care conference. My name is Greg Renza, one of the biotech equity research analysts here at RBC, and we're pleased to have Verastem with us today. And joining us from the company is the Chief Financial Officer, Dan Calkins, as well as the Chief Commercial and Business Strategy Officer, Mike Crowther. Gentlemen, it's good to see you, and thanks for joining us. Absolutely.
Good morning.
Thank you for having us. Great. Well, look forward to the discussion. Certainly a great deal going on with Verastem today, especially with avutometinib. But maybe before we dive in, just have you provide an overview of Verastem, just the origin of the oncology platform, the asset of focus with avutometinib, that would be great.
Sure. So, I mean, the company acquired defactinib, did a lot of monotherapy work with it, found some single agent activity, but also did a lot of preclinical work and found that its best synergies were with MEKs. And we acquired a next-generation RAF MEK clamp from Chugai, avutometinib, and that's been the development platform since. And then more recently, we've entered a collaboration with GenFleet, with up to three targets, the first of which we've already nominated as the G12D.
Great. Great. And certainly, avutometinib and RAMP 201 has been the aspect of focus for investors. But maybe for those less familiar, just walk us through the differences between low-grade serous ovarian cancer and high-grade serous ovarian cancer. I think that there are some important distinctions and etiologies that are worth exploring, especially as we think about the current treatment paradigm in LGSOC.
Sure. So high-grade is your typical form of aggressive tumor with high mitotic index, rapid growth, which means two things: One, obviously, it is highly treatable in alone therapy, but obviously, if you're unfortunate enough to progress through those treatments, then your ability to live with the condition over time reduces dramatically, and obviously, most recent advances have been among the ADCs with Elahere entering that space. Low-grade is more recently described, back from 2015. It's often historically been called an indolent disease, but we prefer to think of it as insidious. While it is relatively slow-growing, it is ultimately fatal. And women as young as 20 can be diagnosed with LGSOC, so it's bimodal distribution, women of 20-30, those of 55 and older.
And so obviously, unfortunately, like with some other conditions, patients die of this disease, not with this disease. Unlike high-grade, that has been the subject of much more research, low-grade has been somewhat neglected in that way, at least historically, and so there are no currently FDA-approved therapies specifically for low-grade. Fingers crossed, our doublet will be the first specifically approved therapies for that condition.
While no approvals today, what is the current standard for care management?
So in frontline, you'll experience debulking surgery, followed by usually the provision of platinum-based chemotherapy. Unfortunately, given that low mitotic index, the disease is generally insensitive to chemotherapy, with very low response rates, somewhere between 6%-13%. So there's been a lot of, shall we say, investigator-sponsored studies that have led to the adoption of therapies and not specifically improved in low grade, such as aromatase inhibitors, bevacizumab, and in much later lines, MEK-only inhibitors. But all of them are generally very low in terms of response rate, but... and come with both high short-term and long-term cumulative side effects, often lead patients to discontinue therapy over time.
Mm-hmm. Okay. And just walk us through some of the epidemiology as we think about the market potential for an approved therapy.
So, well, the data and research tends to suggest is that, firstly, women are, shall we say, slowly diagnosed, so the constellation of symptoms is relatively nonspecific.
Mm-hmm.
Particularly given the younger age of many women, they're often being told they can't have cancer at their age. It's more likely to be some other, you know, colon or gynecological disorder. It takes, on average, three years for them to be first identified as suffering from a cancer. Then generally, because of the poor provision of gyn-trained pathologists across the U.S., they're often given a general diagnosis of ovarian cancer, not otherwise specified, and then frontline chemotherapy is used as part of the differential diagnosis package. As I said, less than one in 10 women have any decent level of response to that. Once they reach the point of recurrence, and about 80%+ of women who've had a single episode will recur-
Mm-hmm
... and recur multiple times, they're then given variations on a theme. So they get combinations of aromatase inhibitors, of further chemotherapy, of bevacizumab, of these, the MEK inhibitors in very late line. And because they can receive multiple treatment episodes in their lifetime with the disease, they often see repeats and updated combinations where they're just trying to mix mechanisms, shall we say.
Mm-hmm. And this certainly appears to be a market which lends itself well to the building of awareness and maybe setting forth some degrees of initiative to understand the diagnosis, the insidious nature, the nonspecificity that you allude to. And frankly, if there aren't any approved therapies, then maybe the utility of those efforts or maybe less fruitful. How do you think about those initiatives and the awareness build and maybe the obligation to do so before-
Yeah
... an approved therapy?
