Compugen Ltd

NASDAQ:CGEN

Earnings Call Transcript 2024-Q3

[Operator]

Ladies and gentlemen, thank you for joining us today. Welcome to Compugen's Third Quarter 2024 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.

[Yvonne Naughton, executive]

Thank you, Joni, and thank you all for joining us on the call today. Joining me from Compugen for the prepared remarks are Dr. Anat Cohen-Dayag, President and Chief Executive Officer; David Silberman, Chief Financial Officer; and Dr. Michelle Mahler, Chief Medical Officer. We're also delighted to be joined by Dr. Oladapo Yeku, Assistant Professor of Medicine, Harvard Medical School and Director of Translational Research, Gynecologic Oncology Program, Massachusetts General Hospital, Boston, who is also an investigator on our triple IO combination ovarian cancer study, which we'll discuss today. Dr. Alan Ofira, Chief Scientific Officer, will join us for the Q&A.



Before we begin, we would 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 potential outcome, the company's discovery platform, anticipated progress and plans, results and timelines for our programs and studies, 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 our SEC filings for more details on these risks, including the company's most recent annual report on Form 20-F. The company undertakes no obligation to update projections and forward-looking statements in the future.



And with that, I'll turn the call over to Anat.

[Anat Cohen-Dayag, executive]

Thank you, Yvonne, and thank you, everyone, for joining us on our third quarter 2024 call. We're fresh back from the SITC conference in Houston, Texas, where we had lots of discussions around our encouraging data presented on COM701, COM902, and Pembrolizumab in patients with platinum-resistant ovarian cancer.



I'm delighted to welcome Dr. Yeko to our call today to be part of our discussion on this data and our development plans. We were able to confirm in an additional cohort of platinum-resistant ovarian cancer patients, the data we previously presented supporting our triple blockade hypothesis. We're highly encouraged by the consistency of the data between our 2 platinum-resistant ovarian cancer studies, demonstrating COM701-driven activity and safety in more than 40 advanced and heavily pretreated patients.



When looking only at the overall response rate, we recognize that the 20% range may not be considered high. However, it is important to consider that this study was in a patient population with historically poor clinical outcomes and typically not responding to immunotherapy. What stands out in the totality of this data, consistent with other data we have presented is the durability of responses and the good tolerability of the drug combination. This was also exemplified in one of our prior studies evaluating COM701 as a single agent where we reported a disease control rate of 67% in 6 patients, including a partial response lasting more than 18 months in a patient treated with COM701 for 24 months.



In addition, the translational data supporting a robust pharmacodynamic activation of the immune system further reinforces a COM701-driven effect. This overall data in advanced disease indicates that PVRIG has a clinical relevance in this indication and supports further development of COM701, but in a path where we would expect its unique mechanism of action to be most effective.



An earlier setting of ovarian cancer where there is a significant unmet need and where the disease biology fits COM701 mechanism of action offers such an opportunity. I will now explain the rationale supporting this.



Firstly, there is a gap in care for maintenance therapy in relapsed platinum-sensitive ovarian cancer patients where safe and durable treatment options would have an advantage for women who have received prior maintenance treatment and have no options for additional maintenance treatment. COM701's durability and tolerability profile may fit this maintenance therapy need and has the potential to be highly differentiated in this setting and consequently, may face less competition.



Secondly, these patients are less heavily pretreated than more advanced patients and therefore, are less immune compromised, providing the opportunity for COM701 immunotherapy to harness its unique mechanism of action to potentially increase the time to disease progression and change the trajectory of the disease. In addition, platinum-based chemotherapy has been shown to induce tertiary lymphoid structures and T memory stem cells and therefore, has the potential to sensitize the tumors of the patients previously treated with chemotherapy to COM701 by leveraging its unique mechanism of action on these cells.



Advancing COM701 in this maintenance setting of platinum-sensitive ovarian cancer has a strong clinical and biological rationale and it also takes into consideration the less competitive landscape. Our trial is planned to be an adaptive platform trial in relapsed platinum-sensitive ovarian cancer patients who have received at least 2 prior lines of platinum-based chemotherapy regimens and are not candidates to receive standard-of-care maintenance treatment.



Our development approach will be stepwise, starting with a randomized double-blinded sub-study initially enrolling 60 patients who will be randomized 2:1 to COM701 monotherapy or placebo. The primary endpoint will be median progression-free survival, where the placebo benchmark is expected to be approximately 6 months. Such a platform design allows for assessing COM701 as a single-agent maintenance therapy and for opening additional substudies in the future, providing a regulatory and commercial opportunity.



Additional substudies would permit the evaluation of COM701 as a backbone treatment in combination with agents like anti-PD-1 TG checkpoint inhibitors, further testing our DNA triplet combination hypothesis. Additional substudies would also permit exploring additional combination options like bevacizumab, PARP, ADCs, or others potentially with partners to extract the full potential of COM701. As part of the platform design, we plan to continue employing exploratory assessment of various potential biomarker enrichment strategies.



We are encouraged by the feedback from ovarian cancer experts who have been very supportive of this selected path forward. We plan to initiate the trial in Q2 2025 and expect to have data from the interim analysis of the randomized COM701 maintenance therapy arm in H2 2026.



