Good morning, everyone. Thank you all for being here, and for those of us who are attending online, nice to have you. My name is Paul Choi. I'm a team member on Chris Shibutani's biopharma research team here at Goldman Sachs, and it's my pleasure to have Barbara Weber, CEO of Tango Therapeutics, here with me today. Barbara, good morning.
Good morning, thank you for having us.
Of course. Maybe just to start here, if you could provide an overview of the company, the synthetic lethality platform that you're built on, and, you know, it's been an exciting year so far. You've had some clinical data, so maybe just an overview to get us started here.
Yeah, it's gonna get even more exciting over the next 12 months.
Absolutely.
Tango Therapeutics is a company that we founded more than 5 years ago now, based on the concept of synthetic lethality. Coming from my long-term interest in tumor suppressor genes and thinking that this was a huge space of potential targets for precision oncology that had really not been tapped. PARP, as you know, being the first synthetic lethal target that's really been clinically validated, came from a hypothesis-driven observation by Alan Ashworth back in, you know, 2005. Until there was big genomic CRISPR-based platforms, the ability to sort of industrialize that approach didn't exist. That's how we built.
That's what we built Tango on, and what we've done over the past 5 years is build a pipeline from that platform that's now, by the end of this year or very early next year, will be fully into the clinic with the first four programs.
Excellent. Let's start with the first program, TNG908, your first PRMT5 inhibitor. PRMT5 is not a new target in oncology, but this asset is kind of the first of the next generation of PRMT5 inhibitors, so this has to do with the concept of MTA cooperation. Could you maybe describe what makes the MTA-cooperative mechanism important in PRMT5 signaling?
Yeah, of course, it's a bit of a headwind always for us to come behind five drugs that didn't work and explain why ours is different and it's gonna work. You guys have heard that.
Mm-hmm.
Enough times before when it wasn't true, but this time it's gonna be true.
Absolutely.
The real difference, if you think back on the whole basis for precision oncology, is to find something that's different in tumor cells than normal cells and use a mechanism that allows you to target only the tumor cells, or very selectively the tumor cells. When the original PRMT5 inhibitors were made and starting to go into the clinic, they were all made to be epigenetic cytotoxics in the era when everyone thought those were going to be the great new wave of targets. By the way, I do think their epigenetic targets are important, it's just that no one was able to figure out exactly how to use them initially. The observations made by a team jointly working at Novartis and Broad to show that PRMT5 and MTAP deletion were a strong synthetic lethal hit.
None of those five molecules, when people tested them, recapitulated the genetic finding. People say: Oh, that experiment is wrong, Broad is wrong, Novartis is wrong. Genetics are never wrong, right? What's wrong is the molecules. It was clear, and it was actually postulated by the group that reported the finding, that what you need is a drug that takes advantage of the difference between the normal cells and the cancer cells that's created by the MTAP deletion. That is very high levels of this cofactor called MTA, and the next generation, which for us is 908 and 462, it's also the Mirati compound in Amgen, but really only bind effectively to PRMT5 when MTA is bound, not when the normal cofactor SAM is bound, and that's how you get that selectivity.
That's why we all think it's gonna work, because it gives you a very big therapeutic index.
Absolutely. Maybe in terms of tackling that question of whether or not this is going to work, on your last earnings report, you provided some proof of mechanism for this mechanism of action for 908. Maybe could you provide an overview of what we found with this proof of mechanism readout?
It goes exactly to what we were just talking about, which is that with the original SAM competitive or SAM cooperative PRMT5 inhibitors, you equally inhibit PRMT5 in normal and in tumor cells. With the new generation, with 908, what we showed was what we hypothesized should happen and what we certainly have seen in animal models, that you can very much suppress PRMT5 activity in MTAP-null tumor cells, getting almost no suppression in normal cells. Those two cohorts that we showed data from were not yet in the predicted to be efficacious dose ranges.
Mm-hmm.
We are already seeing pretty profound suppression of the PD signal for the PRMT5 activity.
