Yes, sir.
Yep.
Okay. Hi, everyone. My name is Maury Rayc roft, one of the Biotech Analysts at Jefferies. It's with great pleasure that I'd like to welcome Barbara Weber, the CEO of Tango Therapeutics. Thanks so much for joining us today, Barbara.
Thanks for having us.
We're going to do a fireside chat format. Maybe for those who are new to the story, if you can give a one-minute intro to Tango.
Tango is a company that was founded a number of years ago based on the concept of synthetic lethality. The whole idea was to identify and develop drugs against targets that were relevant to tumor suppressor genes. This would fill the space after many years of progress against activated oncogenes. Our lead program is vopimetostat, an MTAP-selective PRMT5 inhibitor.
Got it. Yeah, it's a great intro. For vopimetostat, it's being developed for MTAP-deleted PDAC and lung cancer. You just provided an update from that program in second-line PDAC. Can you provide an overview of the data you showed in that update?
Yes. The overall data, it's quite a large study now, even though it's a phase one, two study, because it includes so many different histologies. We provided the overall update on the whole patient population, which was an ORR of 27% across a number of difficult-to-treat cancers, including pancreatic and lung cancer, which compares very favorably, I think, to our competition at Bristol Myers Squibb. We provided some detail as well on the pancreatic cancer subset, which particularly was focused on second-line pancreatic cancer, as that's our plan for a first registration study with an ORR of 25% and a median PFS of 7.2 months. Also compares very favorably to current standard of care and supports our second-line study.
Got it. Yeah. For the 7.2 months PFS and response rate as well, there were two unconfirmed PRs, which are now confirmed post-cutoff. Is there anything more you could say on how the PFS curve is maturing over time and how are you setting expectations for a durability update in 2026?
In terms of the update, you know, I think that will occur at some point in 2026. We haven't given any more specific guidance as the data matures. It's one of the sort of more frustrating things about PRMT5 inhibitors is the data matures slowly, and it continues to mature. The more you wait, the better the data get. In terms of the PFS curve for the second-line pancreatic cancer, I mean, we'll just continue to follow. At the time that we showed the PFS curve, a lot of people asked about the patients that were censored. All those patients were still on the study. They were not censored for other reasons.
Got it. Okay. You mentioned the second-line PDAC pivotal study that you're planning. You're planning to meet with FDA to discuss this. You mentioned that it could be about 300 patients. Revolution Med is also enrolling a study. It's much larger with 460 patients. I think one of the key differences is how they're analyzing the primary endpoint versus how you guys plan to do it. Maybe just talk about that and talk about the confidence of getting stat/sig on PFS and OS with a smaller study versus RevMed.
Yeah. I can say, actually, we have already had the end-of-phase meeting with the FDA. That happened just recently. We do have buy-in on that design. The RevMed design, as you said, has two co-primary endpoints of PFS and OS. To do that, you just need the bigger sample size. We talked to them about using this hierarchical design that allows you to use fewer patients but still have PFS and OS readout. They were positive about that.
Got it. Okay. Anything more you can say on just the assumptions for PFS and OS for the study, for the treatment arm and the control arm? Yeah, you can talk about that.
In terms of the early PFS that we have, the median of 7.2 months, again, I think that compares very favorably to sort of the two- to three and a half-month PFS range. I think, you know, the way I think about it is you want to at least double the PFS in your study to ensure or have a high likelihood of success with the phase three study. There is another piece of information that started to emerge, however, about MTAP deletion as a negative prognostic marker. It's not the MTAP itself. It's the linked CDKN2A deletion. There have been a couple of studies, including a big retrospective study, that has shown that there's sort of a 30-ish, 30-40% difference in overall survival between MTAP wild type and MTAP-deleted pancreatic cancer patients, with the MTAP-deleted having the less favorable prognosis.
Where I'm going with that is to say that if our median PFS of 7.2 months compares favorably to the two and a half to 3.5 months in a mixed population of MTAP wild type and MTAP-deleted, that control curve may, in fact, move even further down and give us a bigger space.
Got it. Okay. Is that factoring into your phase three?
We did not power the study that way, but I think it's one way that it could read out and add to the probability of success.
Got it. What else are you saying about powering for the study?
Nothing.
