I think we're getting started. Great. All right, everyone, welcome to this session of the Guggenheim Healthcare Conference, fireside chats. I'm very pleased. Oh, my name is Paul Jeng. I'm a member of the Biotech Research team at Guggenheim. And I'm very pleased to welcome our next presenting company, Verastem. And with us today is Dan Paterson, President and CEO of Verastem. Dan, welcome. Thanks. Great to be here. Great. So just to sort of kick it off, Verastem is in a pretty unique position right now with the potential upcoming launch of the first treatment for a rare cancer. But could you perhaps pull back and provide a brief overview of the company's lead assets and where the company is now in terms of its opportunity in low-grade serous ovarian cancer? Sure. Our focus for the last couple of years has been on the RAS pathway, and our lead program is the combination of avutometinib, which is a RAF/MEK clamp, kind of unique mechanism in that it actually blocks two nodes in the pathway, and then in combination with a FAK inhibitor, which we've been in the clinic for a while with the FAK inhibitor, and it's a challenge developing a drug that doesn't have a lot of single-agent activity, but I think what's emerging over the last couple of years, and there was some really interesting data at ASCO around another FAK inhibitor, is that FAK seems to be a master regulator of resistance, and so a lot of excitement about the program. It is really exciting for the team to be developing the first drug specifically for what's a relatively new indication. Historically, low-grade serous ovarian cancer was lumped in with the rest of ovarian cancer, and it was a number of years ago that the World Health Organization recognized that it was a very distinct and different disease. It's morphologically different. It behaves differently. It actually arises in a different area, the anatomy, and we were successful within the last year getting Orphan Drug Designation and getting the FDA to recognize it's a distinct and different disease, and the hallmarks of the disease are it tends to strike younger women. It's a slower-growing but very insidious disease, and because it's slower-growing, it's very non-responsive to chemo, so standard of care is either AIs or chemotherapy, and you see a 6% - 13% response rate. PFS is pretty short, and unlike more kind of benign, what are benign? You are benign? You never want to say it's a benign disease when someone has it. Unlike a CLL or an FL, it's very symptomatic. These women go through, they basically cycle through therapies through the entire length of the disease. There aren't a lot of good treatments. Being able to develop a new therapy that seems to be quite a bit more effective than what's available and more tolerable, which is important because they have to be on therapy for quite a long time, has been really rewarding for the team. We completed our rolling submission in October. Very excited and preparing to launch really mid next year. Great. Thanks for that sort of overview. So just on LGSOC, given that it's a relatively new indication, how well-defined is the sort of diagnostic journey and patient pool for LGSOC? And where do you see the key gaps in how patients are now treated? Yeah, it's a great question. If you step back for a second and look just generally at ovarian cancer, unfortunately, it is a disease with nonspecific symptoms. And the diagnostic journey for ovarian cancer itself is not really straightforward. You hear these awful stories of women being pushed from one doctor to another till they finally get diagnosed. And then for low-grade serous ovarian cancer, since there aren't specific therapies for that right now on the market, there isn't a lot of awareness around the difference in the disease. And what typically happens is, unfortunately, women go through this diagnostic journey. They get diagnosed with ovarian cancer. The pathologist may put on the pathology report that it's low-grade serous ovarian cancer because the criteria pathologically is very clear. But there may not be a lot of awareness of it because there isn't that different therapy, as I mentioned. Often, they'll go through one or two therapies. The therapies will fail the patient. Then they revisit. They say, oh, wait a minute. This isn't run-of-the-mill ovarian cancer. It's something very different. So it's not a straightforward journey. It's unfortunate. We've put a lot of effort over the last 18 months into raising awareness both with patients. We've had a patient website up for about 18 months. Then on the health care provider side, just to really raise awareness that it is a different disease. It deserves a different treatment. Then really preparing the market for when we do have that different treatment. OK. So your lead asset in the space is, as you mentioned, avutometinib plus defactinib. And that hits sort of the MEK pathway. And there have been some use of off-label MEK inhibitors based on randomized phase III studies in this setting. How broadly is that used currently in practice? Do they pose any meaningful competition? Or is it more sort of validation of the pathway here? Oh, good question. I would say trametinib, which was better than standard of care therapy from an efficacy perspective in a randomized phase III, has not been broadly adopted because of the toxicity. I think traditionally, MEK inhibitors have had a fair amount of toxicity. Best estimate we have from the market research we've done and analysis of claims data, its usage is probably in the single digits. It does get used more in some of the large academic medical centers that participated in the trials that you referenced. And so in our trial, about 20% of patients had had a prior MEK inhibitor. So we allowed that in our trial. But that was probably artificially high because it was the same centers that participated in those trials. Binimetinib also has some