Good morning, everyone. Welcome to B. Riley Securities Oncology Conference and listening to our fireside chat. I'm Yuan Zhi, a healthcare equity research analyst at B. Riley Securities. Today it's my great pleasure to have Barbara Weber, CEO of Tango Therapeutics. Thank you for joining us today. We will talk more about synthetic lethality, which I'm very excited about, especially after the success of PARP inhibitors. First, Barbara, can you give us a quick overview of Tango Therapeutics and your pipeline? Thank you. Thank you for inviting me to join you today. Tango Therapeutics is a precision oncology company that we started now almost 6 years ago to address the issue of tumor suppressor gene loss in cancer. You know, as you know, a lot of progress has been made targeting activated oncogenes. We have, with the exception of PARP inhibitors, largely had to ignore tumor suppressor gene loss or loss of function in cancers, which is equally important to the ability to successfully treat cancer patients. To do that, we built a very substantial state-of-the-art functional genomics platform for both in vitro and in vivo screening in specific tumor suppressor gene loss settings to identify novel targets. Over the past 5 or 6 years, we've built what is now a clinical stage pipeline from those discoveries and those novel targets. Got it. I know Tango has an amazing drug discovery engine, a platform that are underappreciated by many investors. It will probably take more than 30 minutes to talk about it, but in a nutshell, can you give us some highlight of this discovery engine and platform? Apparently, we will see the proof of concept very soon with the first in-human clinical data. Yes. Thank you. As you say, it is a large and sort of complex platform, but I maybe I could summarize by saying that we use really all of the CRISPR tools at our disposal to address both, specifically sort of classic tumor suppressor gene loss and in vitro screening, as well as addressing the question of tumor suppressor gene loss and its role in immune evasion with in vitro screening. Now, we actually have an in vivo screening platform that allows us to do whole druggable genome screening in animals, which is a big step forward to be able to identify both cell-autonomous and non-cell autonomous drug targets in that system. The only other thing I would add to that is the fact that we realized early on that we also could and needed to use our platform for target validation, because discovering novel targets is really exciting, but it turns out that it's very hard to validate them, in the absence of a tool compound. We have also developed a very extensive system for really validating these targets so we can understand upfront what the effect size is, what the penetrance of the synthetic lethal target will be, all of those things, because not all synthetic lethal hits are created equal, and it's very important to understand that before investing in a drug discovery program. Got it. I know there are many drug clinical candidates within your pipeline, but first maybe we can dive right into targeting PRMT5 in the context of MTAP deletion. PRMT5 is not a new target. Can you first touch on the rationale for focusing on PRMT5 inhibition? Well, our rationale for choosing PRMT5 is that PRMT5 is a very strong synthetic lethal hit with MTAP deletion. An MTAP deletion is one of the most common genetic alterations that's found in human cancers, meaning that if you can make a good PRMT5 inhibitor that's synthetic lethal with MTAP, it has a very big potential for patients. In addition to that, PRMT5 itself is an essential gene, which means that if you can inhibit adequately PRMT5 in any cell, that cell will die. The problem in the past has been trying to get a differential effect between normal cells and tumor cells. This is what the new generation of PRMT5 inhibitors can do that wasn't possible with the previous PRMT5 inhibitors that have been tested in the clinic. Got it. Maybe we can talk about the uniqueness of your molecule, how it's working to inhibit the PRMT5? The mechanism of our molecule, TNG908, which is going into the clinic, and a second generation one, TNG462, which we'll be filing an IND on the first half of this year, is that it follows a sort of a key tenet of precision oncology, which is that you have to identify something that's fundamentally very different between a normal cell and a tumor cell and take advantage of that difference to be able to kill the tumor cell more effectively than what is usually, sort of the weak link in normal cells is the bone marrow. The mechanism of action of our PRMT5 inhibitors is it takes advantage of the very high levels of a substrate called MTA that builds up only in the presence of an MTAP deletion. Those inhibitors bind to PRMT5 in the presence of MTA and lock it into its inactive conformation. Makes it so that you can inactivate PRMT5 at much lower exposures in MTAP null cells than in wild type cells, bone marrow cells. Meaning that you can get very big therapeutic index for this mechanism of action that again, wasn't possible in the past with other PRMT5 inhibitors. If I understand it correctly, from the enzyme perspective as a baseline, the