Q4 2021 Agenus Inc Earnings Call

Ladies and gentlemen, thank you for standing by and welcome to the <unk> fourth quarter 2021 financial results.

Operator: Thank you. Ladies and gentlemen, thank you for standing by and welcome to the Agenus fourth quarter 2021 financial, At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer. To press a question during the session, you will need to press star 1 on your telephone.

At this time all participants are in a listen only mode.

After the speaker's presentation, there will be a question and answer session.

Can I ask a question during the session you will need to press star one on your telephone keypad.

If you require for any further assistance please press star zero.

I would now like to hand, the conference over to your speaker today.

Operator: If you require any further assistance, please press star zero. I would now like to hand the conference over to our speaker today, Ms. Divya Vasudevan. And please go ahead.

Steve you have as a device.

Ma'am. Please go ahead.

Thank you.

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.

And thank you all for joining today today's call is being webcast and will be available on our website for replay I.

Divya Vasudevan: 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 filing for more details on these risks. As another reminder, this call is being recorded for audio broadcasts.

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.

Divya Vasudevan: 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 Harjeevan, Chief Operating Officer of Saponix, 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.

Joining me today are Dr. Garo, Armen, Chairman and Chief Executive Officer, Dr. Stephen <unk>, Chief Medical Officer, Dr. Jennifer Buell, Chief Executive Officer of <unk> Therapeutics.

<unk> <unk>, Chief operating officer of <unk>, and Christine Class, Kim 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.

Sure.

Thank you. Thank you all for your participation and your interest in <unk>.

Garo Armen: Thank you, Divya. Thank you all for your participation and your interest in Agenus. As I go through our poll today, I'll be referencing the 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.

As I go through our call today I'll be referencing slide numbers from time to time on the presentation.

It 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.

Garo Armen: 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 mark. The first pillar consists of our value creation, are fully or majority-owned programs such as Fulton Sillimap.

And based on that our business model is comprised of four pillars. This approach allows us to strategically develop our pipeline.

Independently as wetlands with partners.

Value while de risking development.

And accelerating our path to market.

The first pillar.

Garo Armen: 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 Agent 1777, our tiget 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.

Some are value creators.

Our fully or majority on programs such as.

So the map.

That's our next generation <unk> four <unk>.

Previously known as <unk> 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 a gen. One triple seven.

Our tissue 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 years six years.

And are eligible for an additional two 8 billion and 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 while still a map.

Garo Armen: Three, the third pillar consists of enablers, such as our PD-1 antibody, Balsillumab. 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.

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.

For the fourth pillar is.

Garo Armen: For the fourth pillar is represented by our subsidiary. Mink Therapeutics and Saponics. While Agenus retains majority ownership in these entities.

As represented by our subsidiaries, mainly therapeutics and <unk>.

While Genesis retains the majority ownership in these entities they are structured for independent financing, which allows for focus and accelerated development of their respective products.

Garo Armen: They are structured for independent finance, 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, Botancilumab. As you know, we have treated, well over 100 patients in phase one trials, evaluating botensilimab as monotherapy and in combination with balsilimab. We presented data at the SIDSI meeting last year, which demonstrated that botansilamab, 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, Botencilla map, by the way, you can advance these slides on your own. We don't have the means to do that from here for you.

I would like to begin the call by addressing the first pillar, which is driven by our flagship program <unk>.

As you know we have treated well over 100 patients in phase one trials evaluating what kind of silly map as monotherapy and in combination with bulk still a map.

We presented data at the city meeting last year.

<unk> demonstrated that Morten <unk>.

Hasnt improved efficacy and safety profile compared to what has been reported with previous <unk> four antibodies.

It is one of the first generation.

And the next generation.

As shown on slide three.

Garo Armen: As shown on slide three, botanical map is FC enhanced, to improve the efficacy, and safety of CTLA-4 blockade through three primary mechanisms, is both insulin map is designed to extend, The curative benefits of immuno-oncology to cold tumors, that do not typically respond to approved immunotherapy. 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 CITSI, botensilumab is the first CTLA-4 inhibitor to demonstrate clinical responses across nine, nine cold and treatment-resistant cancers.

<unk> by the way you can you can advance the slides on your own.

We don't have the means to do that from here for you.

As shown on slide three potentially map is FC enhanced to improve the efficacy and safety of <unk> four blockade through three primary mechanisms.

First is potentially mab is designed to extend that.

The curative benefits of immuno oncology to cold tumors that do not typically respond to approve new 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 <unk>.

<unk> is the first <unk> four inhibitors could demonstrate clinical responses.

Across nine <unk>.

Nine cold and treatment resistant cancers.

Second.

Garo Armen: Botansilumab is designed to expand clinical benefit in hot tumors, such as melanoma, where CTLA-4 is already approved, but, resulting 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.

So the map is designed to expand clinical benefit and hot tumors, such as melanoma, whereas <unk> is already approved.

Results in clinical benefit and only a third of our patients and long term survival in less than a quarter of the patients. So there is a lot of room to improve here.

We haven't observed responses across both hot and cold cancers in patients, who expressed a biomarker associated with poor outcomes.

