Agenus (AGEN) Q4 2021 Earnings Call Transcript

Agenus (AGEN -10.49%)
Q4 2021 Earnings Call
Mar 01, 2022, 8:30 a.m. ET

Contents:

• Prepared Remarks
• Questions and Answers
• Call Participants

Prepared Remarks:

Operator

Ladies and gentlemen, thank you for standing by, and welcome to the Agenus fourth quarter 2021 financial results. [Operator instructions] I would now like to hand the conference over to your speaker today, Ms. Divya Vasudevan. Ma'am, Please go ahead.

Divya Vasudevan -- Senior Director, Oncology Strategy and Investor Relations

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 relief 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 Dr. Garo Armen, chairman and chief executive officer; Dr. Steven O'Day, chief medical officer; Dr.

Jennifer Buell, chief executive officer of MiNK Therapeutics; Chandresh Harjivan, chief operating officer of SaponiQx; 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?

Garo Armen -- Chairman and Chief Executive Officer

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 tried 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 derisking development and accelerating our path to market. The first pillar consists of our value creators are fully or majority-owned programs, such as botensilimab.

That's our next-generation CTLA-4, previously known as 1181. 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 AGEN1777, our TIGIT bispecific license to BMS. We have received over $800 million in cash through upfront and achieved milestone payments from these types of transactions over the past five, six years and are eligible for additional $2.8 billion 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-1 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 derisking development through one centralized entity. Four, the fourth pillar is represented by our subsidiaries, MiNK Therapeutics and SaponiQx.

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, botensilimab. As you know, we have treated well over 100 patients in phase 1 trials, evaluating botensilimab as monotherapy and in combination with balstilimab. We presented data at the SITC meeting last year, which demonstrated that botensilimab has an improved efficacy and safety profile compared to what has been reported with previous CTLA-4 antibodies, that is both first generation and the next generation.

As shown on Slide 3, botensilimab, 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 3, botensilimab is FC-enhanced to improve the efficacy and safety of CTLA-4 blockade through three primary mechanisms. First, is botensilimab is designed to extend the curative benefits of immuno-oncology to consumers 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, botensilimab is the first CTLA-4 inhibitor to demonstrate clinical responses across nine cold and treatment-resistant cancers. Second, botensilimab is designed to expand clinical benefit in hot tumors, such as melanoma, where CTLA-4 is already approved, but result in clinical benefit in only a third of patients and long-term survival in less than a quarter of the patients. So there is a lot of room to improve here.

We have observed responses across both hot and cold cancers in patients who expressed their biomarker associated with poor outcomes to first-generation CTLA-4. And finally, botensilimab 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, Dr. Steven O'Day, who is one of the global experts in this field to review our upcoming plans for botensilimab.

Steven?

Steven O'Day -- Chief Medical Officer

Thank you, Garo. Building upon the data observed in our phase 1 trial, we are continuing to expand disease-specific cohorts in the phase 1b component of the trial, and we will be initiating phase 2 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 of a single agent. Second, build upon the signals observed in our phase 1 study by pursuing botensilimab in combination with our PD-1 antibody in MS stable colorectal cancer.

And three, established botensilimab as a superior combination agent for chemotherapy in cold tumors, by evaluating botensilimab 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-1 progressed within a year and are, in need -- and are in need of more effective treatment options.

Response rates with ipilimumab monotherapy are approximately 15%, and most patients' progress within months. At SITC, we reported a confirmed partial response in PD-1 relapsed refractory melanoma. Since SITC, we have observed the second melanoma patient responding to single-agent botensilimab with more than a 40% tumor reduction at their first six-week scan. This patient had been -- previously progressed after ipilimumab in the adjuvant setting and subsequently ipilimumab and nivolumab in the metastatic study.