Nothing. Okay. Fair enough. Anything else just based on the FDA meeting that you can comment on that came out of that?
I mean, Adam's here. He was the one who was in the meeting. I think one of the things that was positive about it was what they said was they agreed to the design, which allows you to read out PFS first and then OS, assuming the PFS is positive. They said you may need OS for approval, which I thought we could take at least as a slightly positive statement as opposed to you will need OS. Yeah, we'll see. It was a very positive meeting.
Got it. For OS, presumably, you'd still need a positive trend on that, or?
I would think so. The other thing about second-line pancreatic cancer is that PFS and OS are not very far apart. Assuming the PFS is positive, which we expect it would be, you know, the OS readout would not be very much longer.
Got it. Okay. Yeah, I guess maybe talk about getting the study started and how you think enrollment could look for the study, maybe bookend scenarios for that.
Yeah. In terms of getting the study started, we've been working on this at risk for quite a while. You know, we're trying to move that forward as quickly as we can. I think everybody knows that there's a bit of a window there coming from the presumed daraxonrasib approval in second-line pancreatic cancer, that the sooner we can get that study started and the more U.S. patients we can get enrolled before daraxonrasib approval occurs, the better. That's really what we're pushing hard against.
Got it. Okay. Obviously, a lot of interest in the combo studies that you're running as well. Maybe talk about just how those studies are going right now and just talk about what the combos are.
Yeah. The combination studies are vopimetostat plus the pan-RAS inhibitor from Revolution Medicines, daraxonrasib, and the G12D-specific RAS inhibitor zoldonrasib. There's a lot of interest from investigators, patients, investors, everybody, us. We're excited about that as well in that study. The enrollment has been going very quickly. It is a dose escalation study, though. We're limited in time for the DLT observation period and then a little bit more time to get the PK. Given that, I think the enrollment has been very fast.
Got it. You'll have a data update from this program next year?
Correct.
Is there anything more you could say on just how many patients you've enrolled so far in dose for cohorts one and two?
Yes. For cohort one, the two dose escalation cohorts are filled and finished. Both combinations were very well tolerated. We've almost completed the backfill for cohort one for both the daraxonrasib and the zoldonrasib combinations. We now have completed enrollment for the dose escalation for cohort two. We do not yet have the full observation period in PK yet. Also well tolerated. We will make a decision about next steps once those data are available in a few weeks.
Got it. Okay. You will have both cohorts data in a few weeks from that. Is there anything more you are saying about timing for the data update for next year then?
No. I mean, it just really depends on what the data look like, whether the ORR is convincingly different from single agent or whether we're going to need PFS as well. Our goal is to make sure that when we do disclose the data, it's clear that any effects that we would be able to show would be due to the combination and not solely due to the contribution of one at a single agent. That is the most important driver of when we disclose the data.
Right. Yeah, it makes sense. I guess how are you what do you want to see on response rate then to get that confidence?
If you think about second-line vopimetostat, let's say that ORR in second-line pancreatic cancer is 25%. Actually, the combo study is second, third-line plus, but let's be generous, say 20-25% for vopimetostat given that, and sort of the 30-35% for daraxonrasib. You want to see something that's convincingly better than either one of those single agents, right? I think the bar is going to be in the 45-50% if it's the ORR that is convincing.
Got it. That is for pancreatic?
Pancreatic. Now, there are lung cancer patients as well, particularly in the daraxonrasib combination. The vast majority of the patients on the study are pancreatic cancer.
Got it. Okay. For numbers of patients, you're not saying much more on exact numbers yet.
Exactly.
Can you just talk more about the doses? What are the active dose levels of vopi, daraxonrasib, and zoldonrasib that were evaluated in the first dose cohort? What about the second dose cohort as well?
Yeah. In the first cohort, what we've said is the exposures for, and notice I've said exposures not doses, but exposures are all in the active dose range. For vopimetostat, we've started at 200 mg a day. Our go-forward dose is 250, and we won't go above that with the second cohort, which is what we did. We dose escalated vopi from 200 to 250 in the second cohort.
Got it. Okay. When you do the data update, it's going to sound like it's going to be data-driven, but can you bookend how many patients could be in the update at this point?