Garo Armen: We have observed responses across both hot and cold cancers in patients who expressed a biomarker associated with poor outcomes to first-generation CTLA-4. And finally, botansilamab is designed to improve safety by reducing or eliminating side effects that cause treatment discontinuation. Notably, no pneumonitis, carditis, or 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 PotensiolaMap. Stephen.

First generation <unk> four.

And finally, Bob.

<unk> is designed to improve safety by reducing or eliminating side effects that cause treatment discontinuation, notably <unk>.

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 a potential amount.

Steven.

Thank you Garo.

Stephen O'Day: 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 as a single agent.

Building upon the data observed in our phase one trial, we are continuing to expand disease specific cohorts in the phase one b component of the trial and we will be initiating phase III study in melanoma.

All of our wet cold cancer and pancreatic cancer.

We are carefully chosen these indication in order to one first demonstrate superiority.

In melanoma, where if <unk> is approved and it's been studied the most of the single agent.

Second build upon the signals observed in our phase one study.

Stephen O'Day: Second, build upon the signals observed in our Phase 1 study by pursuing botanistilumab in combination with our PD-1 antibody in MS-stable colorectal cancer, and third, establish Bowton still as a superior combination agent for chemotherapy in cold tumors by evaluating botanistilamide in combination with standard of care chemotherapy in pancreatic cancer.

Fueling both film.

In combination with our PD, one antibody in MF stable colorectal cancer.

And three established boat and still about as a superior combination agent for chemotherapy and cold tumor.

By evaluating <unk> in combination with standard of care chemotherapy in pancreatic cancer.

First I will elaborate on our approach in melanoma.

Stephen O'Day: 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 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.

As a melanoma position I am, particularly interested in leveraging my background and my network to rapidly enroll and execute the study.

The majority of melanoma patients treated with single agent PD, one progressed within a year and our need.

Are in need of more effective treatment option.

Response rates would there be liberal about monotherapy or approximately 15%.

And most patients progressed within months.

At <unk>, we reported a confirmed partial response and PD, one relapsed refractory melanoma.

Stephen O'Day: At CITSE, we reported a confirmed partial response in PD-1 relapsed refractory melanoma. Since CINCI, we have observed a second melanoma patient responding to single-agent botanistilumab 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 setting.

And then thirdly, we have absorbed the second melanoma patients responding to single agent, both boat and fill them up.

With more than a 40% tumor reduction at their first six weeks.

This patient had brief which can be previously progressed after <unk> in the adjuvant setting and subsequently it would deliver mab in Ebola in.

In the metastatic study.

Yes.

We have designed a phase III trial in melanoma evaluating both still about mono therapy and bowl PD, one resistant refractory setting.

Stephen O'Day: We have designed a phase two trial in melanoma, evaluating Bowden-Stilamab 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 botanistilumab compared to historical ipilimumab. We are targeting a response rate of 25% or greater. The second cohort in PD-1 and CTLA-4 relapse-resistant patients.

As well as our PD, one <unk> four resistant refractory setting.

The first cohort in PD, one refractory resistant patients.

Allow us to quantify the superiority of both film.

Compared to historical MP level map.

We are targeting a response rate of 25% or greater.

The second cohort and PD, one and <unk> four.

Relapse resistant patients.

Stephen O'Day: We'll explore whether botanistilumab can rescue ipi-nevo failures, a patient population with very limited treatment options. In addition to our Bowdoin still about monotherapy study, We have expanded our AGEN 2373 Phase 1B trial and are now recruiting a cohort of PD-1 resistant refractory melanoma patients, to receive Agent 2373 in combination with our Bowdoin Stillamath. Agent 2373 is a CD137 agonist antibody designed to be conditionally active in the tumor microenvironment.

Or whether it's still a mab can rescue.

Knievel failures Ah patient population with very limited treatment option.

In addition to our boat and still have a monotherapy study.

We have expanded our age and $23 73 phase one b trial and are now recruiting a cohort of PD, one resistant refractory melanoma patients.

We received a gen 2373 in combination with our boat and still amount.

Agent to 373 is a CD 137 agonist antibody designed to be conditionally active in the tumor microenvironment.

Stephen O'Day: 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, and antagonist, botanistilumab, in melanoma, an immunogenic tumor, as this represents a potential novel scientific advance. Next, we are planning a study in MS-stable colorectal cancer, where our Phase I data with botanistilumab and our PD-1 valstilumab 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.

David a gen. Two three 703 has demonstrated early single agent clinical activity without evidence of liver toxicity that has stalled other clinical stage CD 137 therapy program.

I'm, particularly excited about the combination of a checkpoint agonist CD 137 antagonist, both still a mab in melanoma and immunogenic tumor.

This represents a potential novel scientific advance.

Next we're planning a study in MF stable colorectal cancer, where our phase one data with both <unk> and our PD one by Phil about combination has shown best in class potential compared to standard of care and other <unk>.

<unk> and development.

Colorectal cancer claims over 50000 lives annually in the U S.

Approximately 95% of stage four colorectal cancers are classified as microsatellite stable or F F, which correlates with poor responses to immunotherapies.

