Q4 2020 Mersana Therapeutics Inc Earnings Call

Keith Human Resources officer who joined us in January before we start I want to take the opportunity to introduce Carla, brings with her substantial organization in college development experience, which would be crucial if we scale messana to accommodate our robust and maturing pipeline of most recently, when we supposed to talk to her what she played an integral role in building the organization before joining Alexia. She served in multiple roles of life for over a decade including ahead of international human resources where she was instrumental in helping build the vertex European organization to over 250 employees in just two years Welcome to our love. We are thrilled to have not moving on to the business update.

Bisogna, we aspire to become an engine built by leveraging us in order to start from to bring important medicines to cancer patients 2028 transformational here for us to establish the potential of our benefit heavily pretreated ovarian cancer patients and advanced and Innovative pipeline of them addressing can be so quiet that meat including XLT 1592 xt60 60 and XLT 2056 all one strengthening the office location to deliver on the next date of the volition of Masada in 2021. We're taking the next step in our journey. Our focus is to be building up and building out the pipeline with respect to building up. We we will be initiating uplift a single armoured display off.

Addition would set into motion studies designed to bring up with a patient in earlier lines of therapy as we seek to establish it as a foundational medicine and ovarian tissue are removed describe the design of a place and the significant potential advantages over differentiate is designed. It was also described upgrade off first step in a life cycle management plan. We will share with you over time with respect to building out the pipeline. We will work to complete the evaluation of our teenage to be targeted agents and of course, you know and exiting 1592 and set a clear strategy for next steps and as well as work truck bomb, it could be 1666 to India mobile. We will continue to leverage. Okay, nobody platform to discover and rebirth

With additional that address areas of unmet medical need both arvind and 10:00 would describe in more detail on efforts in continuing to build out of pipelines off you'd be accomplishment of a 2021 gold. We could achieve another transformational year from a sauna 12 months from now, we could be substantially long enough people said before I agree with multiple lifecycle management studies underway and we anticipate having a clear strategy for the potential of napping to be long until across my patience and having two in molecules in the accomplishment of these goals would put the next stage of transformation of my son inside the potential took the first pivotal study and preparing to launch our first commercial ABC

With that I would like to turn the call over to our Victory uplift up real life cycle management studies. We are planning and then to Tim to the advancement of our pipelines. Thank you. And thank you everyone for joining us today. Let me start by summarizing the data we've generated to date that support the potential for upgrading to become the foundational medicine in ovarian cancer. As you recall, we've disclosed this substantial data from the ongoing study and four different disclosures in the past 12 months including a comprehensive disclosure on the January 5th of this year, these data support the potential of operate provide significant benefit for heavily pretreated ovarian cancer patients who've exhausted other options, including benefits of life in park Inhibitors and have a poor prognosis specifically, we have consistently shown robust activity substantially above the current standard-of-care including complete responses suck.

Tolerability profile without the severe neutropenia neuropathy and ocular toxicity that limit other platforms. This has the potential to facilitate. The combined ability of upbringing agents used in earlier lines of ovarian cancer treatment. Let me start with uplift our single-arm registration strategy in heavily pretreated platinum-resistant ovarian cancer the first step. Jective to building operate as a foundational medicine in the treatment of ovarian cancer with FDA feedback and with strong support from the Co-operative group's both in the US and in Europe, we are well on our way to initiating dosing and uplifted much

Let me summarize the key features. I'll clicked first the page.

In population addresses substantial unmet medical needs and affords us the potential for significant label differentiation uplifted designed to enroll platinum-resistant patients who have received 4 lines of therapy consistent with the population in the expansion cold where where we've already seen data supporting the potential for robust activity the inclusion of patience with for prior life differentiates uplift from other ongoing and historical studies in late-stage ovarian cancer note that services are not pretreated and Beverages and and naive patients are included in the bath cohorts in a manner consistent with the Beverages and have label this is another important differentiator because it allows us to explore the potential of upgrade to address the unmet medical need of patience. I have and have not been previously treated with scepticism a VIN a single study second the design allows for the robust evaluation of the relationship between the biomarker and patient outcomes dead.

We plan to enroll patients regardless of not be to the expression which we believe will also contribute to the speed of enrollment nevertheless. The role of the biomarker will be evaluated in uplift purchase. If eccle the primary endpoint for the uplift cohort will be objective response rate in the higher not be to be population while the key. Secondary endpoint will be the objective response rate in the overall population. This design allows us to more fully evaluate the role of the biomarker to enhance patient outcomes. It's a two shot on goal approach. We expect to enroll approximately 100 patients with higher wage be to be expression in the uplift cohort which can include up to a hundred eighty patients in total depending on the higher Nephi to be prevalent other secondary endpoints will include the duration of response in a safety in both. The higher not be to be and the overall population thirdly off list is designed to ensure that we have a systematic and robust strategy for a commercial diagnostic dead.

Specifically the substantial dataset generated in the ongoing expansion cohort will be used to establish the final cut off for the plan commercial a say that will be used in Upland this approach. Should I ask for the evaluation of both the higher not be to be and the overall population we expected to pull either a companion diagnostic or a complimentary diagnostic depending on which strategy we think with most beneficial to patients as well as feedback from the regulator. We are on track to finalize the biomarker strategy and the cut off for the proposed commercial Diagnostic and upwards

Lastly uplift will be initiated as an amendment to the current study allowing us to capture the enrollment momentum. We are seeing in the ongoing expansion cohort in addition to the the strategy. We are focused on the lifecycle management plan that have the potential to build up re into a foundational medicine in ovarian cancers. This plan starts with the upgrade Faith umbrella study designed to evaluate operate in combination with other ovarian cancer therapies. We first intend to combine with platinum as Platinum therapy is currently the Mainstay therapy in earlier line item sensitive ovarian cancers. Our goal is to initiate upgrade in the third quarter of 2021. However over the next few months, we will be sharing with you a more complete lifecycle management plan as we leverage the potential of our free to address patients in earlier lines of therapy. These studies are important next steps in building up reading as a foundational medicine and ovarian wage.

Hang on to our ongoing efforts to build out the pipeline. We continue to advance as planned on our nappy to be targeted. Do listen to XM T 1592 in the phase one dose of situations, but we are on track to generate the data set that allows us to make decisions on the password and lung adenocarcinoma as we evaluate both up re and xmt $50 in this in a station with higher Medical Group in addition as him will describe. We are preparing to advance xmt 1660 + XM T20 56 into the clinic early next year. We're encouraged with a high level of interest that these two exciting molecules are generating among the kol permitted.

I worked out trying to call to Tim to discuss our exciting early-stage pranks arvind and good morning everyone. We made significant progress in advancing our pipeline a 2022 Focus for 20 21 is to build out the pipeline and further demonstrate our position as leaders in innovation.

Today, I will focus on xmt. 2056 our first mm. You know Simpson sting see an ex ante 1660 are be 745. Ktc.

We're very excited about the potential of our immune o Simpson platform as a reminder in November. We have the webinar highlighting the characterization of this platform and I'd like a briefly summarized the key takeaways from that webinar that explain why we are so excited about this platform and the potential of staying Agonist ABCs

We believe that an ATC approach to activating the innate immune system to fight cancer in a targeted manner with a potential game-changer and could be a dramatic next step in faith in college.

