Q3 2024 Compugen Ltd Earnings Call
Ladies and gentlemen, thank you for joining us today.
Speaker Change: Welcome to CompuGen's third quarter 2024 results conference call. At this time, all participants are in a listen-only mode.
Speaker Change: 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: Thank you, Joni, and thank you all for joining us on the call today. Joining me from CompoGen for the prepared remarks are Dr. Anat Cohen-Diak, President and Chief Executive Officer, David Silberman, Chief Financial Officer, and Dr. Michel Maler, Chief Medical Officer.
Yvonne Naughton: We're also delighted to be joined by Dr. Ulla Dapu-Yekul, Assistant Professor of Medicine, Harvard Medical School and Director of Translational Research, Gynelogic Oncology Program, Massachusetts General Hospital, Boston.
Yvonne Naughton: who is also an investigator on our triple IO combination ovarian cancer study, which we'll discuss today. Dr. Aran Ophira, Chief Scientific Officer, will join us for the Q&A.
Speaker Change: 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
Speaker Change: Business Outlook, Development Efforts and Their Potential Outcome, The Company's Discovery Platform, Anticipated Progress and Plans, Results and Timelines for our Programmes and Studies, Financial and Accounting Related Matters, as well as Statements regarding our Cash Position.
Speaker Change: 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 Change: 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.
Speaker Change: 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. Thank you, Yvonne. And thank you, everyone, for joining us on our third quarter 2024 call.
Anat Cohen-Diak: We're fresh back from the CITI 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.
Anat Cohen-Diak: I'm delighted to welcome Dr. Yekul to our call today to be part of our discussion on this data and our development plan.
Anat Cohen-Diak: 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.
Anat Cohen-Diak: We're highly encouraged by the consistency of the data between our two platinum-resistant ovarian cancer studies demonstrating COM701-driven activity and safety in more than 40 advanced and heavily pretreated patients.
We're looking only at overall response rate.
Anat Cohen-Diak: 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.
Anat Cohen-Diak: 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.
Anat Cohen-Diak: including a partial response lasting more than 18 months in a patient treated with COM-7-1 for 24 months. In addition, the translational data supporting a robust pharmacodynamic activation of the immune system
further reinforce a COM-701 driven effect.
This overall data in advanced disease
Anat Cohen-Diak: but in a past where we would expect its unique mechanism of action to be most effective.
Anat Cohen-Diak: An earlier setting of ovarian cancer, where there is a significant unmet need and where the disease biology FITCOM71 mechanism of action offers such an opportunity.
I will now explain the rationale supporting this.
Fergie
Speaker Change: 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.
Speaker Change: COMP701's durability and tolerability and has the potential to be highly differentiated in this setting and consequently may face less competition.
Secondly,
These patients are less heavily
Speaker Change: and therefore a less immune compromised, providing the opportunity for COM701 immunotherapy to harness its unique mechanism of infection to potentially increase the time to disease progression and change the trajectory of the disease.
Speaker Change: In addition, platinum-based chemotherapy has been shown to induce tertiary lymphoid structures and T-memory stem cells, and therefore,
Speaker Change: has the potential to sensitize the tumors of the patients previously treated with chemotherapy to COM701 by leveraging its unique mechanism of action on deep cells.
Speaker Change: Advancing COM 701 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 Change: Our trial is planned to be an adaptive cancer patients who have received at least two prior lines of platinum-based chemotherapy regimens and are not candidates to receive standards of care maintenance treatment.
Speaker Change: Our development approach will be step-wide, starting with a randomized double-blinded sub-study, initially enrolling 60 patients who will be randomized 2 to 1 to COM-711 monotherapy or placebo.
Speaker Change: The primary endpoint will be median progression-free survival, where the placebo benchmark is expected to be approximately six months.
Speaker Change: Such a platform design allows for assessing COM701 as a single-agent maintenance therapy and for opening additional sub-studies in the future providing a regulatory and commercial opportunity.
Speaker Change: Additional sub-studies would permit the evaluation of COM701 as a backbone treatment in combination with agents like NTPD1-PAGE-A checkpoints inhibitors.
Further testing our DNAMM triplet combination hypothesis.
