Relay Therapeutics, Inc. (RLAY) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to Relay Therapeutics Corporate Call, RLY-2608 Corporate Update. As a reminder, this conference call is being recorded. I would now like to introduce your host for today's conference, Mr. Peter Rahmer, Chief Corporate Development Officer at Relay Therapeutics. Sir, you may begin.

Thank you, operator, and good morning, everyone. Thanks for joining. We are excited to share these data for RLY-2608 in combination with fulvestrant with you today. You can access the press release from today, the slides we are reviewing and replay of this call by going to the Investor Relations section of our website. As a reminder, during this call, we will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including expressed or implied statements regarding our strategy, business plans and objectives, the expected therapeutic and clinical benefits of our product candidates and the potential of our platform and our product candidates and progress in timing and execution of our clinical trials. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. I refer you to the SEC filings and our website for a discussion of the risk factors that could cause our actual results to differ materially from those discussed today. The forward-looking statements in this presentation speak only as of the original date of this presentation. We undertake no obligation to update or revise any of these statements. On today's call with me are Sanjiv Patel, our President and CEO; and Don Bergstrom, President of R&D. We will share data from the RLY-2608 + fulvestrant doublet arm of the ReDiscover study in HR+/HER2-PI3Kalpha-mutated breast cancer. We will also take you through our preliminary plans to initiate a second-line pivotal trial next year and our continued preparation for future first-line studies. I would also like to note that the data we will be sharing today have been submitted for presentation at the San Antonio Breast Cancer Symposium in December and will be shared with the clinical community at that time, pending acceptance. I will now turn the call over to Sanjiv to get started.

Thanks, Pete. Before we get into the details, let me summarize today's headline that we're excited to share with you. RLY-2608 has a 9.2-month median progression-free survival in the second-line plus metastatic hormone receptor positive HER2-negative setting. This is nearly a 4-month improvement in the median PFS relative to capivasertib, which is the regulatory and fast becoming the commercial standard of care in this population. With that said, let's start at the beginning and remind you that PI3K-alpha represents a very significant commercial opportunity, spanning 3 separate sizable pillars, collectively addressing more than 0.5 million patients in the U.S. alone, across PI3K-alpha-driven breast cancer, solid tumors and vascular malformations. This represents one of the largest unaddressed treatment areas left in targeted therapeutics. Unfortunately, these markets remain poorly addressed, despite several approved therapies because these nonselective first-generation agents have a high degree of meaningful toxicity, which limits their efficacy and makes it difficult or impossible for them to be combined with other agents. We believe we have addressed these liabilities by using our Dynamo platform to create 2608, the first selective allosteric pan-mutant and isoform selective inhibitor of PI3K-alpha. Today, we are showing clinical data with RLY-2608 to support our hypothesis. The doublet arm of the ReDiscover trial enrolled a heavily pretreated patient population with a significant proportion of patients having seen at least 2 prior lines of therapy and a prior cert. The selectivity of 2608 continues to be demonstrated with longer follow-up with 2608 showing limited off-target toxicity. The recommended Phase II dose, only 25% of patients experienced a Grade 3 treatment-related adverse effect with no Grade 4 or 5 events seen, and only 1 out of the 64 patients at the recommended Phase II dose having a Grade 3 hypoglycemia event, which, of course, is the toxicity that we want to minimize. As a result, 2608 leads to greater target coverage with a 95% dose intensity. This in turn leads to greater efficacy, including, as we've already stated, a 9.2-month median progression-free survival, as well as a 57% clinical benefit rate and a 33% objective response rate. Across all of these measures, we are showing results that are meaningfully higher than anything that's previously been seen in the class. Taken together, these data's -- these data give us great optimism that 2608 will be able to demonstrate superiority against the newly emerging commercial standard of care capivasertib in the second pivotal trial. As a next step, we will now take these data to the FDA to gain alignment on dose and pivotal trial design. Our proposal will be that the trial is a superiority trial powered to show a clinically meaningful PFS benefit for 2608 relative to capivasertib. In PI3K-alpha mutated hormone receptor positive HER2-negative breast cancer patients that have previously been treated with a CDK4/6 inhibitor. We are moving forward as quickly as possible and anticipate being ready to begin the pivotal study in 2025, of course, pending regulatory feedback and alignment. There are 3 distinct significant PI3K-alpha opportunities, and we have robust development plans across all 3 areas. Let me summarize our clinical plans, beginning with breast cancer. As we've already said, next year, we intend to initiate the second line doublet pivotal trial that we just talked through. We also continue to advance our efforts to demonstrate 2608's first-line potential through in our CDK4/6 triplet trial, we're now dosing at biologically active doses of 2608 with ribociclib and fulvestrant, and are on track to identify a dose of 2608 is combinable with full dose ribociclib. We plan to share initial safety and tolerability data from this triplet later this year in Q4 and open expansion cohorts in 2025. We also remain on track later this year to initiate a triplet combination with Pfizer's novel selective CDK4. In the second pillar of 2608, genetic disease, our vascular malformations team is pressing ahead and on track to initiate the 2608 trial in vascular malformation in the first quarter of 2025. And in the third pillar, as we mentioned, we have reinitiated monotherapy dose escalation in solid tumors and are pleased with what we've seen so far with PRs across multiple tumor types and mutations, and we're continuing to enroll more patients and collect data and look forward to moving into monotherapy dose expansion soon. As you can see from all of these 3 pillars in broad execution, we're leaning into our demonstrated precision medicine clinical execution expertise across our multiple PI3K programs. In addition to the large opportunities across the 3 pillars of 2680, we have a robust portfolio of preclinical programs, all created in-house using our Dynamo platform. Let me highlight the recently disclosed non-inhibitory chaperone that has the potential to serve Fabry's patients and the selective NRAS inhibitor that can serve a broad range of patients with NRAS driven solid tumors. We remain well funded with nearly $700 million at the end of the last quarter. However, we continue to make careful capital allocation decisions to focus our dollars and effort on significant medium-term catalysts. To this end, we continue to focus our research footprint and reduce spend to focus on the highest value next-generation targets and with differentiated data in cholangiocarcinoma and across other fusion tumor types and a positive FDA interaction, we've made the decision to seek a global commercial partner for RLY-4008, lirafugratinib. All of this enables us to focus our capital and execution resources on the near-term value-creating 3 pillars of 2608, are newly disclosed and soon to be in the clinic programs of NRAS and Fabry's as well as on a small number of high-value early-stage programs. Our current balance sheet will carry us into the second half of 2026, and this assumes that we continue to wholly own all our assets, achieve success on all fronts and prosecute fully all of our current programs. Given all of these levers, we continue to have plenty of internal options to extend our runway and this allows us to have great confidence that we can execute the second line 2608 pivotal trial and get 2608 to patients as rapidly as possible. With that now said, I'll turn it over to Don Bergstrom to take you through the data and our pivotal plans in more detail.

