Tango Therapeutics, Inc. (TNGX) Earnings Call Transcript & Summary

Thank you. Good day and welcome to the Tango Therapeutics conference call. [Operator Instructions] Please note this call is being recorded. I would like to turn the call over to Elizabeth Hicken, Vice President of Investor Relations. Please go ahead.

Thank you. Good morning, everyone, and thank you for joining us on today's call. This morning we issued a press release describing the data we will present at ESMO, which can be found on the investors and media section of our website www.tangotx.com. Before we begin, let me review our safe harbor statement. We will make forward-looking statements on this call that are subject to important risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. This call is being recorded, and a replay will be available on our website. The agenda for this morning's call is as follows. Malte Peters, Tango's President and CEO, will share some introductory remarks. We are pleased to be joined today by Dr. Brian Wolpin, Director of the Hale Family Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute, who will present the clinical data. Adam Crystal, our President of R&D, will discuss our registration process and expansion strategy for Vopimetastat and PDAC, and then Matt Gall, CFO, will share some financial highlights and provide an overview of important upcoming events. Malte will then conclude the call, and we will open it up to Q&A. I will now turn the call over to Malte.

Thank you, Liz, and good morning, everyone. Since I joined Tango as CEO in January 2026, we have developed a clear mission to deliver Vopimetastat to patients with pancreatic cancer as quickly as possible. In order to achieve that goal, we need to accomplish three things. First, build on the body of clinical data. The updated clinical data that we are sharing today and that will be presented at ESMO this weekend confirm what we believe to be an unprecedented and potentially best-in-class safety and efficacy profile. This strong clinical profile may be attributable to some of Vopimetastat's unique properties that have created a favorable drug-drug interaction with Darovasertib that has yielded impressive clinical activity and a safety profile that, to date, appears to be superior compared to that of single-agent Darovasertib. We believe we are seeing a 1 plus 1 equals 3 type synergy with this combination, exceeding our expectations across all metrics. Second, establish an innovative and efficient registration strategy. Based on recent FDA feedback, we are preparing to start a Phase 3 study for this combination in first-line pancreatic cancer. Our discussions with the agency were productive and collaborative, and we now have a study design that is ready to go. We are committed to starting the study in the first half of 2027. In addition, we plan to seek FDA's guidance regarding a possible accelerated approval for the combination in second-line pancreatic cancer patients. Lastly, to support these efforts, we need to grow and evolve our organization to execute against these goals. We have evolved the organization significantly from a pre-commercial CRO. We have an experienced leadership team in place, and we are laser-focused on operational excellence and execution as we enter late-stage clinical development and become a pre-commercial organization. But that is not enough. While executing against our pivotal study in frontline pancreatic cancer is our primary goal, the data and evolving landscape, along with a strong biological rationale, position us to further advance novel scientific approaches into the clinic. We aim to begin these efforts studying the combination in MTAP wild-type pancreatic cancer, supporting our ambition for Vopimetastat to be a PRMT5 combination partner of choice for any RAS inhibitor. Over time, this may create the potential to evaluate combinations beyond RAS and to extend the impact of the PRMT5 program into additional tumor types and treatment settings. Tango is well positioned to move into the next stage of Vopimetastat development and to continue on the path to creating meaningful benefit for patients and value for shareholders. On today's call, we are primarily focused on pancreatic cancer, and so I wanted to set the stage and outline the opportunity here. In the United States alone, each year approximately 60,000 people are diagnosed with metastatic pancreatic cancer. And approximately 40% of those patients harbor an MTAP deletion. As standard of care evolves, we believe the percentage of patients receiving treatment at each line of therapy will increase, with treatment options that have the potential for greater patient benefit without cytotoxic chemotherapy. On the call today, we are very pleased to have Dr. Brian Wolpin of Dana-Farber Cancer Institute join us to present the updated clinical data for this combination. Dr. Wolpin is the director of the Gastrointestinal Cancer Center at Dana-Farber and will be the lead investigator in our planned Phase 3 trial.