PRMT5 was already inhibited, and adding TNG908 here is the last draw to completely crush PRMT5 and kill the cell. Is that right? That's exactly right. In the absence of an MTAP deletion, that doesn't happen without this special mechanism. In addition, you're quite correct that it's easier to do in MTAP null tumor cells because PRMT5 is already about 50% inhibited by that MTA that's just floating around in the cells. Got it. In the past, there have been some other molecules, inhibitors developed for PRMT5. Can you maybe talk about what those molecules are and what we can learn from those molecules? Especially what went wrong. There were 4 that were tested in the clinic. There was 1 from Prelude, 1 from Pfizer, 1 from GSK, and I always forget the last 1. Let's use the GSK 1 as an example, because GSK published the data on the full trial called METEOR-1 this last summer at ESMO. What we can learn from that is that that drug is an active drug. There are only 3 partial responses, but 40% of those patients had prolonged stable disease, some of them over 2 years. That's telling you that that drug can actually inhibit the growth of cancer cells. What it couldn't do was differentiate between cancer cells and normal cells. 70% of those patients had dose interruptions or dose reductions. That's why I think we believe that the activity was not sufficient to move that compound forward. It does tell us that inhibiting PRMT5 is active in cancer cells. What that taught us is that, and that and our own preclinical data, that PRMT5 has to be fully inhibited over fairly long periods of time and at least 18 out of every 24 hours, and probably for several days at least at a time, if not weeks, to get the kind of strong antitumor efficacy that we can see in our preclinical models. That's what's not possible with the other PRMT5 inhibitors that didn't have this mechanism that distinguishes between normal and MTAP null cells. Got it. That's very helpful, this rule from other molecules. Now we can focus on your drugs enforcing human clinical trial. I know it's ongoing in dose escalation, can you talk about the trial design for this compound and the dose being tested here? The trial design is that all patients being enrolled in the dose escalation phase, and ultimately, when we get there to the dose expansion phase, have a solid tumor with an MTAP deletion. Any solid tumor is allowed, but MTAP deletion is required. We haven't discussed yet any of the details around the dosing and where we are in dose escalation, but I'm happy to say that things are progressing well. Got it. Maybe to ask this question in a different angle. For your compound, TNG908, it has a IC50 of 110 nanomolar. When you converting the highest dose to concentration, would that estimated concentration in tumor be significantly higher than this IC50? Where we think we'll be between the minimally efficacious dose range projected from the preclinical xenografts and the maximally effective dose, meaning sort of maximally tolerated in mice, is somewhere in the 150-500 nanomolar range. We have been fortunate in that sometimes it happens that you can underestimate exposure that you'll get with a specific dose, and the exposures that we're seeing per dose are higher than we predicted. I think we're pretty happy as well that we're gonna end up with a reasonable human dose, probably somewhere in the 100-200 milligram twice-a-day range. It is a twice-a-day drug to keep that coverage that we need. Got it. Just to clarify, the max tolerable dose you observed from preclinical study in mice, was it about 500 nanomolar? The key piece here is that the dose-limiting toxicity is bone marrow toxicity. When you look at the mice, right, the mice just simply start losing weight and so on if you go above too high of a dose, which in mice is about 120 milligrams per kilogram. No, sorry, 120 milligrams BID. The key thing from the safety studies, which is what will predict the MTD in humans, is that the maximum tolerated dose happens when you hit the dose-limiting toxicity of bone marrow suppression. What we know is that when you give enough of TNG908 that you can eventually start to inhibit PRMT5 in normal cells, that's when you get the bone marrow suppression, and that's where you'll get to the MTD. That dose is quite a bit above where we expect the optimal efficacious range in human tumors. That's where that big therapeutic index of sort of 5-10x comes from, depending on what dose we select in people. Yep, got it. When we talk about MTAP deletion in patients, I'm curious how that is defined or determined. For patients, for example, for patients with glioblastoma, is the detection assay the same for patients with solid tumor in other parts of the organ? Yes, it does require a tumor biopsy, but it can be done on archival tissue, and the MTAP deletion is on all the major commercial, cancer genomic sequencing panels. Most of the academic centers as well have MTAP deletion on their panels or can run an MTAP IHC. Because MTAP deletion is a homozygous deletion, even the IHC is very clear. You know, it's either there or it's not. Got it. Maybe just to clarify that, one thing that came up from discussion with investor is the heterogeneity