Right.
That was essential for us to show.
Absolutely. These first two cohorts that you described not being in the efficacious range, you were still already seeing this SDMA PD biomarker essentially being reduced.
Correct.
Cohorts 3 and 4 that are ongoing, do you expect those to be within that therapeutic window at this point?
Well, we haven't disclosed any further information about cohorts 3 and 4, except that we didn't see a safety signal in any of them.
Mm-hmm.
Our guidance is for more data in 2024 and closer to the end of this year, early next year, we'll disclose sort of better granular, more granularity on the timing and what that's gonna look like. What you can expect is that it's gonna be a proof of concept, clinical activity data release. When we're convinced, we'll show you guys.
Okay.
Convince you.
Sure. That sounds great. On the safety that you just referred to, was clean safety so far profile for 908, including an absence of bone marrow suppression, which was part of the issue with the dose-limiting toxicities of the prior generation.
Mm-hmm.
Can you maybe elaborate a little bit further on what the safety profile looks like and whether, like, do you think bone marrow suppression is going to be the eventual dose-limiting toxicity still, and it's just a wider window at this point?
We do, you can see that pretty much any way you look at it, whether it's the knockout mice, whether it's preclinical safety data from the first or second generation PRMT5 inhibitors, or whether it's the clinical data from the first generation, the dose-limiting toxicity is anemia and thrombocytopenia.
Mm-hmm. Okay, great. With respect to these SDMA paired biopsy data that you were seeing, you are seeing a selective inhibition or reduction in this marker with respect to tumor tissue, correct?
Correct.
Can you characterize, like, how robust these selective inhibitions of SDMA signaling, like, that you're seeing? Is this a robust signal? Is this something that you expect to be clinically meaningful at this point, at least in the, you know, getting into the cohorts 3 and 4 range that you're talking about?
Well, it's very selective. It's only a marker of PRMT5 activity.
Mm-hmm.
Not of any of other PRMT or other methyltransferase activities. It's very robust in terms of its reproducibility. What it is, isn't, is very sensitive. It's an IHC assay.
Mm-hmm.
That doesn't have a great... You know, the lower limits of detection of the assay are not great, so you can't really tell the difference between 90% suppression and 100% suppression. That's important with this target and this mechanism, because you need to really fully suppress the activity of PRMT5. We're now in a range, though, with SDMA suppression, the PD biomarker, where you can't really see the bottom of that range yet.
Right. The SDMA suppression that you are seeing, do we know how that compares with the non-MTA-cooperative inhibitors of the prior generation? Are we seeing a greater degree of suppression comparably?
Yes, the big difference also is the differential between the normal and the tumor. In all of the previous PRMT5 inhibitors, what was generally reported was serum SDMA, which is mostly coming from normal cells, right? The average is sort of 70% to 80%, 85% reduction. That's telling you that's where you start to see bone marrow suppression, is when you get down to around 80%, 85% serum SDMA suppression.
Right.
We are not even close to that. We saw very little change in the normal SDMA reduction.
Got it. Maybe at this point in time where, you know, you're not the only company out there with an MTA-cooperative PRMT5 inhibitor, can we talk about how TNG908 compares with respect to some of your competitors out there? I know that typically you see, you know, these preclinical studies with cell line MTAP selectivity, MTAP-null selectivity for in terms of cell viability assays. You know, how should we be thinking about that sort of an efficacy readout for these different competitors? You know, is it really fair to compare these programs by that measure?
Well, we certainly think it's fair to compare us and Mirati.
Mm-hmm.
Mirati has released enough data that we can actually put the data up head-to-head. Amgen, we know the mechanism is the same. They've just released very little data on their preclinical program, so it's harder to judge on that. I think you can expect significant read-through between us and Mirati.
Okay, great. For 908, at this point, we're awaiting additional clinical results next year, 2024. Is there any chance that we might see any sort of other, mechanistic, like interim readout between now and then? Is this really just a 2024 story at this point?