Thanks, Sanjiv. Today, we will focus on results from the hormone receptor positive HER2-negative breast cancer patients treated with the doublet of fulvestrant plus 2608 in the ongoing rediscover clinical trial. As Sanjiv mentioned, the trial also continues to enroll solid tumor patients treated with 2608 monotherapy as well as breast cancer patients treated with the triplet of fulvestrant plus ribociclib plus 2608. And we remain on track to initiate dosing of the triplet of fulvestrant plus Pfizer's investigational CDK4 selective inhibitor, atirmociclib plus 2608 prior to the end of 2024. To date, more than 200 patients have been treated with 2608 across these 3 groups. As previously disclosed, the 2608 fulvestrant doublet arm of the trial initially performed dose escalation at doses ranging from 100-milligram BID up to 1,000 milligram BID of RLY-2608. No MTD was identified, but we opened our first expansion cohort at the 600-milligram BID dose as the totality of the data, including PK, PD, safety and efficacy, suggested this was potentially an optimal dose for the RP2D. And this is the dose level we will focus on today as we prevent -- as we present efficacy data for 2608 plus fulvestrant in PIK3CA mutant hormone receptor positive HER2-negative breast cancer. As would be expected for a patient population enrolled in a Phase Ib clinical trial, patients were heavily pretreated, with half of patients having received 2 or more prior lines of therapy in the metastatic setting and over half of patients having been treated with fulvestrant or a novel served. Almost 2/3 of patients had visceral metastases. The distribution of PIK3CA mutations reflected the natural distribution of these mutations reported in the literature and just under half of patients had a kinase domain mutation. And critically, more than 1/3 of patients had BMI of at least 30 and/or baseline hemoglobin A1c of at least 5.7%. The population we will focus on for Phase III development of 2608 are patients with any PIK3CA mutation, either kinase or nonkinase, and based on our understanding of pathway biology and 2608 mechanism, we will exclude patients with co-occurring P10 or AKT mutations from the pivotal trial. We treated 52 patients with this genotype at the RP2D of 2608 plus fulvestrant and observed a median PFS of 9.2 months with a landmark 6-month PFS of 64% and a 9-month landmark PFS of 60%, which is the longest PFS yet reported for any PI3K pathway agents combined with fulvestrant in patients previously treated with a CDK inhibitor. Additionally, CBR was 57%, which compares favorably to other trials, testing fulvestrant plus a PI3K pathway inhibitor in patients previously treated with a CDK4/6 inhibitor, where the CBR has ranged from 37% for alpelisib Group C to 48% for inavolisib Phase Ib RMD. And with the caveat of small end, PFS in second-line patients is trending toward being longer than in third line patients, as would be expected. We have also assessed objective response rate for the RP2D in patients with measurable disease by RECIST 1.1. Reduction in tumor dimensions has been observed in 73% of patients and objective responses have been observed in 10 out of 30 patients for an ORR of 33%. This includes 2 ongoing unconfirmed partial responses as of the data cutoff. Subsequently, 1 patient has confirmed and the other remains on treatment in continued response. After the data cutoff, 1 additional stable disease patient has converted to an unconfirmed partial response and remains on treatment. This patient is not included in the ORR. Tumor regression and objective responses have been observed in both patients with PIK3CA kinase domain mutations and nonkinase domain mutations, consistent with the pan-mutant mechanism of 2608. Comparing this to benchmark data sets for PI3K inhibitors in CDK4/6 experienced patients. This is the highest ORR that has been reported for a PI3K pathway agents in combination with fulvestrant. Additionally, we have observed a complete response in a patient with nonmeasurable disease who is, therefore, not shown on this waterfall chart. Consistent with the observation of clinical activity across PIK3CA mutation subtypes, there was robust clearance of circulating mutant PIK3CA DNA in both kinase and nonkinase patients. Nearly all patients treated with the RP2D showed reductions in ctDNA with more than half of patients completely clear in the mutant ctDNA [indiscernible]. Given that some efforts to target PI3K in a mutant selective manner, leverage an allosteric pocket that only targets kinase domain mutations, we chose to also perform a subgroup analysis in kinase