The Sting pathway has been studied extensively and validated to play a central role in the immune activation, but we believe that delivery challenges to date have limited sting away from reaching their full potential.

Ami not sensing leverages our unique expertise in design and optimization to overcome those limitations. Our approach is also differentiated from 8 a.m. Until like receptor Agonist payloads with the immune system. We deliver what we call a one-two punch unlike toll-like receptors r t l r s thing is I pressed in both tumor cells and immune cells and we have demonstrated pre clinically that we can productively activate the same pathway in both these cell types in a concerted and targeted fashion delivering the one-two punch with potential to increase the therapeutic index that's not possible with pilar's because they are not expressed in tumor cells, but only in the immune cells.

Ethically we have validated the broad potential of our immune assistant agency pipeline. Not only for a single Target but across a suite of multiple targets and multiple animal models, straighting robust activity after a single low dose. We've also demonstrated excellent tolerability in multi-dose non-human primate studies with Ivy off at exposure levels far exceeding those the result in complete responses in Mouse models indicating the potential for a wide therapeutic index

XLT 2056 is our first and you know since an ATC that is progressing through ind-enabling studies with the objective of moving into clinical development in early 2022.

I'd like to turn to our novel do listen to and platform in early January. We introduced you to our next door since an ATC xmt 1660, which is the first choice is the targeting be 784. We believe that be 7 H 4 is a well-suited target for a dollar lot ATC for the following reasons. Do you 7 8 4 is expressed on multiple tumors with high unmet medical need and provides us the opportunity to Target these tumors with are cytotoxic anticoagulant, Mexico.

Second we also know based on preclinical studies that are do lock a TCS lead to immunogenic cell death and that are do lock payload can activate dendritic cells in the tumor both of which can prime a potential immune response as well because the 784 is expressed on tumor cells, but also on immunosuppressive tumor-associated macrophages, it provides the potential opportunity to co-op those cells in a targeted matter to further contribute to both the cytotoxic and immunogenic effects and create what we describe as a perfect storm in the tumor microenvironment.

another feature of be 784 is that it is in the same family as pdl1 but literature suggests be seventy-four and PDL one expression our mutual exclusive providing for the potential to address unmet medical needs in patients, who are there do not respond or progress with check point therapy due to lack of pdl1 Express wage is they are likely to express be 7 8 4

leveraging our unique ability Ford are ranging we selected X and p1660 as our development candidate from a range of variant options evaluated based on efficacy and tolerability. We are hard at work and on track to complete ID enabling studies on a time frame that we expect will allow us to initiate clinical studies in early 1222.

we are very

Writing about the potential for both of these Innovative earlier stage development candidates and are pleased to announce that two abstracts 4X and 56 and one abstract 4x + 16 60 have been accepted a Z posters at the aacr virtual meeting to be held in April. We look forward to sharing further preclinical data from these programs at that time. And with that I'll now turn the call over to Brian for an overview of our financial results. Thank you, Tim. Good morning everyone and thank you for joining us. I'll now review some of the bulb lights from our fourth quarter 2020 results and I'll start with our cash position. We ended 2020 with 255 million dollars in cash and cash equivalents net cash used in October activities in the fourth quarter was 17.3 million dollars. We expected our available funds will allow us to meet our current operating plan commitments for approximately the next two years in addition to our correct.

Exposition we have the option to draw funds through the amended existing debt financing agreement with Silicon Valley Bank refinance in August of last year.

And now some of the key highlights from our fourth quarter 2020 Financial results research and development expenses for the fourth quarter of 2020 were approximately 22.9 million month compared to twelve point four million dollars for the same. In 2019. The difference was primarily due to an increase in upgrade and xmt 1592 clinical expenses and increase in a fracturing activities for Opry and our Discovery stage programs increased head count and a non-cash increase in the valuation of stock base towards as a result of stock appreciation. All these were partially offset by a decrease in preclinical development and Manufacturing expenses for X empty 1592 General and administrative expenses for the fourth quarter of 2026. Approximately 5.9 million dollars compared to 4.2 million dollars in the same. In 2019. The increase was primarily due to an increase in Consulting and professional fee and increase in physics.

Billy related costs as a result of the extension of our lease in March 2020 and a non-cash increase in the valuation of stock base towards as a result of stock appreciation net loss for the fourth quarter of 2020 was twenty eight point eight million dollars or forty two cents per share compared to a net loss of 16.2 billion dollars or 34 cents per share in the same. 2019 weighted average common shares outstanding for the quarters ended December Thirty One twenty twenty and December Thirty One 2019 were approximately 69 million and 46 million respectively. I'll now turn the call back to Anna.

Operator: BF-WATCH TV 2021, Good morning, and welcome to Mersana Therapeutics' fourth quarter and year-end 2020 conference call. Currently, all participants are in a listen-only mode.

Thank you Brian before we opened the coke question. I will like to outline our goal to my sales for 2021 which Center on building up as a found dead in the treatment of ovarian cancer and building out of pipelines demonstrate our position as leader in Innovation start with first month plus commissions the black plant uplift single on registration 20in platinum-resistant ovarian cancer this quarter s for a longer-term lifecycle management, you know various have to our goal is to initiate the social condition portion of the upgrade study starting with a combination study with Platinum increase wage. Yes. We are considering additional lifecycle management studies and we will share these details and finalize our plans. We're excited for the potential of this study's authors.

opportunity to build up grades as a foundational medicine for very intense across lines of therapy in the objective of creating a

Just when she'd like the syndication last week for a free we expect to have a new phone number of lung cancer patients that rolled in the extension study and to be able to pull updates from this corporate in the second half of 2021 for excellence in 1592 are not included dollar simple ABC we came to disclose those installation designed the second half of 2021. As you have said in the past our objectives to compare the Opryland adenocarcinoma expansion pack would be excellent in 1592 data to make decisions as to which molecule we will take forward based on their ability as well as activities. We expect to be able to outline for the development plan for exit 15 $92 and the fourth quarter of 2021.

1661 and initiate the same one go to send a 2012 20:56 our first acquisition platform. We plan to complete their study and disclose the fact the end of this year and initiate the same one go to study in early 2022. Finally. We will continue to leverage a proprietary platform and continue to expand our pipeline of the candidates while proactively evaluating potential collaboration for current and future programs. In fact, we have another busy year ahead of us with multiple values driving opportunities as we focus on building up and building out for pipelines with a promising lead acid bath.

Operator: There will be a question-and-answer session at the end of the call. I would now like to turn the call over to Sarah Karmoudi, Executive Director, Investor Relations and Corporate Communications. Please continue.

Speaker: Welcome to Mersana's fourth quarter and year-end 2020 conference call. We issued a press release earlier this morning reviewing our fourth quarter and full year 2020 financial results and business updates, which will be covered on this call. A replay of today's call will be available on the Investors & Media section of our website.

I can't quite like differentiated platform a highly experienced team have a strong balance sheet. We believe we're well-positioned to execute against clothes and who else overarching mission to discover and develop life-changing agency Corporation fighting pasta with that. I will turn the call over to the operator for Q&A.