usage. But in the randomized phase III trial, it actually was inferior to standard of care. And so there hasn't been a lot of uptake. I think it did provide some early proof of concept because if you look at low-grade serous ovarian cancer, about a third of the patients at diagnosis have a KRAS mutation. But about 70% at diagnosis have some kind of alteration in the RAS pathway. And that's really the rationale for that mechanism in that disease. But it's really been the toxicity that's prevented the usage more broadly. In the trametinib phase III trial, about 36% of patients dropped out due to adverse events. And in a slower-growing tumor where you need to be on therapy for a long time, that's really been a barrier. If you look at patients being treated like with a traditional chemotherapy that's maybe four to six cycles, psychologically, it's easier to tolerate therapy when you know there's an end in sight. But when you have a therapy that has a high level of toxicity that you're basically treating till progression, it doesn't get used a lot. And so I think one of the advantages we've shown is really the tolerability of the regimen. So far in our trials, roughly 10% of patients discontinued due to adverse events. And fully half of those were an asymptomatic lab result, CPK elevation, which halfway through the trial, we amended the trial so they could stay on if that happened. And so the feedback we hear is it's quite tolerable relative to the other options. Great. So you mentioned a little bit about the pivotal study. So last month, you had mature data from the RAMP 201 study. Can you just sort of walk us through what you showed in that data set and how the sort of balance of safety and efficacy in the KRAS mutant patients compared to existing treatment options? Sure. So both the KRAS mutant and the wild type had results that were better than standard of care. It was quite a bit better in the KRAS mutant. And what's emerged in the last couple of years, and it's a little counterintuitive relative to what you see in other cancers, is having a KRAS mutation is actually a positive prognostic factor. So patients with wild type do worse than patients with a KRAS mutation. And that's not what you see in other cancers. And that's true across therapies, not just what we've seen with ours. Unfortunately, in the prior studies that were done, there's been some retrospective analysis based on KRAS status. But they weren't prospectively designed to stratify the patients by KRAS status. And so not everybody had a KRAS test. And so our confirmatory study that's underway right now, RAMP 301, will be the first large phase III study that prospectively stratifies patients by KRAS status. And will really, I think, show the drug in a good light when it's compared to standard of care and you're stratifying by KRAS status. Great. I want to touch on the phase III study. But before that, so just on the pivotal RAMP 201 study, it does seem like you saw some slightly different response rates based on patients who had gotten prior Bev or prior MEK versus those that did not. How do you expect your regimen might be sequenced in the real-world setting compared to those current options? And how could that potentially impact duration of therapy? No, that's actually a great point. Our study was the first one because if you go back and look at the two phase III studies that were done in low-grade serous ovarian cancer and even our FRAME study, which is the original study that was done that gave us Breakthrough Therapy Designation, there was very little MEK use in the FRAME study. There was actually no MEK allowed in the phase III studies. And even Bev, there was almost no prior Bev therapy in any of those prior studies where about 50% of our patients had Bev. What we're hearing from the key opinion leaders is for patients with a KRAS mutation, it's likely that our drug gets sequenced in second line and so to be used right after upfront surgery and adjuvant chemotherapy, which is usually cisplatin. Even in the KRAS wild type, it's likely to be used relatively early in the treatment landscape, and you may see frontline therapy, maybe an AI, and then usage of our drug, but if you compare it to the other options, it does appear to be more efficacious, more well-tolerated, and like any of the cancers, the earlier you treat, you tend to have a better outcome, so each progressive line of therapy, patients unfortunately do worse. Makes sense. OK, then looping back to that phase III study, the confirmatory study you mentioned, what gives you confidence that this study could succeed in the PFS population more broadly across KRAS mutant and wild type? What's the sort of bar here for all comers? I would say the bar for all comers, and again, this will be stratified by KRAS mutant and KRAS wild type, and so there is a key difference there. But the bar is probably around anywhere from 7 months-12 months best available therapy. Recognize that the data that we saw in our phase II study, patients had a median of three prior lines of therapy. The other studies had a median of two lines of prior therapy and then again did not have prior Bev usage or prior MEK usage. So we think when we're on an equal footing in a randomized study with stratification by KRAS, we should do quite well. And if you look even at the KRAS wild-type patients in our study, the clinical benefit rate, which is patients who had a CR or PR or stable disease of at least six months, that clinical benefit rate was 50%. And that's probably a decent proxy for PFS. And so again, we think when we have a randomized study, we're comparing patients that are similar across the treatment arms that will do quite well. Great. So then moving ahead to regulatory and commercialization. So at the end of October, you also completed your rolling NDA submission for RAMP201 and requested Priority Review. Can you sort of walk us through your timelines