Agenus Inc (AGEN) 2023 Q1 法說會逐字稿

Good day, and welcome to the Agenus First Quarter 2023 Financial Results Conference Call. (Operator Instructions) And finally, I would like to advise all participants that this call is being recorded.

I'd now like to welcome Mr. Zack Armen to begin the conference. Zack, over to you.

Thank you, operator, and thank you all for joining us today. Today's call is being webcast and will be available on our website for replay. I'd like to remind you that this call will include forward-looking statements. including statements regarding our clinical development, regulatory and commercial plans and timelines as well as timelines for data release and partnership opportunities. These statements are subject to risks and uncertainties, and we refer you to our SEC filings for more details on these risks. Joining me today are Dr. Garo Armen, Chairman and Chief Executive Officer; Dr. Steven O'Day, Chief Medical Officer; and Christine Klaskin, Vice President of Finance.

Now I'd like to turn the call over to Garo to highlight our progress and speak to our outlook for the remainder of the year. Garo?

Good morning, everyone, and thank you for joining us for our first quarter 2023 update. Today, we'll primarily focus on the significant progress we've made with our groundbreaking botensilimab program and its potential to transform cancer treatment across 9 different solid cure types that we've reported on so far. For the past 10 months, we presented data at the plenary or late-breaking sessions of 5 major companies, including ESMO GI, SITC, ASCO GI, SGO and CTOS. We look forward to sharing further insights at the upcoming conferences such as ASCO in June and ESMO GI in July.

Botensilimab, our innovative and multifunctional CTLA-4 antibody aims to revolutionize cancer treatment by extending clinical benefit to cold tumors, which have historically been unresponsive to standard of care and other immunotherapy agents, including other CTLA-4 antibodies. And impressively, botensilimab has demonstrated clinical responses in both cold and hot tumors. In a diverse patient population of nearly 400 individuals across 9 solid tumor types, all of them had exhausted prior treatment options. Botensilimab has made significant strides in eliciting responses, offering renewed hope for those who have failed all other available treatments.

Let's take a quarter look at response rates achieved with botensilimab. Across all 9 solid tumors, we've observed remarkable response rates of up to 50% in highly refractory cancers. This is truly an impressive accomplishment considering the patient population involved. Notably, many of these responses have proven to be durable responsive. This is a critical factor in evaluating a treatment's potential to transform patients' lives in a meaningful way.

But the story doesn't end there. Preliminary data suggests that botensilimab may be exceptionally effective in colorectal cancer patients with home tumors that have historically been unresponsive to immunotherapy. Even in hot tumors that have failed standard of care, including immunotherapy, of course, with or without chemotherapy, we are witnessing unprecedented response. Similarly, deep responses are being observed in melanoma patients who fail PD-1 therapies as well as ipi/nivo. For such patients, who have exhausted all available therapies, botensilimab holds the potential to be a game changer. 

Moreover, early clinical data indicates that potent responses may be achievable in the neoadjuvant setting, possibly introducing an entirely new treatment approach and enhancing patient outcomes. The clinical data generated with botensilimab is truly inspiring, and we're thrilled with the progress we've made thus far. We certainly believe that botensilimab has the potential to reshape how we approach treating solid tumors, and we eagerly look forward to further advancements in this crucial program. With our more advanced programs, as well as on the regulatory front, we're also making significant strides. Our Phase II ACTIVATE studies in colorectal, melanoma and pancreatic cancers are set to conclude enrollment in 2023. And we are expediting enrollment to our refractory non-small cell lung cancer cohort where we have previously reported 50% response rates in patients who have failed prior PD-1 and chemotherapy. We plan to launch a randomized Phase III study if the observed response rates persist in the expanded cohort, in non-small cell lung cancer. 

We're also proud to announce the fact that bot/bal combination has generated or has been granted fast-track designation by the FDA for treating non-MSI high colorectal patients without active liver metastases. This acknowledgment of our potential to fulfill a significant unmet medical need could accelerate the development and review of our application for approval. In conclusion, our unwavering commitment to advancing our clinical pipeline and delivering innovative treatment for cancer patients remains stronger than ever. We are enthusiastic about potential match progress and its potential to profoundly impact the lives of patients with solid tumors.

