I'm Charles Zhu, one of the senior biotech analyst here at Guggenheim Securities. For our next session, we have Tango Therapeutics here for our next fireside. With us here today is Barbara Weber from Tango. Thanks for your participation and for joining us. Perhaps just to kick us off, could you provide an overview of your company platform and pipeline?
Yeah, sure. Thanks, and thanks for the invitation. Tango Therapeutics is a company that we started back in 2017, supported by Third Rock Ventures, with the idea behind it that a lot of progress had been made in targeting activated oncogenes in cancer over the last 10 or 15 years, but that all those cancers also have tumor suppressor gene loss, and that there was no other way other than synthetic lethality, really on a large-scale effort to get at those potential targets. Tango was built on the concept that using a large CRISPR-based functional genomics platform, we could identify novel targets and build a sustainable pipeline of synthetic lethal targets to target cancer specifically. That's exactly what we've done. Now we are in the clinic with our first program.
Our second IND just cleared. We've got two more INDs this year coming off of those novel targets that we've discovered from our own platform.
Great. Perhaps, just to start off with your lead clinical stage asset, TNG908. It's an MTA-cooperative PRMT5 inhibitor. I guess, could you help us understand what's different about 908 relative to some of the prior experiences that we've had with PRMT5?
Right. And many people are familiar with the fact that four PRMT5 inhibitors have been tested in the clinic with not particularly striking results. The difference between those PRMT5 inhibitors and the new ones, which are being developed simultaneously by us, Amgen, and Mirati, goes really back to the fundamentals of precision oncology, that you have to identify something that's fundamentally different in the cancer cell from the normal cell and target that. The MTA-cooperative inhibitors do specifically that. They take advantage of very high MTA levels that come from the MTAP deletion in the cancer cells that make it much easier to inhibit PRMT5 in the cancer cells than the normal cells. The previous version of PRMT5 inhibitors equally inhibited PRMT5 in normal and tumor cells, which meant that you could kill bone marrow just as easily as you could kill tumor cells, leading to...
have essentially no therapeutic index, which is what the problem was.
Got it. Great. Also, I guess, you know, to that effect, could you also, you know, talk about, you know, your current status as well as progress for TNG908 in the clinic, as well as how you're setting expectations for your data readout later this year?
Yep. We just started dosing patients last summer, I think we initially saw some headwinds in getting investigators to identify those patients, mostly because they're just weren't familiar with using MTAP deletion as a patient selection strategy. We have put a lot of effort into that, in addition, worked with the testing companies now to change the report so people understand that MTAP is an actionable mutation, I'm very happy with how things are going now. I think we are seeing very nice enrollment, waiting lists for slots, I think that's all good.
Mm-hmm.
In terms of the data update for this half, we will still be in dose escalation, but the purpose of this update really is around proof of mechanism. People have been quite skeptical about this mechanism and the question of can you inhibit this target differentially in normal cells and tumor cells? That's really the purpose of this first data update. We're guiding to a full data update in 2024 on our expansion cohort for a clinical proof of concept, but this first data update is around the mechanism and can we in fact show that we can get strong inhibition of PRMT5 in the tumor without getting it in the normal cells.
Can you also talk about, you know, how that potentially translates in terms of, you know, what we should be looking for in terms of pharmacodynamic data, which markers, as well as, you know, how we should think about it from a safety perspective?
Well, I think the way to explain that maybe the easiest is what you should be disappointed about. If we can't show you that we can get a big difference in the amount of PRMT5 inhibition that we get measured by SDMA in tumor versus normal, you should not be convinced that this is gonna work, right? That's really the key point. What we expect to be able to show is that we can really significantly reduce PRMT5 levels, activity levels in MTAP null cells without getting near the level of inhibition of activity that would be associated with bone marrow toxicity, and we should not be seeing bone marrow toxicity at those levels as well.
We do have the advantage of having the data from the previous trials and knowing exactly at what exposures and what SDMA levels people were starting to see bone marrow suppression. We can also compare to that.
Great. You know, also, I guess in addition to that, you know, how should investors perhaps think about, you know, not only the extent, but also maybe the duration of PRMT5 or SDMA suppression, and how that could potentially translate to longer term signs of efficacy?
