Good day, and welcome to the Agenus First Quarter 2023 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. [Operator Instructions] And finally, I would like to advise all participants that this call is being recorded. I'd now like to welcome Mr. Zach Arman to begin the conference. Zach, 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 time lines, as well as time lines 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 nine different solid tumor types that we've reported on so far. Over the past 10 months, we've presented data at the plenary or late breaking sections of five major company, including ESMO-GI, SITC, ASCO-GI, SGO and CTOS. We look forward to sharing further insights at upcoming conferences such as ASCO in June and ESMO-GI in July. Botensilimab, our innovative and multi-functional CTLA-4 anybody 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 anybody. And, impressively, botensilimab has demonstrated clinical responses in both cold and hot tumors. In a diverse patient population of nearly 400 individuals, across nine 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 closer look at response rates achieved with botensilimab. Across all nine 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 responses. This is a critical factor in evaluating a treatment potential to transform patient's lives in a meaningful way. But the story doesn't end there, preliminary data suggest that Botensilimab may be exceptionally effective in colorectal cancer patients with whole 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…

Thank you, Garo. Together with our investigators, we presented updates from the bot/bal development program at two 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. At 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 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-1and 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 USC Norris Comprehensive Cancer Center and the Keck School of Medicine at USC presented our latest update of botensilimab program in colorectal cancer at ASCO-GI. The cohort of 70 evaluable patients had a medium of four prior lines of therapy and a third 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 2 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…

Thank you, Steven. We ended our first quarter 2023 with a cash, cash equivalents and short term investment balance of $189.2 million, this compares to $193.4 million as of December 31, 2022. Since quarter end, we have raised $13.6 million through sales under our aftermarket 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 non-cash 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 bat/bal combination therapy has shown remarkable potential and 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 translate to improve survival in many and all of the cancers that we've studied so far. Our continued innovations 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 combinations of our checkpoint antibodies with MiNK's, our generic (ph) 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 candidate, agent-797, and off-the-shelf iNKT cell therapy. These data underscore the launch of a clinical trial in 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 non-dilutive 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 as dividend of MiNK 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…

Thank you, speakers. [Operator Instructions] Your first question comes from the line of Emily Bodnar of Wainwright. Emily, please go ahead.

Hi. Good morning, and thanks for taking the questions. Maybe could you expand 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 its monotherapy. And then maybe can you just discuss if there's any other Phase 2 or Phase 3 studies that you think you could initiate this year besides the long and colorectal cancer studies? Thanks.

So let me make a couple of more comments and then I'll turn it over to Steven. As you know, Emily, 2373 is a very important product. Very important product because it adds some very complementary attributes to patient care and patient treatment. For example, with potential amount, we're activating T-cells, wireless will also generating memory and depleting regulatory T-cells, but activating T-cells better than the first generation CTLA-4. What 2373 does is an addition, there is really concentrate on memory component of the immune system, which becomes critically important in the durability of immune response and durability of patients benefit. So that's one bucket and I think that what they can expand on it. But secondly, you asked about other Phase 2 trial. Now we haven't really publicly announced any of our plans with regard to additional Phase 2 trials or data from other programs. But just as we do very properly, until, for example, we get the abstract accepted at major conferences, we won't talk about it because it jeopardizes obviously indeed, acceptability of an abstract if we publicly discuss these things. So that's what we do. But what's very encouraging also to us that remember, as we said during our call today, since late June of last year, we have presented data at oral plenary opening sessions at 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 2373 and other plans that we may have.

Yes. Thank you for the question. So our CD137 were incredibly excited about and as you said, we will be updating the Phase I monotherapy trial at ASCO and a poster discussion session in the coming weeks. The Iowa 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 combination 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.

Great. Thank you very much.

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

Hi guys. Good morning, and thanks for taking the questions. 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 said some kind of a bar for response rates or some other criteria that would motivate you to move into a randomized trial and 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 colorectal, warm tumors also are a target. And in lung cancer, we've shown that in PD-1 resistant as well as PD-1 plus chemo unresponsive of resistant tumors. We're showing with a small denominator admittedly but we're showing about 50% response rates, which is really a very, very major improvement for depletion. Now as I said, the denominator is slow, as well 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 we've seen in about 10 patients prior. In 40, 50, 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 potential amount. These 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 3 trial that we include both 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. All right. Super. I mean, I 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 the one year response at 53%. Are we going to get those updated? Is the end going to change it 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.

