whatever you think. Oh, okay. Great. Well, why don't we start? Thanks everyone for joining us today. I'm here with Barbara Weber, Chief Executive Officer of Tango Therapeutics. We'll be doing a fireside chat, so going through some questions and then happy to open it up for some Q&A at the end. So I guess, Barbara, maybe just starting with some questions around the competitive landscape. As you've undoubtedly watched Amgen, Mirati, and others, what would you consider to be some of the more interesting observations from the data that we've seen thus far? Yeah, well, I think that what's out there so far is actually pointing to PRMT5 as a really important target in this space, and I think that's a couple different pieces of information. One is the early updates last year from Mirati and Amgen. So Mirati was out there first with really just vignettes around patients, but what we started to see clearly was, A, there was sensitivity across histologies, and that there was interesting evidence of responses deepening over time and early hints of significant durability. Then Amgen presented some more complete data, when they presented at the Triple Meeting last year, but basically some of the same kinds of things. And finally, IDEAYA, a few months ago, had a limited update, but actually showed that even with a MAT2A inhibitor, which indirectly inhibits PRMT5 in some particularly sensitive tumor types, they got some interesting responses. So I think the target itself is, you know, I think something that's really clinically validated at this point. And then the next one is going to be ESMO, with Amgen presenting on Monday with a more complete data set on their dose escalation cohort. So I think we'll be looking at all of those things. Okay, great. Yeah, and that update on Monday will obviously be closely watched, but maybe if we just focus for a second on the Mirati compound, how would you say that 908 and 462 compare preclinically to that program? Yeah, and so maybe just to line that all up, we have two PRMT5 inhibitors. One is 908, which went into the clinic first, which is brain- penetrant. 462, which went into the clinic last summer, which is not brain- penetrant, but which is more selective and potent than 908. And then Mirati and Amgen with one each. Mirati's molecule is, has sort of a similar selectivity and potency to 462, and similarly, is not brain- penetrant. Mm-hmm. Amgen is more... I, I'd say it's sort of in the middle in terms of potency and selectivity, but some evidence that, of PK, suboptimal PK properties that may be challenging for them. We'll see. Okay. And maybe before we go into your programs, in a little bit more detail, just for the benefit of the group, could you briefly describe the trial design for both 908 and 462, and then specifically what tumor types you're looking at in the expansion cohort? Sure. So the phase Is are pretty similar. Both of them were dose escalations in any solid tumor with an MTAP deletion. That's obviously critical. The drugs simply don't, the molecules don't work in the absence of an MTAP deletion. And then backfilling, particularly in 908, with GBM patients, so that we could look at those patients early on as well. As we put both molecules into dose expansion, for 908, the expansion cohorts are lung cancer, glioblastoma, and pancreatic cancer. Thank you, Daniella Beckman, our CFO. And for 462, it's lung, pancreatic cancer, and histology- agnostic cohort, which is focused on a few of the tumor types where there's some evidence of increased sensitivity that are more rare types, which are cholangiocarcinoma, mesothelioma, squamous lung. Okay. And what's the status of the dose expansion for both trials, and how many patients will this, the update coming second half of this year have? So the two studies started about a year apart, but the 462 trial went much faster for multiple easily definable reasons. So their expansion cohorts are not that far apart. The expansion cohort for 908 started in March or April. But the expansion cohort for 462 started in June or late June, early July. Okay. In terms of the updates, it'll be the full dose escalation updates for both of them. For 908, the first one, there's about 65 patients in that dose escalation. There's a lot of backfill patients in there. That's why there are so many, and a lot of escalation steps, and then the expansion cohorts we talked about. Mm-hmm. Same for 462. It's just a shorter dose escalation because the starting dose was closer to the active dose and the FDA let us dose double. Okay. Can you provide more detail as to what the second half update will entail? So what we intend to disclose are the data around clinical efficacy, as well as the pharmacokinetics of both molecules. To the extent we have it, the durability, and also our plans for future development for both molecules. Okay. Can you tell us what the safety profile looks like for 908 and 462 so far? Yes, and I can, even to the extent that we have the information, sort of contrast that with the competitor molecules as well. I think, first of all, just to start, the known on-target toxicity of hitting wild type