translational data set stand out to me. First, our most recently presented translational data demonstrating immune activation across our COM701 studies with the most potent immune activation in triple blockade of PVRIG, TIGIT and PD-1 supports our suggested drug mechanism of action, as well as the differentiation of PVRIG from that of TIGIT and PD-1.

Second, I'm pleased that our approach to develop our anti-TIGIT antibody using an IgG4 backbone similar to the leading anti-PD-1 antibodies with less effector function than IgG1 appears to be an appropriate strategy. Indeed, in our COM902 dose escalation study, which we presented at SITC, we show that there is no depletion of the CD8+ T cells, the most effective anti-tumor immune subset. We were the first to present clinical data with an IgG4 anti-TIGIT antibody with low Fc-effector function, and we believe this may also come with additional benefits on the safety side to be confirmed in the clinic.

Third, our initial data suggested COM701 may have potential to address less inflamed tumor types, where other immune checkpoint inhibitors have not been successful in line with supportive data from our PVRIG research. In addition, we achieved encouraging signals of anti-tumor activity in our studies with several notable durable responses in heavily pretreated patients who have exhausted all available therapies with a good safety profile.

To summarize, our translational observations coupled with our encouraging data to-date suggest a differentiated profile for COM701 and COM902 with the potential to unlock the value of DNAM axis as a game changer in the treatment of cancer. I'm enthusiastic about our program and look forward to sharing the results of our ongoing studies with you.

Before I turn the call over to Ari, I would like to thank the patients and their families, caregivers, investigators and study sites.

Thank you, Anat. I'm happy to summarize our financial results. I'll start with our cash balance. As of December 31, 2021, we had approximately $118 million in cash compared with approximately $124 million as of December 31, 2020. The company has no debt. Our cash balance reflects Bristol Myers Squibb's strategic investment of 20 and $6 million milestone payment from AstraZeneca received during the fourth quarter. Going into 2022, we expect our cash burn to be in the range of between $44 million to $46 million.

Financially disciplined, we are a company targeting our extensive and unique knowledge in this space on specific tumor types and comprehensive clinical strategy to increase our probability of success of our drugs to help patients. At the current level of operations, we expect current cash will be sufficient to fund our operating plans into 2024. For revenue, we reported no revenue for the fourth quarter of 2021 and of $6 million for the year ended December 31, 2021, compared with $2 million for each of the comparable periods in 2020.

2021 revenues are related to the milestone payment from AstraZeneca for dosing the first patient in their Phase I/II study of a TIGIT bispecific monoclonal antibody derived from our COM902.

With respect to R&D, R&D expenses for the fourth quarter and year ended December 31, 2021, were $5.8 million and $28.7 million respectively compared with $8.1 million and $22.8 million for the comparable periods in 2020. The increase in R&D expenses during 2021 is attributed mainly to higher expenses associated with our various clinical studies, as well as increase in headcount as we continue to grow our U.S. based clinical team to support the extension -- expansion of our studies. The decrease in the quarterly period is due to a decrease in manufacturing and related expenses.

Our G&A expenses for the fourth quarter and year ended December 31, 2021, were $2.7 million and $10.9 million respectively compared with approximately $2.7 million and approximately $9.8 million for the comparable periods in 2020. The increase is mainly due to increased D&O insurance premium cost that affected the overall industry. During the fourth quarter of 2021, we reported a net loss of $8.6 million or $0.10 per basic and diluted share similarly to a net loss of $8.6 million or $0.10 per basic and diluted share in the comparable period of 2020. Net loss for the year ended December 31, 2021, was $34.2 million or $0.41 per basic and diluted share compared with a net loss of $29.7 million or $0.37 per basic and diluted share in the comparable period of 2020.

Now, I'll turn the call back to Anat.

Compugen has done groundbreaking work on the discovery of the PVRIG pathway and the DNAM axis hypothesis, and we're well positioned to maintain our leadership in this new area of cancer immunotherapy. We're actively enrolling in 3 important combination studies that will guide our registration strategy, and we expect to report the first clinical results in Q4 2022. We have a solid balance sheet with a cash balance of $118 million that will support our clinical program and our operations into 2024.

