Tango Therapeutics, Inc. (TNGX) October 23, 2026 Conference Transcript

Good day and welcome to the Tango Therapeutics conference call. At this time, all participants are in list-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question, you will need to press star 11 on your touchstone telephone. Please note this call is being recorded. I would like to turn the call over to Liz Hicken, Vice President of Investor Relations. Please go ahead.

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. Malsa Peters, Tango's president and CEO, will share some introductory remarks. We're pleased to be joined today by Dr. Brian Holton, director of the Hale Family Center for Pancreatic Cancer Research, St. Farber Cancer Institute, who will present the clinical data. Adam Crystal, our president of R&D, will discuss our registration and expansion strategy for VOPA metastat and PDAC. And then Matt Gaul, CFO, will share some financial highlights and provide an overview of important upcoming events. Malta will then conclude the call and we will open it up to Q&A. I will now turn the call over to Malta.

Thank you Liz and good morning everyone. Since I joined Tango as CEO in January 2026, we have developed a clear mission to deliver vocal medicine 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 Opium Malastat's unique properties that have created a favorable drug-drug interaction with Dirox and Rasif that has yielded impressive clinical activity and a safety profile that, to date, appears to be superior compared to that of single-agent Darx and Russell. 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 registrational 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 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 it 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 M-TAP wild-type pancreatic cancer, supporting our ambition for Vopimedaset to be a PMT5 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 pmt5 program into additional tumor types and treatment settings tango is well positioned to move into the next state of opium of opium development and to continue on the path to creating meaning 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 m-tap 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 Volpin of Dana-Farber Cancer Institute join us to present the updated clinical data for this combination. Dr. Volpin is the director of the Gastrointestinal Cancer Center at Dana-Farber and will be the lead investigator in our Plan Phase III trial. Dr. Volpin.

Thank you, Malta, very much. I appreciate the opportunity to present the data on behalf of all of the investigators and the patients and the team at TANCO. 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-aging chemotherapy. therapy. 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. And 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 VOPA metastat, which is a MTA cooperative PRMT5 inhibitor. 30 to 40 percent of pancreatic cancers have a biallelic deletion in MTAP. This deletion leads to an accumulation of the substrate for this enzyme, MTA. MTA then binds to PRMT5 and causes a partial inhibition of PRMT5 function. Lopametastat as an MTA cooperative PRMT5 inhibitor that 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 are data in a PDX model of a cell line that is MTAP null and KRAS G12V mutant, and you can see the benefit in this model to both the metastat and to DRAX and RASIB, 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 Vopametistat and Zoldan 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 Volpomatostat plus Dirax on RACIP. We're going to focus on that aspect of the Phase I dose escalation trial. Additional data with Zold on RACIP will be presented in the poster at ESMO. And as you can see, these are patients with second or third line treatment of metastatic pancreatic cancer. They must all have MTAP biololed 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 zero or one, and no prior therapy with similar agents. On the right of the slide, you can see the dose escalation range, with opametastat given at either 200 milligrams once daily or 250 milligrams once daily, and daraxon-rasib 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 immunosomchemistry 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 Vopometastat and Diracxon RASIB in patients with pancreatic cancer. In the middle, you see Vopometastat and Diracxon RASIB in patients with non-small cell lung cancer. And in the rightward column, Vopometastat and Zoldan 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 percent of patients having liver metastases. If we now look at the waterfall plot for Vopometastat plus Diracxon RASIB, 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 VOPA metastatin and Diracxon RASIB, 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 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 VOPA metastat and diraxin racib, 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 one, so 100 milligrams of diraxin racib and 200 milligrams of VOPA metastat 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 two. So this is now an increase in the VOPA metastat dose to 250 milligrams daily and duraxon or acid at 100 milligrams daily. Again, we can see no new safety signals compared to the prior report and that very few grade three events with most of the side effects that have been seen in grade one or two and no grade four or five events is we now 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 three rash events so the rash that is identified has all been grade one or two and similar for stomatitis and mucositis no grade three events and the events that have been identified were grade one or two we can also see that the only grade three events at dose level one were related to blood count suppression anemia and thrombocytopenia we can see as we get to dose level two some increase in rash and stomatitis mucositis as one might expect with greater exposure to a ras multi inhibitor i mean again no greater or grade four or five 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 three events. And again, the gastrointestinal toxicities also are relatively modest without grade three events to the right you can see that the PK data which we'll see on the next slide for directs on RASM in the combination demonstrates that at the dose of a hundred milligrams once daily there's a very similar area under the curve as with single agent directs on RASM 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 Duraxone RACIB and VOPA Metastat now in the combination. So I'm going to pass this on to Dr. Crystal for the next part of the presentation.

