Good to go? All right, well, welcome to this session. My name is Michael Schmidt, Senior Biotech Analyst with Guggenheim, and it's my great pleasure to welcome the Verastem team to this fireside chat. With us, we have Dan Paterson, President and CEO, as well as Jonathan Pachter, Chief Scientific Officer. Welcome. Thanks for joining us. Great. Thanks for having us. Before we jump into Q&A, Dan, maybe just if you could provide a quick introduction of the company and an overview of the pipeline, that'd be great. Sure, sure. So Verastem is targeting small molecules in the RAS pathway, which is the most commonly implicated pathway in cancers tend to be hard-to-treat cancers. We've both got a commercial product that, by all measures, in the first three quarters since launch, has been a successful launch, and then what we believe is a best-in-class G12D inhibitor in, you know, a very competitive and very tough space. But I think as we get into a little more detail, I think you'll find they tend to be really large molecules, and, you know, there's a lot of preclinical data, but a lot of them are falling out once they get in the clinic, so we'll go into that in more detail. But pretty exciting time for us. Great. Thank you. So maybe then starting out with your commercial business and the LGSOC launch of avutometinib and defactinib, which has been on the market now for about eight months, and maybe just remind us how the experience has been so far. Obviously, you reported you know, good early sales figures last year. Yeah, what are you seeing in the market right now in terms of uptake of the drug with the patients and prescribers? So we've been really pleased with what we've seen so far. We beat analyst consensus three quarters in a row. We get a lot of questions around, you know, was there any seasonality? We don't know yet. We don't have enough of a track record, but we had over a 50% increase Q2 to Q3 to Q4, and, you know, we think that's a good growth trajectory. It's, you know, for those who don't know much about LGSOC, it's a relatively rare form of ovarian cancer. It tends to strike younger women, tends to be pretty resistant to treatment. Standard of care is anywhere from 5%-16% response rate. We've seen over a 40% response rate. I think importantly for the launch and the launch dynamics, you know, patients on the trial stayed on for an average of 18 months, which, for a cancer drug, builds into more of an annuity than one traditionally sees in a cancer launch, so we're really pleased with what we're seeing so far. Can you just provide a bit more color on where you've seen prescriptions coming from today? It has been taken up by specialists predominantly or perhaps also in the community, and yeah, what are you seeing in terms of you know, reimbursement as well? Yeah. So we're seeing pretty broad adoption, both in what we call our top 100, which tends to be the biggest academic institutions and large practices that are responsible for probably half the population. The rest of the population is distributed out in the community, but the good news for us from a sales and marketing perspective, they tend to be in the large national practices that allow us to work through their infrastructure, and it's easy for us to identify within those groups. They tend to have a small number of gyn docs that drive what the treatment decisions are, and so both working with those gyn docs, who tend to be the key opinion leaders within their practices, and then, because we have agreements with their GPOs, we get invited into their meetings, and we're able to sit down with the entire group of physicians and talk to them, and between those two things, we're able to reach those without doing one-to-one detailing with every physician in the community. From a reimbursement perspective, I think we've been relatively pleased with what we've seen. You know, when you get a new-to-market product, you tend to get blocks and things, and they always require prior auth, but we've been seeing reimbursement both on-label, which is KRAS mutant, and then off-label, KRAS wild type, and then early on, we had some really off-label pancreatic lung brain. We're seeing a little less of that now, but that was never in our model, and they tend not to stay on therapy as long as the on-label patients, which again, you know, with 18+ months, you're building an annuity there, and we think over time, revenue should be more predictable and more steady because the percentage of patients that are continuing patients that drive that growth gets higher over time. Yeah, I know KRAS wild type is not on label, but you have some interesting data there as well. So can you comment about what you've seen so far in terms of wild type use, and is it a big proportion of sales as well? It's a little hard to tell because, you know, when we get the prior auth in, it either says KRAS mutant, KRAS wild type, or KRAS unspecified. And the percentage we're