So, welcome to Cantor's Global Healthcare Conference. I'm Pete Stavropoulos, a biotech analyst with Cantor. With us, we have Verastem. We have Dan Paterson, our President and CEO, and Mike Carruthers, Chief Commercial and Strategy Officer. So, welcome.
Great.
Thank you.
Happy to be here. I thought I'd bring Mike with me since market opportunity and how we're gonna attack it is a big question everybody has.
All right, we'll get into it in a minute. But, you know, first let's start off with a brief intro, you know, of yourselves and a synopsis of the company, including the origins of the oncology platform.
Sure. Dan Paterson, President and CEO. Been with Verastem pretty much since the beginning. Most of my career in oncology starting in the mid-'80s, so I am that old. Our focus really for the last couple of years has been small molecules targeted at the MAPK/ RAS pathway. The first molecule is really avutometinib, which is really the lead along with defactinib, and it's really the combination of those two that forms the basis of most of our programs. The lead program is a rare form of ovarian cancer called low-grade serous ovarian cancer. It's actually quite a different disease than high-grade. High-grade has gotten a lot of the attention over the last few years with PARP inhibitors and platinum, and whether it's platinum resistant, platinum sensitive.
Low grade, really, it arises in a different place. Molecularly, it's very different, and it's quite resistant to chemotherapy, with standard of care responding about 6%-13%, and it has a very different disease course. It tends to arrive in younger women. You know, we have some women in our trials in their early 20s, and you don't think of that when you think of ovarian cancer.
So you mean LG...
LGSOC is-
Okay, yeah.
Yeah.
Yes.
It tends to have a long disease course. Mean survival is about 10 years, and it's just this course of you get debulking therapy, you get upfront therapy, and then it's just a constant battle going from one therapy to another. Standard of care is really the chemotherapy plus some hormonal therapy. None of them work particularly well, a lot of toxicity involved, and it really matters in this disease because you take treatment for a long time.
Mm-hmm.
And when you talk to patients, if you're going through four to six cycles of chemo, you see the end in sight, and you can tolerate a lot. When you know you have to take a treatment until you basically go on the next treatment, tolerability matters a lot. And so in this lead program, we reported out some interim data in our pivotal study earlier this year. We'll have an update with the definitive data mid-October. We just announced that it's gonna be an oral presentation at IGCS in Dublin in mid-October. We have started a rolling submission, it's rolling NDA for accelerated approval. We started that late May, and what we've guided towards is the last module that will be this mature data with at least twelve months follow-up that we'll have before the end of the year.
So very excited about that.
Okay, I'm gonna ask you a couple of details-
Sure
... about that in a minute. But, you know, sort of coming backwards, step a couple, let's step back for a little bit.
Yeah.
You know, so it's been difficult, you know, in terms of, one of the more difficult pathways to drug are coming in the RAS signaling pathway. So, you know, what have been the challenges in actually drugging this pathway?
I mean, it's one of these pathways that's been called undruggable. You know, I'm not a scientist. Without going into a lot of the detail, the binding pockets are very difficult. They can change, and, you know, the first success in KRAS was really the G12C inhibitors, Amgen and Mirati, now BMS. You know, kind of modest success as single agents. There's a lot of work going on in combination. You know, we decided that combination was probably the way to go with ours, and, you know, I would say just in general, you know, when you look at that pathway, it's responsible for about a third of all cancers. It is hard to treat.
In many ways, the activity in this area is what was going on with the immune therapies, you know, starting with PD-1, PD-L1, getting approved, and so lots of activity, modest success, even coming out of ESMO, you know, this week. Some of the data was not particularly exciting, and so a lot of work left to do.
Okay. You know, besides LGSOC, low-grade serous ovarian cancer, I just need to say that,
Yeah. We have to come up with a shorter name for it.
You know, besides that indication, you know, what are the other opportunities?
Yeah. So, pancreatic is our next one kind of coming up. We reported data at ASCO, arguably early data, but frontline metastatic pancreatic cancer, combining avutometinib and defactinib with standard of care gem Abraxane.
Mm-hmm.
We reported an 83% response rate. We noticed that Immuneering had data this week with a 43% response rate. People are very excited. So we're continuing to optimize the dose in that. We're looking at a number of different dosing levels that really mimic what happens with gem Abraxane in the community. So there's the label dose of gem Abraxane, and then it's quite common to either drop out, it's day 8, 15, 28, and it's common to drop out one of the doses or to lower some of the doses, and so we're looking at a couple of dosing levels there. We'll probably have updated mature data near the end of the year, early next year.