Speaker Change: Additional sub-studies would also permit exploring additional combination options like Bevacizumab, PARP, ADCs or others, potentially with partners, to extract the full potential of COM701.
Speaker Change: As part of the platform design, we plan to continue employing exploratory assessments of various potential biomarker enrichment strategies.
Speaker Change: We are encouraged by the feedback from ovarian cancer experts who have been very supportive of this selected path forward.
Speaker Change: We plan to initiate the trial in Q2 2025 and expect to have data from the interim analysis of the randomized COM701 maintenance therapy R in H2 2026.
Speaker Change: This development path ticks all the boxes we believe are important for the development of COM701.
Speaker Change: It has a strong biological and clinical rationale, may open the door for partnering options for various combinations, and enables engagement with regulatory authorities to agree on a registration path.
Speaker Change: Importantly, it also makes sense from a financial perspective, allowing a gradual investment in future additional combo arms, while we focus on COM 7-1 as a backbone.
Speaker Change: Cash Runway, assuming no further cash and anticipated to reach potential key catalysts, including projected COM701 monostudy interim analysis.
Speaker Change: and support of advancement of COM543 in the clinic, together with continued investment in our earlier pipeline.
Speaker Change: Before handing over to David to run through the financials, I want to briefly relate to the other great progress we had this quarter.
Speaker Change: Starting with COM543, our differentiated approach to harness cytokine biology to treat cancer, which is partnered with Gilead.
Speaker Change: In the third quarter, we received a $30 million maximum 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
Speaker Change: Presentation of data at the World These data shows an unpromising efficacy, and a manageable safety profile in both lung and gastric cancer from our partner AstraZeneca with the Gaskt-O-MIC. We thought that it was best to intervene to remember the importance of protecting the health of the patient.
Speaker Change: the PD-1 T-gauge bi-specific, where the T-gauge component is derived from our FC-reduced COM902.
Speaker Change: In addition, AstraZeneca recently announced its fourth and fifth phase three trials with rivagastamine.
Speaker Change: Tropion Lung 12 which we'll assess with combination with ADC Gatodix D as adjuvant therapy in patients with high risk early stage resected non squamous non-small cell and cancer
Speaker Change: and Artemide 3, which will assist with the gastrointestinal tract in combination with chemo, compared to pembrone chemo in frontline non squamous non-small cell cancer expressing PD-L1.
Speaker Change: This broad development strategy of Real Vagastomid by AstraZeneca represents a significant potential revenue source for Compigen as we are eligible for both future milestone payments and mid-single digit tiered royalties on future sales.
Speaker Change: With that, I will hand over to David for the financial update.
David Silberman: Thank you, Anat, and good morning and afternoon to everyone. I would like to start by saying that I am extremely pleased to be here today as part of the Computing team.
David Silberman: I will now summarize our financial results and start with our cash balance.
David Silberman: 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.
David Silberman: Our cash runway is expected to fund our current plans into 2027. The company has no debt.
David Silberman: Revenues for Q3 2024 were approximately $17.1 million compared with no revenues for the comparable period in 2023.
David Silberman: 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 IMD clearance achieved in July.
David Silberman: Expenses for the third quarter of 2024 were in line with our plans.
David Silberman: R&D expenses for the third quarter of 2024 were $6.3 million, reduced from $8.3 million in the third quarter of 2023.
David Silberman: 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.
David Silberman: 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.
David Silberman: 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.
Speaker Change: With that, I will hand over to Michel to go into more details on the data and moderate the fireside chat with Dr. Yacoub.
Michel Maler: Thank you, David. I'm very happy to provide an overview of the encouraging data which Dr. Yekou presented at TZITZI last Friday, and I'm delighted to be joined by Dr. Yekou 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.
Michel Maler: 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.
Michel Maler: There is significant unmet medical need for women with ovarian cancer who could benefit from alternative potentially safe tolerable efficacious and durable treatment options
Michel Maler: Using our computational capabilities, we identified ovarian cancer as a high-priority indication for PBRI-G blockade, justifying the initiation of our first study evaluating the triplet blockade of anti-PBRI-G, TIGIT, and PD-1 antibodies in platinum-resistant ovarian cancer patients.
Michel Maler: 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.