seeing as unspecified is quite a bit higher than we would have expected. We are seeing reimbursement for those and wild type, and so, you know, so far so good. When we first launched, we just had our specialty pharmacy channel. Our specialty pharmacies are really, really good at getting reimbursement. We've now opened the specialty distributors, which work with the GPOs and the large practices. But we're advising a lot of the practices to get their first prescription in through the specialty pharmacy, let our folks who've been really good at reimbursement do the hard work, and then flip the script over, so that they can do it through their own pharmacy. And so that seems to be working well, and, you know, we're just gonna continue, doing what we're doing. We're refining things. You know, when we had accelerated approval, we were really limited in what we could say promotionally. And now that we're past the initial period, we're launching a new campaign that's really focused on, this should be the preferred therapy after frontline, progression. And so that's a real push this year. Yeah. And how do you think about potential inclusion in NCCN guidelines? You know, how big of a lever could that be to continued growth, and where are you? Do you give a sense of when that might occur? You know, it's one of these things, you know, when we were going through our NDA, we had almost daily close dialogue with the FDA, and it was very transparent. We're not really allowed to ask. We're waiting. You know, we've been told it'll be early this year. You know, at this point, would it incrementally help? Absolutely, I think it would. But we're doing really well where we are right now, and I think the big push for us is getting the results out of our confirmatory trial. So we've completed accrual. Just to remind everyone, the confirmatory trial is a randomized trial against standard of care therapy, and it includes both wild type and mutant, and we'll have a readout from that, you know, kind of probably around mid-next year, maybe even a little earlier, and that would allow us to actively promote. But without the promotion, you know, we are allowed to hand out the publications we have, and we have two that include both wild type and mutant. And the original FRAME study, which is what we used to get Breakthrough Therapy Designation at the FDA, actually has a higher response rate in wild type than the RAMP study, and it had a population that was somewhat more similar to some of the other studies that were done, and we think that's a good comparator and makes us feel pretty good about the confirmatory study. Okay. Maybe then a good segue to talk about RAMP 301. I know there's been some, excuse me, some debate last year, about an upsizing that had happened, an incremental upsizing- Yeah ... that happened in the study. You know, I think you finished enrollment at this point. So remind us of the rationale for this increase in enrollment, and what does it tell us about how the study might be doing? Yeah, so when we actually started the study, as typically happens now because you have to get your confirmatory studies done early, we did not have the final results of RAMP 201. And if you look at the comparators that were used for accelerated approval, they tended to be slightly different populations, and they weren't prospectively broken out by wild type and mutant, and so there wasn't a great comparator. So we built into the study the ability, roughly halfway through, so half of the events, to be able to resize based on our actual results. Because accrual went faster than projected, we ended up doing the interim before we had 50% of the events, because what would have happened, we would have had to shut the trial down for probably three months, and if we had to increase, you would have lost your sites. They'd be on to something else. So we made the decision to do it early. Because we didn't have 50% of the events yet, in order to get back to the conditional power of 85%, we added roughly 30 patients. The good news is, the data monitoring board recommended we add patients to both wild type and mutant, which meant they were both in the zone of goodness, if you will. And, adding only 30 patients, it was a very small number. We felt it was the prudent thing to do. We did get some blowback from that. People were like, "You know, knee-jerk reaction, you upsize a trial, it's probably not good." It was planned, and instead of kind of oversizing the trial at the beginning, we decided we could use actual data to get in. So we're feeling really good about it. As you mentioned, we did complete accrual, and now we're just monitoring for events. And sometime, you know, again, mid or maybe a little earlier next year, we'll have the final PFS result, and it is powered. Primarily, primary endpoint is PFS. It's a hierarchical analysis, so we do mutant first, all patients, and then wild type, and we're feeling pretty good about it