Tango Therapeutics, Inc. (TNGX) Earnings Call Transcript & Summary

I'm Eric Schmidt, and my pleasure to introduce our next presenting company, Tango Therapeutics. We're delighted to have with us Barbara Weber, the company's CEO. We also have Daniella, the company's CFO, in the front row here. So Barbara, Daniella, thanks for spending some time with us today. And as we were just talking about, Barbara, if there is a day of the year that I would love to have Tango here at my conference, it would be today because we're just coming off, obviously, some very important data from Amgen in the PRMT5 inhibitor space, which I'm sure we'll talk about. But before we get into those details and that granularity just give us the elevator pitch, if you would, on Tango and what it is you guys are up to.

So the big picture is that we really started Tango to address tumor suppressor genes, a whole new space that outside of PARP has not been addressed in oncology, that is to say almost all of the approved oncology drugs in the last 10 or 15 years are targeting activated oncogenes. All those same cancers have tumor suppressor genes, but you can't directly target them because they're missing, or they're inactivated. So this is a way to get at some of those other cancer genes.

Okay. And let's start then with your lead program, probably where you're spending the bulk of your time these days, which is a PRMT5 inhibitor for MTAP deletions. Just talk to us about the biology of MTAP and what's happening on a molecular level with regard to this pathway?

Yes. And the biology for PRMT5 is complicated, right? What makes it synthetic lethal is the presence of an MTAP deletion. And what MTAP does is -- when MTAP is deleted a metabolite called MTA accumulates in cancer cells that partially inhibits PRMT5. That allows the ability to make a PRMT5 inhibitor that takes advantage of that partial inhibition in the presence of MTA to fully inhibit PRMT5 in cancer cells but not in normal cells. And that's really the basis of everything in any precision oncology drug is trying to identify something that's different between a normal cell and a cancer cell and kill the cancer cell without harming the normal cells.

Okay. And if we're talking about MTAP deletions in oncology, what's the size of that opportunity? What histologies might feature MTAP deletions more frequently?

It's big and it's very common. So it depends on the histology but anywhere from, say, 40 or so percent of glioblastomas have MTAP deletions, 15% to 20% of lung cancers. Overall, 10% to 15% of all solid tumors will have an MTAP deletion.

Okay. And then moving on to some of the strategies directed at PRMT5 inhibition previously. Maybe just a quick recap of what went wrong with the first-generation compounds?

Well, going back to what I was saying a minute ago about one of the key things about a successful oncology drug is to find something that's different between a normal cell and a cancer cell. The original -- the first generation of PRMT5 inhibitors didn't do that. They inhibited PRMT5, which is an essential gene, meaning if you inhibit it, will kill any cell. Inhibited PRMT5 equally in normal cells and in cancer cells. So that there was essentially no therapeutic index, and it was not possible to hit the target hard enough in cancer cells to not cause severe toxicity in normal cells.

Okay. At this point, we've got a number of next-generation of PRMT5 inhibitors that are cooperative binders. What -- maybe just give us a quick lay of the land there, and then we'll get into your programs after that.

So in terms of mechanism, they all are the same. They're called MTA cooperative. They bind when MTA is bound to PRMT5. They lock PRMT5 into an inactivated state and they have this differential effect on cancer cells that are MTAP deleted versus not. In terms of the first 3, that's us. We have 2 PRMT5 inhibitors currently in the clinic. One is our -- first one, which is TNG908, that one is brain penetrant. The second one, TNG462, went into the clinic about a year behind 908, is more potent and selective than 908, but is not brain penetrant, so we're looking at those 2. And then our competition Amgen, which you mentioned update yesterday, they went into the clinic, probably the earliest of all of them. And then what was Mirati, now BMS.

And then AstraZeneca has one that's coming behind, I guess...

Correct.

At the end of the pack. At this point, would you say PRMT5 inhibition is validated? Is the strategy in oncology?

To me, 100%, right? I think that is the question that's out there for investors. But I think 100% is a validated clinical target. I believe these molecules are going to be good important oncology drugs. There's a bit skirmishing about that right now. And I think part of that is because they look a bit different than what people are used to from targeting oncogenic drivers. The biology is different that -- and the landscape of the effect on patients is different as well.

Different how so?

I think overall, the RECIST response rate is generally lower than what people have gotten used to. I mean, think about EGFR inhibitors or ALK inhibitors where you're seeing upwards of 70%, 80% response rates now. But the durability, I think, is what will differentiate these, and there are some interesting points to think about that are present in the Amgen update from yesterday.

