I'd like to welcome everybody back to our H.C. Wainwright's BioConnect conference. Again, my name is Andres Maldonado. I'm a Senior Biotech Analyst here at the firm, and I welcome you back to continue our afternoon session. Next up is Verastem Oncology, and I'm happy to welcome Dan Paterson, President and Chief Executive Officer, and we're also joined by Nate Sanburn, Chief Business Officer. Welcome to both of you, and glad to have you.
Great.
Happy to be here.
I guess a great place to start would be giving us a brief overview for those who may not be as familiar with Verastem. Can you walk through some of the company's current strategy for building around the RAS/MAPK cancers?
Sure. We've had a strategy for the last probably four years of targeting the RAS pathway. We've got two main programs, one that's commercial, which is AVMAPKI FAKZYNJA. We're actually told it was the worst brand name they'd ever heard. We tend to call it the CO-PACK, but it's two drugs that are approved for a relatively rare form of ovarian cancer called low-grade serous ovarian cancer. One of the things I'm quite proud of is we did a lot of work to actually work with the FDA to get it defined as a separate disease. When we first went down this path, the general consensus was, you know, it's just ovarian cancer. If you look about 10 years ago, the WHO defined it as a separate disease.
If you look at the standard of care for high-grade, which is a very different disease, and it's interesting, it's molecularly different, it arises in a different place, and it reacts very different to standard therapy that's given for high-grade. It's not BRCA related. It's actually very different. It's more MAPK mutations. We got it approved on a single arm study. It was an accelerated approval that we got two months early, two months before our PDUFA date last May. It was actually the first truly novel in oncology, so neither drug had been approved for anything before, and we had to show the sum of the parts and all of that.
We had a 44% response rate in KRAS mutant low-grade serous ovarian cancer, very long duration or response, in a setting where, you know, it's a disease that's relatively insensitive to chemotherapy. You know, in the relapse setting, you know, it's a 3%-6%, maybe up to 15% response rate for some of the agents and, you know, we're in at a 44% response rate. The launch has gone quite well. We did have a tough Q1. There was some seasonality.
You know, for those who don't follow it really closely, there were some changes to Medicare recently where, used to have the so-called donut hole where you'd get coverage for Medicare Part D, and then after you went through a certain amount, there's a period of time with no coverage, and then catastrophic coverage would kick in. With the new structure of Medicare at post-IRA, one of the good things about IRA is there's a limit in the out-of-pocket costs for patients. It gets capped, and then everything gets paid for. Unfortunately, when you think of seasonality, it all gets reset January 1. All of a sudden, all of our Medicare patients, were paying out of pocket January 1.
The phenomenon that we're all learning with oral drugs, and this is a relatively new thing, is a lot of them got their prescription late December, so they'd avoid that, and then once January hit, they may be delayed until they went through the out-of-pocket. We had a rough January. We recovered in February, March, so we were slightly up quarter-over-quarter, but it wasn't the quarter we wanted to deliver and, you know, we're back on track. We made some changes and expect, you know, Q2 through the rest of the year to go quite well. In addition to our commercial product, we do have a KRAS G12D inhibitor, so specific for the G12D isoform.
You know, it's a pretty crowded space if you look at it from a high level, but if you look at drugs actually in the clinic that have reported clinical data, it's a much smaller space. Obviously, Rev Med in the lead with their pan-RAS. The data that they just reported in PDAC was phenomenal, good for everybody, patients, for the industry, for anybody targeting RAS. It really was proof of concept. We believe, you know, based on the preclinical profile and the data that's been developed by our partner in China, they've treated about 300 patients, that we have a best-in-class G12D inhibitor. It is an on/off inhibitor. It has a really long residence time. The preclinical data is really phenomenal. The data we've seen out of China is phenomenal.
We're seeing in second line PDAC response rates of, you know, 58%, in lung cancer, 69%. You know, we're replicating that in the U.S. and looking forward to more data coming out this year. Really when you look at, you know, kind of where we are as a company, the Q1 earnings was almost a clearing event. You know, we didn't have a great quarter. We are back on track now. We've reset the timing on when we'll have some of the data, 'cause one of the things that we found is even though 600 mg was declared the phase II dose in China, we're seeing much better tolerability in the U.S., and we've cleared both 600 and 900, and our likely phase II dose will be 900 mg.