Stephen O'Day: Approximately 95% of stage four colorectal cancer, 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 today in our MS stable colorectal cohort. We observed a 20% response rate and 70% disease control rate for Bowton Stillamab and our Bout Stillamab combination, with the majority of responses ongoing at six months.

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 MF stable colorectal cohort.

We observed a 20% response rate and 70% disease control rate for both <unk> and our <unk> combination.

With the majority of responses ongoing at six months.

This favors positively to the competitive landscape, where first generation <unk> four PD one combination have reported only rare responses.

Stephen O'Day: This favors positively to the competitive landscape where first generation CTLA-4 PD-1 combination, have reported only rare responses and limited disease control. Our study will be designed to evaluate the contribution of components of botanistilumab and balistilumab in this combination.

Limited disease control.

Our study will be designed to evaluate the contribution of components of both <unk> and <unk> in this combination.

We anticipate that the outcome of the study will strengthen the efficacy signal and safety signal and demonstrate.

Stephen O'Day: We anticipate that the outcome of the study will strengthen the efficacy signal and safety signal and demonstrate.., demonstrated 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 4 pancreatic cancer is about 3%. This disease claims 50,000 lives annually in the U.S. alone.

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 3%.

This disease claimed 50000 lives annually in the U S. Hello.

Stephen O'Day: 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 CITSE, 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 C-Tele4. We plan on evaluating botanistilumab in combination with standard of care chemotherapy in metastatic pancreatic cancer.

And there has been no new drug approved with a broad label in seven years.

Multiple trials evaluating first generation <unk>, four or PD, one agent as monotherapy.

Demonstrated no objective responses when evaluating the broad all comer pancreatic population.

At 50, we reported a confirmed partial response.

Ongoing at six months and a pancreatic ambulatory cancer patient that also expressed a low affinity CD 16, a lille.

Which has been reported to result in an inferior benefit to first generation <unk> four.

We plan on evaluating both fill them in.

In combination with standard of care chemotherapy in metastatic pancreatic cancer.

This trial will enable the expansion of our Cta for franchise into cold tumors, which represent a significant addressable population and we're immunotherapies have been largely ineffective.

Stephen O'Day: 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 CTA-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, to gather these trials in different settings with different combinations, set up Bowdoin Stilamab across both IO and non-IO combinations, and de-risk phase three trials.

Our combination strategy with approved chemotherapy could accelerate the path forward, while tapping in to the synergistic potential of <unk> for next generation with chemotherapy combinations across.

Multiple solid tumors.

Now we are actively working with the agency to finalize these phase III trial design.

Together these trials in different settings with different combinations.

Setup mode still.

Across both Io and non Io combination and.

And Derisk phase III trial.

As shown on slide five positive data in these studies can unlock the franchise potential of boat and still about <unk>.

Stephen O'Day: As shown on slide 5, positive data in these studies can unlock the franchise potential of Bowdoin Stilamap, supporting further development in indications where IPI-11ab has been approved as a single agent or in combination, or Demonstrated Benefits, as well as expansion into indications where botanistilumab has shown clinical benefit but other CTLA-4 agents have not. I will now turn the call back over to Garo, as Dr. O'Day articulates.

Reported further development in indications, where <unk> has been approved as a single agent or in combination or.

<unk> demonstrated benefit.

As well as expansion into indications, where Bolton filling map has shown clinical benefit but other <unk> four agents have not.

I will now turn the call back over to Garo.

Thank you very much Steven.

Doctor they articulated.

Garo Armen: 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 potential impact, including, for example, our internal manufacturing capacity to support what will be potentially over $10 billion in annual sales at our Emervil 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. Let me also talk about Agent 1571. This is a new clinical program that is about to start. And it is. Agen 1581.

If you look at each one of our development programs that are being contemplated.

Either working with in house global experts or outside global experts to attend to these trials to design the trials and to determine.

<unk> high profitability successful outcomes.

In parallel to our clinical efforts. We are building also the infrastructure to support planned development and potential launch of potentially.

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.

We will be approximately 50 miles north of our Embraco facility.

Let me also talk about aging $15 71.

This is a new clinical program that is about to start.

And it is.

Garo Armen: 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 iotherapy. 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 doable responses in PD-1 resistance cases, with agent 1571. We continue to advance additional discoveries targeting myeloid, sells blood. If you would turn to slide six.

Again, 50% to 81, it will happen this year.

And it's a novel program targeting tumor associated macrophages, which promote resistance to PD one.

And CLA for therapy.

And so there is a very strong rationale as to why we have gone. This route.

Address needs that are not being currently addressed with Io therapy.

The importance of this target class has been validated by Merck's Iot for antagonist discovered by Genesis and license to Merck.

And that program has shown durable responses in PD, one resistant cancers.

With Asia and 15 71.

We continue to advance additional discoveries targeting myeloid sales.

Sales rod if.

If you turn to slide six I will now move to our second pillar strategic partnerships.

Garo Armen: I will now move to our second pillar, strategic partnership. Strategic partnerships: why do 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 our PIDGET by Specific, Agent 1777.

Strategic partnerships while.

We retain ownership in the majority of our program 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 to date.

Reflecting our innovation and pipeline productivity.