Dr. Thank you, Dr. Wolpen, for joining us this morning and for your leadership in helping advance this combination for 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 clearer. These data validate that the addition of VOCA metastats to diraxon RASIV 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 Vopometastat may improve the tolerability of thiraxon RAPSF 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 Diraxxon RASIV 300 mg single aging. The dose reduction rate is 20%, also lower than reported with Diraxxon RASIV alone. Of course, these are cross-trial comparisons, and we recognize their limitations. Nevertheless, the magnitude and consistency of the differences across the data set 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 phospho-ERF 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 Diracxon-Rasif, 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 Diracxon-Rasif 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 III study to be a global randomized control trial evaluating 200 milligrams of bofometastat plus 100 milligrams of diraxon RACIP 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 MCAP-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 II 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 Bocometastat plus Daraxon Rassib as the first-in-class PRMT5 plus Rass inhibitor combination. The underlying biology led us to predict that combining PRMT5 and Rass pathway inhibition would produce synergistic antitumor activity. The emerging clinical data in pancreatic cancer have now provided compelling validation of that hypothesis, demonstrating not only remarkable antitumor 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 an mtap wild-type pancreatic cancer. Critically, pre-clinically, PRMT5 inhibition is synergistic with RAS pathway inhibition regardless of MTAP status. Although VOPA metastat was designed to selectively inhibit PRMT5 and MTAP deleted tumors, our data, some of which are shown here, demonstrate meaningful PRMT5 target inhibition in MTAP wild-type cells at exposures achieved with the 200 milligram dose used in dose level one. Importantly, we believe these findings establish the pharmacologic foundation for extending the synergy between PRMP5 and RAS inhibition beyond MTAP-deleted cancers. The critical question then is whether voca metastat can inhibit PRMP5 sufficiently in MTAP wild-type tumors to enhance the activity of Diracxon RACIV or other RACS inhibitors? To answer that question, we evaluated the combination across 12 mTAP wild-type KRAS mutant pancreatic cancer cell lines using concentrations of Vopametistat achieved in our clinical dose of 200 milligrams. In each of these models, Vopametistat enhanced the anti-tumor activity of Diracxon RACIV. The graph on the right summarizes these findings, comparing the activity of voca metastat alone, diraxone rapsip alone, and the combination across all 12 models. Together, these data demonstrate that voca metastat at clinically achievable concentrations consistently potentiates the activity of diraxone rapsip and mtap wild-type pancreatic cancer models. In the first half of 2027, we intend to evaluate VOCA metastat in combination with a PAN-RAS inhibitor in approximately 25 to 30 patients with mTAP wild-type pancreatic cancer in the second mindset. 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 that hypothesis with the potential to substantially expand the population of patients who could benefit from PRMT-5-based combination therapy. We're particularly excited about the potential to pursue this study within our existing collaboration with the rest. 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 araska and with the evolving landscape of pure mt5 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 vulcometastat lung cancer monotherapy, as well as with TNG456, our brain penetrant PRMP5 inhibitor, which we are studying in lung cancer and glioblastoma, as well as other tumor types. We believe those data and our development strategies in both lung cancer and GBM could be meaningful value creation opportunities for pain. 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 Bova Metastaf 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 PRMT-544. forward. 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 Malta 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 Voping Matterset 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 one plus one equals three level of synergy we are seeing in the MTAF-deleted pancreatic cancer has opened up a multitude of possibilities for VOPi metastat as a backbone of cancer therapy, potentially across multiple cancer The first area we plan to evaluate is an MTAF-Y 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 PMT-5 programs and the opportunities we see ahead with Wopi Metastat and TNG-456 have led us to focus our organization solely on those programs. Both Wopi Metastat and TNG-456 were invented by the drug discovery team at Tango, built by our own medical chemists and brought all the way to the clinic by our team here. So it is with that acknowledgment 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. If you'd like to ask a question, please press star 11. If your question has been answered and you'd like to remove yourself from the queue, press star 11 again. Our first question comes from Eric Schmidt with Canter. Your line is open.

