Okay. Good morning, everyone. My name is Eric Schmidt. I am one of the biotechnology analysts at Cantor. We want to welcome everyone to day one of our conference. We are thrilled and very privileged to have with us the Tango team today. We have Malte Peters, the company's CEO, Adam Crystal, the company's President, Head of R&D, and Matt Gall, the company's Chief Financial Officer, with us up on stage here. Wow, it has already been a terrific year for Tango. I think we are looking forward to much more to come in the remaining four months. Malte, why do not we just start off with a quick overview on how you see the state of the company?
Yeah. Thanks, Eric. First of all, thanks for having us. It is a great event. We had a great dinner yesterday also with a lot of investors present. Tango is at a very important and crucial moment in its history. We have started out, not even 10 years ago, as a discovery organization, utilizing our approach of synthetic lethality, of finding new drugs against cancer. We have now crystallized a very promising PRMT5 inhibitor as our lead compound and started publishing data about that compound two years ago. Earlier this year, we have shared data of vopimetostat, which is the name of our lead product, in combination with daraxonrasib and zoldonrasib, Revolution Medicines' RAS inhibitors, in patients with second and third-line pancreatic cancer.
At that time, we had published a 92% overall response rate in that population in a data set consisting of 12 patients, so essentially 11 out of 12 patients responded. That was an unprecedented data set, which generated a lot of excitement. The entire company, I think, is focused laser sharply on evolving that data set. We have ESMO coming up, where we plan to give an update. We are in full gear of getting vopimetostat approved. So the entire company is moving into the approval and also pre-commercial phase. We have recently hired a Chief Commercialization Officer, Fatma Ocak, who joined us from BioNTech. So, we are fully determined to get vopimetostat approved, and we are fully determined to start thinking about how we want to commercialize that drug. So that is, I would say, where our head is at the moment.
Very clear priorities. Maybe just a quick overview on vopimetostat, obviously a PRMT5 inhibitor. Why is this class of agents interesting? Within that class of agents, how is vopimetostat maybe differentiated? We know it is one of the most advanced PRMT5 inhibitors in development.
Yeah. PRMT5 is a target that is important in patients who have MTAP deletions. MTAP deletions are reported in approximately 30%-40% of patients with pancreatic cancer, 15% of patients with non-small cell lung cancer, 45% of patients with glioblastoma, and in many other cancers. Overall, in the United States of America, approximately 60,000 patients per year could benefit from treatments with PRMT5 inhibitors. We think we have a very high chance of developing a first-in-class and best-in-class product. Our PRMT5 inhibitor is very well tolerated. The tolerability and combinability with other products for PRMT5 inhibitor may be a very important component of this class of drugs, and we are extremely pleased about the very benign safety and tolerability profile of vopimetostat.
You are correct that other PRMT5 inhibitors are emerging, which gives us confidence that we're working on the right thing because it was not always the case that PRMT5 was considered a compound class of interest. Now I think the entire field and the entire market understands the importance of PRMT5 inhibition. We are very happy that we have more than one year headway, particularly considering our combination activities with respect to other companies who are following our lead and combine PRMT5 inhibitors with other compounds.
Okay. Let's go a little bit deeper into the tolerability aspect.
Yeah.
I think at dinner last night, some facets of that came out that I was unaware of. You actually think that potentially your PRMT5 inhibitor is not only combining well with other agents, but potentially improving the safety profile of a RAS inhibitor. How might that be?
Yeah. Adam, maybe you want to take that question? Adam is an expert in explaining that very well.
Sure.
This is a clinical observation that we made that has a preclinical mechanistic underpinning. What we observed, I would say to our surprise but great delight when we added vopimetostat to daraxonrasib, is that the rate and severity of daraxonrasib-mediated toxicities like rash, stomatitis, and even nausea, vomiting, diarrhea were lower in combination with PRMT5 than daraxonrasib single agent. To be clear, that's at the effectively same exact exposure of daraxonrasib, so it cannot be a PK-mediated effect. By way of example, daraxonrasib as single agent has approximately a high 80% rate of rash with a 14% of Grade 3 rash. What we observed in our data set, which we presented in June, was a rate of rash of about 50% with zero Grade 3 rash. So explanation one could fairly be small data set early in the study.