Okay. Maybe we'll talk about that. It sounds like you want to hold off on durability until we get a little bit more into the Amgen data.

Sure.

But before we go there on a tumor-by-tumor type, is there a reason that PRMT -- certain tumors or histologies would be more sensitive to PRMT5 based on biology or MTA levels endogenously or anything of that sort that you're learning about?

There's not an obvious reason that's been explained, but I think that is true that there are some tumor types that are more sensitive than others. Most tumor types are sensitive, a few are the most sensitive and, in my mind, a few are the least sensitive explanation for that sort of has yet to emerge.

So that will be empirical that we just to understand...

It's spherical, exactly.

That certain are more or less sensitive. Nothing common in those tumor types yet that we can better [indiscernible]?

Nothing at all. We and others did a lot of preclinical work looking at the genetic architecture other mutations, anything like that. It's just not possible. But it is interesting that some of the tumor types, well, I think maybe all of the tumor types that are particularly sensitive to PRMT5 inhibitors are tough tumors to kill, things like cholangiocarcinoma, malignant glioma, lung cancer, those things are -- those are not easy solid tumors.

And just sticking with the pathway, is there any one thing that you think we really need to know, or you want to know to move your programs forward? Is there biologic unknown that you say you go, gee, if we just solve for that or knew that I'd be able to be a better drug developer.

I think I can always be a better drug developer. It's a humbling job, as you know. But I think that for me, sitting where I sit, I feel very convinced about the data that are already out there. And of course, what I know from our own data that hasn't yet been disclosed, which is this is a -- and I think this is going to be an important target. I think it's going to be developable and approvable in pancreatic cancer and in lung cancer and a number of other tumor types. It's -- at least our molecules have the potential for being, I think, good combination partners in addition to being good single-agent drugs because they're so well tolerated, and we're started -- we're really actively moving forward on that -- those plans as well.

And in terms of combination partners, one potential combination is within the pathway, a MAT2A inhibitor. And of course, IDEAYA is doing that with Amgen is what's your latest thinking on that combination?

Yes. That combination, I think we probably talked more about that combination in the last 5 years and anything, and have not prioritized that as a clinical priority. The reason for that is, as you said, it's an intra pathway combination. So the idea is that by adding a MAT2A inhibitor, you can further inhibit PRMT5, directly on PRMT5. I think our feeling and our all [indiscernible] start feeling. The preclinical data strongly supports the fact that if you can inhibit PRMT5 fully with a single agent, you can get to the same place when we do, it's a little harder to do without a picture behind me. But when we do those experiments, in order to show the synergy, which is real between PRMT5 inhibitors and MAT2A inhibitors, we have to cut the dose about in half of our PRMT5 inhibitors. We get full dose; we get the same effect as the combination. So going back to drug development, just wait easier to start with a singlet when you go into other combinations than a doublet and then you're instantly into triplet.

And then in terms of the biology, is there a combination with PRMT5 that you think makes the most sense?

In terms of the biology less so -- the MAT2A is probably the most biologically driven, but thinking about genetically driven then -- it's a couple of really interesting ones that we are actively working on. The CDK4/6 inhibitors are a particular interest because all and almost all MTAP-deleted tumors also have a CDKN2A deletion and their strong synergy or combination benefit, I should say, preclinically. So that combination could be quite active and at least applicable to all patients with an MTAP deletion. The other -- sorry, go ahead.

Are they chromosomally close to each other?

They are right next to each other. And in fact, the reason that it's true is that CDKN2A is the driver deletion. That's a tumor suppressor gene that's commonly lost. MTAP is lost as a passenger next to it. So we get into that too Amgen ran into a little bit of trouble screening for that reason. The other thing that's really interesting for me is orthogonal combinations of other oncogenic drivers. So particularly the RAS inhibitors and in pancreatic cancer, that's another going to be a big focus for us.

Okay. So let's unpack this Amgen data. It's by far, I think the biggest data set we've seen from a PRMT5 inhibitor. It's hot off the presses at ESMO just yesterday. I'm sure you haven't had full time to digest everything there, and there was a lot of detailed information, especially in the footnotes, but what are your first maybe high-level thoughts on what they've shown us?