I will now hand it over to Dr. Steven O'Day, who will provide further details on the latest data, and then I will be coming back with my concluding remarks after that. Steven?

Thank you, Garo. Together with our investigators, we presented updates from the bot/bal development program at 2 major medical meetings last quarter. including a late-breaking oral session at the American Society of Clinical Oncology Gastrointestinal Cancer Symposium in January in San Francisco and an oral plenary session at the Society of Gynecologic Oncology Annual Meeting in Tampa in March. I'll now briefly describe these data updates beginning with colorectal cancer. As Garo said, metastatic non-MSI high colorectal cancer patients treated with standard of care, have a reported 12-month survival rate of only 25% and an overall reported response rate to third-line treatments of 1% to 2%.  Immunotherapy treatments of combinations, PD-1 and CTLA-4 have similarly reported poor response rates of only 1% to 5% in comparable populations. 

Dr. Anthony El-Khoueiry, Associate Director for Clinical Research at the USC Norris Comprehensive Cancer Center and the Tech School of Medicine at USC, presented our latest update of botensilimab programming colorectal cancer at ASCO GI. The cohort of 70 evaluable patients had a median of 4 prior lines of therapy and 1/3 of the patients had already failed immunotherapy. Patients who received the bot/bal combination showed a 12-month overall survival rate of 63%, more than twice the reported rate of 25% for standard of care.

In the subgroup without active liver mets, the 12-month overall survival was 81%. This is the targeted population for our Phase II study where we recently received fast-track designation from the FDA. Even in patients with active liver metastasis, the 12-month overall survival was 40%, indicating a survival advantage over standard of care for all patients regardless of the presence of liver metastasis. The overall response rate for the 70 patients was 23%, with 69% of the objective responses ongoing at the time of the data cut. The disease control rate, which is inclusive of complete responses, partial responses and stable disease was 76%. We will share updated data from this cohort at an oral presentation at ESMO GI Conference on June 30 in Barcelona, Spain. 

Next, moving on to ovarian cancer. The reported response rate for standard of care in recurrent platinum-resistant refractory ovarian cancer with chemotherapy is only approximately 10%. PD-1 and CTLA-4 combinations have reported response rates of 3% to 10% in comparable patient populations. Dr. Bruno Bacon, Assistant Professor, Harvard Medical School, presented the update of the botensilimab program in ovarian cancer at SGO's Annual Meeting in Tampa in March. 24 evaluable patients were presented who had a median of 4 prior lines of therapy and 21% had already failed immunotherapy.

The majority of patients, almost 80% were high-grade serous histology, which is the most common and most aggressive form of advanced ovarian cancer. The overall response rate was 33% in this porous group and the disease control rate was 67%. Responses were durable like colorectal cancer with median duration of response not reached. This cohort continues to expand and enroll in our Phase Ib study.

While our primary focus remains advancing the clinical development of bot and bal as we continue to progress a focused -- we also continue to progress a focused number of additional programs and combinations to further expand the therapeutic potential of botensilimab and to unlock the full potential of our portfolio. Several of these programs have been selected for presentation at the upcoming ASCO conference in June in Chicago. AGEN2373 is our CD137 agonist designed to stimulate the activation of both cytotoxic T cells and NK cells, while mitigating the liver toxicities, which is common to the first-generation target class. Complete results from the first-in-human dose escalation study of AGEN2373 monotherapy in patients with advanced solid tumors will be presented during an ASCO poster discussion session on Saturday, June 3.

We expect to complete enrollment of the Phase Ib study of AGEN2373 in combination with botensilimab in PD-1 relapsed refractory melanoma in the first half of 2023. Dr. Breelyn Wilky, Director of the Sarcoma Medical Oncology at the University of Colorado School of Medicine will deliver an oral presentation on a single-arm open-label Phase II study of balstilimab with zalifrelimab, our first-generation CTLA-4 antibody plus doxorubicin in patients with advanced sarcomas at ASCO on Monday, June 5. Finally, Incyte will be presenting 3 poster presentations of our clinical partnered programs during the ASCO conference.

