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Operator
Ladies and gentlemen, thank you for standing by and welcome to the Agenda's fourth quarter 2021 financial results. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you will need to press star 1 on your telephone keypad. If you require any further assistance, please press star 0. I would now like to hand the conference over to your speaker today. Ms. Divya Vasudevan, please go ahead.
Divya Vasudevan
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 Dr. Gerald Arman, Chairman and Chief Executive Officer, Dr. Stephen O'Day, Chief Medical Officer, Dr. Jennifer Buell, Chief Executive Officer of Mink Therapeutics, Chandresh Harjeevan, Chief Operating Officer of Saponix, and Christine Klaskin, Vice President of Finance. With that, I'll turn the call over to Gero to highlight the progress that we've made to date this year. Gero?
Gerald Arman
Thank you, Divya. Thank you all for your participation and your interest in Agenis. 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 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 Fulton Sillimab. 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 de-risk development. The second pillar consists of potential cash generators through strategic partnerships. such as what we have done with AGEN 1777, our TIGIT by specific 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, Bostilumab. 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 Saponix. While Agenis 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, Botansilomat. As you know, we have treated well over 100 patients in Phase I trials evaluating botansilumab as monotherapy and in combination with bostilumab. We presented data at the CITSE meeting last year, which demonstrated that botansilumab 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 three, botansilumab, 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, botansilumab is FC-enhanced to improve the efficacy and safety of CTLA-4 blockade through three primary mechanisms. First is botansilumab 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 immunosuppressive activity of regulatory T cells, all in one antibody. As presented at CITC, Botansilumab is the first CTLA-4 inhibitor to demonstrate clinical responses across nine, nine cold and treatment-resistant cancers. Second, botansilumab is designed to expand clinical benefit in hot tumors, such as melanoma, where CTLA-4 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 is a lot of room to improve here. We have observed responses across both hot and cold cancers in patients. We expressed a biomarker associated with poor outcomes to first-generation CTLA-4. And finally, Botansilumab 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. Stephen O'Day, who is one of the global experts in this field to review our upcoming plans for PotencilaMAP. Steven?
Divya
Thank you, Garo. 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 botanstilumab in combination with RPD1 antibody in MS-stable colorectal cancer. And three, establish botanostilumab as a superior combination agent for chemotherapy in cold tumors by evaluating botanostilumab in combination with standard of care chemotherapy in pancreatic cancer. 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 progress within a year and are in need of more effective treatment options. Response rates with ipilimumab monotherapy are approximately 15%, and most patients progress within months. At CITC, we reported a confirmed partial response in PD-1 relapsed refractory melanoma. Since CITC, we have observed a second melanoma patient responding to single-agent botanstilumab 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 two trial in melanoma, evaluating botanostilumab 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 botanostilumab 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 botanostilumab can rescue ipinevo failures, a patient population with very limited treatment options. In addition to our botanostilumab monotherapy study, We have expanded our AGEN 2373 phase 1B trial and are now recruiting a cohort of PD-1 resistant refractory melanoid patients to receive AGEN 2373 in combination with our botanostilumab. AGEN 2373 is a CD137 agonist antibody designed to be conditionally active in the tumor microenvironment. To date, AGEN 2373 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, an antagonist, botanostilumab, 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 botanostilumab and our PD-1-balstilumab 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 US. Approximately 95% 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 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 botanostilumab and our bostilumab 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 botanostilumab and baostilumab in this combination. We anticipate that the outcome of the study will strengthen the efficacy signal and safety signal and demonstrate it to date and could support further phase three 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 3%. This disease claims 50,000 lives annually in the US alone, and there's 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 CITC, 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 botanstilumab 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 represent a significant addressable population and where immunotherapies 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 two trial designs. Together these trials in different settings with different combinations set up botanstilumab across both IO and non-IO combinations. and de-risk phase three trials. As shown on slide five, positive data in these studies can unlock the franchise potential of botanstilumab, 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 botanstilumab has shown clinical benefit, but other CTLA-4 agents have not. I will now turn the call back over to Garo.
