Yeah, I'd love to hear your take.
Yeah, first of all, thank you for the invitation. I think, as you know, I mean, the weight of news and changes, you know, is, like, kind of unprecedented at the moment, very similar to the time, back five years ago, when we were dealing with COVID. I think it taught us a lot of lessons back then to try and diversify our supply chain, and make sure that, you know, we did not have a kind of single point of failure. As yet, we have not seen any, you know, real impact on the work that we do. I think we are, as an industry, better set up, having been through those COVID years, to cope with anything that comes our way. As yet, we have seen no real impact on the work we do day to day.
Gotcha. I guess the other question around the FDA and if there's, you know, layoffs or threats of layoffs.
Yeah.
change in leadership, if that's changed the communication pattern in any way or speed or, you know, process there?
Yeah. Again, as you know, like, these things are very kind of discrete events. And obviously, we had a very successful end-of-phase II meeting for RLY-2608. We continue to have dialogue with them on some of our other programs. Again, we've seen absolutely no difference, but it's gonna be very hard to judge, and it's gonna kind of be an industry-wide question. As yet, for us, no difference.
Okay. I guess, final kind of macro question would just be around NIH budget recalculations, if that has any kind of near-to-mid-term impact on the company and also clinical trial sites.
Again, I think, again, very, very kind of acutely, we've seen no impact. Obviously, as an industry, we don't think this is gonna be positive for us in that a lot of the innovation that, that we, you know, build our company on has, you know, has been funded at some point in the past, through these grants. I think for our industry, this is definitely not a positive. Hopefully, this is a short-term reversal, and that we can get back to something that's closer to normal.
Gotcha. Thank you. I'd love to talk around, maybe I can dovetail into this question around RLY-2608, the trial design. Before then, maybe just, like, Arvinas' oral SERD data, how that changes the landscape for you? They didn't hit significance on the intent to treat population. Is that positive, negative for you?
Yeah, absolutely. I mean, obviously, the VERITAC-2 trial, the readout was this morning at the top line. Those of you who didn't follow it closely, I think the market and patients were all looking for a broad kind of ITT win, which is what we did not see, unfortunately. It was, like, the other oral SERD trials that have read out over the last couple of years, positive in the ESR1 mutant population. I think, you know, what we were hoping for was one of these SERDs kind of steps forward and really truly differentiates. This one looks like more of the same, which is they're gonna be niched into later-line ESR1 mutant-only patients, which is still a reasonable market. Kind of 35%-40% of those patients have the ESR1 mutation.
For us, I think what it means is our choice of fulvestrant, as the choice of our combination partner, is one that is gonna be valid for a while. There isn't gonna be a SERD with a broad label anytime soon. The trial is kind of future-proof there. I also think it opens up the window for us to be used in earlier lines. The worry has always been that, you know, would you be able to have, you know, a true, three-branded drugs as a triplet, given the financial implications of that? We don't think that the oral SERDs will be kind of broadly used with the data that we've seen in earlier lines, and therefore opens up an opportunity for RLY-2608.
Is there any kind of read-through, you know, of the, Arvinas had a degrader, so it was potentially dissimilar to the other.
Yeah.
Oral SERDs, but in fact, it looks a lot more similar to the other oral SERDs than we thought about, you know, a week ago, essentially, or six hours ago.
Yeah.
Is there any worry for that, for the PI3Ks, that, you know, you've got a targeted PI3Kα, but, you know, longer run, it starts looking more and more similar to a PI3Kα?
I don't think we see any read-through there. I mean, I think on the true differential mechanism of action of Arvinas's degrader from the other SERDs, it was a real question. Would a different mechanism of action really lead to a different outcome? I think what we saw this morning is no. I think the question around would a mutant-selective PI3Kα inhibitor look different from a non-selective PI3Kα inhibitor, I think we've answered the question. The data we showed at San Antonio showed that you get a truly differentiated safety profile. It was early, nine and a half months' worth of follow-up, but still enough to show, you know, very minimal rates of hyperglycemia. Obviously, you know, we saw a dear doctor letter yesterday night for inavolisib from Roche, showing that, you know, the problem of diabetic ketoacidosis exists in those patients.
Hyperglycemia is real, in the non-selective inhibitors. I don't think we see this as any risk, in kind of the mechanism of action will prove out later to not be valid. Mutant-selective inhibitors lead to truly differentiated safety profiles. What we saw at San Antonio was the data then translated into truly differentiated efficacy.