Well, there's always a chance that it'll be data before then.
Mm-hmm.
It won't just be proof of mechanism data. Whatever the next data release we do, it's going to be about clinical activity.
Okay. Could you provide any further color in terms of what to, what we might expect in that 2024 readout in terms of patient counts or follow-up time, anything like that?
Again, I'm gonna stay away from specifics.
Mm-hmm.
To tell you that when we think we have convincing clinical proof of concept, that's what we'll be sharing.
Sure. Then what?
I just want to comment, too.
Yeah.
It's, I'm hedging a little bit more than usual.
Mm-hmm.
Because MTAP deletions are so common across multiple different tumor types.
Mm-hmm.
As of the update we just gave in May, we had 16 patients on study in 12 different histologies.
Right.
You know, there's a scenario where it looks great in every histology, that's perfect. We, you know, t here's also a scenario where it works better in some than in others.
Right.
It just may take us longer to put enough patients of any single histology on.
Sure
To come up with some convincing data.
Sure. One of those histologies that might be important for TNG908 in the future is glioblastoma.
Absolutely.
Can we count on a glioblastoma representation in the data cut in 2024?
Yes, we are already enrolling GBM patients.
Okay, that's excellent. Maybe just a couple of more conceptual questions just in terms of the utility or potential development path for 908, and especially in terms of potential combinations. One of your competitors is combining their MTA-cooperative PRMT5 inhibitor with a MAT2A inhibitor. Just wondering if you could provide your thoughts on that sort of a development path, the rationale behind that, and whether that's something you might pursue potentially in the future.
It's something we've thought a lot about for a long period of time. It's clear biologically that there's strong synergy between MTA-cooperative PRMT5 inhibitors and a MAT2A inhibitor. What MAT2A inhibitors do is reduce SAM levels, so it increases the difference between MTA and SAM levels in a given cell, and it might give you a little bit more selectivity in the combination. I think the thing is, though, and we have data from these now that we're showing publicly, that if you can fully inhibit PRMT5 with a PRMT5 inhibitor, you probably don't get much from adding a MAT2A inhibitor.
Mm-hmm
Except potentially toxicity. If you have a MAT2A inhibitor, there's no possibility that you can fully inhibit PRMT5 that way, so you have to combine it with a PRMT5 inhibitor. If we give our inhibitors at full dose, you can't see any added benefit.
Mm-hmm.
If we cut our doses in half and then give a MAT2A inhibitor with it, you see significant effect. We'll see.
Okay, understood.
It's not our top priority combination.
Sure
We're keeping an eye on it.
Optionality going forward. Okay, great. Are there other combinations that would make sense in terms of PRMT5 inhibition that you're considering?
Yes, there are a couple that are pretty high priority for us. In one category are activated oncogenes that are double mutant tumor types. A tumor that has an MTAP deletion and an EGFR mutation, a combination of TNG908 plus an EGFR inhibitor or a RAS mutation with a RAS inhibitor, those I think are of high interest to us. I think I'm certainly of the camp that think You can't cure solid tumors with single agent, right? We want single and expect single agent activity, but to really get significant complete responses in these, some of these tumors, we expect we'll need those kinds of combinations. The other combination that's really interesting to us is with a CDK4/6 inhibitor.
Because of the genetic structure of the deletion with MTAP, CDKN2A is always lost when you've lost MTAP. That means that any patient with an MTAP deletion may have an increased sensitivity to a CDK4/6 inhibitor, and we have some preclinical data showing that there are tumors that have the double deletion of CDKN2A and MTAP that don't respond at all to a CDK4/6 inhibitor, but have strong synergy with the combination. That's a very high priority combination for us, and particularly in GBM, with abemaciclib, which is brain-penetrant. That's something we'd think about doing earlier rather than later with 908 .
Right. That code deletion would really just garner a vulnerability to CDK4/6 inhibitors in particular. This, are there other cell cycle inhibitors that might make sense, or is this really specific to CDK4/6?