This development path ticks all the boxes we believe are important for the development of COM701. It has a strong biological and clinical rationale, may open the door for partnering options for various combinations, and enable engagement with regulatory authorities to agree on a registration path. Importantly, it also makes sense from a financial perspective, allowing a gradual investment in future additional combo arms, while we focus on COM701 as a backbone.



Cash runway, assuming no further cash inflow is expected to suffice into 2027 and anticipated to reach potential key catalysts, including projected COM701 mono study interim analysis and support of advancement of COM503 in the clinic, together with continued investment in our earlier pipeline.



Before handing over to David to run through the financials, I want to briefly relate to the other great progress we had this quarter.



Starting with COM503, our differentiated approach to harness cytokine biology to treat cancer, which is partnered with Gilead. In the third quarter, we received a $30 million milestone payment from Gilead for achieving the FDA IND clearance, and we are on track to initiate the Phase I study in this quarter. And we were excited to see presentation of data at the World Conference of Lung Cancer and ESMO showing promising efficacy and a manageable safety profile in both lung and gastric cancer from our partner, AstraZeneca's Rilvegostomig, their PD-1 TIGIT bispecific, where the TIGIT component is derived from our Fc-reduced COM902.



In addition, AstraZeneca recently announced its fourth and fifth Phase III trials with Rilvegostomig, TROPION-Lung12, which will assess Rilvegostomig as monotherapy or in combination with ADC Dato-DXd as adjuvant therapy in patients with high-risk early-stage resected non-squamous non-small cell lung cancer and ARTEMIDE-3, which will assess Rilvegostomig in combination with chemo compared to Pembro and chemo in frontline non-squamous non-small cell lung cancer expressing PD-L1.



This broad development strategy of Rilvegostomig by AstraZeneca represents a significant potential revenue source for Compugen as we are eligible for both future milestone payments and mid-single-digit tiered royalties on future sales. With that, I will hand over to David for the financial update.

[David Silberman, executive]

Thank you, Anat, and good morning and afternoon to everyone. I would like to start by saying that I'm extremely pleased to be here today as part of Compugen team. I will now summarize our financial results and start with our cash balance.



As of September 30, 2024, we had approximately $113.2 million in cash, cash equivalents and investments compared with approximately $51.1 million as of December 31, 2023. Our cash runway is expected to fund our current plans into 2027. The company has no debt.



Revenues for Q3 2024 were approximately $17.1 million compared with no revenues for the comparable period in 2023. The revenues reflect recognition of a portion of the upfront payment from the license agreement with Gilead and of the $30 million milestone payment received from Gilead for COM503 IND clearance achieved in July.



Expenses for the third quarter of 2024 were in line with our plan. R&D expenses for the third quarter of 2024 were $6.3 million, reduced from $8.3 million in the third quarter of 2023. The decrease is mainly due to the classification of COM503 R&D activities to cost of revenues, coupled with lower COM503 expenses mainly related to CMC.



Our G&A expenses for the third quarter of 2024 were $2.6 million comparable to $2.3 million in the third quarter of 2023. For the third quarter of 2024, we recorded a net profit of $1.3 million or $0.01 per basic and diluted share compared to a net loss of $9.9 million or $0.11 per basic and diluted share in the third quarter of 2023. With that, I will hand over to Michelle to go into more details on the data and moderate the fireside chat results with Dr. Yeku.

[Michelle Mahler, executive]

Thank you, David. I'm very happy to provide an overview of the encouraging data, which Dr. Yeku presented at SITC last Friday, and I'm delighted to be joined by Dr. Yeku to discuss the significant unmet medical need in ovarian cancer and his experience with using the triple combination of COM701, COM902 combined with Pembrolizumab to date and the future opportunity for patients.



I think we all know that, without doubt, the diagnosis of cancer is frightening with the drug of treatment and its associated toxic side effects. There is significant unmet medical need for women with ovarian cancer who could benefit from alternative, potentially safe, tolerable, efficacious and durable treatment options. Using our computational capabilities, we identified ovarian cancer as high-priority indication for PVRIG blockade, justifying the initiation of our first study evaluating the triplet blockade of anti-PVRIG TIGIT and PD-1 antibodies in platinum-resistant ovarian cancer patients. Given the significant unmet need in these patients, investigators were excited when they reported durable shrinking or stabilization of tumors in a small number of patients.



The goal of the ongoing platinum-resistant ovarian cancer study was to assess whether we could demonstrate a similar clinical benefit in triplet the combination of COM701, COM902 and our Fc-reduced anti-TIGIT and the anti-PD-1 Pembrolizumab in another cohort of platinum-resistant ovarian cancer patients a validation of our previous findings.



The data Dr. Yeku presented at SITC in platinum-resistant ovarian cancer patients included 25 patients treated with the triplet combination of COM701, COM902 and Pembrolizumab. Patients were heavily pretreated with a median of 4 prior therapies and had no alternative treatment option. 80% of patients had prior bevacizumab and 68% had prior PARP inhibitor. Notably, 34% of patients had prior treatment with either an ADC or other investigational agent, suggesting that they had limited treatment options prior to entering the study and were thus heavily pretreated with advanced disease.



