And just, you know, maybe to level set, just an overview of the Dynamo platform and what we'll see from your pipeline over the next 12 months.
Yeah, thanks to Goldman for the invitation. I think we've all enjoyed the last 24 hours stuck in this building. And so to come back to your question, the Dynamo platform, there's a lot talked about the computational tools and their impact on broader society. We see the platform as just a constellation of tools. Those tools are both experimental and computational. They're combined together to solve very discrete problems slightly better than they're currently solved. And as you know, it takes hundreds and hundreds of steps to make a medicine. And so if you just stack it all together, you know, we do things slightly more efficiently, slightly more effectively, and hopefully in the end, it results in solving challenges and problems that others can't solve. And so we target the platform towards as low a risk as we can take in the clinic and on the biology side.
It's validated targets with genetically defined patient populations where we think the market opportunity is significant and that's amenable to our approach. That has led us to traditional precision oncology, which is why again last week what you saw us stacking on top of our PI3K alpha franchise, a selective NRAS inhibitor because it fits exactly the phenotypes that we've just described. Several years ago, we used the same criteria to identify genetic diseases as an area of interest for us. Again, what you saw last week was our unveiling a program with Fabry disease. It fits the criteria that we have described. Finally, we unveiled a PI3K alpha mutant selective program targeted against vascular malformations. We believe these are all very attractive markets, low biology risk in the clinic, significant opportunities commercially, and amenable to our platform.
And so maybe I'll hand it over to Pete and talk about just the kind of data that we're going to see over the coming 12 months.
Yeah. So probably the most anticipated data set we have upcoming is for our PI3K alpha mutant selective inhibitor, RLY-2608, in our ongoing breast cancer study called the ReDiscover study. There, just to remind folks, that molecule went into the clinic in early 2022, and we showed pretty clear and definitive differentiation across safety, tolerability from the non-selective inhibitors. And kind of the open question here is, given that the regulatory endpoint is progression-free survival, is generating enough data at an optimized dose with enough follow-up to give us all a bit of a sense of what that durability and potential PFS difference looks like? And that's really what we're aiming towards doing in the back half of the year with the 2608 disclosure we have coming up. So it'll be a pretty robust data set at an optimized dose for us.
That's 600 mgs twice daily in combination with fulvestrant. What we are guiding towards is having at least 40 patients that will have had at least six months of potential follow-up. That's relevant because the comparator, the most likely comparator in a potential registrational study in this setting, does 5.5 months immediately for us. It's working towards this data set of hopefully very clear and interpretable differentiation also on the efficacy side. The other guidance that we have, milestones in place for the year upcoming, is an update on our FGFR2 inhibitor, RLY-4008.
And so you may recall when we showed our initial tumor agnostic data in the fall of last year, we said at that time we were going to deprioritize the regulatory and commercial efforts for cholangiocarcinoma and let the tumor agnostic data mature and minimize the spend against that program until we get a clear picture of what the full profile of the molecule is across tumor types and then also have a regulatory interaction and really understand the regulatory path forward. Both those things are continuing to happen and guiding towards that update in the second half of this year also. So a pretty rich kind of data strategic update coming across these are two lead clinical programs. And then the new programs that Sanjiv mentioned for vascular malformations will be going into the clinic in Q1 of next year with RLY-2608 initially.
We do have an additional pan-mutant selective molecule that we can move into development there and would likely take forward for any pivotal studies in that indication. Then the Fabry's program will go into the clinic in the second half of next year and also the NRAS program.
Let's start with 2608. You've spoken about the knowledge and experience that you've built up over time with PI3K alpha. Could you walk us through your strategy for the franchise, including how you plan to position yourself in the evolving HR positive, HER2 negative breast cancer paradigm?