Yeah. Thanks again for the question. Yeah. So we did report 70 patients at ASCO-GI and obviously that trial was it continuing to enroll at the time, it has since completed enrollment as we've launched our Phase 2 pivotal trial. So you can expect more patients and longer follow-up with the next update at ESMO-GI.

Okay. Great. All right. Thanks. I'll jump back in the queue.

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

Good morning, team. Thanks for taking our questions and congrats on the progress. So just a couple of quick follow ups, two questions being asked before and then I have a couple more. So it 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 breakthrough therapy or others that are being explored as you get close to getting randomized controlled data from the Phase 2 study?

Mayank, I think I'm give wise (ph) not to elaborate your question because of the sensitivity of many levels. But suffice it to say that we are obviously keeping not just the FDA, but other agencies abreast 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 indications. But these patients are typically third, fourth, fifth line patients. They have been treated with 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 patient. 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 patient that has exhausted all options particularly to the kind of durable responses we're seeing of the magnitude that I just talked about, they are very meaningful, but we're also diligently pursuing that these responses will translate to longer term benefit to patients enough. Of course, the data that we showed at ASCO-GI with survival curves indicates, and of course, mind 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 may 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 higher treatments or other cancer treatments. But with CTLA-4 targeting agents, generally and that we're going to collaborate on this, that it would be impossible to think about a trial where response rates will now translate to 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 classic RECIST 1.1 response and yet the survival curve showed a hazard ratio of 0.67. So about one in three 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 base therapies whether alone or in combination with PD-1s have correlated well with survival and we -- 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. Thank you. And secondly on the non-small cell lung cancer cohort interesting to hear you're thinking of a randomized Phase 3 there. Could you talk to what sample size you need to see here to confirm this 50% response rate over time and we 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, that's a factual as you 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. And the only risk here is, are we preferentially putting patients that are best prognosis and the answer is categorically to that question, no. So the 50% response rates, 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 [indiscernible], which as I said shows a variable bar of 9% response so far. And those 9% responses are likely not to really show a major benefit for patients, so that's the bottom line. And of course, we haven't released all details on this and move well. But we are seeing responses in the worst patients with low TMB and low PBL1 expression, which gives you a sense of what mechanism of botensilimab is in terms of both lighting up tumors, making tumors harder. So if you can take more TMB patients and treat them with botensilimab to make them harder, which we seem to be doing in our trial. And you're dealing with patients that typically don't response PD-1 with low PDL-1 expressions. Those are two very important indicators as to the status of the patients being a very poor prognosis patient. So we're very encouraged with this outcome actually. And clearly outside groups that we're working with who 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 direction.

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 into 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. Thank you. And my final question on the 2373 bot combination study that is approaching enrollment completion in melanoma, PDL-1 refractory. Could you comment on what appropriate benchmarks are Dr. O’Day, since this is [indiscernible] 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 till later in the year at the earliest. But in terms of that cohort, obviously these are very extensively treated melanoma patients that are very -- a refractory to IO and BRAF if they are 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.

Okay. That's very helpful. Thanks for taking our questions.

Our next question comes from the line of Matt Phillips from William Blair. Please go ahead.

Thanks for taking my question. I know the Phase 2 in CRC has done a good job of showing contribution to components through different arms. But I'm wondering as you move into more indications such as if you launched a Phase 3 and non-small cell lung cancer, would you have to show contribution of components in those additional arms with the -- until that monotherapy arm?

So the answer is no, we do not have to show that all over again in each and every indication method.

All right. Great. Thanks, Garo. Can you remind us on the timing of any Gilead opt-in decision? Is it completion of this Phase 1 or does it also include the next study in combo with botensilimab and melanoma?

Okay. So I think it's reason for the couple of things here. One is will our interests and Gilead's interest converge here and we don't know the answer to that question from their perspective. But we regard 2373 as a pretty green post 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. Thanks, Garo. And last one, I know we're going to get the bot/bal (ph) sarcoma data at ASCO. Is there any steps forward for that combination? I know the focus is rightly switch to botensilimab, but just curious.

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.

Yeah. That makes sense. Thanks, Dr. O’Day.

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, but also very importantly, investigators, KOL’s 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 there prior to approval and certainly post-approval as well. So we're very, very grateful to all of your support. The biotech market has 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 we'll 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 conference is, as well as in our next earnings conference call. Thank you.

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