domain patients. As you can see on the waterfall plot, 2608 efficacy in kinase domain patients was consistent with the activity observed in the overall population of PIK3CA mutated patients, with an observed ORR of 53% and median PFS of 10.3 months. The subgroup data, again, give us confidence as we prepare to initiate a Phase III superiority trial versus capivasertib in 2025. One of the hallmark toxicities of PI3K pathway targeted therapies has been hyperglycemia. For 2608, we maintain continuous daily dosing and greater than 1/3 of the patients on the study had baseline BMI of at least 30 and/or hemoglobin A1c of at least 5.7%. A population shown to be at increased risk of hyperglycemia in the Phase I trial of inavolasib, where patients with this metabolic profile had a 44% rate of grade 3 plus hyperglycemia, despite metformin prophylaxis and arm F of the inovolisib Phase Ib trial. And we see very little perturbation of glucose levels at the RP2D of 2608, as shown in this graph of mean glucose level versus time for each dose level. In fact, of 64 patients treated with the RP2D, we have observed only a single case of Grade 3 hyperglycemia and a patient receiving concomitant steroids, which is an independent risk factor for hyperglycemia. 2608 plus fulvestrant was well tolerated overall with only 20% of patients across all dose levels, experiencing any Grade 3 TRAE and only 25% of patients at the 600-milligram BID dose experiencing any Grade 3 TRAE. There were no observed Grade 4 or Grade 5 TRAEs. As mentioned earlier, there's only a single case of Grade 3 hyperglycemia at the RP2D and the majority of hyperglycemia AEs were Grade 1 and required no medical management. TRAE rates were low for AEs commonly seen for the PI3K pathway class, including diarrhea, rash and stomatitis, with Grade 3 rates for these AEs in the low single digits or 0. The favorable overall tolerability profile is associated with the ability to maintain dose intensity, which is critical for driving long-term clinical benefit. Median dose intensity at the RP2D was 95%. Dose interruptions when they occurred were brief, and only 2 out of 64 patients discontinued treatment due to TRAEs. The majority of discontinuations were due to disease progression. The totality of the efficacy and safety data gives us confidence to initiate a randomized pivotal Phase III trial of fulvestrant plus RLY-2608 versus fulvestrant plus capivasertib. This trial will be a superiority trial powered to show a clinically meaningful PFS benefit for 2608 relative to capivasertib and PIK3CA-mutated hormone receptor positive HER2-negative breast cancer patients previously treated with a CDK4/6 inhibitor. Capivasertib is a relevant regulatory standard of care for these patients given its recent FDA approval in November of 2023 and qualitative feedback from physicians as well as the dynamics of the capivasertib launch, suggest it is becoming the commercial standard of care as well. We will align with health authorities on trial design and anticipate initiating the pivotal trial in 2025. Earlier this year, we initiated triplet dose escalation of 2608 combined with fulvestrant and ribociclib. Ribociclib has become the standard of care CDK4/6 inhibitor for the treatment of newly diagnosed metastatic hormone receptor positive HER2-negative breast cancer patients as it is the only CDK4/6 to have demonstrated survival benefit in this setting. We are encouraged by the progress we have made and dose escalation, and are currently administering biologically active doses of 2608 with full label dose of ribociclib. We have observed a favorable interaction of 2608 with ribociclib, meaning that the dose of 2608 will be lower in combination with ribociclib and fulvestrant than the 600-milligram dose we have characterized in the fulvestrant doublet. And we are confident that we will be able to identify a dose of 2608 that is combinable with full dose ribo and look forward to sharing initial safety and tolerability data from this triplet in the fourth quarter. We also remain on track to initiate dose escalation of 2608 in combination with the atirmociclib, Pfizer's investigational selective CDK4 inhibitor by the end of this year. As you've heard, we are incredibly encouraged by the data we shared today and believe that, coupled with our strong clinical execution and broad 2608 development plans, are very well positioned for an exciting future with the potential to significantly improve treatment for these patients in both the first- and second-line settings. With that, I'll turn it over to Pete to share more on our corporate go-forward strategy.