Yeah, I mean, I think we've always seen PI3K alpha as a significant precision medicine opportunity. And I think, again, we've laid out kind of three areas. There's obviously breast cancer. Inside of breast cancer, there are multiple lines of therapy and there are multiple combination partners. And so just having a suite of assets there, especially in the age of IRA, is important to us. Second, opportunity is distinct and sits outside of solid tumors in vascular malformations. And so obviously that consists of a range of different diseases inside of that. So again, a different molecule that's distinct may be advantageous to us. And then the final pillar is solid tumors outside of breast cancer. So we think that all three of these represent significant commercial opportunities. And maybe we'll just walk through them one at a time.
So maybe, Don, you can just take the landscape around breast cancer.
Right. So in breast cancer and hormone receptor positive, HER2 negative breast cancer, current first line standard of care in the metastatic setting is usually an aromatase inhibitor combined with a CDK4/6 inhibitor. And then in the second line, in patients who have PI3K pathway mutations, we've now seen two approved agents. Alpelisib, marketed as Piqray by Novartis, is a non-selective PI3 kinase inhibitor. Again, used primarily in second line patients post-CDK4/6 inhibitor. Real world PFS is about six months and comes with significant toxicity liabilities. And a real challenge for patients to stay on that drug with one of the hallmark toxicities being hyperglycemia and especially grade 3 hyperglycemia, which oncologists are very uncomfortable managing and frequently will discontinue use of the drug once they encounter that.
The more recently approved agent that Pete mentioned would be our most likely comparator is capivasertib, which is an older, relatively non-selective AKT inhibitor marketed as Truqap by AstraZeneca. I think we're seeing the market move towards that, largely driven by the fact that the rate of grade 3 hyperglycemia is reportedly lower than what you see with alpelisib. And again, that's a toxicity that treating physicians want to try to avoid. And that is in the setting of no better PFS than what you see with alpelisib. The clinical trial PFS was 5.5 months for capivasertib. So as we think about how you position 2608 in this landscape, what we've already shown with 2608 is proof of mechanism that we can achieve our target inhibition of mutated PI3K alpha while sparing hyperglycemia and not seeing grade 3 hyperglycemia.
And that's at our 600 mg dose as we move forward. So I think that positions 2608 well to be a treatment paradigm for the PI3K mutant patient population. The first pivotal trial that we could likely start would be a doublet with fulvestrant in patients who have previously been treated with a CDK4/6 inhibitor. And most likely the comparator could be capivasertib, again, with a benchmark of 5.5 months progression-free survival. There's also opportunities to move earlier in the treatment paradigm. We have seen positive data from Roche with inavolisib, their non-selective PI3K inhibitor in front line in combination with palbociclib, a CDK4/6 inhibitor. But that was a place where their patient population was very, very heavily selected for patients with good metabolic fitness using metabolic inclusion criteria that would exclude 50% or more of atypical Western population.
We think there's opportunities to move earlier into the front line setting in combination with a CDK4/6 or a CDK4 targeted therapy. That comes back to the other news that we disclosed last week that we've entered into a clinical trial agreement with Pfizer to combine RLY-2608 with their selective CDK4 inhibitor, which we view as an emerging standard of care in the treatment of positive, HER2 negative breast cancer.
There's clearly been a lot of interest in the pan-mutant isoform selective PI3K alpha inhibitor RLY-2608, as you talked about. At the phase 1/2 update last July, you reported a clinical benefit rate, response rate, and safety data in combination with fulvestrant. At this point, what are your thoughts on the dose level and efficacy profile?
You want to take that one?
Yeah. So when we made that disclosure last August, it was based on the data that we were seeing across our dose escalation cohorts where we had identified 600 mgs as being a potential optimal dose. Based on the fact that we were achieving our target inhibition, we were clearing the mutant ctDNA. We were seeing early efficacy data that was promising. We were starting to see responses. We were seeing good duration of benefit. And importantly, on the tolerability side, we weren't seeing grade 3 hyperglycemia. Overall, we were seeing a good overall tolerability. And importantly, in this disease, patients were able to stay on drug with their scheduled dose intensity. And that's really what you need to be able to win in a PFS driven environment, especially as you move early where you're looking at patients potentially having to take your drug for two or even three years.
