Compugen Q3 2024 Earnings Call Transcript

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Provided by Quartr
November 12, 2024

There are 10 speakers on the call.

Operator

Ladies and gentlemen, thank you for joining us today. Welcome to Compugen's Third Quarter 2024 Results Conference Call. At this time, all participants are in a listen only mode. 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.

Operator

I would now like to introduce Yvonne Naughton, Head of Investor Relations and Corporate Communications. Yvonne, please go ahead. Thank you, Yoni, and thank

Speaker 1

you all for joining us on the call today. Joining me from Compugen for the prepared remarks are Doctor. Anat Cohen Dayak, President and Chief Executive Officer David Silberman, Chief Financial Officer and Doctor. Michel Malher, Chief Medical Officer. We're also delighted to be joined by Doctor.

Speaker 1

Oladapu 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 I O combination ovarian cancer study, which we'll discuss today. Doctor. Arano Fira, Chief Scientific Officer, will join us for the Q and A. Before we begin, we would like to remind you that during this call, the company may make projections 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.

Speaker 1

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 Annette.

Speaker 2

Thank you, Yvonne, and thank you, everyone, for joining us on our Q3 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 Doctor. Yeko to our call today to be part of our discussion on this data and our development plan. 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.

Speaker 2

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 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 outcome 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 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 60 7% in 6 patients, including a partial response lasting more than 18 months in a patient treated with COM701 for 24 months.

Speaker 3

In addition, the translational data supporting a robust pharmacodynamic activation of the immune system further reinforce

Speaker 2

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 the past, where we would expect its unique mechanism of action to be most effective. In 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.

Speaker 2

Firstly, there is a gap in care for maintenance therapy in relapsed platinum sensitive ovarian cancer patients were 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 sensors 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.

Speaker 2

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 regimen 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 to 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

Speaker 3

as

Speaker 2

a single agent maintenance therapy and for opening additional sub studies in the future, providing a regulatory and commercial opportunity. Additional sub studies would permit the evaluation of COM701 as a backbone treatment in combination with agents like anti PD-one, TEG checkpoint inhibitors, further testing our genome triplet combination hypothesis. Additional sub studies would also permit exploring additional combination options like belacizumab, PAP, ADC or other 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.

Speaker 2

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 arm, 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 monosum study interim analysis and support of advancement of COM-five thirteen in the clinic together with continued investment in our earlier pipeline.

Speaker 2

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 COMF-five forty three, our differentiated approach to harness cytokine biology to treat cancer, which is partnered with Gilead. In the Q3, we received the $30,000,000 milestone payment from Gilead for achieving the FDA IND clearance and we are on track to initiate the Phase 1 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 vilzagastomib, the PD-one TIGIT bispecific, where the TIGIT component is derived from our FcReduced COM902. In addition, AstraZeneca recently announced its 4th and 5th Phase 3 trials with rivzagastomib.

Speaker 2

TROPION LUN12, which will assess rivzagastomib as monotherapy or in combination with ADC DATODXD as adjuvant therapy in patients with high risk early stage resected non squamous non small cell lung cancer and artenoid 3, which will assess rilvigastomy in combination with chemo compared to pembro in chemo in frontline non squamous non small cell lung cancer expressing PD L1. This broad development strategy of rilzagastamide by AstraZeneca represents a significant potential revenue source for Compugen as we're 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.

Speaker 3

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 point $2,000,000 in cash, cash equivalents and investments compared with approximately $51,100,000 as of December 31, 2023. Our cash runway is expected to fund our current plans in 2027.

Speaker 3

The company has no debt. Revenues for Q3 2024 were approximately $17,100,000 compared with no revenues for the comparable period in 2023. The period in 2023. The revenues reflect recognition of the portion of the upfront payment from the license agreement with Gilead and of the $30,000,000 milestone payment received from Gilead for COM 503 IMV clearance achieved in July. Expenses for the Q3 of 2024 were in line with our plan.

Speaker 3

R and D expenses for the Q3 of 2024 were $6,300,000 reduced from $8,300,000 in the Q3 of 2023. The decrease is mainly due to the classification of COM 503 R and D activities to cost of revenues coupled with lower COM503 expenses mainly related to CMC. Our G and A expenses for the Q1 of 2024 were $2,600,000 comparable to $2,300,000 in the Q3 of 2023. For the Q3 of 2024, we recorded a net profit of $1,300,000 or $0.01 per basic and diluted share compared to a net loss of $9,900,000 or $0.11 per basic and diluted share in the Q3 of 2023. With that, I will hand over to Michelle to go into more details on the data and moderate the science I chose with Doctor.

Speaker 3

Yeko.