The data that we reported at ASCO is the only cohort that had a full six months follow-up, and then following that, we are very excited about the combinations we have with the G12C agents. We have partnerships with both Amgen and then Mirati, now BMS, where we're combining first avutometinib with their G12C agent, so sotorasib and adagrasib, and then recently, we added defactinib to the one with Amgen, so with sotorasib, that was primarily based on some really exciting preclinical data we had at AACR, showing that adding defactinib onto that doublet really increased the efficacy, and then there was actually data from a Chinese company at ASCO that combined a G12C inhibitor with a FAK inhibitor just as a doublet in non-small cell lung cancer. In frontline, they had about a 90% response rate.
So based on those pieces of data, we really pushed to get defactinib added. And then we've got some earlier studies that are signal finding in some other gynecologic cancers related to LGSOC, as well as colorectal and breast. So, you know, leveraging some of the investigator-sponsored trials we're using for signal finding, we've got other things coming down the pike. And then, as different agents, but earlier in the pipeline, we did announce our G12D inhibitor that we had licensed from GenFleet last year, that did go into the clinic in July. They just held an investor day in Shanghai, and we're quite optimistic on early progress there. Patients are going on quite quickly.
One of the investigators there anecdotally was talking about tumor shrinkage in the first patient, and so we're quite excited about that and believe we can bring that into the United States, late this year, early next year. We're writing the IND right now, and the intent is to take all of the dose escalation work done in China and build on that to accelerate our development program.
Okay, so a lot going on at Verastem.
A lot going on.
But, back to avutometinib and defactinib. Just so, you know, for those that don't know, can you just sort of discuss the mechanism of action and sort of the unique properties that sort of will have been sort of translating into a clinical benefit?
Sure, sure. What's unique about avutometinib is, unlike traditional MEK inhibitors, it actually, in addition to binding to MEK, it blocks RAF. And so if you think of the pathway, it's almost like playing Whac-A-Mole. You block one node, and it gets around it and reactivates it, and this is the only molecule that's in later stage clinical development that blocks two nodes, and it keeps the feedback mechanism from reactivating the pathway. And then, based on some early preclinical work we did, and then work in the clinic, out of the Royal Marsden that came out of the original FRAME data that we reported, we showed that if you actually treat with avutometinib, phospho-FAK goes up, and so we believe it's an escape mechanism related to the PI3K pathway.
And then, when you add in defactinib, it knocks it back down, and we did this with serial biopsies in patients, where we showed baseline active FAK going up with avutometinib and then back down with defactinib. And that was borne out in our initial part one of our study, where we randomized between avutometinib as a single agent and adding in defactinib. And frankly, it actually recapitulated what we saw preclinically, which with the single agent, you see a certain amount of tumor shrinkage, and then when you add the two agents in, you get deeper-
Yeah
... and down to more responses. And that's really the key here with this pathway, is trying to block multiple nodes and then trying to find the parallel pathways where it escapes.
All right. Great explanation, and so, you know, with that, you had mentioned that, you know, you may file an NDA, you know, not too distant future, but before, you know, you get there, you need to complete a study, RAMP 201, and so just, you know, for, again, those that aren't familiar with the story, just a brief explanation of the study design.
Sure
... and yeah, and sort of the data that you've presented to date.
Sure. So RAMP 201 is actually completed. It actually had four parts to it. Part A, we randomized between the combination of avutometinib and defactinib versus avutometinib by itself. Part of that was really to satisfy the FDA guidance on two novel agents together. You have to show the contribution of the parts.
Mm-hmm.
We completed part A, where we clearly showed that the combination was better than the single agent. Then we went to an expansion, which was part B, where we added more patients and then decided to keep going as we were discussing our plans for a confirmatory study with the FDA. Because we're going for accelerated approval, and the requirement there is, if you go for accelerated approval, you have to be well underway with a confirmatory study that's a randomized Phase III. The totality right now of the RAMP 201 study, which is part A, B, and C, we reported early data with a minimum of five months follow-up earlier this year. At that point, even with the immature data, our overall response rate was 27%. In the KRAS mutated population, it was 37%. In the KRAS wild type, it was about...
It was 15%. Interestingly, in low-grade serous ovarian cancer, see, I can say it. It actually turns out that a KRAS mutation is a positive prognosis factor, not negative, so patients do better if they have a KRAS mutation.
Okay.