I mean, at the small end would be the dose escalation and backfills for the dose cohort one for both combinations, which is in the 25-patient range, or it could be beyond that depending on how many dose cohorts we disclose.
Got it. Okay. Yeah, I guess what are your thoughts on a front-line PDAC or lung opportunity? Maybe.
That's the primary reason for us to be doing this combination study with the RAS inhibitors. I think that we feel vopimetostat as a single agent in second line is going to be a good alternative for patients to chemotherapy. Our path to first line would be best in our minds as the combination with the RAS inhibitor as opposed to combination with chemotherapy. This combo study is specifically, in our minds, being designed to enable a first-line study in pancreatic cancer.
Got it. Okay. When would you potentially be able to start that type of study?
We were just talking about that. You know, I think if everything went perfectly, one could imagine the possibility of starting a study like that by the end of next year. I think that would be a big push. Probably more likely into 2027. We have not given any specific guidance.
Got it. Okay. We'll have the second-line study started pretty soon next year. And then maybe front-line toward the end of next year.
Again, I think that's a best case scenario, not a guidance.
Okay. Makes sense. For the lung cancer population, not a lot of patients, but just how are you setting expectations for what data could look like from those patients and what you want to see there as well?
I mean, my expectation is that the combination in lung cancer will be equally as effective as it is in pancreatic cancer. And as you know, the lung cancer patients overall tend to respond a little bit better. So it could even be that the numbers are higher in the lung cancer patients. It's hard to say ahead of time. That could well be a strategy, right, because there is no first-line RAS approval right now in lung cancer. If the data are strong there and that looks like a path forward, it's something for us to think about for the RAS mutant first-line lung population.
Got it. Okay. You could make decisions on that next year as well. Okay. For the front-line pancreatic opportunity, it seems that the RevMed combo is probably the most obvious choice, but you're also evaluating vopimetostat in combo with Servier's MAT2A in biliary tract cancer and a couple other tumor types. Can you talk about your strategy with the PRMT5-MAT2A combination? Are you going to show any data from that next year?
To be clear, the MAT2A combination study is being run by Servier. That is a clinical collaboration supply agreement that we have with them. We are supplying them with vopimetostat, and they are running the study. The disclosures on that study would be totally up to them. You know, over the years of developing PRMT5 inhibitors, we thought a lot about MAT2A inhibitors and finally made the decision for Tango that our focus would be on developing this best single-agent PRMT5 inhibitor that we could, as opposed to trying to take two different approaches to inhibiting PRMT5 simultaneously. I think there are some advantages to that just in terms of complexity of development, if nothing else, because if you start with a PRMT5-MAT2A combination, then everything else you do is at least a triplet, right?
I think the other issue, and I'm very interested to see the data the first time somebody releases it, which we haven't ever seen yet, but you should theoretically get additive or synergistic toxicity at the same time you get additive or synergistic activity because you get the same effect in normal cells as you get in MTAP-deleted tumor cells. I think that's another complication with the combination. It's a question that needs to be answered, and we'll see what vopi looks like with the Servier combination. We'll hopefully eventually see what Ideaya has from their new combination, go from there.
Got it. Okay. Just back to maybe lung cancer, could you show DOR to compare and contrast versus Bristol Myers Squibb's data where they showed about 10.5 months for median DOR? And yeah.
We did not disclose the lung cancer data with this most recent update. It is just too immature. I think we enrolled quite a lot of patients. We enrolled 40 lung cancer patients this year, but they take a little bit longer to enroll than the pancreatic cancer patients. The follow-up is generally shorter. We have said that we will update on the lung cancer data next year.
Got it. Okay. Bristol Myers Squibb is running a front-line pivotal study with their PRMT5 drug plus pembro and chemo. B1 also said that they expect to run a pivotal with their brain-penetrant PRMT5 drug with the same combo. How much of the decision to pursue the front-line opportunity hinges on the RAS combo data? Are there other combos that you think could be competitive?