Thank you, Don. As you heard from Sanjiv and Don, we are very excited by these data and the opportunity in front of us. So I want to spend a moment putting these data into context as the breast cancer market is dynamic, but one constant is PI3K-alpha is the most commonly mutated kinase in cancer and the driver mutation in over 150,000 breast cancer patients each year just in the United States. It has long been a goal of the industry to find a novel selective inhibitor of this critical driver mutation to serve these patients. And today, we have been the first to demonstrate the impact such an inhibitor could have across second-line patients in the near-term, with a clear path and efforts already underway to be able to serve earlier lines of therapy. We believe the profile presented today clearly demonstrates how 2608 can become a backbone therapy for all PI3K-alpha mutated patients across all lines of therapy in breast cancer regardless of the combination partner, which represents a very significant multibillion-dollar global commercial opportunity and is just 1 of the 3 pillars in our PI3K-alpha franchise. The confidence is clear when you consider the data just presented in the context of other options for patients today. The selective nature of 2608 leads to a differentiated safety profile compared to other PI3K pathway inhibitors. We have shown an overall low rate of Grade 3 AEs with very low rate of treatment related discontinuations due to AE. And for the first time, a PI3K pathway inhibitor, we have demonstrated the ability to sustain continuous high-level inhibition of PI3K-alpha mutant signaling, while avoiding the high rates of Grade 3 hyperglycemia that have generally limited the class. And we've been able to do this in a patient population representative of the typical western oncology patient population, including patients with high BMI and/or elevated baseline HbA1c. As we look more closely across key AEs that have been an issue for the class, 2608 demonstrated a differentiated safety profile across the board with low overall rate of any grade hypoglycemia, and less than 20% of patients requiring any medical management and lower rates of diarrhea, rash and stomatitis. Lastly, when we put the efficacy data in the context of other PI3K pathway inhibitors in this population, it further strengthens our conviction in 2608's differentiation from these first-generation agents. As you can see in these cross-trial comparisons, 2608 has demonstrated the highest PFS, CBR and ORR ever seen from a pathway inhibitor despite being in a heavily pretreated Phase Ib population. As such, we are optimistic that we can generate a positive result in a head-to-head clinical trial with capivasertib, which we plan to initiate in 2025. Today's data validate the mechanism and impact of 2608 and further increases our optimism at being able to address the additional large areas in solid tumors outside of breast cancer and vascular malformations. We are moving rapidly to realize 2608's potential across these areas. Today's data also further validate the productivity of our Dynamo platform, which over the past years has continued to evolve its collection of cutting-edge computational and experimental techniques, and successfully coscute some of the most challenging drug targets known today. We recently announced 2 new first-in-class programs targeting Fabry and NRAS that have been discovered in-house and are wholly owned. These programs will move into the clinic in the second half of 2025. So combined with our Q1 initiation in vascular malformations, we'll have 3 new programs entering the clinic next year. This is where you'll see us focus the majority of our time, effort and capital. Therefore, as Sanjiv mentioned earlier, we have chosen to seek a global commercialization partner for lirafugratinib. Lira has shown differentiated data in cholangiocarcinoma and the data for fusions outside of CCA continue to be promising. These data will be shown in detail at the upcoming triple meeting in October. We use these data sets to have a positive interaction with the FDA, who have recommended that we first filed an NDA and CCA based on the existing pivotal data, and then generate additional data and follow-up for a subsequent tumor-agnostic fusion, supplemental NDA. Given this will require internal efforts and dollars, we have decided to focus our own effort and money on the large near-term opportunities for 2608 and the other pipeline programs. All of this leaves us with a focused precision medicine portfolio addressing large commercial markets. We have a broad set of catalysts over the next 18 months. We also have a team and balance sheet that over the last 8 years, has shown it can deliver. That said, we remain diligent in how to deploy our team and capital. We will always retain flexibility to confidently execute the second-line pivotal trial and have multiple strategic levers to extend our cash runway further. In closing, you can see why we are very excited by the data we've shown today and what they could mean for the nearly 0.5 million patients in the U.S. alone across PIK3-alpha-driven disease. In each of these settings, we believe the planned or ongoing studies will produce meaningful and interpretable efficacy data throughout the next 2 years. I would also like to recognize and thank the team for their relentless efforts on this challenging target that has taken many years to crack as well as all of the patients, families, investigators and center care team who have participated in the study. As we move all of these programs forward, it is going to be an extremely busy next couple of years, and we look forward to updating you on our progress as we go. With that, we will open it up to questions. Operator?