I don't know the answer to that. We really focused on CDK4/6 because of that deletion. It's certainly possible that there are others.
Sure. Okay. In terms of the proof of mechanism data that you presented for TNG908, this was, you know, based on the SDMA paired biopsy data. As these other competitors in the MTA-cooperative space come to their first readouts, if they were to provide similar SDMA paired biopsy data, would you say that it would be fair to compare your data with theirs?
I would be surprised if it didn't look similar.
That's great. Maybe we could move on now to your next PRMT5 inhibitor program, TNG462, which is said to have a greater selectivity for MTAP-deleted cells. Maybe can you comment on this difference in terms of selectivity, described as being 40x, 45x for TNG462 and 15x or so for TNG908. What do you expect to gain from this increased selectivity? Maybe, you know, this is kind of something that you see a lot of MTA-cooperative PRMT5 inhibitor programs kind of commenting on their selectivity and the full selectivity that they have over non-MTAP-null cells. Maybe can you comment on whether there's a point potentially of diminishing returns in terms of this selectivity?
Like, how much certainly 15x- 45x seems different, but how much different is 45x- 50x?
Yeah. Well, 45x-50x is really not different at all.
Right.
One of the things to just bear in mind for how we measure this, I think we and Mirati use the measurement that comes from the HCT116 isogenic lines. Actually, if you put any of these molecules into a panel, you'll see a whole range of selectivity, and actually, usually, 116 is the lowest selectivity. With 908, you can see a range between 15 and 25. With 462, you see a range between 45 and 70. The question is, does it matter, right?
Right.
I think going back to the beginning, that's why we made 462, was we didn't know.
Mm-hmm.
If it would matter. We still don't know if it'll matter, we wanted to make sure that if it did matter, we had a really selective molecule. I think what we've seen doing a lot of preclinical analysis is it matters a little bit, it doesn't give you three times more selectivity. It doesn't give you three times more complete responses, for example.
Right.
It doesn't normally change a xenograft from being very relatively resistant, which I have to say, none of the 60 or so xenografts we've done grow through this.
Mm-hmm.
You know, if you only get some small amount of tumor growth inhibition with TNG908, you don't get then a complete regression with TNG462. You get usually a little bit more activity, and there are a few where you get better activity with TNG908. How much it's gonna matter? We still don't know.
Right.
We'll find out. We're about to find out.
Sure. Yeah. We'll stay tuned. TNG462, you have slated for first patient dosing sometime in the middle of this year, correct? As you have now 2 PRMT5 inhibitor programs that are both in the clinic essentially and progressing further, how are you thinking about the developmental decisions between the parallel development between these two?
Well, yeah, as you say, they're about 1 year apart in terms of patient dosing. We expect them to converge a little bit more, in part because one is we're starting closer to the minimally efficacious dose because of the selectivity and potency, also because the investigators are both more comfortable with the MTAP patient selection strategy, and also there's tons of patients out there now. You know, we're accruing very rapidly to TNG908, so that we should expect that will be true with TNG462 also. I think that over the next 2 years, we'll be able to make a decision about what makes sense. There are, each of the molecules has unique features. For example, TNG908 is brain penetrant, TNG462 is not.
462 has a little bit more straightforward profile in terms of potential for drug-drug interaction and a longer half-life. I think we're just gonna have to see both what the clinical data look like and what the competitive situation is.
Right. Okay. When you think about this decision that's potentially coming in the next two years, can you comment on what in particular you're looking for? Is this a matter of dose expansion data? I guess maybe any clarification on what you're looking for to make that decision?
Yes, we'll be using clinical activity data in the expansion cohorts, as well as our competitors' data, right?
Right.
I think there's enough read-through that it'll help us understand what, where to look and what to look at.
