Andrew Berens, Senior Research Analyst, Targeted Oncology at Leerink Partners. Very excited to have with us Tango Therapeutics, the CEO, Malte Peters. Thank you for joining us.
Thank you, Andy. Thanks, Leerink, for having us. We are excited to be here and share some updates on our end.
Great. Well, why don't we start with an overview of your company, for those in the audience who may not be familiar with it?
Yeah. Tango Therapeutics was founded in 2011. I've been on the board of Tango since 2018 and have been part of the amazing journey the company has been delivering so far. We are mainly focusing on a PRMT5 pathway, and we have several very exciting compounds in that area, and I'm happy to speak about that pathway in a little bit more detail. The company's based in Boston. We have roughly 160-170 employees, and we are now in a clinical proof of concept stage, having multiple clinical trials ongoing.
My goal as an incoming CEO, I still consider myself fairly new in my role as of January this year, is to transform the company into a late development, approval-ready, launch-ready, organization.
Great. Well, I guess the first question is, and we have Barbara in the audience. What is it? It sounds like you've been involved with the company for a number of years before assuming the CEO position.
Yeah.
What, what's gonna change?
Yeah. I like that question actually, and I always say, since I've been on the board for almost eight years, don't expect a major strategic shift with me coming in and Barbara stepping up to the executive chairman role. We are not going to see dramatic strategic changes. As I said in my opening remark, I'm ready to help the company to become a fully late development, approval-ready company with the clear goal of getting vopimetostat approved, and we have a couple of options of doing that. That's really the main goal for the organization for the next couple of years.
Okay. Why don't we start with an overview about the PRMT5 pathway? There were some products initially developed that ran into some toxicity issues. Your approach, along with a couple of other molecules, is different. What do we know about the PRMT5 pathway, and why is it such a desirable pathway to target?
Yeah. PRMT5 is an essential gene, and if it's inhibited, cells die. MTAP deletion are present in roughly 40% of patients with pancreatic cancer, 15% of patients with non-small cell lung cancer, and numerous other indications. Overall, roughly 60,000 patients annually in the United States alone could potentially benefit from a treatment with a PRMT5 inhibitor. You're correct that we had a steep learning curve in terms of developing several PRMT5 inhibitors. We believe the one we have now in front of us, vopimetostat, could potentially be first in class, maybe best in class in certain areas. We are very pleased with where we are, also from a I would say, competitive point of view.
Okay. Some of the challenges of the initial drugs were myelosuppression. How do the new compounds circumvent that?
We have with vopimetostat, a compound in our hands which behaves very well from a safety tolerability point of view. We see very little activity, we see very little safety and tolerability issues that would present a problem for treating physicians. We have a molecule here that is very well combinable with other agents, and we may come back to that point when we speak about our combination trials with RAS inhibitors. The fact that vopimetostat has such a benign safety and tolerability profile is extremely important when we think about how we wanna develop this drug and what potential combinations could arise in the natural history and in the clinical development future for this compound.
Okay. Why don't we start, I guess, with how you're positioning that drug now? What does the program look like?
Yeah. End of last year was a very important moment for Tango. We disclosed our monotherapy trial results for vopimetostat in patients with pancreatic cancer. We reported a 25% response rate in patients with second-line and higher pancreatic cancer, with a 7.2-month PFS, which is extremely exciting considering that patients with pancreatic cancer in second line have almost no therapeutic options available. That was very exciting. Excuse me. We have a very large, I would say, monotherapy program which focuses not only on pancreatic cancer but also on non-small cell lung cancer and potentially other indications. Later this year, we will share, excuse me.
We will share our data from patients with non-small cell lung cancer with the public, and we are picking up some important signals in patients with other indications such as head and neck cancer. I'm sorry. I have to drink a little bit.
Okay. In terms of the collaborations, you had one initially and you expanded. You were collaborating with RevMed.
Yeah.
What's the rationale for combining their drugs with your PRMT5 inhibitor 462?