Perfect. Thank you so much. That's really helpful. Kind of going back to your trial, you reduced the recommended phase III dose.
Yes.
from 400 to 600, just if you could walk through the rationale there and kind of pill burden, etc.
Yes. All of the work that we have done in the public domain up until a couple of weeks ago was dosed fasted. As we went through dose escalation back in 2022 and 2023, all the work that we did was fasted. As we came into running the expansion cohorts, we ran those at 600 mg BID fasted. Obviously, we were using 100 mg capsules, so the pill burden was six capsules twice a day. As we came into 2024, we started thinking about dosing with Pfizer's CDK4, palbociclib, which is dosed with food. We also started thinking about dosing in vascular malformations, where these patients will be younger, adolescents. We started to think about the food effect study and accelerating it.
We did it, and we saw a positive food effect, showing that, over the course of the year, doing a kind of bridging PK study across mono and combination therapies with a range of different oncology indications, solid tumor indications, we saw 400 mg BID with food had exactly the same PK profile as 600 mg BID fasted. Given all the benefits of dosing with food, it allows us to dose better with combinations such as the atirmociclib. It's probably better for patients, especially the adolescents, and if you could dose with food, not. We went to the FDA with a pretty robust data package of, you know, a large number of patients that we dosed fasted, and then this equivalent study that shows that, 400 mg BID
With food is equivalent, and asked the FDA the question, we'd like to move forward with 400 mg BID fed, and they agreed. It does lead to a slightly differentiated safety profile as well because obviously, the pill burden does come down. Some of the upper GI toxicities, nausea, vomiting, loss of appetite, are significantly reduced. We think all round, this is good drug development. Did take us a little bit of time to do it, but we're in for the long term, and obviously, we want to dose, you know, multiple pivotal trials over time in breast cancer and vascular malformations, so it was the right thing to do.
Gotcha. Thank you. What are the next steps that we should be thinking about for starting the pivotal trial?
I think we're kind of, you know, all systems go now. We're obviously recruiting the team to do this: clinical operations, clinical development, medical affairs, patient advocacy. We really want to get this trial up and running and recruited as rapidly as possible. We'll be using a global CRO to help us, all of the contracts that we need to put in place, all of the different vendors, getting the supply in place. Obviously, we're gonna go head to head with capivasertib, and so getting the capivasertib supply across the world. It's all of the kind of mundane, dull things that you would need, but our entire company is focused on moving as fast as we possibly can here.
Gotcha. Thank you. There's no unexpected hurdles there or?
No, absolutely not.
Perfect. The hierarchical testing, kind of just the rationale before behind the domain, kinase domain, and then drop down to intent to treat.
Yeah, a couple of points behind the reason for that. One, we know there are sponsors that exist today with kinase-only drugs, so H1047R selective molecules, and we'll be bringing those, they'll likely be bringing those forward into the clinic, and potentially could end up sometime in the future with labels for kinase-only patient populations. Therefore, by having the kinase hierarchical testing, it allows us to potentially, upon a successful study, to be able to make direct label claims on the kinase population. Additionally, you know, we have seen, obviously, some activity, the kinase population has been performing even better than the total population, which is already almost doubling the median PFS of the control arm.
Therefore, we built this study to make sure that we win on multiple different parameters. We built it a bit conservatively on the end, and we built it a bit conservatively on having this hierarchical testing, knowing that in the worst-case scenario, if we just had the kinase population, that would still be a huge market for us too. We have the base case as complete confidence in the total population, and then the ability to make some label claims to the kinase population on the other side of the successful study, knowing that there will be sponsors with kinase-only drugs coming behind us.
Gotcha. What drives that, our difference that we saw between the mutant domain or patients with mutant domain and then patients with the non-kinase mutations?
Yeah, I think, look, there's, when you get into subpopulation analyses of a study this size, you get into some imperfections in looking at different patient populations. For instance, in the non-kinase population, those patients in this study tend to be a bit more heavily pretreated, so they're more likely to have seen multiple CDK4/6 inhibitors. They're more likely to have seen fulvestrant, and multiple endocrine therapies. They're more likely to have seen chemotherapy. I don't know as though we can say for certain that there really is any performance difference between the kinase and the non-kinase population because when you then look at the PFS, our second-line non-kinase patients perform almost exactly the same as our total population, median PFS of 9.2 months.