I do not believe that is what is causing it. I think that the ESMO data will be important to understand it more deeply, but the mechanistic rationale is really quite simple in the end. Duraxonrasib causes rash and other such toxicities by shutting down the MAP kinase pathway in normal tissue. It inhibits HRAS, for example, and phospho-ERK goes down. It is published in the literature and very clear that PRMT5 inhibition upregulates that pathway. So Duraxonrasib makes phospho-ERK go down in skin. We're positing that our molecule makes phospho-ERK go up in skin and abrogates that toxicity. There is an analogy, which is important. It's not exactly the same thing, but RAS inhibitors plus MEK inhibitors work exactly the same way. MEK inhibitors are intolerable for rash as single agent, but in combination with a RAF inhibitor, that toxicity is abrogated.
Very well explained. Very clear. Thank you. Let's get to ESMO, which is just a little over a month away. You referenced the Duraxonrasib data set that you showed us back in early June. What kind of scope of information can we expect at the conference?
Yeah. We haven't really shared publicly what the data set will consist of. We haven't actually seen the data ourselves, so we are in the middle of cutting the data and cleaning the data. We are also, of course, good partners with Revolution Medicines, so everything is a joint team effort between the two companies. But I think we can say one thing that in June, we had an efficacy data set of 12 patients, and we had a safety data set of 25 patients. I think the 25 patients that we published in the safety data set is certainly a good estimate of a data set that we will continue to give updates on.
That would seem to be the minimum data set. Will you continue to enroll patients and-
We continue to enroll patients. The study is open for enrollment. But I just wanted to give some kind of ballpark assumption of what you can assume. Then, of course, we will do our good diligence work, analyze the data, clean the data properly, and then we hopefully have a very robust data set that will excite everyone.
And similar to in the past, the strategy would be to show us patients that have been treated for four months or longer.
Yeah, that's still our mantra. We know that both compounds, actually, vopimetostat and daraxonrasib, take a little while to exhibit their full efficacy potential. And we want to give each patient the highest probability of showing whether or not he or she responds to the combination treatment. So, doing the data cut too early does not do justice to the treatment paradigm here and to the class of compounds. We need to allow a little bit of time for the patients to benefit from the treatment.
Will we see data in combination with zoldonrasib as well? And we did see a lower response rate with zoldonrasib in the initial data set. How might you explain that?
Yeah. Adam, you want to take that?
Sure. So in the initial data set we presented in June, the overall response rate in pancreatic cancer with daraxonrasib was 92%. With zoldonrasib, in more patients, it was 52%, which we would consider positive, but different and not as high as 92%. There are a lot of reasons that could be the case. I think I would certainly point to the fact that we don't yet know in full how daraxonrasib single agent compares to zoldonrasib single agent. As those data emerge and mature, we'll have more insight. But it's also the possibility that the mechanistic underpinnings are at play here. And by that, I mean daraxonrasib inhibits wild type RAS isoforms. Zoldonrasib does not.
It may be the case that because of the signaling involved here, when one inhibits either KRAS G12D specifically or PRMT5, the upregulation of the MAP kinase pathway that results makes daraxonrasib so important because it also inhibits those wild type RAS isoforms.
Okay. In terms of the focus being, again, on daraxonrasib for the ESMO update, what should we be looking for? What types of metrics do you hope to show us that might even further extend what we learned in June?
Yeah. We have not really given out a number as a guidance. I think when we published our data in June, we did very well that we did not sort of set any expectations in the market, so we are going to follow the same principle. But of course, we would be delighted to see some form of a confirmation of the direction the data was in June. Of course, we would be delighted also to have meaningful durability of responses. As you know, the efficacy measured by response rate is not the whole story. It is also important that patients benefit from the treatment for a clinically meaningful duration of time. We hope we will have meaningful data on both components. The last component, of course, is the safety and tolerability.