Our most recent partnership was executed with BMS last year, when we exclusively licensed to BMS hour to catch it by specific a gen. One triple seven seven.

Similar to Brooklyn, and map a gen. One triple <unk> FC enhanced to promote single agent antitumor immunity and.

Garo Armen: Similar to Botanicillumab, Agent 1777 is FC-enhanced to promote single-agent anti-tumor immunity, an area where clinical stage TIGIT therapies are yet to show promise as single agents. 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 indication, including a very large indication in the form of non-small cell lung cancer.

An area, where clinical stage therapies.

Yet to show promise as single agent.

It also addresses the secondary inhibitory receptor and <unk>.

Key and NK cells to promote to improve antitumor immunity.

Adrienne one triple seven is currently in phase one dose escalation trials and BMS intends to advanced development and high priority tumor indications.

Clothing, 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.

Garo Armen: We have already received $220 million from BMS in the past 12 months, across upfront and achieve milestones and retain the option for co-development, co-funding for increased royalties, and with U.S. co-promotion. Another molecule..., which we referred to just a little while ago is MK4830.

Across upfront and achieve milestones and regain the option for co development co funding for increased royalties.

With a U S co promotion.

Another molecule.

Which we refer to just a little while ago is MK 4830.

As I mentioned earlier.

Garo Armen: As I mentioned earlier, Merck is advancing a myeloid targeting anybody MK-4830 discovered by Agenus. This ILT4 antagonist.., is in clinical development across a range of cancer, including pancreatic, lung, renal, breast, ovarian, gastric, and glioblastoma. Then we have our Insight Program, that was one of our first partnerships.

Merck is advancing in myeloid targeting antibody MK 4830, we discovered by Genesis.

This IL <unk> four antagonist is in clinical development across a range of cancers, including pancreatic lung Reno.

First ovarian and gastric and Glioblastoma.

Then we have our insight program because that was one of our first partnerships.

Garo Armen: Insight is advancing our clinical stage programs and clinical recently initiated a unique combination trial evaluating the agent discovered TIM3, and Agenus 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 Mayofer, optionality for future participation. Development and Commercialization. Let me also now make a few comments about Bustillaman.

Insight is advancing our clinical stage programs in clinical recently initiated a unique combination trial evaluating the Adrian discovered temporary.

And Genesis discovered last three antagonist with PD one.

PD, one relapsed refractory melanoma.

Across our partner programs, we are as I said earlier eligible for $2 $8 billion in milestone plus royalty.

These partnerships to 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.

Maybe also now make a few comments about <unk>.

This is <unk>.

Garo Armen: This is, One of the third pillars of our business. Enabler, such as PD-1 antibody while still a map, 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, Balspilimab 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 zoliferolimab. Our first generation of CTLA for anybody.

One of the third pillars of our business model.

Enablers, such as PD, one antibody muscular map.

As exhibited strong clinical activity and excellent safety profile in over 400 patients evaluated to date.

In our phase two trial in second line cervical cancer, while still a map demonstrated a response rate of 20%.

In PD lone positive patients, which represents a 40% improvement to the response rate reported for <unk>.

The only approved PD one agent for these patients.

Now in combination with Zelle, it's really map.

Our first generation <unk> four antibody.

Garo Armen: The response rate.., with zolothrilumab plus PD-1, or osthrilumab, has increased to 33%, in PD-L1 positive. These, we believe, are major improvements for, Metastatic Cervical Patients who have very limited or no opportunity. 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 therapies. Next, I will briefly summarize the fourth pillar of our business model, our subsidiary.

The response rate.

Zealous really map plus PD one are all still in map.

Has increased 33%.

<unk> PD L. One positive patients.

These we believe are made.

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.

Sure.

Next I will briefly summarize the fourth pillar of our business model, our subsidiaries <unk> therapeutics and <unk>.

Garo Armen: Mink Therapeutics, and Stepanek. Mink Therapeutics last year, launched an IPO to support clinical development of allogeneic INKT cell therapies in cancer and immune related diseases. Establishing Minkwood Independent Financing, a 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, 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 saponic, 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. Thank you, Garo.

<unk> therapeutics last year.

Launched in IPO to support clinical development of our G&A I N T cell therapies in cancer and immune related diseases.

Establishing menke with independent financing and leadership.

Has provided greater resources for our 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 and solid tumors.

As well as multiple myeloma.

And lastly, before I turn it over to a trend.

The address upon X.

I will refer to <unk> Chen who is the chief operating officer of supplies and China. If you can make some comments about the progress we're making it to products.

Thank you Garo and really excited to be part of the team.

Chandresh Harjeevan: I'm really excited to be part of the team. I joined Soponix 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.

I joined <unk> last year, serving as an advisor to the government on the Covid response broadly and.

Working at the partner at the Boston Consulting group.

Was really drawn to this opportunity to build an integrated vaccine platform to discover novel adjuvant and build more effective vaccine something close to my heart.

Pandemic threats and other diseases.

The need for vaccines offering long lasting efficacy and efficient production has to come.

Grossly <unk> in the current pandemic we.

We can boost the world every six months.

The durability offered by our Qs 21, <unk> has been validated over the years by chambers with protection exceeding nine years.