PRMT5 cleanly in normal cells is expected to be hematologic toxicity, specifically anemia and thrombocytopenia. That is what we see with 462. So really good tolerability, very few side effects up to the dose-limiting toxicity of thrombocytopenia, and that's at 600 milligrams once a day. For 908, Amgen, and Mirati, all three other molecules never get to that level of target inhibition that's required to see bone marrow suppression of platelets. And so in the case with 908, our dose-limiting toxicities were in two patients. One was a mental status change in a patient with a CNS tumor, not glioblastoma, but another CNS tumor and CK elevation in patients with some evidence of rhabdomyolysis. For Amgen, Mirati, in both cases, significant GI side effects, nausea, vomiting, diarrhea, and fatigue, which we see, but not in any way problematic. Okay, very helpful. Focusing a little bit on GBM, where there's currently significant unmet need, could you briefly discuss what therapeutic options are available for patients that have recurrent disease following resection? And what do we typically see from those patients from an ORR and PFS perspective? Yeah, and I have to say, it's, as an oncologist, even I didn't realize just exactly how bad the situation is for relapse refractory GBM patients. There's basically nothing that works. There's bevacizumab, which has a relatively short, less than four-month PFS, higher response rate, 40%-50% more probably to do with tumor edema reduction than actual tumor shrinkage. So I would really not think about the ORR there so much as the PFS and then lomustine, also ORR, less than 10% and PFS, less than four months. So the bar is really low in that setting. Mm-hmm. I think the question with anyone developing a drug for glioblastoma has to ask is not just can you beat that bar? Because that bar is like non-existent, but do you have something that is going to be a really meaningful development going forward? Yeah. Well, we're all looking forward to the updates coming later this year. Moving to the pipeline, can you provide an update on Tango 260? Yeah. So 260 is our CoREST inhibitor, which is in development for STK11- mutant cancers, particularly lung cancer. About 15% of non-small cell lung cancer is STK11- mutant. And it's been shown in multiple settings, there's another paper coming out soon that's been accepted but not yet published, that will address this in yet a bigger data set. But patients whose tumors have STK11 mutations are not very sensitive to checkpoint inhibitors. So the preclinical data that we have is that this CoREST inhibitor reverses the checkpoint inhibitor resistance, the primary checkpoint inhibitor resistance that's caused by STK11 mutations. And the question asked by the trial is: can you then sensitize those tumors to checkpoint inhibitors? And then lastly, I guess pivoting to the financing side, can you briefly review your current funding, what your cash runway, and what cash runway that you will have to support? And then what key milestones do you expect to achieve during that runway? We have about $320 million in cash right now. That gets us into 2027 and allows us to complete all phase I, II studies that are currently ongoing. Okay. Ongoing. Got it. Great. I think that was it in terms of kind of planned Q&A that we wanted to go through. Does anyone... Maybe I'll open it up to see? Yeah, go ahead. Um, It's a really interesting question. I don't know that I can address it from the standpoint of synthetic lethality as a whole, but from the standpoint of PRMT5, it's interesting. PRMT5 is an essential gene, so if you can fully inhibit it, you'll kill any cell with a PRMT5 inhibitor. Obviously, in this setting, the synthetic lethality approach, the idea is to kill the cancer cells without killing any of the normal cells. But in terms of resistance, looking at it preclinically, it's been hard to generate resistance. And one of the reasons may actually be that somewhere between 30%-50% of resistance that develops regularly to tyrosine kinase inhibitors happens because of mutations in the enzymatic pocket that prevents the drug from binding. Looking at the active pocket of PRMT5, it's sort of hard to imagine how that would happen, because any site that would alter, mutation that would alter drug binding in the pathophysiological setting will alter client protein binding in the normal setting. Anything that mutates so that MTA can't bind will then cause the mutation that keeps probably SAM from binding. So there's a lot of pressure against the development of an enzymatic pocket mutation in PRMT5. That suggests that resistance mutations will, or resistance mechanisms will come from all the many different individual pathways in which proteins are regulated by PRMT5, and the extent to which that occurs will sort of wait to see. But as I hinted at, there's some interesting data out there, and I think it's one of the things we're all waiting to see from Amgen, that the durability associated with these molecules, whether it's in patients with stable disease or partial responses, is going to be notable... which suggests it may in fact