Excellent. Thank you, Malte, very much. I appreciate the opportunity to present the data on behalf of all of the investigators and the patients and the team at Tango. So, to start out with, to think about how the standard of care in pancreatic cancer is evolving, really historically this has been a disease treated with chemotherapy. And in metastatic disease, the vast majority of patients really had limited options, and these options generally were multi-agent chemotherapy. However, in recent months with the approval of now the first RAS inhibitor for patients with pancreatic cancer, in particular metastatic pancreatic cancer, we see that the landscape starts to shift toward a more targeted approach toward treatment of patients with this disease. Now I think really as the next step comes additional options to add drugs to RAS inhibitors to create even greater durability, higher response rates, and ultimately more benefit for patients facing this difficult disease. So this slide provides some of the mechanism as background to Vopimetastat, which is an MTAP cooperative PRMT5 inhibitor. 30% to 40% of pancreatic cancers have a biallelic deletion in MTAP. This deletion leads to an accumulation of the substrate for this enzyme, MTAP. MTAP then binds to PRMT5 and causes a partial inhibition of PRMT5 function. Vopimetastat as an MTAP cooperative PRMT5 inhibitor then has a selectivity toward further reduction in PRMT5 function in tumor cells, therefore providing a therapeutic window for treatment in cancer cells compared to normal cells. There is now substantial preclinical data looking at the combination of PRMT5 inhibition and RAS inhibition across a host of different models and different scenarios. You can see on the left our data in a PDX model of a cell line, as MTAP-null and KRAS G12V mutant. And you can see the benefit in this model to both Vopimetastat and to Darovasertib, but then really the appearance of a synergistic benefit with the two of them together. On the right, you see a similar type experiment, again, another cell line-derived xenograft model, again, MTAP-null, in this case KRAS G12D mutant. And you see data for Vopimetastat and Zol-da-rasib, in this case a G12D-specific RAS inhibitor, again, showing similar results with an apparent synergistic effect between a RAS inhibitor and PRMT5 inhibitor in these cell line xenograft models. Today, we'll show data for Vopimetastat plus Darovasertib. We're going to focus on that aspect of the Phase 1 dose escalation trial. Additional data with Zol-da-rasib will be presented in the poster at ESMO. As you can see, these are patients with second or third-line treatment of metastatic pancreatic cancer, they must all have MTAP biallelic deletion and RAS mutation. You can see from the key inclusion criteria that MTAP loss was defined either by next-generation sequencing or by immunohistochemistry, ECOG performance status of 0 or 1, and no prior therapy with similar agents. On the right of the slide, you can see the dose escalation range with Vopimetastat given at either 200 milligrams once daily or 250 milligrams once daily, and Darovasertib administered at 100 milligrams once daily. We'll talk about 34 patients in the safety analysis, 27 in the efficacy analysis, with those patients defined as patients who had at least 14 weeks since the initial administration of the combination. And you can see in the bottom right that MTAP status was defined largely by next-generation sequencing and also with a smaller proportion by immunochemistry with very high concordance between these two methods for defining MTAP loss. So if we now look at the baseline patient characteristics for those enrolled to the study, you'll see in the first column is Vopimetastat and Darovasertib in patients with pancreatic cancer. In the middle, you see Vopimetastat and Darovasertib in patients with non-small cell lung cancer. And in the rightward column, Vopimetastat and Zol-da-rasib in patients with pancreatic cancer. You can see relatively common characteristics to what you would expect for patients with metastatic disease. I think most notably is that many of these patients had two lines of therapy already prior to enrollment on the trial. And then you can also see the KRAS mutation distribution at the bottom of the slide. And then finally, liver metastases are very common in patients with pancreatic cancer, and you can see the percentage, which is very much in line with most studies in this setting, with 70% to 75% of patients having liver metastases. If we now look at the waterfall plot for Vopimetastat plus Darovasertib, again in patients with MTAP deletion and a KRAS mutation, this is in the second and third-line setting. You can see at the top line the response rate is around 80%. If we look at the waterfall plot, you can see within the bars are the dose levels, dose level 1 and dose level 2. The arrows indicate those patients who are still on therapy receiving treatment. You can see the darker bars are the partial responses and the lighter bars are those patients with stable disease. You can see again that many of these patients, actually the majority, were receiving this treatment as their third line of therapy. And you can see at the bottom an indication for each individual patient, a line of therapy for this treatment. And importantly, the median duration of follow-up has now increased from the last report up to around seven months. If you look in the upper right, among the 22 patients with metastatic pancreatic cancer, the objective response rate was 82%, disease control rate was 100%, and all of these partial responses are now confirmed. If we now add in the patients who had non-small cell lung cancer, so this is a very similar plot to the prior one, the main difference is that the five patients with non-small cell lung cancer are now also included in the waterfall plot. They are the patients with the additionally darker bars that you can see. And what we can see is that four of five patients with non-small cell lung cancer had an objective response to the combination. And you can see the now overall response among all patients of both pancreatic and non-small cell lung cancer, again, is over 80%. If we now look at the swimmer's plot for Vopimetastat and Darovasertib, again, the top-line result is nearly 90% at a nine-month progression-free survival rate. Again, we can start to see now with larger time for follow-up really some durable responses. And with all of the arrows to the right of the screen, we can see that the swimmer's the bars, we can see many of these patients, nearly all, remain on therapy and have continued opportunity for further durability. And again, to emphasize, the majority of these patients are receiving treatment in the third-line setting. If we then look at the Kaplan-Meier curves, regression-free survival, these are divided into three different lines. We can see the second-line treatment as the blue bar at the top. The third-line treatment is in the red, and then the purple line is the combination, so meaning all of the patients together. And again, we can see very few progression events thus far as follow-up begins to lengthen. And again, a nearly 90% nine-month progression-free survival rate across these patients. If we now look at the toxicity and the events that we see with Vopimetastat and Darovasertib, again, the top line is that these agents together were well-tolerated. We can see, again, similar format that on the left, in the leftward column, is dose level 1, so 100 milligrams of Darovasertib and 200 milligrams of Vopimetastat in patients with pancreatic cancer. The middle column, same doses, but now the patients with non-small cell lung cancer. And then to the right is dose level 2. So this is now an increase in the Vopimetastat dose to 250 milligrams daily and Darovasertib. Again, we can see no new safety signals compared to the prior report and that very few grade 3 events with most of the side effects that have been seen being grade 1 or 2 and no grade 4 or 5 events. If we now look at the specific toxicities as graded by CTCAE criteria, we can see, I think, some notable signals here. One is that for rash, there's no grade 3 rash events. So the rash that is identified has all been grade 1 or 2. For stomatitis and mucositis, no grade 3 events, and the events that have been identified were grade 1 or 2. We can also see that the only grade 3 events at dose level 1 were related to blood count suppression, anemia, and thrombocytopenia. We can see as we get to dose level 2, some increase in rash and stomatitis mucositis as one might expect with greater exposure to a RAS multi-inhibitor. And then again, no grade 4 or 5 treatment-related adverse events and a relatively low incidence of gastrointestinal side effects also, including nausea, vomiting, or diarrhea. If we then look at this in a way that is structured to think about some of the toxicities we see with pan-RAS inhibitors, again, we can see that stomatitis, mucositis, and rash are at lower levels than have been seen previously, and there's no grade 3 events, and again, the gastrointestinal toxicities also are relatively modest without grade 3 events. To the right, you can see that the PK data, which we'll see on the next slide, for Darovasertib in the combination, demonstrates that at the dose of 100 milligrams once daily, there's a very similar area under the curve. As with single-agent Darovasertib at 300 milligrams daily, which has been the dose that is now FDA approved in patients with metastatic pancreatic cancer. These are now the formal PK curves that you can see, and again, very stable, appropriate PK properties as has been shown previously for both Darovasertib and Vopimetastat now in the combination. So I'm going to pass this on to Dr. Crystal for the next part of the presentation.