We want to provide updates on response rate, on duration of response, and on safety and tolerability.
Do you think this data update will be very clear in terms of outlining proof of concept for a pivotal study?
We hope so. That's clearly why we come to work every day. That's why we are super 100% motivated of doing our job. The data is the data, but we are very optimistic that the reception of the data will be very positive.
How are you thinking about the design of a pivotal study, cooperation from your partners at Revolution Medicines, et cetera?
Our strategy regarding our regulatory future has not changed. We have started speaking about this, I think, in February, March at some of the investor conferences. We have given some more color in June when we disclosed our data. It's still true today that our main focus is on developing the combination in frontline pancreatic cancer. That's really our number one priority. That's how we think we will provide most value to patients and also to shareholders. Secondly, we will certainly attempt to open a discussion with regulators around the globe about opportunities of an Accelerated Approval in second line. That's also something we spoke about quite frequently, and that's still true to this day. Clearly, we are in a partnership here with Revolution Medicines and with AstraZeneca, by the way, as well.
Since we have such a big headway consisting of our collaboration with Revolution Medicines, it is clearly a desire that we want to be aggressive here, and we will try to move forward together with Revolution Medicines in the frontline and second line direction, as I just mentioned.
Do you feel, Malte, that Revolution Medicines' priorities and interests are aligned with you in moving forward quickly as possible with a frontline combination study?
We have a very good and open relationship. We are speaking at all levels between the two companies. I do not want to preempt any discussion that are going on at the moment between the two companies. So far, we are communicating at all levels. I speak to Mark all the time. The teams are speaking to each other. I am hopeful that we will reach a good place here, and we will continue to enjoy the big time advantage we have as for the two companies.
In terms of the design itself, what might a control arm look like? Would you have to use a RAS inhibitor in that control arm, or can you do chemotherapy?
At this moment, I think we would be, design wise, fairly independent from the daraxonrasib label. Daraxonrasib is indicated for the treatment of second-line pancreatic cancer patients and also for occasional patients who are not eligible for the treatment of other frontline treatment regimens. We do not have a frontline label at the moment for daraxonrasib. We think because of that fact, we are currently fairly independent of the daraxonrasib label when it comes to design strategies for our frontline study. Of course, that could change in the future. FDA's guidelines are clear that as long as you do not have a full approval of a compound, FDA will probably not require inclusion of these therapies in your pivotal trials.
You also referenced your timeline advantage of 12+ months over the competition. How important or how is that important in a first-line development setting?
I think it is very important. I think the amount of data that we have generated so far is already extremely exciting and interesting and will be a significant component in our discussions with regulatory authorities. I think the advantage we have, the amount of data we have generated and we are continue to generate is going to be a very crucial component when we speak to authorities.
In either the first or second line setting, how do you demonstrate contribution of parts? How do you think about that?
Yeah. I think we spoke to that also a couple of times in the past. I think the contribution of components is going to be an interesting discussion with regulators because it has not been many times in the past that you are looking at an effect size of 90% for a combination therapy where the individual components have effect sizes of something around 30%. It will be an interesting discussion with FDA and other authorities of what they would like to see in terms of contribution of components. We have been clear that we are willing to listen to authorities, and we are willing to contemplate input from authorities regarding what kind of data set they would like to see. But so far, these discussions are in very early stages, so I think it's a bit premature to disclose any details here.
I think if you told us a year ago that we'd be talking about 90% response rates in second, third line plus pancreatic cancer, we would never, ever have possibly believed that.
We wouldn't have believed it ourselves, right? I think we would have never dared to assume that kind of effect size. Now we have a good problem to have. Now we have a very exciting situation, and I think the whole field is changing. It started all with the daraxonrasib approval just a couple of weeks ago, and it will evolve into a situation where authorities need to be very smart about the combination and the level of effect size that the combination can provide.