of tumor tissues. In a solid tumor, do we know what proportion of the tumor tissues have MTAP deletion versus those don't have MTAP deletion? Is it very homogeneous, like over 100% of it will be MTAP deletion? It is very homogeneous because MTAP deletion is a truncal mutation. It's actually tied to loss of CDKN2A, which is the tumor suppressor p16. It is very homogeneous, yes. Yeah. Maybe we can take one step back here. For nearby cells, either normal cell, adjacent cells or tumor cell that don't have MTAP deletion, what would happen to them? Could MTA be transported from cells with high concentration of MTA to neighbor cell and thus make those cells vulnerable to TNG908? Yeah, that's a really interesting question and something that we addressed a few years ago, because obviously it was a very important question affecting the ability of this drug to be given safely in the clinic. The experiment we did, and we showed these data at the Triple Meeting in 2021, I think, was that you could take an admixture of normal cells and MTAP null cells that were tagged with green or red fluorescent protein. Any ratio. Mm-hmm. Whether they were 50-50, whether they were 90-10, either direction, and you could expose them to TNG908 and show that in every case, within a few days, the MTAP null cells would die out and the normal cells would take over, showing that there was no ability of the MTAP that was being generated by the MTAP null cells to leach into and make those wild type cells vulnerable to TNG908. We know that that does not happen, that the MTA is metabolized very quickly by normal cells because MTAP is intact, and therefore they never develop the levels of MTA that are needed to make them vulnerable to TNG908 or TNG462. Yeah. That's very helpful insight. Maybe we can talk about the upcoming data readouts. First and foremost, can you maybe talk about the timeline to share data on TNG908? Is there any particular medical conference you guys have in mind? I think it's very likely that it'll be a company update. You know, we are still in ongoing dose escalation, you can probably think of this data release more as a proof of mechanism kind of update than expecting a lot of clinical activity data or to the proof of concept. I think what we'll be able to share is safety, tolerability, PK, and we do have tumor biopsies to identify the differences in SDMA before treatment and after treatment on both normal cells and tumor cells, to be able to show that we can actually get that differential effect in tumor cells. Of course, if we have activity, we would disclose it, but I think that the trial is not at a stage where, particularly because there's so many different histologies that have MTAP deletions and that are being entered onto the trial, that we'll really have much of a comprehensive picture by the end of the first half of this year. Got it. How was the enrollment for this trial so far? In a rough estimation, can you share how many patients worth of data will be shared or evaluable when you share it with investors? I think you should expect that it probably will be less than 20 patients. In terms of the enrollment, it's been interesting. I think early on, and we started dosing last summer, that it was a little bit difficult to identify patients with MTAP deletions, not because there weren't a lot of them, there are, but because people hadn't really been thinking about MTAP deletion and screening for trial enrollment. We also realized that the major genomic sequencing panels, those companies were still reporting out MTAP deletion as an inactionable mutation. We worked with all three of them to get those readouts to be now changed to an actionable mutation and to include the clinical trials that patients with an MTAP deletion would be eligible for. I think the last report that converted was Foundation Medicine in September, and that's made a really big difference. I think we've seen a big uptick in our ability to identify patients and now generally have more patients than we have slots. I think that's been good. I also think everybody who's doing this right now is aware that academic centers still are still sort of resource limited in terms of clinical trial specialists. Again, I'm very happy with how things are going now in terms of the availability of identifying MTAP null patients. Got it. A notable biomarker, like you mentioned, related to PRMT5 is the PRMT5 specific methylation in the form of SDMA. When you share your clinical data, how will you share those biomarker data and how should the investor read into it? We'll share the full data, both the images and the data that we have from the image analysis. The nice thing is that that biomarker, SDMA, is very specific for PRMT5, and it will allow us to really determine where we are with inhibition of PRMT5 with those measurements. Got it. Since TNG908 targets PRMT5 selectively, I'm wondering will it inhibit PRMT9 as well? It's in the same family, and I'm asking because it could catalyze the formation of SDMA. We are just curious what's the portion of SDMA that is generated via the pathway of PRMT9? Sorry. TNG908 is very specific for PRMT5. It turns out that PRMT5 is quite a bit different from the other PRMTs in