Okay, great. Thanks, everyone, for continuing to join us at the Stifel Healthcare Conference. My name is Brad Canino. Very happy to be joined by Pete, the Chief Corporate Development Officer at Relay Therapeutics. Thanks so much for joining us.
Yeah, thanks for having us, Brad, and the rest of Stifel. Great to be here.
Can we kick off with just an intro to Relay? And then maybe discuss how the portfolio has evolved over this past year.
Yeah, I mean, you know, rewinding the clock eight years ago, we launched the company with the idea of bringing together cutting-edge experimentation and computational techniques and tools. And now, here, eight years in, it's been an extremely productive research organization and platform. And I think we were able to show continued advancement of that in our R&D event in June, where we, for the first time in a couple of years, announced two very innovative new programs with our Fabry and NRAS molecules. You know, there, again, discovering novel mechanisms to bring about very differentiated profiles for molecules that I think, you know, the through line that you've seen in all our programs, we identify the ability to gain selectivity that is obvious that you would want to do it.
But heretofore, the tools and capabilities that have been available to the industry have not been able to discover molecules of that profile. And so that was obviously the case with our PI3K alpha franchise, certainly with our FGFR2 inhibitor, our SHP2 molecule, and now continuing to see that productivity in both the NRAS and Fabry molecules, which we continue to progress preclinically on track to bring those into the clinic later next year. And then also, you know, continuing to expand the PI3K alpha franchise, the PI3K alpha mutant selective franchise, where we will be bringing 2608 into genetic disease vascular malformations. So announced that also in that June event. And so continuing to evolve the pipeline and continuing to have a very productive research organization against very difficult targets.
And then obviously, what gets most of the attention is the continued advancement of 2608, our PI3K alpha pan-mutant selective molecule in HR+/ HER2-, PIK3CA-mutated breast cancer, and showing, you know, in September, pretty definitive and clear data that for the first time it demonstrates the power and potential of mutant selectivity for PIK3CA mutations. So being able to show for the highest PFS, the highest ORR, and the highest CBR seen to date with a pathway inhibitor in combination with fulvestrant in second-line plus breast cancer patients. So very, very excited for what's in front of us, both with 2608 and the breast cancer opportunity, but then the rest of the pipeline and the opportunity in front of us over the coming years, and having obviously the balance sheet and infrastructure and team in place to execute against all of that.
Yep. Maybe let's expand on the 2608 data. And can we talk about that framed against the Phase 3 trial that you have sketched for investors? I think we're still waiting for total regulatory clearance on that. But why do those data give you confidence against the backdrop of the trial you're planning on running?
Yeah, very specifically to the trial we are planning to run, which is going to be 2608 plus fulvestrant versus capivasertib AstraZeneca's AKT inhibitor plus fulvestrant. In, you know, ostensibly second line, there will be some, you know, third line plus patients in there, but ostensibly a second line patient population. So knowing that that's the design that we're going to run, and if we now think about the Phase 1b data that we announced a couple of months ago, there we're in a slightly more heavily pretreated population than what that Phase 3 population would be. And even still, in being in more heavily pretreated population in a cross-trial comparison, have been able to compare quite favorably against the progression-free survival that capivasertib was able to produce in the CAPItello-291 study.
Really, any way you slice the PI3K alpha pathway altered patients from that study, you know, you can get to a median PFS of 5.5 months across all pathway altered patients or 5.6 months. If you look at the PI3K pathway, PIK3CA mutated CDK4/6 experienced only, you know, our 9.2 months median PFS, again, in almost a 50% third line plus patient population is really probably the biggest point that drives our confidence in the potential for success in the Phase 3 study. We think that that 9.2 months has the potential to improve further once you get into a more second line patient population.
Okay, and now, just looking at the data, again, I think one of the questions you've gotten and I've gotten is, what is the confidence level that 2608 has reached the maximum efficacy threshold that could be available for the mutant selective PI3K alpha inhibitor class?