Speaker: After our prepared remarks, we will open the call for Q&A. Before we begin, I'd like to mention that our call will contain forward-looking statements within the meaning of federal securities laws. These are not statements of historical fact and are based on management's beliefs and assumptions and on information currently available. They are subject to risks and uncertainties that could cause the actual results and the implementation of the company's plans to vary materially.

Speaker: Including the risk that preclinical testing or early clinical results may not be predictive of the results or success of our ongoing or later preclinical or clinical studies. Additionally, that the identification, development, and testing of the company's product candidates and new platforms will take longer and or cost more than planned, and that our clinical studies may not be initiated or completed on schedule, if at all. These risks are discussed in the company's SEC filings, including, without limitation, the company's annual report on Form 10-K, filed on February 26, 2021, and subsequent filings.

Thank you. Ladies and gentlemen, if you wish to ask a question at this time, please press * then 1 on your touchtone telephone if your question has been answered or you wish to remove yourself from the queue, please press the pound key to prevent any background noise. We ask that you please place your line on you. Once your question has been stated. Our first question comes from the line of Jonathan Chang was s d b lyric here line is open, please go ahead hi team. This is John Barrett on for Jonathan congrats on the progress in 2020. My first question is now that you're closer to the edge of uplift. What are your expected time lines for the trial related to full enrollment and then obviously a potential read out of of top-line data.

Yeah, great question Jonathan. I think we're very focused or

Speaker: In addition, while we expect that the COVID-19 pandemic might adversely affect the company's preclinical and clinical development efforts, business operations, and financial results, the extent of the impact on the company's operations and the value and market for the company's common stock will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time, such as the ultimate duration of the pandemic, travel restrictions, quarantines, physical dist Except as required by law, the company assumes no obligation to update these forward-looking statements publicly, even if new information becomes available in the future. With that, I will turn the call over to Anna Protopapas, Mersana's President and Chief Executive Officer.

Getting uplift of a burning. We're really on the cusp of beginning to those patients we have is no agreed to the FDA that we could do. This is an amendment to the existing trial and if you recall we indicated on January 5th, and we had about forty sites already as part of the expansion cohort. We're working with the corporate group to Europe and will be bringing additional sites up in Europe. And we feel quite good about the momentum behind the agent of the momentum. We hope will complete into enrollment uplift at this point. We're holding back from giving specific guidance. We just want to get the trial up and running but I think life and loss of support to meet corporate group the momentum. We see in enrollment in the expansion corporate makes us, you know, domestic that again from ma'am.

Anna Protopapas: Thank you, Sarah. Good morning, everyone, and welcome to our fourth quarter and full year 2020 Corporate and Financial Update call. Joining me today with prepared remarks are Arvin Yang, our Chief Medical Officer; Tim Loinger, our Chief Science and Technology Officer; and Brian DeSchuytner, our Senior VP of Finance and Strategy. I'm also joined by the rest of the executive team, who will be available for your questions, including the newest member, Carla Paulson, our Chief Human Resources Officer, who joined us in January.

Substantially enrolled in the study, but I think would like to wait a little bit before we give definitive guidance.

That that's helpful in following your given. This is more for clarity given the two endpoints of Orr in the higher net worth of the population and the or in the overall population. Is it possible that you have to Topline data readouts where you have a Noir top line for further with the higher population and then later on the Orr for the entire population or do you expect those to be coming at the same time?

Anna Protopapas: Before we start, I want to take the opportunity to introduce Carla. Carla brings with her substantial organizational and talent development experience, which will be crucial as we scale Mersana to accommodate our robust and maturing pipeline of ADC candidates. Most recently, Carla was Chief Human Resources Officer at AXSIA Therapeutics, where she played an integral role in building the organization. Before joining AXSIA, she served in multiple roles at Vertex for over a decade, including as Head of International Human Resources, where she was instrumental in helping build the Vertex European Organization to over 250 employees in just two years. Welcome, Carla.

I live down from the answer the question, but I think it might be that would be coming out of the same time. But our main maybe you can confirm that. Yeah. No, thank you Anna and and just to confirm that's correct. You need that based upon the way the study is designed. We would have both endpoints at the same time.

Got it. And just one last one. What do you see is the bar for a go no-go decision in lung cancer and what gives you confidence that he could succeed in life. So, let me see your second question and maybe I'll ask Brian to answer your first question. So what do we know about how Long Beach Blanket so we know that it's expressed there in Long adenocarcinoma not in other histology and we publish data where we in we showed the work we've done to understand the expression we saw in if you recall back at the data we disclosed in March at the MTV. We had several months since we have one partial response. We have multiple patients with prolonged stable disease. So the target is there we've seen early signs of activity log.

Anna Protopapas: We are thrilled to have you on board. Moving on to the business update, at Mersana, we aspire to become an ADC leader by leveraging our innovative platforms to bring important medicines to cancer patients. 2020 was a transformational year for us.

Anna Protopapas: We established the potential of our group to benefit heavily pre-treated ovarian cancer patients and advance an innovative pipeline of ABCs addressing areas of high-end medical need, including XMT-1592, XMT-1660, and XMT-2056, all while strengthening the organization to deliver on the next stage of evolution of MRSAD. In 2021, we're taking the next step in our journey. Our focus is twofold.

We are enrolling in expansion Cooperative about 40 to 45 patients. We did say that work with

Anna Protopapas: Building UPRE and Building Out Our Innovative Pipeline. With respect to building UPRE, we will be initiating UPLIFT, a single-arm registration study informed by FDA feedback. In addition, we will set into motion studies designed to bring UPRE to patients in early lines of therapy as we seek to establish it as a foundational medicine in ovarian cancer. Arvin will describe the design of UPLIFT and the significant potential advantages of our differentiated design. Arvin would also describe UpGrade, a first step in a lifecycle management plan we will share with you over time.

As well as that with patience is that the distribution of the prevalence of not busy Hai is different in ovarian that is in London his wage area, you know, very very soon were to take the disposition of that. We could be high as being that it's score of about 110, you know that there's no variance about two-thirds of patients are about that. I think would receive the clearances that more like 14% of patients are above that that threshold in our only nappy to be high side off. So I think we need to complete the expansion cohort and really understand the profile of latent, but the target is there and we've seen some early signs of a cult Brian he wants to talk about the ball.

Anna Protopapas: With respect to building out the pipeline, we will work to complete the evaluation of our two NAPI-TP-targeted agents in Long Island, NY, Carcinova, UpGrade and XMT-1592, and set a clear strategy for next steps, as well as work to advance XMT-1660 and XMT-2056 through IND-enabling strategies. In parallel, we will continue to leverage our innovative platforms to discover and bring forward additional ADC Both Arvin and Tim will describe in more detail our efforts in continuing to build out our pipeline.

Sure, so in non-small cell lung cancer, the the standard of care following progression on checkpoint Inhibitors, platinum-based chemotherapy or or failure of targeted therapy for patients with tumors Palm Harbor the oncogenic driver mutations that make those appropriate is is docetaxel alone or in combination with targeted therapy, you know, this standard of care is an overall response rate of somewhere between 49 a 23% in a median PFS and three to four months. So remarkably similar actually, so the performance of the single-agent chemotherapy standard Terran platinum-resistant with varying cancer, so that the unmet need in a space remains very significant and I you know to your question about the bar it really comes down to the totality of uh of data, right? There's the activity there's the tolerability profile where we think we showed some real differentiation over over other other platforms that that also come into play.