Yeah. I think it goes back to a time when Barbara was on the board of RevMed and had very good scientific discussions with the RevMed team. Looking at the genetics and also at some very exciting preclinical data, the immediate impetus and idea was to combine vopimetostat with their RAS inhibitors. We have preclinical data generated between the two companies suggesting that there's truly a synergistic potential when you combine a RAS inhibitor with a PRMT5 inhibitor. In this case, RevMed's zoldonrasib and daraxonrasib with vopimetostat. These preclinical experiments were so powerful and so strong that we initiated a clinical trial in June of last year.
As of June last year, we have a study ongoing combining both Revolution Medicines RAS inhibitors with vopimetostat, and we are very happy with how the study does, how the enrollment goes, and we are also quite pleased already to see some exciting preliminary clinical activity. We are seeing very encouraging benign safety and tolerability signals.
Okay. You mentioned synergistic activities.
Yeah.
That would suggest that it's better than what we would expect, just 1 + 1 equaling 2. It could be 2.5, could be 3.
Yeah.
You guys have shown 26% in the second line, so it could be pretty impressive frontline data. Is that?
Yeah.
What you expect?
I think when you look at preclinical data, and you see strong signal that points in the direction of synergy, it's obviously always the question. Is this translatable into the clinical situation? We know where the benchmark is in terms of what RAS inhibitors can do alone in second-line pancreatic cancer. We understand and have digested the RevMed data quite well, so we're seeing a 29 or 30% response rate of RAS inhibition as monotherapy in second-line pancreatic cancer. We always said that combining a RAS inhibitor with a PRMT5 inhibitor, we want to see a significant step up compared to these numbers. I always say if we bring this number up to 35%, this would not be enough. This would not be clinically meaningful.
We are hoping, and of course also expecting to see a significant increase in efficacy.
Something with a 6 handle or greater on it.
Well, we have done a good job avoiding giving out a number because in my past, the moment you give out a number, you have shot yourself a little bit in the foot because when you come home with 1% lower than the number you have mentioned, it's not a good signal. We always try to avoid giving a number as an expectation. I would reiterate and say we want to see a significant increase in efficacy beyond what the RAS inhibitors can do as monotherapy and, of course, also beyond what vopimetos has shown as monotherapy in pancreatic cancer.
Is it another way of looking at it, though, how they compare to? You know, it would be chemo-free, so obviously get rid of the chemo.
Yeah.
I guess in terms of efficacy, you would want the efficacy to be probably as good as what they'll show with chemo plus the RAS inhibitor too.
That may be a good benchmark, but I like your keyword of chemo-free because if you think about the opportunities that arise from the data that we are generating at the moment and assuming that the data will be excellent or will be supportive, we could actually contemplate of moving this combination into frontline treatment in pancreatic cancer as a chemo-free option for patients. That's something that's very important for everyone at Tango. We believe in a chemo-free drug development objective, so I think it's extremely important to have that goal in front of us to see can we potentially develop a treatment for cancer patients that is devoid of chemotherapy.
Here we could actually have such a case in front of us, and we are hopeful that the data will allow us to move into that direction.
I mean, I would assume that the toxicity with chemo and the known toxicity with their RAS inhibitors, especially the multi-RAS would be mainly GI, and myelosuppression.
Yeah. I think GI and also for the RAS inhibitors, we know the toxicity quite well. It's mainly rash and GI toxicity.
Yep.
We are also quite content and happy that our PRMT5 inhibitor does not have a strong signal in these two toxicities, right? We don't see a lot of rash, and we don't see a lot of GI toxicity, which is something that is now paying off when we combine vopimetostat with the RAS inhibitors. We are not seeing a lot of overlapping toxicity, which is good for patients because the tolerability seems to be very, very attractive as a combination.
Okay. Certainly, I would think even in patients that are unable to take chemo, even if the data are good.
Yes
Similar, it would be an option.
That's absolutely correct. Yes.
Okay.
Yes.
Now, in terms of this update, how can you describe how many patients we're gonna see?
Yeah. We currently have 30 patients enrolled, 14 in the vopimetostat/daraxonrasib RAS(ON) arm, and 16 in the vopimetostat/zoldonrasib RAS(ON) arm. We continue to enroll. The study is open. I just want to make one comment about the drugs that we combine here because all of the players in that combination study are a bit special in the sense that they need some time to deliver their full efficacy potential. These are not chemotherapy drugs, so they need a little while to unveil its full potential.