So we had to separate those two populations. In talking to the FDA, you know, it's clear that when you have a response, and in this disease, being a slower growing tumor, it takes a while for the response to happen, and so you have to treat patients for six plus months, and then they clearly wanted us to follow all responders for at least six months.
Mm-hmm.
So we felt we needed a minimum of 12 months follow-up. We now have that, and that'll be the data that will be presented in mid-October. That'll be the mature data. That is the data we'll use to go into the rolling NDA submission. We started the rolling NDA submission in late May, where we put in the earlier modules, with the last module that's going in before the end of the year being the clinical module.
All right. And so I guess, like you mentioned, you need to get a full approval, you need a confirmatory study that's RAMP 301. Overall, just describe that study design.
Sure. It's a randomized Phase III. Patients will be randomized one to one versus avutometinib and defactinib versus standard of care, and what we've defined in consultation with the FDA and our steering committee is five different agents that are either chemotherapy or hormonal therapy that will be standard of care, and those are the agents I referenced earlier, that tend to have a 6%-13% response rate, normally, and so we'll be randomizing against those. We will allow crossover from standard of care to the experimental arm, but only on progression that's been independently confirmed based on blinded independent central review.
There's quite a sensitivity because there have been issues in other studies when, you know, in this day and age, where patients actually can access the data, with patients going on a Phase III and feeling disappointed that they got the standard of care, and they want to just cross over. And that's been an impact. It's impacted the validity of some earlier studies, and so working with the FDA, we wanted to make sure we set up a mechanism to preserve both the validity of the study, but also allowed patients to get the experimental arm, so they'd be willing to go on the study. And so we started the study last year. It's well underway. The primary endpoint for the study will be progression-free survival.
We're also gonna look at response rate, survival, toxicity, patient-reported outcomes, and so there's a number of secondary outcomes to the study, but the primary outcome is progression-free survival.
Okay. All right, that's great. I think we're gonna draw Mike out right now. You know, so, you know, from the data that's presented to date, and, you know, including the LGSOC patients that responded to drug, you know, what do you believe is the market opportunity for avuto and defac?
Sure. So, a lot of oncology types are measured by their incidence population, and that you do that because obviously either you're cured of frontline or you tend to die very quickly, unfortunately. Historically, LGSOC was largely called an indolent disease, but when you think of indolence, you often think of long treatment holidays, drug intervals, et cetera. LGSOC, unfortunately, is very insidious, so it takes a long time to be diagnosed. It's very persistent, so 90% plus of patients experience a recurrence, and once you've had your first recurrence, you tend to unfortunately progress and ultimately die. And this is a condition you die from, not with, unlike, say, prostate cancer in the case of many patients. So we measure the marketplace largely initially by the prevalent population, so those patients living with the disease today who have experienced at least one recurrence.
There's about 6,000-8,000 , arguably as high as 10,000 patients in the U.S. living with the condition today. As Dan indicated, you know, there is a prognostic difference between KRAS mutant and KRAS wild type. Over time, that initial 70-30 split shifts in favor of KRAS mutant patients, so it's at least 60-40, potentially 50-50 in that prevalent population. You know, we see through our clinical data, high levels of response, low dropout rates due to toxicity and very long durations of therapy. We measure that opportunity as somewhere up to $3 billion once we have accessed all those patients, and those patients see multiple treatment opportunities, so they recur for treatment at least maybe on an annual basis, based on the current PFS and durations of therapy.
And then on an annual basis, about 1,500 patients unfortunately experience their first recurrence. And so in a steady state, there's another 1,500 patients dropping in. So on an annual basis, they're probably worth between $500 million-$700 million per year. And that's using a price point, which is, I would say, on the low end of expectations. So we can extend that opportunity further, moving forward. Plus, as most people anticipate, our current study is showing what we're like after at least three prior lines of therapy and exhaustion of all available therapies. So as we move up in the order of use, obviously we'll experience better response rates and better durations of therapy.
All right. Apologize if I asked a redundant question. My attention was deviated to that direction. So again, cutting the KRAS and wild type mutant patient market sizes, you know.
So in essence, we're seeing durations of therapy in mutant of 18 months and in wild type of about 11 months. So if you factor in the different sizes of the population between that incident and prevalent population, they're equivalently in size of value. So that $3 billion opportunity is in favor of mutant, so about $1.7 billion is in mutant and about $1.3 billion in wild type. And it's a little bit flipped in the incident population just because it's 70-30 at that point in time. So it's a roughly a 50-50 revenue split between the two opportunities.