Chandresh Harjeevan: The durability offered by our QS21 Stimulon 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 it's the product.

Clinical and preclinical data support broad applicability of Qs 21 across more than 20 disease settings.

However, <unk> 'twenty, one supply is constrained due to its reliance on a complicated and expensive extraction process.

From a Chilean soap box.

So it's the products we have developed a.

Chandresh Harjeevan: 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 vs. Bark-X-Fac. 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.

Culture method of manufacturing <unk>, 'twenty, one and next generation adjuvant.

When cell culture offerings, and more sustainable scalable and cost effective method of manufacturing <unk> 21 versus market.

We expect to have GMP material manufacturing process. This year stable partner clinical trial.

And very exciting we are 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-19, but also vaccination efforts throughout the world and other disease categories.

We built a strong leadership and advisory team to achieve these objectives with rich experience in vaccine.

Chandresh Harjeevan: 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 financial... Thank you, Tom. We ended the year 2021 with a cash and short-term investment balance of $307 million.

That's one 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 Clarke skin to discuss our financials.

Christine Klaskin: This compares to $100 million at December 31st, 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 agreement. Our cash provided by operations for the year ended December 31, 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.

Yes.

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 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 upfront license fees received noncash royalties earned and revenue recognized under our collaboration agreements.

Yeah.

Our cash provided by operations for the year ended December 31, 2021, with $10 million with a reported net loss of $29 million or <unk> 11 per share compared to cash used in operations of $139 million and a net loss for the year ended 2020.

$183 million alright dollars five per share.

Noncash operating expenses for the year ended December 31, 2021 were $49 million compared to $37 million for the year ended 2020.

Christine Klaskin: 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 with $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.

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 <unk> 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.

Garo Armen: 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. 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 two trials, as Dr. O'Day mentioned, evaluating botansilamab in melanoma.

I'll now turn the call back to Darren.

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 III trials as Victor or they mentioned.

Garo Armen: Microsatellite Stable Colorectal Cancer and Pancreatic Cancer, complete enrollment of a proof of concept study, evaluating potentially mapping combination with our conditionally active, CD 137, Agonist, in melanoma. Three [inaudible] Initiate a phase one study for agent 1571, a novel program targeting tumor-associated macrophages, for generate GMP grade QS21 stimuli.

Valuation both hands similar map in melanoma.

Microsatellite stable colorectal cancer and pancreatic cancer.

Two.

Complete enrollment of a proof of concept study evaluating <unk> mapping in combination with our conditionally active CD 137 agonist in melanoma.

Sure.

Three in.

Initiate a phase one study for <unk> 71.

And novel program targeting tumor associated macrophages.

For.

Generate GMP grade <unk> 'twenty, one the stimulus.

To support offices.

Garo Armen: Through Saponics's Plant Cell Culture Manufacturing Method to enable Partnership Trial, and five, pursue additional strategic collaboration, which we have done consistently, over the last five years. In the medium term... One, we will pursue multiple paths to market for potential. Two, we will continue to advance our vision platform, for more efficient and effective clinical trial designs. Three.

<unk> 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 both hensler map.

Two we will continue to advance our vision platform.

Or more efficient and effective clinical trial design.

Three.

Garo Armen: We will advance several first-in-class programs targeting stromal and myeloid biology, for, We expect to complete construction of our commercial GMP facility in Emeryville under the tutelage of our Chief Manufacturing Officer, Dr. Al Datsou. 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. At this time, if you would like to ask a question, please press star 1 on your telephone keypad. Again, that is star one in your telephone. And your first question comes from the line of Kelly Shi, your line is open. Hi, good morning. This is Jason Bouvier on for Kelly Shi.

We will advance first in class programs targeting strong MAU 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.

<unk>.

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.

At this time, if you would like to ask a question. Please press star one on your telephone keypad.

Again that is star one on your telephone keypad.

And your first question comes from the line of Kelly.

Your line is open.

Hi, Good morning. This is Jason Bouvier on for Kelly. She thank you for taking my question and I apologize if I missed this but on the <unk> zone.

Jason Bouvier: Thank you for taking our question. And I apologize if I missed this, but on the bowels-owl 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. Very good question, actually, unfortunately.

<unk> combo and.

In cervical just wondering if you've had any conversations with the FDA on our FDA on possible path forward or if you are still considering development path forward for that combination. Thank you.

Very good question actually.

Unfortunately.

Garo Armen: 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 Bosphilimap, as a single agent therapy, or Bostelumab plus our Zoliferumab as combination therapy in cervical cancer in the USA. Got it.

Cause of the changes and the agencies.

Guidance over the last two years, we believe the path for <unk>.

Single arm trials, even randomized trials that don't meet our strict criteria is.

Is closed.

Unfortunate.

Cause patients will not benefit from clear benefit that has been strong in for example, our trial that has been published in the journal of clinical oncology and presented at major conferences.

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 GLA 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 approvals.

<unk> still.

Still a map.

As a single agent therapy.

Or muscular map plus.

So a thriller Mab as combination therapy.

Cervical cancer in the USA.

Got it thank you very much.

Yeah.

And your next question comes from the line of Mike.

Maintaining your line is open.

