Good morning and welcome, everyone. I'm Calef van Buichem. I'm an associate on the healthcare team at J.P. Morgan in New York. Today it's my pleasure to introduce Tango Therapeutics. With me on stage, we have Malte Peters, CEO, Barbara Weber, Executive Chairman and former CEO, and Adam Crystal, President of R&D. Barbara, I'll pass it over to you. Thank you.
Thank you very much, and thanks for the opportunity to be here today. As you just heard, until last Thursday, I was the CEO of Tango Therapeutics. And I just want to mention that we will be making forward-looking statements today, and this is our disclaimer. As of last Thursday, Malte Peters is our new CEO, and I just want to mention a few words about him, and then I'm going to hand it over to Malte for the presentation. Malte and I have been friends and colleagues for a long time, worked together at Novartis, and in 2018, I asked him to join the board of Tango Therapeutics. He's been a thought partner for me and part of building Tango since then.
And he has most recently served as the Chief R&D Officer at MorphoSys, where he did quite a lot of development work that's relevant to what Tango needs to do next. So, as I let the board know at the beginning of 2025 that I was looking to step down, as we got to the end of this year showed that both Metastat was really an important drug moving forward and the company would be well capitalized, it was clear after a significant search that Malte was the right person to take over for me. And I want to introduce Malte today, who will tell you more about where we are at Tango Therapeutics. Thank you.
Thank you, Barbara, for your very kind introduction. I'm very excited and honored to take over the leadership at Tango at this really exciting time. The company is moving very rapidly into its next phase of growth, and we are moving and developing and evolving the company from a phase of successful clinical validation into a phase of late-phase drug development, regulatory activities, and potential approvals, of course, with the attempt to have a commercial product. My single focus at Tango as CEO will be to translate the clinical achievements into significant value for patients and for shareholders. Now, let's look a little bit into the pipeline and into the science that had brought Tango to where it is today. MTAP deletion is one of the most common genetic alterations observed in patients with cancer.
60,000 patients are diagnosed each year in the United States of America with tumors related to MTAP deletions. You can see the frequencies displayed here. Non-small cell lung cancer, pancreatic cancer, and GBM are among the most frequently mutated tumors. Tango has developed a very exciting pipeline addressing these indications and designed to attack cancers with MTAP deletion. You see here our current pipeline, and we are very excited about where we are. TNG462 is in dose expansion studies. A combination study of TNG462 with Revolution Medicines' RAS inhibitors is in dose escalation. We have a molecule called TNG908, which is a blood-brain barrier penetrant molecule that's also in dose escalation. We have an HBS1L degrader molecule, which is ready to enter phase one clinical trials this year. Now, the year 2025 was a very successful year for Tango.
Tango has developed a clinically validated PRMT5 pipeline with a best-in-class potential, both from an efficacy perspective, but also from a safety and tolerability perspective. In addition, there is a unique opportunity of combining PRMT5 inhibitors from Tango's portfolio with RevMed RAS inhibitors. Strategically, we are focusing our work and development activities on indications with a high unmet medical need in difficult-to-treat cancers and potential fast-to-market opportunities. Moreover, the company is well capitalized with a cash runway into 2028. Now, what are we going to do in the year 2026 moving forward? We are going to deliver on four critical milestones. First of all, we are going to launch a second-line pivotal trial in pancreatic cancer. Secondly, we will complete our TNG462 RAS inhibitor combination studies to potentially support activities moving directly into front-line development activities in pancreatic cancer.
Thirdly, we will expand our knowledge base in patients with lung cancer and potentially other indications to investigate if ubim atastat has a role for treatment of patients with other indications. And lastly, we will evaluate TNG 456 efficacy in patients with glioblastoma. Now, we have a very attractive competitive angle or advantage that allows us to do our work. First of all, we have a pivotal trial protocol, which has received a lot of support from FDA. Secondly, we have a potentially best-in-class molecule based on MTEP selectivity and also potency. Thirdly, we have a potentially best-in-class safety profile, which is very important when you think about combining ubima tastat with other molecules, and I'll come back to that in a moment.