Michel Maler: COM-902, and our SC-reduced anti-TIGIT and the anti-PD-1 pembrolizumab in another cohort of platinum-resistant ovarian cancer patients as validation of our previous findings.
Michel Maler: 25 patients treated with the triple combination of COM-701, COM-902 and pembrolizumab.
Michel Maler: patients were heavily pre-treated with a median of four prior therapies and had no alternative treatment options.
Michel Maler: 80% of patients had prior bevacizumab and 68% had prior POP inhibitor.
Michel Maler: 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 pre-treated with advanced disease.
Michel Maler: However, patients in this study had more advanced disease, as most of them had had prior exposure to POP inhibitors as well as ADC and other investigational agents than in the previously reported study.
Michel Maler: The objective response rate was 17%, all responses were confirmed, with disease control rate of 46% including a patient with a complete response.
Michel Maler: Five of the patients were in treatment for more than 200 days, and four patients remained on treatment at data cutoff, including the patients with the complete response.
Speaker Change: 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.
Speaker Change: Overall response rates of less than 10% reported in the past for PD-1 blockers or with a combination of PD-1 tiget blockade in a similar setting.
Speaker Change: In terms of safety and tolerability, the triple combination showed a favorable safety profile and was well tolerated.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: I would like to extend our sincere thanks to the investigators, study staff, patients, and their families for participating in our clinical trials.
Speaker Change: It is my pleasure to welcome Dr. Yacou for a short fireside chat to discuss the data just presented and our future development plans. Welcome Dr. Yacou.
Thank you so much for having me.
Speaker Change: 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 Change: 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.
Speaker Change: And the first relapse a lot of these patients have is referred to as platinum-sensitive disease, which indicates that at the very least, their disease was suppressed for a minimum of six months from their prior platinum-based chemotherapy.
Speaker Change: These fishes are typically retreated with a platinum-based combination, usually a doublet or a triplet with bevacizumab.
Speaker Change: 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 six months.
Speaker Change: at which time these patients are subject to, in the past, chemotherapy and now more recently, antibody drug conjugates, rivirtuximab being the prime example.
The key thing to remember is that
In patients with platinum-sensitive disease, most of our efforts...
Speaker Change: 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.
Speaker Change: 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 Change: Can you comment a little bit more about the challenges and bothersome toxicities
Speaker Change: Of course. So one of the reasons that we had to continue to explore other maintenance therapies is because of the side effects of Theracizumab. Now I mentioned that triplet therapy in combination with carboplatin and another chemotherapy is typically used in platinum sensitive disease.
Speaker Change: What is typically swept under the rug is that with bevacizumab, a lot of our patients have side effects such as migraines, myalgias, and arthralgias. They have nosebleeds, and that's...
Speaker Change: 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 Change: 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.
Speaker Change: So we moved these drugs into the platinum-sensitive and platinum-resistant setting. But unfortunately, as the data continued to mature over time, we found that for the vast majority of these patients,
Speaker Change: 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.
Speaker Change: There's concern for myelodysplastic syndrome and AML. Later down the line, our rates have increased because of our use in this disease.
Speaker Change: and their day-to-day side effects. These drugs cause significant fatigue. They're 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.
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Well, it does not sound very good for those patients.
So let me switch gear with that.
Speaker Change: 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 CITSI last week? What specifically excites you about the data?
Speaker Change: And then, are there any anecdotes you could share with us from some of the patients that you've treated?
Speaker Change: 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 antibody drug conjugates like mervetoximab if they have the requisites for the receptor expression.
Speaker Change: On chemotherapy, and single-agent chemotherapy in this particular setting, the response rate outside of weekly Taxol is around 10%.
Speaker Change: So the vast majority of these patients were looking at toxic chemotherapy with low response rate and low durability of effect, which is what in part spurred the enthusiasm for participating on this study.
Speaker Change: 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.
If we need our drugs that have high response rates,
It's that response rate, 30% to 35% response rate.
Speaker Change: Ignoring the toxicity of weekly Taxol, the durability leaves a lot to be desired, the average being about six to eight months. Let's fast forward and look at Rivertuximab, which is currently approved for patients with high folate receptor, and that shows improvement in overall survival.