Thank you, Dr. Wolpin, for joining us this morning and for your leadership in helping advance this combination toward pivotal development. As this data set has matured, the results have become increasingly compelling and the potential to transform the treatment of pancreatic cancer has become clear. These data validate that the addition of Vopimetastat to Darovasertib results in a marked improvement in overall response rate, to an impressive confirmed overall response rate of 82% in a mixed population of third-line and second-line patients. Perhaps more importantly, the potential durability of the combination is now apparent. Across all patients, the median PFS has not yet been reached. The nine-month landmark PFS rate is 88%, and in seven second-line patients, zero progressions have been observed. Critically, with longer follow-up, the evidence that adding Vopimetastat may improve the tolerability of Darovasertib has become even more compelling. At dose level 1, we have observed no grade 3 or higher related rash or stomatitis. In addition, rates of rash, nausea, vomiting, and diarrhea are at least 20 percentage points lower than those reported with Darovasertib 300 milligrams single agent. The dose reduction rate is also 20% lower than reported with Darovasertib alone. Of course, these are cross-trial comparisons, and we recognize their limitations. Nevertheless, the magnitude and consistency of the differences across the dataset are encouraging. Ultimately, what matters to patients is the clinical profile of the combination. However, we also have a compelling biologic hypothesis that may explain why combining two active anti-cancer agents could actually improve tolerability. Preclinical findings demonstrate that PRMT5 inhibition can increase MAP kinase pathway signaling, including phosphoERK and MTAP wild-type cells. We hypothesize that this effect may partially counteract RAS inhibitor-mediated suppression of MAP kinase signaling in normal tissue, potentially explaining some of the improved tolerability we're observing clinically. We also believe that the lower oral dose of Darovasertib, 100 milligrams rather than 300 milligrams, may contribute to the improved gastrointestinal tolerability. This, of course, cannot explain the change in systemic effects like rash, given that the exposure of Darovasertib is equivalent to the 300 milligram single agent dose. Importantly, what initially appeared to be a pharmacokinetic challenge, the DDI, may actually prove to be an advantage, contributing to a differentiated and potentially best-in-class clinical profile. Taken together, the PK, efficacy, durability, safety, and tolerability data give us increasing confidence that we have substantially de-risked the clinical development path for this combination. In the first half of 2027, we intend to launch a pivotal study in patients with MTAP-deleted pancreatic cancer in the frontline setting. The design of this study reflects both the strength of the clinical data set and our highly collaborative and productive interactions with regulatory agencies. We believe these discussions have helped establish a clear path toward pivotal development with shared recognition of the significant unmet need in pancreatic cancer. We are planning for the Phase 3 study to be a global randomized control trial evaluating 200 milligrams of Vopimetastat plus 100 milligrams of Darovasertib once daily versus standard of care chemotherapies. The dual primary endpoint of this study are overall response rate and progression-free survival with overall survival as a key secondary endpoint. The study is anticipated to enroll 484 patients. In addition to the pivotal study in first-line MTAP-deleted pancreatic cancer, our first priority, we also intend to explore the possibility of an accelerated approval in second-line pancreatic cancer, which could be done through a small Phase 2 study, which would also allow us to assess contribution of components. We plan to discuss this further with the appropriate regulatory authorities. Together with the clinical data we announced today, we believe this development strategy will solidify our lead and position Vopimetastat plus Darovasertib as the first-in-class PRMT5 plus RAS inhibitor combination. The underlying biology led us to predict that combining PRMT5 and RAS pathway inhibition would produce synergistic anti-tumor activity. Emerging clinical data in pancreatic cancer have now provided compelling validation of that hypothesis, demonstrating not only remarkable anti-tumor activity, but also an unexpected improvement in tolerability compared with RAS inhibitor alone. We believe this combination of efficacy and tolerability creates an opportunity well beyond our initial indication, including in MTAP wild-type pancreatic cancer. Critically, preclinically, PRMT5 inhibition is synergistic with RAS pathway inhibition, regardless of MTAP status. Although Vopimetastat was designed to selectively inhibit PRMT5 and MTAP-deleted tumors, our data, some of which are shown here, demonstrate meaningful PRMT5 target inhibition, and are in MTAP wild-type cells at exposures achieved with the 200 milligram dose used in dose level 1. Importantly, we believe these findings establish the pharmacologic foundation for extending the synergy between PRMT5 and RAS inhibition beyond MTAP-deleted cancers. The critical question is, then is whether Vopimetastat can inhibit PRMT5 sufficiently in MTAP wild-type tumors to enhance the activity of Darovasertib or other RAS inhibitors. To answer that question, we evaluated the combination across 12 MTAP wild-type KRAS mutant pancreatic cancer cell lines using concentrations of Vopimetastat achieved in our clinical dose of 200 milligrams. In each of these models, Vopimetastat enhanced the anti-tumor activity of Darovasertib. The graph on the right summarizes these findings, comparing the activity of Vopimetastat alone to Darovasertib alone, and the combination across all 12 models. Together, these data demonstrate that Vopimetastat at clinically achievable concentrations consistently potentiates the activity of Darovasertib in MTAP wild-type pancreatic cancer models. In the first half of 2027, we intend to evaluate Vopimetastat in combination with a pan-RAS inhibitor in approximately 25 to 30 patients with MTAP wild-type pancreatic cancer in the second-line setting. This study will test whether the compelling clinical activity we've observed thus far in MTAP-deleted pancreatic cancer can extend to patients whose tumors retain MTAP activity. A positive proof of concept result could open the door to developing the combination across the broader pancreatic cancer population while also supporting exploration of similar strategies in other cancers, including MTAP wild-type non-small cell lung cancer. This represents a capital efficient opportunity to test a hypothesis with the potential to substantially expand the population of patients who could benefit from PRMT5-based combination therapy. We're the potential to pursue this study within our existing collaboration with Rasca. With that, I'll turn it over to Matt to walk through our upcoming catalysts and financial highlights.