Got it. Understood. You mentioned the blood-brain penetrance of TNG908 as being a differentiating factor, and that's why it has a potential future in glioblastoma, correct? One question that we had, just out of curiosity, was. One of the specific histologies that's potentially important for PRMT5 inhibition are these peripheral nerve sheath tumors, correct? We were wondering if you could comment, if there's anything that we know about TNG462's ability to penetrate the blood-nerve barrier. Is that something that has been assessed preclinically?
There's really not very much data about that. I think in general, there are other tumors that derive, neuronal tumors that derive, that once they start to grow, the nerves, they just really flow through the nerve sheath.
Right.
Unlike the brain, where it's actually the blood vessels in the brain that create the blood-brain barrier.
Mm-hmm.
What we know from preclinical models of MPNST that are being done with a collaborator at Washington University in St. Louis is that 908 and 462 are the most active agents she says she's ever tested in those xenografts.
[audio distortion] Presumably.
To the extent that we can judge preclinically, we don't expect it to be an issue.
Okay. Okay, that makes sense, and that's helpful clarity. With first patient dosing for 462 coming in the middle of this year, just trying to gauge maybe when we.
Which, by the way, is out now.
Yeah, exactly. I can't even believe it. We have, you know, I'm just trying to gauge the timing for when we might hear first clinical results for 462. I think for 908, it was about a 12-month timeframe between first patient dosing and when we learned that first glimpse of data. Wondering, you know, should we be expecting 462 data sometime in the frame of mid-2024? Does that sound fair?
We haven't given specific guidance, but, you know, it's in that range.
Okay.
It wouldn't be an unreasonable guess.
Okay.
We don't know.
You mentioned.
It depends on too many factors we can't control.
Of course, of course. You also mentioned the fact that with 462's dose escalation, that you expect to be able to initiate that dose escalation close to the therapeutic window there. Just wondering how that sort of dynamic might play into what sort of data we might see when we do eventually see clinical data? Does that mean that we might have maybe more mature clinical data for 462 by the time we get to a clinical readout? Or should we expect, you know, a similar, like, mechanistic readout with SDMA paired biomarker?
I mean, we haven't actually really talked about this. I don't think we would do a mechanistic readout like that because we would certainly expect it would look exactly the same.
Right. Right.
In terms of the data, I think the standards are the same. Once we are convinced of a clinical POC there, we would share the data. What people are gonna be more interested in 462, though, is the comparison, is it better than 908?
Right.
That's gonna take a little bit longer.
Sure
Than just a clinical POC readout.
Right. Right. When you think about comparing with 908, is that comparative, comparison gonna be kind of like a combination of SDMA and actual anti-tumor data, or are there maybe safety considerations where you might expect a differential?
I think it would be safety and clinical efficacy. The SDMA, we expect from this point forward, is gonna in a way, in some ways, be the tumor SDMA irrelevant.
Mm-hmm
Because we already know we're there.
Right.
We just need to keep dose escalating to fully inhibit the enzyme.
That might also be due to the IHC's kind of limited, dynamic range, I guess.
Exactly
As well. Right, that makes sense. As you have, you know, now you're gonna have 2 PRMT5 inhibitors in the clinic going after MTAP-null tumors. You, as we've discussed, also have competitors that are going after these patients as well. Is there any sort of a risk, I guess, in terms of patient enrollment for these MTAP-null tumors out there when you have all of these different clinical trials going after that same pool of patients?
I don't think so, because there's just such a large number of those patients.
Right. Right.
We're talking about 10%-15% of all solid tumors, so that's just a huge number of patients. If anything, you know, as a marker of that, the sites that are probably enrolling the best for us are places where we have overlap with Amgen and Mirati.
Okay
Because that engine of identifying the patients is there.
That's excellent. That's great to hear. In terms of those sites that you are enrolling, for these MTAP-null tumors, I'm wondering when it comes to the 462 trial, is that going to be enrolling at the same sites as 908, or Is there, like, how, what's the Venn diagram of overlap between those sites?
Yes, some of them are the same.
Some.
Some of them are different.
Okay.
If the TNG908 sites wanted TNG462 also, we open there.
Mm-hmm.