We're wrapping up our phase I study. We'll be starting phase IIs in both PDAC, lung, and CRC in the June timeframe, hopefully accrue most of that this year with phase IIIs to start next year. We do believe there's a path to accelerated approval in each of those diseases based on the very high response rates we've seen. We will be starting the phase IIIs that'll either be confirmatory studies or if for some reason we're not able to get accelerated approval because, frankly, with all the changes at the FDA and the leadership vacuum, anyone who says they can predict what's gonna happen at the FDA is kinda making stuff up at this point, 'cause we really don't know.
I've been dealing with the FDA for 30-plus years, and I've never felt as much uncertainty around what's gonna happen, 'cause you don't know who's gonna come in and what's gonna happen. It's gonna be an interesting rest of the year for us, but we've got a lot of nice catalysts coming up and pretty excited about where we are.
Great. Appreciate that incredibly comprehensive and important overview there. I guess starting with a couple of granular questions on the CO-PACK. You know, it's been on the market for roughly about a year. Can you talk about what you've learned about the real-world kind of patient journey and how that has influenced kind of some of your expectations for commercialization on the back half of the year and maybe starting to look into 2027?
Yeah. You know, as I said, the first three quarters actually went quite well. Things we've learned, there's definitely patients out there. The interesting thing, it's a bit of a game of numbers, where if you think of our target patient, we want patients coming off frontline therapy. Patients can stay on frontline therapy for a couple of years. Early in the launch, you always get sicker patients. Time was not our friend here with being on the market a year. A lot of the patients who are frontline haven't had the chance to get onto our drug yet. You know, as we look at the levers we have to pull for 2026, it's obviously education because there weren't, there wasn't infrastructure built up around this.
Even though it's a different disease and the patients now can get a different treatment, because the treatments were always the same as high-grade before, there may be buried in somebody's chart a path report that says they have low-grade serous ovarian cancer and the diagnostic criteria is very clear, but they haven't looked at it in a couple of years. We have to remind them that if the patient's relapsing, if the course of disease looks slightly different than what they expect for high-grade, go back and is this a low-grade patient? We're doing a lot of effort, not only with education, but working with the practices to identify the patients.
You know, we had always said, given the ultra-long course of therapy patients got on the clinical trial, they stay on over a year, that we needed to put as much effort into keeping the patients on as finding them. You know, I think we were spending too much time finding patients and not enough keeping on. We've kinda recalibrated how both our sales force, our MSLs, and our market access folks are spending their time. The focus is getting patients on, getting the right patient early enough in their course of therapy, then we've got a lot of mechanisms in place to help educate to keep the patients on, and those are really the efforts that are underway now.
Great. along those same lines, I guess, how should we be thinking about, you know, the balance in our projections of new patient starts, duration of therapy, refills, and continuations and discontinuations as the most important drivers, you know, when we start to, you know, project further out now, further throughout the year?
Well, we have to continue to grow the new patients coming on, and that's both getting repeat patients from the physicians who are prescribed. That's really important 'cause they tend to put the sicker patients on first till they get experience, and we really have to mind that. We have to expand the prescriber base and then really make sure that we're keeping the patients on and starting to replicate what we saw in the trial. Even though in the trial we had patients who had from 1- 10 prior therapies, the thing you can do in a trial is you can say they have to have ECOG performance status of zero or one. That's not real world. You're gonna get sicker patients early on. We have had data come out at the Society of Gynecologic Oncology in April.
We had long-term follow-up from our pivotal study that showed really great duration of therapy, especially if you get the patients early on. Using that publication as a way to educate. We did also have data that we presented that showed dose intensity matters. I think one of the learnings for us is even though our protocol was very clear and what we did in the clinical trial was clear, which is if you have a side effect, you delay the dose and you restart at full dose. That's not how a lot of oncologists approach chemotherapy, which they're used to giving. They drop the dose first. There's a lot of education we've had to do with the oncologists to make sure that they don't do a delay and then lower the dose.
