All right, so welcome to this fireside chat with Tango Therapeutics. My name is Michael Schmidt, senior biotech analyst with Guggenheim, and I'm very pleased to welcome Malte Peters, the new CEO of Tango Therapeutics. Malte, thanks for joining us. Welcome.
Thank you, Michael, and thanks for having us.
So as I just mentioned, you just recently took on the CEO role at Tango, but you've been on the board for several years. Maybe just remind us of your high-level vision for the company as you step into this new role, and what are some of the key priorities for you this year?
Yeah, thanks. I think at first, I want to highlight that I'm a board member since 2018 at Tango Therapeutics. I came on when the company was still a research based organization, and as a board member, of course, you witness, and to some extent, you participate in setting the strategy and the priority for the company. So I was part of what Barbara and the company has accomplished so far. And that is an important statement, always, from my end, to say that you should not expect a drastic strategic change after me taking over from Barbara.
Also, the second thing I would like to mention is that Barbara and myself, we know each other for 15 years. The board and Barbara and myself did a very good process in terms of finding a successor, and we all agreed at some point that I would be qualified to take Tango into the next era, I would say, of development. Tango is now a company that has achieved clinical proof of concept for vopimetostat, and it is going to be my task in collaboration with the team at Tango and the board, of course, to help evolve Tango into a phase of being a full-blown, late-phase drug development company with the attempt of achieving regulatory approval for vopimetostat.
And that's going to be a key priority for myself, for the entire team at Tango, to achieve regulatory approval for vopimetostat, either in monotherapy or potentially, hopefully, in combination with a RAS inhibitor. So that's what we are doing, and that's what the focus will be for the next foreseeable future at the company.
Yeah. Maybe elaborate a little bit more about how you prioritize registration opportunities for vopimetostat across MTAP-deleted cancer types?
Yeah. So we are very content and excited to have developed a pivotal trial protocol in second-line pancreatic cancer. We had very good interactions at the end of last year with FDA, where we had an opportunity to share the trial design, the statistical analysis plan, our thinking around dose selection and sample size calculation with the agency, and we have received a lot of support. So that's a very good signal for us, I would say, going forward, and we are on track in launching this study this year. At the same time, you know, and many other people know, that we have very recently started a combination trial of vopimetostat in combination with RevMed's RAS inhibitors, daraxonrasib and zoldonrasib.
We are, of course, in early days here, but based on the early encouraging signs of clinical activity, there could be, under certain circumstances, additional opportunities of drug development going forward in combination.
Yeah. Great. And so maybe just a few follow-up questions on your monotherapy study-
Sure
... first. I think in the past, you spoke about a 300 patient study, maybe just confirming that. Is that still the case?
That's still the case. We have publicly spoken that we have selected a hierarchical design, looking at PFS first and then overall survival. Based on the sheer number of patients that suffer from pancreatic cancer, we believe that we can enroll this study very rapidly. Based on the sample size, which you just mentioned, we think that's a reasonable task-
Yeah
... that's ahead of us.
Yeah, that already kinda partly answers my next question. Obviously, you know, we, we don't know yet, but it, it's possible or maybe unlikely that the treatment landscape changes in pancreatic cancer-
Yeah
... in the foreseeable future. And so I, I guess, what is your confidence level that you can still enroll a study in, in a second-line setting that is randomized against chemotherapy?
We are confident that that's a trial design that will fly, that will be supported and that will be executable. We, of course, know how the treatment paradigms and treatment field in pancreatic cancer may change in the next future. The study is a global trial. It will not only be conducted in the United States of America, but also in Europe and in Asia -Pacific. So while we expect to see potential drug approvals from Revolution Medicines in second-line pancreatic cancer this year in this country, we also recognize that the global nature of the study will enable us to, you know, to do well on the recruitment side.
Yeah. I think Tango last year reported some very promising monotherapy data in PDAC. I think it was 25% ORR, 7 months or so PFS. You planning to update the monotherapy data set at some point this year?
Yes, we do. We have not really decided when this will be. FDA typically encourage company against very frequent data cuts. So we are spreading out the data cuts a little bit. Maybe we will speak about the monotherapy data at the same time at which we will show the combination data. That's a possibility, but we have not really decided of when we will provide an update of the monotherapy data, but we will come out with an update later this year.
Yeah.
That's for sure.
Okay. And then, obviously, switching perhaps to the ongoing combinations with RevMed's RAS(ON) inhibitors, so the pan -RAS inhibitor, daraxonrasib, and then the 12D inhibitors, zoldonrasib. And, yeah, maybe just stepping back, remind us of what you're trying to achieve in this study. And I know you've made some comments earlier this year about, you know, how the study's been progressing. So can you just remind us of that?
Yeah. So the study is clearly a result of very encouraging and exciting preclinical data, where both companies collaborated and combined both drugs. So we have seen synergy preclinically when we combined RevMed's RAS inhibitors with vopimetostat. And this synergy was a clear, I would say, starting point for us to launch a clinical program. We have been very fast in implementing this. Remember, the first patient of that combination study was enrolled only in June of last year, so that's not too long ago. And since then, we have made enormous progress in terms of enrollment. There is a lot of excitement. We have more requests for patients coming on than we can accommodate at this moment.