Speaker Change: But, however, the median PFS is still six months. So these patients, it's always a great concern that even when I have drugs that have high response rates, durability is an issue.
Speaker Change: So this study, based on our prior experience with other COM701 trials, I knew always had the prospect for durable effect.
Speaker Change: And this was one of the things that really excited me about this study.
Speaker Change: I'll leave you with two anecdotes of two 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 have to wait a few months.
Speaker Change: so they had symptomatic relief from their disease. Because the paradigm had always been that immunotherapy takes a little bit of time to get going.
Speaker Change: And to my pleasant relief, this particular lady who had significant abdominal pain was
I'd pay relief within a matter of weeks.
Speaker Change: So, even before she received her second infusion or second cycle of treatment, her day-to-day life, which is what I really, really focused on in the platinum-resistant setting, was already getting better. She was able to get around more.
Speaker Change: , and combined with a study that showed that women who 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 will leave you with is that
Speaker Change: 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.
Speaker Change: The disease comes back, they're a little bit weaker, a little bit more depleted.
Speaker Change: We treat them again in that platinum-sensitive setting. And we continue this process into the platinum-resistant setting.
Speaker Change: When we've watched people sort of lose their function, degrade, I mean worn down over time.
Speaker Change: 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 mirtoximab because they're afraid of oculotoxicity and their ability to drive at night, for example.
And to my relief, this was also another patient.
Speaker Change: who remained unstudied 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. 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's several others, but both of those
Speaker Change: 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 in this area of drug development.
Wow.
Speaker Change: 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 CITSI? 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?
Speaker Change: Of course. You know, as I mentioned, I think, in one of your prior questions, these were patients for whom we had exhausted most reasonable treatments.
Speaker Change: 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 the platinum sensitive setting. They'd all been exposed to bevacizumab with all of its toxicities. Many of these patients had also been exposed to PARP inhibitors. And because of when the trial started, we'd also seen patients who had progressed.
These stations are still coming off.
Speaker Change: and then becoming like any other fat-numb resistant patient for whom the only options left are chemotherapy or investigational drugs. And we had a few of those patients represented here as well.
Speaker Change: The key histologies are representative of the people we treat in clinic, which is high-grade carcinomas or high-grade epithelial cancers.
Speaker Change: And many of them, you know, 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.
Thank you.
Now, this study also captured patients in real life.
Speaker Change: So, if we look at some of the eligibility criteria on this study, including hemoglobin levels of around 8, creatinine clearance of around 40, 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 who have not been exposed to multiple lines of treatment.
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Thank you, Geku.
I wanted to just put...
Speaker Change: 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 COM 701 or a combination with COM 701 versus the antibody drug conjugates for ovarian cancer and where would you see the use of such agents in the course of the patient's journey?
Speaker Change: I think it comes down to toxicity and tolerability, Michelle. You know, I'll remind people on the call that in the past, we've actually tried maintenance therapy.
Speaker Change: with more chemo, lower dose chemo given with different schedules because we really wanted to prevent recurrence.
Speaker Change: And what we found was that even though you can stretch it out a little bit by just giving 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.
Speaker Change: And I think about your conjugates, we're all grateful for them. They've solved some of our temporary problems, some of our urgent problems with ovarian cancer. But they're still toxic drugs, and you have to pick the domain of toxicity. For some patients, any time they have a cough, they're worried about pneumonitis. That is no way to live your day-to-day life.
Speaker Change: Oculotoxicity 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. Thank you. Bye-bye.
that has a very tolerable schedule,
Speaker Change: Side effects, where people can continue to work, really fits the best definition of maintenance.
Speaker Change: And even with the newer ADCs, where we don't tend to see a lot of pneumonitis or a lot of oculotoxicity or hyponotoxicity, we're seeing decrements in blood counts.
So these patients, every now and then, will get...
Speaker Change: Anemic and will need transfusions and already by itself these are side effects that impact people's daily function
Speaker Change: 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,
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: 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?
Speaker Change: to this patient population B by increasing the PFS and hopefully delaying them from becoming platinum resistant.
Speaker Change: There are two big things in my mind, and the way I think about this is in two big domains. One is thinking about the immunologic terms, the host or the patient, is the people we live with, the people we know.