Having that chronic tolerability is key. So the 600 mg dose looked very promising to us. We had announced last August that we would open 600 mgs as our first expansion cohort. We opened that, and by the end of last year, we had dosed about 40 patients at the 600 mg dose. We also did simultaneously open a 400 mg cohort. 400 mgs is really what we consider the minimal biologically effective dose. We did open that cohort, not because we feel it's an optimal cohort, but to provide us with a data set that would make us well positioned for interactions with regulators, especially in the Project Optimus era.
You next plan to present data from the doublet in the fourth quarter where you guided that at least 40 patients treated at 600 BID will have at least six months of follow-up. What are the relevant clinical benchmarks here? How are you thinking about the interpretability of the upcoming efficacy data?
Pete, you want to say that?
Yeah. The beauty of this one is it's quite simple. It's 5.5 months. So the clear burgeoning commercial standard of care in this setting is capivasertib, as Don alluded to. And they had a very robust clinical study, CAPItello-291. And in the true second line patients that are pathway altered, they had a median PFS of 5.5 months. And so we do believe that the data that we intend to present, as you outlined it, will be quite interpretable against that benchmark. And again, our goal is unequivocally to show differentiation against that. We can do that in a couple of ways in this data set. First and foremost, one metric we can report on is 6-month PFS landmark analysis. And that is extremely relevant here given that the benchmark median PFS is 5.5 months.
So if we can see a 6-month PFS landmark analysis rate decently north of 50%, it starts to give us all confidence that in a head-to-head study, in a well-controlled randomized trial, that we could beat that 5.5 months mark. And so I think that's going to be probably the key metric that folks will be looking for. We'll also report on clinical benefit rate. Again, that's a 6-month endpoint. So it's the stable disease or better at 6 months, which is helpful in this comparative cross-route comparison context. And then we will report on the typical metrics of response rate and other supportive endpoints, safety and tolerability, full update. We should have over 100 patients in a safety database at that point in time, over 60 of them at 600 mg twice daily. So it should be a pretty robust and interpretable data set.
You'll also have triplet data with CDK4/6. Maybe help us understand what you hope to learn from this data set and whether it can enable you to move to earlier lines?
Yeah, I mean, as we've seen over time, we don't think a mutant selective PI3K inhibitor, sorry, a non-selective PI3K inhibitor has been able to combine, which is fast becoming the established market leader in the CDK4/6 world. Obviously, for us, we feel very confident that we can demonstrate that we could get a combinable dose of RLY-2608 with ribociclib. And so that would be the goal in any disclosure to show safety and tolerability. Obviously, as we announced last week, we've also now have a clinical trial collaboration with Pfizer to combine RLY-2608 with their first in class selective CDK4. And so our goal is obviously to show that if you want to go earlier and earlier, the kind of safety and tolerability is important as you stack on each of these various AEs on top of each other.
So again, the selective approach that we have with RLY-2608, and we believe the early data we've shown clearly shows that there could be a potential safety and tolerability advantage over the non-selective inhibitors, makes it better for patients that are going to be on therapy for long periods of time in early and earlier lines. So I think that's the goal of the disclosure would be to show combinability and obviously safety and tolerability.
Once you do have these two data sets in hand, how are you thinking about the registrational pathway from there?
Pete, you want to take that one?
Yeah, I think we have a couple of regulatory interactions ahead of us. One, kind of as a part of your question earlier on dose, we have to go have a conversation with the FDA on dose. That's why we're accumulating these data at both 600 and 400 just to enable ourselves to have that conversation in the back half of the year. And then additionally, we are currently thinking about and designing a potential registrational study in the second line setting. And so once we have that, once we've had the dose conversation, we also need to have kind of an end of phase 2 conversation around the phase 3 trial design. And so those will probably be sequenced.
