We're going to get going here with our next company presenter at the B of A Annual Healthcare Conference. Pleased to be introducing Relay Therapeutics and Pete Rahmer, Chief Corporate Development Officer. My name is Jason Gerber. I'm one of the Smidcap Biotech analysts. Peter, thanks for joining us once again at the conference. You know, it's timely that we have you here, you know, in terms of Relay and its story and some, you know, recent developments in terms of the strategic cost structuring of the business and prioritization. Maybe we could start there, you know, as we think about, you know, where you guys have come as a company. There's been some challenges, I guess, over the years with precision oncology and changing kind of regulatory landscape, which has ultimately led you to prioritize and focus on your PI3K program for breast cancer.
There are some other opportunities behind that, but it does seem like the lion's share of your capital now will be devoted to this program. You know, maybe we could start there and then we'll jump into more specific questions.
Yeah, first of all, thank you to Bank of America, Jason, and Chief for having us. We're really excited to be here. You're right. It's been a pretty interesting period, not just for us, but for the entire sector and obviously a lot of macro events shaping how companies are operating today, which is a bit unusual for our sector. You know, for us, had to make the difficult decision to dramatically reduce our research footprint. What made that particularly difficult was the fact that, you know, that research organization had, you know, I would put forth, you know, be one of the most productive research organizations in small molecule oncology development in a long time. We, you know, find ourselves in an environment where we can't rely on the normal course access to capital and the equity capital markets anyways.
As we looked at the ways to create value with our balance sheet over the next, call it three- five years, it was clear, like you said, that 2608, our PI3Kα immune selective molecule, was going to be a key driver to that. We really needed to focus our effort and our capital against that. You know, one of the key objectives we were trying to achieve in this restructuring was to make sure we were able to get meaningfully past the top line data of our upcoming ReDiscover-2 phase III study for RLY-2608. That is what really drove us to make the decisions that we made and now sit here with $710 million in cash on the balance sheet, cash guidance into 2029, which should get us meaningfully past top line data in the phase III.
It'll also allow us to run additional supportive breast cancer studies as we think about potential other treatment regimens or even moving into earlier line settings within HR positive or HER2 negative metastatic breast cancer. We also recently started a vascular malformation study, which is a PIK3CA mutant driven genetic disease. There's about 170,000 of those patients in the U.S. You know, we are just in the very early innings of that clinical exploration. You know, that's a very interesting area where the biology has been de-risked. You know, we have a lot of the same tenets and hallmarks of target oncology that we can draft off of there. We will also continue to progress our NRAS and Fabry molecules preclinically to at least IND readiness and kind of at that point assess the environment and the landscape.
We also have one unnamed preclinical program that the research team, the core research team that's left, will focus on. It's a very exciting target that has to date been pretty undruggable. Excited for the research team to try to tackle that.
Yeah. Maybe talk about what the next two years for the company looks like, because you've got this, you know, your pivotal study and that'll take some time. I guess we can look to trials like CAPI and things like that to sort of form some sort of benchmark for how long it takes to enroll studies and get the data. Imagine, you know, what are the sort of data de-risking milestones and things that investors can look to get more confidence either, you know, in things like vascular malformation or some of the alternative data sets you might be generating in, say, the breast cancer setting between now and ultimately when you get to some pivotal data that's really going to be the key thing for the company.
Yeah, I think one of the things that we are most excited about is that these opportunities have been largely de-risked by the existing data. And so we're fortunate in a sense that the data has played out the way that we had hoped it would. In the case of the breast cancer opportunity, you know, the ReDiscover data that we presented last San Antonio Breast Cancer meeting in December, and we'll update that data a little bit further in ASCO coming up in a couple of weeks. You know, those data, in our view, look extremely strong in the potential for success in the phase three study against Capivasertib and fulvestrant. They're pretty mature data at this point. At ASCO, we'll have median follow-up out past 12 months. We're just looking for a consistency of that data from what we presented at SABCS.
The timing of that is really helpful given that we're going to be on the precipice of launching that phase three study and we'll have an audience with global investigators to be able to share that updated data with at ASCO. In the case of vascular malformations, we're fortunate that we've been able to see that biology get validated through the clinical data that's been generated by alpelisib in that setting. They've shown clearly across the accelerated approval data set and now in the recent EPIC P2 confirmatory study that unfortunately failed, but still provided clear clinical proof of concept that through different dose levels, you're seeing at least a dose response with alpelisib, which plays into our thesis that if we can drive to greater target coverage, we should be able to see to drive to greater benefit for those patients.