We also opened some sites that don't have TNG908, just to make sure, especially in the early part of the dose escalation.
Mm-hmm
That there's not, y ou know, it's tricky if you're the physician and you have a TNG908 slot.
Mm-hmm
Which is at a higher exposure level, right?
Sure.
I think we want to make sure that we can quickly enroll the dose escalation.
Great. Maybe in the time that we have remaining, we can move on to the rest of the pipeline beyond PRMT5. TNG260 is your CoREST complex inhibitor that you're developing.
Mm-hmm
For STK11 mutant tumors. You know, this is a novel mechanism of action that I don't think anyone else is really pursuing. Probably something that many investors are not familiar with. Maybe if you could just-
No one's really paying attention to it because of PRMT5, which is okay for us.
Sure. Would you like to highlight, I guess?
Yeah.
Explain the mechanism and what makes it an interesting target to pursue?
I think it's a really interesting riff on the concept of synthetic lethality, which is the idea was to say. Can we find tumor suppressor gene loss event that alters the ability of a cell to respond to checkpoint inhibitors or in a immune destruction?
Mm-hmm.
We've been able to do that with multiple examples beyond what, this one, which is STK11, and in fact, a group at Dana-Farber just published a similar finding with PTEN loss and PI3Kβ. Very identical in a different context to the same concept. yeah, what this is, and it's really unique, is a trial that selects patients for STK11 mutations. The patients get treated from the beginning with checkpoint inhibitor and TNG260, and what the mechanistic changes are occur, TNG260 drives the regulation of the gene expression that gives you the cytokines and the immune milieu that the tumor have to be able to be responsive to immune cell killing. It's a cell, it's a cancer autonomous target that alters the ability of that tumor to respond to the immune system, which is very unique.
Very great. This inhibition of CoREST, so CoREST is an HDAC complex, correct?
Mm-hmm.
Maybe can you describe what are the different so there are different subunits to the complex, right? You know, what makes CoREST inhibition unique, I guess, in the sense of, you know, we have pan-HDAC inhibitors out there, so, you know, why not pursue this sort of a biologic rationale with a pan-HDAC inhibitor, and why with CoREST?
Well, I think it has mostly to do in a way, if you think about sort of the same thing as what I call dirty kinase inhibitors, right?
Mm-hmm.
There's, I think there's 11 HDAC. Each HDAC has 3 or 4 different complexes that it's functional in. The actual hit in our screen with HDAC1, which has 3 different complexes, and CoREST is 1 of them.
Mm-hmm.
If you look at gene regulation for a pan-HDAC inhibitor like vorinostat, you actually alter the regulation of about a 3rd of the genome, and a bunch of, you know, apoptosis and other DNA damage repair kind of mechanisms that you might expect. They give you this broad-based toxicity that you get with the pan-HDACs. In the case of CoREST, you see very specific upregulation of things like the antigen presentation complex that you need to be able to respond to a checkpoint inhibitor. It's an issue of very strong selectivity. 260 is about 200-fold selective for the CoREST complex. Vorinostat hits all the complexes of 11 HDACs.
That selectivity for CoREST, you suspect is going to be sufficient to be able to avoid some of, like, the heme toxic, the pan-HDACs.
It's what creates the therapeutic index, which is sort of the basis for all of the drugs.
Right. Right.
Bring.
Kind of the point of, I guess, synthetic lethality, right?
Exactly.
Yeah, exactly. As we are moving into the clinic with this unique mechanism in the second half of this year, you know, the unique mechanism, this is not expected to have any sort of monotherapy activity on its own, right? It's really a matter of resensitizing the tumor to checkpoint inhibition, right? That renders kind of an interesting scheme for the way this trial was designed, right? Could you maybe talk about how the trial was designed, the considerations that the FDA wanted you to be taking into account as the trial was designed, and I guess, what the implications are for that in terms of the clinical trial?