Anna Protopapas: With the accomplishment of our 2021 goals, we could achieve another transformational year for Mersana. 12 months from now, we could be substantially enrolled in our pivotal study for APRI with multiple life cycle management studies underway. And we anticipate having a clear strategy for the potential of NAPI to be lung adenocarcinoma patients and having two new molecules in the pipeline. Accomplishment of these goals would put the next stage of transformation of Mersana in sight, the potential for completing our first pivotal study and preparing to launch our first commercial ADC. With that, I would like to turn the call over to Arvind to review Uplift and our upper life cycle management studies we are planning, and then to Tim to review the progress of our pipeline.

Got to thank you.

Thank you. And our next question comes from the line of concertina Velasquez with stifel your mind is open, please go ahead.

Good morning. Thanks for taking my questions as we wait for uplift to initiate. Can you disclose how many additional patients have been enrolled into the ongoing expansion cohorts since your last read out and then what are the current plans if any for additional data disclosures from the upgrade extension cords, you plan and present presenting any preclinical data, that would be further validating to potential combinations in upgrade. Yeah. Thanks Cosentino for the correct question. So we're continuing to see momentum in enrollment all the expansion cohort. So I think we've always said that's encouraging in terms of converting extension cord into the uplift in terms of data disclosures. We have a few different opportunities and religious out of our consideration. Yes, we've done for data disclosures between March of 2020 in January 5th. I think we've disclosed the very we've shown of

Arvin Yang: Thank you, Anna, and thank you everyone for joining us today. Let me start by summarizing the data we've generated to date that support the potential for upbringing to become a foundational medicine in ovarian cancer. As you recall, we've disclosed substantial data from the ongoing study in four different disclosures in the past 12 months, including a comprehensive disclosure on January 5th of this year. These data support the potential of OPERATE to provide significant benefit for heavily pre-treated ovarian cancer patients who have exhausted other options, including bevacizumab and PARP inhibitors, and have a poor prognosis.

Arvin Yang: Specifically, we have consistently shown robust activity substantially above the current standard of care, including complete response, and A Tolerability Profile Without the Severe Neutropenia, Neuropathy, and Oculotextile that limits other ADC platforms. This has the potential to facilitate the combination ability of upbringing with agents used in earlier lines of ovarian cancer.

Very quick system and call me, please.

Profile for a pre Ware now single-mindedly focused on getting a place up and running and rolling as quickly as possible and you know bringing this page agen promise to pay option as we could work up to a place that happening on a side-by-side basis. So what some point we're going to close down the expansion cohort, we're going to lock and clean the database and I think that could give an opportunity for us close to think that either it's the publication of the scientific conference. Also, I think that this exact point we're not in a position to know what the exact timing is of that dispatch, but obviously we have that option in front of us. We are also finalizing the expansion cohort the cutoff. Sorry the cut off for the birth.

Arvin Yang: Let me start with Uplift, our single-arm registration strategy in heavily pretreated platinum-resistant ovarian cancer, the first step in our objective of building Opry as a foundational medicine in the treatment of ovarian cancer. With FDA feedback and with strong support from cooperative groups both in the U.S. and in Europe, we are well on our way to initiating dosing and uplift in March. Let me summarize the key features of Opry.

Arvin Yang: First, the patient population addresses substantial unmet medical needs and affords us the potential for significant label differentiation. Uplift is designed to enroll platinum-resistant patients who have received up to four lines of therapy consistent with the population in the expansion cohort, where we've already seen data supporting the potential for robust activity. The inclusion of patients with four prior lines differentiates Uplift from other ongoing and historical studies in late-stage ovarian cancer.

The biomarker and I think that's another opportunity for us to share more data with you and I think we are we're trying to determine what is the right Forum wage closed. But that would be another opportunity for data disclosure. But again, this is the year. We're we're very focused on initiating uploads initiating software upgrade and putting in motion to study that will bring this ate into patients and we will of course it's located along the way but on top priorities, that would be something

Arvin Yang: Note that Bevacizumab pre-treated and Bevacizumab nave patients are included in the Uplift cohort in a manner consistent with the Bevacizumab label. This is another important differentiator because it allows us to explore the potential of upbreeding to address the unmet medical need of patients who have and have not been previously treated with Bevacizumab in a single study. Second, the design allows for the robust evaluation of the relationship between the biomarker and patient outcome. We plan to enroll patients regardless of NatB2B expression, which we believe will also contribute to the speed of enrollment. Nevertheless, the role of the biomarker will be evaluated in a...

I think sure that that was very helpful. And then I guess just coming at it from just a different angle for upgrade. You know, how should we think about the other potential combination partners that you're that you're thinking about in the umbrella study off again just going to be sort of preclinical data to support those decisions that we would see or you know, I guess just under underlying rationale for the for the combinations that you that you pursue.

Arvin Yang: Specifically, the primary endpoint for the uplift cohort will be objective response rate in the higher NAPI 2B population, while the key secondary endpoint will be objective response rate in the overall population. This design allows us to more fully evaluate the role of the biomarker to enhance patient outcomes. It's a two-shot on goal approach.

So we're working through all those additional combination and I think we'll be able to share more data in the in the near-term but there multiple options here and I know that our pin and Tim are collaborating to do what is necessary from a clinical standpoint to understand the potential of some additional compensation.

Arvin Yang: We expect to enroll approximately 100 patients with higher NatB2B expression in the Uplift cohort, which can include up to 180 patients in total, depending on the higher NatB2B prevalence. Other secondary endpoints will include the duration of response and safety in both the higher NAPI-2B population and the overall population. Thirdly, Uplift is designed to ensure that we have a systematic and robust strategy for a commercial diagnostic assay. Specifically, the substantial data set generated in the ongoing expansion cohort will be used to establish the final cutoff for the planned commercial assay that will be used in Uplift. This approach should allow for the evaluation of both the higher NAPI 2B population and the overall population.

All right. Perfect. Thank says congrats on the progress. Thanks.

Thank you. And our next question comes from the line, of course speaker with Colin your line is open, please go ahead good morning. My first question is on the diagnostic side. You mentioned that there is a possibility here or companion versus a complimentary diagnostic. Is there a difference from there be a regulatory perspective for either of those diagnostic approaches?

Do you want to take this?

Sure, let me start and we're just to address the question between a companion versus the complimentary diagnostic for a companion diagnostic. The guidance. Julie is a relationship to that test is utilized to identify and select patients that would then have an indication in order to be treated with the drug. So in the instance that the companion diagnostic would be utilized it would be primarily based on the fact that the benefit-risk is focused specifically on those patients the higher net B2B status now in a secondary instance where a complimentary diagnostic would have values is we're by the benefit-risk is considered a supportive to approved in the broad indication a meaning regardless of not be to be status. However, having a diagnostic available may be helpful for Physicians to understand if there's differential benefit-risk within the Popular Song

Arvin Yang: We expect to deploy either a companion diagnostic or a complementary diagnostic, depending on which strategy we think will be most beneficial to patients, as well as feedback from the regulators. We are on track to finalize the biomarker strategy and the cutoff for the proposed commercial diagnostic in-office. Lastly, Uplift will be initiated as an amendment to the current study, allowing us to capture the enrollment momentum we are seeing in the ongoing expansion cohort.