So that would enable us to be ready to enter into a phase three study, start a phase three study in the second line setting, likely in the middle of the back half of next year. That trial we believe is some of the considerations of that trial that we need to really continue to think through is in such an evolving landscape. It's the level of pretreatment with CDK4/6, level of pretreatment with chemotherapy, prior fulvestrant, the studies that have come before us that we will be compared to, particularly CAPItello-291, had very minimal CDK4/6 pretreatment, 30% had no prior CDK4/6, and the rest had one. On the fulvestrant side, they had 0% of patients had prior fulvestrant treatment. Chemo was below 20%. And on our ongoing ReDiscover study, we do have patients that have seen multiple CDK4/6 inhibitors, have seen 50% or so prior fulvestrant.
The chemotherapy pretreatment range in the metastatic setting is upwards of 30%. So it's going to be pretty important for us to think about running a phase 3 trial in really a contemporary patient population. And our goal here is to design a study that the outcome can be interpretable and have utility for the broadest patient population possible. In the second line setting, in HR positive, HER2 negative PI3K alpha mutated patients, there's 14,000 patients a year in that setting. And so if you can provide a differentiated treatment for those patients and one that they can stay on for a good amount of time, that's an extremely meaningful market opportunity for a company of our stage and size.
Let alone starting to look into the future, and this is what some of these supportive triplet studies are doing, is really enabling us to think about that next pivotal study, which would be in the front line setting. That would start to unlock 18,000-20,000 patients per year. And then you're talking about years of potential treatment in that setting. So this is kind of the building blocks we're putting in place now to enable us to do over the next couple of years.
I know it's early days, but can you speak to the timelines of the combination program with Pfizer CDK4?
You want to take that?
Yeah. So obviously that deal was just signed. We're guiding towards initiating that study by the end of this year. So I think let us get a little bit closer to treating a patient in that setting, and then we can start to think about guiding to potential data there.
Don, was there anything to add with regard to the trial?
No.
You plan to start the clinical development program in vascular malformations driven by PI3K alpha in the first quarter, as you mentioned. How are you thinking about which indications to initially pursue and the path to proof of concept?
I mean, it's a big, again, opportunity for us. Over 170,000 patients with PI3K alpha altered vascular malformations. It's a spectrum of different conditions. Maybe, Don, you can just kind of help us educate around the different diseases involved here.
Yeah. So I think we're really, when you're looking across the spectrum, the first that we'll talk about is PROS or the PI3K related overgrowth spectrum, which is really a collection of distinct diseases. But the one commonality is all of them are driven by mutated PI3K alpha. So that's a population that's 100% mutated. It's a population where today there's existing proof of concept from alpelisib, where there's an accelerated approval in this patient population. And that was based on a retrospective cohort review of 37 patients that were treated in a compassionate use program using a primary response endpoint of radiographic response in the lesions, 20% volumetric reduction. They saw a 27% response rate. So one of the first questions we can ask is, we actually have a benchmark in that population. We know PI3K is the driver in that population.
One of the first questions is, in patients with severe PROS, coming in with a mutant selective inhibitor, can you take advantages of having, again, that chronic tolerability that comes from sparing wild type PI3K alpha and ultimately drive the response to a higher than 27% response rate using the same endpoint? As you then go across the other subtypes of vascular malformations, the one with the next most frequent PI3K mutations is lymphatic malformations, where about 80% of patients have a PI3K mutation. There's not an existing benchmark today. There is an alpelisib trial running in that population. But again, this is a place where we think early on we'd want to try to include patients with PI3K mutated lymphatic malformations to establish the breadth of signal with 2608. As you get into venous malformations and cerebral cavernous malformations, the PI3K mutation rate gets lower.
I think you'd have to do some prospective selection of those patients to identify the PI3K mutated patients. Our trial, we anticipate, would be open to those patients, but we anticipate they would not be represented at the same rate as PROS and lymphatic malformations.
Delve a little further into that. Maybe speak to the commercial aspect here, the ability to identify these patients where they are now, and how you think of the ability to kind of initially go and get then target that large market that you mentioned.
Yeah, I mean, we believe it's a very attractive commercial model for a company of our stage and size. Maybe Pete can talk through the details.