And currently, we have 14 patients enrolled in the daraxonrasib arm, and 16 patients in the zoldonrasib arm. So we're, we are very happy with where we are, and we are also, of course, very, very pleased with the excitement we hear and see from our academic collaborators.
Yeah. So you mentioned this preclinical synergy that's been observed. Is that something that you expect to translate into the clinic? Generally, I think, when you combine two orthogonal mechanisms of action, most people think about additive activity, not necessarily synergistic activity. So how do you think that may translate into the clinic?
Yeah, so that's, that's obviously a very, interesting question, which we hear, often. There are clear examples in clinical development where, you have seen synergistic, activity, both in preclinical and also in clinical data. So sometimes you see a one-to-one, transformation or, translation, I should say, of the preclinical data into the, clinical setting. Is it going to happen in our case here? We don't know that yet because the data is, not mature enough to make that statement. But I would say, I would not rule out that we will see a significant upside potential in the combination compared to each component alone.
Right. And then, based on what criteria do you plan on selecting an RP2D? How do you approach that question in the study?
Yeah. So the only thing we are confident about is the benchmark we are looking at in terms of RAS inhibitor monotherapy data in second-line pancreatic cancer patients. It's around 29%-30%, depending on what compound you look at. And we expect and hope to be significantly better than that. So that's clearly an expectation we have. And again, right now, at this moment, it's premature to speculate about this because we haven't seen enough data points-
Yeah
... to make that call.
I think one unique aspect of PRMT5 inhibition is that I think the responses that have been seen as a monotherapy are very long duration.
Yeah.
In fact, I think it takes a long time for people to respond in the first place, on average. So to what degree does, you know, DOR or PFS factor into, you know, your decision-making for RP2D selection? And yeah, how do you think duration could evolve, just given... I think both therapies as monotherapies have reported very impressive PFS and PDAC specifically.
Yeah. So it's a very important point for us. The fact that you don't see a chemotherapy-like response with these treatments is extremely important. And if you recall how Revolution Medicines reports on their data, I think, if I'm not mistaken, they report data who have been on treatment for 14 weeks or longer. That also shows that even for the RAS inhibition, it's not an overnight response situation, so you need to allow patients a little bit of time to benefit from that treatment. And we want to provide that time to patients also in the combination setting.
So that's why it's also important for us to be patient at this time and not to jump the gun, but to wait until we are all convinced that the data set is mature enough to convince us internally and also the external world that we have a robust data set in hand.
... And then, I think you got it to presenting some data from the combination study this year.
Yeah.
How do you, you know, at a high level, how do you think about next steps, you know, in terms of exploration of expansion cohorts, and then even think about perhaps potential paths to registration?
Yeah. So that's a very good question, and, of course, our desire and plan is to not only show a data point in its isolation, but ideally, we want to show a data point connected to a plan. That's something we are working very hard on. I cannot really, at this moment, speculate what the plan is going to be. But of course, you mentioned it, there may be situations in which the data is so exciting that you could consider discussions with authorities, or other follow-on clinical experiments, trials. Again, at this moment, it's a bit early to say really where this will guide us, but our attempt is...
Our desire, our plan is to come out with the data connected to a robust clinical development plan.
Right. And then obviously, you're combining with a pan-RAS inhibitor and with a 12D-selective inhibitor.
Yes.
How do you think about the two options to combine, and how does that factor into your registration strategy?
So at this point, we have no reasons to assume that we will see a significant difference in efficacy between the two molecules, at least from what we hear and read about daraxonrasib and zoldonrasib. There is not a big difference in efficacy. I think in terms of development opportunities, we would need to see the data in its entirety to understand if, you know, one would go, you know, maybe a little bit into one indication and the other one in another indication, or how we would potentially differentiate our development strategies between these two compounds.
Yeah. I think there's a fair amount of interest by physicians in this space for chemotherapy-free regimen.
Yes.
Is that an opportunity that you think is feasible for frontline PDAC?
Absolutely. I think that's one of the most exciting topics at the moment in pancreatic cancer. If you think about pancreatic cancer as a disease, most patients are frail and advanced stage when they are diagnosed with this disease. So the opportunity of potentially developing a chemo-free regimen is super exciting, and I think patients would benefit enormously from chemo-free options, treatment options, if they were becoming reality.
Yeah. And then, I know, it sounds like the combination study is predominantly enrolling pancreatic cancer patients-
Yeah
... but I think it's also open for lung cancer patients. And so, yeah, how do you think about the lung cancer opportunity for vopimetostat, you know, either on its own or in combination with the RAS inhibitors?