The characteristics of this study population are similar to the prior presented data set where most of the patients had a histology known to be immune checkpoint treatment resistant. However, patients in this study had more advanced disease as most of them had had prior exposure to PARP inhibitors as well as ADC and other investigational agents than in the previously reported study.



The objective response rate was 17%. All responses were confirmed with disease control rate of 46%, including the patient with a complete response, 3 patients with partial responses and 7 patients with stable disease, one of whom presented with a target lesion of 29.6% reduction in their last tumor assessment and is still on study treatment, 5 of the patients were on treatment for more than 200 days and 4 patients remain on treatment at data cutoff, including the patients with the complete response. This data excites us as it confirms that what we previously presented. COM701 is active and safe and particularly notable of the durable responses and the good tolerability profile.



Also important to remember that these are advanced heavily pretreated patients who historically have not been responsive to immunotherapy with overall response rates of less than 10% reported in the past for PD-1 blockers or with a combination of PD-1 TIGIT blockade in a similar setting. In terms of safety and tolerability, the triple combination showed a favorable safety profile and was well tolerated. The majority of treatment-emergent adverse events were grade 2 or less. There was one serious Grade 3 immune-related encephalopathy resulting in treatment discontinuation. There were no grade 4 or 5 treatment-emergent adverse events. Treatment-related discontinuation was 4%. This safety profile contrasts to the well-known toxicity associated with chemotherapy and stacks up well compared to the SMART chemo ADCs.



The totality of our data confirms that COM701 is active and, importantly, that durable responses and a good tolerability profile observed justify the further development as monotherapy and in combination in platinum-sensitive ovarian cancer, a setting which is particularly relevant for immunotherapy as the immune system is less compromised, lending to an opportunity for COM701 to change the course of disease.



In addition, the favorable safety profile of our drugs becomes an even greater point of differentiation in this earlier setting and as a maintenance regimen. I would like to extend our sincere thanks to the investigators, study staff, patients and their families for participating in our clinical trials. It is my pleasure to welcome Dr. Yeku for a short fireside chat to discuss the data just presented and our future development plans. Welcome, Dr. Yeku.

[Oladapo Yeku]

Thank you so much for having me.

[Michelle Mahler, executive]

I will start with my first question. Would you please briefly describe the current treatment landscape for patients with ovarian cancer moving from platinum-sensitive to becoming resistant in ovarian cancer?

[Oladapo Yeku]

Thank you, Michelle. I think it's important to establish that unfortunately, despite our best efforts, most patients with advanced ovarian cancer are going to relapse. And the first relapse a lot of these patients have is referred to as platinum-sensitive disease, which indicates that the very least their disease was suppressed for a minimum of 6 months from their prior platinum-based chemotherapy. These patients are typically retreated with a platinum-based combination, usually a doublet or a triplet with bevacizumab. And unfortunately, because of the relentless progressive nature of this disease, these patients inevitably progress to a platinum-resistant state, which means that over time, that interval, we call it the platinum-free interval, decreases such that it's less than 6 months, at which time these patients are subject to, in the past, chemotherapy and now more recently, antibody drug conjugates, mirvetuximab being the prime example.



The key thing to remember is that in patients with platinum-sensitive disease, most of our efforts strive towards preventing that inevitable progression to platinum-resistant disease. And this has been an area where we've explored several types of maintenance therapies, again, to preserve quality of life, to preserve function. And as to date, only bevacizumab is most commonly used. There used to be an indication for PARP inhibitors, but this has become more restricted as late. Thank you.

[Michelle Mahler, executive]

Can you comment a little bit more about the restrictive of late as well as some of the challenges and bothersome toxicities that your patients point out to you?

[Oladapo Yeku]

Of course, so one of the reasons that we had continued to explore other maintenance therapies is because of the side effects of bevacizumab. Now I mentioned that triplet therapy in combination with carboplatin and another chemotherapy is typically used in platinum-sensitive disease. What is typically swept under the rug is that with bevacizumab, a lot of our patients have side effects such as migraines, myalgia and arthalgias, they have no sleeps. And that's -- those are the more common ones. They are the more serious side effects, perforations, fistulas, strokes, heart disease, which, again, because of our patient population that tends to be more above 65 tends to be serious concerns.



For this reason, we explored several other types of maintenance therapies, including PARP inhibitors. PARP inhibitors that initially showed promise when patients with BRCA mutations and homologous repair deficiencies were exposed to this drug, it showed a lot of promise. So we moved these drugs into the platinum-sensitive and platinum-resistant setting. But unfortunately, as the data continue to mature over time, we found that for the vast majority of these patients, especially the ones that do not harbor these mutations, PARP inhibitors could actually be detrimental. And this led to FDA withdrawal of several indications for PARP inhibitors.



For the patients who are candidates for PARP inhibitors, there is concern for myelodysplastic syndrome and AML later down the line, our rates have increased because of our use in this disease and their day-to-day side effects. These drugs cause significant fatigue, their cytopenias. In fact, many of our patients who receive PARP inhibitors and bevacizumab in the upfront setting where it's FDA approved, really count down to the 24 months when they can be complete with these therapies and move on.