Tim Loinger: In addition to the UPLIFT strategy, we are focused on the life cycle management plans that have the potential to build UPRI into a foundational medicine in ovarian cancer. This plan starts with the UPGRADE Phase I Umbrella Study, designed to evaluate UPGRADE in combination with other ovarian cancer therapies. We first intend to combine it with platinum, as platinum therapy is currently the mainstay therapy in earlier line platinum-sensitive ovarian cancer. Our goal is to initiate the upgrade in the third quarter of 2021.

Me to be status. And so the clear distinction here is that in the complimentary diagnostic there would not be a requirement for a test result in order for a physician to be able to put off or utilize Opry impatience assuming it was approved in that broader implication.

Tim Loinger: However, over the next few months, we will be sharing with you a more complete life cycle management plan as we leverage the potential of UPReE to address patients in earlier lines of therapy. These studies are important next steps in building UPReE as a foundational medicine in ovarian cancer. Moving on to our ongoing efforts to build out the pipeline, we continue to advance as planned on our NAPI-2B targeted dolusynthin ADC XMT 1592 in the phase one dose escalation study.

Gotcha, and my second question is for the upgrade study is to go to ultimately find a combination for running a future pivotal study for that combination. Would you judge plan to generate enough data for compendia listing in parallel with the uplift regulatory study so that you could complement the approval based on uplift.

Tim Loinger: We are on track to generate the data set that allows us to make decisions on the path forward in lung adenocarcinoma as we evaluate both OPRI and XMT 1592 in this indication with high-end medical. In addition, as Tim will describe, we are preparing to advance XMT 1660 and XMT 2056 into the clinic early next year. We are encouraged by the high level of interest that these two exciting molecules are generating among the KOL community. I will now turn the call over to Tim to discuss our exciting early stage ADC campaign.

Thank you for the question. We were actually finalizing the designs of our confirmatory trials and we will have an opportunity to share it with externally in the in the near-term. So I would ask you see a little patient with us as we finalize those plans, but our objective is to have a confirmatory trial in the earlier life of therapy and be able to move up least in as a treatment in Platinum sensitive.

Tim Loinger: Thanks, Arvin, and good morning, everyone. We made significant progress in advancing our pipeline in 2020. The focus for 2021 is to build out the pipeline and further demonstrate our position as leaders in ADC innovation. Today, I will focus on XMT-2056, our first immunosymptom sting agonist ADC, and XMT-1660, our B7H4 dololox. We are very excited about the potential of our immunosymptom ADC platform. As a reminder, in November, we held a webinar highlighting the characterization of this platform, and I'd like to briefly summarize the key takeaways from that webinar that explain why we are so excited about this platform and the potential of Sting Agonist ADC.

All right. Thank you very much for taking my question.

Thank you. And our next question comes from the line of Jessica fee with JPMorgan your line is open, please go ahead.

Hey guys. Good morning. Thanks for taking my question. First is when do you expect to solidify the cut off for higher than happy to be expression and second is 6/10 at the cutoff for hire not be to be expression changes relative to what you have to using can we expect you to update the extension data analyzed using that new cut-off so investors so you get a clearer sense of potential efficacy this group.

Yeah, just as a great question. We are in the process of finalizing that cut off and we will we will be sharing that data. We are trying to you know, completed wrap up our work and then find the right form to do that as well as really describe the whole strategy around the diagnostic the commercial diagnostic. So in that context, we will also show the whole analysis which includes really showing that function composite that that that led to the determination of the cut off.

Tim Loinger: We believe that an ADC approach to activating the innate immune system to fight cancer in a targeted manner is a potential game changer and could be a dramatic next step in immune oncology. The STING pathway has been studied extensively and validated to play a central role in immune activation. However, we believe that delivery challenges to date have limited Sting agonists from reaching their full potential.

Tim Loinger: Immunosensing leverages our unique expertise in ADC design and optimization to overcome those limitations. Our approach is also differentiated from ADCs carrying toll-like receptor agonist payloads. With the Immunosynthon, we deliver what we call a one-two pump.

Great. Thank you.

Thank you. And our next question comes from the line of Tom Schrader with btig. Your line is open, please go ahead thank you. Let me congratulate wage what I'm on a nice year. I had a question kind of triggered by your careful language about prior avastin use and uplift who's not going to have avastin that patients with platinum-resistant cancer and then three lines of chemo.

Tim Loinger: Unlike toll-like receptors, or TLRs, sting is expressed in both tumor cells and immune cells. And we have demonstrated preclinically that we can productively activate the sting pathway in both these cell types in a concerted and targeted fashion, delivering the one-two punch with potential to increase the therapeutic index. That's not possible with TLRs because they are not expressed in tumor cells but only in immune cells.

And they going to be sicker.

Brian would you like to pick this question or RV?

Sure, I can I can certain that are when you can you can join in so Tom, thanks for the question. And I think this is a really important differentiator here in in how we're pursuing uplifting and what we think is important for for a label. So you will notice from the demographics of our expansion data that about 70% of patients that we enrolled had had prior of accidents and now there are dead or maybe there's there's reasons. It's that high of a sedan improved in the front line gets approved and platinum sensitive relapse and it's approved in platinum-resistant disease, but not everybody may be a candidate for of acid, but that's a minority of a patience and that might be because of a comorbidity or concerns about bowel obstruction or or wound healing or hypertension. That's what we wanted. The important thing here though is in a single study and a very Capital efficient way. We want to be able to address both populations that people who have had of acid previously and the people who had

Tim Loinger: Preclinically, we have validated the broad potential of our immunosynthin ADC pipeline, not only for a single target, but across a suite of multiple targets and multiple animal models, demonstrating robust activity after a single low dose. We've also demonstrated excellent tolerability in multi-dose non-human primate studies with ID dosing at exposure levels far exceeding those that result in complete responses in mouse models, indicating the potential for XMP2056 is our first immunosymptom ADC that is progressing through IND-enabling studies with the objective of moving into clinical development in early 2022. Now, I'd now like to turn to our novel Dola-Simpson platform.

the higher or lower now.

Not had a passing previously and because of the nature of the events and labeled we're able to do that in one study avastin in platinum-resistant disease is only approved for patients who have had only one or two prior life therapy. So for patients with three or four we can pursue uh, a fast pet the market while also included patients who may not have seen a month before and this is a really important point. It allows us to go after a very broad patient population in a single single arm study.

Tim Loinger: In early January, we introduced you to our next dolicentin ADC, XMT1660, which is a first-in-class ADC targeting B7H4. We believe that B7H4 is a well-suited target for a donor-locked ADC for the following reasons. First, C7H4 is expressed on multiple tumors with high unmet medical need and provides us the opportunity to target these tumors with our cytotoxic antitubulin mechanism. Second, we also know, based on preclinical studies, that our Dololoc ADCs lead to immunogenic cell death, and that our Dololoc payload can activate dendritic cells in the tumor, both of which can prime a potential immune response as

All right, great. Got it. Right and then a question on upgrade if if you are combining with Platinum to get this through and stuff. Will you have or give patients full dose platinum and then tie trade in your drug or can you start at lower levels of both drugs do you think?

