TANGO THERAPEUTICS, INC. (TNGX) - GUGGENHEIM 3RD ANNUAL HEALTHCARE INNOVATION CONFERENCE - TANGO THERAPEUTICS INC

with Tango Therapeutics this morning. I'm Michael Schmitt, senior biotech analyst with Guggenheim. And with us today, we have Malte Peters, CEO of Tango. Malte, welcome, and thanks for joining us. Thanks, Michael, for having us. It's an honor to be here on a beautiful, sunny morning in Boston. So I'm looking forward to the chat. Great. So it's been a very busy year so far for Tango, especially this fall. As you look at where the company is today, how would you describe the stage Tango is in now and what are your top priorities as you look forward? Yeah, so Tango in a full pre-submission, pre-commercial mode and we have really done a lot of work since I joined in January as CEO to transform and evolve the company into a late stage drug development pre-approval pre-commercial organization so we have added significant expertise to our team we are focused extremely in a laser sharp manner on execution and we are very happy with the fact that we have data that allows us actually to think about getting a drug approved I remember when I joined the board in 2018 of tango the company was a discovery organization nobody would have thought how soon the organization would evolve into a late-stage mature development organization and here we are so I think all of us at tango are extremely happy with where we are and we are all walking in the same direction we have the same goals we want to get vocal medicine approved and that's what we come to work for. Okay, and obviously you did have an important data presentation recently at ESMO. Maybe just remind us what have you learned from this combination study with Terax and RACEP and the updated ESMO data and what gives you confidence now heading into Phase 3? Yeah, thanks. So remember we started speaking about the data back in June, on June 8 was the first day when we disclosed the combination data. At that time, we had a denominator of 12 patients. At that, time we had 92% response rate and three months later or four months later in October, we presented an update of that data set with a denominator of 22 patients in pancreatic cancer. So out of 22 patients, we have now a response rate of 82%. We have four out of five patients with non-small cell lung cancer responding, so that makes an 81% response rate combining PDAC and non- small cell lung cancer patients. That's a very, very reassuring data set and the data set is corroborated or reinforced or supported by the fact that the responses are very durable. So we have a PFS rate at nine months of 88%. If you look at the second line patients only, not a single patient has progressed so the curve is actually at the 100% mark and we still have a very attractive and very favorable safety profile. We have no grade 3 rash, we have no grade 3 stomatitis and mucositis and that's why we feel very strongly about the data set and that is why at ESMO we disclosed our plan to start a frontline study, a phase 3 study in frontline pancreatic cancer in the first half of next year. I think the combination worked broadly across KRAS M-tab double mutation patients, but I don't think there were KRAS G12D patients in the cohort specifically. How confident are you that the combination works there as well? Yeah, that's true because remember the study is a two-armed study. We have the Dyrex and Rasip combination arm and we have the Zoldon-Rasip combination arms and so far all of the G12d patients flowed into the Zoldan arm, but we have now put a handful of G12D patients on the Dioxazone RACEP arm as well. It's a bit early to say what the efficacy is. We have no reason to really believe or assume that the responses will be any less than in the other mutations. That position is also supported by the fact that we have a very high efficacy rate in the G12R patients. So G12 R patients are very difficult to treat. Dioxin RACEP monotherapy yields a 7% response rate in R patients, and we have observed 50% response right in these patients. So we are very confident that we see a high degree of synergy in the G12D patients as well. Yeah. And true synergy is not very common, I think, in oncology drug development. We've seen it in the MEK-BRAF space, where you see synergy. But I guess, is there a mechanistic explanation that could explain why this combination is so synergistic? We think, so there's no real one mechanism where we say, OK, that's the secret to explain the synergy. We know that the pathways are interacting and that the degree of synergy is tightly related to where the drugs actually operate in these pathways. Our preclinical experiments suggested a high degree of symmetry, and we are super happy that we could confirm the synergy in the clinic, which, as you know, sometimes is not the case, right? If you have extremely, you can have extremely encouraging data in the laboratory, which then fail to translate in the clinic. In our case, we actually confirmed the synergy in the clinical experiments, in the clinical setting of the study. And can you remind us what you've seen in combination with Zolder and RASIB, the 12D inhibitor? In general, the mutant selective inhibitors have been generating higher response rates on their own than the pan-RAS inhibitors, and I'm just curious what your thoughts are on that other part of the combination study. Yeah, so we have, if you look at the waterfall plot of the Zolder and RAS-HIP combination, it's still extremely attractive, but the response rates are lower than in the Dirac's and RAs-Hip curve. We think we understand why. We think, we think we need to hit the Ras-Y type component of the whole pathway. And we think we do this very effectively with daraxanracep and not as strongly with zoldanracept. So we think that we understand why there's a difference in response rate between daraxa-racept combination with VOPI and zolda-racep with Vopi. Okay. And then tolerability, as you mentioned, looked very good for the daraxo-racet-Vopi-metastat combination. Do you think there's real potential differentiation compared to the known monotherapy efficacy of each drug? Yeah, we think so. And if you look at the safety tolerability profile of Dioxin RACP alone, it's now very well understood and very well published. We see significantly less skin toxicity and mucositis and stomatitis. We think we understand why. Our hypothesis is that