Thank you, and congrats on some truly exceptional data. This is going to be life-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 III 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?

Yeah. Thanks, Eric. Thanks for your kind words. For the supply agreement situation, we have an existing supply agreement for the ongoing We do not have a supply agreement for the phase three study that we mentioned. RevMed and Tango are discussing at the moment there are a couple of topics that are that deserve a 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 worked with ResMed, but includes also other options. For the second part of your question, can I turn it over to Adam?

Absolutely. So the second part of your question was after our interactions with the FDA, what are we needing to see in terms of our primary outcomes to achieve a regulatory approval? We haven't disclosed the details of our statistical analysis plan and that is 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 endpoints. 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, one-to-one 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 Stiefel. Your line is open.

Hey, guys. Congratulations on the exciting update. Can you provide more color on the DDI, particularly as early to 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 regard it regarding or you find any of them you you broke up entirely with 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 the second part sounds good regarding the regarding the ddi um to start with the very important high level details we know that boca metastat is a moderate cip 384 inhibitor and anticipated that it would increase the exposures of dirax on rancid in a manner similar to that which we observed. It increases the exposure approximately threefold, meaning that the exposures we achieve in terms of key PK parameters, including AUC, are very similar to Diracxon RACID 300 milligram single agent. It also has no more variability than Diracxon RACID 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 on the road sorry if i was breaking up a bit uh yeah we were just referencing you know there's been some dialogue in the ras inhibitor space regarding the connection of oral ras inhibitors to gi talks um is there anything you can point to that you find you know particularly like externally validating of this thesis there are a couple of pieces of information that i think are interesting um 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 rats 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 Behrens with Lyric. Your line is open.

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 other PRMT5 inhibitors that RCNS Penishin are seeing and Bopee avoids?

Sure. Regarding wild type, we certainly acknowledge that it is in some ways counterintuitive to the reason that MTA cooperative PRMP5 inhibitors have been developed. But I also think that the data support that is a clinical experiment that has a likelihood of succeeding. And effectively, the first piece to recognize is that the synergy between rats 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, in 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 and MCAP wild-type cells, we asked the question if we were modifying PRMT5 enough to increase the activity of diraxone or acid. And we did not know what the answer to that question might be before we did the preclinical experiment. 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 expansion arm of the study.

The second question was, I think, regarding the tox profile of other PMG5 inhibitors. Yes. I think we can elaborate a little bit what we know.

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 at single agent. at 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, nablometastat, Nablometastat has a rash signal. It is a low-grade rash, but it is present. Nablometastat has a little bit more GI tox, 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 one, but it is present, and we believe this will differentiate non-brain penetrant molecules like voca metastat 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 agents do you think you are in PDAC with the DAROX combos at this point?

I think, you know, when you think about when we started our combination study between Volpe Metaset and DAX and RASIP, that 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 um i think we are um determined uh to keep the headway um attractive for patients and for tango to be honest and we're looking forward to starting the the first line study as we outlined earlier in the first half of 2027.

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

Yeah, thank you, Andy.

Thank you. Our next question comes from Brian Chang with J.P. Morgan. Your line is open.

Hey, guys. Congrats on the data, and thanks for taking our question today. You know, just first, I wonder if you can comment a little bit more about the durability response here. the PFS curves looks a lot more stable than there are some RASP alone in the second line back in the RASP 302 study. So 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, you know, at this juncture, as we think about your partnerships with ResMed and URASCA. How do you prioritize each one today? And then moving forward, that your combo strategy is pretty clear laid out with the RASM and RASM.

Ryan, you want to speak to the durability?

Yeah, I would say, as you know, 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 directs and RASIV 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 who are still on therapy.