Tim Loinger: Because B7H4 is expressed on tumor cells but also on immunosuppressive tumor-associated macrophages, it provides the potential opportunity to co-opt those cells in a targeted manner to further contribute to both the cytotoxic and immunogenic effects and create what we describe as a perfect storm in the tumor microenvironment. Another feature of B7H4 is that it is in the same family as PD-L1. But the literature suggests B7H4 and PD-L1 expressions are mutually exclusive.

I've been you want to take that. Yeah that sure so so we'll be coming out with obviously our trial design in relationship to the the upgrade but what I would want to start wage and point has remember one of the key differentiators for all three is really from the standpoint again, the fact that our safety profile has been quite consistent with the lack of that severe neutropenia a new peripheral neuropathy as as well as the argument toxicities. So it sets us up in a way to really fully appreciate and maximize the potential to combine and particularly with time where there can be Associated neutropenia as as one example, and so will be coming out with the trial design obviously safety is Paramount in relationship to these phase one studies and so certain age escalation is quite standard just in relationship to how these studies are designed in order to ensure that we're appropriately dos escalating and maximizing the ability for these 2 khong

Brian C. DeSchuytner: Providing for the potential to address unmet medical needs in patients who either do not respond or progress with checkpoint therapy due to lack of PD-L1 expression if they are likely to express B7H4. Leveraging our unique ability to do DAR ranging, we selected XMP1660 as our development candidate from a range of variant options evaluated based on efficacy and tolerability. We are hard at work and on track to complete IND-enabling studies on a timeframe that we expect will allow us to initiate clinical studies in early 2022.

Has to be either additive or potentially synergistic.

Okay, great. Thank you.

Thank you. And our next question comes from the line of David with wedbush Securities, please go ahead.

Brian C. DeSchuytner: We are very excited about the potential for both of these innovative earlier stage development candidates and are pleased to announce that two abstracts for XMT 2056 and one abstract for XMT 1660 have been accepted as e-posters at the AACR virtual meeting to be held in April. We look forward to sharing further preclinical data from these programs at that meeting. And with that, I'll now turn the call over to Brian for an overview of our financial results. Thank you, Tim. Good morning, everyone, and thank you for joining us.

Thanks for taking a question. Maybe a follow-up to a couple other ones on upgrade steady. Do you do you anticipate or is there a possibility to get free as a maintenance therapy or or you know extend the dosing beyond the fixed Platinum Cycles, or are you planning to focus in on dosing wage Platinum for that fix second set of Cycles. Thanks.

Brian C. DeSchuytner: I'll now review some of the key financial highlights from our fourth quarter 2020 results, and I'll start with our cash position. We ended the year with $255 million in cash and cash equivalents. Net cash used in operating activities in the fourth quarter was $17.3 million. We expect that our available funds will allow us to meet our current operating plan commitments for approximately the next two years, in addition to our current cash position. We have the option to draw funds through the amended existing debt financing agreement with Silicon Valley Bank, which was refinanced in August of last year.

David yeah, go ahead. Oh sure. I was just going to say I think it leads back to the response. We've mentioned just from the standpoint that song again that tolerability profile lends itself toward the ability to to dose really till potentially progression in regards to upgrade. So as we're evaluating that those escalation should be here. We're really going to maximize the characteristics of of each of these compounds to make sure that we're trying to maximize the benefit for patients per se so certainly from a combined ability perspective if we just believe that there is going to be the potential to combine and that's how we're thinking about approaching this and again, I think with the line of sight toward the idea that we will try to maximize each of these agents in a way to benefit most of those patients.

Brian C. DeSchuytner: And now, some of the key highlights from our fourth quarter 2020 financial results. Research and development expenses for the fourth quarter of 2020 were approximately $22.9 million compared to $12.4 million for the same period in 2019. The difference was primarily due to an increase in UPRI and XMT-1592 clinical expenses, an increase in manufacturing activities for UPRI and our Discovery Stage programs, increased headcount, and a non-cash increase in the valuation of stock-based awards as a result of stock appreciation.

Brian C. DeSchuytner: All of these were partially offset by a decrease in preclinical development and manufacturing expenses for XMT-1592. General and Administrative expenses for the fourth quarter of 2020 were approximately $5.9 million, compared to $4.2 million in the same period of 2019. The increase was primarily due to an increase in consulting and professional fees, an increase in facility-related costs as a result of the extension of our lease in March 2020, and a non-cash increase in the valuation of stock-based awards as a result of stock appreciation.

Okay, and I mean would there be I know you're disclosing details later, but would there be an option do you think for patients to continue on maintenance therapy anything like that? As long as part of the study assuming you begin with a fixed if it's fixed set of Cycles to combine with Platinum short answer is Faith is definitely under consideration from the standpoint that remembering that for chemotherapy is it's it's typically a fixed number of cycle and we have not seen that type of treatment approach with with up remodel therapy.

Thank you, and I'm showing no further questions at this time, and I would like to turn the conference back over to Anna for any further remarks.

Brian C. DeSchuytner: The net loss for the fourth quarter of 2020 was $28.8 million, or $0.42 per share, compared to a net loss of $16.2 million, or $0.34 per share, in the same period of 2019. Weighted average common shares outstanding for the quarters ended December 31, 2020, and December 31, 2019, were approximately $69 million and $48 million, respectively.

I just want to thank you all for listening and this is another really exciting year for us as we really built up and built out the pipeline sober. Thank you very much for your continued support.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program and you may all disconnect if you would have a great day.

Anna Protopapas: I'll now turn the call back to Anna.

Anna Protopapas: Thank you, Brian. Before we open the call to questions, I would like to outline our goals and milestones for 2021, which center on building up Root as a foundational medicine in the treatment of ovarian cancer and building out our pipeline to demonstrate our position as leaders in ADC innovation. I'll start with... First, we are on track to initiate the planned UPLIFT single-arm registration strategy in platinum-resistant ovarian cancer this quarter. As for our longer-term life-cycle management studies for UPRI in ovarian cancer, our goal is to initiate the dose-escalation portion of the upgrade study, starting with a combination study with platinum in Q3 of this year. We are considering additional life-cycle management studies, and we will share these details as we finalize our plan.

Anna Protopapas: We are excited about the potential of these studies and the opportunity to build UPRI as a foundational medicine for ovarian cancer across lines of therapy with the objective of creating a differentiated label for this indication. Lastly, for UPRI, we expect to have a meaningful number of lung cancer patients enrolled in the expansion study and to be able to provide a data update from this cohort in the second half of 2021.

Anna Protopapas: We plan to disclose dose escalation data in the second half of 2021. As we have said in the past, our objective is to compare the upper lung adenocarcinoma expansion data with the XNT1592 data to make decisions as to which molecule we will take forward based on PK, tolerability, as well as activity.

Anna Protopapas: We expect to be able to outline our further development plan for XMT 1592 in the fourth quarter of 2021. For XMT 1660, we plan to complete the IND-enabling study in 2021 and initiate the phase 1 dose escalation study in early 2022. For XMT 2056, our first-stage agonist ADC from the Lunar Symptom Platform, we plan to complete the IND-enabling study and disclose the target by the end of this year and initiate the phase 1 dose escalation study in early 2022.