Dioxins RACPs leads to a downregulation of phosphoeric in the skin. Vopimericet or PMT-5 inhibition does the opposite. It upregulates phospho-ERK in the skin. So we counterbalance or counteract mechanistically the way how patients develop skin toxicity. So that's the reason why we think we have such an attractive safety and tolerability profile. And that's extremely attractive for patients because a grade 3 rash, grade 3 stomatitis, mucositis is not nice. It's not a good toxicity to have. So if we can make it more acceptable for patients, I think we have something extremely attractive for people. Yeah. And then could you walk us through the frontline phase 3 trial design in pancreatic cancer? So you obviously did have interactions with the FDA. Maybe remind us what their feedback was that then resulted in this particular study design. Yeah, and maybe I go a tiny bit into the past and say that Tango has developed a very, very good report with FDA. It started actually when we had our first monotherapy discussions with FDA, so FDA knows the safety profile of vocal metastat very well, and they're very comfortable with the data set that's I think a reason why FDA was very supportive when we presented our trial design so the study we suggested to FDA was one-to-one randomized clinical trial of 240 patients in each arm the Vopimelastat, Dax and Rashev combination in one arm and chemotherapy of investigators choice in the other arm we are proposing and FDA was fully in line with this response rate and progression free survival as dual primary endpoints and we basically had no major area of discussions with the agency so they were very comfortable with our dose proposal they were very comfortable with a statistical analysis plan. So it was one of the nicest meetings I can recall with the agency. And what is the gating factor at this point to starting the study? Operations, operations, operations. The reason why we focus so much on discussing the frontline study with FDA is that we know all the details that now have to be worked on to get the study started so we needed to have an agreement on the protocol design in order to approach the sites, in order work with the CROs, in order get the study off the ground and luckily we are at that point and the study startup activities are in full swing and that's a great place to be. Okay and I'm not sure if you can answer this question but obviously we don't yet have PFS from your Phase 2 study, what are the underlying PFS powering assumptions for the Phase 3 and frontline? Yeah, so that's a topic we typically try to avoid to discuss in public, essentially because FDA doesn't really like companies to go into the details of statistical analysis plan discussions. They prefer that companies are a little bit uptight about this or confidential about it. So I will follow that advice and will not disclose any details of the SAP here. Okay. And can you comment on how the response rate analysis is being done and could that lead to an early filing or an accelerated approval application? So I think what I would say is that the choice of the endpoints, response rate and PFS as dual primary endpoints gives us flexibility to monitor the trial and to have a discussion with FDA about what the ideal moment could be to have submission as early as possible. So I think that's really attractive. Of course, we will do the PFS and over-survival analysis. We think it will strengthen our data package. But the design itself gives us great flexibility to discuss with the agency about their willingness to consider an earlier time point of submission. Okay. And something we get asked sometimes is, so given the drug-drug interaction, the Raxon Rasp is dosed at one-third of its single-agent dose at 100 mgs per day. I guess, in practice, how would you handle necessary dose reductions in that case, given this is already the lowest tablet strength that's available? Yeah, it's actually very convenient because we have very good data showing that if you decrease the Vopimedastat dose, you contemporaneously decrease the Raxin-Rasip exposure as well. That's the nature of the drug-drug interaction. So this works in our favor here. So we intend, in case we need it, to lower the volpimedicet dose. And by lowering the volpemedicet dos, we automatically will reduce the exposure to drugs and RACEP. So that's a fairly easy way to react in case patients develop toxicities that make that necessary. Okay. And in phase three, obviously, comparing doublet compared to chemotherapy, therapy. Is there anything else necessary to show contribution of components for the combination? So that's a part that we have not yet discussed with FDA, so that's potentially a topic that we will address when we talk to FDA about a possible accelerated approval in our second line study. We did not have enough time in our first meeting with FDA to touch on all the components of the second line submission or second line strategy. We will do this very soon. And then we know how FDA is thinking about the contribution of components. But today, we don't have a real yay or nay on a potential way forward here or on potential solution. So we are a little bit vague on the contribution of components side. My next question then was, where are you with your second line PDAC plan? So it sounds like the study and potentially accelerated approval there is still a priority for you? It's still a priority. We ranked the order of priority by frontline first and then second line second because of the operational complexity of starting a big phase three study in frontline. But we are highly committed to move as quickly as we can in second line. Again, we expect to have a moment with the FDA before the end of the year potentially to discuss our second line strategy. FDA is very interested in that component, in that discussion, so they have indicated that they are highly interested in discussing with us. We have a study that's open for enrollment as we speak, as you know. So we will discuss various options with the agency of how we could potentially discuss an accelerated approval and second line. Okay. And so there's been some invested focus on the fact that you actually do not have a supply agreement with Revolution Medicines in place today for the phase three study with the Raxin Recip. talk about your ability to execute on a study without that and you know is that still something that