[Operator Instructions] And the first question comes from Salveen Richter with Goldman Sachs.

Could you provide more detail on why you see Capi as the comparator for this data and why you'll power against capi instead of alpelisib? And what the limitations are with evaluating 2608 in inavolisib and alpelisib in the Phase III studies, just given the efficacy data that you've seen versus kind of on your comparator -- a as your comparator on Slide 25, just kind of putting that in context for us?

Thanks, Salveen. I'll hand that one over to Don.

Yes. Thank you, Salveen. So as we think forward to the planned Phase III clinical trial in the timeline, we're looking to start the trial, there are 2 approved standards of care for this patient population. Either alpelisib or capivasertib, inavolisib is still running a Phase III trial in this population, and we don't anticipate that it will be approved agent -- an approved agent and the timeline we're looking to start this trial. So as we look at alpelisib versus capivasertib, I'd point out first that the performance of those agents and heavily pretreated patient population is actually quite similar to each other. In the BYLieve Cohort C of alpelisib in heavily pretreated patients, median PFS was 5.6 months. For capivasertib in the CAPItello-291 trial in CDK4/6 pretreated patients, median PFS was 5.5 months. So I think it's fairly consistent what the benchmark is that we'd be looking to improve upon with 2608 as we move into a pivotal trial. With that being said, as we've solicited feedback from investigators and KOLs, the consistent feedback we've been getting is that capivasertib would be the desired agent to be randomized against given their preference for treating patients with PI3K mutations with Capi versus alpelisib. And I think that is largely consistent with some of the market dynamics since we've seen the launch of capivasertib last November, where we see that commercially capivasertib is faring with a fairly successful launch.

And the next question will come from Brad Canino with Stifel.

Great to see the durability update. Don, you briefly touched on this on the call and caveat of the small end, but can you walk through in more detail any differences you saw in patients who are less heavily pretreated? And really, I'm trying to get your thoughts on how 2608 could perform in a more true second-line population or vice versa, how capivasertib might look in this population that you studied that were half third line plus?

Thanks for the question, Brad. As we said, obviously, we are in a more heavily pretreated patient population. And as you rightly point out, the end is still small, but there are some trends that we can discern. Maybe Don, you can just detail what we've seen.

