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

All right. Good morning, everyone. Welcome to B. Riley Security Oncology Conference and listening to our fireside chat. I'm [ Yuan Zhi ], the health care 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. But first, Barbara, can you give us a quick overview of Tango Therapeutics and your [indiscernible]?

Thank you, and 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. As you know, a lot of progress has been made targeting activated oncogenes, but we have, with the exception of PARP inhibitors, largely had to ignore tumor suppressor gene or loss of function in cancers, which is equally important to the ability to successfully treat cancer patients. And to do that, we built a very -- a substantial state-of-the-art functional genomics platform both -- for both in vitro and in vivo screening in specific tumor suppressor gene loss settings to identify novel targets. And 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 is 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 first-in-human clinical data.

Yes. Thank you. As you say, it is a large and sort of complex platform, but maybe I could summarize by saying we use really all of the CRISPR tools at our disposal to address both -- specifically, for 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 invasion with in vitro screening. And 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 noncell 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. So 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 our pipeline. But of course, maybe we can dive right into [indiscernible] PRMT5 in the context of MTAP deletion. Now PRMT5 is not a new [indiscernible]. 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. And 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. And 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. And then 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 on TNG462, which we'll be filing an IND on the first half 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 as the bone marrow. And so 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. And those inhibitors bind to PRMT5 in the presence of MTA and lock it into its inactive confirmation, 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.

So if I understand it correctly, from the enzyme perspective as a baseline, the PRMT5 is already inhibited. And adding TNG908 here is the last straw to completely crush PRMT5 and [ kill ] this out. Is that right?

That's exactly right. In the absence of an MTAP deletion, that doesn't happen without this special mechanism. But in addition, you're quite correct, that it's easier to do in MTAP null tumor cells because it's about -- PRMT5 is already about 50% inhibited by that MTA that's just floating around in the cells.

Got it. And 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 and especially what went wrong?

So there were 4 that were tested in the clinic. There was one from Prelude, one from Pfizer, one from GSK, and I always forget the last one. But let's use the GSK one as an example because GSK published the data on the full trial called METEOR-1 this last summer at ESMO. And 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. But what it couldn't do was differentiate between cancer cells and normal cells. And so 70% of those patients had dose interruptions or dose reductions. And that's why I think we believe that the activity was not sufficient to move the compound forward. But it does tell us inhibiting PRMT5 is active in cancer cells. So 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. And 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 [indiscernible] through from other molecules. And now we can focus on your drugs in first-in-human clinical trial. I know it's ongoing in dose escalation. And 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 their dose expansion phase have a solid tumor with an MTAP deletion. The -- any solid tumor is allowed, but MTAP deletion is required. And 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 50 or 110 nanomolar. When you can work in the highest dose through concentration, would that estimate concentration in tumor be significantly higher than this [ assay ] 15?

Where we think we'll be between the minimally efficacious dose range projected from the preclinical xenograft and the maximally effective dose, meaning for maximally tolerated in mice, is somewhere in the 150 to 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. So I think we're pretty happy as well that we're going to end up with a reasonable human dose probably somewhere in the 100 to 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?

Well, the dose -- the key piece here is that the dose-limiting toxicity is bone marrow toxicity. So 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. So 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. So that's where that big therapeutic index of sort of 5 to 10x comes from, depending on what dose we select in people.

Yes. Got it. And when we talk about MTAP deletion patients, I'm curious how that is defined or [indiscernible] for patients -- for example, for patients with glioblastoma, is the detection -- has been 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 our [indiscernible] 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. And because MTAP deletion is a homozygous deletion. Even the IHC is very clear. It's either there or it's not.

Got it. Then maybe just to clarify that, one thing that came up from discussion with investors is the heterogeneity of the tumor tissues. In a solid tumor, we know that a portion of 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. And so it is very homogeneous, yes.