[Michelle Mahler, executive]

Wow, does not sound very good for those patients. So let me switch gear with that background in place. What are some of your key takeaways from our triplet study with COM701, COM902 and Pembrolizumab in patients with platinum-resistant ovarian cancer, which you presented at SITC last week? What specifically excites you about the data? And then are there any anecdotes you could share with us from some of the patients that you've treated?

[Oladapo Yeku]

Of course. So many of the patients that we treated on this study were patients for whom single-agent chemotherapy. So these are patients with platinum-resistant disease, which I mentioned, have only antibody drug conjugates like mirvetuximab if they have the requisite folate receptor expression or chemotherapy. And single-agent chemotherapy in this particular setting, the response rate outside of weekly taxol is around 10% but the vast majority of these patients were looking at toxic chemotherapy with low response rates and low durability of effect, which is what in part spurred the enthusiasm for participating on this study.



Now the key thing that excited me about this study was the potential for long-term benefit. And this has always been a key power point in many of our therapies for relapsed ovarian cancer. Even in our drugs that have high response rates, let's say, the weekly taxol, I mentioned, with 35% response rate, 30% to 35% response rate, ignoring the toxicity of weekly taxol, the durability leaves a lot to be desired, the average being about 6 to 8 months.



Let's fast forward and look at mirvetuximab, which is currently approved for patients with high folate receptor, and that shows improvement in overall survival. But however, the median PFS is still 6 months. So these patients is always a great concern that even when I have drugs that have high response rates, durability is an issue. So this study, based on our prior experience with other COM701 trials, I knew always had the prospect for durable effect. And this was one of the things that really excited me about this study.



I'll leave you with 2 anecdotes, our 2 particular patients that come to mind. The first one that I counseled on this study, I had warned them that typically with immunotherapy, at least our experience to date, patients had to wait a few months until they had symptomatic relief from their disease because the paradigm had always been that immunotherapy takes a little bit of time to get going. And so my pleasant relief, this particular lady who had significant abdominal pain was, in fact, on opioids when she started the study, had pain relief within a matter of weeks. So even before she received her second infusion or a second cycle of treatment, her day-to-day life, which is what I really, really focus on in the platinum-resistant setting, was already getting better. She's able to get around more, take less opioids and in turn, had a better quality of life. So we knew that this was somebody who was going to have a positive outcome on the study right away. She didn't have to wait.



The second anecdote that I'll leave you with is one of the sobering things as a physician taking care of these patients is watching a degradation in their quality of life. We treat somebody with newly diagnosed disease, they get better, they finish maintenance therapy or they forgo maintenance therapy, the disease comes back. They're a little bit weaker, a little bit more depleted. We treat them again in that platinum-sensitive setting. And we continue this process into the platinum-resistant setting, where we've watched people sort of lose their function, degrade and be worn down over time.



And in many cases, most of my patients, by the time they reach that platinum-resistant setting, they're retiring from their jobs, even though they don't want to, they're withdrawing or quitting activities that they otherwise loved. I have patients who stop driving when they start taking mirvetuximab because they're afraid of ocular toxicity and the ability to drive at night, for example.



One of the nice things about this study is that I was able to have a patient who -- we had the same conversation, I said, "Don't quit your job quite yet. We haven't seen a lot of toxicity with the COM701 triplet in prior studies. I'm optimistic that you can cautiously continue to work and let's see how you do." And to my relief, this was also another patients who remained on study for a very, very long time and walked throughout the process. Every week or so, she sent us a message and say, "I'm waiting for side effects. I'm not even nauseous. I don't have to take any preliminary medications for my infusion. I just show up, get my treatment. I go home, I get back on my laptop. The next day, I'm back at work. I've not lost my hair." But I think both of those stories, and there are several others, but both of those really gave a lot of hope. And I think it's those one-on-one stories, patients you know by name, you know their family, that really, really keep you in this area of drug development.

[Michelle Mahler, executive]

Wow. I'm really glad to hear that these patients did well. Can I transition a little bit and just help those on the call to understand a little bit more about the background of this particular patient population from the data that was presented at SITC? Can you comment on the relevant baseline characteristics, including the prior exposure to antibody-drug conjugates and the investigational agents as well as the patient's histology and the responses observed in this patient population?

[Oladapo Yeku]

Of course. As I mentioned, I think, in one of your prior questions, these were patients for whom we had exhausted most reasonable treatments. And in this case, meant that most of them have been exposed to bevacizumab, either in the upfront setting or in the platinum-sensitive setting or even in [indiscernible], they've all been exposed to bevacizumab with all of its toxicities.



Many of these patients have also been exposed to PARP inhibitors. And because of when the trial started, we've also seen patients who have progressed on PARP inhibitors. Again, remind you that these are PARP inhibitors that -- excluding mirvetuximab, that have been shown to have overall survival.



So in the real world, these patients are still coming off and then becoming like any other platinum-resistant patients for whom the only options left are chemotherapy or investigational drug. And we had a few of those patients represented here as well. The key histologies are representative of the people we treat in clinic, which is high-grade carcinomas or high-grade epithelial cancers. And many of them were not patients who harbored germline or somatic BRCA mutations. So again, these are patients that we know wouldn't have been rescued very early on with PARP inhibitors and have generally very aggressive disease.