I think we really need to get into a larger study like we're about to do, and probably that will be the place where we can start to really learn in a well-controlled way if there's any difference in the performance of these patients. On the surface of it, we don't think there's gonna be a meaningful difference between the two.
Does?
In terms of just the, the kind of reference numbers there, obviously, capivasertib is doing five and a half months of PFS in that population. You know, we were saying that the overall and the non-kinase are in the zone of 9.2, so there's still a significant buffer between the kinase is doing even better than that. So in the kind of head-to-head randomized controlled trial, we feel very confident that both subpopulations will do, you know, significantly better than the standard of care.
Gotcha. We should mostly probably think about it as disease control rates because that probably translates better to the PFS number.
Yeah, clinical benefit rate is definitely a, a much better predictor of eventual progression-free survival. I think in the case of our study, the ReDiscover phase I study, what we are seeing is a bit more consistency between kinase and non-kinase when you look at CBR and PFS. Yes, the response rates do differ as it stands today.
Gotcha. Do you think that also that similarity in PFS, does that also translate to OS as well, or do you think there's a delta there when you think about the kinase versus non-kinase?
As you know, OS measurements have other factors that come into play, the subsequent treatments, the geographies you exist in, maintaining balance, and making sure that you have similar follow-on treatments that these patients go on to. I think, on an absolute basis, assuming all else being equal as to what treatments these patients go on to afterwards, we would also expect not too much of a difference between OS performance between the two populations.
Gotcha. How should we think about, as the trial enrolls, timelines for enrolling and kind of running that day, that trial?
Yeah, I think, you know, what we can say today, not having enrolled a single patient yet, is if you look at some precedented studies in this space that sit in this 500-patient end, they take about three years to get from first patient enrolled to top-line data. I think, you know, we might be able to refine that as we get a year or two into the study and really understand patient enrollment, but I think as we sit here today, you know, pointing to that precedence is probably the best we can do for now. Obviously, as Sanjiv said, this is the sole focus of our company, and so we'll use every tool at our disposal to accelerate this as much as possible.
Gotcha. And then the pretreatments the patient or prior treatments the patients have had, would you include patients with prior capivasertib, prior other PI3Ks? Kind of just how should we think of how that shakes out?
Yeah, we don't allow prior treatment with pathway inhibitors onto the study, similar to the ReDiscover study. We do allow up to, you know, we require at least one CDK4/6. That can be either in the adjuvant setting or in the metastatic setting. Up to one or two prior endocrine therapies, they can see up to one, patients can see up to one round of chemotherapy in the metastatic setting, and that's kind of to allow this ability in certain geographies to, you know, in the metastatic setting, if a patient is coming on to the study, but there's any mechanics waiting for a diagnostic test to come back, you know, you could allow for a couple of cycles of chemotherapy, and those patients would still be eligible to be into the study.
I think what we're really trying to solve for is getting to a patient population that looks and feels like a true kind of second-line metastatic patient population, as to where in the ReDiscover study, as you'll recall, we had, you know, about 45% of our patients were third-line plus.
Yeah, okay. Perfect. Can we get the full phase I data at some point this year, I guess, I assume, like towards the year end? Is that how should we think of, one, the timing of that data, and then what should we be looking at in that data set?
Yeah, I, you know, they go hand in hand. As you recall, the last update we gave was at SABCS, so just in December 2024, and that was from a data cutoff of early November 2024. We want to make sure whatever next data update we give is enough time to let that data mature a bit further. The median follow-up at that time was nine and a half months, and, you know, we think letting the data get to in and around about a year's worth of median follow-up is probably a meaningful update to the existing data, and, you know, showing consistency of within the median PFS, at even further maturity probably would give us all comfort in continuing to increase the POS of the phase III study. I think that's how we think about that update.
Still not answering your question directly on timing, but you can kind of hear some of the thought process.
Yeah.
That goes into what we're hoping for by the time we show that data.
Is that something you'd have submitted to ASCO or?
We don't really talk about our, you know, abstract submission strategies. I think ASCO and SABCS are rational bookends for where this update would make sense. As you can imagine, one of the key things, one of the key reasons for doing this update is in support of awareness for the phase III study, and so putting it at a major global medical meeting would be prudent, to continue to raise awareness and excitement around the phase III.