based on- Yeah ... where we are. Just remind us the total number of patients in the study. It was 270. Now it's up to 300. Right, so an incremental adjustment. We did just report we had done a bridging study in Japan, and, you know, it's a relatively small study, but we were really happy to see that the results really reconfirmed what we saw in our larger study, and now we're putting additional patients on Japan to get to 15% of the population. So, you know, we're likely to get conditional and approval based on the bridging study and then full approval in Japan based on the confirmatory study, but there should be no differences in reimbursement or anything- Right ... once we have the conditional approval. The Japanese bridging study is done in all comers or just KRAS mutant? It was all comers. Okay. And we actually saw a better response rate in wild-type, you know, again, as we saw in FRAME, and so, you know, feeling relatively optimistic about that. Yeah, interesting. So for the 301 study, so what is the bar for PFS here in all comers compared to standard of care? You know, it's all gonna depend on the population we get, because if you look at the phase 3s that we used as comparators, they had less prior lines of therapy. So we've never had a fair comparison where we have like patients, where we're able to stratify by number of lines of prior therapy, by KRAS status, and by geography. So it's the first kind of fair head-to-head, and so if you look at, again, depending on number of lines of prior therapy, PFS is probably in the 7-8-month range... standard of care, and, you know, we feel pretty good about being able to beat that bar. Okay. And then just remind us about the size of the overall opportunity that could be addressed with the RAMP 301 indication, you know, if approved? Yeah, so if we increase the indication to include wild type, which again, we're getting wild type now, but we expect greater penetration, frankly, on both wild type and mutant, when you have a randomized study that has both PFS and, and an OS endpoint. We believe there's somewhere between 6,000 and 10,000 patients in the U.S. You know, it, it's interesting to size this market because there's no specific ICD-10, and so you've got to approach it from a number of different ways. But I would say based on the quick accrual we saw in the studies, what we're seeing commercially so far, we're feeling pretty confident that the patients are out there. Yeah. Okay. Right, then I had a couple of questions on the RAMP 205 study. I know, so this is sort of moving the combination into pancreatic cancer, and just remind us where you are and what the learnings have been so far from the 205 study. Yeah, so there are a couple of really important learnings from RAMP 205 that I think people need to pay attention to when you're comparing the data to other studies. So we looked at 5 different cohorts where we altered the chemo, and these weren't random alterations. We, you know, we had a really great steering group and group of KOLs who said, "In the community, we tend to do this." You can give the full dose, you know, the chemo can be day 1, 8, and 15. A lot of times, they drop out day 8. They play with the chemo. We found in the 5 cohorts we studied, that giving the full dose of gemcitabine/nab-paclitaxel made a big difference in the response rate. So what we reported at ASCO last year was an 83% confirmed response rate, which is unprecedented in PDAC. What we did see is when you played with that chemo dose, you saw a pretty good decrement in response. And others who are going forward with phase 3 studies, combining with their agents in the RAS space, have had to lower the dose of chemo and frankly lower the dose of their agent. And so we think the important learnings were that our drug combines well with Gem/Abraxane. It had a great response rate. We have to confirm durability. And mid this year, when we put out our data set, it'll be roughly the same size of the data set that RevMed used for their phase 3. And so if we can maintain a response rate anywhere close, it's well above what others have reported. And again, we think it's good evidence that we're likely to have a successful Phase III, and we think strong evidence that we chose the right dose, and, you know, this is a really competitive space. For those less familiar with RAMP 205, it's avutometinib, defactinib, the same drugs that were approved for low-grade serous ovarian cancer in combination with gemcitabine/nab-paclitaxel, standard of care chemo and frontline metastatic pancreatic cancer. So 83% response rate is unprecedented. That was 12 patients. Now, we've upsized it to 29 patients. By the middle of this year, we'll report out on, with some reasonable durability for those 29 patients. Yeah, and you know, this is a competitive space. We would love to be first and best. If we have to choose between the two, we want to be best, and we're making sure that we're doing