Now this study also captured patients in real life. So if we look at some of the eligibility criteria on the study, including hemoglobin levels of around 8, creatinine class of around 40,000, platelets of 50,000, these are the patients that you meet in the platinum-resistant setting. These are not sort of your early platinum-sensitive patients, your patients with -- who have not been exposed to multiple lines of treatment. And the fact that we were able to see the responses that we did in this almost real-life population of ill patients who had very few alternatives, I think is very important to highlight.

[Michelle Mahler, executive]

Yeku, I wanted to just pick on something else here in terms of thinking about -- before we talk about -- a little bit more about future plans and what could be exciting, I wanted to just ask you again to think about if you had a choice, especially with the emerging landscape, what are some of the reasons that you would maybe choose COM701 or a combination with COM701 versus the antibody drug conjugates with ovarian cancer? And where would you see the use of such agents in the course of the patient's journey?

[Oladapo Yeku]

I think it comes down to toxicity and tolerability, Michelle. I'll remind people on the call that in the past, we've actually tried maintenance therapy with more chemo, lower dose chemo given with different schedules because we really wanted to prevent recurrence. And what we found was that even though you can stretch it out a little bit by just giving you the same chemo you gave at a lower dose or a gentler schedule, the side effects became so cumulative that people could not reasonably get on with their daily lives. And antibody drug conjugates, we're all grateful for them. They've solved some of our temporary problems, sort of our urgent problems in ovarian cancer, but they're still toxic drugs, and you have to pick the domain of toxicity.



For some patients, every time they have a cough, they're worried about pneumonitis. That is no way to live your day-to-day life. Ocular toxicity is real. And many of my patients, as I mentioned to you before, are very concerned. They don't drive at night anymore. They're very concerned about degradation in their vision. They live alone, they take care of themselves. It's a real concern.



So any treatment that has a very tolerable schedule, it's not a daily or a weekly infusion. It has side effects where people can continue to work really fits the best definition of maintenance. And even with the newer ADCs, where we don't tend to see a lot of pneumonitis or a lot of ocular toxicity or hepatotoxicity, we're seeing decrement in blood counts. So these patients every now and then will get anemic and will need transfusions. And already by itself, these are side effects that impact people's daily function.



So to my mind, the best we could have done with maintenance therapies was bevacizumab and already elucidated some of the side effects of that. But having a drug that has the potential for that combined or clinical benefit rate or disease control rate like we've seen with the COM701 combinations but yet have the side effects that allow people to continue to live their life, I think for me, it's what we've been looking for, for a very, very long time, both in the upfront setting and more urgently in the platinum-sensitive recurrent setting where we don't have many options.

[Michelle Mahler, executive]

So you just touched on my next question because as you heard earlier, we are moving forward with respect to a follow-on study evaluating COM701 in a relapsed platinum-sensitive setting for maintenance. So I wanted to touch on a little bit with you in terms of what are the various elements that excite you about this and also understand your thoughts in terms of this setting as the target population for our study. And do you believe that there is potential to change the course of disease? What would the impact to this patient population, be by increasing the PFS and hopefully delaying them from becoming platinum-resistant?

[Oladapo Yeku]

Of course, Michelle. So there are 2 big things in my mind. And the way I think about this is in 2 big domains. One is thinking about in immunologic terms, the host or the patient, these are people we live with, the people we know. As I mentioned, as they go through each round of chemo, as they go through diagnosis, recurrence after recurrence, people's lives change. They get weaker, they get frailer, their bone marrows are exposed to round after round after round of cytotoxic and myelotoxic chemotherapy. We know that this affects the immune system and affects the ability to mount responses to common illnesses. And for the same reason, there is early data or early translational data that associates sort of worsening response to immunotherapy, the further out you go.



Many of our fledgling immunotherapy studies, when you break them down by platinum-sensitive versus platinum-resistant, universally, the response rates and the benefits are greater in the platinum-sensitive setting. When you break them down by number of lines of therapy, less than 3, greater than 3, universally, all of them have shown a preference for fewer prior lines of cytotoxic treatment. So we know that there's something about the immune system, something about the bone marrow, something about the lymphoid compartment that changes with each subsequent exposure to chemo. That's the first big thing.



The second thing is the disease itself. With each iteration or each exposure to chemotherapy, the cancer gets worse. We know this from [indiscernible] reduction surgeries where we find organizing stroma, organizing fibrosis even after 3 cycles of chemo. So we know that with each subsequent exposure, the tumor evolves for the worst. And anybody who knows somebody of taking care of somebody with cancer will tell you this. This is something a [ little ] person will observe that with each line, each exposure, each recurrence, both the patient in immunologic terms of host and the disease itself sort of diverge in opposite fashion leading to worse outcomes.



The advantage of moving a less toxic maintenance option treatment to an earlier setting means we can capture people when they're at their best, right? We can give them drugs, maintain them, keep them in their homes, keep them working, keep them engaged with the family, stave off the disease. And in solid tumor oncology, that is really the next best thing to curing somebody is where you can achieve some sort of either a stalemate, if you will, where the person converts their trial cancer into a chronic problem like you might consider diabetes or hypertension, where it's stabilized in the background, but yet people are able to function.