I'm very enthusiastic for what's to come for Compugen and look forward to updating you on our progress throughout the year. I want to send a special thank you to the amazing team at Compugen, whose dedication has enabled our remarkable accomplishments and to you all for joining us today and taking time to follow the company.

And with that, we'll now open the call for questions.

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

Can you maybe just share with us what your current expectations are regarding efficacy data that will be emerging out of the colorectal cohort by year-end? And I guess what needs to be seen to potentially inform a go-forward decision? And then, I guess second to that, can you make that decision about going forward before you see combo data from the 701, 902 combo in the same tumor type?

Thank you, Steve. I'll just say I'll refer this question to Henry, I'll just say that in general for all the -- most of the tumor types that we're addressing, these are tumor types that are not responsive to checkpoints and the patients do not have many options. So we think the bar is not very high in terms of numbers. Obviously, this is a very hard to treat patient population. But I'll let Henry relate to more specifics.

Yes, thank you very much, Anat, and thanks, Steve for the question. Yes, I just want to remind you and everybody else listening that these are signal-seeking studies, even though they're expansion cohorts, right. So we have 20 subjects in each of these -- 20 patients in each of these cohorts that you're mentioning. So it's actually what we're looking for are a combination of various things. So number one, we're looking for efficacy in terms of a partial response. We're also looking for anti-tumor activity in terms of stable disease and the durability of the stable disease. So it will be premature to start assigning numbers that will be of interest to us.

But that being said, I think it bears mentioning just like Anat mentioned in her prepared comments that a particular tumor type where you see a patient with a partial response, for example, colorectal cancer, that stays on for 44 weeks is actually notable. It is notable for the following reasons. And one of it being that this tumor type is typically not responsive to immune checkpoints or they have very limited activity. So that itself shows that we have a signal is just that, that's for one patient.

And the other reason that's important is the fact that we've also disclosed that at ASCO just last year, the caliber of patients that we enrolled into the colorectal cancer cohort. Of the 12 patients we enrolled, we saw patients -- this is also listed in our swimmer plot. Those patients that actually surpassed what is typical for the median progression-free survival in this patient cohort. So that's -- those are -- these are the parameters that we're interested in. And we'll continue to accrue into all other cohorts and then see what the results are and be able to make a more informed judgement as to anti-tumor activity and the next steps for Compugen.

I'll just add -- Steve, I'll just add one more thing that relates not only to the clinical data, but also, as you know, we have a comprehensive translational program that we apply on all the different studies in -- on all the cohorts. So we really look also on the translational data as a very important parameters. So this will be taken into consideration as well. And obviously, for COM701 and COM902 combination, the data it's open studies, we see the data. So definitely, this is a parameter that will take into consideration.

And then maybe just lastly is the year-end '23 guidance that you're providing here for completing enrollment in all cohorts. Is that in any way rate limited by the diagnostic work that you're doing to establish a PVRL2 expression threshold for enrollment into the basket cohort?

That's not limited, the program is ongoing. We're doing a lot of work in order to make sure that we have the samples and then we can test the expression profiles of the DNAM axis members, specifically PVRL2. So at the time, that we feel that we have enough in order to correlate expression to response, we will start the basket study.

The next question is from Reni Benjamin of JMP Securities.

I guess just starting off, the timing for the dose expansion studies has kind of thrown me off a little bit. Can you just give me a sense as to what are the factors that are leading you to think that enrollment would only be complete by the end of 2023? I always assumed that once the dose expansion was done, that the expansion studies would enroll a lot quicker, so if you can give us a sense of that and then I have a follow-up.