Well, I think there's two different maybe answers to that question. In terms of actually inhibiting the target, what we believe from our preclinical data is that you have to keep PRMT5 continuously inhibited over long periods of time to get efficacy. That's a little bit different than some targets where you can hit them intermittently and get good activity. What you don't wanna have are dose interruptions, right? You wanna be able to have an efficacious dose exposure range where you're fully inhibiting PRMT5 in tumor and not having to give dose interruptions to protect against marrow toxicity. In terms of understanding what do we need longer term, one of the important things about this target is it's a very big patient population across multiple histologies.
That's good on the one hand 'cause it's a big patient population that could potentially benefit. It also means that it is gonna take some time to understand in all those different histologies what the activity looks like. What we're seeing in the trial is a wide range of histologies. Having multiple patients from any one cancer type, it's gonna take some time.
Great. Yeah. I guess that makes sense just given your clinical trial enrollment criteria. I guess to that effect, you know, could you provide, I guess, any additional color around, you know, perhaps not only the distribution of histologies that you could potentially be seeing in your dose escalation, but, you know, at time of readout, how that could perhaps, you know, be cross-correlated with, you know, perhaps patients at high potential therapeutic doses?
I mean, I think what we'll see during dose escalation is probably a pretty big smattering of all different histologies, and I'm not sure we're gonna have enough of any one to determine whether activity is different between histologies. For the expansion cohort, that'll be different 'cause we've selected five different tumor types where we have histology-specific cohorts to answer those questions in and then a histology-agnostic cohort for everybody else. I do also think that there's gonna be significant read-through from the Mirati and Amgen compounds. When all three companies actually have data out there, I think it will be possible to have some translation across companies.
Great. We'll definitely touch upon that, but maybe one quick follow-up on, you know, across the different histologies. I guess, you know, to the extent that you can comment based on your clinical experience, but maybe mostly on your preclinical experience, how should we think about, you know, the potential effect of SDMA suppression across the different histologies? Are there some tumor types that could be more or less sensitive? Is this like the direct translatable biomarker?
I think more and more we're coming to think that complete SDMA suppression is necessary, may or may not be sufficient, right? You can suppress SDMA levels to essentially zero. I mean, I'm not aware of histology or a tumor type where we've not been able to do that. We still see a very significant range of sensitivities, right? We see everything from sort of minimal tumor growth inhibition to stasis to deep sustainable regressions such that you can even remove drug after those regressions and the tumors don't recur. The sensitivity of individual tumors is not coming. SDMA doesn't give you that. We don't know yet what will give us that. It's not histology. It's not any known genetic alterations. It's not SDMA.
Okay. I think you also referred to, you know, five different tumor types, for your expansion cohorts. Can you talk about, you know, I guess, when you might start them and also how you selected them?
How we selected them was actually more challenging and a little bit of guesswork than usual because there's so many different histologies and there's no guide to which one might be more sensitive or less sensitive. We selected five histologies for different registration sort of strategy thinking. The first pre-IND was MPNST. It's a rare sarcoma that has no other approved therapy, very high frequency of MTAP deletion, and a potential for an accelerated approval strategy. The second one is non-small cell lung cancer because that's the biggest patient population. The next two were cholangiocarcinoma and mesothelioma also because in those two tumor types, there's a relatively straightforward path to registration. What's the last one I'm forgetting? Glioblastoma. We selected glioblastoma because TNG908 is a very brain-penetrant molecule.
40% of GBM has MTAP deletion, a good opportunity for patients and a path for us based on very strong preclinical data.
Great. Perhaps following up on some of your prior commentary, you know, how do you see TNG908, positioned relative to the Mirati as well as Amgen compounds? As a related segway, where does your next gen come into place?
Well, we don't know very much about Amgen. They just haven't said much publicly. We know from their patents which have published and Mirati's compound, which they've been made publicly available, the structure, that all three are completely different chemical backbones, but they are all three MTA-cooperative molecules, so the mechanism should be the same. The relative merits of the three, I think we're just gonna have to wait and see. I think our compound, to me, but of course, I would say this, right, looks a little bit better than Mirati. I think, you know, we'll just have to see what they look like in the clinic. If our molecule works, I would expect Mirati's and Amgen's would work and vice versa, but the relative strengths and weaknesses of each, we'll just see what they look like in the clinic.
Great. What about your next gen TNG462?
