Agenus - Earnings Call - Q4 2021

Transcript

Speaker 0

Ladies and gentlemen, thank you for standing by, and welcome to the Agenus Fourth Quarter twenty twenty one Financial Results. I would now like to hand the conference over to your speaker today, Ms. Divya Vasudevan. Ma'am, please go ahead.

Speaker 1

Thank you, 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, including 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. As another reminder, this call is being recorded for audio broadcast.

Joining me today are Doctor. Geralt Armen, Chairman and Chief Executive Officer Doctor. Steven O'Day, Chief Medical Officer Doctor. Jennifer Buell, Chief Executive Officer of Mink Therapeutics Chandraseh Harjeevan, Chief Operating Officer of Saptonix and Christine Klaskin, Vice President of Finance. With that, I'll turn the call over to Garo to highlight the progress that we've made to date this year.

Garo?

Speaker 2

Thank you, Divya. Thank you all for your participation and your interest in Agenus. As I go through our call today, I'll be referencing slide numbers from time to time on the presentation that appears on your screen. You can also find slides on the Events and Presentations page of our website. To start with, at last year's shareholder meeting, we try to streamline our business model.

And based on that, our business model is comprised of four pillars. This approach allows us to strategically develop our pipeline independently as well as with partners to build value while de risking development and accelerating our path to market. The first pillar consists of our value creators, our fully or majority owned programs such as flotetuzumab, that's our next generation CTLA-four, previously known as eleven eighty one. We intend to develop and commercialize these programs that fall into this category in certain geographies ourselves and partner in other geographies in order to create upfront value for the company and derisk development. The second pillar consists of potential cash generators through strategic partnerships, such as what we have done with AGEN 1,077, our TIGIT bispecific license to BMS.

We have received over $800,000,000 in cash through upfront and achieved milestone payments from these types of transactions over the past five, six years and are eligible for additional $2,800,000,000 in milestones and royalties, as well as the option to participate in development and commercialization of these products. Three, the third pillar consists of enablers, such as our PD-one antibody, balstilimab. These backbone therapies are being evaluated in combination with our pipeline and through clinical collaboration with other partners. They provide additional opportunities for commercialization and revenue generation, while de risking development through one centralized entity. Four, the fourth pillar is represented by our subsidiaries, Mink Therapeutics and Saponics.

While Agenus retains majority ownership in these entities, they are structured for independent financing, which allows for focus and accelerated development of their respective products. I would like to begin the call by addressing the first pillar, which is driven by our flagship program, Botancilimab. As you know, we have treated well over 100 patients in Phase I trials evaluating botanicalimab as monotherapy and in combination with balstilimab. We presented data at the SITC meeting last year, which demonstrated that botanzilimab has an improved efficacy and safety profile compared to what has been reported with previous CTLA-four antibodies. That is both first generation and the next generation.

As shown on Slide three, by the way, you can advance these slides on your own. We don't have the means to do that from here for you. As shown on Slide three, botaniclimab is Fc enhanced to improve the efficacy and safety of CTLA-four blockade through three primary mechanisms. First is botanicizumab is designed to extend the curative benefits of immuno oncology to cold tumors that do not typically respond to approved immunotherapies. This is achieved by increasing potency through improved T cell activation, priming, memory formation and counteracting the immune suppressive activity of regulatory T cells, all in one antibody.

As presented at SITC, botancilimab is the first CTLA-four inhibitor to demonstrate clinical responses across nine, nine cold and treatment resistant cancers. Second, botanicizumab is designed to expand clinical benefit in hot tumors, such as melanoma, where CTLA-four is already approved, but results in clinical benefit in only a third of patients and long term survival in less than a quarter of the patients. So there's a lot of room to improve here. We have observed responses across both hot and cold cancers in patients who expressed a biomarker associated with poor outcomes to first generation CTLA -four. And finally, Botanicilimab is designed to improve safety by reducing or eliminating side effects that cause treatment discontinuation, notably no pneumonitis, carditis, neurological toxicities have been observed so far.