Anna Protopapas: Finally, we will continue to leverage our proprietary platform and continue to expand our pipeline of innovative ADC candidates while proactively evaluating potential collaborations for current and future programs. In closing, we have another busy year ahead of us with multiple value-driving opportunities as we focus on building our pipeline and building out the platform. With a promisingly diverse and exciting pipeline, differentiated platforms, a highly experienced team, and a strong balance sheet, we believe we are well positioned to execute against these goals and to ultimately reach our overarching mission to discover and develop life-changing ADCs for patients fighting cancer. With that, I will turn the call over to the operator for Q&A.

Operator: Thank you. Ladies and gentlemen, if you wish to ask a question at this time, please press star then 1 on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. To prevent any background noise, we ask that you please place your line on mute once your question has been stated. Our first question comes from the line of Jonathan Chang with SBB Lyric. Your line is open, please go ahead.

John Barrett: Hi team, this is John Barrett on behalf of Jonathan. Congratulations on the progress in 2020. My first question is, now that you're closer to the initiation of Uplift, what are your expected timelines for the trial related to full enrollment, and then, obviously, potential readout of top-line data?

Anna Protopapas: Yeah, great question, Jonathan. I think we're very focused on getting Uplift up and running. We're really on the cusp of beginning to dose patients. We have, as you know, agreed with the FDA that we could do this as an amendment to the existing trial. And if you recall, we indicated on January 5th that we had about 40 sites already as part of the expansion cohort. We're working with the cooperative groups in Europe, and we'll be bringing additional sites up in Europe.

Anna Protopapas: And we feel quite good about the momentum behind the agent and the momentum we hope will translate into enrollment in Uplift. At this point, we're holding back from giving specific guidance. We just want to get the trial up and running, but I think a lot of support from the cooperative groups and the momentum we've seen in enrollment in the expansion cohort make us optimistic that a year from now, we'll be substantially enrolled in the study. But I think we'd like to wait a little bit before we give definitive guidance.

Anna Protopapas: That's helpful. And following up, given the two endpoints of ORR in the higher NetP2B population and ORR in the overall population, is it possible that you have two top line data readouts where you have an ORR top line for first the higher population and then later on the ORR for the entire population, or do you expect those to be coming at the same time?

Arvin Yang: I'll let Arvin answer the question, but my expectation is that it would be coming out at the same time, but Arvin, maybe you can confirm that.

Arvin Yang: Yeah, no, thank you, Anna. And just to confirm, that's correct, meaning that based upon the way the study is designed, we would have both endpoints at the same time.

Anna Protopapas: And just one last one, what do you see as the bar for a go, or no-go decision in lung cancer, and what gives you confidence that UpRe could succeed in lung cancer?

Anna Protopapas: So, let me answer your second question, and maybe I'll ask Brian to answer your first question. So, what do we know about NAPI-2B in lung cancer? We know that it's expressed there in lung adenocarcinoma, not in other histologies, and we've published data where we showed the work we did to understand the expression.

Anna Protopapas: We saw in, if you recall back to the data we disclosed in March, at the MTD, we had several lung patients, we had one partial response, and we had multiple patients with prolonged stable disease. So, the target is there with senior designs of activity.

Brian C. DeSchuytner: We are enrolling an expansion cohort of about 40 to 45 patients. We did say that what we've seen both in tissue banks as well as with patients is that the distribution and prevalence of NAPI TBH is different in ovarian cancer than in lung and tissue cancer. In ovarian cancer, if we were to take the definition of NAPI TBH as being that age score of about 110, you know that in ovarian cancer, about two-thirds of patients are above that.

Brian C. DeSchuytner: I think what we're seeing in the clinic is that more like 40% of patients are above that threshold and are on the NAPI TBH side. So I think we need to complete the expansion cohort and really understand the profile of the agent, but the target is there, and we've seen some early signs of activity. Brian, do you want to talk about the bar?

Brian C. DeSchuytner: Sure, so in non-small cell lung cancer, the standard of care following progression on checkpoint inhibitors and platinum-based chemotherapy or failure of targeted therapy for patients with tumors that harbor the oncogenic driver mutations that make those appropriate is dosotaxel alone or in combination with targeted therapy. You know, this standard of care is an overall response rate of somewhere between 14 and 23 percent with a median PFS of three to four months. Single-Agent Chemotherapy, Standard Care, and Platinum-Resistant Ovarian Cancer

Brian C. DeSchuytner: So the unmet need in this space remains very significant. And to your question about the bar, it really comes down to the totality of data, right? There's the activity, there's the tolerability profile where we think we've shown some real differentiation over other platforms that also come into play. Thank you.

Operator: Thank you. And our next question comes from the line of Constantinos Apalaskas with CFL. Your line is open. Please go ahead.

Constantinos Apalaskas: Good morning, thanks for taking my questions. As we wait for Uplift to initiate, can you disclose how many additional patients have been enrolled in the ongoing expansion cohorts since your last readout? And then what are the current plans, if any, for additional data disclosures from the upgrade expansion cohorts?

Anna Protopapas: Do you plan on presenting any preclinical data that would be further validating for potential combinations in upgrade?

Anna Protopapas: Thanks, Costantino, for that question. We are continuing to see momentum in enrollment of the expansion cohort. So I think we've always said that that's encouraging in terms of converting the expansion cohort into the uplift. In terms of data disclosure, we have a few different opportunities, and let me just outline our considerations here. We've done four data disclosures between March of 2020 and January 5th. I think we've disclosed a very, we've shown a very consistent and promising profile for UPRIE. We're now single-mindedly focused on getting Uplift up and running, enrolling as quickly as possible, and, you know, bringing this promising agent to pace.

Anna Protopapas: As we convert the expansion cohort to Uplift, that's happening on a side-by-side basis. So at some point, we're going to close down the expansion cohort. We're going to lock and clean the database.

Anna Protopapas: And I think that could give an opportunity for us to disclose the data, either as a publication at a scientific conference or both. I think at this exact point, we're not in a position to know what the exact timing is of that disclosure. But obviously, we have that option in front of us.

Anna Protopapas: We are also finalizing the expansion cohort, the cutoff, sorry, the cutoff for the biomarker, and I think that's another opportunity for us to share more data with you. And I think we're trying to determine what the right forum is to disclose that, but that would be another opportunity for data disclosure. But again, this is a year where we're very focused on initiating Uplift, initiating Upgrade, and really putting in motion the studies that will bring this agent to patients. And we will, of course, disclose data along the way. But our top priority is getting the studies up and running.

Anna Protopapas: And then, I guess, just coming at it from just a different angle for upgrade, you know, how should we think about the other potential combination partners that you're thinking about in the umbrella study? And, again, is it going to be sort of... Preclinical data to support those decisions that we would see or, you know, I guess just the underlying rationale for the combinations that you pursue.

Anna Protopapas: So, we're working through all those additional combinations, and I think we'll be able to share more data in the near term, but there are multiple options here, and I know that Arvin and Tim are collaborating to do what is necessary from a preclinical standpoint to understand the potential of some of the additional combinations.

Operator: All right, perfect. Thanks, guys. Congratulations on the progress.

Anna Protopapas: Thank you. Thank you.