Yes. I mean I'll first; I think as you alluded to in your question, Brad, just pointed out that with regard to pretreatment, our patient population is more heavily pretreated than the CAPItello-291 population on which we base that 5.5-month number for capivasertib. I think it's been fairly common in this space to see that with subsequent lines of therapy and more heavily pretreated patients. You typically see PFS go down and become shorter. Obviously, there's a precipitous drop off after first-line CDK4/6 inhibitor therapy, where you go from PFS in the 20s down to PFS in mid-single digits. And then as patients get into subsequent lines of therapy in the third line plus, typically, you see that PFS number continue to drop. And I think consistent with what we've seen externally when we do a subset analysis of PFS by line of therapy in our patient population. The trend is towards having -- is towards second-line patients having longer PFS than first-line patients. So we see separation of those curves, third line patients.

Great. Maybe a quick follow-up because you had the 12 patients that had the PI3K AKT mutation, is that 19% co-mutation rate consistent with the background rate just as we think about the market opportunity size here?

Yes, Brad, this is Pete. No, it is not actually. In larger studies, characterizing co [indiscernible] mutations in the second line, those studies with thousands of patients characterized, which suggests a commutation rate in the neighborhood of 7% to 10% at most.

And our next question will come from Yaron Werber with TD Cowen.

Thanks for the update and congrats on the data. Maybe just a couple of questions. Number one, can you give us a sense next year is going to be a pretty busy year for you. How fast can you start the Phase III? Is there any way to pull it into the first half of the year as opposed to the second half of the year? And then secondly, the -- when we look at the pivotal study for Truqap, it's now about 355 patients or so, are you envisioning sort of a similar size study?

Thanks for the question, Yaron. I mean, as you know, we're moving as fast as we possibly can as the data update today is obviously driven by the fact we want to engage the regulator. And maybe I'll ask Pete to comment on just how fast we can go.

Yes. Suffice to say, we'll move -- certainly going to move as expeditiously as possible. I think once we're on the other side and interaction with regulators, we can come back and put a little bit of a finer point on the exact timing of that clinical start, but we want to move fast. And I think it's more likely to be early in the middle of next year than later next year, but we'll see how that -- how it comes into the side of conferring with regulators on that front. On the -- in terms of size, I think, sure, the CAPItello-291 study, the total size of that study is actually approaching 700 patients when you take into account the wild-type patients included. So that was a pretty large study. And on par with other all-comers studies you see in the second line setting. I think when you look at probably the best other most closest analog would be INAVO120, the inavolisib plus fulvestrant versus alpelisib plus fulvestrant second-line study that started early last year. That study is about 400 patients. So I think study size is ranging between 400 to 500 in a genomically identified population in the second line is a fair analog for now until we have a conversation with the regulators and come back for more detail.

And the next question comes from Peter Lawson with Barclays.

Thanks for the update today. Just on the Grade 3 hyperglycemia from the 1 patient, anything you can tell us about the patient from morbidities any way to kind of mitigate that going forward?

Yes, absolutely. We can -- as you remember, it was 1 out of 64. Maybe Don can talk us through that.

Yes. So this was a patient who is being treated with concomitant steroids. So it was a patient with [ Brian Matusz ] who was on a stable dose of steroids, and of course, the steroid -- concomitant steroid use is an independent risk factor for hyperglycemia. But the patient was able to be managed medically, they were able to continue treatment with 2608, and ultimately, at our RP2D, we did not see any dose discontinuations for hyperglycemia. So when we look across the profile, the only 1 out of 64 Grade 3, and in general, the most of the hyperglycemia we're seeing being medically insignificant and not being needed to be managed in a patient population that included over 1/3 of patients at risk for hypoglycemia. I think we're very encouraged by the hyperglycemia profile we're seeing. And as we move forward, to the pivotal trial, our intention is to use metabolic inclusion criteria that will be relatively broad and will allow enrollment of patients who are reflective of a western breast cancer population.

And then just a follow-up, just be around drug-drug interactions. If you -- if there's anything we should be thinking about as regards to combination drugs that you can or can't work with?

No. No, not at this point. I think as I mentioned, with ribociclib, specifically, we've seen an interaction that actually works in our favor. So in this case, 2608 is a victim of ribociclib as opposed to this being a more generalized effect of 2608. And what we anticipate we'll see is to reach the same blood concentration of 2608 that we achieve at the 600-milligram doublet dose with fulvestrant will actually have a lower dose of 2608, which is why we consider it to be favorable.

The next question comes from Jason Gerberry with Bank of America.