And in so doing, we are hopeful that we can also alter the disease biology because now that we're not giving chemotherapy, the patient has more function, they have more vitality. And then the evolution mechanisms that the tumor has to employ, mutations, et cetera, to get through chemotherapy also does not get deployed. So we see less cachexia, less sort of fatigue and all of these other things that eventually culminate in patients who are heavily pretreated. That is really the hope, and that's how I see this, Michelle.

[Michelle Mahler, executive]

Thank you so much, Dr. Yeku I really, really appreciate your insight. To summarize, I want to thank you for helping us to put platinum-resistant and sensitive ovarian cancer into context as well as understand the evolving landscape and the different drugs that are being used as well as helping us to understand our results in this context and also the place for us to go next with respect to our maintenance future study.



Also very grateful to the patients that have participated on our study and for the support that you have provided, and we really look forward to continuing to work with you. Now I will turn the call over to the operator for questions.

[Operator]

[Operator Instructions] The first question is from Stephen Willey of Stifel.

[Stephen Willey, analyst]

Michelle, I think you may have been mentioned in terms of the number of prior platinum lines that you would be requiring for the proposed Phase 2, but could you just remind me what that number is?

[Michelle Mahler, executive]

Sure. So we will be targeting patients who have had 2 prior lines of chemotherapy with platinum-containing regimens and the patients must have either have had maintenance with bevacizumab or a PARP inhibitor and not be a candidate for additional maintenance therapy with a bev or PARP. So this basically addresses predominantly the third-line patients, but there may be exceptions in the second line where patients may not be eligible for conventional or standard-of-care maintenance and wish to get maintenance therapy with our study. Do you have any additional questions?

[Operator]

The next question is from -- there is a follow-up question from Stephen Willey of Stifel.

[Stephen Willey, analyst]

Yes. Sorry about that. I think the operator dropped out of the queue. So just given you're going to be pursuing third line, and I'm not sure if Dr. Yeku is still on the line and can answer this, but what's your understanding of the proportion of patients who get to third line are still platinum-sensitive and have exhausted prior bev and/or PARP within the maintenance setting?

[Michelle Mahler, executive]

So I'm just going to check if Dr. Yeku is on the line and would like to take that. Otherwise, I'm happy to answer.

[Oladapo Yeku]

Okay. I can offer an opinion. So the vast majority of patients will progress. We do have a very small population of patients after diagnosis, they get chemotherapy and their first recurrence is platinum-resistant. That is a completely different biology that is horrible to see in clinic. Fortunately, that is relatively rare. Most patients will have a platinum-sensitive recurrence first. And then over time, after that therapy is exhausted, become platinum-resistant. So the vast majority of the patients, especially the ones with Stage 3 and Stage 4 on diagnosis, which also incidentally are the most common stages of diagnosis for ovarian cancer, will, at some point in their journey go through a platinum-sensitive phase.



Now we've brought up because of the concerning indications for PARP inhibitors that I mentioned before, most patients will have had their PARP inhibitor actually with first-line maintenance. That's where we think it has the least amount of risk or the least amount of danger. So most patients would have had it there and many patients with Stage 4 disease on diagnosis, especially those who might have ascites or plural fusions would have already received bevacizumab. So the vast majority of patients in that first-line platinum-sensitive setting, which is the second line of therapy, we always cut the first one, would have been exposed to either PARP or bevacizumab.



There may be a few who declined a PARP inhibitor because they didn't have any germline mutations or those who declined bevacizumab because of concerns for toxicity, choosing to reserve it for the platinum-resistant setting. But the vast majority of our patients will be passing through at platinum-sensitive waypoint, and many of them would have received either a PARP inhibitor and/or bevacizumab if they were HRD positive.

[Stephen Willey, analyst]

Okay. And then maybe just for Anat and Michelle again. I know you're pursuing the single-agent development path here. I know you mentioned there may be an opportunity to potentially build on combo. So is this really an opportunity for you to kind of get a better understanding of what the single-agent activity of COM701 in this setting is and then perhaps look to layer on additional combination-based therapies once you have that data?

[Anat Cohen-Dayag, executive]

Yes, that's as well. And Michelle, feel free to add. But for us, it is really a great opportunity in this patient population to try that are getting nothing to try to start with single agent that may open a path for us for monotherapy, but irrespective to that, it opens the door for the contribution of effect for mono and have a COM701 centric design where we go into combination. So it really tick all the boxes for us from a clinical perspective and potentially regulatory perspective.

[Operator]

The next question is from Daina Graybosch.

[Daina Graybosch, analyst]

Two questions for me. The first, and I'll take them one at a time. The first is, can you remind me, Dr. Yeku and Michelle, what we learned from trials with PD-1 or PD-L1 antagonist? I seem to remember that there were some relevant similar trials with bevacizumab. So what's already been done? And what did we learn about those trials in this setting?

[Oladapo Yeku]

I can offer a response. So we've done multiple different combinations. Monotherapy is a nonstarter. I wouldn't even discuss that. It's bad. We've done combinations with other immune checkpoints. We've done combinations with bevacizumab and combinations with chemotherapy in multiple different lines. And the common lessons that we've learned is that in some patients, responses can be durable, although response rates overall are typically very low, generally around the 10% to 14% range for your PD-1 class drugs in combination.