Yeah, I think it's the totality of the evidence that's been presented to date by the non-selective inhibitors in the class. You know, one of the, from a preclinical standpoint and assessing, you know, the breadth of clinical data that alpelisib, so Piqray from Novartis has produced, really has shown nicely that once you get above that 80% threshold of inhibition, you don't see much difference in efficacy as you continue to increase in target coverage. They demonstrated that very nicely from their preclinical profile into also assessing PK and clinical efficacy data from their own clinical experience. We've then recapitulated that preclinically ourselves, and then clinically, we went into the, when we did our dose escalation, our 600 mg twice daily dose, which is our recommended Phase 2 dose, gets us well above that IC80 throughout the dosing interval, on average sitting closer to IC85.
And we also went to a higher dose above that, 800 mg twice daily. And really didn't, you know, we got incrementally more target coverage there, but didn't see any meaningful difference in efficacy. So again, we've been able to see the breadth of data produced by Novartis with alpelisib. We've recapitulated that preclinically in our own studies. We're now seeing it manifest clinically ourselves. And so I think that is really what is driving us to be comfortable with this idea that, you know, once you get above the IC80 threshold for the dosing interval, you're likely getting as much efficacy as you're going to be able to out of hitting the PI3K alpha mutant. You know, fall short of seeing clinical data from a molecule that meaningfully gets above that and disproves that theory. You know, we haven't seen any additional data to suggest otherwise.
You know, I think we should see some data from LOXO-783 at San Antonio Breast Cancer. That molecule is being discontinued, but it's a very selective molecule. And so it'll be, I think, a little bit informative against this question. That's obviously a kinase-only molecule, specifically even more specific to H1047R. You know, in our own clinical data, we're very active across all mutations. But specifically also in the kinase-only patients, we're seeing even greater activity. So again, it'll be interesting to, you know, compare as some of these more selective molecules produce clinical data that are all further behind us.
Okay. And now back to your trial. Why do you believe that Truqap capivasertib is the right comparator arm instead of Piqray/alpelisib?
Yeah, there's a couple, probably two driving factors there. One, as you can imagine, we've had a large number of interactions with physicians as we get ready for this Phase 3 study. And overwhelmingly, physicians globally are telling us that capivasertib is the preferred pathway inhibitor for PIK3CA mutated patients in the second line. It's further supported by, if you watch the first few quarters of sales from Truqap, in contrast to those same quarters of sales for Piqray, and you see a pretty strong launch by Truqap. So about $40 million in the first quarter, up to $90 million in the second quarter of launch. And then most recently, I think it was last week, they announced $125 million in the third quarter being on the market. In contrast, you've seen for each of those quarters, Piqray sales have declined.
I think it's the feedback we're hearing from physicians globally, plus the dynamics we're seeing commercially, strongly support that capivasertib is the preferred comparator in today for pathway altered patients.
Okay. And now what is your timeline for regulatory discussions? And when do you hope to be enrolling the first patient pending sign-off?
As soon as possible. So I'm not going to comment on specifics of regulatory interactions, but it's corporate priority number one to get this trial up and running. We have a clear advantage, a speed advantage over the other peers in the space, and we will continue to maintain that. And so, you know, we have to go have the regulatory interactions to get aligned on dose and trial design. We're moving as quick as we can. And once we get on the other side of that, with written minutes in hand, we'll find a way to get that feedback and outcome in the hands of the public.
Okay. Now, a two-parted question. First part is, how should we think about the potential timeline of the second line study, given that it is the first Phase 3 in breast cancer where a targeted therapy will be used in the control arm where I think a lot of our analogs that will just have been fulvestrant monotherapy?