take longer to develop resistance, that it at least secondary resistance than it does to tyrosine kinase inhibitors. Okay, Yes. So, the way we did this was empirically with in vivo CRISPR screening, looking at resistant and sensitive, a model that was resistant and sensitive to checkpoint inhibitor because of an STK11 knockout. What we got out of that was that the STK11 mutation changes the transcriptional profile of tumor cells such that they don't have any of the things that you need to be responsive to, immune cell killing. And what the CoREST inhibitor does, which is a subset, it's a isoform- selective inhibitor of HDAC1, is it modifies the transcriptional profile of those cancer cells, so they go back to looking like sensitive tumor cells, meaning they upregulate PD-L1, they upregulate cytokines that attract T cells. There's a whole range of immunologic mechanisms that the transcriptional regulation profile of a CoREST inhibitor changes in those tumor cells, so they're able to respond to a checkpoint inhibitor. It's an HDAC inhibitor that's very selective for a subset of the CoREST complex of HDAC1. So if you think about HDAC inhibitors that have been developed in the past, they're pan-HDAC inhibitors that hit basically all isoforms of usually six, seven, or eight HDAC. So it has a very different profile than vorinostat or previous HDAC inhibitors. Okay, with that, we appreciate everyone's time. I, you know, I think Barb and Daniella will probably be around for a few minutes here if anyone wants to chat with them, one-on-one until we wrap up the time. Thank you. Great. Thank you. We don't have any information on IDEAYA. You know, that's MAT2A, and I think that's a little bit different. I mean, it's obviously secondarily inhibiting PRMT5, but how that's gonna look in terms of, durability and resistance could be quite different from the PRMT5 inhibitors. Yes, here, I'll sit back down. Since we have another couple of minutes. Yeah, please. Can you just go over your answer, your response again to the question about durability and specifically about mutations emerging in the enzymatic pocket? These are mutations, I assume, that are emerging during the course of treatment, or how should I think about this? Yeah. So let me back up a little bit and just say the background being that for many oncology drugs, a significant proportion of the resistance develops because the target protein develops a mutation in the enzymatic pocket that affects either ATP binding or usually drug binding, right? And that happens often fairly quickly after patients have been on drugs. The issue with PRMT5, and I don't have a picture with me, but if you look at our corporate deck, the pocket, it's essentially requires three pieces, right? So, if you sort of think about two sides of the pocket, one side binds the protein, one side binds the cofactor. In the setting of an MTAP deletion and the binding of a PRMT5 inhibitor, the PRMT5 inhibitor goes in where the client protein would go, and MTA, which is what the cofactor is that's created by the MTAP deletion, goes in where SAM goes, so it's hard to explain without a picture, but wherever you mutate that pocket, that would prevent either a PRMT5 inhibitor or MTA binding, would then markedly affect the function of the protein in the normal setting, so that it wouldn't either bind protein, a client protein, or it wouldn't bind SAM. So I think there's a lot of pressure against developing drug resistance through an enzymatic pocket mutation with PRMT5, and we didn't see that preclinically either. If you take cells in culture and culture them with low levels of a TKI over time, you'll develop a significant number of clones that grow out with those resistance mutations. PARP inhibitors are the same, but you don't see that in the PRMT5 setting. Maybe because it's an essential gene, so you either can't function with these mutations that alter drug binding because they alter too much the function of the normal function of the enzyme. There's well, it's called a tripartite inhibitor because you need to have PRMT5, the inhibitor, and the cofactor binding as a tripartite complex. Amgen calls it a glue because it, the, these molecules, the PRMT5 inhibitors, sort of stick that whole complex together with pretty long off rates. There's many. I think people have estimated there's more than 90 client proteins for PRMT5. PRMT5 is the only. This is also why it's an interesting drug target. It's the only methyltransferase, protein arginine methyltransferase, that does symmetric methylation. All the other PRMTs do asymmetric methylation, so it's a single enzyme that has no backup molecule for its function. But it's pretty essential. It is an essential gene, that's right. If you knock it out, any cell will die. So the goal with these MTA- cooperative molecules are Amgen and Mirati's, is that you get, you use the biologic effect created by the MTAP deletion to selectively inhibit PRMT5 in the tumor cells without inhibiting it in normal cells. And that's why you get this better efficacy and nice side effect profile that you can see compared to the first generation