Gerald Arman
Thank you very much, Stephen. 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 planned development and potential launch of Potentiolumab, including, for example, our internal manufacturing capacity to support what will be potentially over $10 billion in annual sales at our Emeraldville 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 Emeraldville facility. Let me also talk about AGEN 1571. This is a new clinical program that is about to start, and it is AGEN 1581. 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 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 ILT-4 antagonist discovered by Agenis and licensed to Merck. And that program has shown durable responses in PD-1 resistant cancers. With Agen 1571, 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 by specific AGEN-1777. Similar to Botanicellumab, AGEN-1777 is FC-enhanced to promote single-agent anti-tumor immunity, an area where clinical stage TIGIT therapies are yet to 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-1777 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 million from BMS in the past 12 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 a genus. 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 TIM3 and Agenis discovered LAT3 antagonists with PD-1 in PD-1 relapse refractory melanoma. Across our partner programs, we are, as I said earlier, eligible for $2.8 billion in Milestone Plus royalties. 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 Bostilumab. This is one of the third pillars of our business model. Enablers such as PD-1 antibody, Bostilumab, has exhibited strong clinical activity and excellent safety profile in over 400 patients evaluated to date. In a Phase II trial in second-line cervical cancer, Bostilumab 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 zoliferilimab, our first-generation CTLA-4 antibody, the response rate with zoliferilimab plus PD-1, our ostilimab, 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 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 Saponix. 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 Chen, to address saponics, I will refer to Chen, who is the chief operating officer of saponics. And Chen, if you can make some comments about the progress we're making at saponics.
Potentiolumab
Thank you, Gero, 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 QS21 stimulant has been validated over the years by Shingrix with protection exceeding nine years. Clinical and preclinical data report broad applicability of QS21 across more than 20 disease settings. However, QS21 supply is constrained due to its reliance on a complicated and expensive extraction process from a Chilean soap tree, bark. So at Saponix, we have developed a plant cell culture method of manufacturing QS21 and next generation adjuvants. Plant cell culture offers a more sustainable, scalable, and cost-effective method of manufacturing QS21 versus bark extracts. We expect to have GMP material from this manufacturing process this year able to partner clinical trials. 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 vaccine, platform design, innovation, and pandemic response from inception to commercial launch. Thank you. With that, Gero, I'm going to turn the call over to Christine Klaskin to discuss her financials.
Gero
Thank you, Tom. We ended the year 2021 with a cash and short-term investment balance of $307 million. This compares to $100 million at December 31st, 2020. We recognized revenue of $296 million and $88 million for the years ended December 31st, 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 31st, 2021 was $10 million with a reported net loss of $29 million or 11 cents 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 31st, 2021 were $49 million compared to $37 million for the year ended 2020. Net loss for the fourth quarter ended 2021 with $68 million or 26 cents per share compared to a net loss for the same period in 2020 of $38 million or 20 cents 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.
Gerald Arman
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 Dr. O'Day mentioned, evaluating botansilumab in melanoma, microsatellite stable colorectal cancer, and pancreatic cancer. Two, Complete enrollment of a proof-of-concept study, evaluating botansilumab in combination with our conditionally active CD137 agonist in melanoma. Three, initiate a phase one study for agent 1571, a novel program targeting tumor-associated macrophages. Four, Generate GMP-grade QS21 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 Botansilumab. 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 Emeraldville under the tutelage of our chief manufacturing officer, Dr. Al Dutson. 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 questions.
Operator
At this time, if you would like to ask a question, please press star 1 on your telephone keypad. Again, that is star 1 on your telephone keypad. And your first question comes from the line of Kelly Shih. Your line is open.
Kelly Shih
Hi, good morning. This is Jason Bouvier on for Kelly Shih. Thank you for taking our question. And I apologize if I missed this, but on the bow-zowel 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.
Gerald Arman
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 bostilumab as a single agent therapy or bostilumab plus our zoliferulamab as combination therapy in cervical cancer in the USA.
Kelly Shih
Got it. Thank you very much.
Operator
And your next question comes from the line of Mayank Montani. Your line is open.
Mayank Montani
Good morning. Congrats on the progress, and thanks for taking our questions. So maybe just starting with incremental updates on PotentialMap, if I said the name right. Could we just get a bit more color on some of these initial indications in terms of, you know, path to actual approval? As I understand, you look to engage with regulators still You know, 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 in, is it first line with chemo or is it later lines? And then I have a follow-up.
Gerald Arman
Sure. I think these are excellent questions for Dr. Stephen O'Day. So if I can ask Stephen to address them.
Divya
Yes, thank you for the question. So in melanoma, as I indicated, we think that this is an optimal opportunity for testing single-agent botanostilumab activity in two settings. One is the PD-1 resistant refractory, but CTLA-4 naive 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-nevo frontline or have had sequential nevo 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 Boten-Stilumab 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 one trial a patient who had received ipi11mab in the adjuvant setting and then progressed and then received ipinevo 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 I data and look forward to testing the next-gen CTLA-4 in both of these important melanoma cohorts. And then in terms of pancreas, you know, 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 Montani
Thank you for that level of detail. And maybe just to follow up on 1181, could you, as you think high level, you know, going beyond the initial three tumor types, like lung, like prostate, what in your view is that complementary therapy, you know, that is not an established IO or non-IO that, you know, could make sense to synergistically from a mechanistic standpoint?