Yeah, thanks, Brian. And to your second question, Brian, with respect to the partnership between Tango and ResMed and Jurasca, I think we are very happy that we are working with the two leading companies in the field of RAS inhibition. That was clearly 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 RedMet and Tango collaboration. That's the foundation of today's presentation, as said earlier. But we think Erasca is a very attractive molecule as well. they're probably going to be more data released soon and Adam spoke to the fact that you know the y-type hypothesis for example is a moment of intensifying our collaboration with with Araska 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. And congrats again.

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

Hey, guys. Thanks so much for this call, and congrats on the update. 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 three 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 can get some copy number data from that. That usually has a turnaround of about 7 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 immunistic chemistry has a quite rapid turnaround right within a couple days few days you can get that information the next generation sequencing tends to be in approximately two week kind of timeframe 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 Cassie to

your second question of whether or not we can start a phase three study which the erasca 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 darks and russes and bofimel set combination our discussions with fda regarding the frontline study design were based based on the data that we have shared today. So I would say we are ahead of the curve with the DAX and ERASCA-0015 combination. But in theory, it's totally possible to start a phase three study with ERASCA-0015 as combination.

Okay, great. Thank you so much. And congrats again on the consistency of the data. That's really great.

Yeah, thank you.

Thank you. Our next question comes from Michael Schmidt with Guggenheim. Your line is open.

Oh, hey, guys. Thanks for taking my questions. Maybe just one more on the data. I noticed there was really no difference in response rate in the second or third line patients during the mid-80s for both cohorts or both subsets. is there something going on there or do you think that's just coincidence given the small sample size um and then i had a question on the phase three study anything else that's gating to starting the phase three i'm just wondering you know the the start next year is it is it just purely operational to get the study up and running at this point or do you still need to see some of the frontline PDAC data before commencing the study? And how fast do you think you could reach this possible ORR analysis in the phase three? Thanks so much.

You want to go?

Sure. So the question regarding the overall response rate in second and third line patients, they are very similar. We are at very high numbers, and perhaps it's hard to differentiate 80 from 85 when you're in that range. I do think it's fair to say it works very well in both second and third line patients. It is interesting to note the response rate of single agent directs on RAS of across the line, 20% in third line plus, 32, 33% in second line, 47% in front line, or sitting at about 80 in second and third line, one could postulate it might be higher in front line and you see hints of that in the pfs curve um where although they are small numbers we have had three progression events in third line patients and zero in second line patients if that trend continues it's interesting to speculate how good a front line kaplan-meyer curve could look like in the eventual um pivotal study for the second question i'll go

back to market yeah so with respect to the to the gating factors I think it's fair to say that the main factors really operational execution right now so we have clearance from from FDA regarding the protocol design as we as we mentioned earlier so the clinical operations team are a lot under the microscope here Tango and they're working day and night to get this off the ground. To start a phase three study is a complex undertaking. We're running this study in three geographies in the United States, in Europe and in Asia Pacific. So all of this needs to be orchestrated and we don't need any frontline data in pancreatic cancer to start the study. So that's very clear. With respect to your last question of when we could potentially have a more response rate in that study, we haven't really spoken about our forecasting or timelines of when certain endpoints would become mature. FDA doesn't really like the, you know, companies being ahead of themselves of sharing forecasts and sharing details of, you know, when data will become available. So stay tuned, Michael, and we will share, of course, you know, how good the progress is we make, and we will share with the public of when we intend to approach FDA for meaningful discussions regarding evaluating these endpoints.

Maybe just ask a quick follow-up. I guess in that context, does it even make sense to run a second line study at this point, given that you might have an interim readout on the front line study at some point?

I think we have a window of opportunity here for the second line space. I don't know. I don't know. Brian can maybe also add to this. I think it depends, of course, on the timing of when a second line approval would occur, right? Eventually, that window would close and the attractiveness of a second line approval would go away. But right now, we believe that patients would benefit from a combination in second line. I don't know, Brian, if you want to add to that.