Yeah. Just to go back a little bit in the story of these PRMT5 inhibitors, the initial PRMT5 inhibitors, as we've talked about, were not MTA-cooperative and don't have this differential effect. There was a lot of question about whether you could even make an MTA-cooperative PRMT5 inhibitor because some companies tried and failed, the med chem aspects of it are tricky. It's actually a tri-complex. It's the PRMT5 enzymatic pocket, it's the cofactor MTA, it's the molecule, all three bound. 908 is our first molecule, very good quality, lots of good properties. About 110 nanomolar potency 15x selectivity. The question we and everyone else had is that enough? With a more potent selective molecule, could you do even better?
Now that we've really come to understand how to make molecules in that pocket, that's where TNG462 came from, not because there's anything wrong with TNG908, just because TNG462 is even more potent, even more selective, has longer half-life, smoother PK, all those things.
Great. As you also advanced 908 as well as 462 through the clinic, what are your thoughts around developing one versus developing both? How do these two stand relative to each other?
We certainly expect 908 to be more active in glioblastoma. In fact, we're not even including glioblastoma in the 462 study because it isn't brain penetrant, whereas 908 is. In other solid tumors, the preclinical data suggests you can get incrementally better responses from most cell lines and xenografts from 462, but not categorically different. You can't take a resistant line and make it sensitive. What you can do is we have one or two examples where on 908 a tumor will start to regrow while still on drug. You retreat that animal with 462, and it regresses again. I think it just gets at how hard can you hit the target. That's pretty consistent in all precision oncology.
The more selective and the more potent the molecule is, usually the more target inhibition you can deliver.
Great. Great. Perhaps shifting gears a little bit now over to your CoREST inhibitor going after STK loss of function tumors. Can you talk about, you know, this target, as well as, you know, your rationale for reversing immune evasion?
Yeah. Thanks. I'm actually really excited about this. I think it's one of the most novel things that we or anyone's done in precision oncology recently. That is the whole idea of going back to synthetic lethality. With tumor suppressor gene loss, what are the effects of tumor suppressor gene loss that you could potentially reverse with an inhibitor? Because you can't bring the tumor suppressor gene back most of the time. We always have thought about this in a cell-autonomous way. If you think about that separately as what about the non-cell autonomous effects, what about the role, as we now understand how important it is, of the immune system in killing tumors, can you in fact identify tumor suppressor genes that induce immune evasion?
They keep the tumor protected from the immune system as they grow. What would those look like? Using in vivo CRISPR screening platforms, we discovered STK11 as one of those. Actually, quite exciting to us, about six months after we identified that internally, the group at MD Anderson published the clinical data supporting that STK11-mutant lung cancer patients have a very low response rate to checkpoint inhibitors, very short PFS. We then did a second screen to identify a cellular target, so a tumor cell-based target that would reverse that immune evasion effect induced specifically by STK11 mutations. That's how we identified the CoREST complex.
TNG 260 targets the CoREST complex, and through basically transcriptional reprogramming that both upregulates certain cytokines that changes the T cell infiltration of the tumor associated with PD-1 and blocks Tregs from coming in. It also upregulates PD-L1. It upregulates the antigen presentation complex very specifically related to this STK11 loss of function mutation. Preclinically, we can show that tumors that are STK11 mutant, very resistant to checkpoint inhibitors. You can induce complete regressions in those tumors. You can actually stop the drugs. Tumors don't regrow, and you can re-challenge those animals with the same xenograft tumor cells, and they don't graft because presumably those animals now have immune memory.
Got it. Could you also perhaps provide a little bit more color around, you know, what gives you confidence in reversing the immune evasion conferred specifically by STK11? Because I'm sure as many folks in the audience know that anything plus checkpoint inhibitor has been a very common strategy and few have panned out.
I think this is the very first one that's been targeted at that mechanism by design from the beginning. The way we screened for this was to say what genetic change induces checkpoint inhibitor resistance. The model we used for the discovery was the MC38 model. STK11 wild type MC38s are very sensitive to checkpoint inhibitor. You knock out STK11, they become very resistant. That alone tells you the effect is driven by STK11. With the TNG260, you can reverse that in specifically in STK11 mutant tumors, but it doesn't do anything when you treat STK11 wild type. Yes, there's been a big effort to just like pembro plus everything, but it's pretty empiric. This is very mechanistic and will be focused only on patients whose tumors have STK11 mutations.