Yeah, you're correct. We have made more progress in pancreatic cancer in the combination studies compared to lung cancer. I think it's mostly related to the fact that there are more pancreatic cancer patients available at this time. Lung cancer is also a bit more fractionated in terms of genetic alterations. So I think we see just a reflection of the natural history of pancreatic cancer and non-small cell lung cancer. I think Revolution Medicines is also excited about non-small cell lung cancer, and we look forward to seeing more data from the RAS inhibitor monotherapy trials. But we are making now some progress also in lung cancer, so we will see where the data will guide us going forward.
Yeah. Some of your competitors are pursuing a chemotherapy combination strategy-
Yeah
... in both PDAC and in lung. And so how do you think about, you know, that opportunity, perhaps in lung cancer more so? Is that something that you're planning to evaluate?
Yeah. So I think you mentioned—you referred to BMS development programs. BMS, of course, is a big company with, you know, many resources. They have decided to go in both indications in a chemo combination strategy. These are big trials, long trials with a long lifetime. We at Tango have chosen a different path for several reasons. Scientific reasons is one aspect, but also, of course, financial reasons. I'm excited to see what the outcome will be of the BMS trials, but at the same time, I'm more excited to wait for the outcome of our own studies.
I think, again, coming back to your chemo-free remark, if we could accomplish that in the next couple of years to provide patients in lung cancer and pancreatic cancer a chemo-free treatment option, I would love it.
Yeah. And, I know that, CNS metastases are more frequent in lung cancer than in, in PDAC. And obviously, you do have your, your CNS, active, molecule in the clinic as well, TNG456. And, you know, how do you think about, you know, vopimetostat, as an opportunity in lung cancer versus, 456, and, you know, how much value is there, in, in advancing, vopi versus, 456, and how do you think about that?
Yeah. So the 456 clinical trial has just started. It's in dose escalation, and we have just achieved dose levels at exposures that are clinically meaningful. And we have just enrolled the first couple of patients with GBM, glioblastoma, and also with non-small cell lung cancer. So I think we have promised and guided the market to release and to publish some data for 456 this year. And I think then it will be possible to see how vopimetostat and 456 may differentiate in non-small cell lung cancer, and if there's activity, hopefully, of 456 in glioblastoma. That would be, of course, a component, a data point that would guide us heavily towards that opportunity.
Right. And have you commented on how much or how rich will this data set be for 456 that you're planning to share later this year?
We haven't really said. I think it's a normal dose-escalation study. We have two arms in GBM and non-small cell lung cancer, and then we would have an opportunity to expand. But it will not be an enormous trial. So based on what I just said, you can expect to see, I would say, a fairly robust data set later this year.
Okay. And then how do you think about other opportunities? So Vopi has demonstrated very high, actually, single-agent activity in other tumor types-
Yeah
... that are MTAP deleted. I think it was a 49% ORR in Phase I . And so, yeah, where are you in the process of evaluating other opportunities?
Yeah. So, we have a sort of tumor-agnostic cohort in the ongoing study, where we accept patients with MTAP deletions, irrespective of their histology. And, we have seen a couple of quite interesting signals in that study. For example, three out of three patients with head and neck cancer responded in that study. So, that's a signal that we like, and we are going to dig a bit deeper and to enroll in order to enroll more patients with head and neck cancer, for example. We are in the process of enrolling more patients with other indications.
So I think long story short, is we want to expand our data set a bit in other indications so that we may understand potential signals in other indications that we could pursue going forward. Technically, there's always a possibility of thinking about a tumor-agnostic approval. It has been done before. But also to pursue individual indications, if you see a very strong signal in smaller individual indications. So we will generate more data that will help guide us in that respect.
Okay, and then maybe jumping around a little bit and going back to 456.
Mm-hmm.
I think in the past, you spoke about also looking into a combination with abemaciclib. Is that still something that you're planning to pursue? And if so, you know, what is the rationale for that combination?
Yeah. So that is part of the clinical trial. It's still our planning, and we have preclinical data suggesting that that is a, I would say, interesting combination. So we will pursue that path going forward.
Okay. And then maybe just in the last minute, touching on another pipeline program, TNG961, which targets HBS1L. And so, yeah, I mean, what makes that an interesting target, and what are your plans for that program?
So, that program is a FOCAD deletion program. There are co-deletions of FOCAD and MTAP. There is overlap in approximately 10%-12% of pancreatic cancer patients and something like 6%-8% of lung cancer patients. So it could be a very interesting clinical question to ask if the combination of these two compounds would be attractive for patients with both genetic alterations. So that's something we are thinking about. And that's something we are, you know, happy to have in our pipeline and in our portfolio.
Okay, great. So maybe then, just to summarize, so in terms of updates this year, obviously, there will be the pancreatic cancer update for the more mature monotherapy data, plus the Revolution Medicines combination data.
Yes.
The lung cancer update or the lung cancer monotherapy data-
Monotherapy data, yes.
And then TNG456 dose escalation data.
That's correct. We have a lot on our plate. We are working very hard, and I think this year is going to be an exciting year for Tango because we have a pretty exciting news flow.
Sounds good. Well, thank you, Malte. I really appreciate the time.
Thank you, Michael. Thank you for having us. Much appreciated.