We have designed a phase 2 trial in melanoma evaluating botensilimab monotherapy in both PD-1 resistant refractory setting as well as a PD-1 CTLA-4 resistant refractory setting. The first cohort in PD-1 refractory resistant patients will allow us to quantify the superiority of botensilimab compared to historical ipilimumab. We are targeting a response rate of 25% or greater. The second cohort in PD-1 and CTLA-4 relapsed resistant patients will explore whether botensilimab can rescue ipi/nivo failures, a patient population with very limited treatment options.

In addition to our botensilimab monotherapy study, we have expanded our AGEN2373 phase 1b trial and are now recruiting a cohort of PD-1 resistant refractory melanoma patients to receive AGEN2373 in combination with our botensilimab. AGEN2373 is a CD137 agonist antibody designed to be conditionally active in the tumor microenvironment. Today, 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 botensilimab in melanoma, an immunogenic tumor as this represents a potential novel scientific advancement.

Next, we are planning to study in MS-stable colorectal cancer, where our phase 1 data with botensilimab and our PD-1 balstilimab combination has shown best-in-class potential compared to standard of care and other drugs in development. Colorectal cancer claims over 50,000 lives annually in the U.S. Approximately 95% of Stage IV colorectal cancers are classified as microsatellite stable, or MS stabs, 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 2% with median progression-free survival of only two months.

In 20 patients treated to date in our MS-stable colorectal cohort, we observed a 20% response rate and 70% disease control rate for botensilimab and our balstilimab combination with the majority of responses ongoing at six months. This favors positively to the competitive landscape where first-generation CTLA-4 PD-1 combinations have reported only rare responses and limited disease control. Our study will be designed to evaluate the contribution of components of botensilimab 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 3 development.

Finally, I'll provide an overview of our approach in pancreatic cancer. The five-year survival rate for Stage IV pancreatic cancer is about 3%. This disease claims 50,000 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-4 or PD-1 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-4. We plan on evaluating botensilimab in combination with standard of care chemotherapy in metastatic pancreatic cancer. This trial will enable the expansion of our CTLA-4 franchise into cold tumors, which represents a significant addressable population and where immune-therapies have been largely ineffective.

Our combination strategy with approved chemotherapy could accelerate the path forward while tapping into the synergistic potential of CTLA-4 next-generation with chemotherapy combinations across multiple solid tumors. Now we are actively working with the agency to finalize these phase 2 trial designs. Together these trials in different settings with different combinations set up botensilimab across both I-O and non-I-O combination and derisk phase 3 trials. As shown on Slide 5, positive data in these studies can unlock the franchise potential of botensilimab, 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 botensilimab has shown clinical benefit, but other CTLA-4 agents have not.

I will now turn the call back over to Garo.

Garo Armen -- Chairman and Chief Executive Officer

Thank you very much, Steven. As Dr. O'Day 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 plan development and potential launch of botensilimab, including, for example, our internal manufacturing capacity to support what will be potentially over $10 billion 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 AGEN1571. This is a new clinical program that is about to start, and it is an AGEN1581. It will happen this year.

And it's a novel program targeting tumor-associated macrophages, which promote resistance to PD-1 and CTLA-4 therapy. And so there is a very strong rationale as to why we have done 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 license to Merck. And that program has shown durable responses in PD-1 resistant cancers.

With AGEN1571, we continue to advance additional discoveries targeting myeloid sales, cells rather. If you turn to Slide 6, 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 strategic bispecific AGEN1777. Similar to botensilimab, AGEN1777 is Fc-enhanced to promote single-agent antitumor 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 antitumor immunity. AGEN1777 is currently in phase 1 dose escalation trials and BMS intends for advanced 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 million from BMS in the past 12 months across upfront and achieved milestones and retained 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 MK-4830. As I mentioned earlier, Merck is advancing a myeloid targeting antibody, MK-4830, 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 Incyte program. That was one of our first partnerships. Incyte is advancing our clinical stage programs and clinical recently initiated a unique combination trial evaluating the AGEN-discovered TIM-3 and Agenus discovered LAG-3 antagonist with PD-1 in PD-1 relapsed refractory melanoma.