Yeah. Lung cancer is a complicated space for a couple different reasons, as you know, both competitively and also because for us, pancreatic cancer is a single group, right? MTAP-delete patients, all RAS mutant, go forward with the whole thing. In lung cancer, you have to really separate it into four different groups. You have the non-oncogene-driven population. That is the chemo pembro. To address that, we are working now on the tolerability studies of adding pembro to vopi, which looks good. We will add the chemo so we have the tolerability and the dose. I think for the RAS, the lung cancer patients are in the RAS combo study. For ALK, we are working on an IIT with an investigator, Dana-Farber, in a combination with lorlatinib, which we will not pay for. The last is EGFR. We will have to see how it goes.
I'm very anxious to see the AstraZeneca data. Because they have osimertinib and they have their own PRMT5, that may be more than we can feel competitive with.
Got it. Okay. Okay. Helpful. Maybe just back to the RevMed combos, I guess, how do you think about just the safety profile there? How's that shaping up? Any concerns or thoughts on just overlapping toxicity?
Yeah, zero concerns. I think it's shaping up really well. I would say if we start with vopimetostat and zoldonrasib, both of those molecules have extremely clean AE profiles and are very well tolerated in combination. There's essentially no overlapping toxicity. I think that that's very straightforward. In terms of daraxonrasib, there's a little bit of overlapping toxicity with anemia, but it's 10% or less for both compounds. Otherwise, there is non-overlapping toxicity. I would say that we also feel confident there's no potentiating effect of any toxicity of the combination. Both combinations are very well tolerated at this point at the dose levels we've treated.
Got it. Okay. Let's talk briefly about 456. It's your next-gen blood-brain penetrant PRMT5 MTA-cooperative inhibitor that you've got in phase one in glioblastoma. How many dose cohorts have you enrolled so far for this study?
We haven't given specific cohort numbers, but I will tell you we got stuck with a frustratingly slow dose escalation cohort that I'm still a little bit at a loss to explain why. In any case, it's enrolling well. We're getting close to the active dose levels. We have PK that's at least as good, if not better, than we predicted. What we don't have yet is clinical confirmation of the brain penetrance. Given the PK we have, if the brain penetrance is within the range we predicted, we should get exposures that would be active theoretically in glioblastoma, which is what we're looking for.
Got it. I guess what's the bar for success here on efficacy?
Glioblastoma, the bar is extremely low, but I think that what we'd be looking for, at least in the relapse refractory population, is a convincing improvement in median PFS in that patient population, which I think is somewhere in the three to four months range.
Part of the plan.
Maybe not even that good.
Yeah. Part of the plan here could be to combine with abemaciclib.
Right. We will do that as soon as we have evidence of activity with the monotherapy. We have an agreement with Lilly to supply the abemaciclib, and we'll start dosing that as soon as we have that step accomplished, activity as a single agent.
Got it. Okay. How do we think about the catalyst cadence then for 2026?
I think there's a lot. You know, we have the RAS combo coming. We have the updates on the lung cancer and more fulsome data set on the pancreatic and overall data set. We have the 456 glioblastoma data. There is a lot coming for next year.
For pancreatic data, could you potentially do for the combo studies, could you do two updates there, maybe like an early one and then?
Theoretically, could, right? Because it depends on what it is that's driving the data update. You know, it could be that if the ORR is strong, we would talk about that, and then we would have more durability data later on. Or we'll just have to see. It'll be a data-driven decision.
Got it. Any other perspective on what you have to do to get these phase three studies up and running just from an operational?
The combo or the mono?
For the mono and then, yeah.
The mono is very straightforward execution, right? It's literally just site activations and getting that going. For the combo, I think we need, well, we obviously need a dose for both combinations, and we need some discussion with the FDA on what that pivotal study would look like. You know, the simplest thing would be the combo versus gemcitabine. We don't know what else they might require us to do in a pivotal study.
Got it. Okay. We'll have those conversations next year as well, probably.
Right. Exactly.
Okay. This has been a great conversation. Maybe in closing, if you want to just highlight cash position and runway going forward.
Yes. We have audited numbers of $155 million, $153 million, Liz is looking at me, $153 million. We just raised $225 million, net proceeds of $212 million. Our cash runway is now into 2028, which includes all the enabling studies I've talked about, the combo we're doing, and the second-line pivotal, but does not include any additional pivotal studies.
Got it. Okay.
We have to talk to RevMed about that. They have money, right?
Yeah. Yeah. Okay. Thanks so much for joining us today, Barbara.
Thank you.