Thanks, Adam. 2026 has been a transformative year for Tango, and we have many meaningful catalysts ahead of us. Staying with pancreatic cancer, before the end of the year we plan to initiate our combination study with Rasca, and with the evolving landscape of pure MTAP inhibition and the multitude of opportunities it may provide, we are pleased to soon have multiple clinical combination studies underway that will enable us to learn more about the power of this combination approach and where different agents may fit into the treatment paradigm. As we turn to 2027, we plan to launch our proof of concept study in MTAP wild-type patients in the first half of the year. And most importantly, also in the first half of '27, we plan to launch our Registrational Study in First-line PDAC that Adam outlined earlier. Beyond pancreatic cancer, we are excited by the additional clinical data still to come with both Vopimetastat lung cancer monotherapy, as well as with TNG-456, our brain penetrant PRMT5 inhibitor, which we are studying in lung cancer and glioblastoma, as well as other tumor types. We believe those data and our developments in cancer are going to be very, very important. Strategies in both lung cancer and GBM could be meaningful value creation opportunities for Tango. In order to fully inform our strategy, we made a decision to enroll additional lung cancer patients in our study with TNG-456. These data will take a little longer to mature but are critical to our development strategy, and we intend to provide these data sets and our go-forward development plans at an investor conference in January. With so much opportunity to create near-term value for shareholders and patients with Vopimetastat and TNG-456, we have made a decision to heighten the focus of our efforts on these two lead programs and devote our resources to accelerating and expanding their clinical impact. To support this focus, we have made the decision to stop certain preclinical and research activities and dedicate our resources to our PRMT5 portfolio. We believe that these opportunities offered by these programs will benefit from our full attention and fully dedicated resources. Our ambitions are supported by a strong balance sheet, and we have a disciplined approach to capital allocation that allows us to efficiently de-risk the clinical hypotheses that Adam laid out while retaining financial capacity to accelerate our lead programs. I'll now turn it over to Malte for closing remarks.