Lastly, we are the first company combining a PRMT5 inhibitor in a clinical trial with a RAS inhibitor, and in our case, we're using two Revolution Medicines RAS inhibitors. Now, diving a little bit deeper into the pipeline, I spoke already a bit about TNG462. TNG462 is targeting a patient population of approximately 60,000 patients each year. We have a potentially best-in-class molecule in our hands from a safety perspective, but also from an efficacy perspective. TNG908, our brain-penetrant PRMT5 inhibitor, remember, 45% of patients with glioblastoma have MTAP deletions, and we are currently in dose escalation with this molecule. Our HBS1L degrader, TNG961, has produced very exciting single-agent and TNG462 combination activities in multiple preclinical models, and this molecule is ready to start in clinical trials this year.
Now, let's take a short look at the data, at the clinical data situation, and we're very excited about what we're seeing. TNG462 demonstrates a clear monotherapy activity across multiple tumor histologies. You see here a waterfall plot displaying 94 patients with different tumor histologies, all patients at active doses with a follow-up of six months or longer. In this population, we are observing a response rate of 27%, a median progression-free survival of 6.4 months, and we've seen very good tolerability with no discontinuation at drug-related events at 250 milligram doses.
Now, if you think about this from a time-dependent endpoint perspective and look at Kaplan-Meier curves that show you median progression-free survival, you see a doubling of the median progression-free survival Kaplan-Meier curve of TNG462 or TNG462 compared to standard of care or historic treatment regimens that patients would get with pancreatic cancer when they're treated with chemotherapy regimens. We're seeing a response rate of 25%, 7.2 months of median progression-free survival, and it's interesting to note that the patient populations that we're displaying here for the standard of care are MTAP unselected patients, right? So there are wild-type patients and mutated patients, and because we know that MTAP mutation confers poor prognosis to treatment with chemotherapy, we think that the curves that you see here for the standard of care is actually an overestimate.
The true median progression-free survival for standard of care treatment with patients with MTAP deletion may actually be lower than what you see here. Based on this data, we have designed a pivotal trial in second-line pancreatic cancer. It's a very straightforward design, two-arm study with TNG462 and standard of care control. 300 patients will be enrolled in the study. We have discussed the design of this trial with FDA and got a lot of support regarding the trial design, the statistical analysis plan, the dose selection, and the overall study design. We believe that we are in a very good position for a very rapid enrollment given the high unmet medical need in this patient population and the sheer high number of patients that are unfortunately available with this disease.
Now, I want to show a couple of data points related to our combination activities of TNG462 and Revolution Medicines' RAS inhibitors. You see here preclinical data of an experiment where we treated a CDX model with suboptimal doses of TNG462 and zoldonrasib, and you see that there is almost no activity, but when you combine both components, there's a striking combinatorial activity of both compounds. Pancreatic cancer is a RAS-addicted cancer, and almost all MTAP-deleted pancreatic cancers have also a RAS mutation, and roughly 40% of MTAP-deleted pancreatic cancer is KRAS G12D mutated. Now, based on this information and based on this data, we have designed the study that you see on display here. It's a dose escalation. The study is currently in dose escalation, and we are combining TNG462 with daraxonrasib and with zoldonrasib. We are very happy with where we are in terms of enrollment.
30 patients have been dosed to date. Both combinations are very well tolerated, and we have achieved active exposures for all components in this study, and we have seen no unexpected adverse events. We are very pleased with the early signs of clinical activity. Now, if you think a little bit about this combination strategically, a couple of points are important. First of all, I said it already, more than 90% of patients with pancreatic cancers are RAS-driven, and RAS inhibitors are likely to transform the way of how pancreatic cancer patients will be treated in the future.