Yeah. I think one thing to make very clear is this is a pretty nascent disease setting. For those that tuned in last week to our R&D event, we had a KOL there, Dr. Adrienne Hammill. She was one of the first KOLs in this space, was trained under the pioneer in the space, Denise Adams. The very first study actually looking at vascular malformations was only conducted in 2009. So I think, and I preface my answer with that because there's still going to be some learning to do here, especially in terms of commercial setting, how to find these patients.
But today, it sounds like in talking to some of these KOLs, there's about 12 or so centers of excellence that exist in the United States that are seeing a large bulk of these patients, especially those that have reached that severity level of seeking the very paltry systemic therapies that are available today. And so I do think within PROS, there's about 15,000 of these patients in the United States completely driven by PI3K alpha mutations. In lymphatic malformations, as Don mentioned, 80% of them are driven by PI3K alpha mutations. And so in both of those settings, they're clinically diagnosed with their presentation, not necessarily needing a genetic test to confirm that diagnosis. And there, if you add those two together, you get into the neighborhood of 70,000-80,000 patients in total just in those two disease settings.
Today, it seems like about 25%-40% of them are seeking systemic therapy. Those that are seeking the systemic therapy seem to be concentrated across these centers of excellence where you have a vascular anomaly specialist team. So there's definitely a good large proportion of, at least in those two disease settings, where the commercial model is really amenable for a company of our stage and size. It truly is a rare disease-like commercial model. We have some precedents on the; it's always too early to talk about pricing when you haven't even treated a patient in that disease setting, but there is some precedent on the pricing side there too. Vijoice, which is the brand name of alpelisib in this setting, charges about $350,000 a year.
Switching over to your selective FGFR2 inhibitor, you will have data as well as commentary on the regulatory side in the second half. I guess, where will you stand with regard to alignment with the FDA? What can you disclose at that time point?
You want to take that one, Don?
Yeah. So I think what we disclosed at the end of last year was that we are active in patients outside of cholangiocarcinoma that have tumors that are driven by FGFR2 alterations. With a response rate that we reported at the time last year in patients with FGFR2 fusions or rearrangements, that was consistent with some of the recent approvals that we've seen in a tumor agnostic setting. So as Pete mentioned, we made the decision at that time to continue to build the database outside of cholangiocarcinoma to enroll more patients, to get more follow-up, to get a more precise and robust estimate of duration of response, to give us the ability to then take these data to FDA and really ask a few key questions. Ask about the agreement that there's unmet need in this setting, which would be the benchmark for being able to pursue accelerated approval.
Ask about the data that we've generated. Is it sufficient in terms of the number of patients and, importantly, the distribution of tumor types to be able to be considered for an accelerated approval path? So those are really the key questions that we need to come to agreement with the FDA. And we anticipate we'll have a regulatory interaction this year to be able to ask those questions.
And just to add on top of that, then I think with that information in hand, with the data we have in hand, it is then incumbent upon us to take a step back, look strategically at the entirety of the portfolio and the opportunity sets we have in front of us, and just really ask the capital allocation question, and where can we produce the most value? And so I think that is the third piece of this that we'll be, one, discussing internally, and then part of when we report out data and kind of an outcome of regulatory interaction is really kind of try to give some guidance on the strategic path forward and how this fits into our very large growing opportunity of medicines to put our capital behind.
On the Fabry and NRAS programs, there are clinical bars, but there are also competitive bars in some cases. So help us understand how you're going to demonstrate differentiation through the studies initially so we can understand the proof of concept here.
Maybe we take them one at a time. Maybe start with Fabry's, Don?
Yeah. So in Fabry disease, I think you're looking at a setting today where there is an approved small molecule, chaperone. It is an inhibitory chaperone of the alpha-gal protein, which is the mutated protein that's disease-causing in Fabry disease. And that's important because it comes with some limitations of that therapy. It's got a very strict every other day dosing schedule. It's only active in a subset of mutations representing about 40% of patients or so. And our hypothesis and the data we showed last week is if you could identify a more potent and robust non-inhibitory activator of alpha-gal, you should be able to do three things. One is you should be able to increase relative to what you can do with migalastat, increase the amount of alpha-gal that's active and stabilize it, increase activity, and show a greater effect on substrate reduction.