you're hoping to do yeah so that's one of the most frequently asked questions we we get we have an existing supply agreement with revmed for the ongoing study we do not have one for the frontline study that is that is scheduled to start next year. We always said, I personally spoke to this many times, that our preference would be to continue the collaboration with RevMed. We like it, we like their drug, so we are currently figuring out the two companies of how we can continue the collaborations. Negotiations are ongoing going as we speak so that's clearly one option but we also understand here at Tango that in case something gets in the way of you know finding an agreement for a continuation of a supply agreement we will not lose any time and we will continue to start and execute without any delay. That's why we had confidence enough at ESMO to say that we're going to start the frontline study in the first half of next year. Here for us at Tango, the key component is speed. So we think the data is so significant and so important for the field and for the patient that we have to do everything in our power to get the study started as quickly as we can. We would love to do it with RevNet, clearly our preference, but if something gets in the way we will do it without. Okay and how does your collaboration with Arasca fit into the picture and the development path? So we like the Arasco collaboration a lot. We think they have a very attractive molecule. I think one of the very smart decisions at Tango was to enter an agreement with Eraska at the beginning of this year. We just released information I think was last week that we started the frontline, excuse me, the first in-man study of Eraska 0015 and Vopio Metastat, so we are moving very quickly. The interest at Eraska is very high, the interest at Tango is very, high to move the collaboration forward and I think we need a tiny bit more to figure out a comprehensive development plan, but as soon as we have agreement between the two companies, we will declare ourselves and we will show a bit more details. Okay. Then obviously the data that is presented has not gone unnoticed by other companies and so there are a number of other PureMT5 inhibitor, PanRAS combinations in the works, Contemplate already ongoing. And so how do you see the PureMt5 inhibidor landscape evolving as these other combinations are being developed as well. Do you see differentiation of Vopimedastat, for example, from other PMT5 inhibitors or are these all going to be similar? So we are a very confident organization now and we can say we strongly believe that we have the best PMT-5 inhibitor and we are convinced that we will be able to bring the best PMG-5 inhibitor to the market first. So the reason I'm saying that is that we think the combinability of PMT5 inhibition with other molecules is going to be probably the key differentiator between the different PMT 5 inhibitors that you currently have available or that are currently in drug development. Our molecule has an extremely good safety and tolerability profile, it has a very high potency, and the combination data that we have disclosed with Dioxin RACIP and Zolder and RACIV are supporting that notion. So we don't think that there's going to be a lot of differentiation between the different PMT-5 inhibitors on the efficacy side, but we think the differentiation will probably emerge in the safety and tolerability and combinability side. And we think on that front, we are ahead of everybody else. Okay. And so beyond pancreatic cancer, how do lung cancer and GBM fit into your program? Yeah, so lung cancer is a very attractive indication. At Tango, we are in a lucky position that we have two very good PMT5 inhibitors. We have Vopimetastat, which in our eyes is the ideal molecule for pancreatic cancer. It does not cross the blood-brain barrier. It has a very good safety tolerability profile, the right drug-like properties for patients with pancreatal cancer. We have TNG456, which crosses the blood-brain barrier, and that's a feature that you need if you develop a PMT5 inhibitor in non-small cell lung cancer, because 30 to 50 percent of patients with non-Small Cell Lung Cancer have brain meds. So the brain medts are horrible for patients, and they are a very big headache for doctors treating these patients. So when we speak to lung cancer docs, they say, oh, give us a PMG5 inhibiter that potentially can address the brain metastasis, and we're very happy that we have that with TNG456. So, beginning of 27 in January, we are going to share some ideas of how we develop TNG 456 in non-small cell lung cancer, and it may come to a point where we say we have a dichotomy. Vopimacet for pancreatic cancer, 456 for non- small cell lung cancelling. And just help us understand what you've guided to this first lung cancer update to be, how many patients, any comments you can provide there. We haven't really spoken about it, but the number will be high enough for us to make a decision of which drug we want to take where. So that's the reason why we waited a tiny bit longer until we were confident to stick our head out. We think January is the right time, and we will have a good data set that will be informative for the market. Okay. And what is the bar for TNG456 to advance in glioblastoma, which is another MTAB-driven condition? Yeah, gliobastoma is a difficult indication. It's very clear. Our study is in relapsed refractory patients. glioblastoma docs are convinced that the truth lies in the adjuvant setting. So we will see if the data will be attractive enough to go forward into GBM. And we will share some thoughts on our GBM development strategy also in January. Okay. So maybe then just to wrap up, Which of the two or three key milestones of the next 12 months or so matter most for Tango, in your opinion? So it's clearly the initiation of the frontline study in pancreatic cancer. It's clearly our understanding of a comprehensive regulatory strategy in frontline and second line pancreatal cancer. It's clear that we're going to have to do a lot of work to make sure that we have a It's really our understanding of where we will go forward in non-small cell lung cancer. So I think these are the three biggest components of our catalyst. Okay, great. Well, thank you, Malte. We'll wrap up here, but I appreciate it. Thank you, Michael. Pleasure being here, and thanks again. Great. Thank you.