Speaker 4

Thank you, David. I'm very happy to provide an overview of the encouraging data which Doctor. Yeko presented at SITC last Friday, and I'm delighted to be joined by Doctor. Yeko 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 dread of treatment and its associated toxic side effects.

Speaker 4

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-one 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 ovarian cancer study was to assess whether we could demonstrate the similar clinical benefit in trypta combination of POM701, POM902 and our SC reduced anti TIGIT and the anti PD-one pembrolizumab in another cohort of platinum resistant ovarian cancer patients, a validation of our previous findings. The data Doctor.

Speaker 4

Yeku presented at SITC in platinum resistant triple 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 debasizumab 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.

Speaker 4

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.

Speaker 4

This data excites us as it confirms that what we previously presented. COM701 is active and safe and particularly notable are 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 less than 10% reported in the past for PD-one blockers or with a combination of PD-one digit 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.

Speaker 4

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 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 of monotherapy and 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 become 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.

Speaker 4

It is my pleasure to welcome Doctor. Yeku for a short fireside chat to discuss the data I just presented and our future development plans. Welcome, Doctor. Yeku.

Speaker 5

Thank you so much for having me.

Speaker 4

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?

Speaker 5

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 the 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 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 as 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.

Speaker 5

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.

Speaker 4

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? Of course.

Speaker 5

So one of the reasons that we had continued to explore all the maintenance therapies as because of the side effects of bevacizumab. Now I mentioned that triplet therapy in combination with carboplatin and another chemotherapy is typically using 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 arthralgias, they have nose fleas. 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.

Speaker 5

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.

Speaker 5

For the patients who are candidates for PARP inhibitors, there's 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. And 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.

Speaker 4

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?

Speaker 5

Of course. So many of the patients that we treated on this study were patients for whom single agent chemotherapy. So these were patients with platinum resistant disease, which I had mentioned, have only antibodies or conjugates like mirvetuximab, if they have 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 PowerPoint in many of our therapies for relapsed ovarian cancer.

Speaker 5

If we look at our drugs that have high response rates, let's say the weekly taxol I mentioned with 35 percent 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.

Speaker 5

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 of 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 till they had symptomatic relief from their disease, because the paradigm has 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.

Speaker 5

So even before she received her her second infusion or second cycle of treatment, her day to day life, which is what I really, really

Speaker 3

focused on in the platinum resistant setting was

Speaker 5

already getting better. She was able to get around more, take less opioids and in turn had a better quality of life. So we knew that 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.

Speaker 5

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 love. I have patients who stop driving when they start taking mirvetuximab because they're afraid of ocular toxicity and their 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.

Speaker 5

We haven't seen a lot of toxicity with the COM701 triplet in prior studies. I'm optimistic that we can cautiously continue to work and let's see how you do. And to my relief, this was also another patient who remained on study for a very, very long time and worked throughout the process every week or so she would send us a message and say, you know, I'm waiting for side effects. I'm not even nauseous. I don't have to take any preliminary medications for my infusion.

Speaker 5

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. So 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 1 on 1 stories, patients you know by name, you know their family that really, really keep you in this area of drug development.

Speaker 4

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 investigational and the investigational agents as well as the patient's histology and the responses observed in this patient population?

Speaker 5

Of course. As I mentioned, I think in one of your prior questions, these were patients for whom we had exhausted most reasonable treatment. And in this case, this meant that most of them had been exposed to bevacizumab either in the upfront setting or in the platinum sensitive setting or even in platinum that 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 including mevituximab that have been shown to have overall survival.

Speaker 5

So in the real world, these patients are still coming off and they're 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.

Speaker 5

Now this study also captured patients in real life. So if we look at some of the eligibility criteria on this study, including hemoglobin levels of around 8, creatinine clearance of around 40, plitmas 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.

Speaker 4

Thank you, Geku. 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?

Speaker 5

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 the gentler schedule, the side effects became so cumulative that people could not reasonably get on with their daily lives. And I think what you are conjugates, we're all grateful for them. They've solved some of our temporary problems, some of our urgent problems in ovarian cancer, but they're still toxic drugs and you have to pick the domain of toxicity.

Speaker 5

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.

Speaker 5

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.

Speaker 5

It has 5 effects where people can continue to work really fits the best definition of maintenance. And even with the newer ABCs 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 impacts people's daily function. So to my mind the best we could have done with maintenance therapies was dacizumab 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.

Speaker 5

I think for me, it's what we've been looking 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.

Speaker 4

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?

Speaker 5

First, Michelle. So there are 2 big things in my mind and the way I think about this is in 2 big domains. 1 is thinking about the immunologic terms, the host or the patient is the 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 friller, frail, their bone marrows are exposed to round after round after round of cytotoxic and myelotoxic chemotherapy.