Only patients with tumors that have functional STK11, loss of function STK11 mutations are eligible to be enrolled. All patients will have a 21-day run-in with the single agent just to assess the PK for the single agent. We actually wanted to start in combination right from the start.
Mm-hmm.
They wanted that 21-day run-in. And then at 21 days, we will add pembrolizumab to those patients and then assess for efficacy. This is not for patients that don't have STK11 mutations, have been on a checkpoint inhibitor, responded and failed. That's a whole different mechanism. Some of those patients have acquired STK11 mutations, which could be interesting for us down the road. This is for tumors that are primarily, have primary resistance to checkpoint inhibitors because they have an STK11 mutation.
Right. All of these patients are gonna be checkpoint inhibitor experienced in that sense.
They will be, for the most part, because that's standard of care for first-line lung.
Mm-hmm.
That's what's in the protocol. There are investigators who recognize that the data are pretty strong, that if you have an STK11 mutant tumor, your response rate is near 0 for a checkpoint inhibitor.
Mm-hmm.
Some of those patients may have gotten just chemotherapy without the checkpoint inhibitor. I think most of them will have gotten both.
Okay. That's an interesting point, I guess, but the checkpoint inhibitor-naive population, whether this. You know, it seems like there could be the potential for this to be a frontline opportunity for STK11 mutant patients.
Absolutely.
Are there any implications in terms of what that would mean in terms of how these patients would respond to TNG260 in combination with CPI? Is this kind of like a matter of, I guess it would automatically be, like, increasing the ORR for this population? Would it also increase, like, the duration of response for these patients in terms of thwarting eventual sensitization to checkpoint inhibitor?
It's all speculative.
Mm.
It's certainly possible. You get patients with better performance status. You get patients that haven't failed multiple previous lines of therapy, which we all know usually what translates into an increased response rate.
Right.
The mechanism is so novel.
Mm-hmm.
I think we'll just have to wait and see.
Yeah. Yeah, there's gonna be a lot of interesting learnings.
Yeah.
Okay.
The other interesting thing about this is that even though the FDA asked for a 30-day washout in any patients that gotten a previous checkpoint inhibitor, the half-life of those checkpoint inhibitors is, like, 6 months.
Right.
So realistically.
Mm
Most of them will have checkpoint inhibitor on board anyway.
Interesting. Good point.
Which we will measure, so we know what we're doing.
Okay, great. Maybe just quickly going back to the 21-day screening period on the monotherapy, is that something that you're going to need to maintain throughout the dose escalation trial, or is that something that could potentially be dropped?
Right now, it's throughout the dose escalation.
Okay. Okay. I guess as we think about this mechanism of action with checkpoint inhibitor resensitization, and we think about the potential for what that could mean for a safety profile, you're kind of reactivating the immune system in a sense. Is there a chance that this sort of, you know, as you're reactivating the immune system, I guess we should be expecting the potential for immune related adverse events to be occurring? Just wondering, you know, what are your expectations for that? Have you explored that possibility in preclinical models, and are there prophylaxis regimens that you could be doing to try to mitigate those?
Well, the really interesting thing about this is it shouldn't be any different than just the standard, tox profile for pembrolizumab, because the effect only occurs in the STK11 mutant cells.
Mm-hmm.
Which means it should be limited to the tumor.
Right.
The rest of the side effect profile should be unchanged, in terms of the interaction between pembro and a normal cell.
Okay. Great.
Yeah. Unlike the mechanism of action for pembro normally, which is to be a T cell activator.
Mm-hmm.
Right? That's not changed, but the ability to respond to it is limited, in this case, to the tumor.
Right. As you think about maybe more speculatively, like, future opportunities for TNG260, are there other immuno-oncology regimen, like, kind of combination regimens that you could imagine TNG260 being applicable in?
I think it's something that we will keep an eye on as we sort of see how that field evolves. Right now, I think single-agent checkpoint inhibitors are the best combination for making TNG260 effective. Thinking is the combination with something else, like a RAF inhibitor or an EGFR inhibitor.