Speaker Change: As I mentioned, as they go through each round of chemo, as they go through diagnosis, recurrence after recurrence...
Speaker Change: 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 their ability to mount responses to common illnesses.
Speaker Change: 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.
Speaker Change: When you break them down by number of lines of therapy, less than three, greater than three, universally, all of them have shown a preference for...
Speaker Change: 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.
Speaker Change: with each iteration or each exposure to chemotherapy, the cancer gets worse.
Speaker Change: We know this from interval cytoreduction surgeries where we find organizing stroma, organizing fibrosis, even after three cycles of chemo. So we know that with each subsequent exposure, the tumor evolves for the worst. And anybody who knows somebody or has taken care of somebody with cancer will tell you this. This is something a layperson will observe, that with each line, each exposure, each recurrence...
Speaker Change: both the patient, in immunologic terms the host, and the disease itself sort of diverge in opposite fashions, leading to worse outcomes.
The advantage of moving
Speaker Change: 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...
Speaker Change: 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.
Speaker Change: 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 Change: 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...
Speaker Change: 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.
Speaker Change: Thank you so much, Dr. Yeko. I really, really appreciate your insight. And I, to summarize, want to thank you for helping us to put
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: Thank you. Ladies and gentlemen, at this time we will begin the question and answer session. If you have a question, please press star 1. If you wish to decline from the polling process, please press star 2. If you are using speaker equipment, kindly lift the handset before pressing the numbers.
Please stand by while we poll for your questions.
Speaker Change: The first question is from Stephen Wiley of Stiefel. Please go ahead.
Speaker Change: Yeah, good morning. Thanks for taking the questions. Anat and Michelle, I think you may have been mentioned in terms of the number of prior platinum lines.
Speaker Change: that you would be requiring for the proposed phase 2, but could you just remind me what that number is?
Michel.
Sure.
Speaker Change: So, we will be targeting patients who have had two 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?
Dr. Prada Graybosch, Asthika Goonewardene,
The next question is from...
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Speaker Change: And there is a follow-up question from Steven Wiley of Steeple. Please go ahead.
Speaker Change: Yeah, sorry about that. I think the operator dropped me out of the queue.
Speaker Change: So just given you're going to be pursuing third line and I'm not sure if Dr. Yakey was still on the line and can answer this but...
Speaker Change: 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?
Speaker Change: So I'm just going to check if if Dr. Yakoub is on the line and would like to take that otherwise I'm happy to answer.
Speaker Change: Okay, I can I can I can offer an opinion. So the vast majority of patients will progress, you know, we do have a very small population of patients.
Speaker Change: 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.
Speaker Change: 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 diagnosis, which also incidentally are the most common stages of diagnosis for ovarian cancer,
Speaker Change: 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 Change: So, the vast majority of patients in that first platinum sensitive setting, which is the second line of therapy, we always cut the first one, would have been exposed to either PARP.
Speaker Change: 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.
Speaker Change: choosing to reserve it for the platinum-resistant setting but the vast majority of our patients will be passing through a platinum-sensitive waypoint and many of them would have received either PARP inhibitor and or Bevacizumab if they were HRD positive. Thank you.
© transcript Emily Beynon
Speaker Change: Okay, thank you for that. And then maybe just for Anat and Michelle again, you know, I know you're pursuing the single agent
Speaker Change: development path here. I know you mentioned there may be an opportunity to potentially build on combos. So is this really an opportunity for you to kind of get a better understanding of what the single agent activity of COMP 701 in this setting is and then
perhaps look to layer on additional
additional combination-based therapies.
Once you have that data in there though.
Speaker Change: Yes, that 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 to start with single agent.
Speaker Change: It opens the door for the contribution of effect for mono and have a COM71 centric design where we go into combinations. So it really tick all the boxes for us from a clinical perspective and potentially regulatory perspective.
Thank you for watching!
Michel Maler: Yeah, I think you said it all, Anat. I don't have, I don't have anything else to add on that.
[inaudible]
The next question is from Dana Graybosh. Please go ahead.
Speaker Change: Hi, two questions for me. The first, and I'll take them one at a time, the first is can you remind me, Dr. Yakoub and also Michelle, what we learned from trials with PD-1 or PD-L1 antagonists?