That was my question. How are regulators recognizing this even off-the-charts result relative to daraxonrasib's massive step function gain and in efficacy?
Yeah. I don't want to go into any sort of real-time feedback from authorities here, but I can say that the level of excitement that we see at regulatory agencies is very high. I think they are very cognizant about what's happening here. Of course, you have seen the speed at which daraxonrasib made it to the market. That already showed some extreme confidence at the level of agencies about this compound class, and we are picking up a similar momentum regarding the combinations.
Does that go for non-U.S. regulatory agencies too, or are you mostly focused on the FDA at this point?
We are focusing on a global regulatory strategy that involves U.S. FDA, that involves EMA, but that involves also Japanese regulatory authorities.
Do you think you'll be in position at the time of ESMO to disclose more about your regulatory strategy?
Potentially, yes. I think we always said we will speak more about the regulatory strategy before the end of the year. I think that commitment is still valid. I think stay tuned, and we will stick our head out as soon as we have the high enough confidence of sharing the strategy going forward.
Okay. We've got about nine minutes left, so let's turn our focus to lung cancer.
Yeah
which has probably gotten its due and deserved attention. We're going to get some updates toward the end of the year here as well. Maybe either of you want to just scope out what we'd hope to learn.
Sure. In October of last year, we presented single-agent data for vopimetostat, and in that dataset, we disclosed an overall response rate across indications of 27%, but we did not break out non-small cell lung data specifically. We will be doing that this year, and we will be doing that in the 41 patients that we had disclosed we had dosed last October. The reason that we've waited this time is because we want to share mature PFS curves. We believe that PFS in a single-agent, late-stage non-small cell lung cancer study is incredibly important, so that we, and I would say the rest of the community, can gauge how it compares to available second-line therapies like docetaxel.
One could look at those data as we generate them and come to the conclusion that there is a reason to conduct a high likelihood of success study versus docetaxel, or one could look at it and say, "We do not have the confidence that we will get there. This is not the best place to allocate our resources." What we are confident of is that regardless of a single-agent strategy, there are very important combinations which are developable with PRMT5 inhibitors. We believe based on the preclinical data, much of which we've shared and a lot of which has been published by other groups, that the observed synergy with RAS inhibitors is not a RAS synergy, it's a MAP kinase pathway synergy. As such, we believe that synergy will translate to other spaces with, for example, TKIs in the non-small cell lung cancer space.
With the data that we present from TNG462 in non-small cell lung cancer, as well as the data that we aim to present this year for our blood-brain barrier penetrant molecule, TNG456, in both GBM and other solid tumors, including non-small cell lung cancer, we will be able to articulate our development plans for non-small cell lung cancer going forward. We think, based on all of the data, that there is incredible opportunity for PRMT5 inhibitors outside of MTAP-deleted pancreatic cancer, and I think the most obvious first place is MTAP-deleted non-small cell lung cancer.
Okay, thank you. A lot to chew on there. Just first, in terms of the monotherapy experience, the 41 patients that you'll show and the potential comparison to docetaxel. PFS on docetaxel, what? three or four months? Is that median?
That's fair. I tend to use five. When I think of it, the more recent studies tend towards the higher end of that range, likely because standards of care in the first line have changed, as well as supportive care.
With MTAP deletion being a negative prognostic factor even for docetaxel treatment, right? We think that the four or five months is probably a bit of an overestimate, considering the fact that we would screen for MTAP deletion. Yeah, but that's-
Three, four, five months, somewhere in there.
I would say that three to five months is probably a good assumption. Just embarking on what Adam said, I think for lung cancer, we have a very luxurious situation at Tango because we have two compounds that are extremely exciting. When we speak to investigators, the fact that TNG456 crosses the blood-brain barrier is of very, very high relevance because 30% of patients have brain mets, that is a big headache and big problem for physicians treating patients with non-small cell lung cancer. Of course, it's devastating for the patient. So when we look at our portfolio, we're excited that we have two shots on goal here, but we need to do a good job in figuring out what's the best way forward, as Adam just alluded to.