Sure. Basically, there are 2 parameters. The enrollment rate that is very different for different indications and CRC by nature is more prevalent, less rare treatment, so it is enrolled faster. There are indications that are harder to enroll, and the pace is slower. So this is one parameter. And also I want to remind everyone, through these studies, these significant study, and we have 20 patients -- per cohort, but we have many cohorts and many studies ongoing. So the total number of patients that we're enrolling is very large.

So it is important for us to make sure that we do this analysis of the DNAM axis in a way where we maximize the opportunities, and that we maintain the leadership in this -- evaluating this axis and also to make sure that these are not only significant studies, so we can really relate to the contribution of components. But let's make sure that we remember that these are not small studies, and we're really enrolling faster, we're on execution. And we restart sharing data in Q4, and these studies will continue to enroll, and we will continue to share guidance and data, but that's the 2 promises, the enrollment and the size of the studies.

And just as I think about news flow, have a sense of obviously, how the news flow from the company is coming out. Could you talk a little bit about maybe your partnership programs, and any sort of a sense as to when we might see news flow from those programs? And I understand, these are partner programs, you might not have as much control or insight into that. I guess just related, you have an early pipeline, I think you have some myeloid candidates and the like, can you give us an update as to how those might be progressing, and when we might see an IND for a new agent?

Sure. So for the partner program, there's the AstraZeneca program, which is a bispecific that is based on our COM902, it's a TIGIT/PD-1 bispecific. And it just recently started clinical studies, and it's obviously, I'd say that now and it's also related to Bayer and you rightly -- so you mentioned that, the progress of this program is really dependent on our partners, and the sharing of information is dependent on our partner. So obviously, we cannot relate to it, but they're progressing. And the Bayer program, the last update that we shared was the fact that it is being tested in combination with Keytruda. So it has there 2 antibodies that is being tested in combination with Keytruda. And Bayer is focusing on first line IO-naive head and neck squamous cell carcinoma. And again, in this case, the progress is dependent on Bayer and they control the news flow, but this program progressing as well.

With respect to our early stage pipeline, so yes, we did not share information about it. I repeat what you were saying and I'll relate to the reasons why we're not discussing it in the public domain. But basically, we're focusing these and number of programs. We're focusing all of them are programs that were predicted by our computational discovery capabilities. Remember, we're not a me too company. We're focusing on modulating the immune suppressive cells in the tumor microenvironment. And we will share information about these programs depending on their development stage and also depending on the competitive landscape. And it is clear to us that it's like PVRIG, right, at the time that we shared information about PVRIG. The clock starts ticking with respect to competition. And you now see it is validating as well the various competitions on new targets that we identified, but we also want to make sure that the development stages as such that we can maintain our leadership.

The next question is from Mark Breidenbach of Oppenheimer.

This is [Jacqueline] for Mark from Oppenheimer. My first question is, are you taking any steps to limit the number of prior therapies for patients enrolling in the expansion cohort versus what we saw in the all-comers study population at the SITC conference?

Henry, I guess you'll address that one.

Yes, I will. We are not taking any active steps to limit the number of prior therapies. If you -- what we're doing actively is sticking with the investigators in ensuring that the subject, the patients were enrolled onto this clinical trials, patients who need all the eligibility criteria for the particular studies that we're doing. And in addition to that, we are also ensuring that they're hitting us for the -- as the eligibility for the clinical trial.

And then the other thing that we're also doing is ensuring that the appropriate therapies have been administered to these patients before they come on to the study. And we look within the investigators very, very frequently, and we review each patient before they come on. Now, if you remember, and I'll just go back to the guidance documents by the FDA. For Phase 1 studies where we're testing, investigation on new drugs, the guidance from the FDA is that the patients who are enrolled onto this studies must have exhausted all available standard-of-care therapies.

Therefore, you can see that depending on the tumor type, the number of prior therapies that patients have been exposed to, it will vary. So including in those instances, where the standard-of-care is shifting, even as we conduct the study. So for example endometrial cancer, where the standard-of-care has now shifted to patients receiving Lenvatinib and pembrolizumab. We do encourage the investigators to do and this is why we speak to them is that when patients have exhausted those available standard-of-care therapies that they consider the clinical trials that we're doing, and they seriously considering this.