these trials the right way, we're choosing the right doses, and we're being really careful about where we're going. Mm-hmm. And just remind me, so the Gem/Abraxane dose, is that the full dose, or is it an alternative regimen? No, it was the full dose and the full schedule. Okay. And so now you have, you said 29 patients worth of data. Do you have sufficient follow-up to report on PFS as well, or is it mainly an OR focus at mid-year on this update? We'll give a sense of the durability because we'll be more than six months for all the patients. Okay. Then what are potential next development steps for this combination, the triplet of- Well, depending if we decide to take it forward, and there's really... You know, we're gonna have to look at the results of RAMP 205. We're gonna have to look at the evolving results in our G12D inhibitor, which is, again, as a single agent in the relapse setting, and second line has shown, you know, fifty-f- Plus, yeah ... 58% response rate, and again, really great data, and then look at the competitive set. You know, we'll have a high bar for taking it forward. We don't want to be spending money we don't need to spend, but we think it's incredibly competitive, and if the durability matches up with the response rate, I think we've got something really special here. Okay. That's a good segment to talk about, 73 75, your KRAS G12D inhibitor. And so maybe just stepping back, you know, a lot of the data has been obviously generated by your partner, GenFleet, in China. And just remind us of the learnings and what are you doing, where you are in the U.S. studies. Maybe just to set the context again, KRAS is the most prevalent oncogene in human cancer. KRAS G12D is the most prevalent KRAS mutation in human cancer. It's a really substantial proportion of pancreatic cancer, about 40% of pancreatic cancer patients, but also a high percentage of colorectal and lung cancer patients. So really large market cancers, a multibillion-dollar opportunity. Our partner, GenFleet, has Chinese rights. We have ex-China rights. They've enrolled more than 200 patients. Really exciting data. They've shown that in second-line pancreatic, as we just mentioned, a 58% response rate. In advanced metastatic lung cancer, a 69% response rate. These are unprecedented response rates, even looking at the other RAS inhibitors. I should highlight that the agent itself, VS-7375, is really special and well-differentiated based on three things. One is that it has a dual on/off profile, which turns out to be really important relative to, for example, the on-only inhibitors that others are, are developing. Also, excellent bioavailability. There are some that have already fallen out of the clinic for lack of, of sufficient bioavailability, some G12D inhibitors, notably BMS and, and AstraZeneca. And then thirdly, there's a really long residence time, a really long time occupying the target. So those three things really make it special as a well-differentiated agent. That really correlates well with the really strong clinical response rate. Yeah. Yeah. There has been some discussion of the tolerability profile last year, especially some of the GI AEs. There was also some ALT elevations, I think, in the lung cancer cohort. But yeah, any view on that, and, you know, how much of that could be mitigated potentially in the U.S.? Yeah, we feel very good about that. So I think our goals with the US trial are simply showing that we continue to see best-in-class efficacy, but also, doing better in terms of tolerability. We're certainly seeing that. I think we reported after completion of the first two dose escalation cohorts that we didn't see any nausea, vomiting, diarrhea greater than grade one. But I, I'd say that without going into a lot of detail, we're seeing across the board the tolerability looks much better than what's reported in the Chinese trial, which is really exciting for us. It might allow us to even push the dose higher, and that's something that we're looking at well. I mean, we're—GenFleet took 600 milligrams forward as a QD, and those really exciting data I mentioned were based on 600. Based on the excellent tolerability we're seeing, we're thinking we might be able to push to 900 milligrams QD, for example, to really maximize the efficacy even further. Yeah, and I think it, it's important to point out, because of the single-agent activity that we're seeing in the relapse setting, we think there's the potential for going for accelerated approval, which others haven't really been able to go in that direction. And then we also think it may translate into a single-agent frontline, and so it's likely that our phase 3's will do the combination with standard of care versus standard care and single agent. Being able to have a single-agent chemo-free regimen frontline for lung or pancreatic, I think, would be transformative. Yeah. Yeah, some people noted some higher rates of neutropenia and anemia as