Thanks, Matt. The clinical data for this combination that we first disclosed in June and now updated today has been a tremendous catalyst for Tango on several fronts. I believe that Vopimetastat has the potential to be a novel treatment component for patients with pancreatic cancer in the near future. First, since those initial data, we have been laser-focused on getting this combination to patients, engaging with regulatory authorities, designing the clinical development plan, and building the organization to prepare for late-stage clinical development and commercialization. I'm tremendously proud of the team at Tango for what has been accomplished so far. This is important progress in our journey that has the potential to have tremendous impact for patients with pancreatic cancer. Second, the power of the combination and the 1 plus 1 equals 3 level of synergy we are seeing in MTAP-deleted pancreatic cancer has opened up a multitude of possibilities for Vopimetastat as a backbone of cancer therapy, potentially across multiple cancer types. The first area we plan to evaluate is in MTAP wild-type pancreatic cancer, and we look forward to, in the future, sharing more details about our aspirations beyond pancreatic cancer. Third, the early success of our PRMT5 programs and the opportunities we see ahead with Vopimetastat and TNG-456 have led us to focus our organization solely on those programs. Both Vopimetastat and TNG-456 were invented by the drug discovery team at Tango, built by our own medical chemists, brought all the way to the clinic by our team here. So it is with that acknowledgement of this potentially paradigm-shifting work in drug development that I extend my gratitude to the research organization at Tango and all who have contributed to it, past and present. I want to close by thanking the patients and their families who participated in this study, clinical investigators, as well as employees and partners who have worked tirelessly to get us to this inflection point. This is a very exciting time for the advancement of treatment for pancreatic cancer, and all of us at the company are united on our mission to bring life-changing treatments to patients. Operator, let's start Q&A.