Yeah, so there's some precedence here. It's not perfect. But generally speaking, if you look at CAPItello-291, you can get a little bit of a sense of how long these trials generally take to enroll. We have been able to see some enrollment updates from the inavolisib second line study they have ongoing. So INAVO121, they gave an update on their enrollment at their ASCO trials and progress poster. You know, that is probably the closest analog to what we're contemplating in terms of design and size. So I think generally you see these studies enroll in about three years. And because you're talking about a control arm that does somewhere in the neighborhood of six months of median PFS, you know, you tend to get your top line readout in and around the same time as full enrollment.
There's some other peers in the space in both the next-gen oral SERD and also in the CDK4 space that are seeing similar kind of timelines to enrollment and top-line data.
Okay. So we're seeing a 2025 start, potentially 2028 around the time first top line can be available. So talk about that in relation to your balance sheet. Does the balance sheet allow for full funding of that second line study to that time point? And then how does the rest of the portfolio that you're starting to put into the clinic now be managed within that balance sheet?
Yeah, so just reported our Q3 numbers, had $840 million in cash on the balance sheet as of Q3, and what we've said is that in totality, that will take the company well into the back half of 2027. And that's presuming you continue to progress everything wholly owned to its fullest extent. The way we will operationalize that $840 million is we will ring-fence the cash necessary to run the phase three trial through top line data and then some cushion, and we will advance the rest of the portfolio, you know, along the way as far as we can without touching the amount of cash needed to run that phase three study, and we do think that'll bring the rest of the portfolio through meaningful inflection points, and then, you know, we'll have to make some strategic decisions along the way to continue to capitalize those programs.
But even with ring-fencing the cash necessary for the Phase 3 study, it still allows us to meaningfully advance the rest of the portfolio.
Okay. And now how do you size the market opportunity for second-line HR+ breast cancer with the mutation and especially with the better drug that you're anticipating to be more durable?
Yeah, we frequently get the question of like, sure, your second line data is great, but how do you, when you go into front line, because that's a large setting, and it's certainly a, we expect to move to the front line over time, but I think what we continue to educate folks around is the magnitude of the second line opportunity. There's over 13,000 PIK3CA-mutated patients in the second line in the U.S. alone in the U.S. here, and so we think that, you know, that is where the largest unmet medical need is. We've had agents continue to get approved in the second line that haven't really moved the standard of care meaningfully. You know, fulvestrant, single agent, got you two to three months. We've had a plethora of other agents approved, and we're still only sitting at five to six months of median PFS.
In contrast, in the front line endocrine sensitive patients, we're two plus years of median PFS. So this is where the largest unmet medical need is. We have hopes to get meaningfully above 10 months of median PFS if our data continues to progress in the way that it currently is and as we move into more second line patients. So that, you know, the peak sales of that class today with, you know, median PFS at around six months is probably sitting in a, you know, $2 billion range. If you can meaningfully advance that PFS to 10 plus months, you know, you start to substantially grow that peak sales opportunity. And that's our intention.
Okay. And now should we anticipate any further updates to the Phase 1b for the doublet? And I guess, will that be further informative or will it most likely just be confirmative of what we've seen?
Yeah, I do think at some point in time we will update the Phase 1b again, you know, once we reach more greater maturity, if we think it continues to be informative against, you know, the potential POS, but probably success of the Phase 3, so we will do that at some point in time, not precisely guiding to it today, but, you know, certainly feasible to do that again sometime in 2025 as we round out that portion of the study. I think it'll be, you know, it'll be more confirmatory than revelatory, I suppose. The data is pretty mature as it was. You know, it had a seven and a half months median follow-up when we reported data in September, so, and we see potential for that to improve and strengthen.
But I don't think you're going to see, you know, dramatically different looking data coming out of that study with further maturity.
Got it. Okay. And now what is the status of the 2608 triplet combinations and what should be the focus of the first data updates that you provide for these?