So in terms of the patient pathway. There's probably. We estimate there's about 1000-2000 women a year who are diagnosed potentially having LGSOC in their first experience. But given the three-year journey, there's possibly two-three times as many women living with the disease that have yet to be diagnosed and treated for their condition. So most of them are diagnosed at a very late stage. Once they've experienced that frontline therapy, as I said, most of them then will have a recurrence and potentially multiple recurrences. And there are somewhere between 6000-10,000 patients alive at any point in time, living with the disease under active management, because generally, this is not a watch-and-wait condition. The constellation of symptoms that then evolve into the situation that will ultimately lead to your mortality are unpleasant.
They're under active management the vast majority of the time.
Great. Great. Maybe let's talk some of the avutometinib data and the programs. What's the latest on the release for the RAMP 201 data coming sometime in the second quarter?
So the study was fully enrolled in August, September of last year. It was split into three cohorts. So the last of those three cohorts fully enrolled. So at the moment, obviously, in at least in the patients who enrolled later on, the data is not yet mature, and we want to present the full data package to the FDA. We have a Breakthrough Therapy Designation, so we're in a constant dialogue with the FDA, and our current conversation is around the best way to approach submitting the data.
Okay.
Our intention and our anticipation is that we'll reach an agreement with the FDA before the middle of the year.
Okay.
We'll start whatever submission process that we agree to with them. Our basic, base case is a rolling submission.
Mm-hmm.
We will release very high-level top-line data in conjunction with that, but then present the mature data across all three cohorts at a medical meeting in the second half of the year.
Okay. All right, and just as far as the 201 data, maybe just outlining just some of those steps towards it. Any steps that are remaining now between now and then? It certainly mentioned just the-
Yeah
... the FDA engagement.
Well, we've started the confirmatory trial that we agreed with the FDA last year.
Mm-hmm.
That's been open and enrolling since the end of last year.
Mm-hmm.
Obviously, we have the maturing 201 dataset. We've done all of the other requirements, shall we say, for the other modules that would need to go in, in terms of CMC and quality, et cetera. So we, we don't believe that there's anything predominantly substantially outstanding, but obviously, the FDA-
Sure
... will have their own opinions on that, so we'll find out their feedback in the relatively near future.
We've talked a bit about just the concept of avutometinib and defactinib as a contributor here. And to what extent does that play a role in these discussions?
As far as we're concerned and aware in our conversations, we've clearly demonstrated the contribution of the two separate agents, you know, clearly before. Defactinib actually had an extensive development program as a monotherapy with a couple of 100 patients minimally exposed.
Mm-hmm.
Part A of the study was designed to show the contribution of avutometinib in combination versus avutometinib alone.
Mm-hmm.
That was cleared, so there was an opportunity to continue that in cohort B, but we shut that down based on clearing that hurdle during cohort A.
Okay.
That data was presented at ASCO in 2023.
Yeah. And speaking of ASCO, we have a presentation coming up with RAMP 205. Maybe just walk us through the treatment in pancreatic and the rationale with the avutometinib and defactinib.
Well, of all of the, you know, RAS pathway mutations are experienced in up to 30% of different tumor types. Pancreas is where it's at its strongest in 95% of patients.
Mm-hmm.
So the rationale as a disease to explore it with our assets is clear. We chose to go in combination, obviously, with gemcitabine and nab-paclitaxel-
Mm-hmm
... in frontline metastatic cancer, because as all of us accept, there are so-called graveyards of drug development, and when you get into later lines, even second line beyond a pancreas, the opportunity to demonstrate effect is more challenging.
Sure.
So we're doing that in frontline in the phase 1 study. The phase 1 study is designed to describe the correct dose and scheduling of our doublet in combination with that chemotherapy backbone.
All right. Great. Great. And then, certainly as we think about LGSOC, working with the FDA, there have been several appointments, including yourself over the last several months. Just talk a bit about sort of that planning process, the significance of a potential launch into market and how Verastem is building for that.
Well, Verastem is obviously doing the right thing by preparing itself to move from a clinical stage to a commercial stage company. So the appointment of myself and a couple of other people are a recognition of the need to enter the commercial phase, and in sufficient advance to make sure that you do the right market preparation and organizational build to access that. And then, you know, our most recent appointment, which is John Hayslip, is obviously, he's a profoundly skilled and experienced drug developer and clinical developer in mid to late-stage drug development, which is where we are right now. And then we still retain strength and depth in the existing leadership, including Jonathan Pachter, our CSO, who is one of the leading lights around pathway management in, you know, the RAS pathway.