Okay. So, you know, the phase IB data at ASCO, I think you referenced, you saw on a median PFS basis, almost a doubling, I think, of what is sort of the competitive benchmark in the space. I guess like sort of the preview here is look for some consistency and more robustness of data, data follow-up. I know that I guess some of the questions when you last updated the street, maybe it was around some patient censoring and duration of follow-up. Do you feel like those questions will be largely addressed, you know, as we come out of ASCO and get that installment?
I think so. I think we'll be able to continue, you know, at the time, as most folks know, you know, when patients are still ongoing, the way they're treated in the Kaplan-Meier curves, they're censored. At SABCS, we said that the majority of our patients that had been censored remained on treatment and a good number of them remained in response on treatment. I think we'll be able to continue to address that with, you know, median follow-up now out past 12 months, which we think should probably start to be out further than the current median PFS, which is always a good barometer of data maturity.
Yep. Okay. Which is like the competitor benchmarks for like five or six months, right?
Yes. The CAPI, capivasertib 291 data in the PIK3CA mutant subset is 5.5 months.
Yeah.
That's, I think, you know, that's kind of, that's the benchmark we use to guide us as we moved into the phase three design for ReDiscover-2.
Yep. In terms of the PI3K competitive landscape, how do you sort of characterize your clinical data is obviously very, very intriguing. There are earlier stage competitors that you probably, you know, people compare you to, one of which got acquired by Eli Lilly. How would you kind of frame for investors how you think, you know, your molecule 2608 is different than the now Eli Lilly drug?
Yeah, you know, specific to the now Eli Lilly drug, I think the key conclusions that we have based off of the data, so you have both molecules have a preclinical manuscript published in Cancer Discovery. And then the Scorpion data set was about 60 patients of phase one monotherapy with a month and a half worth of follow-up. That's not a lot to actually evaluate, to be honest. There is no monotherapy regulatory or commercial path here in this setting. So really the onus is on, you know, now Lilly to, as it moves into combination data, to be able to meet or in this case have to substantially beat the benchmark that we have now set of, you know, closing in on somewhere in the neighborhood of 10-11 months in median PFS in combination with fulvestrant.
I think what we would say is these molecules are likely not that different. That is what both the preclinical and early clinical data would suggest. You did see some idiosyncratic toxicity with the Scorpion molecule. You know, it is somewhere in the neighborhood of two years behind.
Okay.
You know, just to, you know, there are a number of other competitors further behind. There was a number of them profiled at AACR a few weeks ago. I think, you know, we continue to see molecules that just look like fast followers to either the Loxo H1047R selective approach or to our pan-mutant selective approach.
Yeah. The two years behind on differentiated is always a tough sell on oncology.
Yeah. I think, you know, we've seen this playbook before. In targeted oncology, it is very clear. You need to put up a next generation profile to the existing therapies, which we believe we've done in comparison to alpelisib, capivasertib, fulvestrant. Once you get into that next generation class, you have to be first to market. That is what we are focused on, the execution to make sure we get to be first to market in a very large patient population in the CDK4/6 experience setting.
Okay. As you're about to embark on starting the phase three ReDiscover-2 trial for 2608 in metastatic breast cancer, maybe how are you thinking about the types of patients that you'll end up enrolling and prior exposure to CDK4/6, some of which could be thinking the adjuvant setting, some of which could be frontline setting exposure. Your trial, could it have a meaningful proportion of frontline patients? You know, obviously the proportion of frontline patients, could that drive a line agnostic approval? It's more of a CDK4/6 exposed patient population as standard of care shifts.
Yeah, you know, I will, I'll probably fall short of trying to predict labels in regulatory decisions. But, you know, what we are endeavoring to do here is if you observe the evolution of the landscape right now, you've got both ribociclib and abemaciclib with adjuvant labels. The ribociclib label, the label would address about 40% of that adjuvant population. There is going to be a growing number of patients in the first line metastatic setting that have seen CDK4/6 in the adjuvant setting. We wanted to construct a study that had the ability to enroll those patients with the potential to think about being able to have a CDK4 experience line agnostic conversation with the agency should we end up with a positive study and have a sufficient data set there.
Yeah. Yeah. We see this with the competitor in the post-inheritance setting, like running a post-inheritance trial with Zanidatamab in breast cancer and sort of a similar goal of having a, as therapy evolves and shifts, sort of a validated post-standard care option. It sounds like that's kind of a similar strategy you're employing.
Yeah. Yes. I think that's a good analog there. The goal is to try to be, you know, running the right contemporary study, but also skating to where the puck is going a little bit.