Now with that, I would like to turn the call over to our Chief Medical Officer, Doctor. Steven O'Dea, who is one of the global experts in this field to review our upcoming plans for Botenaclimab. Steven?

Speaker 3

Thank you, Varro. Building upon the data observed in our Phase I trial, we are continuing to expand disease specific cohorts in the Phase Ib component of the trial and we will be initiating Phase II studies in melanoma, colorectal cancer and pancreatic cancer. We have carefully chosen these indications in order to one, first demonstrate superiority to ipilimumab in melanoma, where ipilimumab is approved and has been studied the most as a single agent. Second, build upon the signals observed in our Phase I study by pursuing odansilimab in combination with our PD-one antibody in MS stable colorectal cancer and three, establish botanstilimab as a superior combination agent for chemotherapy in cold tumors by evaluating botanstilimab in combination with standard of care chemotherapy in pancreatic cancer. First, I will elaborate on our approach in melanoma.

As a melanoma physician, I am particularly interested in leveraging my background and my network to rapidly enroll and execute this study. The majority of melanoma patients treated with single agent PD-one progress within a year and are in need of more effective treatment options. Response rates with ipilimumab monotherapy are approximately fifteen percent and most patients progress within months. At we reported a confirmed partial response in PD-one relapsedrefractory melanoma. Since SITC, we have observed a second melanoma patient responding to single agent botanstilimab with more than a 40% tumor reduction at their first six week scan.

This patient had previously progressed after ipilimumab in the adjuvant setting and subsequently ipilimumab and nivolumab in the metastatic study. We have designed a Phase II trial in melanoma, evaluating botanistilimab monotherapy in both PD-one resistant refractory setting as well as a PD-one CTLA-four resistant refractory setting. The first cohort in PD-one refractory resistant patients will allow us to quantify the superiority of botanstilimab compared to historical ipilimumab. We are targeting a response rate of twenty five percent or greater. The second cohort in PD-one and CTLA-four relapsed resistant patients will explore whether botanstilimab can rescue ipi nivo failures, a patient population with very limited treatment options.

In addition to our botanstilimab monotherapy study, we have expanded our AGEN2373 Phase Ib trial and are now recruiting a cohort of PD-one resistant refractory melanoma patients to receive AGEN2373 in combination with our bodinstilimab. AGEN2373 is a CD137 agonist antibody designed to be conditionally active in the tumor microenvironment. To date, AGEN2373 has demonstrated early single agent clinical activity without evidence of liver toxicity that has stalled other clinical stage CD137 therapy programs. I'm particularly excited about the combination of a checkpoint agonist CD137 and antagonist botanstilimab in melanoma, an immunogenic tumor as this represents a potential novel scientific advancement. Next, we are planning a study in MS stable colorectal cancer, where our Phase I data with botanistilimab and our PD-one balstilimab combination has shown best in class potential compared to standard of care and other drugs in development.

Colorectal cancer claims over fifty thousand lives annually in The U. S. Approximately ninety five percent of stage four colorectal cancers are classified as microsatellite stable or MSS, which correlates with poor responses to immunotherapy. In the second and third line setting, standard of care options are poor and response rates are in single digits, approximately two percent, with median progression free survival of only two months. In twenty patients treated to date in our MS stable colorectal cohort, we observed a twenty percent response rate and seventy percent disease control rate for botanstilimab and our balstilimab combination, with the majority of responses ongoing at six months.

This favors positively to the competitive landscape where first generation CTLA-four PD-one combinations have reported only rare responses and limited disease control. Our study will be designed to evaluate the contribution of components of botanstilimab and balstilimab in this combination. We anticipate that the outcome of the study will strengthen the efficacy signal and safety signal and demonstrated to date and could support further Phase III development. Finally, I'll provide an overview of our approach in pancreatic cancer. The five year survival rate for stage four pancreatic cancer is about three percent.