for acceptance of the NDA through potential approval? Yeah, we would expect that the NDA would be accepted by the end of the year, so two months after we complete our filing. If we get Priority Review, which we've requested and given our breakthrough therapy designation, we would hope we would get. That would be a six-month review cycle, which would give us approval mid next year. And so all of our commercialization efforts are geared towards being ready by mid next year. Great. So then on those efforts, where are you now with your sort of infrastructure launch? And now that the NDA has been submitted, how are you planning sales force buildouts, targeted outreach, et cetera? So we're well underway with the commercial planning. We have started work really 18 months ago with the unbranded campaigns around raising awareness of the disease, the fact that it's distinct and different from broad ovarian cancer. We've brought on the commercial leadership team: Chief Commercial Officer, Head of Sales, Head of Market Access, Head of Marketing. Those plans are underway. All of the normal things you do that have a longer timeline, mundane things like getting a drug wholesaler license in all of the states, getting our supply chain in place, our third-party logistics provider, our specialty distributor, specialty pharmacy hub, those are all in process and in place. And the last step along the way, we'll be bringing on a sales force. We'll bring them on a couple of months ahead of the projected launch so they have time to get up to speed to hit the ground running. But we're on track with all those preparations. Again, balancing spend versus being ready and being really prudent there. But we'll be ready to launch and hit the ground running. We've had medical science liaisons in the field for 18 months or more working with doing scientific exchange with the key opinion leaders, making sure there's awareness of the study results, gathering information from the physicians around what they feel is important and things we should highlight in the data. And then also outreach to patients. Our patient website, as I mentioned, has been up for over 18 months. It allows patients to sign up and opt in. And we've signed up over 2,500 patients already. In a relatively rare disease like this, the way we look at the market is there's really three legs to the stool. There's the large centers that see a lot of these patients. And that will really be the focus of the sales force. So we need a relatively small sales force. And they'll focus on those large centers, as will the MSLs and the market access folks as well. And that gets to about half the population. The other half is really distributed out in the community. And they're disproportionately at the very large practices like U.S. Oncology or Florida Cancer Specialists that are aligned with the GPOs. And you really get to those practices by working with them through the GPOs where they'll have in-services every month or so. And you go in and you educate on the drug, as well as they tend to practice using practice guidelines that are embedded in their electronic medical record. And so that's why NCCN guidelines are so important for us because that then translates into the guidelines that get into the electronic medical records. And then the third leg of the stool is the patients themselves. As in any rare disease, you want to have a good base of patients that you can reach out to. Great. So then maybe following up on the comment on the guidelines, so I think you've talked about an important aspect of the commercial launch is that you do expect that there could be usage for your regimen in all patients, not just the KRAS mutant patients. And that would be largely guideline-driven. So can you walk us through why you think that that may be the case and sort of timelines for guidelines? Sure. And to be very clear, we can't promote the drug off-label and would never do that. But there are many instances where the NCCN guidelines and other guidelines are broader than the label. And that's pretty common in oncology. About 30% of usage in oncology is off-label. And in LGSOC in particular, there is a specific guideline within NCCN for low-grade serous ovarian cancer, even though it's not included in the label specifically for any drug. And so that will be important. And that's really what guides a lot of treatment decisions right now. The way NCCN works is they need a peer-reviewed publication. And we intend to have our publication out before we get approval. And they'll typically have an ad hoc meeting when a new drug gets approved. And so hopefully in 7 days-10 days after approval, that would happen. We'd be on the guidelines relatively quickly. We hope that'll allow for a seamless launch and allow reimbursement should physicians choose to use it regardless of what the ultimate label looks like. Great. And then on the launch trajectory, given the absence of approved therapies in this setting, how should we think about those early months and quarters? Is there any potential for a bolus or pent-up patient demand? Yeah, I mean, with a disease like this that, again, a very insidious disease, yet I don't want to imply that slow growing means benign in any way. Patients will stay on therapy even if it's suboptimal if they don't have other choices. And we do believe, and we've seen this dynamic with our clinical trial when we open a new cohort, there'll be patients that are kind of waiting in the wings ready to go on. And there may be some of that that will go on. And based on the market research that we've done, we do believe that when the drug is available for the patients that, as we characterize the market, there's kind of the incident population, which are newly first relapsed. And then what we call the prevalent pool, which is that larger pool of patients that have been on multiple therapies and are really waiting for something