So I think that's where the change will come from. So that they are offered the opportunity to enroll on our clinical trials earlier on before they receive other investigational agent. So for example, for the COM902 studies that we're doing, we're ensuring this for the triplet study that we're doing, the same thing for the COM701 pembrolizumab study. So it's ongoing engagement with the investigators that we're insuring.

And my second question is R&D expenses were chopping down in 4Q. How should we think about modeling going forward in 2022?

So, yes, we had a slight reduction in the fourth quarter, it's mostly shifting between quarters, it's a good question. And basically going forward, you should assume that the run rate would be more similar to the third quarter, which was roughly $8 million, $9 million and that's fairly what you're going to see in 2022 as well.

The next question is from Tony Butler of ROTH Capital.

Couple of questions, if I may. The basket trial for -- with the PVRL2 to high level. How are you defining or please remind us how you're defining high? And then I have 2 follow-ups, if I may.

So yes, Tony, thank you. This is exactly what we do now. So we need to explore what does it mean high and low for enrollment. And this is defined in correlation with anti-tumor activity. So we're now evaluating the expression levels as compared to response in all the studies that we have. And when we will set the threshold, we will then initiate enrolling for the basket study. So this is still not being enrolled.

In the doublet for non-small cell lung cancer, it's interesting to enroll the cohort and treat them with the doublet assuming that they have of course failed prior PD-1 therapy, but I am curious, why it may not also be in the triplet? And the second -- and part B to that question, do you think that anti-PD-1 actually drives at least in combination with anti-TIGIT in anti-PVRIG actually drives increased exhaustion for T-cells? In other words, they become no longer I guess, CD8, CD28 positive?

So, I would relate to the triplet first and/or maybe as you eluded from the doublet of the COM701, COM902, there is an PD-1 3 regimen. For the triplet, we focused on the triplets on tumor types that are not responsive to PD-1 inhibition other than the head and neck that is more inflamed as compared to the other indications that we have. We limited the study. It does not mean that we will not expand triplet assessment in non-small cell lung cancer, but at this point in time we're not assessing non-small cell lung cancer in the triplet. Later on related to the triplet or blocking with the free pathways with respect to driving increased exhaustion. Eran?

Yes, so, overall, PD-1 like many other checkpoints are reinvigorating exhausted cells. And PVRIG, actually which fits also an exhaustive cells like other checkpoints. But what's interesting is PVRIG in a more dominant expression is tested earlier differentiation. And these cells normally have higher [refreshing] space. So if you block PVRIG and we start to see some clear early signals into clinical trials, you're able to enhanced interaction of early memory cells less exhausted with dendritic cell. This could induce additional ways of effector cells as we penetrate to micro environment.

And over there the cells probably will adopt a PVRIG and PD-1 triple expression and the triple blockade or maybe in some cases there would be less dominance of cells depart -- maybe the specific doublet could be meaningful. Overall, I think that PVRIG could bring to TIGIT and PD-1 or maybe in some cases, even in the absence of PD-1, to bring treatment options to patients that normally are not responding to checkpoints, because of this unique expression profile and this is now truly biologically clinical.

Last question is around abscopal effects, especially in CRC? I don't know and I don't think this has been addressed. But were any of the patients, stage IV colorectal cancer patients, at least previously treated and importantly, to assuming then by definition, they have liver mets? Has it been determined at all or observed that those mets also were in fact stable and/or were maybe part of that partial response patient that was observed in the previous cohort of CRC patients?

Henry?

Yes. So I will not be able to point to specific patients. But what I can point to is to go back and remember -- remind all of us about the way the assessments are conducted, and that will probably provide a reasonable answer to your question. Just remember to me, when we're using to -- what the investigators are using to determine responses on this various studies that we're doing, and in particular colorectal cancer is to look a resist version 1.1. So in that case, they're looking at patients who have -- especially in the expansion cohort, patients who have target lesions. So all the patients that we have enrolled in the colorectal cancer cohorts, now by definition stage IV disease. So stage IV disease, that means they are disease sometimes in the liver, or sometimes in the lungs, and other particularities also. So, those target lesions are then accounted for in terms of the assessments.