This disease claims fifty thousand lives annually in The U. S. Alone, and there has been no new drug approved with a broad label in seven years. Multiple trials evaluating first generation CTLA-four or PD-one agents as monotherapy have demonstrated no objective responses when evaluating the broad all comer pancreatic population. At SITC, we reported a confirmed partial response ongoing at six months in a pancreatic ampullary cancer patient that also expressed a low affinity CD16 allele, which has been reported to result in an inferior benefit to first generation CTLA-four.

We plan on evaluating botanstilimab in combination with standard of care chemotherapy FDA FDA

Speaker 2

approved approved

Speaker 3

have been largely ineffective. Our combination strategy with approved chemotherapy could accelerate the path forward while tapping into the synergistic potential of CTLA-four next generation with chemotherapy combinations across multiple solid tumors. Now we are actively working with the agency to finalize these Phase II trial designs. Together, these trials in different settings with different combinations set up odinstilimab across both IO and non IO combination and derisk Phase III trials. As shown on Slide five, positive data in these studies can unlock the franchise potential of botanstilimab, supporting further development in indications where ipilimumab has been approved as a single agent or in combination or demonstrated benefit, as well as expansion into indications where botanstilimab has shown clinical benefit, but other CTLA-four agents have not.

I will now turn the call back over to Garo.

Speaker 2

Thank you very much, Steven. As Doctor. Ode articulated, if you look at each one of our development programs that are being contemplated, we're either working with in house global experts or outside global experts to attend to these trials, to design the trials and to determine potential high probability successful outcomes. In parallel to our clinical efforts, we're building also the infrastructure to support planned development and potential launch of Botanicalimab, including for example, our internal manufacturing capacity to support what will be potentially over $10,000,000,000 in annual sales at our Emeryville site with an additional 80 acres of land that we have allocated for future manufacturing expansion. And our Vacaville site, which is not constructed yet, will be approximately 50 miles north of our Emeryville facility.

Let me also talk about AGEN fifteen seventy one. This is a new clinical program that is about to start and it is AGEN fifteen eighty one, it will happen this year. And it's a novel program targeting tumor associated macrophages, which promote resistance to PD-one and CTLA-four therapy. And so there is a very strong rationale as to why we have gone this route to address needs that are not being currently addressed with IO therapy. The importance of this target class has been validated by Merck's ILT4 antagonist discovered by Agenus and licensed to Merck.

And that program has shown durable responses in PD-one resistant cancers. With AGEN1571, we continue to advance additional discoveries targeting myeloid cells. If you turn to Slide six, I will now move to our second pillar, strategic partnerships. Strategic partnerships, while we retain ownership in the majority of our programs so far, we have accelerated the development of select programs through partnerships with industry leaders. Our partners are advancing six of our discoveries in clinical trials today, reflecting our innovation and pipeline productivity.

Our most recent partnership was executed with BMS last year, when we exclusively licensed to BMS our TIGIT bispecific AGEN1007. Similar to Botanicimab, AGEN1007 is Fc enhanced to promote single agent anti tumor immunity, an area where clinical stage TIGIT therapies are yet to show promise as single agent. It also addresses a secondary inhibitory receptor on T and NK cells to promote to improve anti tumor immunity. AGEN-one thousand seventy seven is currently in Phase one dose escalation trials and BMS intends to advance development in high priority tumor indications, including a very large indication in the form of non small cell lung cancer. We have already received $220,000,000 from BMS in the past twelve months across upfront and achieved milestones and retain the option for co development, co funding for increased royalties and with a U.

S. Co promotion. Another molecule, which we referred to just a little while ago is MK4830. As I mentioned earlier, Merck is advancing a myeloid targeting antibody MK4830 discovered by Agenus. This ILT4 antagonist is in clinical development across a range of cancers, including pancreatic, lung, renal, breast, ovarian, gastric and glioblastomas.