Yep. Makes sense. Maybe can you talk about the hierarchy testing for the phase three primary endpoint as you design the trial and look to maximize success for the phase three outcome?
Sure. We, you know, we had seen very exciting data across all mutants. And so we're sitting like we talked about earlier, near doubling of the existing standard of care today across all mutation types. And within the kinase subtype, we seem to have, at least in the existing data set, a bit of a super performance, if you will. And we also, in the competitive landscape, there are a number of players coming behind us with H1047 selective molecules. And so given the slight, even, you know, outperformance of kinase and these potential competitors coming behind us, we felt it was prudent to be able to have the kinase evaluation in the statistical analysis so that we could make label claims to the kinase population once we get there. And so we will test the kinase population first, and then we'll move to the ITT population.
Do you, would you anticipate that CAPI performs differently in the kinase versus the non-kinase populations based on kind of what you know? Is it well understood?
They've never broken out that level of subset analysis. The data-driven answers, we don't know biologically and mechanistically from the molecule. We would not anticipate that it performs differently because of the, you know, the molecule based off how we think RLY-2608 looks to be equally potent between the kinase and non-kinase population along with wild type and a lot of other kinases.
Okay. In terms of your phase I efforts with triplet combinations, maybe just remind us, you know, sort of what the current objectives are with different triplet cohorts and when we might start to see some data generated on that front.
Yeah. We currently have ongoing two triplet regimens, one with palbociclib, Pfizer CDK4/6, and with ribociclib. Both those studies continue to remain ongoing and kind of a dose finding portion of the study. We have not guided to when we'll share data from those regimens, likely not in 2025. The goal there is to, again, thinking about that eventual CDK4/6 frontline metastatic population, you know, what's that future regimen look like and what's the right registrational study to eventually run there. The tough thing there is it's a bit of an unsettled regimen in that, you know, you have some oral SERD studies ongoing in the frontline. Early evidence has not been playing out that favorably of those molecules being effective in the ESR1 wild type population. We, you know, whether it be Pfizer CDK4/6 or BeiGene CDK4/6 and others, haven't seen a lot of data yet.
I think we're going to see some updated data at ASCO. You know, you'll likely see us continue to do those studies and potentially some other oral endocrine therapy studies, but still kind of weighing with some of the options there and where's the right place to place resources.
Okay. And you know, with those triplets, are you interrogating the 400 mg, I guess, fed state regimen?
Yes. All of our ongoing studies are with the fed dosing regimen.
Okay. Any additional combination strategies? I think you outlined some of them that are, I guess, like contemplated at the moment.
Yeah. I think the most interesting ones would be oral endocrine therapies, whether it's just, you know, establishing combinability and just some dose confirmation with as simple as doing some aromatase inhibitor work or, you know, potentially some of these next generation endocrine therapies if it makes sense there. Although it's, you know, with some of the recent data, I think it's been tougher to get too excited about putting resources against it.
Yeah. Just like one macro topic on this point, right? I mean, you guys would have presumably always from an IRA perspective fallen within the biotech exemption single product, right? So the nine-year pill penalty possibly changing and going to 13 years is probably not immaterial from your perspective. Although if Relay was ever to be acquired and that pill penalty changes, that could change the attractiveness, I suppose, of the asset in the eyes of external eyes. Is that a fair way of putting it?
Yeah. I think that is as fair of analysis as any of us could make today in this volatile, unpredictable environment we exist in.
Yeah. Yeah. At least it's not speculative at this point. Like now we've finally gotten this put into legislative proposals and Trump has clearly indicated that this is a distortion that needs corrected and fixed.
Yeah. You know, it still requires in normal times legislative action, but yeah.
Yeah. Okay. Maybe shift gears to genetic diseases in the final 10 minutes here. So you've initiated a phase I evaluating 2608 in vascular malformation. I guess we know the mechanism, right? Has the potential to, I mean, it's driven off of competitor data that we've seen with alpelisib. They were able to get accelerated approval for a subset of vascular malformation. You know, as we think about what aspects of 2608, you know, might be an improvement on alpelisib beyond just the broader development approach and lens, what are the inherent aspects of the molecule? Is it really just the impact on hyperglycemia that allows you to study maybe more broadly?
Yeah. It really is, it's pretty simple in that a lot of the same reasons as to why we've been able to demonstrate differentiation against alpelisib thus far in oncology, why we think that we should be able to do that also in vascular malformations. It's a more selective molecule, which should let us drive to greater target coverage, better dose intensity while sparing the toxicity profile of a non-selective molecule. You know, as you know, in targeted therapy, efficacy and safety are two sides of the same coin. Our hypothesis is that should also benefit vascular malformations with PIK3CA-driven disease.