Speaker 5

We know that this affects the immune system and affects their ability to melt 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.

Speaker 5

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 interval side of reduction surgeries where we find organizing stroma, organizing fibrosis, it was after 3 cycles of chemo. So we know that with each subsequent exposure, the tumor evolves for the worst.

Speaker 5

And anybody who knows somebody who has taken care of somebody with cancer will tell you this. This is something a lay person will observe that with each line, each exposure, each recurrence, both the patient in immunologic terms, the host and the disease itself sort of

Speaker 3

diverge in opposite fashion is leading to worse outcomes.

Speaker 5

The advantage of moving, 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 in giving the family, stave off the disease. And in solid tumor oncology, that is really the next best thing to curing somebody is when you can achieve some sort of either a stalemate, if you will, where the person converts their terrible cancer into a chronic problem, like you might consider diabetes or hypertension, where it stabilize in the background, but yet people are able to function. And in so doing, we're 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.

Speaker 5

And then the evolution mechanisms that the tumor has to employ mutations, etcetera, to get through chemotherapy also does not get deployed. So we see less cachexia, less fatigue and all of these other things that eventually culminate in our patients who are heavily treated. That is really the hope and that's how I see this, Michelle.

Speaker 4

Thank you so much, Doctor. Yeko. I really, really appreciate your insight. And I 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.

Speaker 4

Now I will turn the call over to the operator for questions.

Operator

Thank you. Ladies and gentlemen, The first question is from Stephen Willey of Stifel. Please go ahead.

Speaker 6

Yes, good morning. Thanks for taking the questions. Anat and Michel, 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 II, but could you just remind me what that number is?

Speaker 4

Michelle? Sure. So we will be targeting patients who've 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 3rd line patients, but there may be exceptions 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.

Speaker 2

Steve, do you have any additional questions?

Operator

The next question is from and there is a follow-up question from Stephen Willey of Stifel. Please go ahead.

Speaker 6

Yes, sorry about that. I think the operator dropped me out of the queue. So just given you're going to be pursuing 3rd line and I'm not sure if Doctor. Yeki is still on the line and can answer this, but what's your understanding of the proportion of patients who get to 3rd line are still platinum sensitive and have exhausted prior bev and or PARP within the maintenance side? Yes, exhausted prior bev and or PARP within the maintenance side?

Speaker 4

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

Speaker 5

I can offer an opinion. So the vast majority of patients will progress. We do have a very small population of patients who 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.

Speaker 5

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 your 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 into your 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 pleural effusions would have already received bevacizumab.

Speaker 5

So the vast majority of patients in that first platinum sensitive setting, which is the 2nd line of therapy, we always count 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 PARP inhibitor and or bevacizumab if they were HRD positive. Thank you.

Speaker 6

Okay. Thank you for that. 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 combos.

Speaker 6

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?

Speaker 2

Yes, that's as well. And Michel, feel free to add. But for us, it is really a great opportunity, 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.

Speaker 3

Yes, I

Speaker 4

think you said it all, Anat. I don't have anything else to add on that.

Operator

The next question is from Dana Graybosch. Please go ahead.

Speaker 7

Hi. Two questions for me. The first and I'll take them 1 at a time. The first is, can you remind me Doctor. Yeku and Asa Michelle, what we learned from trials with PD-one or PD L1 antagonist?

Speaker 7

I seem to remember that there were some relevant similar trials with avelumab. So what's already been done and what did we learn about those trials in the setting?

Speaker 5

I can offer a response. So one of the things, so we've done multiple different combinations. Monotherapy is a non starter. I wouldn't even discuss that. It's bad.

Speaker 5

We've done combinations with other immune checkpoints. We've done combinations with rivarizumab and combinations with chemotherapy in multiple different lines. And the current 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-one class drugs in combination. However,

Speaker 3

some

Speaker 5

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 resistance 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, I started testing platinum sensitive and or platinum resistant, we saw better responses and we saw more durability.

Speaker 5

So we made the connection also, again, the second lesson is that the earlier you use it in the less sick patient, less earlier in their

Speaker 3

course of disease, the more likely you are to have a benefit. In terms of our exploration with

Speaker 5

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.

Speaker 5

In fact, our only compendium listed combination right now is a combination of oral cytoxet, which is a type of chemotherapy plus bevacizumab plus pegralizumab. 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 to 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.

Speaker 5

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

Speaker 3

those combination partners. One final

Speaker 5

example is that our most recent study 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 percent, again, approaching chemo, but the response rates progression free survival was in the range of like 3 to 4 months. So again, nobody wants the toxicities of colitis, etcetera, with CTLA-four inhibition just to be on the study for 4 months, which if put yourself in the 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.