Then we have our INSIGHT programs that was one of our first partnerships. INSIGHT is advancing our clinical stage programs and clinical recently initiated a unique combination trial evaluating the agent discovered TIM-three and Agenus discovered LAG-three antagonists with PD-one in PD-one relapsed refractory melanoma. Across our partner programs, we are, as I said earlier, eligible for $2,800,000,000 in milestone plus royalty. These partnerships accelerate the development of our drug candidates, generate capital to further support our pipeline development and may offer optionality for future participation in development and commercialization. Let me also now make a few comments about balstilimab.

This is one of the third pillars of our business model. Enablers such as PD-one antibody, balstilimab has exhibited strong clinical activity and excellent safety profile in over 400 patients evaluated to date. In a Phase two trial, in second line cervical cancer, balstilimab demonstrated a response rate of twenty percent in PD L1 positive patients, which represents a forty percent improvement to the response rate reported for pembrolizumab, the only approved PD-one agent for these patients. Now in combination with zolifrelimab, our first generation CTLA-four antibody, the response rate with zolifrelimab plus PD-one, our balstilimab, has increased to thirty three percent in PD L1 positive patients. These we believe are major improvements for metastatic cervical patients who have very limited or no options.

While a BLA submission based on single arm trials has been challenging in The US, given the changing regulatory environment, these data suggest a meaningful improvement over currently available therapy. Next, I will briefly summarize the fourth pillar of our business model, our subsidiaries, Mink Therapeutics and Saponics. Mink Therapeutics last year launched an IPO to support clinical development of allogeneic NKT cell therapies in cancer and immune related diseases. Establishing Mink with independent financing and leadership has provided greater resources for a complementary yet distinct technology, while retaining very importantly, our flexibility and advantage of cell therapy and antibody combinations. This will be a very exciting program.

Clinical programs are underway in solid tumors, as well as multiple myeloma. And lastly, before I turn it over to Chen, to address Sapponix, I will refer to Chen who is the Chief Operating Officer of Saponix. And Chen, if you can make some comments about the progress we're making at Saponix.

Speaker 4

Thank you, Garo. And really excited to be part of the team. I joined Saponix last year after serving as an advisor to the U. S. Government on the COVID response broadly and working as a partner at the Boston Consulting Group.

I was really drawn to this opportunity to build an integrated vaccine platform to discover novel adjuvants and build more effective vaccines, something close to my heart, to address pandemic threats and other diseases. The need for vaccines offering long lasting efficacy and efficient production has become grossly amplified in the current pandemic. We can't boost the world every six months. The durability offered by our QS-twenty one stimulant has been validated over the years by Shingrix with protection exceeding nine years. Clinical and preclinical data support broad applicability of QS-twenty one across more than 20 disease settings.

However, QS-twenty one supply is constrained due to its reliance on a complicated and expensive extraction process from a Chilean soap tree bark. So at Zaponics, we have developed a plant cell culture method of manufacturing QS-twenty one and next generation adjuvants. Plant cell culture offers a more sustainable, scalable and cost effective method of manufacturing QS-twenty one versus Bark X Act. We expect to have GMP material from this manufacturing process this year enable partner clinical trial. And very exciting, we're also developing new novel adjuvant with the potential to increase mucosal immunity through intranasal delivery, which is particularly critical for addressing respiratory pandemic threats such as COVID-nineteen, but also vaccination efforts throughout the world and other disease categories.

We've built a strong leadership and advisory team to achieve these objectives with rich experience in vaccine, platform design, innovation and pandemic response from inception to commercial launch. Thank you. With that, Garo, I'm going to turn the call over to Christine Klaskin to discuss our financials.

Speaker 5

Thank you, Tom. We ended the year 2021 with a cash and short term investment balance of $3.00 $7,000,000 This compares to $100,000,000 at 12/31/2020. We recognized revenue of $296,000,000 and $88,000,000 for the years ended 12/31/2021 and 2020 respectively, which includes revenues related to our upfront license fees received, non cash royalties earned and revenue recognized under our collaboration agreements. Our cash provided by operations for the year ended 12/31/2021 was $10,000,000 with a reported net loss of $29,000,000 or $0.11 per share compared to cash used in operations of $139,000,000 and a net loss for the year ended 2020 of $183,000,000 or $1.5 per share. Non cash operating expenses for the year ended 12/31/2021 were $49,000,000 compared to $37,000,000 for the year ended 2020.