well. Is that something you think that is an artifact, perhaps, of the Asian data, or is there something- I think the Chinese data, there are issues in terms of what's treatment-related versus treatment emergent. I think recent prior therapies and con meds can affect that. So I'll just say, just generally, we've been pleased with what we're seeing with- Okay ... tolerability across the board in the U.S. trial. Then, yeah, remind us what you've said, where you are with your U.S. phase I study. I think you're as high as 900 mg QD now, but remind us how far into this you are. So we completed a single-agent dose escalation, 400, which was an active dose based on the China trial, 600 and 900 QD. No DLT is seen there. So we've taken 600 forward into single-agent dose expansions, but we're continuing to look at 900 again, given the good tolerability. So we're currently in single-agent expansions in second-line pancreatic, in advanced lung, and in actually, interestingly, in a tumor-agnostic- Mm-hmm ... cohort, which includes things like, biliary tract cancers. We think that accelerated approval might be an option in these- Yeah ... which is also quite exciting. That's single agent. As far as combinations, we are moving as quickly as we can with cetuximab combination, which will be our main approach to second- and third-line colorectal. And we also think that accelerated approval might be an option there as well. Okay. Yeah, maybe then could you expand a little bit about the longer-term development strategy? I'm just thinking, so obviously Revolution Medicines has phase 3 studies ongoing in first-line PDAC. Incyte has committed to a study as well with their molecule. So how do you fit into this space? You mentioned colorectal. Are you planning to go broad into multiple opportunities? Are you focusing on certain categories? How do you think about that? So we're, you know, as John mentioned, we're doing the cetuximab combo in second- and third-line CRC. We will go front line as both single agent and combination with standard of care chemo in both lung and PDAC. And so we're pursuing the broad opportunity. As I mentioned earlier, love to be first and best, but if I have to choose one, we wanna be best, and we're making sure we've got the right doses and everything as we go forward. Do you see opportunity to combine with perhaps the RAMP 205 combination? Is that something that makes sense, or is this too many drugs, together? I mean, it's so spectacular as a single agent, VS-7375. I think that might be overkill. I think with chemo, which should be sufficient. Yeah. And, I should highlight, I mean, if it's 58% or anything like that in second line, potential to be even better in front line, which is really best relative to anything out there. Yeah. So what have you said, how much data from the U.S. phase I study you'll be able to share this year? I think they'll be in order of what we know, based on maturation of the data. So... And obviously, it's dependent on both enrollment and maturation of the data. We'll know PK early on, we know safety and recommended Phase II doses early on. But then to get to a reasonable denominator and maturity of the data for efficacy will come behind, I think. Mm-hmm. So single agent and cetuximab combination are the most advanced among what we've discussed. Okay. Will this be a medical conference update or a corporate- Likely a company-sponsored event, so we can put them into context of what our development plans are as well. Okay, great. And then will we learn anything else from GenFleet's activities this year, and what are they doing beyond the phase I data that we've seen so far? They will be giving updates. I think they haven't said publicly specifics on those, and they're now in a Phase II trial, comparing to gemcitabine in, I think, second-line pancreatic. Okay. And then you mentioned, your own study, in combination with cetuximab. What other combinations are you evaluating in your own sponsored studies? Right. So cetuximab, which will be for colorectal. For pancreatic, it's combination with nab-paclitaxel, gemcitabine. Right. To get into front-line lung, it's chemo with pembrolizumab, which is standard of care for front-line lung. Okay, and are- Each of those would have potentially the single agent as an arm as well. Okay. Are you enrolling front-line patients in those combination expansion cohorts? Well, on the front line, right now for pancreatic, we're using second-line patients because we can do it more quickly. But ultimately, the goal is to be in front line in combination with gemcitabine. Okay, great. Okay, great. Well, thank you. So, again, looking forward to more information on 7375 around midyear, from the US phase I study, and then obviously on the RAMP 205 study as well, the 29 patients that you mentioned, and then the LGSOC launch on the next earnings call, presumably. A lot going on. Thank you so much. Really appreciate it. Thank you. Thank you.