Okay, perfect. Thank you so much. Just as we think about your data versus Scorpion, kind of where do you think you are? You know, who's ahead by how many months or years, or how do you think about that?
I mean, I think all we've seen so far from Scorpion is kind of the dose escalation monotherapy data sets that they have, and those are obviously done in a range of different tumor types, and I think a follow-up of, you know, close to two months. Very early, obviously very kind of similar to our data set that we showed back in early 2023 at AACR, where we had roughly 30 or 40 patients, but we did ours mainly in combination. If you think about, you know, what they need to do, obviously dose in combination, get, you know, very kind of good, robust, long-range follow-up, against different expansion cohorts, before they're kind of set to go and do a pivotal trial. Obviously, they've been through, you know, a sale process and an integration, which is probably still ongoing.
We think we're somewhere kind of close to 18-24 months ahead, and I don't think we're gonna see anytime soon a robust long-term data set in combination with fulvestrant in hormone receptor positive, HER2- negative breast cancer patients that you could compare with what we've got.
Yeah, I think to be very clear, that molecule's at best similar, and it's 18-24 months behind. There's been a lot of conversations around target coverage, safety, efficacy, and if you go right down the list, you can't find any credible set of data that supports any meaningful differentiation. To the contrary, many open questions remain for that molecule, ones that we've already answered pretty clearly with our longer-term follow-up mature data.
Thank you. As we think about your triplet data, have you seen any kind of drug-drug interactions between RLY-2608 and ribociclib?
Yeah, we've discussed the ribociclib one last year. We are a victim of ribociclib where ribociclib is increasing the exposure of RLY-2608, and so therefore, you know, to get to the equivalent exposure of 600, the 400 mg BID fed likely requires a lower dose in combination with ribociclib. We're still working through that. We know that that DDI exists. That study was started in the early part of 2024. Once we discovered the DDI with ribociclib, we had to kind of take our time and lower the dose and understand that. We are moving forward. All studies moving forward will be in the fed state, so that's also, you know, changing, shifting that over to being in combination at doses in the fed state, is also something that we're doing.
Obviously, with, as Sanjiv alluded to, dosing, atirmociclib , it fed is important given that drug is also dose fed.
Gotcha. Does that confound dosing in the real world in any way, just having that interaction? And if patients drop off of one of the combination agents, does that perturb or change the way physicians think about using the drug or dosing the drug?
Specifically with ribociclib, it does bring that into consideration because obviously, if for some reason, if a patient went off ribociclib for a week, it's gonna change the exposure of RLY-2608, but it's something we think through and have been working through. You know, the benefit of atirmo ciclib is that's dosed continuously, and, you know, obviously, they're now both being dosed fed , and it's a, you don't have some of the safety TI and side effect issues that you have with ribociclib, so it's an exciting combination to be exploring.
Gotcha. Remind us where you are for dosing and when you start generating the recommended phase II data.
Atirmociclib was just more recently started at the very, very end of last year. This year is all about execution of those combinations, and I think sets us up well to probably be able to talk more about these triplets as we get into 2026.
Good. Are there other combination agents we should be thinking about? I guess there's potentially one less today, but.
Yeah, I mean, if you go full circle back to the beginning of this conversation, we imagine the oral SERDs will be present in kind of later lines in the ESR1 mutant patients, and so, you'll see us do, you know, some combination in with, with these oral SERDs so that we can be present in some of these indications. Obviously, you know, the choice of those is going through our thought process at the moment as we see the data.
Gotcha. We've got 30 seconds on the clock. Vascular malformations, just kind of where are you in that process? Like, what type of patients will you initially enroll in the particular subsets?
It's a really exciting opportunity for us. Over 170,000 PIK3CA mutated vascular malformation patients in the U.S. alone. The initial study is set to start imminently. Alpelisib's current accelerated approval is in a specific subset, PIK3CA-related overgrowth syndrome, so we'll have probably some bias in our initial study, our initial randomized dose exploration towards those patients. They also tend to be a bit more the severe patients, so the ones kind of seeking systemic therapies, especially, you know, early experimental ones in a first-in-human study. We see a broad opportunity to cross all the different subtypes of vascular malformation: PROS, lymphatic malformations, venous malformations, and cerebral cavernous malformations over time.
Perfect. Thanks so much.
Thanks again for the invite.
Thank you.
It was a pleasure speaking.