Net loss for the fourth quarter ended 2021 was $68,000,000 or $0.26 per share compared to a net loss for the same period in 2020 of $38,000,000 or $0.20 per share. For the fourth quarter ended 12/31/2021, our cash used in operations was $23,000,000 compared to $36,000,000 for the same period in 2020. I'll now turn the call back to Garo.

Speaker 2

Thank you, Christine. As we head into 2022 and beyond, we are focused on several near term and medium term value drivers. As outlined on Slide seven, in the near term, I'll give you a sampling of what we plan to accomplish. One, to launch Phase two trials, as Doctor. Ode mentioned, evaluating botensilimab in melanoma, microsatellite stable colorectal cancer and pancreatic cancer.

Two, complete enrollment of a proof of concept study evaluating botanicizumab in combination with our conditionally active CD137 agonist in melanoma. Three, initiate a Phase one study for AGEN1571, a novel program targeting tumor associated macrophages. Four, generate GMP grade QS-twenty one stimulant through Saponix's plant cell culture manufacturing method to enable partnership trials. And five, pursue additional strategic collaborations, which we have done consistently over the last five years. In the medium term, one, we will pursue multiple paths to market for botancilimab.

Two, we will continue to advance our vision platform for more efficient and effective clinical trial designs. Three, we will advance several first in class programs targeting stromal and myeloid biology. Four, we expect to complete construction of our commercial GMP facility in Emeryville under the tutelage of our Chief Manufacturing Officer, Doctor. Al Dudson. And five, we will continue to progress existing collaborations and pursue new partnerships.

Thank you very much for your attention, and we will now open up for questions.

Speaker 0

And your first question comes from the line of Kelly Shee. Your line is open.

Speaker 6

Hi, good morning. This is Jason Bouvier on for Kelly Shee. Thank you for taking our question. And I apologize if I missed this, but on the Balzac combo and cervical, just wondering if you've had any conversations with the FDA on a possible path forward or if you are still considering development path forward for that combination? Thank you.

Speaker 2

Very good question, actually. Unfortunately, because of the changes in the agency's guidance over the last two years, we believe the path for single arm trials, even randomized trials that don't meet their strict criteria is closed. It's unfortunate, because patients will not benefit from clear benefit that has been shown in, for example, our trial that has been published in the Journal of Clinical Oncology and presented at major conferences. But in The US, we believe that window is closed. And just like for example, some of our competitors indicated recently by pulling their own PLA from randomized trials, some of the new trial requirements are so onerous that it makes no sense to spend the money to bring them to conclusion.

So to answer your question very directly, we will not pursue the approval of balstilimab as a single agent therapy or balstilimab plus our zolifrelimab as combination therapy in cervical cancer in The USA.

Speaker 6

Got it. Thank you very much.

Speaker 0

And your next question comes from the line of Mayank Montani. Your line is open.

Speaker 7

Good morning. Congrats on the progress, and thanks for taking our questions. So maybe just starting with incremental updates on birtamimab, if I said the name right. Could we just get a bit more color on some of these initial indications in terms of path to actually approval? As I understand you look to engage with regulators still, is it PD-one refractory melanoma where it seems like you already identified single agent target ORRs?

Or and also like if you could clarify the pancreatic metastatic setting you're going in, is it first line with chemo or is it later lines? And then I have a follow-up.

Speaker 2

Sure. I think these are excellent questions for Doctor. Steven O'Dea. So if I can ask Steven to address them.