Great. Can you also perhaps talk a little bit about the CoREST complex specifically? I believe it's one of several HDAC complexes.
Okay.
you know, HDAC inhibitors also have a history there. You know, how is 260 differentiated on that front?
Yep. Absolutely. CoREST is one of three complexes that includes HDAC1 or HDAC2. The complex that particularly for HDAC1 probably is responsible for bone marrow toxicity associated with HDAC inhibitors is not CoREST, it's Sin3 and NuRD. The other thing is that the range of HDACs that are hit by previous inhibitors such as vorinostat, there are 11 or something different HDACs and multiple different complexes. We are specifically hitting the one complex that regulates immune function. I mean, our preclinical data and our GLP tox studies are complete. We know what the dose-limiting toxicity is. It's bone marrow toxicity that comes from hitting either HDAC3 at higher doses or the other HDAC1 complexes, and we have about a 10-fold window over that.
Great. Could you also quickly remind us the current status of the program and when you could potentially enter the clinic?
We'll be filing the IND for that program this half.
Okay, great. Perhaps moving on to USP1. What makes this a great target and, you know, perhaps how do you think about the synthetic lethality with the BRCA?
Great. USP1 now goes back to a classic synthetic lethal interaction, which is just exactly that, BRCA1 and 2 and USP1. It's the same concept as the PARP synthetic lethality, but it's a different target. It's a different DNA damage repair mechanism. If you think about it as sort of somewhat simplistically as BRCA1 and 2 mutations interfering with double-strand break repair and homologous recombination, PARP recurring with base excision repair, single-strand break repair. The third mechanism that we're going after here with USP1 is called translesion synthesis repair. What you can see, it's like a kind of like a chair, right? Your DNA damage repair is really important in cells, and there are multiple mechanisms. You've got a chair, and a BRCA1/2 mutation knocks out one leg. A PARP inhibitor knocks out a second leg. A USP1 inhibitor knocks out a third leg.
You get single agent activity with either PARP or USP1, but you get also synergy with both 'cause now you got only one leg left, right? It's all pieces of the same thing to continuously disable the backup systems that are in place to protect cells when they have a BRCA1/ 2 mutation.
How should we think about the potential for on target or on mechanism toxicities associated with USP1 and, you know, inhibition of translesion synthesis?
It's a good question 'cause there are really no clues from either the knockout mouse models or in some ways even the GLP tox studies. They're very safe compounds that, you know, at high doses the mice get, you know, knee effusions and things like that. We'll have to see what it looks like in the clinic. There's no previous clinical experience for this. We do know that KSQ is the one company that's gone into the clinic with a USP1 inhibitor. They announced only that they've completed their dose escalation, which was not done in BRCA1/2 mutant patients. I think there's no way to think about efficacy read-through from that, and that they've now started a combination trial with PARP. I mean, we hear very little from them, but we certainly haven't heard anything about safety signals.
Great. Great. Could you remind us the status of your USP1 and when you might enter the clinic?
The IND filing for that program is midyear of this year.
Got it. This also sounds like you could have potentially both single agent as well as a PARP combination approaches to your strategy.
That's fully what we expect. We see single agent activity in both PARP-sensitive and PARP-resistant BRCA1 and 2 models. We see strong combination activity as well in both PARP-sensitive and PARP-resistant models. Now we have some evidence of activity in the broader HRD positive realm. I think it'll be a similar picture to PARP.
Great. Maybe on the business development front, can you talk a bit about, you know, your collaboration with Gilead, how that's going, and perhaps when we could potentially hear more from that?
Yeah. The Gilead collaboration is a good one and very productive, it's very early. It's a target discovery deal, they were very interested from the beginning in our immune evasion targets, additional STK11-like programs. We fully own the 260 program, the CoREST program, they own the rights to additional other immune evasion reversal targets. That's their... Once they select targets, it's development and communication is in their court.
Got it. Great. Perhaps just to close out, could you remind us of your cash balance as well as a runway relative to near-term upcoming milestones?
Yeah. We haven't had updated financials since 9/30, at which point we had just under $400 million in cash. Tell me if I'm saying the wrong thing here. Runway into 2025.
Great. All righty. Well, with that, let's wrap it up. Barbara, I wanted to say thank you very much again for coming down to participate at our conference, and I hope you have a nice rest of your day.
Yeah. Thanks very much.
Oh.