It's really delay, come back with the full dose and make sure that they're comfortable that the other thing with this drug is we don't have cumulative toxicity. If you start getting toxicity early on with chemotherapy, you think it's gonna get worse, where we tend to have some transient side effects that will get better over time and just making sure that we're into the office enough educating the physicians and the nurses and the pharmacists on what to expect and how to really make sure they're staying on therapy to get the benefit, which can take two to three or four months.
You know, when we look at the seasonality previously pointed out, you know, the launch did, however, have strong uptake across both gynecologic oncologists and med oncs. I guess, where do you still see the largest opportunity to expand that prescriber depth, especially, you know, through the lens of either the academic and the community settings?
Yeah, I mean, it's, you know, one of if you go where the patients are, it's the gyne oncs in the academic setting that'll have a big group of patients. Those were obviously the physicians who participated in the clinical trials, and the focus there is making sure that they continue to prescribe it for more of their patients. Out in the community and the med oncs, they may see less patients each, but there's a lot of patients out there. Making sure whether it's digital, we're doing a lot of peer-to-peer programming where we can get, you know, one expert out talking to 30 docs at the same time. You know, I had said prior to the launch, and we're still really doubling down on this, if you look in the community, a lot of the community docs belong to large organizations.
It's either a large practice, a large GPO. They don't want you calling on their doctors. They want them treating patients. When we contract with a GPO or a large practice, part of that contracting is they invite us into their meetings. It's a one-to-many selling opportunity instead of trying to get to every single doc that may see two patients a year. The other thing, you know, we had a good sense of this based on the work we did pre-launch, but we've even learned more over the last year. Each of these large organizations will have three, four or five go-to gyne oncs that when you get one of these rare patients, you pick up the phone and call them and say, "What do we do?" We're making sure we've gotten to those folks.
We've equipped them with the information so they can educate their peers.
Great. maybe one last quick question on the CO-PACK before we move to VS-7375. help us understand, you know, if the RAMP 301 study reads out positively. You know, help us contextualize how that could change the long-term CO-PACK opportunity, you know, in both the KRAS mutant approval and potentially expanding, you know, into broader recurrent, patient populations.
Yeah. If you look at LGSOC at diagnosis, about a third of the patients are KRAS mutant and about two-thirds are wild type. Patients with a KRAS mutated tumor actually live about 12 years on average versus seven for the wild type. It's not that a third of the opportunity is in the mutant, but a third of the patients at diagnosis, because over time, the population enriches for mutant. We are getting wild type now because they really don't have a lot of treatment options and we do believe this is still the best option for them. We can't actively promote.
We do have wild type in the confirmatory study because even though the response rate was 17% compared to 44% in the mutant, what happens with those patients is they almost all, in our trial, about 82% of all the patients had tumor shrinkage. In the wild type, it's not as deep a response, they might not get to a PR. For an accelerated approval, you had to have response rate. In our confirmatory study, the primary endpoint's PFS. What we found is even in the wild type patients, when they had stable disease, they stayed on therapy for a long time. We believe that that bodes really well for a PFS endpoint. We're pretty bullish on the study.
When the study reads out, which should be mid-next year, we'll file for a supplemental NDA to expand the label. We'll go back to NCCN with that data. We think that'll open up our ability to actively promote for the entire population.
Great. I guess turning to VS-7375, which is your KRAS G12D on/off inhibitor. I think it would be great to provide context to the audience of how important it is to have engineered an on/off inhibitor, and how that really competes in the RAS landscape, which as you said yourself, was becoming exceedingly crowded from a bird's eye view, but it's still relatively crowded. Has some first movers in the clinic right now. How should we be thinking about that?
Yeah. I think, you know, at a high level, what we're seeing in the clinic is an isoform-specific molecule does not have the on target effects of a pan-RAS. RAS is in the skin, it's in T cells, it's in a number of things. We believe, and we're starting to see this in the clinic, that it'll have an improved safety profile over pan-RAS. I think that it's also important that about 40% of PDAC is G12D, and so it's a significant opportunity. You know, maybe Nate can talk a little more about some of the preclinical differentiation we saw, and then we can talk a little bit about what we're doing in the clinic in the U.S.