Good morning, Congrats on the progress and thanks for taking my questions, maybe just starting with intent to update them, but then from the mob if it had been in could we just get a bit more color.

Jason Bouvier: Thank you very much. And your next question comes from the line of Mayank Mamtani. Your line is open.

Mayank Mamtani: Good morning, congrats on the progress and thanks for taking our questions. So maybe just starting with incremental updates on Potentially Mapped, 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, paths 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 and target ORRs and also like if you could clarify the pancreatic metastatic setting you're going into the first line with chemo or is it later lines and then I have a follow-up. Sure, I think these are excellent questions for Dr. Stephen O'Day. Uh, so if I can, uh, ask Stephen to address.

Some of these initial indications in terms of.

Bob gasoline approval as I think I missed.

And youll have to engage with regulators.

In the PD, one refractory melanoma.

<unk> already identified single agent <unk>.

And also like if you could clarify the pancreatic metastatic setting youre going into the first line with key volume at Midnight and then I have a follow up.

Sure I think these are excellent questions for Dr. Steven.

So if I can.

Ask Stephen to address them.

Yes. Thank you for the question.

Stephen O'Day: Yes, thank you for the question. So in melanoma, as I indicated, we think that this is an optimal opportunity for testing single-agent botanistilumab 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.

In melanoma as I indicated we think that this is an optimal opportunity for testing single agent fill them Act.

Activity in two settings, one is of the PD, one resistant refractory, but CTO laid for naive setting where single agent <unk>.

Stephen O'Day: 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 IPI-libemab in the second-line setting, and where response rates would be expected, essentially, to be zero. And we look forward to seeing if botanistilumab can perform in this setting, where the bar is very low, and the unmet need is even higher.

Ultimately, 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 are equally exciting as a cohort of actual cta for refractory patients for patients who have received either it be knievel frontline or have had sequential Nemo, our keytruda and then had single agent it would be <unk> in the second line setting.

Where response rates would be expected essentially to be zero and we look forward to seeing if our boats film that can perform in this setting.

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 at below <unk> in the adjuvant setting and then progressed and then received <unk> in the metastatic setting. So we're very excited and exploring those.

Stephen O'Day: And as I indicated in the call, we already have, in our Phase I trial, a patient who had received IPI-libemab in the adjuvant setting, and then progressed, and then received IPI-NEVO 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.

Both of those areas.

I have a world class group of melanoma Kols that I have been part of for 30 years.

Are getting energized by our phase one data and look forward to testing the nexgen <unk> four in both of these important melanoma cohort.

Stephen O'Day: 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. Thank you for that level of detail.

Then in terms of the pancreas, we see this as a cold tumor with the opportunity to really prime with our Nexgen <unk> 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.

Static once we establish safety of combination in initial responses in this setting.

Stephen O'Day: 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 that is not an established IO or non-IO that, you know, could make sense to synergistically from a mechanistic standpoint? You know, that's thanks. That's another great question.

Thank you for that level of detail and maybe just a follow up on.

And I need one.

Do you think at a high level going beyond the initial deal with.

Like land light prostate what in your view is that complementary.

Therapy.

That is not an established Io and non Io.

It could make sense.

Synergistically from a mechanistic standpoint.

Stephen O'Day: You know, CTA-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, we're 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 high 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 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.

Yes.

Thanks, that's another great question.

<unk> four we think.

With our next Gen molecule that has better pricing in memory T cell regulatory depletion and a better safety profile can be a foundational combination partner not only with PD, one where obviously in MF stable colorectal, we're seeing some very exciting signal, but we think it can be a foundational partner with chemo.

All therapy 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 about single agent sort of demonstration in a hot tumor like melanoma combination with a more typical PD one.

One combination in and are very difficult to treat MF 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 on the very cold tumor.

Stephen O'Day: So we're very strategic about outlining three different experiments with three different tumor types that set up next-gen CTA-4 as a single agent and a combinational both with NIO and XIO. And obviously our collaborative partners that are in discussion, 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, big unmet needs. Great, and if I could also ask a quick 1571 question, have you disclosed the target, specific target for that and more broadly, how might Murk's ILD4 data, media, inform, you know, how you plan to develop it this year in clinic, would appreciate the color there.

We're very strategic about outlining three different experiments with three different tumor types that setup nexgen <unk> four as a single agent and a combination of both with Nio in exile and obviously, our collaborative partners that are in discussion.

<unk>. This is very interesting because it will move.

Potentially the asset forward with much deeper resources across other tumors like lung and <unk>.

<unk> and other big Big unmet need.

Great and if I could also ask a quick.

171 question.

View.

I disclose the target specific dug into that and more broadly how might.

<unk> died before data midyear.

How you plan to develop this year.

Would appreciate the color there.

So we are.

Stephen O'Day: So, we're currently contemplating the path forward, including potential partnerships with this compound, Mayank, and we're not disclosing any details just yet. Okay, great, and my final question was on, just quickly on Suponic UX, how far are you from the clinic? you know, particularly for the intranasal vaccine.

We're currently contemplating their path forward, including potential partnerships with this compound and.

And we're not disclosing any details just yet.

Okay great.

My final question was on display at <unk>.