So my first high-level thought was great. This is excellent, right? This is continuing to be convincing data on the validity of the target. Second is, I was really happy to see all those lung cancers and pancreatic cancers in the green part of the waterfall plot. That's been a big question out there of whether is this going to be just a niche drug in some of these rare tumor types like cholangio and Meso or is this going to really work in pancreatic cancer and lung cancer? And to me, that those questions were -- those answers are really starting to unfold. And there's certainly no reason or previous evidence that it wouldn't. So I think that those were really important. As you know, I focus very much on the durability and there's a lot of important information on durability in the Amgen data also. So I was really happy to see it. What we wanted from Amgen was data that was good, but not too good. And we feel like that's what we got.

So let's talk about the not too good. I assume you're referring to tolerability, GI nausea, but what are your thoughts there?

I think they clearly have GI toxicity, that's their dose-limiting toxicity and that is obviously problematic for patients. But it is biologically important also because the fact that they're having to stop dosing because of GI toxicity and not getting to on-target toxicity, tells us that they're not hitting the target as well as it could be hit.

Okay. So they went up to 1,200 and actually went up 1,600 milligrams and then had to dial back down to 1,200 milligrams and called out their MTD. What biomarker or other data did you see at that lower 1,200-milligram dose that leads you to think you can do better, from an efficacy standpoint?

Well, maybe I could actually in that standpoint talk about our own data and our own dose escalation, and I'll use 462, as the example here, our more potent and selective MTAP inhibitor. So we went up to 600 milligrams once a day with very good safety and tolerability until 600, and then we hit anemia and thrombocytopenia. So we feel that was what we were looking for, right, clean profile up to on-target toxicity, dialed back then to 200 and 300 milligrams, again, clean and sort of now parsing through what's the optimal dose there to manage the heme tox. So I think the biomarker, if you will, is actually the on-target bone marrow toxicity.

Okay. If I were Amgen, I'd say, well, you just have on-target heme toxicity. But what do you see in their biomarker data that suggests that maybe you want to be more potent at hitting PRMT5 or suppressing the pathway [indiscernible] that they're not hitting?

I think it's hard to know based on the biomarkers, the SDMA maybe what you're asking about. I just -- I don't think SDMA is a good biomarker. It's really the only PD biomarker we have. But I don't think it's sensitive enough to get into the -- into that range where we're seeing how -- whether or not PRMT5 has been fully inhibited or not. I think you lose SDMA signal well before you fully inhibit the enzyme, which is the problem.

Is there any way you can tell that your own heme tox is on target versus off target?

Well, that's a good question. I have to say, I guess, it's somewhat circumstantial, right, that we have full SDMA inhibition, and we know from preclinical work and mouse studies that's what we expected. So and I guess, to your point, you're right, somebody could claim, well, you just have on-target tox. But in the words of one of my famous clinical [indiscernible] one of the most -- the famous words of one of my favorite clinical pharmacologist. At some point, you want to hit on target toxicity because show me a drug that doesn't do anything, and I'll show you a drug that doesn't do anything.

And no reason to think that GI nausea is going to be a class effect of any sort.

No, I don't think so.

Okay. With regard to the Amgen data, just again, maybe going down another level, we did see some activity in lung and pancreatic. We didn't see much in glioblastoma at least 3 patients that I saw in that database. Is that your view as well? Or any thoughts on -- I know you're looking at -- go ahead with 908 [indiscernible]?

Yes. I mean I think it's a little bit hard to say. It is only 3 patients. And I think the key piece of information there is whether or not they're actually getting drug into the CSF, and that kind of remains to be seen.

They've alternatively called it a brain penetrant or maybe non-brain penetrant compound historically. So...

So I think based on the preclinical data, we would call it that too, it's just a matter of...

Which would you call it the?

I would call it brain -- I think Amgen's molecule is based on preclinical data is brain penetrant and should be called that. The question is the translation between the animal data and the humans, are they really getting enough in.

So in terms of GBM, it's still unclear whether it's the wrong histology or the wrong drug and?

I believe that there's nothing magical about GBM. You'll remember, right, that melanoma, lung cancer and maybe now pancreatic cancer, also used to all be viewed as impossible to treat tumors. Eventually, you find the right drug and they start to fall. The issue with GBM is compounded by finding the right drug and getting it into the CSF. And that's that may be the next challenge for the PRMT5 inhibitors because I believe if we can get enough drug into the CSF, they'll respond like other tumors.

One comment I think the discussion made and perhaps it was just a throwaway comment, was that GBM is such an aggressive and rapidly progressing tumor and that PRMT5 inhibition may be a slower onset mechanism that takes a little bit of time to develop that -- it might be a difficult histology. Is that not your view or?