Again, assuming approval in the first half of 2025, you know, I guess there are other mechanisms, though you may not be approved in a certain, what's it called, population. You know, what I'm really referencing is the NCCN treatment guidelines.
Mm-hmm.
What would you expect there?
Well, I would say two things. One, we will submit for NCCN guideline inclusion. And if you look at the other agents that are approved in there, binimetinib, which was the MEK-only inhibitor that actually had a negative pivotal trial, has got a level 2-B inclusion. And trametinib, which has a limited amount of understanding of its activity between the types, only showed an 8% response rate in wild type, and we're at least double that, and they have got a 2-A level of evidence. The other way of looking at it, though, is that at least in the launch period of, say, the first three years, we'll be largely treating patients who've seen everything that's been currently available.
'Cause they often get a combination of chemotherapy and hormonal therapy in the front line, and then they will receive bevacizumab in combination with other drugs, along with a MEK-only inhibitor in limited numbers in the U.S., and so they'll have exhausted all their available therapies, so we'll make a very good choice for those patients immediately, and one thing to add is that we've done a lot of work in identifying and working with these patients, so of that prevalent pool I was referring to, we already have 2,500 of them signed up with email permissions for communication, and we're using those at the moment for disease awareness and education efforts, but once we get approval, we'll be able to communicate compliantly with them about our approval and availabilities and potential treatment option for them in the future.
An initial bolus of patients.
We're anticipating, both from market research and from the physician point of view, that some of them will... In fact, a significant population of them will reach out to their patients and discuss a potential active switch, and plenty of patients will probably do the same to, spontaneously to their physicians to discuss a potential switch. Because they know that current therapies are helping them from a limited point of view, from an efficacy, but they're often dealing with high levels of toxicity-
Mm-hmm, yeah.
but putting up with it because they have no other choice.
What is the toxicity levels?
30%-35%-
For the MEK inhibitors.
30%-35% discontinuation in the MEKs, and the chemotherapies and AIs have similarly high levels of treatment discontinuation of 17%-20% or more.
Okay.
We're seeing 9-10% in our studies.
All right. And, you know, sort of going back to the NCCN guidelines, you know, so if, you know, for the patients that are not on-label, you know, and you could, you know, introduce into the guidelines, how do payers view that?
So obviously we're still going to make our best argument to get everybody on-label, and that rolling submission was initiated back in May and will complete in the next month or so. But going back to how payers see it, I mean, classically, if you look at the models, if you get a 2B, about 75% of the plans will recognize that. If you get a 2A, 100% of the plans, and NCCN trumps approval in most cases in the U.S.
Okay. And in terms of the U.S. markets, European markets, and other geographies, is this something that you're gonna commercialize on your own, or?
Yeah. So it would be a stretch for a company of our size to commercialize on our own in Europe and Japan, although we are pursuing regulatory approval on our own because we believe that increases the value to a potential partner, and so we'll be seeking advice in the E.U. before the end of the year. The big open question there is whether we'll be able to get approval on the single-arm study 201 , like we are in the U.S., or whether we'll have to wait for the confirmatory study, and Europe can sometimes be a little tougher on requiring either the randomized study or sometimes even survival data. In Europe, we believe...
I mean, I'm sorry, in Japan, we believe we can get approval on a relatively small bridging study for conditional approval, and the plan is to start that bridging study before the end of this year.
Okay, anything else to add about the commercial setting?
I mean, our go-to-market model, to Dan's point, I think is very appropriate for a company of our size, so we're not going to be throwing the classical 50, 70 reps out there. 50% of these patients are managed in only 100 centers by about 400 physicians generating the claims, and we'll concentrate our field presence there. The rest are managed through the GPOs, and largely, you know, classical reps can no longer access those customers. So we're going to be working largely through the access channels and those opportunities those organizations now present to industry, where there's actually a mandate for their members to attend those training sessions, and then lastly, as I mentioned, we'll be going directly to patients and have a great understanding of where those patients are and already have access to many of them.
Okay. All right, we got a couple minutes left. Would you like to touch on some of your earlier stage programs?