Speaker Change: I seem to remember that there were some relevant similar trials with avelomab. So what's already been done and what did we learn about those trials in this setting?
I can offer a response.
Speaker Change: So one of the things, so we've done multiple different combinations, you know, monotherapy is a non-starter, I wouldn't even discuss that, it's bad. We've done combinations with other immune checkpoints, we've done combinations with versizomab and combinations with chemotherapy in multiple different lines.
Speaker Change: 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.
However, some of these patients will have long, durable responses.
Speaker Change: What we've also learned is that the number of lines of therapy, as I mentioned before, really matter.
Speaker Change: Many of these drugs are developed in the deep platinum-resistant setting. Heavily pretreated patients, six, seven 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, one or two of them would have long-lasting responses.
Speaker Change: 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.
Speaker Change: is that the earlier you use it in the less sick patient.
Speaker Change: earlier in their course of disease, the more likely you are to have a benefit.
Speaker Change: 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
Speaker Change: Progression-free survival is still around the same, maybe boosted by a couple months, but you pay the upfront cost of PARP inhibitors and toxicity upfront, which led to less excitement with those combinations.
Speaker Change: We've combined it with bevacizumab. In fact, our only compendium listed combination right now is a combination of oral citoxant, which is a type of chemotherapy, plus bevacizumab, plus pembrolizumab.
Speaker Change: 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 prefer this to weekly Taxol. So we've learned...
Speaker Change: In summary, the earlier we use immunotherapy, especially with checkpoints, the better.
Speaker Change: 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.
Speaker Change: One final example is that our most recent study was a combination of ipilimumab and nivolumab, and many of you will have experience with both of these drugs.
Speaker Change: And again, like I said, with combinations, we saw improved response rates, up to 30%, again, approaching chemo. But the response rates were about... progression-free survival was in the range of, like, three to four months. So, again, nobody wants the toxicities of colitis, et cetera, with CTLA-4 inhibition.
Speaker Change: just to be on the study for four months, which if you 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 Change: Yeah, it does. Maybe one specific follow-up, were any of those studies in this exact same setting, sort of the second and third line platinum sensitive maintenance setting?
Speaker Change: No, no, the maintenance space in after platinum has been really, really lacking in terms of drug development.
Speaker Change: 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.
Speaker Change: in the platinum-resistant setting. So not quite the same thing, but the idea was that they would use the cis-platinum and the gem chemo, almost like you would use the platinum agent, and then you would continue the pembrolizumab as a means of maintenance. But this was also in sort of the deep platinum-resistant setting, so they got a high response rate, but the durability of response, progression-free survival, was around that five 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.
Speaker Change: but we haven't looked at just males. We've looked at it in up-front setting, newly diagnosed disease with PD-L1 combination. I think you had mentioned a fairly amount, or somebody did. And those trials were a few trials, yeah.
Speaker Change: Yvonne, 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?
Speaker Change: and but most of the patients aren't and that's why eventually PD-1 checkpoints have failed in this setting and this is not going to be the way for us.
Speaker Change: PVRIG, which we have shown and actually published quite recently, has a very, very different biology than PD-1. Yes, it is a checkpoint, but actually, because of its unique mechanism of action, driving activity in stem-like memory retices, which have very strong proliferative potential,
Speaker Change: PVRG blockade has the potential to drive T-cells in these really difficult indications, also in the PD-1 negative patients. And even though we didn't test it in many patients, this is what we have seen. We had patients with PD-1 negative ovarian cancer that responded to PVRG blockade monotherapy.
Speaker Change: And we also had other patients tested in monotherapy, and almost all of them were modulated immunologically by Comstovoran monotherapy.
Speaker Change: So, we do think that PVRG blockade has a very deep biology and has the potential to change disease scores, especially in the early settings, after that the platinum-based chemotherapy that was also shown to induce TLS and TSCM, and that synthesized the tumor to PVRG blockade effect.
© The Bulletproof Executive 2013
Thank you.
Thank you. I'll step back from the queue.
Speaker Change: The next question is from Tony Butler of Rodman and Renshaw. Please go ahead.
Thank you.