Thank you. [Operator Instructions] Our first question comes from Eric Schmidt with Cantor. Your line is open.

Thank you and congrats on some truly exceptional data. This is going to be life-saving, changing for many, many patients, that's very clear. Maybe two questions for me. First in terms of the collaboration with Revolution Medicines, is there going to be a supply agreement for the Phase 3 study? And then second, as per your agreement with the FDA, on that first-line study. Could you talk a little bit about what exactly you'll need from either ORR or PFS or even in survival in order to file for approval? Thank you.

Yeah, thanks, Eric. Thanks for your kind words. For the supply agreement situation, we have an existing supply agreement for the ongoing studies. We do not have a supply agreement for the Phase 3 study that we mentioned. Refmet and Tango are discussing at the moment topics that deserve resolution between the two companies. And it's our interest here at Tango to figure out the fastest way possible to bring the combination forward and to achieve a regulatory approval. So that's very important for us here, and that clearly includes the continuation of the work with Refmet, but includes also other options. For the second part of your question, can I turn it over to Adam?

Absolutely. Yes. So the second part of your question was after our interactions with the FDA, what are we needing to see in terms of primary outcomes to achieve a regulatory approval? We haven't disclosed the details of our statistical analysis plan. And those are not details that we intend to share for a number of reasons. But a little bit of detail can be inferred from the details of the study design that we did share. A couple of notable pieces are that the primary readouts, the primary endpoints are overall response rate and progression-free survival, while the overall survival is a key secondary endpoint. There are implications of those and there may be opportunities to register on either of those primary endpoints. The second important piece of information that we did share in this head-to-head 1-to-1 study is the number of patients, which is 484 patients. And we are confident that the study as designed with those number of patients will give us adequate power to readily detect the signal required for approval.

Thank you. Our next question comes from Laura Prendergast with Stifel. Your line is open.

Hey, guys. We got some exciting updates. Can you provide more color on the DDI, particularly as early as two weeks? Seemingly to act more at the level of bioavailability than clearance. And then also, there's been some recent dialogue in the RAS inhibitor space, particularly regarding oral Tepsin.

You broke up entirely with the second part of the question. We simply couldn't hear it. Why don't I answer the first part of the question first and then give you an opportunity to react to the second part? Regarding the DDI, to start with the very important high-level details, we know that Vopimetastat is a moderate CYP3A4 inhibitor and anticipated that it would increase the exposures of Darovasertib in a manner similar to that which we observed. It increases the exposure approximately threefold, meaning that the exposures we achieved in terms of key PK parameters, including AUC, are very similar to Darovasertib 300 milligram single agent. It also has no more variability than Darovasertib single agent. There are many details important around this DDI. One could speculate, and it is reasonable to, whether this is absorption mediated or clearance mediated. It stands to reason that as the half-life is unchanged, much of this is probably not clearance mediated. Beyond that, the details are best spoken to by a clinical pharmacologist. Can I ask you to please re-answer the second part of your question?

Re-answer the second part. On the road, sorry if I was breaking up a bit. Yes, we were just referencing, there's been some dialogue in the RAS inhibitor space regarding the connection of oral RAS inhibitors to GI tox. Is there anything you can point to that you find particularly externally validating of this thesis?