Speaker 3

Yes, thank you for the question. So in melanoma, as I indicated, we think that this is an optimal opportunity for testing single agent botanistilimab activity in two settings. One is the PD-one resistant refractory, but CTLA-four naive setting where single agent ipilimumab has approximately a fifteen percent response rate. And we're targeting a twenty five percent or better response rate in this cohort of patients with an improved safety profile. Even more exciting or equally exciting is a cohort of actual CTLA-four refractory patients, So patients who have received either ipi nivo frontline or have had sequential nivo or Keytruda and then had single agent ipilimumab in the second line setting and where response rates would be expected essentially to be zero.

And we look forward to seeing if Botanstilimab can perform in this setting, where the bar is very low and the unmet need is even higher. And as I indicated in the call, we already have in our Phase I trial a patient who had received ipilimumab in the adjuvant setting and then progressed and then received ipinivo in the metastatic setting. So we're very excited in exploring those areas. Obviously, I have a world class group of melanoma KOLs that I have been part of for over thirty years that are getting energized by our Phase I data and look forward to testing the next gen CTLA-four in both of these important melanoma cohorts. And then in terms of pancreas, we see this as a cold tumor with the opportunity to really prime with our next gen CTLA-four in combination with chemotherapy.

And so this will be looked at initially in the second line metastatic setting. But obviously, we have interest in moving to first line metastatic once we establish safety of combination and initial responses in this setting.

Speaker 7

Thank you for that level of detail. And maybe just a follow-up on November. Could you as you think high level going beyond the initial three tumor types like lung, like prostate, what in your view is that complementary therapy that is not an established IO or non IO that could make sense to synergistically from a mechanistic standpoint? Will you

Speaker 3

make a Yes. That's another great question. CTLA-four, we think if we with a next gen molecule that has better priming and memory and T cell regulatory depletion and a better safety profile can be a foundational combinational partner, not only with PD-one, where obviously in MS stable colorectal, we're seeing some very exciting signal, But we think it can be a foundational partner with chemotherapy or standalone agent in a hot tumor like melanoma or many other potential combinations. So we see these three areas that we've outlined as sort of representative of single agent sort of demonstration in a hot tumor like melanoma, combination with a more typical PD-one combination in a very difficult to treat MS stable. And then whether it can be a foundational and better partner than PD-one in combination with chemo and pancreas, where PD-one chemo combinations have not worked well in the very cold tumors.

So we're very strategic about outlining three different experiments with three different tumor types that set up next gen CTLA-four as a single agent and a combinational, both within IL and ex IL. And obviously, our collaborative partners that are in discussions, obviously, is very interesting because it will move potentially the asset forward with much deeper resources across other tumors like lung and prostate and other big unmet needs.

Speaker 7

Great. And if I could also ask a quick fifteen seventy one question. Disclosed Have the target specific target for that? And more broadly, how might Merck's ILD4 data midyear inform how you plan to develop it this year in clinic? Would appreciate the color there.

Speaker 2

So we're currently contemplating the path forward, including potential partnerships with this compound, Mayank, and we're not disclosing any details just yet.

Speaker 7

Okay. Great. And and my my final question was on just quickly on SUPPORNIQUX. How far are you from the clinic, you know, particularly for the intranasal vaccine?

Speaker 5

So

Speaker 2

if your question is the potential of an intranasal vaccine using the saponin family of adjuvants. We do have, as you may know, a very, very promising adjuvant in the name of QS-seven. And what we have done with QS-seven is really because it's so active as a mucosal adjuvant. We have now developed plant based cell lines to improve the yields from QS7 because for many, many years, Mayank, we have known that QS7 is a very effective vaccine adjuvant, but the yields achievable from the natural source have been very poor to make this a viable candidate. But with our new plant cell culture methodology, we have selected cell lines that actually express QS7 in high enough quantities for this to be promising.

And so we are pursuing this, but I think it will take until perhaps the end of this year to have GMP quantities of QS-seven, so that we can run some experiments and have partnership discussions.

Speaker 7

Thanks so much for taking my question.

Speaker 0

Your next question comes from the line of Mike King. Your line is open.