Speaker Change: Thanks very much. Dr. Yacou, if you're still on, or Michelle, if in fact the median progression for survival in the setting for which you're moving 701 into, that is in the platinum sensitive case of six months,
But what's the most ideal
PFS
Speaker Change: to suggest that an agent is clinically relevant. And I understand you're gonna make comments around durability as well as adverse events. I'm respectful of that, but most importantly, what would that PFS need to be? Is it eight months, is it 10 months, et cetera? That's question one.
And question two is...
Speaker Change: 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? Thanks very much.
You strange?
Okay, I will take that. So, we don't
Speaker Change: 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
Speaker Change: beating the observation arm or the placebo arm by three months.
Speaker Change: As far as the GOG goes, we have engaged key opinion leaders who are heavily involved in the GOG. However, they tend to support...
Speaker Change: later stage development. And this is still a relatively small study, but we are in conversations with several of those investigators.
Speaker Change: Thank you, Michelle. If I might add to the clinical relevancy discussion, so I mentioned before that these patients progress from platinum sensitive to platinum resistant.
Speaker Change: 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 eight months later. Then they get platinum plus something. The second time it comes back, it comes back four months after they finish that therapy. And that's when they make that transition.
Speaker Change: For many patients, if we get them to that nine-month mark, eight, nine-month mark, what that means is that you've kept them platinum-sensitive.
Speaker Change: So ignoring the debate of, you know, what's tolerable and what's clinically, you know, what people live day to day
Speaker Change: 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 keeps...
Speaker Change: less than six, 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 Change: So I think anything above six months, as you approach eight, nine months, making them really platinum sensitive again or maintaining their platinum sensitivity becomes meaningful. In fact, we have data that patients with a platinum sensitive interval
Speaker Change: greater than 12 months, live longer, do better, than patients with a platinum-sensitive interval of six months. Both are platinum-sensitive, but the more platinum-sensitive you are, the better. So that eight, nine month is what we shoot for clinically.
Thank you, Dr. York.
Speaker Change: The next question is from Ashtika Gunwarden of Truist Securities. Please go ahead.
Ashtika Gunwarden: Hi guys, thanks for taking my questions, and I'll apologize up front. I joined the call late. It was a heavy earnings day for us, so...
Ashtika Gunwarden: Thank you so much for joining us today, and apologies if this has been addressed already. Could you maybe talk a little bit about any development in the biomarker understanding here for Fabryg going into this Phase II study, and if there's any sort of what you'd be looking for, any sort of analysis you'd be looking to do there?
Ashtika Gunwarden: Why does digit biology not make sense to also address in this phase 2 study?
© The Bulletproof Executive 2013
Ashtika Gunwarden: So later on I will relate to the first two questions and then we shall relate to the FDA part.
Speaker Change: Yes, thank you Ashik. 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 I.O. probably never had the chance to have any impact to begin with.
Speaker Change: And we all know that 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. And now it's more complex. And we did have this initial signal of PVRL2, the potential biomarker.
Speaker Change: 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 PVR-L2 and at this point the talented data is not enough to have an enrichment-based prospective study.
Speaker Change: So what we did, we are going now to an earlier setting in which the patient should have a more sufficient immune system and all the other attributes we discussed before. So actually we are looking for a response by the study design and not by the biomarker itself.
Speaker Change: But we are going to continue follow-up because we did have this trend and we also had it again in another education So we are going to continue and follow up also in the coming study on an PBL-2 and some other biomarkers 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 Tidget Biology. So, first of all, we think...
Speaker Change: And I think five different randomized phase 2 studies have shown that TIGIT blockade is active. But from what we currently know, TIGIT is active when you have sufficient amount, a bit as I mentioned before for PD-1 blockade, when you have sufficient amount of T-cells in your microenvironment.
So, in the ovarian cancer landscape...
Speaker Change: and the COMM-7-1 activity, one of the most reasonable next steps will be to do PD-1 plus TG blockade, as we also shown previously. So TG definitely could be relevant and this could be done in a stepwise approach.
Speaker Change: 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.
Great. Thanks for taking my questions, guys.
Speaker Change: This concludes the Q&A session and CompuGen's investor conference call. Thank you for your participation. You may go ahead and disconnect.