That, I think, is true. And as you know, that's particularly compounded by the fact that you've got a fast-growing tumor with a lot of swelling inside and enclosed space. So what we would want to see is some hint of activity and then move to the adjuvant setting as opposed to relapsed/refractory, where it may be difficult. But again, I still believe that eventually that will be possible.

Okay. Amgen did show us a number of different biomarker-based endpoints. I guess they were doing some IHC testing. Did I see that -- in the data set? You mentioned SDMA as well, which we don't think is a particularly good. I mean where is the field or where are you heading with regard to what is the right kind of companion diagnostic/biomarker to use to develop these products in terms of the pathway and full coverage?

So SDMA being a PD biomarker. I think, as I said, I don't think is particularly helpful. It tells you you're on target, but it's not particularly quantitative. I think the other IHC that they referenced in the slide deck, has to do with the fact that they were allowing patients on study initially with CDKN2A deletions that didn't have confirmed MTAP deletions. And then they went back and reanalyzed a number of the tumors with an MTAP IHC to tell whether or not those patients were actually MTAP deleted or MTAP wild type. And what they found was that about 1/3 of the patients that had MTAP, that had CDKN2A deletions were MTAP wild type. Those patients would not respond, right? And so what they then went on to as plan, again, in the footnotes, was that those patients that are MTAP wild type then it were inadvertently added on trial or in the toxicity assessments, but they're not in the efficacy assessments, which I think is fair, right? That's right.

And how is your trial conduct different?

We always had required as did Mirati that the patients have MTAP deletion testing. I would say like all genetic testing, there is some inherent error rate and it's particularly tricky when you're looking for homozygous deletions. So on our study as well, we've gone back and looked with MTAP IHC, and we do have a few wild-type patients as well.

Okay. And maybe just want to set expectations with regard to what we'll see and when from your 2 studies, 462 and 908 just to making sure everyone's on the same page?

So we continue to plan to have a data release this year. We have a smaller data set than Amgen for a couple of reasons. One is just comparing directly Amgen versus 462 are more potent and selective molecule. They -- that trial on AMG 193 started about 1.5 years before 462. So the numbers of patients are smaller. I would say that in addition to that, it's mostly our dose escalation.

You said about 30-some-odd patients, 30 plus...

30-some-odd patients, right.

Okay.

In addition to that, our escalation -- our expansion cohort started only a few months ago. So I think the data maturity will be less. And finally, as I've said, as many people know, enrolling lung cancer patients to any trial right now is very competitive. So I don't think that we will have enough lung cancer patients to really compare head-to-head. But that's why I was happy to see them having some responses there.

And 908?

908 has more patients. It started about 6 months after the Amgen trial, so around 65 patients there, about 10 of which are at the dose that we are expanding. And there will be enough GBM patients to address the question of whether it's active in GBM. And then we will finally -- sorry. Finally, we will also say, what are our plans going forward? Which are the 2 are we moving forward with in non-CNS tumors. And are we moving forward with 908 in CNS tumors.

The only reason to move 908 forward would be in a CNS tumor indication.

That's always been our hypothesis that one of the two, we would be able to select 908 versus 462 for non-CNS indications. Now if they were the same, then you might want to use 908, right, because it might be able to manage the CNS metastases. If there was a clear advantage from an efficacy durability standpoint, you might want to go with 462.

Okay. And maybe in terms of the profile that we can expect to see, and I know there's going to be a limited amount of information you can share today. First, the data are coming out toward year-end, and I think you've also said in a company-sponsored forum. But with regard to GI nausea, it doesn't sound like that's been a concern. You already alluded to durability being really critical for this pathway. And I'm wondering first what you saw in the Amgen data set that encourage you with regard to durability and how we might perceive that in your own data set?

Well, I'd start by saying, if you look at the swimmer plot, which is just the dose escalation patients, there is a number of those patients that have crossed the 1-year barrier that have been on -- anywhere from 12 to 16, 18 months, which is pretty remarkable in and of itself. But the other bigger signal to me is if you look at the waterfall plot that has the durability over the top of it. What you can see is that somewhere around 70% of the patients on that study or in that waterfall plot are still on study. And if you parse them into maybe for simplicity of explanation, anybody who's got some benefit, right, to their tumor, either 0 -- no growth or shrinkage some excluding those stable disease patients that are above the line. So all the stable disease or partial responses that are below the line, the percentage of patients that are still on study is the same for the stable disease and the partial responses. And that kind of goes to why do people care about overall response rate because in oncology with oncogene targeted drugs, ORR correlates with PFS, right? The stable disease patients tend to come off quickly. All the arrows in this target point to that potentially not being the case that the patients who have any tumor benefit 0 -- stopping growth or shrinking at any number, 0 to minus 100, have similar durability benefits. And that's an important differentiator if that turns out to be true.