Operator: And our next question comes from the line of Boris Peaker with Cowan. Your line is open. Please go ahead.

Boris Peaker: Good morning. My first question is on the diagnostic side. You mentioned that there is a possibility of a companion versus complementary diagnostic. Is there a difference from the FDA regulatory perspective for either of those diagnostic approaches?

Arvin Yang: Arvin, do you want to take this?

Arvin Yang: Sure. Let me start.

Arvin Yang: And just to address the question between a companion versus a complementary diagnostic, for a companion diagnostic, guidance really is in relationship to that test, which is utilized to identify and select patients that would then have an indication to be treated with the drug. So in the instance that the companion diagnostic would be utilized, it would be primarily based on the fact that the benefit risk is focused specifically on those patients with the higher MAP-B2B status.

Arvin Yang: Now, in a secondary instance, where a complementary diagnostic would have value, is whereby the benefit-risk is considered... are supportive of approval in the broad indication, meaning regardless of NAPI 2B status. However, having a diagnostic available may be helpful for physicians to understand if there's differential benefit risk within the populations of the higher or lower NAPI 2B status. And so the clear distinction here is that in the complementary diagnostic, there would not be a requirement for a test result in order for a physician to be able to potentially analyze Opry in patients, assuming it was approved for that broader indication.

Anna Protopapas: And my second question is, for the upgrade study, is the goal to ultimately find a combination for running a future pivotal study for that combination? Or would you just plan to generate enough data for a compendia listing in parallel with the uplift regulatory study so that you could complement the approval based on uplift?

Anna Protopapas: trial, and we will have an opportunity to share it externally in the near term. So I would ask you to be a little patient with us as we finalize those plans. But our objective, as we said before, is to have a confirmatory trial in the earlier lines of therapy and be able to move up as a treatment for platinum sensitive patients.

Boris Peaker: Great, thank you very much for taking my question.

Operator: Thank you. And our next question comes from the line of Jessica Fee with J.P. Morgan. Your line is open. Please go ahead. Hey guys, good morning.

Jessica Fee: Thanks for taking my question. First, when do you expect to solidify the cutoff for higher NAPI-2b expression? And second, to the extent that the cutoff for higher NAPI-2b expression changes relative to what you have been using, can we expect you to update the extension data analyzed using that new cutoff so investors can get a clearer sense of the potential efficacy in this group?

Anna Protopapas: Yeah, Jess, that's a great question. We are in the process of finalizing that cutoff, and we will. We will be sharing that data. We are trying to, you know, complete and wrap up our work and then find the right forum to do that, as well as really describe the whole strategy around the diagnostic, the commercial diagnostic. So, in that context, we will also show the whole analysis, which includes showing the real expansion corporate data that led us to the determination of the cutoff.

Operator: Great, thank you. Thank you. And our next question comes from the line of Tom Shrader with BTIG. Your line is open, please go ahead.

Tom Shrader: I want to congratulate everyone on a nice year. I had a question kind of triggered by your careful language about prior Avastin use in Uplift. Who's not going to have Avastin? Are those patients with platinum-resistant cancer and then three lines of chemo? And are they going to be sicker?

Brian C. DeSchuytner: Brian, would you like to take this question or Arvin?

Brian C. DeSchuytner: Sure, I can start, and then Arvin you can join in. So Tom, thanks for the question, and I think this is a really important differentiator here in how we're pursuing uplift and what we think is important for a label. So you will notice from the demographics of our expansion data that about 70% of patients that we enrolled had prior Avastin, and now there may be reasons why it's that high.

Brian C. DeSchuytner: Avastin is approved for the frontline, it's approved for platinum sensitive relapse, and it's approved for platinum resistant disease, but not everybody is really a candidate for Avastin, but that's a minority of patients, and that might be because of comorbidities or concerns about bowel obstruction or wound healing or hypertension. The important thing here, though, is in a single study in a very capital-efficient way, we want to be able to address both populations, the people who have had Avastin previously and the people who have not had Avastin previously.

Brian C. DeSchuytner: Because of the nature of the Avastin label, we're able to do that in one study. Avastin in platinum-resistant disease is only approved for patients who have had only one or two prior lines of therapy. For patients with three or four, we can pursue a fast path to market while also including patients who may not have seen avastin before. And this is a really important point. It allows us to go after a very broad patient population in a single, single-arm study.

Arvin Yang: .. .. .. .. .. ....

Arvin Yang: A question on upgrade, if you are combining it with platinum to get this through IRBs and stuff, will you have to give patients full dose platinum and then titrate in your drug, or can you start at lower levels of both drugs, do you think?

Arvin Yang: Arvin, do you want to take this?

Arvin Yang: So, we'll be coming out with, obviously, our trial design in relation to the upgrade, but what I would want to start with from the standpoint of, remember, one of the key differentiators for OPRI is really from the standpoint of, again, the fact that our safety profile has been quite consistent with the lack of that severe neutropenia, peripheral neuropathy, as well as ocular toxicities. So it sets us up in a way to really fully appreciate and maximize the potential to combine it, in particular with platinum agents where there can be associated neutropenias, as one example.

Arvin Yang: And so, we'll be coming out with the trial design, and obviously, safety is paramount in relationship to these phase one studies, and so, certainly, dose escalation is quite standard, just in relation to how these studies are designed in order to ensure that Okay, great, thank you.

Operator: Thank you. And our next question comes from the line of David Nierengarten with Leadbush Securities. Your line is open. Please go ahead.

David Matthew Nierengarten: Thanks for taking the question. Maybe a follow-up to a couple of other ones on the upgrade study. Do you anticipate or is there a possibility to use UpRe as a maintenance therapy or, you know, extend the dosing beyond the fixed platinum cycles, or are you planning to focus on dosing with platinum for that fixed set of cycles?

Arvin Yang: ...

Arvin Yang: Yeah, go ahead.

Arvin Yang: Oh, sure. I was just going to say, I think it leads back to the response we mentioned with Tom just from the standpoint that, again, that tolerability profile lends itself toward the ability to dose really till, potentially, progression in regards to upgrade. So as we're evaluating the dose escalation strategy here, we're really going to maximize the characteristics of each of these compounds to make sure that we're trying to maximize the benefit for patients, per se.

Arvin Yang: So certainly from a combinability perspective, we do believe that there is going to be the potential to combine, and that's how we're thinking about approaching this. And again, I think with the line of sight toward the idea that we will try to maximize each of these agents in a way to benefit most of those patients.

Arvin Yang: Okay, and I mean, would there be, or I know you're disclosing details later, but would there be an option, do you think, for patients to continue on maintenance therapy or anything like that as part of the study, assuming you begin with a fixed set of cycles to combine with platinum?

Arvin Yang: Yeah, so the short answer is that is definitely under consideration from the standpoint that Remembering that for chemotherapies, it's typically a fixed number of cycles, and we have not seen that type of treatment approach with upremodel therapy.

Arvin Yang: Thank you, and I'm showing no further questions at this time, and I would like to turn the conference back over to Anna Protopapas for any further remarks.

Anna Protopapas: I just want to thank you all for listening in. This is another really exciting year for us as we really build UPRI and build out the pipeline. So, thank you very much for your continued support.

Operator: Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a great day!