If you think about how RevMed is reporting their data, they're showing patients that have been on the study for 14 weeks or longer, indicating that you need minimum 14 weeks for patients, for a patient on a RAS inhibitor to benefit from its full potential. We are seeing a little bit of a similar situation for vopimetostat in our monotherapy trials. We see a deepening of response over time. Both components are a little slow actors, but may be super effective. Our strategy is to wait as long as it takes to allow patients to benefit from the full potential of these two, of these two components.
Okay. The 30 patients that you mentioned will have been on the drugs for at least 3.5 months. Is that correct?
I think I don't think we have reported the current time on treatment. If you think about my initial comment that we started the study in June of last year, we are making good progress in having a very, I would say, significant and robust patient population that has two scans or more. That is on drug for a reasonable time that will allow us to assess the efficacy potential of that combination.
Okay.
The team currently at Tango is super busy, sort of, looking into the data and assessing when is the right moment to come out with the data in public and speak about it in public.
Okay. What about the difference, the strategy behind G12D versus and multi-RAS combination?
Yeah. Of course, for the multi-RAS inhibitor, daraxonrasib, from just a pure clinical development perspective, it's fairly easy because we can assume that essentially every patient with pancreatic cancer can be given that drug because potentially 100%, almost 100% of pancreatic cancer patients have some form of a RAS mutation. For G12D, the number is lower. It's in the range of 40%. In that arm, we have to test for both G12D mutation and for MTAP deletion. We currently have no reason to assume that there's going to be a significant difference in efficacy in the respective population. Of course, the proof is in the data, and we are going to see the data hopefully later this.
No, not hopefully, but for sure later this year. That will tell us a little bit if my assumption is correct.
Okay. Would there be a benefit in toxicity by going narrower?
Also, yeah, I think that's a question we hear a couple of times, but we have no reason to assume that these drugs would be different in terms of toxicity at the moment.
Okay.
Yeah.
If the efficacy is the same, the safety is the same, and you don't have to test for one mutation, it certainly seems like it might not be a reason to go with the selective agent.
I mean, yeah. I think as I said, right, from a pure clinical development perspective, it would be great if we were able to say that the daraxonrasib vopimetostat combination is a combination that we like, yeah, and that could go forward in our development and regulatory scenarios. We designed the study for a reason, because we didn't really know what the answer to your questions were. I think at this moment, it's just a bit early to speculate. We are sitting tight. We're excited about, you know, that the study is maturing, and, hopefully, you know, as soon as possible, we will share what the outcome is.
Okay. Well, certainly the doctors are very excited about options in pancreatic cancer, I mean.
Yeah, absolutely. Pancreatic cancer is a horrible disease, as we all know. Many patients at time of diagnosis are frail, elderly, and do not well on chemotherapy regimens. The chemotherapy in some cases is so difficult and so toxic for patients that sometimes you can't even give treatment to a patient. That's how bad it is. If you look at progression-free survival, overall survival data in patients in second-line pancreatic cancer, the numbers are measured sometimes in weeks, telling you how fast patients progress and unfortunately die. If we at Tango can contribute to changing the treatment landscape in this disease, we would be extremely happy.
Okay. Now, you had this relationship in place and the study with Revolution Medicines.
Yep
pan-RAS, multi-RAS, and you recently announced a decision to expand to one of the other ones.
Yeah.
They also similarly announced a decision to expand to one of the other PRMT5s. I guess, how different do you think the pan-RAS inhibitors are?
Yeah. Let me just make a general statement about the field at the moment and say that what we're seeing currently in the RAS and PRMT5 field is very exciting because there's so much movement, there's so much preliminary data coming out that I personally and we at Tango believe that this could totally change the treatment landscape in a couple of diseases, in pancreatic cancer for sure. We are seeing a very, I would say, fluctuating situation where all the companies that are in that space speak to each other. You saw that RevMed, for example, just two weeks ago announced a collaboration with BMS. We knew about their interaction and we announced last week a collaboration with Erasca.