What's the state of your experience now with TNG456 in lung or other tumor histologies?
We're increasingly confident that TNG456 is a very good molecule/drug. We are in the late stages of escalation in a study that was designed to both figure out the right dose at which to give the drug, as well as establish initial efficacy and safety. We have enrolled enough glioblastoma patients that we are confident we will be able to share the update this year on the efficacy of this molecule in relapsed refractory glioblastoma. But we've also enrolled a fair number of other solid tumors with a focus on non-small cell lung cancer, and we aim to share those data at the same time.
As the glioblastoma or as the vopimetostat data in lung or-
I would envision that we share all of the TNG456 data together. But there is an interplay, obviously. When we talk about what TNG462 looks like in lung, it will also be interesting to know what TNG456 looks like in lung.
Is there a path for TNG456 in glioblastoma, recognizing that that is a very difficult indication?
It is an extraordinarily difficult indication. I will start by saying that 45% of glioblastoma is MTAP deleted, so we are talking about 7,000 patients a year in the U.S. who die of glioblastoma with very poor treatment options. The way to develop drugs accepted by the GBM community, which look promising, is in the adjuvant setting. In short, because nothing works in relapsed refractory, and what is available in the adjuvant setting is meager in terms of activity, and it also carries toxicity. The active conversations we are having internally, as well as with the GBM KOL community, is the best way to do exactly that.
What kind of proof of concept can you create to justify a trial in the adjuvant setting from the metastatic indication?
I think that the challenging part about the adjuvant setting is not a regulatory one, right? That is a very low bar to design there. The challenge is that we are dependent on a time-dependent endpoint, and I think that is exactly the challenge that we are working through. Looking forward to sharing how it is we decide to do that.
The proof of concept in the metastatic setting that would give you the confidence to move forward in an adjuvant trial-
Exactly.
Would equate to what? What would that look like?
I think the evidence of activity is really as the bar gets that low. I think that the best available options, one could point to lomustine, which is effectively nitrogen mustard, which is extraordinarily toxic and has an overall response rate of 10%. So, if one has a molecule which is active, safe, getting into brain, it merits exploration in the adjuvant setting.
Okay, thank you. Coming back to lung cancer, realizing that we are going to see a lot more data that may inform your decision-making process, you do have maybe a more erstwhile competitor in lung with Bristol out there in front. How do you think about that competitor and various combination strategies that you might be actually ahead of Bristol in?
Yeah. We know the Bristol data very well. That is obviously a benchmark that is important for us. BMS has elected to go into large chemotherapy combination studies in lung cancer. We would probably follow a different path and would try to embark on combinations with other targeted agents. We are excited to going to be able to share a little bit more updates on the combination of vopimetostat and daraxonrasib in lung cancer. Our approach is a bit different, emphasizing the potential of vopimetostat with other components of inhibitors of the MAP kinase pathway.
Matt Gall, how are you going to pay for all this?
Well, the good news is we ended the second quarter with over $1 billion, and that funds everything needed to get approved in MTAP-deleted pancreatic cancer. That gets us through the phase III, all the overhead and infrastructure, commercial build-out. Another way to say it, if our ambitions were only MTAP del PDAC, I could say we may not have to go to the markets again. We are fully funded. If the lung, the GBM data, other opportunities meet our expectation, we have the luxury of time, we have the ability to tap other structures, we have the equity markets, of course. But that work will need to be funded, it is not contemplated under our current runway.
Okay, guys. Excellent. Thank you for the update. Really important time.
Yeah.
Important time for cancer patients as well as Tango. So, thank you. We will be listening closely at ESMO.
Thank you, Eric, for having us.
Thank you so much.
Thank you very much.