Are you from the clinic.

But the ability for them to enable vaccine.

Yeah.

Sure.

Hi.

So.

Garo Armen: So if your question is the potential of.., intranasal vaccine, using this opponent 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 mucosal adjuvant.

If your question is the potential.

Intranasal vaccine.

Using this accounting.

Family of Av.

Adjuvant.

We do have as you may know.

Very very promising.

Andrew range.

And the name of <unk>.

And what we have done with <unk> seven is really because its so active SME corso.

<unk>.

Garo Armen: We have now, developed plant-based cell lines, to make this a viable candidate. But with our new plan cell culture methodology, we have selected cell lines, that actually expressed QS7 in high enough quantities for this to be promised. 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. Thanks so much for digging that question. Your next question comes from the line of Mike King, your line is open. Good morning guys.

We have now.

Developed.

Plant based cell lines.

To improve the yields from Q seven because for many many years, we have known that Q seven.

Is a very effective vaccine adjuvant, but the yields achievable from the natural shortage has 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 <unk> seven 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.

JMP quantities of <unk> seven.

So that we can run some experiments and partnership discussions.

Thanks, so much for taking our question.

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

Good morning, guys. Thanks for taking the question I just wanted to draw.

Mike King: 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 bolstilumab, is a single arm study with bolstilumab in some of these cold tumors a possibility, or are you considering going from phase two into phase three? Agenus Inc. Schultz, Um, let me.., answer this question, with a very definitive guidance. Given the changing environment, the regulatory environment, my, I think it will be silly for us, to take chances with single-arm trials. Now, we don't believe.

Conclusions, but wanted to ask.

You thought given given the experience that you had with.

While still a mab.

<unk> is a single arm.

Study with <unk>.

So in that in some of these cold tumors, a possibility or are you considering.

Take going from phase two into phase III.

Hi.

Yes.

So.

Let me.

And so this question.

With.

A very definitive.

Guidance.

Yes.

Given.

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.

Garo Armen: Bad 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. Okay, even in populations with unmet need. Yes, this is Steve O'Day.

That is so called the new guidance.

He 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.

Okay, even in populations with unmet need.

Sure.

This is Steve.

Stephen 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.

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 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 in large randomized trials are almost certainly going to be necessary, but the data already.

Stephen O'Day: But the data will be set up to follow as it develops. Okay, Steve, as long as we're talking about that, are the Phase 2s set up in such a way that you could seamlessly, you know, roll them into a Phase 3? In other words, can you, you know, can you use the data in the Phase 2 setting to be supported? of what you might do in a registration trial.

Setup to follow as it as it develop.

Okay, Steve as long as we're talking about that are are the phase two set up in such a way.

That you could seamlessly.

Roll them into phase III in other words can you can you use the data in the phase two setting to be supportive.

What you might view in a registration trial.

Stephen O'Day: 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 and most efficient way into a phase three setting. Okay. Terrific. And then, just shifting gears real quick, Can you say what the mechanism of 1571 is?

We will give more information on that in the coming months. We are in active discussion with the agency around these these trial. So certainly we're very interested in it the signals become strong and these trials to moving them as quickly as possible and most efficient way.

Into a phase III setting.

Okay terrific and then just shifting gears real quick.

Garo Armen: Is it ILT4 or is it another target in the tumor-associated macrophage? It's in the same family, Mike, but I think it's best for us not to yet release a specific target. 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.

Can you say what the mechanism of $15 71 is in Iot for or is it another target in the tumor associated macrophage space.

It's in the same family Mike five.

I think it's best for us not to yet released specific targets.

Fair enough and then finally is there any.

You mentioned all of your wonderful partnerships Gilead insight Merck, but any anything that you can tell us about and Bristol.

About when we might start seeing some some data coming out of those programs to further validate your discovery platform. Thanks.

Garo Armen: I think, I think, I mean, we can't speak, of course, on their behalf, but even the progress, and the speed of patient enrollment in the trials with all of our collaborators, merged certainly with their ILD4 insights with various programs. Gilead with our conditionally active compound, the CD137, and Bristol with Agent 177. 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 we'll defer it to them. Okay, fair enough.

I think 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.

Marilyn certainly with their Iot for.

Gili insight with various programs Gilead.

Our conditionally actives.

Compound CD 137.

And Bristow.

Adrian.

One triple seven.

The enrollment in all of these trials.

This debt.

You may see some clinical activity this year.

However.

Because these are their programs.

Think it would be.

Presumptuous for us to make comments on them.

And we will defer to them.

Okay fair enough thanks for taking the questions.

Mike King: Thanks for taking the question. Your next question comes from the line of Matt Phipps. Your line is open. Hey, good morning, this is Hunter on for Matt.

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

Hey, Good morning. This is hunter on for Matt.

Hunter: Maybe just first, it seems like you switched up your strategy for 1181 a bit from your original plan of starting. A couple of trials.

Just first it seems like us.

It's up your strategy for eliminating one a bit.

From your original plan of starting.

A couple of trials.

Gynecological cancers, so could you sort of speak to what went into that.