Sure. I mean, we're very excited about the early data in pancreatic cancer. Obviously, that's a very tough cancer. It's been really hard to get drugs that work there, and I think the early data that we've seen and, you know, one of the interesting things about that study is we've partnered with the Pancreatic Cancer Action Network. They've funded most of the study, but probably as importantly, we've gotten access to their academic investigators that are-
Mm-hmm
... The world's experts in pancreatic cancer, and they're quite excited about what they've seen, and we're meeting with them regularly to kind of move that study forward, and either by the end of the year or early next year, are hoping to choose the go-forward regimen and then expand there. And then we are looking at some other opportunities in pancreatic cancer, both potentially going later lines of therapy, where we might be able to get a more expedited approval path. And then looking at some settings, like unresectable pancreatic cancer, where you combine with radiation therapy and have some early data that's starting to look interesting. And then the G12C inhibitor studies, particularly the one where we've been able to add the FAK inhibitor-...
We're quite excited about that, and hoping to report data there again by the end of the year, early next year. And then the G12D inhibitor is one where that whole area is getting a lot of attention. Having an oral G12D inhibitor would be huge. These are big molecules, and they're hard to get bioavailability, and one of the things we were able to show preclinically with our molecule is oral bioavailability in three species. And some of the other agents that went into the clinic, they had to dose IP in order to get bioavailability, and so we're quite bullish about that and want to move that forward as quick as we can.
Then, as part of that GenFleet collaboration, the original collaboration was set up to really leverage our expertise in the pathway and their expertise in making molecules, and the partnership was set up around, we could choose up to three targets, and so G12D was the first target. We have chosen our second target, we haven't disclosed it yet, and continue to work with them on moving those molecules forward to get into the clinic and then identify a third target. So, you know, we think this is an opportunity for a company that we think is radically undervalued, that is about to have a first approval, with the ability to increase the label on those first drugs that get approved with pancreatic and lung, and then a pipeline of really interesting molecules that are frankly, in about the hottest space right now.
Yeah.
When you look at the valuations of some of the companies that have those drugs, we think we have the ability to get into that neighborhood by just showing some early clinical proof of concept and really focused on that. The other thing I might add is, you know, obviously it's a very tough funding environment.
Yeah.
We did an equity raise earlier this year. We felt it was prudent to do the equity raise, given where we were wanting to make sure that we were funded through approval, and frankly, the unknowns in the external environment. You know, I think the Fed helped things today with the rate cut today, but that may be overshadowed by some bigger stuff that may happen, and we didn't want to be subject to that.
Of course.
And so we're spending a lot of effort as a management team, working through different non-dilutive and other ways to make sure that we can try and avoid another equity raise at anywhere near the valuation we're at.
All right. So we have a couple minutes. Just one quick question for the pancreatic study. You did have the results. Just, you know, I understand the hazards of cross-trial comparisons, but just, you know, sort of how does this stack up, you know, relative to gemcitabine and nab-paclitaxel in the first-
So gem nab-paxil, if you look at the studies that were done, it's anywhere from, like, a 23% response rate up into the high 30s. And so to see an 80+% response rate, again, in small numbers, that on its own was quite impressive, and then we have heard from the investigators that they just felt like it acted in a way that gem Abraxane by itself hadn't. And what we see is relatively rapid decrease in CA 125, which is a tumor marker in these patients, which obviously isn't an objective response. But in those patients, you know, when we talk about the 80+% response rate, those were the objective response by RECIST criteria.
I think the other thing to keep in mind, and probably more, a more important outcome measure in pancreatic cancer, is PFS is usually pretty short, on the order of five-to-six months, and so we'll have a sense of, you know, if we've gone past that relatively soon. Again, understanding the limitations of a single-arm study. You know, when you have these time-to-event outcomes, you typically should have a randomized study, and we'll go there as soon as we declare the dose. But, you know, there feels like there's a there there.
All right, great. You know, a lot of things going on at Verastem. A whole bunch of exciting agents in the pipeline, earlier stage, you know, moving towards approval. You know, if we're sitting here, a year from now, and I ask you, you know, "What have you achieved in the past twelve months to create value at Verastem?" What would you like to say?
That we have an approved drug. We're making great progress on the launch. That we have a positive study combining with the G12C agent, and, you know, The G12C agents, again, they were the first KRAS agents to ever get approved, but it looks like at least this first generation of agents probably need to be used in combo. So to be able to have shown clinical proof of concept that we can improve those, that we've chosen a regimen and a dose in the pancreatic study, and shown in a larger number of patients that kind of efficacy, and that the G12D inhibitor is in the clinic and showing human bioavailability, tolerability, and hopefully some early responses, that should fundamentally change our valuation a year from now.
All right. Thank you very much for joining us at the 2024 Cantor Healthcare Conference, and always nice to see you.
Always great to see you.
Hear the progress.
Thank you, Pete.
Thanks, Pete.
Thank you.