Um, there are a couple of pieces of information that I think are interesting. One is that, you know, we have not generated data on our own, but we have heard that the IV administration in dogs, for example, of RAS inhibitors can result in emesis and vomiting. So it may be a systemic effect in addition to or rather than a local GI effect. Again, not our data. It's speculation on my part. But I do think it's straightforward to envision that delivering 300 milligrams of any drug could result in local toxicity, nausea, vomiting and diarrhea resulting. And entirely consistent that giving a third of that dose to the GI tract would result in less nausea, vomiting, and diarrhea.

Got it. Thank you very much.

Thank you. Our next question comes from Andrew Berens with Leerink. Your line is open.

Hi, thanks and congrats on the quite stunning data. Maybe a couple questions from me. Adam, can you give a little more color on the scientific rationale for using our PRMT5 agent in the MTAP wild-type setting? And would you expect the results to be as dramatic in these patients without a loss of function? And then I guess, can you also give us some color on the toxicities that and other PRMT5 inhibitors that are CNS penetrant are seen.

That Vopimetastat avoids? Sure. Regarding wild-type, we certainly acknowledge that it is in some ways counterintuitive to the reason that MTAP cooperative PRMT5 inhibitors have been developed. But I also think that the data support that is a clinical experiment that has a likelihood of succeeding. Effectively, the first piece to recognize is that the synergy between RAS inhibition and PRMT5 inhibition is present regardless of MTAP status. So in MTAP wild-type cells, if you inhibit both of those targets efficiently, there is every expectation that they would be equally synergistic. However, with an MTAP wild-type cells, we are hitting PRMT5 less hard. But because the combination is so well tolerated and because we have data clinically that we are exerting pharmacologic activity on PRMT5 in MTAP wild-type cells, we ask the question if we are modifying PRMT5 enough to increase the activity of Darovasertib. And we did not know what the answer to that question might be before we did the preclinical experiments. But the preclinical experiment that we showed across 12 cell lines demonstrates clearly that it does increase the activity. The degree to which that will happen, if I had to predict, might be more measured than the increase of 32% to 82%, which we observed in deleted tumors. However, there is still a wide range of potentially positive results that could be detected with the capital-efficient technology expansion arm of this study.

The second question was, I think, regarding the tox profile of other PRMT5 inhibitors.

Yes. I think we can elaborate a little bit what we know. Yes. So in order to talk about the tox profile of other molecules, I'll talk about the tox profile of our molecule first. It's very well tolerated as single agent. As single agent, the rate of dose reduction at 200 is about 10%. We see on-target toxicities of anemia, fatigue, thrombocytopenia, low grades of nausea, vomiting and diarrhea. I think it's fair to say that it is well tolerated and an easy side effect profile to manage. It is differentiated from other molecules. If one compares the profile to the lead competitor, Navlometastat, Navlometastat has a rash signal. It is a low-grade rash, but it is present. Navlometastat has a little bit more GI. And I think it will be interesting to see the safety profile of that molecule in combination with RAS inhibitors where GI tox and rash are so important. The other highlight I would point to, which we believe will become increasingly important over time, are the difference between PRMT5 inhibitors, which are brain penetrant, and those which are not. When one looks at the safety profile of brain penetrant molecules, you often see a real signal of dizziness and or confusion. This is not overwhelming. It tends to be grade 1, but it is present. And we believe this will differentiate non-brain penetrant molecules like Vopimetastat from the emerging molecules which tend to be brain penetrant. The final thing that I'll say there is that we see very little benefit to CNS activity of our molecule in pancreatic cancer because CNS metastases are very rare, effectively in less than 1% of patients. So if there is a CNS tox signal of other molecules, it could be a liability in pancreatic cancer.

Okay. Thank you. And just one more maybe. I know at this meeting we have seen a number of competitors and some of them have pretty large data sets. How far ahead of some of these other agencies do you think you are in PDAC with the Darovasertib combos at this point?

I think, um, you know, when you think about, um, when we started our combination study between Vopimetastat and Darovasertib, start was in end of June last year. I think we are minimum 12 months ahead of other combinations in the field. That's why I think we are very happy of having such an advanced data set. That's the foundation of today's presentation. And that also contributed to the fact that we have made really good progress in discussing the way to registration with FDA. And we are beginning discussions with other regulatory agencies around the globe. So, I think we are determined to keep the headway attractive for patients and for Tango, to be honest, and we're looking forward to starting the first-line study as we outlined earlier in the first half of 2027.