Garo Armen: Gynecological Cancer. So could you sort of speak to what went into that decision? Sure. I'll really defer this to Dr. Odeh 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 little over a hundred patients, with nine different tumor types having shown activity is almost a remarkable outcome.

Susan.

Sure.

I was really defer this to conductor a day because these programs are.

<unk> 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.

Garo Armen: So given that, we will pursue 1181 across many, many different humor. 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 target. But Stephen, would you like to elaborate more on this?

So given that we will pursue 11 81 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.

Stephen O'Day: 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, you know, good activity in both ovarian and endometrial with limited numbers, obviously, today, but, 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.

Yes.

Great question.

The answer is.

As Gary said, we have broad activity.

Across nine different tumor types.

Strategic in the sense that <unk> malignancies.

We have good activity in both ovarian and endometrial with limited numbers, obviously today, but.

Really comes down to what's our bandwidth what experiments are we trying to do that will move the asset forward.

And the regulatory environment that is 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 state to put in the ground, we think that combination with a PD one our data with MF stable colorectal is.

Stephen O'Day: 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.

Really the farthest along in the most exciting we think that a cold tumor like pancreas as sort of 18, four up better priming agent and we think thats, a huge unmet need but depending on partnership and collaboration which is going to be very dynamic this year.

Stephen O'Day: 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 6 to 12 months, we feel confident that these three important tumor types and experiments will answer some really fundamental questions about our assets. Okay, great. Thanks for that.

We don't want to.

Lose sight that there are many other tumor types, including <unk> malignancies.

That could easily be addressed.

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 of experiments will answer some really fundamental questions about our asset.

Okay, great. Thanks for that and then maybe.

Hunter: 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 two 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 threes in those indications?

Good to hear that you have 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 two 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.

Those indications.

Without getting into too much specifics the phase one trial was really limited to non melanoma patient.

Hunter: 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 diseases, sort of PD-1 refractory and then PD-1 CCLA-4 refractory in just a handful of patients.

Until very recently, so we have already seen these two responses in two separate disease sort of PD, one refractory and then PD, one, particularly for refractory where just a handful of patients and we are actively now expanding the melanoma cohort and won't be.

Stephen O'Day: 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? Oh 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? 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.

Accumulated more data in the coming months.

We hope to update you on as we launch the phase III melanoma trial I'm sorry, what's the.

What's the second part of the question.

Yes, I was just asking about the design of the phase two is coming up.

Whether or not youre thinking those trials will be randomized trials.

So right now we talked about.

In melanoma single arm studies in these two cohorts.

And in terms of.

We will release more details on the design after further discussion.

With the FDA and the other diseases.

Great. Thanks.

Again, if you would like to ask a question. Please press star one on your telephone keypad again that is star one on your telephone keypad.

Stephen O'Day: Great, thanks. 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.

You have a follow up question.

Mayank Mamtani: We have a follow-up question from Mayank Mamtani. Your line is open. Yes, thank you for taking my follow-up. I just have a quick financial question that just came in.

And then Tony your line is open.

Yes. Thank you for taking my follow up I used to have a good financial question that just came in.

Mayank Mamtani: So, in terms of, you know, recognizing what seems like a $2.8 billion in milestones and royalty cumulative, can you just clarify if anything in there is 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 bolus of cash, you know, potentially an upfront payment? 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 payment?

Recognizing.

What seemed like a $2 8 billion.

Also in the NYSE accumulated.

Can you just got it.

In the EMEA.

This year.

And maybe also just if.

If you could provide any color on.

What might be added next to this missed anything you have visibility on that could bring that sort of next bolus of cash with engineering upfront payment.

And if I understand this.

Correctly are you.

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 our guidance yes.

Mayank Mamtani: From existing partnerships during the course of— Kind of—yeah, kind of both. On slide 6-basically, on slide 6-you know, that cumulative number is 2.8, but curious if anything is going to be near term on those milestones. And then—yes, you know, things that are not on this slide that we should keep in mind as we think about 2022 finances. Right.

On slide basically on slide six.

Jim accumulated number two blended but curious if anything is going to be near them.

Milestone.

And then yet.

Things that are not on this slide that we should keep in mind as we think are likely to go into the financials.

Garo Armen: 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 financing, 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.

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.

Or possibly different geographies for different compounds.

In 2022.

So our strategy to make sure that our.

Financings.

Choices are financing.

Our.

Not dependent on one specific thing.

Continues and.

It's one of the reasons for example.

In our filing today, we expanded our options.

Potentially funding the company through equity financing there is 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.

Garo Armen: 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, to be 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.

In generating collaboration income.

Over $800 million in the last five plus years, and we have been consistent and 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 finance the company.

<unk>, a watershed event kirsch and for US a watershed event occurring.

Is obviously, an accelerated path for product approval.

Or a mega cooperation.

Yeah.

Thank you for taking my follow up.

Mayank Mamtani: Thank you for taking my follow up. Thank you, Mayank. 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.

Thank you Mike.

Hey, Dan Good question Mike.

Question. Please press star one on your telephone keypad again that is star one and your telephone keypad.

Excuse me presenters there are no phone questions you may continue.

Operator: Excuse me presenters, there are no more phone questions, you may continue. 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 for your time and interest in our company.

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.

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

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