Now I'll turn the call over to Christine for the financial update.

Thank you, Steven. We ended our first quarter 2023 with a cash, cash equivalent and short-term investment balance of $189.2 million. This compares to $193.4 million at December 31, 2022. This quarter end, we have raised $13.6 million through sales under our asset market issuance sales agreement. For the first quarter ended March 31, 2023, we recognized revenue of $22.9 million and incurred a net loss of $70.9 million, which includes noncash expenses of $24.9 million.

I now turn the call back to Garo.

Thank you both Steven and Christine. In conclusion, we're very, very excited about the progress that we've made in our clinical programs as demonstrated by the updates that Steven and I shared with you earlier. Our bot/bal combination therapy has shown remarkable potential in improving response rates, which indicate deeper benefits for patients. At the ASCO GI conference, we reported that this benefit has translated into improved survival in our metastatic colorectal patients.

And we're very encouraged that it will also try rate to improve survival in many and all of the cancers that we've studied so far. Our continued innovation and progress highlights our unwavering commitment to advancing cancer care. As Steven reported earlier, this progress also includes our ongoing exploration of our diverse portfolio, including a very exciting molecule, our anti-CD137 molecule. This is an agonistic antibody. ILT2 on the other hand, is now in clinical combinations.

And of course, the combination of our checkpoint antibodies with MiNK allogeneic iNKT cell therapies. A moment about MiNK. MiNK's latest update at the AACR conference reported clinical responses in solid tumor cancers with their lead candidates, agenT-797 and of the shelf iNKT cell therapy. These data underscore the launch of a clinical trial with metastatic gastric cancer, led by Dr. Yelena Janjigian, who is the Chief of GI cancer at Memorial Sloan Kettering, and this is externally funded by nondilutive brand financing. 

MiNK will supply the trial with its in-house manufacturing capability, which today can produce 5,000 doses per year with rapidly expanding capacity. To enable access to this exciting portfolio, we've issued a dividend of mix shares to our Agenus shareholders in order for them to have the opportunity to participate in the upside of MiNK directly.

As we recognize our first quarter achievements, we're grateful for the incredible support and momentum we've built with clinical experts and patients. Our determination to bring innovative treatments to cancer patients remains steadfast, and we eagerly anticipate pushing the boundaries of what's possible in cancer care. We're actively exploring discussions with potential partners and collaborators to maximize the potential botensilimab and the rest of our pipeline. Our focus is not only on managing these assets prudently and also on building our internal capabilities.

In conclusion, as an organization, we're deeply committed to revolutionizing cancer treatment by making access to high-quality medicines our very tough priority, being to create a simple progressive model that ensures patients receive the best possible treatment available to them. Drawing inspiration from value-based care, patient-centric care and integrated care systems. We focus on delivering efficient, personalized and top-notch care for everyone who can benefit from it. Together, we strive to transform the cancer treatment landscape by putting patients first and making state-of-the-art medicines accessible to all. All who need it. You will be hearing more about the strategy and how our initiatives will integrate into these strategies in our coming communications.

With that, we'd like to now open the call for any questions you may have. And thank you, everybody, for joining us today once again. Ana.

(Operator Instructions) Your first question comes from the line of Emily Bodnar of Wainwright.

Maybe could you explain a bit more on what we should be expecting you to present on at ASCO for AGEN2373 and how you kind of think about what would be positive data in that study considering it's a monotherapy. And then maybe can you just discuss if there's any other Phase II or Phase III studies that you think you could initiate this year besides the long-end colorectal cancer studies?