Speaker 8

Good morning, guys. Thanks for taking the question. I just wanted to I don't want to draw conclusions, but wanted to ask if your thought given the experience that you had with Bolstilimab, a single arm study with, Botinilimab in some of these cold tumors a possibility, or are you considering, you know, take going from phase two, into phase three?

Speaker 5

All randomized trials, all designed.

Speaker 2

So let me answer this question with a very definitive guidance. Given the changing environment, the regulatory environment, Mike, I think it will be silly for us to take chances with single arm trials. Now, we don't believe that the guidance that is so called the new guidance is necessarily in the best interest of the patients. However,

Speaker 3

that

Speaker 2

is not within our control. So going forward in The U. S, I think it would be a fair conclusion that we will engage in randomized trials for approval.

Speaker 8

Okay, even in populations with unmet need.

Speaker 3

Yes. This is Steve O'Dea. In addition to that, I think obviously we've set these trials up, Phase II trials to follow the data. And we will be if we see data that's clearly very exciting in a significant unmet need, we will be in intensive discussions with the agency around the best path forward. But obviously, we want to be mindful that confirmatory and large randomized trials are almost certainly going to be necessary.

The data will be set up to follow as it develops.

Speaker 8

Steve, as long as we're talking about that, are the Phase II set up in such a way that you could seamlessly roll them into a Phase III? In other words, you use the data in the Phase II setting to be supportive of what you might do in a registration trial?

Speaker 3

Yes. We'll give more information on that in the coming months. We're in active discussions with the agency around these trials. So certainly, we're very interested in if the signals become strong in these trials to moving them as quickly as possible and most efficient way into a Phase III setting.

Speaker 8

Okay. Terrific. And then just shifting gears real quick. Can you say what the mechanism of fifteen seventy one is? Is it ILT4 or is it another target in the tumor associated macrophage space?

Speaker 2

It's in the same family, Mike, but I think it's best for us not to yet release the specific target.

Speaker 8

Fair enough. And then finally, is there any you mentioned all of your wonderful partnerships Gilead, Incyte, Merck, but anything that you can tell us about and Bristol about when we might start seeing some data coming out of those programs to further validate your discovery platform? Thanks.

Speaker 2

I think, I mean, we can't speak of course on their behalf, but given the progress and the speed of patient enrollment in the trials with all of our collaborators, Merck certainly with their ILD4, Gilead, INSIGHT with various programs, Gilead with our conditionally active compound, the CD137 and Bristol with AGEN1007. The enrollment in all of these trials is that a case that you may see some clinical activity this year. However, because these are their programs, I think it would be presumptuous for us to make comments on them and we'll defer it to them.

Speaker 8

Okay, fair enough. Thanks for taking the questions.

Speaker 0

Your next question comes from the line of Matt Phipps. Your line is open.

Speaker 9

Hey, good morning. This is Hunter on for Matt. Maybe just first, it seems like you've switched up your strategy for November a bit from your original plan of starting a couple of trials in gynecological cancers. So could you sort of speak to what went into that decision?

Speaker 2

Sure. I'll really defer this to Doctor. Ode, because these programs are his brainchild with input from his colleagues that have expertise in respective areas. I want to make sure that our audience understands, given the fact that we have seen activity in nine different cancers with our small trial, which is very unusual, small trial meaning a little over 100 patients with nine different tumor types having shown activity is almost a remarkable outcome. So given that, we will pursue eleven eighty one across many, many different tumor types.

But because of regulatory, practical and bandwidth considerations, And because of the early data, the promising data that we've seen in those three indications, the risk reward was such that we should pursue those and make them a priority as the first targets. But Stephen, would you like to elaborate more on this?

Speaker 3

Yes, that's a great question. And the answer is, as Garo said, we have broad activity across nine different tumor types. It's strategic in the sense that GYN malignancies we have good activity in both ovarian and endometrial with limited numbers obviously to date. But it really comes down to what's our bandwidth, what experiments are we trying to do that will move the asset forward and a regulatory environment that's rapidly changing. And we've talked to a lot of KOLs across diseases.