Across our partner programs, we are, as I said earlier, eligible for $2.8 billion 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-1 antibody balstilimab has exhibited strong clinical activity and excellent safety profile in over 400 patients evaluated to date. In a phase 2 trial in second-line cervical cancer, balstilimab demonstrated a response rate of 20% in PD-L1 positive patients, which represents a 40% improvement to the response rate reported for pembrolizumab, the only approved PD-1 agent for these patients. Now, in combination with zalifrelimab our first-generation CTLA-4 antibody, the response rate with zalifrelimab plus PD-1, balstilimab has increased to 33% 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 U.S., 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 SaponiQx. MiNK Therapeutics last year launched an IPO to support clinical development of allogeneic iNKT 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 Chan to address SaponiQx, I will refer to Chan, who is the Chief Operating Officer of SaponiQx. And Chan, if you can make some comments about the progress we're making at SaponiQx.

Chandresh Harjivan -- Chief Operating Officer

Thank you, Garo, and really excited to be part of the team. I joined SaponiQx 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 vaccine, something close to my heart to address pandemic threats and other diseases.

The needs 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-21 Stimulon has been validated over the years by Shingrix with protection exceeding nine years. Clinical and preclinical data report broad applicability of QS-21 across more than 20 disease settings.

However, QS-21 supply is constrained due to its reliance on a complicated and expensive extraction process from the Chilean soap tree bark. So SaponiQx, we have developed a plant cell culture method of manufacturing QS-21 and next-generation adjuvants. Plant cell culture offers a more sustainable, scalable and cost-effective method of manufacturing QS-21 versus bark extract. We expect to have GMP material from this manufacturing process this year able to partner clinical trial.

And very exciting, we're also developing new novel adjuvants with the potential to increase mucosal immunity through intranasal delivery which is particularly critical for addressing respiratory pandemic threats such as COVID-19, but also vaccination efforts throughout the world in other disease categories. We've built a strong leadership and advisory team to achieve these objectives with rich experience in vaccines, 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.

Christine Klaskin -- Vice President of Finance

Thank you, Chan. We ended the year 2021 with a cash and short-term investment balance of $307 million. This compares to $100 million at December 31, 2020. We recognized revenue of $296 million and $88 million for the years ended December 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 December 31, 2021, was $10 million with a reported net loss of $29 million or $0.11 per share compared to cash used in operations of $139 million and a net loss for the year ended 2020 of $183 million or $1.05 per share. Non-cash operating expenses for the year ended December 31, 2021, were $49 million compared to $37 million for the year ended 2020. Net loss for the fourth quarter ended 2021 was $68 million or $0.26 per share compared to a net loss for the same period in 2020 of $38 million or $0.20 per share. For the fourth quarter ended December 31, 2021, our cash used in operations was $23 million compared to $36 million for the same period in 2020.

I'll now turn the call back to Garo.

Garo Armen -- Chairman and Chief Executive Officer

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 7, in the near term, I'll give you a sampling of what we plan to accomplish: One, to launch phase 2 trials as Dr. O'Day mentioned, evaluating botensilimab in melanoma, microsatellite stable colorectal cancer and pancreatic cancer; two, complete enrollment of a proof-of-concept study, evaluating botensilimab in combination with our conditionally active CD137 agonist in melanoma; three, initiate a phase 1 study for AGEN1571 a novel program targeting tumor-associated macrophages; four, generate GMP-grade QS-21 Stimulon through SaponiQx'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 botensilimab; two, we will continue to advance our vision platform for more efficient and effective clinical trial designs; three, we will advance 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, Dr. Al Dadson; 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.

Questions & Answers:

Operator

[Operator instructions] And your first question comes from the line of Kelly Shi. Your line is open.

Jason Bouvier -- Scotiabank -- Analyst

Hi. This is Jason Bouvier here on for Kelly Shi. And I apologize if I missed this, but on the bal-zal combo in 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.