This is Chi on for Jason. Congrats on the update. And so, the 9.2 months PFS looks impressive relative to capivasertib 5.5 months, considering your Phase I trial and romorefractory patients than the comparator Phase III trial. But I want to ask, can you help us understand capivasertib efficacy in PIK3CA auto patients, those who without AKT or P10 commutation. As we compare and contrast your PFS data compared to capivasertib in a more likely like genetic alteration footprint, if I may say? And I guess, secondarily, could you provide PFS, CPR, NOR data for the all-comer population, including those with the AKT and P10 mutations? And just one quick follow-up. Given your numerically better PFS and CBR ways in the kinase mutation subgroup? Are you planning to stratify patients by PIK3CA mutations in your Phase III?

Thank you for that multipart question, Chi. So let me try to tick through them. The 5.5 months we are citing in terms of the median PFS for CAPItello is in the PIK3CA mutated population. The -- they've done one presentation where they isolated PIK3CA only, and that's also at the 5.5-month median PFS range for CDK4/6 pretreated patients. The next part of your question was...

Do we have all the numbers?

Yes, obviously, this is an interim data report as we get to a final Phase I study data output, which we intend to do at full maturity of the Phase I study. We can do a lot of different analyses and subsets. Suffice to say, as we look at the totality of the patient population outside of P10 and AKT mutations, we see very consistent benefit on a PFS basis across all subsets of data. And as you would imagine, given the biological hypothesis that a PI3K pathway inhibitor would not be active or overly active against mutations and the small number of P10 mutations we have, we see the drug not performing as well as you would imagine, in that very small subset of patient population.

And look, as you can imagine, in a kind of dose escalation phase, we included all of the patients to try and move as rapidly as possible to get the safety and tolerability information that we wanted to select the dose. And that's why they're in the trial, even though we hypothesize it would never be in our pivotal population. And I think you see in some of the kind of mutant selective PI3K-alpha trials that are ongoing there, where they're actually excluded from the start of those trials. We thought it was just better to get the information and data. And obviously, as you see now as we go into the pivotal, we'll cover a very, very large range of mutations.

Great. Curious if you're enriching -- sorry, stratifying patients by PIK3CA mutations in your Phase III given you see -- saw numerically better PFS in the kinase mutation subgroup?

Yes, we see no need to enrich or disqualify any PIK3CA mutation as we think about designing the Phase III. We will run a Phase III study in all PIK3CA mutated patients.

We think 2608 is active right across their mutational spectrum of PI3K-alpha mutations.

And the next question comes from Michael Schmidt with Guggenheim Partners.

Yes, congrats on the early data surprise. The -- did the study include any patients that were pretreated with another PI3 kinase inhibitor or Capi? And a quick follow-up, obviously makes sense to exclude the P10 AKT communications also based on the signaling in a mechanism of action, obviously, of the drug. But in the planned first-line setting where you would do the triplet combination? Would it be possible to include the P10 AKT patients in the opinion? Just curious.

Thanks, Mike. Why don't we -- Don, maybe you can take both of those.

Yes. So I'll start with the second question first about P10. I think what has been recorded in longitudinal studies is that P10 mutations tend to be acquired with lines of therapy. I think that's consistent with what Pete just highlighted with our rate in a heavily pretreated population of P10 mutations being higher than what you'd expect based on what we see in the databases. And I think we anticipate, as you go into a frontline population, the proportion of patients presenting with a P10 mutation will likely go down and will likely be a relatively irrelevant patient population just in terms of overall numbers. So whether we include them or not, I think, is a question still to determine, but I think it's unlikely to be a very significant patient population in frontline patients. With regard to your first question, our inclusion criteria did prohibit treatment with a PI3K pathway inhibitor in prior lines of therapy for inclusion in the ReDiscover trial.

And the next question comes from Sean McCutcheon with Raymond James.

Can you speak to the timing of the RECIST responses? And any weighting to responses in patients that were enrolled later in the study and any differences in disposition that may have been enriched in this subset of patients?

Yes. I mean, the timing at our RP2D tends to be relatively rapid with responses generally seen at the first or second scan. So we're scanning every 8 weeks. We're generally seeing the responses in that time window. We do have a number of patients who are ongoing in partial response. As we look at our data and as we look at the PFS number that we've reported today and as you dig in and look at our Kaplan-Meier curves, you will see that they're early sensored patients. Those censored patients are largely patients who are ongoing who have not yet had a progression event and a considerable number of those patients are actually patients with an ongoing partial response, which gives us confidence as we look at this PFS estimate that we reported today that it will hold up with continued data maturity or potentially even improve.

And our next question comes from Billy Smith with JPMorgan.

This is Bill on for Eric. Quick one, firstly, on the safety profile. I just wondered if there's any sort of cumulative safety effects, we saw from this that might have some read across into a PI3K use in VM?