Yeah, so to remind folks, we kind of have two different triplet strategies today, if you will. The first one is with ribociclib. So 2608 plus the CDK4/6 inhibitor ribociclib plus fulvestrant. That started earlier this year. And then the other one is via clinical trial collaboration we engaged in with Pfizer. We will be imminently starting a triplet combination with Pfizer's CDK4 selective inhibitor, atirmociclib. They're kind of both with the lens of being able to address and think about that front line patient population in the future. In the context of the initial update with ribociclib, you'll recall that in our September corporate call, we did disclose that we are seeing a favorable drug interaction with ribociclib to where it is increasing the exposure of 2608. We observed that in the first dose that we brought into the study earlier this year.
Once we saw it, we had to, you know, understand that interaction. We slowed down, took our time, went to a pretty low dose, and have been making our way a bit more cautiously, so the data we'll have in this update is going to be a minimal number of patients, not a lot of follow-up. It really would be focused on continuing to give folks comfort that we are on track to be able to find a dose of 2608 that can be combined with full dose ribociclib, which has not been able to be achieved with the non-selective inhibitors, so it'll be a minimal amount of PK and safety data in the initial update, and I think what you'll really see is as we identify a dose either later this year or more likely early next year, we'll then move into expansion cohorts.
And that's where we'll be able to expand the label, potentially get some CDK4/6 naive patients. You know, it is challenging to convince physicians to use the ribociclib specifically in a CDK4/6 pretreated setting given the limited data and really the strength of our own doublet data. But we're still making our way through it. And we'll give a nominal update that will allow everyone to understand why we continue to feel very confident that we'll be able to identify that dose.
Okay, and now does combinability with full dose ribociclib, does that create a competitive advantage against the other mutant selective inhibitors? Or is it really just against the other wild type inhibitors?
I candidly think it's probably more so against the other wild-type inhibitors. I would anticipate, not knowing, you know, full pharmaceutical properties of some of the other mutant-selective molecules, that they should be able to also find a combinable dose with any of the CDK4/6 inhibitors. You know, their main advantage is time. But yeah, you know, again, not knowing if there's any drug interactions or any other potential limitations to those molecules, I would expect them to be combinable also.
Okay. So maybe moving to mutant selective PI3K alpha inhibitors for vascular malformations. Can you frame this opportunity maybe against the cancer setting, given that it's somewhat of an analogous situation where both have approved wild type pathway inhibitors today?
Yeah, we are very excited about this opportunity. You know, vascular malformations in general is a bit of a nascent field. You know, it's a field that was just, you know, only defined or in earnest probably about 10 years ago. And so there's still a lot for all of us to learn about this space. But we know it's a disease. There's 170,000 vascular malformation patients in the U.S. with PIK3CA driven, mutant driven disease. We know it's generally the same distribution of mutations that you see in oncology. And so there's a lot of the learnings we can take from our oncology experience that gives us a lot of confidence as we move into vascular malformations. We understand the differentiation of our molecule against alpelisib very clearly in oncology.
We would expect that that differentiation from a safety tolerability dose intensity will be an advantage of ours as we move into vascular malformations. You know, it's a very heterogeneous disease that not only do you have the subtypes of, you know, PROS, PIK3CA-related overgrowth spectrum, and lymphatic malformations, venous malformations, but even within those subtypes, there's heterogeneity among the patients. So we have a bit more to learn in terms of exactly what clinical outcomes matter and how to continue to progress this in the best way for patients and physicians. But generally speaking, there's a lot of optimism and confidence we have in the opportunity here because of what we've learned from the differentiation profile in oncology.
I think one of the, you know, of the 170,000 patients, one of the things we want to learn over time is what percentage of those patients would be seeking systemic therapy for the disease. I think that's the one area where, you know, we all have a bit more to learn. This is a chronic disease setting. Even if it's only 10% of patients, that's 17,000 patients in the US taking a drug chronically. We've seen, you know, as you know, we have a, as you said, we have a little bit of an analog with alpelisib accelerated approval in the setting. They price that the vascular malformations brand at about $360,000 a year. The genetic disease pricing paradigm is quite attractive.
It's a commercial paradigm that, you know, a company of our stage and size could also wrap their arms around.