... Great, great. And then also with RAMP 203 and 204 going on, just with synergy exploration, just remind us of the status of those trials and how we're evaluating the combo of avutometinib with KRAS G12C.
So obviously, they're in combination with sotorasib and adagrasib. And the original concept was to show activity, depending on which study you're looking at, in both G12C naive and G12C exposed refractory patients. They are slower to enroll, and obviously, they're collaborations with other companies, so that obviously lends layers of complexity as well. We presented some initial data of the doublet with sotorasib. And we're just currently based on very strong preclinical data, adding defactinib to that particular study. So we anticipate probably not releasing more clinical data until either very late this year or more likely in the first half of 2025.
All right, great. And also what can't be overlooked is some of the early programs. Maybe just walk us through the strategy about fleshing out the pipeline. Certainly, the GenFleet collaboration is another interesting development. What is the latest there, and how may this strategically align to the larger and the later stage programs?
Well, I'll let Dan speak to the structure of the deal because it's a very smartly structured deal. But in terms of the logic of the deal, obviously, you know, we have two assets that are being developed across multiple disease states, but it's still, you know, provenance-wise, up against a certain, you know, composition of matter and other patents. So we wanted to make sure our pipeline is broadened. The RAS space is very active and vibrant at the moment, but in GenFleet, we found a partner who have profound drug development capabilities. And so we did a deal where we could nominate up to three targets with them, and the first that we've disclosed is G12D.
In that particular case, we believe that given its oral bioavailability and the fact it's an on-off product rather than one state or the other, that it has some characteristics that lend it to a potential best-in-class profile. But I'll let Dan speak to the structure of the deal.
Yeah, I would just to add to what you were saying earlier about, you know, GenFleet has got the expertise in drug development, but we've done a lot of work ourselves, developing a who's who network within the RAS pathway. So the GenFleet agreement allows us to tap into that network, see what the next big thing is going to be, and then go to GenFleet and say, "Hey, we want to target X," right? And that's kind of where we started with the G12D. We felt that that was the kind of the next big thing. This obviously allows us to develop two other unnamed targets, but that just gives us that flexibility to continue to, as you said, flesh out the pipeline and expand beyond the avutometinib and the defactinib.
Great. Dan, maybe keeping with you, just talk to us a bit about your resource allocation. Certainly with the focus of avutometinib and the filing, the transition, as Mike, as you mentioned, to a later stage and even commercial company with adding new personnel. Dan, how do you think about the company profile? How do you guide to that burn and the resourcing?
Yeah, we're being very cognizant of that, for sure, right? You know, with low-grade, we want to make sure that we're building out commercial operations that are going to support the launch, but we want to make sure that it's done, that's fit for purpose as well, right? We don't want to, you know, invest in things that aren't going to, you know, be a return for us, right? So, we're doing a little bit of that now. You can kinda see the cash burn ticked up a little bit, but, you know, for the right reasons, right? We're getting the confirmatory trial up and running. That started in Q4, starting to make those investments in the commercial operations, you know, starting in Q4, going into Q1.
Right now, the cash burn is probably right around $25-$30 million per quarter. Anticipate that it'll likely stay around that, into 2024. We'll give a little bit more guidance as we hear more feedback from the FDA in terms of, timing for, for regulatory actions and, and whatnot, but don't anticipate that it's going to, change significantly from that.
Okay. All right. Just want to turn it over to the audience. Any questions for the Verastem team? Okay. Maybe before we break it, any closing remarks, anything that we missed that's worth highlighting?
I would say that the only thing I would say is that, you know, often understanding the commercial opportunity represented by relatively small indications is difficult.
Okay.
But I think in this particular case, you have 6,000-10,000 prevalent patients being refilled at 1,000-2,000 per year, and opportunities within that pathway to enrich those numbers based on elucidation of certain problems in the management of these patients. I think the other thing is that the concentration of that opportunity, at least 50% of those patients, are in 100 accounts being managed by a couple of hundred customers. And so, to Dan's point, you know, we're not going to be one of the companies that launch with 60, 80 reps.
Mm-hmm.
For panoply, that would have been a pre-COVID norm. So we're going to come to it with a smart approach and a very focused, you know, accessing of that opportunity.
Great. Well, we look forward to the updates. Guys, thanks for joining us.
Thank you.
Thank you.
Appreciate it.
Thanks.
Thanks.