No.

Yes, no. And I think at this point, we are reporting data where we have sufficiently long follow-up and sufficiently long exposure that we're getting a feel for what the chronic tolerability profile looks like. I think we're very encouraged with the profile and excited to move into the VM population as well, were obviously, chronic treatment will be the goal. We look forward to [ having ] that trial Q1 in 2025.

Yes. And then quickly, just on the enroll plan, do you anticipate any sort of prophylactic medication needed for hypoglycemia or just -- yes, I'll leave it that.

No. No. I mean, as you know, I mean, this has been a real challenge for the nonselective inhibitors and very high rates of Grade 3 hypoglycemia, causing dose discontinuation and lack of efficacy. The hypothesis that we've always had is if you can create a selective mutant inhibitor, you'd be able to dial out or dial down the toxicity levels, and that's exactly what we've seen. And we will not need any kind of prophylactic treatment or exclusion criteria that we've seen in some of the other studies.

And the next question comes from Silvan Tuerkcan with Citizens JMP.

Congrats on this great update. Could you please contrast your discontinuation rate and dose reduction rates to the other PI3K-alpha inhibitors? And at a dose intensity of 95%, what does that mean for the combo -- for the triplet combo with full dose rival?

Yes. I think as you saw us present on the total modification rate, we compare very favorably to what has been seen with the other non-selective agents in terms of interruptions or reductions, very much in line with first-in-human oncology studies. And most importantly, the treatment-related discontinuations where we've only seen 2 in the entirety of the 64 patients treated at 600 milligrams twice daily compares quite favorably to the over 10% you saw in alpelisib and capivasertib and we're strongly encouraged with that as we move into the Phase III study. And with regard to combined ability, similarly, I think we've seen an overall safety profile with a low burden of overall toxicity and then a very low burden of PI3K related AEs, you would expect from the profile we've seen that you're not going to see significant overlapping toxicity with the CDK4/6 class, and we anticipate we'll be able to maintain a high degree of dose intensity with full dose ribociclib or other combination agents in the CDK4/6 or CDK4 class.

And the next question comes from Akash Tewari with Jefferies.

This is Amy on for Akash. So what is the reason for the 22 patients having nonmeasurable disease at the recommended Phase II dose? Was it just not enough follow-up? And then an additional one, if we could, have you conducted any drug-drug interaction studies with 2608 with [indiscernible] inhibitors you expect any dose adjustment in combination with CDK4/6 inhibitors or other combination regimens?

We will take both questions separately. And maybe -- Pete, maybe you can take the first one and just explain the natural history of breast cancer.

Yes. As [indiscernible] so folks are aware, an HR+/HER2-negative breast cancer, there's a natural distribution of about 1/3, 2/3 nonmeasurable disease to measurable disease. Our patient population very closely mirrors that natural distribution. And so that's the reason for having -- given that we want to treat the entirety of the HR+/HER2-PIK3CA-alpha mutated breast cancer population. That's why we have a patient population that mirrors the natural distribution of patients here. By definition, just so folks are aware, RECIST criteria 1.1 clearly defines what it is measurable and nonmeasurable and we follow those criteria closely when reporting data.

And we're trying to be as inclusive as we can in the population. And then on the second question.

On the drug interaction front. So again, the interaction that I mentioned with ribociclib is an interaction where 2608 is the victim to something that ribociclib is doing, that will lead to a lower dose of 2608 to achieve the same exposure that we have at 600 milligrams. It is not SIP mediated. And as such, we don't anticipate there are SIP mediated issues for 2608. And again, this is a specific interaction that we're seeing with ribociclib, where 2608 is the dictum.

I show no further questions at this time. I would now like to turn the call back to Sanjiv for closing remarks.

Thank you for taking the time this morning. As you know, this has been a long time coming. It's been one of the most difficult drug discovery challenges in the industry. We believe that the data we showed today shows clearly that we've been able to create a mutant selective inhibitor the dialed up that some of the challenging toxicities that have plagued the nonselective inhibitors. And that today, we've shown translate into a 9.2-month median PFS and we're excited now to take an RLY-2608 into a pivotal trial in the second line, continuing to push forward in the triplets to try and see if we get it into earlier lines, open the vascular malformations trial in Q1 of 2025, and then finally, explore tumors outside of breast cancer. So it's an exciting time for the company, and we hope that we look and able to continue to update you with all the catalysts over the coming year. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.