that SDMA is symmetric dimethylation, and all the other PRMTs, including PRMT9, is asymmetric methylation. PRMT9 or the other PRMTs don't generate SDMA, they generate ADMA, and that's what gives us such a good read from the SDMA. Got it. Although you mentioned that, at the very beginning of the data sharing, there might not be enough data to make the go, no-go decision, but just want to check, is there a benchmark your team are internally thinking to make the go, no-go decision? Understand you are still in the early phase of dose escalation. I think we're very far from a go, no-go decision, in the sense. Well, certainly from anything that would make us say, no go, because, first of all, I think we have a lot of confidence that the preclinical data that we have will translate into clinical activity. What we don't know yet is whether that will be histology specific or that that would be limited to some histologies and not others, or whether that will be across the board. I would say that our preclinical data, and we've done a lot of work on this, more than 200 cell lines and more than 70 xenografts, including a mixture of cell line derived and patient-derived xenografts, suggest that there isn't a histology selection. You know, there could be. Because as of now, almost every patient on the trial has a different histology, it's gonna take us quite a while to sort that out. We also have so much conviction in this target that, as I mentioned, we have a next generation PRMT5 inhibitor that we'll be filing an IND on shortly. I think that molecule has even more potency and selectivity for MTAP null cells and allows us, for some other pharmacologic reasons, to further flatten out a PK curve that gives us a huge window to inhibit PRMT5 and MTAP null cells without hitting PRMT5 in normal cells. You know, we've asked ourselves, and been asked many times, how big of a window do you need? How big of a therapeutic index do you need? The answer is, we don't know yet. We have somewhere in the range of in humans, probably of about a 5-10-fold therapeutic index with 908. With 462, it'll be two or three times that. I think even if we weren't able to get to the activity we would like with 908, and hopefully we will, we have a whole another shot with 462 that has multiple reasons why we think that could be even better. Got it. Maybe another follow-up question here is, with the positive data, what's the plan moving forward with the TNG908? Well, my first answer to that question is, with positive data from TNG908, first plan of action is have a party. That's gonna be a big celebration for us, obviously. I think that moving forward, and thinking about that, the first thing is we want a comparison between the clinical data for 908 and 462. We'll keep moving forward with 908 until we have a good expansion cohort data set from 462. That's probably into 2025 almost at that point, before we have both of them fully evaluated. What we do know also is that only 908 and not 462 is brain penetrant. Glioblastoma is a tumor type that we're very interested in pursuing. 40% of those patients approximately have MTAP deletions. We would, regardless of the TNG462 data, continue progressing TNG908 in glioblastoma. If TNG462 looks, has a meaningfully better clinical activity, we would switch the other solid tumor efforts over to TNG462. It's gonna be a while till we have good comparator data sets for those two molecules. Got it. In addition to the glioblastoma, is there any other cancer target or cancer indication you guys are thinking could be a good candidate that have a more, a higher percentage of MTAP deletion and a good candidate for clinical trial development? There's quite a number of common solid tumors. Lung cancer is probably the most common. The intersection of the most common tumor with the highest frequency of MTAP deletion, and it occurs in both adeno carcinoma and squamous or squamous and non-squamous non-small cell lung cancer. That might be the biggest one. There's a number of other really very important ones. A number of the GI tumors, including esophagus, a whole range of tumors that are in that range of 10%-40% MTAP deletion. Got it. Maybe one last question from us is, can you provide us with your current cash balance as well as guidance on the cash runway and other catalysts that we didn't get a chance to talk about here? Our cash balance, I think we're in a very fortunate position, still reporting 9/30 numbers, but in the range of $390 million. In terms of our runway, we're well into 2025. That is what gives us the opportunity to evaluate both of these molecules fully, we can make the best decision on those. In terms of other data events, we've got 3 INDs this year. We've got our initial dose escalation read on what's happening with TNG908. I think by the end of the year, we and our competitors will also have a better read on what's happening with those next set of PRMT5 inhibitors. Next year, all those INDs will turn into clinical programs, and we'll again have an early readout on those and a fuller readout on 908 next year. Got it. Yeah. Thank you very much for the time. Thank you for the audience for listening today. That's all. Thank you. Thank you, Barbara. Bye-bye.