However, some of these patients will have long durable responses. What we've also learned is that the number of lines of therapy, as I mentioned before, really matter. Many of these drugs are developed in the deep platinum-resistant setting, heavily pretreated patients, 6, 7 lines in, which is not what we did here, but that's where we typically started. And we found that those patients tended not to respond very well. But still, 1 or 2 of them would have long-lasting responses. When we moved it up a little bit and started testing platinum-sensitive and/or platinum-resistant, we saw better responses, and we saw more durability. So we made the connection also, again, the second lesson is that the earlier you use it in the less sick patient, earlier in their course of disease, the more likely you are to have a benefit.



In terms of our exploration with different combinations, the effects have been mixed. When we combine it, for example, with PARP inhibitors, we get a little bit more response rates. The progression-free survival is still around the same, maybe boosted by a couple of months, but you pay the upfront cost of PARP inhibitor toxicity upfront, which led to less excitement with those combinations. We've combined it with bevacizumab. In fact, our only compendium-listed combination right now is a combination of oral cytoxan, which is a type of chemotherapy plus bevacizumab plus pembrolizumab.



And again, many of those patients have long-lasting benefits, but at the cost of the side effects of bevacizumab and oral chemo. Some patients refer this to weekly taxol. So we've learned in summary, that the earlier we use immunotherapy, especially with checkpoints, the better. We've learned that some of these patients will have durable long-standing responses at the cost of decreased response rates overall. We've also learned that if you want to boost response rates, we can combine it with other things, but then we have to allow for the toxicities associated with those combination partners.



One final example is that our most recent study was the combination of ipilimumab and nivolumab, and many of you will have experience with both of these drugs. And again, like I said, with combinations, we saw improved response rates up to 30%, again, approaching chemo, but the response rates were progression-free survival was in the range of like 3 to 4 months. So again, nobody wants the toxicities of colitis, et cetera, with CTLA-4 inhibition just to be on the study for 4 months, which if you put yourself in a patient's perspective, that's really one scan, thinking about it. So again, there's been a little bit of skepticism around where next to go with that. I hope that answered your question.

[Daina Graybosch, analyst]

Yes, it does. And maybe one specific follow-up. Were any of those studies in this exact same setting sort of the second to third line platinum-sensitive maintenance setting?



No. The maintenance space after platinum has been really, really lacking in terms of drug development. We haven't done a lot of maintenance trials. The closest I can think of is a study that looked at cisplatin gem and Pembrolizumab in the platinum-resistant setting. So not quite the same thing, but the idea was that they would use the cisplatin and the gem chemo, almost like you would use the platinum agent and then you continue the Pembrolizumab as a means of maintenance. But this was also in the sort of the platinum-resistant setting. So they got a higher response rate, but the durability of response, progression-free survival was around that 5 months again, which is typical for what we see in the platinum-resistant setting.



So they felt that the toxicity of cis and gem wasn't really worth the whole ride. But we haven't looked at sustenance. We've looked at it in upfront setting, newly diagnosed disease with PD-L1 combination. I think you mentioned [indiscernible] or somebody did. And those trials were not futile.

[Anat Cohen-Dayag, executive]

Eran, maybe just before the next question, while we're looking at it from a PD-1 angle, maybe you want to say why we believe COM701 should be employed in this setting and why we believe it should work there?

[Eran Ophir, executive]

Yes, sure. So as Dr. Yeku mentioned, yes, some patients do respond to PD-1 therapy. Mostly, this will occur if you have sufficient T cells and tumor environment, the PD-L1 CPS above 10 or above 1 at least. And -- but most of the patients aren't. And that's why eventually PD-1 checkpoints have failed in these settings, and this is not going to be the way for us. And PVRIG, which we have shown and actually published quite recently, has a very, very different biology than PD-1.



Yes, it's a T cell checkpoint, but actually because of its unique mechanism of action, driving activity in stem-like memory T cells, which are very strong proliferative potential. PVRIG blockade has the potential to drive T cells into in these really difficult indications also in the PD-L1 negative patients. And even though we didn't test it in many patients, this is what we have seen. We had the patients with PD-L1 negative ovarian cancer that responded to PVRIG blockade monotherapy.



And we also had other patients tested in monotherapy and almost all of them were modulated immunologically by COM701 monotherapy. So we do think that the PVRIG blockade has a very different biology and has the potential to change disease course, especially in the earlier settings after that platinum-based chemotherapy that was also shown to induce TS and TSCM and that synthesize the tumor to PVRIG blockade effect.

[Operator]

The next question is from Tony Butler of Rodman & Renshaw.

[Tony Butler, analyst]

Dr. Yeku, if you're still on or Michelle, if, in fact, the median progression-free survival in the setting for which you're moving 701 into, that is in the platinum-sensitive case is 6 months. But what's the most ideal PFS to suggest that an agent is clinically relevant. And I understand you're going to make comments around durability and as well as adverse events, I'm respectful of that. But most importantly, what would that PFS need to be? Is it 8 months? Is it 10 months, et cetera? That's question one. And question two is, in enrolling the 60 patients, is it necessary actually to engage the GOG such that in theory, I guess, speed of enrollment would be rather rapid?