Garo Armen -- Chairman and Chief Executive Officer

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 U.S., 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 zalifrelimab as combination therapy in cervical cancer in the USA.

Jason Bouvier -- Scotiabank -- Analyst

Got it. Thank you very much.

Operator

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

Mayank Mamtani -- B. Riley Financial -- Analyst

Good morning. Congrats on the progress and thanks for taking our question. So maybe just starting with incremental updates on botensilimab, 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 accelerate approval, as I understand you look to engage with regulators still? Is it PD-1 refractory melanoma where it seems like you've already identified single-agent target ORRs. And also like if you could clarify the pancreatic metastatic setting, you're going and is it first line with chemo or is it late lines? And then I have a follow-up.

Garo Armen -- Chairman and Chief Executive Officer

Sure, I think these are excellent questions for Dr. Steven O'Day if I can ask Steven to address them.

Steven O'Day -- Chief Medical Officer

Yeah. Thank you for the question. So in melanoma, as I indicated, we think that this is an optimal opportunity for testing single-agent botensilimab activity in two settings. One is of the PD-1 resistant refractory but CTLA-4 naïve setting, where single-agent ipilimumab has approximately a 15% response rate.

And we're targeting a 25% 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-4 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 botensilimab 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 1 trial, a patient who had received ipilimumab in the adjuvant setting and then progressed and then received ipi/nivo 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 30 years that are getting energized by our phase 1 data and look forward to testing the next-gen CTLA-4 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-4 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.

Mayank Mamtani -- B. Riley Financial -- Analyst

Thank you for that level of detail. And maybe just a follow-up on 1181, 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 I-O or non-I-O that could make sense to synergistically from a mechanistic standpoint? Will you may be...

Garo Armen -- Chairman and Chief Executive Officer

That's another great question. CTLA-4, we think if we -- with the 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-1, 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 stand-alone 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-1 combination in a very difficult to treat MS-stable. And then whether it could be a foundational and better partner than PD-1 in combination with chemo and pancreas, where PD-1 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-4 as a single agent and a combination of both within I-O and ex I-O. And obviously, our collaborative partners that are in discussions.

Obviously, this is very interesting because it will move the -- potentially the asset forward with much deeper resources across other tumors, like lung and prostate and other big unmet needs.

Mayank Mamtani -- B. Riley Financial -- Analyst

Great. And if I could also ask a quick 1571 question. Have you disclosed the target -- specific targets for that? And more broadly, how might Merck's ILT4 midyear inform how you plan to develop it this year in clinic. I would appreciate the color there?

Garo Armen -- Chairman and Chief Executive Officer

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

Mayank Mamtani -- B. Riley Financial -- Analyst

OK, great. And my final question was on -- just quickly on SaponiQx. How far are you from the clinic particularly for the intranasal vaccine?

Garo Armen -- Chairman and Chief Executive Officer

So your question is the potential of 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-7. And what we have done with QS-7 is really because it's so active as a mucosal adjuvant. We have now developed plant-based cell lines to improve the yields from QS-7 because for many, many years, Mayank, we have known that QS-7 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 QS-7 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-7 so that we can run some experiments and have partnership discussions.

Mayank Mamtani -- B. Riley Financial -- Analyst

Thanks so much for taking our question.

Operator

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

Unknown speaker

Good morning. 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 balstilimab, is a single-arm study with botensilimab in some of these cold tumors a possibility or are you considering take, going from phase 1 into phase 3?

All randomized trials.

Garo Armen -- Chairman and Chief Executive Officer

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, that 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.

Unknown speaker

OK even in populations with unmet need?

Steven O'Day -- Chief Medical Officer

Yes, this is Steve O'Day. In addition to that, I think, obviously, we've set these trials up phase 2 trials to follow the data, and we will be -- if we see data that's clearly very exciting and 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. But the data -- we set up to follow as it develops.

Unknown speaker

OK. Steve, as long as we're talking about that, are the phase 2 set up in such a way that you could seamlessly roll them into a phase 3? In other words, can you use the data in the phase 2 setting to be supportive of what you might do in a registration trial?