Yeah, sure. So I do think there are opportunities in the second line to improve what we're doing. I think the data for directs on RACEP have been really important to the field and important to patients, but there is still substantial room there for improvement and greater durability of responses. Also, certainly if it came with less side effects with treatment, that's a benefit to patients too. So I do see certainly a window of opportunity to improve care for patients in the second-line setting, and I think that that would be valuable to patients and to their, you know, treating providers. Thank you.

Thank you. Our next question comes from Alethea Young with William Blair. Your line is open.

Hey, guys. Thanks for taking my question, and congrats on these data this morning. One for Dr. Walden. I guess, you know, these different grades, like when it's like grade 1-2, I feel like not all grades are created equal so I was just wondering if you'd give us some color like maybe on like you know even the grade 1 2 events you're seeing in the combo versus like what you see with Dara itself and my second question for the company is you know obviously like when you think about the totality of your announcements today you know it seems you're certainly centralizing upon at least three indications and all in on pancreatic cancer so can you talk a little bit about how these data increase potentially your confidence and what you're doing in glioblastoma and non small cell which have data events this year as well sure thank you for the question so I would say overall we certainly see a shift towards less high

grade toxicities with the combination again we do have to keep in mind these are still small relatively small data set we now have quite large data sets with directs and RASM so the estimates there are a bit more stable however I would say we do see a shift towards less high-grade toxicity events. As you said, CTCAE is not, you know, being in front of a patient that you really only can do when you're, you know, taking care of patients. But I would say that these are less high-grade, and that really has been across the toxicities that have been most difficult in patients receiving direct sonaracib so far, right, particularly rash, mucositis, and then some of the gastrointestinal side effects, too. And obviously, I think this will be important as we go forward, not just for combinations with directs and racibs. Some of these are class effects with RAS inhibitors. So seeing less toxicity, I think, will be beneficial to patients and providers.

And your second question, I think you are spot on in saying that we certainly have a reason to have increased confidence in the entire franchise, in the entire portfolio of PMT-5 inhibitors. We are very happy that we have two big focus areas. One is in pancreatic cancer where we concentrate the development on the bulking medicine, darks, and racets combinations, and the second area is clearly in non-sportal lung cancer and glioblastoma. For lung cancer, as Matt alluded to earlier we're going to share our development plans and ideas in January of 2027 and it will involve both TNG 456 and will be metastat so we think we have a pretty good idea of how we develop these molecules and the confidence here at Tango is very high that we will make meaningful contributions for patients not only with pancreatic cancer, but also with lung cancer and other tumors.

Just one quick follow-up. Is there anything to make of the combination data with lung? I know it's a very small number, but is there anything to think about there?

I think it's a very small number, but it's consistent with what we've been seeing with pancreatic cancer. The combination works better than either single agent. I think it is notable that four or five patients had informed responses. The fifth was a staple disease with, I think, minus 26%. All of those patients, it's fair to say, seem to be benefiting from the drug. That's in contrast to single-agent direxon rapsid, which has a response rate of about 40% in a comparable group of non-small cell lung cancer patients. The other thing that I would say is that lung cancer is very different from pancreatic cancer in one critical way, which is that there are multiple different oncogenic drivers. It's almost universally RAS in pancreatic cancer, but in addition to RAS, as we know in lung cancer, EGFR, ALP, and other kinases are important. And one important scientific fact to recognize is that this synergy observed with RAS inhibitors isn't best thought of as a RAS synergy. It's probably best thought of as a MAP kinase pathway synergy. And it's our expectation, based on our preclinical data and others, that it would translate beyond the RAS inhibitor space to combinations with, for example, EGFR or alkinase.

Thank you. Our next question comes from Maury Raycroft with Jeffries. Your line is open.

Hi, this is James on from Maury. Congrats on the update, and thanks for taking our questions. Going back to the data, can you provide more detail on the 40% dose interruption and 20% dose reduction rates at dose level 1, including the duration of interruptions and whether the modifications involved both the diraxone RASIB or Vopimetastat and the doses to which patients were reduced? And are you seeing any effect from the reductions in eruptions on the magnitude of tumor reductions or duration response?