Now, looking at the combination that I mentioned before, combining a PRMT5 inhibitor, TNG462 with a RAS inhibitor, we can say that this could be a potential path to justify and support a front-line study with a combination of TNG462 and a RAS inhibitor, potentially giving access to a chemo-free treatment regimen for patients with pancreatic cancer early on. Now, we're very often asked when we speak to investors and analysts, "What activity are you actually looking for? What would you be excited about?" Our answer is that we always first look at the baseline, at the baseline of what the Revolution Medicines RAS inhibitors deliver. We know that second-line pancreatic cancer patients treated with these molecules have a response rate of roughly 30%. And of course, we are interested and excited to potentially significantly increase that response rate, hopefully with a clinically meaningful durability of response, and of course, we are interested and excited to potentially significantly increase that response rate, hopefully with a clinically meaningful durability of response.
Now, that's not all we are excited about. There is one more piece of data related to TNG462. We have observed a 49% response rate in a histology selective cohort that enrolls multiple different histologies. In this population, we have seen a median progression-free survival of 9.1 months, and we are excited about this data and are committed to enrolling more patients with all different histologies to find more data points that could guide our thinking in terms of what indications are also potentially benefiting from a treatment with a PRMT5 inhibitor, TNG462. Now, here again is a comparison of the PFS curve of what I just described to you in this histology-agnostic patient population with standard of care treatment, and you see that again, we are doubling the median progression-free survival compared to standard of care treatment.
Now, let's switch gears a little bit and speak about TNG908. That is a compound, and that's a PRMT5 inhibitor, which has very good blood-brain barrier penetration. The potency is very good. The MTAP selectivity is even better, and we have observed preclinically a very comfortable CNS exposure. Based on this data, we have designed a phase one-two clinical trial in patients with MTAP-deleted solid tumors, and in this study, we were clearly focused on patients with glioblastoma. Remember, 45% of patients with glioblastoma have an MTAP deletion. This study is ongoing, and we are very happy that just a couple of days ago, we put the first patients with glioblastoma on this study. Now, the last component of our pipeline, which I want to mention briefly, is TNG961, our HBS1L degrader.
FOCAD deletion and HBS1L are a synthetic lethal pair, and FOCAD deletion occurs in one-third of MTAP-deleted cancers. Basically, in patients or in tumors that are FOCAD-deleted, you need HBS1L for ribosome lifetime, and if you delete or abolish HBS1L, that process can no longer be done, and cells die. We have delivered or shown very strong xenograft activities across multiple lineages, and this program has now completed IND-enabling studies so that we are ready basically to start a clinical trial with TNG961. Now, in summary, in the year 2026, we will deliver a couple of very important clinical milestones. First of all, we will start a pivotal trial in second-line pancreatic cancer. Secondly, we will show data of our combination of TNG462 with Revolution Medicines' RAS inhibitors. Thirdly, we will expand our knowledge base of TNG462 clinical activity in lung cancer and in other cancers.
And lastly, we will show the activity of TNG 456 in patients with glioblastoma. All of this is possible because we are well capitalized, and we have a cash runway into 2028. So with this, I stop, and I guess there are maybe one or two questions that we hope we can answer. Thank you.
Great. Thank you very much, Malte. We'll open the floor for any questions that you might have. The mic is coming.
Thank you. Is it on? The initial hypothesis for the PARP inhibitors was based on a synthetic lethal approach with BRCA, but ultimately, it's been found that there's a utility and benefit for patients beyond BRCA mutations. Have you guys ever tested, or do you have any plans to test the PRMT5 inhibitors in non-MTAP-deleted tumors, say those with low levels of SDMA for non-MTAP-deleted reasons? Thank you.
Adam, you want to take that question?
Sure. It's an excellent question. Thank you. The mechanism of this molecule, as well as the other PRMT5 inhibitors, relies heavily on the accumulation of MTA to establish the therapeutic index. So that suggests that in the absence of MTA accumulation secondary to MTAP deletion, one would lose the therapeutic index the molecule is built to create. We also have looked extensively preclinically to determine whether or not baseline SDMA levels may predict responsiveness, whether it be in MTAP-deleted or MTAP wild-type cells, and in our hands, the answer to that question has been no.