So let me make a couple of broad comments, and then I'll turn it over to Steven. As you know, Emily, AGEN2373 is a very important product, a very important product because it adds some very complementary attributes to patient care and patient treatment. For example, with botensilimab, we're activating T cells. Whilst, we're also generating memory and depleting regulatory T cells, but activating T cells better than the first-generation CTLA-4. What AGEN2373 does in addition is really concentrate on the memory component of the nonsystem, which becomes critically important in the durability of immune response and durability of patient benefit. So that's one bucket, and I think that way they can expand on it.

But secondly, we asked about other Phase II trials. Now we haven't really publicly announced any of our plans with regard to additional Phase II trials or data from other programs. But just as we do very properly, until, for example, we get the abstracts accepted at major conferences, we weren't programmatic because it jeopardizes obviously the acceptability of an abstract if we publicly discuss these things. So that's what we do.

But what's very encouraging also to us is that remember, as we said during our call today, since late June of last year, we have presented data at oral primary opening sessions and so many major conferences, which is really unprecedented, for a single product, if you look at it. So very encouraged, but stay tuned for the rest of it. But Steven, would you like to add any comments about AGEN2373 and other plans that we may have?

Yes. Thank you for the question. So our CD137 we're incredibly excited about. And as you said, we will be updating the Phase I monotherapy trial at ASCO in a poster discussion session in the coming weeks. The IO world has been focused on inhibitory checkpoints, obviously, for good reason for a long time with CTLA-4, PD-1 and the other.

The agonists have struggled mightily with toxicity issues, particularly around liver toxicity with first generation. And there was great promise that by pushing the accelerator in addition to blocking the break of the T cell, more extraordinary things could happen. So we've designed a next-gen CD137 that really will hopefully be an important combinational partner in our arsenal and obviously, for patients. So what we're looking for, just from my perspective is, obviously, we want to see safety with this new drug design. And obviously, single-agent activity would be great and is very important, I think, in any IO asset, and we'll be updating our data in a few weeks, so stay tuned.

Our next question comes from the line of Mike King of EF Hutton.

Congrats on the progress. Just real quick. Two things, Garo, you had said -- you made a comment about your inclination to move forward with a randomized trial in non-small cell lung cancer based on the results of the single-arm study, but I didn't catch quite what you had said. And if you had set some kind of a bar for response rates or some other criteria that would motivate you to move into a randomized trial in non-small cell.

Sure. Very good question, Mike. Thank you. So as you know, lung cancer is a hot cancer, relatively hot cancer. And so while botensilimab has shown profound activity in cold tumors like, warm tumors are also our target. And in lung cancer, we've shown that in PD-1 resistant as well as PD-1 plus chemo unresponsible resistant tumors. We're showing with a small denominator admittedly, but we're showing about 5% response rates, which is really a very, very major improvement for the patient. Now as I said, the denominator is so small. And so what we're doing is really expanding the cohort of lung cancer patients, so that in a relatively short period of time, we can move the denominator up to 40, 50 patients.

And of course, if we can maintain the kind of response rates, which you have seen in about 10 patients far in 2050, you will see a huge level of game-changer interest in this. Now with the early data, a few outside groups have shown significant interest in doing randomized trials with botensilimab. This will be multiple arm trials with standard of care in the earlier-stage setting. So stay tuned. We have not yet announced the specific plans, but these plans are well underway for a randomized Phase III trial that will include botensilimab plus a current standard of care versus the other arms that we haven't disclosed yet. But that trial should be initiated sometime this year.

Sometime this year. Okay. I mean I've got a ton of questions, but I guess on ASCO -- I'm sorry, the ESMO GI, I think the last time you showed data -- at ASCO GI in colorectal was 70 patients, and you had a 1-year response at 53%. Are we going to get those updated? Is the end going to change? Maybe qualitatively, can you tell us what the data is going to look like, what the complexion will be at the ESMO GI meeting?

I'll turn this to Steven.

Yes. Thanks again for the question. Yes. So we did report 70 patients at ASCO GI. And obviously, that trial was continuing to enroll at the time. It has since completed enrollment as we've launched our Phase II pivotal trial. So you can expect more patients and longer follow-up with the next update at ESMO GI.

Our next question comes from the line of Mayank Mamtani of B. Riley.