We've shown preclinical data supporting that for our molecules. So that would be one of the questions as we got into patients in early development. As you look at the biomarkers for alpha-gal activity, you see superior levels to what's been shown previously. We've also shown that we can address a broader range of mutations. So that obviously would be another question as you get into some patients who today are considered non-amenable to migalastat therapy. And then finally, and this is more of a longer-term question from the development perspective, we've shown the ability to be able to combine with enzyme replacement therapy. So in the minority of patients that aren't appropriate for a small molecule activator or chaperone, can you combine with enzyme replacement therapy and increase the activity that you see there?
So I think as we get closer to the clinic, we'll come forward with more specific clinical designs. But I think those three pillars of what we're trying to do with this program will be a goal to establish the differentiation early in the development of the asset. And then on the NRAS, it's more of a classic precision medicine play, which is we think there are a large amount of over 25,000 patients in the U.S. that have NRAS-driven solid tumors. If you could exquisitely selectively inhibit NRAS, we believe that should translate into better clinical efficacy than the current kind of drugging other parts of the pathway. But you could do it without the associated tolerability challenges associated with this kind of non-selective and other nodes in the pathway. So it's a classic play. Deeper inhibition, less tolerability challenges should translate into a better outcome for patients.
Don, if you want to just talk about how we see it.
Yeah. I think as we look across the spectrum of NRAS-mutated tumors, you see concentration in melanoma, colorectal cancer, non-small cell lung cancer. It's actually a distribution that's very similar to what you see for BRAF mutations, the V600E mutation. And we would anticipate that as you are starting to look towards development of the asset, you'd focus especially on those three diseases with the goal, as Sanjiv mentioned, of being able to show that you can hit NRAS hard without seeing the associated toxicity associated with either pan-RAS inhibition or downstream node inhibition. And skin toxicity is one of the major categories of AE that you see in that space with the pan-RAS inhibitor from RevMed showing about 80% rate of skin toxicity. We would believe, based on everything we know about NRAS, that if you hit NRAS selectively, you should be able to avoid that class of toxicity.
So that will be a key question we'll look to answer early on. And then I think we anticipate that you'd be looking for monotherapy responses across those NRAS-mutated patient populations to establish proof of concept.
Speak to the business development side here where you have acquired and partnered to acquire technologies. How are they being integrated at this time point? Are you looking for more going forward?
I think, as you know, the platform consists of this kind of constellation of different tools and approaches. And so we're probably one of the most experienced kind of exponents of using the tools in combination with each other to make INDs and ultimately clinical compounds. So I think we see pretty much everything that's out there. We acquired almost three years ago now a company called ZebiAI that helped us build an internal capability around using big data and DNA-encoded library screens in a much more kind of insightful way, using machine learning to try and get to starting points much more rapidly. And so we've been able to successfully integrate that. Over time, our platform continues to evolve. We continue to incorporate new approaches, double down on things.
I think, for example, the molecular dynamics that we do now internally, we pretty much have all the capabilities that we need in-house. And so we can build things. There are plenty of tools that we've used over time that we have found to be not productive. And so it's a constant evolution. I think on the business development side, probably our bigger focus is what to do now with this kind of very broad set of assets that we have in the clinic. Obviously, we've talked about the three pillars of PI3K alpha, vascular malformations, breast cancer, other solid tumors. We have our FGFR2 inhibitor. Obviously, now we have Fabry's and NRAS. So that's a lot of assets to prosecute ourselves. So probably our focus is much more on how do we bring all these assets to patients as rapidly as possible.
We'll continue to look at platform assets, but the threshold for us to bring one of them inside is high.
Great. Well, with that, Sanjiv, Don, and Pete, thank you so much. Really appreciate the time today.
Great. Thank you.
Thank you.
Thank you.