We at Tango do what everybody else does. We speak to you know those companies who we believe have competitive molecules, and Erasca is an example of that. Now in terms of the RevMed collaboration as opposed to the Erasca collaboration, we still have a situation where our RevMed combination study is probably, I would say, give or take 12 months ahead of everyone else combining a PRMT5 inhibitor with a RAS inhibitor. That's a very big head start, I would say, that time advantage, I would say.
At the same time, we are happy to have started a collaboration with Erasca, because we think it's a competitive and interesting molecule. We are excited to entering this collaboration with Erasca, and we are working hard to get that study off the ground.
Okay. Do you think that there is a difference between the two?
At this point, I think it's really quite early to say that. We know a couple of publicly disclosed data points. We know the Erasca molecule is quite potent. It has activity at a tenth of the dose of the RevMed molecule. I think at this moment it's too early to say if that difference in potency will translate into efficacy. The molecules are quite similar structurally. I think at this moment we expect that they are going to be highly competitive. We will be excited to see what the clinical data will yield with both compounds. I think at this moment it's hard for me to speculate on, you know, if one is better than the other.
I think we are excited to have now the option of doing both clinical experiments.
Okay. Now, if the data are really strong and eventually end up in the front-line setting, does that eliminate a lot of the opportunity in the second line for a PRMT5 inhibitor? I mean, I would think patients are not gonna get sequential PRMT5 inhibition if they get it in the front line.
I think pancreatic cancer is going to evolve into a disease where patients have multiple treatment options over time. Today we don't fully understand what the treatment sequence will be. I think similar to other diseases like lymphoma or melanoma or renal cancer, pancreatic cancer will also hopefully become a disease where a patient will start on treatment A, and then in case of a progression, will move to treatment B and then to treatment C, potentially significantly prolonging that patient's life. I think we are in a good spot at the moment. We are super happy that we are in this phase of drug development with many other exciting compounds.
Hopefully, our work at Tango and at other companies will pay off for cancer patients.
For sure. It's always good to have multiple options to go.
Yeah
to the prom.
Absolutely. Yes.
Yeah. Let's talk about the other molecule you have. The next-
Yeah
The next PRMT5 inhibitor.
Yeah
That's brain penetrant. How is that being developed, and what is the importance of having the brain penetrance?
Yeah. We are very happy to have, first of all, with vopimetostat, a compound that is not blood-brain barrier penetrant, because in pancreatic cancer, we may not want to have a blood-brain barrier penetrant molecule as opposed to diseases like GBM or non-small cell lung cancer. TNG456 is a molecule that of course came out of our own laboratories and is on a potency level quite comparable to vopimetostat, and it has a blood-brain barrier penetrability. That molecule is in clinical trials already. We are approaching exposures that are clinically meaningful, and we have just a couple of weeks ago put the first patients on that study with glioblastoma. But we're also quite interested in the activity of that molecule in non-small cell lung cancer, for example.
As you know, non-small cell lung cancer is a disease in which patients often suffer from brain metastases. Maybe TNG456 could be a meaningful component for patients with non-small cell lung cancer.
Okay. In non-small cell lung cancer, obviously in the metastatic setting, it would be desirable to have brain penetrance for patients that have CNS activity at diagnosis. What about potentially like in an adjuvant setting where patients may not have, you know, to be more preemptive and prophylactically prevent?
Yeah. I think the whole sort of natural history question is a very interesting one. I think as soon as we understand what the activity of these molecules are in more advanced cancer patients, the question will be how can we move these therapeutic agents into earlier lines of treatment? Today I would say it's a tiny bit early to speculate, but as soon as we see clinical activity, we need to think about how soon can we actually start treatment and adjuvant or neoadjuvant treatment is certainly an example of that.
Right. Okay. Let me see if there's any questions for the room before we wrap up the session. Anybody have a question for Malte? All right. Well, congrats on the progress. Very exciting times.
Thank you, Andy, for having us. It was a pleasure and always happy to come back.
Great. Thank you.
Thank you very much. Thank you.