Congrats on the progress. So just a couple of quick follow-ups, 2 questions being asked before, and then I have a couple more. So I was curious to see your fast track designation come in line with how this CRC data is maturing. Could you comment or specify that this updated data was submitted as part of requesting the agency for Fast Track. And if there are any other mechanisms like brachytherapy therapy or others that are being explored as you get close to getting randomized controlled data from the Phase II study?

I think, I'd be wise not to elaborate on your question because of the sensitivity of at many levels. But suffice it to say that we are obviously keeping not just the FDA, but other agencies of rest of developments with CRC and some of the other indications as well. Now one thing that is sure that I think needs to be stressed over and over again. When we treat patients, which are not just metastatic patients, for example, in CRC, but also other indicators.

But these patients are typically third, fourth, fifth line patients. They have been treated pretty much everything that's available and either haven't responded or failed after they have responded to these other treatments. So these are pretty sick patients. And the kinds of responses that we're seeing, which are in the neighborhood of 20% to 50% depending on the indication, is really something very meaningful for the patients.

And of course, from a regulatory perspective, you may say, well, response is not enough, but please explain that to the patient that the response is not a good thing. So we are diligently pursuing of course, the next steps. Response is a very important criteria for patients that have exhausted all options particularly to the kind of durable responses we're seeing of the magnitude that I just talked about, they're very meaningful, but we're also diligently pursuing that these responses will translate to longer-term benefit to patients and after, of course, the data that we showed at ASCO GI with survival curves indicates.

And of course, remind you, this is not a randomized trial, but the differentiation in this patient population in terms of overall survival is such that we are confident that the responses are going to translate to longer term benefit, including survival. And I might add that with CTLA-4s, typically you do see response rates correlate very well with other benefits. The same is not necessarily true with other IO treatments or other cancer treatments. But with CTLA-4 targeting agents, generally and Dr. O'Day could elaborate on this, that it would be impossible to think about a trial where which caspase will not translate into survival. Steven, would you like to bring in your experience with that?

Sure, Garo. Obviously, yes, I would agree CTLA-4 as a target because of the durability of responses and the fact that RECIST 1.1 underestimates clinical benefit because minor responses and stable disease could be significantly durable, has correlated well with overall survival. And just I would redirect people to the initial ipilimumab study in melanoma, of course, only had a 10% or 15% sort of plastic RECIST 1.1 response. And yet the survival curve showed a hazard ratio of 0.67.

So about 1 in 3 melanoma patients were having significant clinical benefit, which is double what the response rate was and it mimicked the plateau of the survival curve at 20% to 25%. So I think in general, CTLA-4-based therapies, whether alone or in combination with PD-1 have correlated well with survival. And based on our duration of response across botensilimab are very hopeful it will continue to do that as we look at survival curves in our different solid tumor clinical trials.

Very helpful. And secondly, on the non-small cell lung cancer cohort, Interesting to hear your thinking of a randomized Phase III there. Could you talk to what sample size you need to see here to confirm this 50% response rate over time? And you get a lot of questions about confirmed, unconfirmed responses. So could you just clarify, there was one unconfirmed PR when you last reported. Has that been confirmed with the recent scans?

Right. So I'll just give you a little bit of a hint which is factual. As you know, daclitaxel is the only approved therapy for patients in non-small cell lung cancer who have failed chemo and PD-1. And so this is a low bar with 9% response rate right now. So the early indications of responses that we're seeing are far in excess of that. And the only risk here is are we preferentially putting patients that are best prognosis. And the answer is category to that question. So the 50% response rate, if continued in a larger denominator will demonstrate a very significant benefit for patients who have failed chemo plus PD-1 and who are otherwise going to be treated with docetaxel, which, as I said, shows a very low borrow of 9% response so far. And those not responses are likely not to really show a major benefit to our patients. So that's the bottom line.