So we've thought this through very carefully. And we think that single agent activity in melanoma is a great stake to put in the ground. We think that combination with a PD-one, our data with MS Stable Colorectal is really the farthest along and the most exciting. We think that a cold tumor like pancreas is sort of aching for a better priming agent, and we think that's a huge unmet need. But depending on partnership and collaborations, which is going to be very dynamic this year, we don't want to lose sight that there are many other tumor types, including GYN malignancies that could easily be addressed.

And we look forward to expanding into those areas. But for our immediate goals in the next six to twelve months, we feel confident that these three important tumor types and experiments will answer some really fundamental questions about our assets.

Speaker 9

Okay, great. Thanks for that. And then maybe it's good to hear that you've seen that additional response in melanoma. Could you maybe say how many melanoma patients have been treated to date now that you've got those two responses? And then maybe just one more.

For these three Phase II trials, I know you said you're still working on the design, but are you thinking that those will be randomized trials? Or are you sort of assuming that you'll have to move to randomized Phase III in those indications?

Speaker 3

So without getting into too much specifics, the Phase one trial was really limited to non melanoma patients until very recently. So we've already seen these two responses in two separate disease sort of PD-one refractory and then PD-one CCLI-four refractory with just a handful of patients. And we are actively now expanding the melanoma cohort and we'll be accumulating more data in the coming months that we hope to update you on as we launch the Phase two melanoma trial. I'm sorry, what's the second part of the question?

Speaker 9

Yes, was just asking about the design of the Phase 2s coming up, whether or not you're thinking those trials will be randomized trials?

Speaker 3

So right now, we talked about in melanoma single arm studies in these two cohorts. And in terms of we'll release more details on the design after further discussion with the FDA in the other diseases.

Speaker 2

Great, thanks.

Speaker 0

We have a follow-up question from Mayank Mamtani. Your line is open.

Speaker 7

Yes. Thank you for taking my follow-up. I just have a quick financial question that just came in. So in terms of recognizing what seems like a 2,800,000,000 in milestones and royalty cumulative, you just clarify if there's anything in there in near term, say, this year? And maybe also just if you could provide any color on what might be added next to this list, anything you have visibility on that could bring that sort of next bolus of cash potentially an upfront payment?

Speaker 2

Mayank, if I understand this correctly, are you asking whether there'll be additional partnerships that we anticipate? Or is it that we will get more payments from existing partnerships during the course of

Speaker 7

Kind of yes, kind of both. On slide basically on slide six, that cumulative number is 2.8, but you know, curious if anything is going to be near term on those milestones. And then, you know, things that are not on the slide that we should keep in mind as we think about 2022 financials.

Speaker 2

Right. So as Christine said, we closed the year with a little over $300,000,000 in cash. And it's possible that we will get additional milestone payments this option exercise payments during the course of this year. It's also possible that we will enter into collaborations or possibly different geographies for different compounds in 2022. So our strategy to make sure that our financings or sources of financing are not dependent on one specific thing continues.

And that's one of the reasons, for example, in our filing today, we expanded our options of potentially funding the company through equity financing. There are no immediate plans for anything right now and other means. So one of the hallmarks of our strategy over the years has been we have been consistent in generating collaboration income over $800,000,000 in the last five plus years. And we have been consistent in not coming into the markets with marketed offerings. We've been consistent with that.

So we will continue to exercise prudence in the way we fund the company until a watershed event occurs. And for us, a watershed event occurring is obviously an accelerated path for product approval or a mega collaboration of sorts.

Speaker 7

Thank you for taking my follow-up. That's helpful.

Speaker 2

Thank you, Mayank.

Speaker 0

Excuse me presenters, there are no more phone questions. You may continue.

Speaker 2

Thank you very much for your time and interest in our company. And please feel free to connect with us. In the future, we may change the format of quarterly communication. And so stay tuned for that. But we're always happy to entertain questions from our investors and other constituencies.

Thank you very much.

Speaker 0

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