[Michelle Mahler, executive]

Okay. I will take that. So we don't actually know the effect size. However, usually, and it's a bit of a rule of thumb, we want to see at least a three month improvement over the control arm. So we are aiming for beating the observation arm or the placebo arm by 3 months. As far as the GOG goes, we have engaged key opinion leaders who are heavily involved in the GOG. However, they tend to support later-stage development, and this is still a relatively small study, but we are in conversations with several of those investigators.

[Oladapo Yeku]

Michelle, if I might add to the clinical relevancy discussion. So I mentioned before that these patients progress from platinum-sensitive to platinum-resistant. And what that means is that after each line of therapy, their interval decreases. So the first time the cancer comes back, maybe it might come back 8 months later, then they get platinum plus something. The second time it comes back, it comes back 4 months after they finish that therapy, and that's when they make that transition.



For many patients, if we get them to that 9 month mark, 8, 9 month mark, what that means is that you've kept them platinum-sensitive. So ignoring the debate of what's tolerable and what's clinically -- what people live day-to-day, by keeping patients in that platinum-sensitive bucket, that means they're eligible for almost a reinduction with platinum with a different maintenance agent or with something else.



It's when patients -- it's when we do nothing to alter that decreasing window and it tips less than 6 and now they are platinum-resistant. That's when we know, at least based on all of our older PFS data, the biology changes, and that's when the clock really starts to tick down. So I think anything above 6 months as you approach 8, 9 months, making them really platinum-sensitive again or maintaining the platinum sensitivity becomes meaningful. In fact, we have data that patients with a platinum-sensitive interval greater than 12 months live longer, do better than patients with a platinum-sensitive interval of 6 months. Both are platinum-sensitive, but the more platinum-sensitive you are, the better. So that 8, 9 months is what we shoot for clinically.

[Operator]

The next question is from Asthika Goonewardene of Truist Securities.

[Asthika Goonewardene, analyst]

I apologize upfront I joined the call late because it's a heavy earnings day for us. So apologies if this has been addressed already. Could you maybe talk a little bit about any development in the biomarker understanding here for [indiscernible] going into this Phase II study? And if there's any sort of -- what you'd be looking for and any sort of analysis you'd be looking to do there or cutoffs to implement? And then a rudimentary question, why does TIGIT biology not make sense to also address in this Phase II study? And if you could also maybe provide any agency feedback on this as well of the Phase II, that would be great.

[Anat Cohen-Dayag, executive]

So I'll let Eran relate to the first two questions, and then Michelle relate to the FDA part.

[Eran Ophir, executive]

Yes. So yes, thanks, Ashik. Obviously, it's a very important point because as mentioned before, a fraction of our patients, roughly 30%, did have clinical benefit, while some of the others actually progressed so fast that the IO probably never had a chance to have an impact to begin with. And we all know that the biomarkers in IO is extremely challenging. It's not like in the case of ADCs in which the target for the antibody is the biomarker itself. And now it's more complex.



And we did have this initial signal of PVRL2 as a potential biomarker, and we followed up in this study. And after 40 patients, we still don't have enough to enrich in the platinum-resistant setting. So one approach would be to enrich for these patients indeed by looking for the biomarker PVRL2. And at this point, the of the data is not enough to have an enrichment-based prospective study. So what we did, we are going now to an earlier setting in which we -- the patient should have a more sufficient immune system and all the other attributes we discussed before.



So actually, we are needing for response by the design -- the study design and not by the biomarker itself. But we are going to continue to follow up because we did have this trend, and we also added again another indication. So we are going to continue to follow up also in the coming study on PVRL2 and some other biomarker potential. So the opportunity to have a biomarker and to substantiate this biomarker still exists for the future studies. But for the coming one, again, we're not going to have it.



For TIGIT biology. So first of all, we think -- and I think 5 different randomized Phase II studies have shown that TIGIT blockade is active. But what we currently know, TIGIT is active when you have sufficient amount -- as I mentioned before for PD-1 blockade. -- when you have sufficient amount of T cells into a microenvironment. So in ovarian cancer landscape, when you use COM71 to block PVRIG and then we have shown that you can drive T cells in the tumor, yes, it could be definitely that TIGIT will be relevant.



If you have sufficient amount of T cells after PVRIG blockade, then treating with PD-1 or PD-1 plus TIGIT blockade could be relevant. And, definitely, that's why we're doing a platform study. After showing the COM71 activity, one of the most reasonable next step will be to do PD-1 plus TIGIT blockade, as we've also shown previously. So TIGIT definitely could be relevant, and this could be done in a stepwise approach.

[Michelle Mahler, executive]

Yes. So I'm going to take the question. So at this point in time, we haven't spoken yet to the FDA. We've designed a clinical trial that's well within the framework of the updated guidance. It's got robust elements with being randomized as well as blinded. And in the event that we have positive data, then it would be a very good conversation to have with the FDA in terms of what would be the next steps.

[Operator]

This concludes the Q&A session and Compugen's investor conference call. Thank you for your participation. You may go ahead and disconnect.