else. Based on our market research, when the drug is available based on the profile we have, it should be the next therapy that they try. And so we intend to hit the ground running and think there's a huge need for this therapy. Great. And so then how large do you think the total market is? And how is that perhaps split between wild-type mutants and perhaps incidence and prevalence? Yeah, it's interesting. So in most cancers that are faster growing, when you look at market opportunity, you tend to look at the incidence because unfortunately, patients aren't available for therapy for that long. In lung cancer, unfortunately, you come along, you get an opportunity to go on the therapy. You're not going to be around for 10 years trying multiple therapies. In this disease, we do classify it as the incident population and the prevalent population, as I mentioned. And we believe that the total prevalent population is somewhere between 6,000 and 10,000 patients in the U.S. And that's split at diagnosis about a third of the patients are KRAS mutant and about two-thirds are wild type. Unfortunately, because of the prognostic implications of KRAS mutant versus wild type, a patient with a KRAS mutant cancer tends to live about 12 years median survival, where patients with wild type live about seven years, so over time, the pool really enriches for KRAS mutant, so we believe if you look at the prevalent population, about 40%-50% are probably KRAS mutant. And again, I think the importance there when you look at characterizing the market is if you look at our data, the patients with a KRAS mutation stay on therapy for quite a bit longer, about twice as long, and so from a market opportunity perspective, those patients will be on longer, but even the KRAS wild type are on therapy for 10-12 months, and so when you look at other cancer therapies, that's a pretty long time on therapy. We think this is a kind of market. We almost look at it like some of the rare diseases where there's almost an annuity that builds over time because patients come on quicker than they come off. You start to build up patients over time. That makes sense. I do want to spend our last few minutes talking a little bit about the early pipeline, perhaps actually starting with the GenFleet collaboration for the KRAS G12D inhibitor. This is rapidly becoming a very competitive space. How do you plan to differentiate the program? And what is your development strategy here? Yeah, so it's currently in phase I in China. And it's kind of all-comer patients with a KRAS G12D mutation. And so the plan is for the dose escalation to be done in China and then get our IND filed early next year and really pick up where they leave off. I think the recent RevMed data has kind of established a benchmark. I think what's unique about our KRAS G12D inhibitor, it is an oral inhibitor. In preclinical studies, we were able to show oral bioavailability across all three species, which has been a challenge. These are quite big molecules. I'd say the biggest differentiator for our molecule, it is a KRAS on-off inhibitor. And so if you look at the G12C inhibitors that were recently approved, they were KRAS off. The RevMed one is KRAS on. We believe that being an on-off, you should be able to both bind active G12D as well as the pool of inactive. It should result in more efficacy. We also believe that the targeted molecules like a KRAS G12D inhibitor instead of the KRAS pan inhibitors should allow you to hit the target harder potentially with less off-target effects. Great. OK, and then maybe with our last minute or so on the RAMP studies, the earlier ones, you recently announced you're prioritizing the RAMP 203 study with sotorasib over the combo with adagrasib. What drove that decision? And what can we expect from the update coming up later? Yeah, when we originally started both of those studies, it was really early on. Amgen had been approved. Mirati, the adagrasib wasn't approved yet. And there weren't many fast followers. You fast forward today, sotorasib and adagrasib are on the market. They're doing ok. But there's a whole second generation coming along. And we felt that that made our program really a proof of concept for the class as opposed to looking at something for a particular drug. And when we compared the two studies, we were much farther advanced in the Amgen study. We completed the G12C naive cohort. We're almost done with the G12C prior therapy cohort with the doublet. So that's avutometinib and sotorasib. We're farther behind on the Mirati one. And that study was also only patients who'd been on a G12C inhibitor prior. And so that and the fact that we were able to add defactinib onto the sotorasib study, and we didn't on the Mirati study, when we looked at it, we were answering all of the scientific questions with the Amgen collaboration. And so felt that as a proof of concept, if we focused our resources on that, we would answer all the questions we want to answer. And again, being prudent with cash, it turned out that it was almost redundant to have the second study if we're looking at really trying to develop proof of concept for the entire class, which is what we're doing. So excited about that study, hoping to have an update both on the doublet and then some early data on the triplet early next year. The rationale for adding the triplet was really the stunning data that we saw in our LGSOC study where adding a FAK inhibitor made a big difference, some preclinical data we reported at AACR, and then there was a Chinese company, InxMed, that reported at ASCO. They had a G12C inhibitor and a FAK inhibitor and had a 90% overall response rate in frontline non-small cell lung cancer, so you add all that up, and it got us very excited about the triplet. OK, super. Well, with that, I think we're up on our time. So, Dan, wanted to thank you for joining us. And thanks, everyone, for tuning in. Thank you.