Speaker 7

Yes, it does. 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?

Speaker 5

No, no. The maintenance space in 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 on the GEM chemo almost like you would use the platinum agent and then you continue the

Speaker 3

pembrolizumab as a means of maintenance. But this

Speaker 5

was also in the sort of maintenance, but this was also in the sort of the deep platinum resistant setting. So they got a high response rate, but the durability of response for pressure free survival was around that 5 months again, which is typical for what we see in the platinum resistant setting. So they felt that toxicity of Sys and JEM wasn't really worth the whole ride. But we haven't looked at just MACE. We've looked at it in upfront setting, newly diagnosed diseases with PD L1 combination.

Speaker 5

I think it mentioned a Verilymab, somebody did. And those trials were not

Speaker 2

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

Speaker 8

Yes, sure. So as Doctor. Iaco mentioned, yes, some patients do respond to PD-one therapy. Mostly, they will T cells in tumor environment, the PD-one CPS above 10 or above 1 at least, and but most of the patients aren't. And that's why eventually PD-one checkpoint have failed in these settings and this is not going to be the way for us.

Speaker 8

And PVRIG, what we have shown and actually published quite recently, has a very, very different biology than PD-one. Yes, it's the tissue checkpoint, but actually because of its unique mechanism of action, driving activity in stem like memory T cells, which have very strong proliferative potential. PVRG blockade has the potential to drive T cells into in these really difficult indications also in the PD-one negative patient. And even though we didn't test it in many patients, this is what we have seen. We had the patients with PDL1 negative ovarian cancer that responded to PVRIG blockade monotherapy.

Speaker 8

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 PVRG blockade has a very different biology and has the potential to change disease course, especially in the early settings after that the platinum based chemotherapy that was recently also shown to induce TSCM and that synthesized the tumor to PVRIG blockade effect.

Speaker 7

Thank you. Thank you. I'll step back in the queue. Thank you.

Operator

The next question is from Tony Butler of Rodman and Renshaw. Please go ahead.

Speaker 9

Thanks very much. Doctor. Yacou, 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 of 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?

Speaker 9

Is it 8 months? Is it 10 months, etcetera? That's question 1. And question 2 is, in enrolling the 60 patients, is necessary actually to engage the GOG such that in theory, I guess, rate of enrollment would be rather rapid? Thanks very much.

Speaker 2

Okay.

Speaker 4

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 3 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.

Speaker 4

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.

Speaker 5

If I may add to the clinical relevance 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.

Speaker 5

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 re induction 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 hits 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.

Speaker 5

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 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 month is what we shoot for clinically.

Speaker 3

Thank you, Doctor. Yako.

Operator

The next question is from Ashthika Gunwarden of Truist Securities. Please go ahead.

Speaker 5

Hi, guys. Thanks for taking my questions.

Speaker 3

And I'll 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 Fibrig going into this Phase 2 study? And if there's any sort of what should be looking for, any sort of analysis you'd be looking to do there or cutoffs to implement?

Speaker 3

And then a rudimentary question, why does TIGIT biology not make sense to also address in this Phase 2 study? And if you could also maybe provide any agency feedback on this as well of the Phase 2, that would be great.

Speaker 2

So I'll later on relate to the first two questions and then Michel relate to the FDA part.

Speaker 8

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

Speaker 8

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 targeted 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 more sufficient immune system and all the other attributes we discussed before.

Speaker 8

So actually, we are in need for response by the design 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 in another indication. So we are going to continue and follow-up also in the coming study on PREVAR-two and some other biomarkers potential. So the opportunity to have a biomarker and to substantiate these biomarkers still exist 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 2 studies have shown that TIGIT blockade is active.

Speaker 8

But from what we currently know, TIGIT is active when you have sufficient amount as I mentioned before for PD-one blockade, when you have sufficient amount of T cells into a macro environment. So in the ovarian cancer landscape, when you use COM701 to block PVRG 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 PVRG blockade, then treating with PD-one or PD-one plus TIGIT blockade could be relevant. Definitely, definitely, that's why we're doing a platform study after showing the COM701 activity, study. After showing the COM701 activity, one of the most reasonable next step will be to do PD-one plus TIGIT blockade, as we also shown previously.

Speaker 8

So TIGIT definitely could be relevant and this could be done in a stepwise approach. Michelle?

Speaker 2

Michelle, do

Speaker 4

you want to take the question? 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.

Speaker 4

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

Speaker 2

would be the next steps.

Speaker 5

Great. Thanks for taking my questions guys.

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