Divya
Yeah, you know, thanks. That's another great question. You know, CTLA-4, we think 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-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 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, you know, a more typical PD-1 combination in a very difficult to treat MS stable. And then whether it can 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 NextGen CTLA-4 as a single agent and a combinational, both with NIO and XIO, And obviously our collaborative partners that are in discussions, obviously this 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. Great.
Mayank Montani
And if I could also ask a quick 1571 question. Have you disclosed the target, specific target for that? And more broadly, how might Merck's IL-T4 data mid-year inform, you know, how you plan to develop it this year in clinic? Would appreciate the color there.
Gerald Arman
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 Montani
Okay, great. And my final question was just quickly on saponic UX. How far are you from the clinic, you know, particularly for the intranasal vaccine? Intranasal vaccine, how far are you from the clinic?
Gerald Arman
So 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 QS7. And what we have done with QS7 is really because it's so active as a mycosal adjuvant, we have now developed plant-based cell lines to improve the yields from QS7. Because for many, many years, 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 QS7 so that we can run some experiments and have partnership discussions.
Mayank Montani
Thanks so much for taking that question.
Operator
Your next question comes from the line of Mike King. Your line is open.
Mike King
Good morning, guys. Thanks for taking the question. I just wanted to – I don't want to draw conclusions, but wanted to ask if – Given the experience that you had with Volstilamab, is a single-arm study with Volstilamab in some of these cold tumors a possibility, or are you considering going from Phase II into Phase III? Okay.
Gerald Arman
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.
Mike King
Okay. Even in populations with unmet need.
Divya
Yep. This is Steve O'Day. You know, in addition to that, I think obviously we've set these trials up, phase two trials, to follow the data. And we will be, you know, if we see, you know, data that's clearly, you know, very exciting in a significant unmet need, we will be in you know, 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 will be set up to follow as it develops. Okay.
Mike King
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 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?
Divya
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, you know, if the signals become strong in these trials to moving them as quickly as possible in the most efficient way into a Phase III setting. Okay. Terrific.
Mike King
And then just shifting gears real quick, can you say what the mechanism of 1571 is? Is it ILT4 or is it another target in the tumor-associated macrophage space?
Gerald Arman
It's in the same family, Mike, but I think it's best for us not to yet release the specific target.
Mike King
Fair enough. And then finally, is there any, you know, you mentioned all of your wonderful partnerships, Gilead, Insight, 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.
Gerald Arman
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 program, Insight with various programs, Gilead with our conditionally active compound, the CD137, and Bristol with Agen 1777. The enrollment in all of these trials is at a pace 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 will defer to them.
Mike King
Okay. Fair enough. Thanks for taking the questions.
Operator
Your next question comes from the line of Matt Phipps. Your line is open.
Matt Phipps
Hey, good morning. 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 cancer. So could you sort of speak to what went into that decision?
Gerald Arman
Sure. I'll really defer this to Dr. O'Day 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 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?
Divya
Steven Felsenfeldt Yes. It's a great question. And, you know, 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, today. You know, 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-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 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 12 months, we feel confident that these three important tumor types and experiments will answer some really fundamental questions about our assets.
Matt Phipps
Okay, great. Thanks for that. And then maybe, you know, 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 IIIs in those indications?
Divya
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-1 refractory and then PD-1 CCLA-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 II melanoma trial. I'm sorry, what's the second part of the question?
Matt Phipps
Yeah, I was just asking about the design of the Phase IIs coming up, whether or not you're thinking those trials will be randomized trials.
Divya
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.
Matt Phipps
Great, thanks.
Operator
Again, if you would like to ask a question, please press star 1 on your telephone keypad. Again, that is star one in your telephone keypad. You have a follow-up question from Mayak Mamtani. Your line is open.
Mayank Montani
Yes, thank you for taking my follow-up. I just have a quick financial question that just came in. So in terms of, you know, recognizing what seems like a $2.8 billion in milestones and royalty cumulative, can 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, you know, what might be added next to this list, anything you have visibility on that could bring that sort of next bonus of cash, you know, potentially an upfront payment.
Gerald Arman
Mayank, if I understand this quite 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 Montani
Yeah, kind of both. You know, on slide, basically on slide six, you know, that cumulative number is 2.8, but, you know, curious if anything is going to be near term on those milestones and then And then, yes, you know, things that are not on the slide that we should keep in mind as we think about 2022 financials.
Gerald Arman
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 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 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 sorts.
Mayank Montani
Thank you for taking my follow-up. That's helpful. Thank you, Mayank.
Operator
Again, if you would like to ask a question, please press star 1 on your telephone keypad. Again, that is star 1 on your telephone keypad. Excuse me, presenters. There are no more phone questions. You may continue.
Gerald Arman
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
This concludes today's conference call. You may now disconnect.
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