Thank you. Anyone else? Otherwise, I have one. Malte, stepping into your new role as CEO, what are your key priorities?
Do I need to turn this on? Oh, it's on. So my key priority is really to help moving the company very rapidly into a phase of late-phase drug development and to make sure that we are well equipped to enter meaningful discussions with regulatory authorities so that we have a team in place who is experienced in clinical development, clinical operations, regulatory affairs, so basically executing very rapidly into a late development organization. Our goal is clearly to get this drug approved. I think I showed you that we have options of doing this. We can, of course, do this based on our pivotal trial as monotherapy, but we've shown you how excited we are about the combination potential. So all of a sudden, we have multiple ways of doing this. So that's the goal really of finding the best way of getting Whoopi Metastat to patients.
Great. Thank you very much. Anyone else in the audience? Otherwise, another question about the pivotal study. Can you narrow the guidance when you plan to start the study for that?
Yeah, so we hear this question a lot, and we have deliberately decided not to be more specific than what I said, so we will do it this year, and we are well on our way and on track of doing this, but we will not be providing more details of when this is going to happen.
Understood. Thank you. Oh, great.
Okay. I want to discuss more about the Revolution strategy because it is also exploring maybe the combination with PD-1, and it extremely increased the ORR. And so what about our strategy? Is that benefit more about the OS or also the ORR? Thank you.
I think in terms of the endpoint, you are referring to the endpoints of the clinical trial. Okay. The endpoints that are meaningful for regulators for granting approval are different, are differing based on from one indication to another. Of course, when you develop a drug in pancreatic cancer, you have to meet the standards of how the drug would get approved based on knowledge and based on discussions with FDA. You have to have an agreement between the sponsor, the company, and the regulatory agency that the endpoints that you are selecting are accepted by the agency to give you an approval. We have done this for our pivotal trial, and we are very confident that FDA will be supportive in case the data allows the agency to give a potential approval.
Thank you. Anyone else in the audience? Otherwise, I have one last question. You provided an enrollment update for the combination study, and you mentioned that you would disclose data for that later this year. What amount of data would you need to disclose that, and would this be in a medical meeting?
Yeah. So that's a very good question. So we are very happy where we are with the enrollment. At the moment, the excitement is really very high. With the company now moving into a more, I would say, late-phase thinking or time, we are committed to share data when we are 100% convinced that the data is robust and mature enough to make a statement regarding its implications for moving forward. So at this moment, I cannot say when this is going to be. We are not tied to any medical meeting. If it falls into place with a medical meeting, then of course, we take that opportunity. But if it's outside of a medical meeting's calendar, we will do it independent from a medical meeting.
Great. Thank you very much. If there are no more questions from the audience.
Any comments on the leadership transition? Barbara?
As I mentioned before, I'm the founding CEO of Tango. I started the company with Alexis Borisy at Third Rock in 2015. It became a private company in 2017, and I've been the CEO ever since. We're very proud of what we've accomplished over that period of time, going literally from a very high-technology genomic target discovery platform into being ready to start pivotal studies with our first compound. It was really a good time for a leadership transition. I think that both my skill set and sweet spot is around early development, and it was really time for somebody who had the focus on the next phase of what Tango needs to do, which is really to get this drug approved and move forward with the company in that direction.
It was with that in mind, as I mentioned, that we selected Malte for his experience, but there are a couple of other things that are really nice about that, which is that he's been very involved in the company, particularly in the last couple of months with the full development team, and it makes for a very smooth transition. He's familiar and comfortable with the board, with the executive team, and with the people who are executing on what we need to do. So I think it's, for me, it's a perfect time, and he's the right person.
Yeah. Maybe one addition from my end. I think Barbara said it extremely well that I was involved as a board member with a company's strategic direction since 2018. So what you see in terms of where the company is at the moment strategically, that was with my contribution in some shape or form. So I don't think you can expect a massive strategic change because I have already been involved in bringing the company to where it is today. So I just wanted to add that we are committed to execute what we have in front of us, and we have enough on our plate to be busy.
Great. Thank you for these closing remarks.