Right. Well, thanks and congrats again. Appreciate it.

Yeah, thank you, Andy. Thank you.

Thank you. Our next question comes from Brian Chang with JPMorgan. Your line is open.

Hey guys, congrats on the data and thanks for taking our questions today. You know, just first, I wonder if you can comment a little bit more about the durability response here. The PFS curves look a lot more stable than the RAS along in the second line back in the RAS 302 study. Curious how we should think about the durability of response over time and how we should think about that in the second line and eventually in the front line. And then second question just related to the partnership side. At this juncture as we think about your partnerships with Refmet and Rasca, how do you prioritize each one today and I'm moving forward that your combo strategy is pretty clear laid out with their RASNA asset. Thank you.

Yeah, you want to speak to the durability? Yeah, I would say, as you know, not not easy and straightforward to compare across data sets. However, I would say here the durability does look notable compared to what we see, whether it's with Darovasertib alone, whether it's with chemotherapy, really against any of the prior treatments we've had available. Certainly that seems true in the second-line setting, where again there were not progression events thus far with the follow-up that's available. But also in the third-line setting, which generally is a very aggressive disease, with third-line pancreatic cancer, so to see that degree of durability with the combination in third-line patients also, I think, is notable. And obviously more follow-up will occur, but those, I think, are notable data thus far starting to show the durability for these individuals, most of which you are still on therapy.

Yeah, thanks, Brian. And to your second question, Brian, um, with respect to the partnership, um, between Tango and Refmet and Rasca, I think, uh, we are very happy that we are working with the two leading companies in the field of RAS inhibition. That's, uh, that was clearly, um, a very good decision on Tango's end to enter collaborations with these two companies. We are super happy where we are and with respect to the headway we have for the Refmet and Tango collaboration. That's the foundation of today's presentation, as said earlier. But we think Rasca is a very attractive molecule as well. There are probably going to be more data released soon. Adam spoke to the fact that the wild-type hypothesis, for example, is a moment of intensifying our collaboration with Rasca and there may be other opportunities as well. So right now we are happy that we are collaborating with these two companies and we intend to pay a lot of attention of moving forward with these collaborations.

Great, thank you and congrats again.

Thank you, Brian.

Thank you. Our next question comes from Kelsey Goodwin with Piper Sandler. Your line is open.

Hey, guys, um, thanks so much for this call, and congrats on the update. That's great. I just have two questions. First for Dr. Wolpin, in practice, can you just remind us what the current turnaround time is for MTAP deletion testing? And then second, for the company, I think building on the last question with the combination plus ARASCA-0015, I guess just kind of given where you stand with that combination and the fact that it's about to start, could you realistically run a Phase 3 trial plus 0015 in the front line? How do you think about that, just given kind of the dynamics of the evolving PDAC space? Thanks so much.

I can take the first part. Thanks for the question. So for patients with first-line metastatic pancreatic cancer, we generally try to obtain data from three sources, one of which is we commonly do circulating tumor DNA to rapidly get mutation status and also copy number data from that. That usually has a turnaround of about seven to 10 days. We also do tumor-based testing in two different ways. One of which is with next-generation sequencing. And then at my own institution, Dana-Farber, we also do immunohistochemistry testing on all new patients with pancreatic cancer, for MTAP as a part of our sort of diagnostic workup at this point. So as you know, immunohistochemistry has a quite rapid turnaround, right, within a couple days, few days. You can get that information. And next-generation sequencing tends to be in the approximately two-week kind of time frame. So generally within one to two weeks, we have data that we can use for both RAS mutation status and for MTAP deletion status. So thanks for that question.

And, Kelsey, to your second question of whether or not we can start, um, a Phase 3 study with the, uh, Rasca, um, molecule as a combination partner. The answer is theoretically entirely yes, but I want to point out again the fact that we have made extremely good progress for the Darovasertib and Vopimetastat combination. Our discussions with FDA regarding the frontline study design were based on the data that we have shared today. So I would say um we are uh ahead of the curve with the Darovasertib Vopimetastat combination. But um in theory, it's totally possible to start a Phase 3 study with Vopimetastat and Eraskin-0015 as a combination.