Yeah. Now, how quickly can you generate data with single arm endpoints in this setting? And what do you hope to show the physician community to increase interest in an alternative approach versus the wild type inhibitor?
Yeah, so I think, you know, there's right now the clinical endpoint being used is really focused on, it's a radiological endpoint of shrinking the volume of these lesions in patients. It is the, it's a 20% reduction, volumetric reduction or greater at six months. We know that in PROS patients specifically, in a limited number of those patients that got alpelisib accelerated approval, they saw a mid-20s% rate there. So I think what we'll do is make sure in our initial clinical experience, we're having a large focus on, or a good focus on the PROS patients initially so that we can get, you know, some cross trial comparison data early on. And that will allow us to compare what we're seeing with our molecule against what we, the limited amount we know with alpelisib.
Then, you know, we will also be looking to expand further across the other vascular malformation subtypes, very specifically the lymphatic malformations is a very attractive one. The lymphatic malformations, 80% of those patients carry a PIK3CA mutation. So that's a very large population that's almost entirely characterized by these PIK3CA mutations. So first, you know, we want to understand our own PK and safety, but then also get into patients where we can start to, in an early way, do some comparisons to what we've been seeing with alpelisib .
Okay. In the mutant-selective attribute, relative to a, you know, second- or later-line cancer setting, is that attribute more important, less important, or equally important in what you described as likely a chronic duration therapy market?
Sure. As soon as you get into any chronic disease where the goal here is to treat these patients as early in life as possible. These are somatic mutations that happen in utero. And so now you're, the aspiration is to start treating children. I think the safety profile, you know, becomes extremely important. And so the, probably the greatest advantage we'll be able to bring is the safety from the mutant selectivity is the fact that it is able to keep at bay some of the toxicities associated with the non-selective inhibitors. And so we'll see, we probably don't need quite as much target coverage too for these patients. We'll see how that plays out clinically, but our hypothesis looking at the alpelisib data, you know, they're using a dose that's about 1/6 of the cancer dose, you know, half to 1/6 .
So we think that we might even be able to, you know, improve upon our existing oncology safety profile if it means that we can go at a slightly lower dose too, but we'll see how that plays out clinically. So I think the biggest thing, the biggest differentiation we bring to bear is the ability to keep at bay the toxicities associated with the non-selective inhibitors.
Okay. Great. Maybe last question for me as time is ticking down. You have the other pipeline programs you announced. I think the non-inhibitory chaperone to stabilize alpha-Gal is interesting because it's got a clear market analog of, you know, what that market actually is in terms of commercial sales. How do you plan to position this new drug in the Fabry treatment paradigm against that?
Yeah, Amicus has done a great job with Galafold. You know, before Galafold, there was not really a great oral therapy opportunity. There's really just the enzyme replacement therapies that didn't work that well for all patients. It does a good job for a subset of patients. But we still see a lot of limitations left on the table with Galafold. It's like, as you rightfully point out, it's an inhibitory chaperone, meaning that it has to hit the active site of the protein and inhibit the protein. And it's only through a dosing regimen of one day off, one day on, one day off when the molecule comes off the protein that they get some transient activity activation of alpha-Gal . We at Relay discovered a novel allosteric pocket that is allowing us to have a non-inhibitory chaperone.
We are getting, we are thus far preclinically, we're seeing greater mutational coverage than what is available on the label of Galafold. And even amongst those that we can compare to that is on the Galafold, we'll see greater activation of alpha-Gal . And then because it's not that it is a non-inhibitory chaperone, it does bring it puts on the table the ability to combine with enzyme replacement therapy. So as opposed to only being able to address 30%-40% of the 8,000 patients with Fabry disease in the U.S., we think the full 8,000 will be available to us with a molecule of the profile that we are bringing to the clinic.
Okay. Well, we will stop it there. Pete, thanks so much. Great to see all the progress this year.
Yeah. Thanks again for having us.