Is that expected by the biology?

I don't think it's something that can be predicted by the biology. There were a few hints. For example, we saw a number of mouse phenograph's that can be truly cured. That's unusual, right, and complete responses that are durable in the mice. Do you really believe that's going to translate into the clinic until you see it? Maybe not. But I think there's starting to be some more than just a few hands that it may.

Okay. So in terms of your data, you'll have, as you mentioned, 30-plus patients on 462, 60-plus patients on 908. We'll get the full dose escalation, safety data. It doesn't sound like there's really any off-target toxicity that you're particularly worried about for either. And then we'll start to see some of the impact on various histologies, but the numbers will be fairly modest. So what would you want investors to kind of take home as potential areas of differentiation versus Amgen after that data set comes out?

I think what we're going to be looking at is the difference that good pharmacological properties can make. So the potency, the selectivity and the tolerability, allowing us to hit the target hard. And we know, again, from preclinical data, that in this target, it's very important to hit the target fully and keep it fully suppressed and that, that we believe will translate into clinical efficacy.

Okay. We're also expecting data updates from Bristol and AstraZeneca. I think AstraZeneca is now going to be at the triple meeting. Bristol hasn't said, to my knowledge, where they might be presenting data, but I think they have committed to date in the fourth quarter. Anything in particular you're looking forward to from those compounds or anything about the profile of those compounds that we should know about?

The Mirati BMS molecule, I think, has qualities -- pharmacological qualities that are more similar to 462 than the Amgen molecule. So and they've released no data essentially on the pharmacology and very little other than those vignettes from last summer. So we're very anxious to see the BMS data. The AstraZeneca data, I believe, is probably going to be preclinical data. We'll see what happens with that. But they've not released anything so far in their molecule except for one slide at AACR in the spring, which didn't look very impressive. So let's see what happens with that.

Okay. Maybe just a little bit deeper dive into the GBM opportunity for 908. What -- I know this is a very aggressive tumor type. Could you frame it for us since we've seen so little that works in GBM, what the benchmark would be that's needed in terms of efficacy to consider development there?

Yes. I think the benchmark is essentially 0. The overall response rate for almost anything in relapsed/refractory GBM is 5% or less. And in general, the PFS is less than 4 months. So the bar is low. The question is going to be for us, not so much the actual bar, but the bar to thinking we have something that really makes a clinical difference for patients.

Thoughts on partnering. There's a lot of clinical development ahead for this class and for you all with potentially 2 different compounds and multiple different histologies, where are you with regard to your needs or desires on a partner?

Yes. I think for a couple of years, I've said the same thing about this. This is a big and very competitive program, and I think to optimally develop these molecules in the broad space in which they can be beneficial would really best be done in collaboration with an organization that has a global development organization and deep pockets. So those are that's both aspirational and ongoing discussions.

Is there a timing that makes sense?

My personal feeling is that the best timing is now, right? Because the sooner that a partner jumps in here, the more the benefits of that partnership can help the competitive nature of the program. But we are and we'll continue to press hard on this ourselves, and we can do that.

Okay. And we've just got a few minutes left remaining, but I don't want to shortchange your other clinical program, TNG260 CoREST inhibitor. Why is that an interesting candidate or target?

Well, it's interesting yesterday when I was waiting for the symposium to start at ESMO with the Amgen data, the discussion was actually about the problem of resistance to immuno-oncology agents and how refractory that problem has been. So that actually is what our third trial is addressing, which is that it's been well described, and I think there's another paper coming out pretty soon that solidifies that, that STK11 mutations, which occur in about 15% of lung cancer confer primary resistance to checkpoint inhibitors. And our molecule TNG260 was actually discovered and designed to reverse that primary resistance in -- caused by caused STK11 mutation.

When will we see first data set on?

Next year?

Any time next year?

We haven't said any further than that.

Any updates on where [indiscernible]?

We're pretty focused PRMT5 right now.

Okay. Maybe just in the last minute, you can remind us of where you are with regard to your cash and runway, and then we'll wait with bated breath for the updates on PRMT5.

As of June 30, we have about $320 million. That gets us into 2027 and completion of all of our ongoing clinical trials.

Okay. Any last questions from the audience? Or, if not, thank you very much. Always a pleasure, especially on a big week like this for PRMT5 inhibition. Thanks for spending time with us.

Thank you.

Thanks, everyone.