Mm-hmm.
In those lung cancer patients that would have a second hit.
Mm-hmm.
That's something to think about.
Okay. Maybe in the time that we have remaining, we can move on to, your newest asset that you have disclosed, which is TNG348.
Mm-hmm.
Your USP1 inhibitor. And this is a program that's being developed in the context of, like, BRCA1 and 2 mutant tumors, correct? Can you talk about what is the unmet need in this population, considering, you know, we have PARP inhibitors that have been out there for, you know, years at this point. What is USP1 trying to address in this population here?
Well, I think you know this, right? As long as there are patients that are dying of those tumors.
Mm-hmm.
There's unmet medical need, and essentially, once you have metastatic disease, that's always the case. We think that with the preclinical data support, that adding either a USP1 inhibitor by itself in PARP-resistant patients is added potential benefit for patients, and in combination with PARP inhibitors, both in sensitive and resistant patients, preclinically markedly deepens responses. I think that what we're hoping to see is that both single agent and combination will expand the options for patients with BRCA1/2 mutant tumors and HRD-positive tumors.
Right. As you consider the potential to move into this space in both monotherapy and combination with PARP inhibitors, what are you looking for to maybe determine whether you want to pursue both those opportunities or one of the other? Is there a different, difference in opportunity between those two programs?
Like, I think, like always, it's two things. One, it'll be our own data.
Mm-hmm.
Which is the expansion cohorts. first of all, the trial is only being done in BRCA one or two mutant tumors or HRD-positive tumors.
Mm-hmm.
We're not doing an all-comer study. We'll have some read on that through dose escalation and then more from dose expansion. We'll just have to see what that looks like. We do have a competitor that is ahead of us there, that's KSQ. Obviously their data will be of interest to us as well.
Right. Got it. When you think about the potential to combine with a PARP, do you see any, like, meaningful differences between the PARPs out there in terms of, like, which one would be a better combination partner, maybe for USP1? If you were to pursue a combination, is there a potential maybe to establish a formal partnership with that pharma player that owns that PARP?
We spent a lot of time thinking and talking about this, and in the end, we decided to just go with olaparib as being the most widely used PARP right now. I think what we'd love to see is the ability to move in combination with one of the PARP ones that has similar efficacy and a lower toxicity profile. You know, again, we'll see how that evolves as we generate data.
Right. Maybe one last question on this program is just that, when you look at what the FDA and the ODAC has done in terms of, like, recent decisions to maybe narrow some PARP inhibitor labels, in terms of, like, removing the HRD population and just limiting it to BRCA1 and 2, how does that change your calculus in terms of what you see as the opportunity for USP1? Does this affect that ultimate opportunity for USP1, or do you think maybe HRD patients are still in play, potentially?
I mean, for me, because this is the core of how I think about everything, I actually, those decisions made complete sense to me. The sort of the trial that got the most attention with chemotherapy versus PARP in patients that have become resistant, ovarian cancer patients resistant to platinum. That is telling you they're not going to respond to PARP, and it's not very surprising that they do better on chemotherapy. I think sticking with the basics of the biology and the genetics is always going to make sense.
Great. Maybe last question, since we're running out of time here, but you've recently extended your cash runway to 2026 there. Just wondering what were the pushes and pulls into being able to extend that runway at this point, and whether there's even further optionality to extend that runway further, if need be?
Well, I think in terms of what made us decide to go through that exercise, I think it's clear, right? The market's been really crap.
Right.
For the last 2 years or something.
Right.
We just want to make sure that we can get through all four readouts, if we need to, without having to raise money in a situation that's really not favorable for us to do so. There's always an opportunity to extend further if needed. That would require probably some more drastic cuts or a BD deal or something like that. Sure, there's always the opportunity. We feel very fortunate to be in the cash position that we are in.
Absolutely.
Yeah.
Yeah. You have plenty of margin around those upcoming catalysts.
We do.
We're out of time, Barbara, thank you very much for being here.
Thank you very much.