PRMT5 inhibitors. Right. So, so that's Mirati and Amgen's post-second generation? Mirati, Amgen and Tango we are the only three at this stage that have those second-generation inhibitors. Neither one of them had a first generation. The first generations were GSK, J&J, Prelude, and Pfizer. Right. The first generations are all SAM- competitive or SAM- cooperative, and the second generations are all MTA- cooperative. Thank you. It, what it does is allow you to take advantage of the big difference between normal cells, which have intact MTAP, and those that are MTAP deleted. So for any precision oncology approach, right, that's what you want to do. You want to find something that's a big difference between the cancer cells and the normal cells. And in this case, the MTAP deletion creates a big high concentration of MTA in cancer cells. Because these are MTA-cooperative, so the inhibitors bind preferentially in the presence of MTA, the inhibitors bind much better to the cancer cell enzymes than to the normal cells. Any other questions? PARP obviously was the first one that's already well out there. I think PRMT5 is the next big one. I think the DNA damage repair, the rest of the DNA damage repair inhibitors have been somewhat disappointing in that regard. We have some preclinical synthetic lethal targets we haven't disclosed yet that could be of interest, but I'm not sure right now there's another one in the clinic that's really striking. I mean, I have to say, I haven't seen any data that are super convincing from those, but I can't tell you that I'm fully well-versed in that yet. MAT2A is another one, right? So I think the MAT2A inhibitors, IDEAYA has one, Servier has one. I can't imagine, based on the biology, a scenario where a MAT2A inhibitor would be better than a PRMT5 inhibitor. But in the sensitive tumor types that IDEAYA, IDEAYA disclosed, the squamous lung and the bladder cancers, they do have interesting activity, so that might be another one. That's our preclinical data support that and our hypothesis that anywhere that a MAT2A inhibitor would work, a PRMT5 inhibitor would be at least as good, if not better. People like us sitting like this and with lots of companies that talk about how they have lots of room clinically, that they can get a product to market. You're describing a much more competitive environment. I think that that's true. How do you look at that? I think that's true. I mean, I think that Amgen, BMS, that has the Mirati molecule, and we are all in the space together at a pretty similar stage of development. And you're right, it's a big development plan and it's fierce competition. And I think that's why A, as always, you need to have the best molecule, but also I think we've said for a while that the optimal path forward for us is a development partnership, because it, in order to remain competitive, particularly with Amgen and BMS, we need to potentially partner with an organization that is a global development organization, strong full development experience around the world, commercialization machines, right? That's what big pharma is good at.... That's right. That's right, for development and commercialization. I think, you know, the PRMT5, the clinical data that are out there, as well as the preclinical data, support the fact that there will be good single-agent activity. But I think, as you know, in oncology today, there's almost no role for single agent therapy except sort of last line, right? Everything has to ultimately and will be most effective in combinations, but these are orthogonal combinations that are not required for activity. They're just to be able to increase the activity, which is exactly what we're looking at. It's hard to say about Mirati. I'd say preclinically, we've looked at the Mirati molecule a lot, using both their own data that they've published and data we've generated internally. Preclinically, the Mirati molecule and 462 are reasonably similar, and we'll just have to see what they look like in the clinic because we just don't know anything about that from BMS or Mirati. The Amgen molecule, I have to say, and again, there's a slide in our corporate deck on this. If you take their own data and put it up against our data and Mirati's published data, I think that molecule may be the weakest of the four, but we'll have to see what that looks like. It's probably mostly because of PK, and they saw that in the clinic, right? They had to give, you know, 800-1200 milligrams every day to get exposures and target inhibition that we can get. I can say the target exposure we get with 462 is probably 10 or 15 times better than they get with the same tolerable levels of 193. With the Mirati molecule, again, we don't know because they haven't released any clinical PK. So I think that molecule has some PK challenges, which they could probably fix. I mean, first of all, I think they give it once a day when it's got a half-life more suggestive of a twice-a-day drug or formulation change. I mean, they're Amgen, they should be able to figure that out. But and they may have. We don't know. We'll see in a few weeks what they've done.