It's a very important point. I think from a profile perspective, the on/off is one particular component that we look at. We also look at the residence time on target. What we've shown in the preclinical setting is that we have a very long residence time. It's you know, 18- 24 hours of drug on target. As we continue to work to deliver a potential best-in-class profile, not only the on/off inhibition, the long residence time, but also we think that if you can get a maximal exposure Cmax as well as steady-state AUCs in the clinic, that you're able to then stay on target for a long time and be able to knock that down in a way that it will have disease, you know, regression.
That's what we saw preclinically. As we have put out, we're seeing at the 900 mg dose that we have recently put out, we're achieving those concentrations, at least when you translate from mouse to human, we're achieving the concentrations at 900 mg that achieved the maximum tumor responses in the mice, which was reduction across all mice, across all models.
Great. Yeah, that makes a lot of sense. I guess, you know, given that you're advancing across multiple tissue types, I guess, how are you prioritizing those settings? I guess the big question is, how do you view, you know, which tumor type gives you the most kind of credibility for truly establishing that first proof of concept?
Well, I mean, I would say the biggest opportunity and the one where, you know, I would say RevMed has established the best benchmark would be in PDAC. You know, that's one that's very attractive. We wanna get to frontline as soon as possible. We're looking at both, combination with standard chemotherapy, so gemcitabine. There's also incredibly compelling preclinical data, and we're starting to see some in the clinic with combining with cetuximab, and we think there's a potential for a frontline chemo-free regimen there. There's obviously a big unmet need in CRC.
We believe in that disease, you're gonna have to combine it with cetuximab. We don't think single agent is gonna be relevant there. Also in lung. You know, we're getting pretty compelling single agent data in the second and third line setting. The current plan is in probably June of this year, we're launching three phase IIs, and this was based on advice from the FDA. We went to expand our phase I to 80 to 100 patients per diagnosis. They came back and said, "It appears you're going for registration with this cohort. They should be broken into separate phase II studies." Those are launching, next year we'll be launching phase IIIs in the frontline setting.
The intent is to go for accelerated approval if possible, and we'll continue to do that, and then the phase III will either serve as confirmatory studies, or if for some reason we can't get accelerated in one of those diseases, it'll be the original approval. We think in CRC in particular, there's a pretty wide open for potential accelerated approval. We believe based on the high response rates we've seen as a single agent that there's a possibility there in PDAC and lung as well.
I guess a follow-up to that would be, you know, based upon your initial commentary about, you know, having discussed the inroads you've made with the 900 mg dosing. You know, how should we be thinking about, you know, your evaluation of the 1,200 mg dosing characterizing that upper range applied to the inroads made in pancreatic and other tissue types? Talk about the optionality there that potentially might give you.
Yeah. The 1,200, you know, we're going there just to make sure, you know, when we saw the PK getting better with each dose level, we wanna keep going up. The FDA wants you to characterize basically an MTD level, which we haven't gotten to yet. We do believe 900 will be the go forward dose, but establishing that we can safely give 1,200 will help with Project Optimus and really making sure that we've characterized what happens when you give more drug than is the dose you go forward with.
You know, just to wrap things up, just for pancreatic cancer and colorectal cancer, could you just maybe outline what internally a compelling, you know, early efficacy signal would be in either of those cases there for, you know, for continued execution?
Yeah, I mean, when you look at CRC and you look at the current treatments in second and third line, I think anything over 20% gets to be really interesting. In PDAC, you know, as a single agent, RevMed was in the 30s. You know, anything above that we think will be interesting. You know, what we've seen in China in the second line so far is 58%. You know, that'll help guide whether we go forward in second line as a single agent, and then obviously we're exploring the combinations. We do believe one of the advantages of the variant specific is that it should be more combinable with other agents. That'll be a big part of the development program.
Very good. I think that's all the time we have. I just want to thank Dan and Nate for joining us and on behalf of the whole Wainwright team, we congratulate you on your progress and we look forward to future updates.
Great. Thanks for having us.