And of course, we haven't released all the details on this, and we will. But we are seeing responses in the worst patients with low TMB and low PD-L1 expiration, which gives you a sense of what mechanism of what botensilimab is in terms of lighting up tumors, making tumors hotter. So if you can take low TMB patients and treat them with botensilimab to make them hotter, which we seem to be doing in our trial. And you're dealing with patients that typically don't respond to the one with low PD-L1 expressions. Those are 2 very important indicators as to the status of the patients being a very poor prognosis patients. So we're very encouraged with this outcome actually. And clearly, outside groups that we're working with would be at least partially or entirely sponsoring the trial are also very encouraged with the data, and that's why we're proceeding in this directory.

Did you say what denominator you might be targeting here? And then just my final -- sorry, go ahead.

We haven't disclosed those numbers yet, Mayank. I think we're in the process of going back and forth and trying to finalize these details. But be rest assured it's not going to be 1,000 patients.

Understood. And my final question on the 2373 BOT combination study that is approaching enrollment completion in melanoma, PD-L1 refractory. Could you comment on what appropriate benchmarks are Dr. O'Day since this is your arena? And what might you be looking to deliver? And if I heard you right, the timeline for that data is within first half 2023? Or is it just the enrollment completion, you said?

So the accrual to the cohort will we expect to complete in the first half of the year, we won't have data until later in the year at the earliest. But in terms of that cohort, obviously, these are very extensively treated melanoma patients that are very refractory to IO and BRAF if they're mutant. So obviously, any responses in this group would be of note, and we look forward to observing this data as it evolves. So heavily pretreated melanoma patients that have had -- the vast majority have had both CTLA-4 and PD-1, and in BRAF mutants have already exhausted BRAF mutant therapy.

Our next question comes from the line of Matthew Phipps from William Blair.

I know the Phase II in CRC has done a good job of sorting contribution to components through different arms. But I'm wondering, as you move into more indications such as if you launched a Phase III in non-small cell lung cancer, would you have to show contribution of components in those additional arms with the botensilimab monotherapy arm?

So the answer is no. We do not have to show that all over again each and every indication Matthew.

All right. Great. Can you remind us on the timing of any Gilead opt-in decision? Is it completion of this Phase I? Or does it also include the next study in combo with botensilimab and melanoma?

Okay. So I think it's reason-- there a couple of things here. One is when our interests and Gilead's interest can very cheer. And we don't know the answer to the question from their perspective. But we regard 2373 as a pretty clean-cost program for us. We also believe that we need to have freedom to operate with 2373 for the best interest of Agenus portfolio. So it will be a question of negotiation and stay tuned towards the end of the year, there will be more clarity as to how and if this option will proceed.

Great. Last one. I know we're going to get the bali/zali sarcoma data at ASCO. Is there any steps forward for that combination? I know the focus has rightly switched to botensilimab.

Matt, obviously, our focus is on the next-generation CTLA-4. Having said that, we think we have an excellent first-generation CTLA-4 that's been in combination in cervical and now this will be the first real data in sarcoma. So again, let's watch the data as it gets presented and obviously, we'll make decisions. But we certainly won't distract from our primary focus, which is botensilimab and getting to market.

There are no further questions at this time. I turn the call back over to Mr. Garo Armen for closing remarks.

Thank you very much, everybody. Thanks again for joining us today. Clearly, there's a lot going on, and we are very eager to communicate things to all of our constituencies, which include certainly our shareholders and also very importantly, investigators, PLs who are major stakeholders in this because of their interest with their patients to either participate in these trials and/or to have these products available to them with the allowances that are their private approval and certainly post approval as well. So we're very, very grateful to all of your support.

The biotech markets have been challenging in the last year or so, but we're proceeding in a way that really supersedes any of these challenges because what we've got in our portfolio is something very important for the benefit of these patients and certainly patients that have exhausted all options, but even patients that are in the earlier stages of disease and can benefit from our compounds in ways that will provide them with an option, which is typically not being addressed properly or effectively with current treatments. So thank you again, and stay tuned. We'll see you at these upcoming conferences as well as in our next earnings conference call. Thank you.

This concludes today's conference call. You may now disconnect.