Tango Therapeutics, Inc. 12th Annual Cantor Fitzgerald Global Healthcare Conference

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.

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 U.S., 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.

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.