Steven O'Day -- Chief Medical Officer

Yeah, 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 move them as quickly as possible in a most efficient way into a phase 3 setting.

Unknown speaker

OK, terrific. And then just shifting gears real quick, can you say what the mechanism of 1571 -- is it ILT4 or is it another target in the tumor-associated macrophage space?

Garo Armen -- Chairman and Chief Executive Officer

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

Unknown speaker

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?

Garo Armen -- Chairman and Chief Executive Officer

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 ILT4 Incyte with various programs. Gilead with our conditionally active compound, the CD137, and Bristol with AGEN1777, the enrollment in all of these trials is at a pace that you may see some clinical activity this year. However, because these are the programs, I think it would be presumptuous for us to make comments on them and we'll defer it to them.

Unknown speaker

OK, fair enough. Thanks for taking the questions.

Operator

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

Unknown speaker

This is Hunter on for Matt. Maybe just first, it seems like you've switched up your strategy for 1181 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?

Garo Armen -- Chairman and Chief Executive Officer

Sure. I'll really defer this to Dr. O'Day because these programs are his brain child 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 1181 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 Steven, would you like to elaborate more on this?

Steven O'Day -- Chief Medical Officer

Yeah, it's a great question. And the answer is, as Garo said, we have broad activity plus 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 the combination with the PD-1, 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 akin 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 media goals in the next six to 12 months, we feel confident that these three important tumor types and experiments will answer some really fundamental questions about our assets.

Unknown speaker

OK, 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 pages have been treated to date now that you've got those two responses? And then maybe just one more for these three phase 2 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 3 in those indications?

Steven O'Day -- Chief Medical Officer

So without getting into too much specifics, the phase 1 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-1 refractory and then PD-1 CTLA-4 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 2 melanoma trial. I'm sorry, what's the second part of the question?

Unknown speaker

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

Steven O'Day -- Chief Medical Officer

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.

Unknown speaker

Great. Thanks.

Operator

[Operator instructions] We have a follow-up question from Mayank Mamtani. Your line is open.

Mayank Mamtani -- B. Riley Financial -- Analyst

Yes, thank you for taking my follow-up. I just have a quick financial question that just came in. So in terms of recognizing it what seem like a $2.8 billion in milestones and royalty cumulative, can you just clarify that 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 in upfront payment?

Garo Armen -- Chairman and Chief Executive Officer

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

Mayank Mamtani -- B. Riley Financial -- Analyst

Yeah, kind of both. On slide -- basically, on Slide 6, that cumulative number is $2.8 million but curious if anything is going to be near term on those milestones. And then yeah, things that are not on this slide that we should keep in mind as we think about 2022 financials?

Garo Armen -- Chairman and Chief Executive Officer

Right. So as Christine said, we closed the year with a little over $300 million in cash. And it's possible that we will get additional milestone payments this year or option exercise payments during the course of this year. It's also possible that we will enter into collaborations for 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. It continues. And that's one of the reasons, for example, in our filings 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 million 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 search.

Mayank Mamtani -- B. Riley Financial -- Analyst

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

Garo Armen -- Chairman and Chief Executive Officer

Thank you, Mayank. Any other questions?

Operator

[Operator instructions] Excuse me, presenters, there are no more phone questions. You may continue.

Garo Armen -- Chairman and Chief Executive Officer

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.

Operator

[Operator signoff]

Duration: 64 minutes

Call participants:

Divya Vasudevan -- Senior Director, Oncology Strategy and Investor Relations

Garo Armen -- Chairman and Chief Executive Officer

Steven O'Day -- Chief Medical Officer

Chandresh Harjivan -- Chief Operating Officer

Christine Klaskin -- Vice President of Finance

Jason Bouvier -- Scotiabank -- Analyst

Mayank Mamtani -- B. Riley Financial -- Analyst

Unknown speaker

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