So what we've observed, actually in some of the patients is that investigators have selected some of the stagnations that are either in the liver or in the lungs, and then they measure this lesions and follow them. And this accounts for how the patients responses assessments are then reported with that stable disease, meaning there's no appreciable increase in the size of this target lesions. Whether there is a reduction as in the partial response, we have -- we observed, we reported in that patient with colorectal cancer microsatellite stable, or whether there was progression. So that's the way it's assessed.

And sometimes, some other lesions that are non-target lesions are also reviewed, to see if there is any -- is there any increase in terms of subjectivity for this lesions. So we cannot rule out the abscopal effect in these patients. But certainly, we're looking -- we're using more refined and more established criteria in the assessment of responses in these patients.

Maybe just to add in this regard and actually linking this to the previous comment about the PVRIG expression on every memory cell. So we have recently actually presented in that CRC patients who're responding clinically. We followed up in non-treating biopsy taken from liver metastasis, which is normally an immunosuppressive environment and we have seen a dramatic immune modulation, we have presented that in the last SITC summit.

So we see actually huge increase of an influx of new multi-cell clones penetrating that specific lesion in the liver. And we saw increasing tolerability, increasing immune activation. And this is one of the observations I mentioned, preliminary observation that supports, especially in this indication that normally you wouldn't expect to see this kind of modulation in liver alone. So this is very encouraging to see such immune modulation and increases in infiltration in such liver mets (inaudible) colorectal cancer patients.

The next question is from Daina Graybosch from SVB Leerink.

I'm going to make a statement that I've been thinking about, and I think a lot of the questions are thinking about, you're enrolling a lot of patients, approximately 220. And I think our worry is collectively that you've set the ambition bar so high, because of your belief and being able to have PVRIG stimulate an immune response. And it's harder to treat patient populations, whether it'd be like colorectal or ovarian, or in lung after they've exhausted other IO treatment. So I think the risk that I and I think a lot of us are considering is could you have a good hypothesis and a good treatment, but then you enroll all these patients, and we'd still fail to see a really strong signal, because the threshold is so high?

And I wonder, as you look at that, can you point to any cohort or combination where you think the threshold is not so high, that we are more likely to see a signal? And I'll make an example like with TIGIT, these cohorts had been a role for TIGIT? I don't think we'd be where we are with TIGIT today. We're excited about TIGIT, because, Roche's Genentech did a frontline study, which they could, because they were combining on top of standard-of-care, in which you guys also have standard-of-care Opdivo that you could do a strategy like that with the combinations that include Opdivo, but have chosen not to. So just I'd love for you to react to that statement and tell us all where we could have some optimism that you haven't set the threshold too high.

And it's a very good question, obviously as always. We picked this strategy of going after the mainly the non-responsive patient population, the less inflamed tumor types, the PD-1 nonresponders and yes, in a data driven manner that is based on the -- what we believe is the groundbreaking science that we have in hand. So that's correct and this is the plan. Yes, we do have more inflamed tumor types that are the head and neck and then also certain cancer. But yes, these are -- in head and neck we have IO naive arm, but indeed this is targeting less inflamed.

I will say that as we move forward, all options are on the table for us also to make sure to pursue inflamed tumor types. It was very important for us with this studies that we pursued this time to go ahead and try to address what we think is the edge that we -- that PVRIG may bring to the table. But it is a higher risk. And as a company, we are considering various options and to also lower the risk and all options are on the table now.

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

Yes. Thank you, operator. Thank you for joining us today and your continued support. Stay safe and healthy.

Thank you. This concludes the Compugen Ltd. fourth quarter 2021 financial results conference call. Thank you for your participation. You may go ahead and disconnect.