So the second part of the question, the answer is no. It would be hard for it to be yes, but there's an implication on the duration of response because effectively nearly all of the patients are benefiting. It's hard to stratify further. In terms of the dose reductions, there have been five at dose level one. The majority of those were for rash or cytopenia. In some cases, we dose-reduced dyraxonracid, typically from 100 to 80 milligrams. And in some cases, we dose-reduced bovometastat from 200 to 150 milligrams. One important point I would note is that all of those doses are in the efficacious dose range. So where we resulted in those cases was with both an effective dose as well as one which was more tolerable. And those patients restarted without further complication.

Thanks. And just one really quick one. For the potential accelerated approval path in second-line PDAC, have you already discussed the specific approach to the FDA already? And has the FDA indicated whether a single-arm study based on response rate durability, for example, could support approval or whether a randomized design would be required? If those discussions have not occurred yet, when do you expect to meet with FDA and discuss the Phase II designs?

So we did not have the detailed discussion, as you just mentioned. We mentioned to FDA that we would be interested in a detailed discussion, a follow-up discussion on the second-line accelerated approval pathway, and we are going to have a separate discussion with the agency on that topic. But the agency indicated that they are very happy to have that discussion quite soon. So we're looking forward to follow up with the agency on these ideas. And then as soon as we are in the position, we can update the public about how that discussion went.

Thank you. Congrats again.

Thank you.

Thank you. Our next question comes from UNG with B. Raleigh. Your line is open.

Well, congrats on the strong durability data. My first question is, in this WAPI plus DARA PDAC cohort, it appears that there are no GE12D patients. Do you anticipate the durability and ORR to be consistent between GE12D and GE12V patients?

Do you want to take this, Ryan? Sure. Yeah, thank you for the question. So I think, as you saw from the design that was mostly to allow for sufficient patients with G12D mutations to receive the Zoldan-Rasiv open metastatic combination. I think for the direxon combination, I would suspect we will see, although we obviously will need to see this in patients, but I would suspect we would see similar results. There really is not a biologic reason to suspect that the combination would perform differently in KRAS G12D mutant patients than it would in those that have a G12B mutation or other mutant allele. So I would suspect we will see similar things, and that will have to play out in the future studies.

I think one additional comment we could make is that we have enrolled and treated six patients with G12R, which are notoriously very difficult to treat, and we've seen 50% of these patients responding to the combination, which is a very encouraging sign, Got it.

Although we don't have any clinical data, what would you expect when you compare VoP plus Dara versus combining Dara at 300 milligram with another PRMT5 inhibitor, which has no drug interaction boost there?

Sure. Sure. As you point out, it is hypothetical. We have the data you've seen today, and there's no data available for any other combination. I think that the efficacy we observe would fairly be expected to be seen with any other very good PRMT5 inhibitor. I think there are subtleties around the degree to which we hit target and the safety profile, which may play out to be differentiating potentially positively differentiating but again data will prove that out I think the first molecule we may see combination data for would be nablometastat what I would point to there I do not expect that there will be a meaningful DDI my expectation would be that they'll be able to reach either two or three hundred milligrams of thiraxon or acid And I think that the efficacy will be comparable, would be my guess. On safety, I think there are a lot of question marks. Will the higher dose of Diracxam Rassib result in more GI tops? And will the little bit of a skin signal with nablometastat carry over into the combination to result in problematic overlapping toxicity?

Thank you for taking our questions.

Thank you.

Thank you. And our last question comes from John Newman with Canaccord Genuity. Your line is open.

Hey, good morning. And let me add my congrats on the really strong and impressive data here. Definitely, as Eric said, a big benefit for pancreatic cancer patients. My question is, in terms of the doses that you would look to test for the MTAP wild-type study, I'm just curious if they would be similar to what you've tested in pancreatic cancer thus far.

The very straightforward answer to that is it would be the same dose. We believe that this combination dose is the ideal dose to bring forward in development and that would be the same for mTAP wild type. One of the reasons we expect that experiment to be rather fast to what could be a meaningful Great.

Thank you. This concludes the question and answer session. I'd like to turn the call back over to Malta for any further remarks.

Thank you. No further remarks from our end. Thank you to all the participants for asking questions and for following our call. Thank you very much.

This concludes the program. You may now disconnect. Good day.