Right. I guess like sort of dose limiting toxicity could be speculated at least in maybe in terms of what limited developmental efforts versus how you're able to interrogate the broader landscape of vascular malformations. Is that?
Yeah. I think that's it. You know, Novartis and alpelisib, I don't think, you know, we have strong corporate focus in this area too. You know, they focused the initial development in PROS or the PIK3CA-related overgrowth spectrum. They also have a phase three study going on in lymphatic malformations, one of the larger PIK3CA mutant-driven subpopulations there. I don't think, I think the shortcomings in PROS would be the shortcomings in any of these other subsets. You'll see us run our first-in-human study here in both a mix of PROS and lymphatic malformation patients. The goal is to be able to meaningfully differentiate on both efficacy and safety.
Do you feel like the work you've done in oncology pretty meaningfully de-risk safety such that, you know, really what you need to learn is sort of the relative efficacy profile here and where you can take the drug from an efficacy standpoint? Or is there just so many confounding variables in oncology trial and differences in dose that it's a little bit difficult to extrapolate the safety?
No, I think proportionately you can look at the difference in safety in alpelisib oncology patients, 2608 oncology patients. You know, if you, the alpelisib doses that have been studied in vascular malformations are lower. And so the safety profile does not look as pronounced as it does in oncology. But similarly, we would, and it's just, it's not a late-stage cancer patient population. These are younger patients certainly burdened with this disease that has a lot of issues that you're both symptomatically that you're trying to resolve with inhibiting the driver of the disease. But, you know, otherwise they're not as burdened with like years of cancer therapy. They should be a little bit more fit. And so therefore you do not see as quite the level of toxicity. They're also on the younger side. You may not see as pronounced hyperglycemia.
We still have seen both with the results that have recently come out and presented with alpelisib. And anecdotally talking to physicians, that tolerability is one of the key issues with alpelisib in this patient population.
Is the dynamic, I remember in breast cancer, I guess it was in breast cancer, the screening criteria ended up being a lot stricter for who would get studied for alpelisib to mitigate some of the AEs like hyperglycemia. In the vascular malformation setting, is it similarly like restrictive in terms of who they've studied to see that, you know, relatively better side effect profile in that setting?
Yeah. They have been similarly restrictive in the metabolic criteria. Again, this is a disease that this mutation happens in utero. It's a somatic mutation. The ideal point in time of clinical intervention is as early as you can detect the mutation in the disease in these patients. Therefore you do not have a lot of, you know, six to 12-year-olds walking around prediabetic as you might in a breast cancer patient population.
Okay. As we think about the phase I study that you're embarking on here, how are you designing this to get answers to kind of proof of an efficacy signal?
Yeah. One of the benefits of taking 2608 into this setting is because of all the oncology experience, instead of moving into a traditional dose escalation phase one, we are moving into a concurrent randomization of three biologically active doses. The highest dose will be the recommended phase three dose in breast cancer. There will be two doses below that, all what we believe to be biologically active. That in and of itself should help us move a little bit quicker than the traditional dose escalation. We are going to try to, our inclusion exclusion criteria, we intend to focus a lot on PROs and lymphatic malformation patients, you know, obviously with known PIK3CA mutant disease. We will be able to get hopefully early indications of efficacy, you know, in the early dose escalation and expansion portion of the study.
Yeah. If you see a signal, and I know you've had backup molecules in PI3K, and I don't know if it makes sense if you see a signal to approach this molecule with different drugs, different pricing structures, things like that to maximize the opportunity in a rare disease setting as opposed to sort of the oncology price kind of bandwidth that you'd fall within. Or maybe you think they kind of like overlap
I mean, that is the reason for having the additional molecules to provide us with that optionality. That way we have another pan-mutant selective molecule that is at such a stage to where if we see that early clinical proof of concept that we hope we will, we'll have the ability to make that strategic decision to bring this additional molecule into this setting. You know, keep them bifurcated for, you know, all the reasons you just highlighted, the ability to have separate brands and IP and distinct chemical entities in these two different settings.
Yeah. How big can this market be? I know you guys provided some insight into this when you did an R&D day about a year ago.
Yeah. The current prevalence in the United States of vascular malformations with PIK3CA-driven disease is 170,000. Now the question here is what proportion of those patients over the course of their life, will they, would they pursue systemic therapy to control their disease? That's a little bit unknown, but when you're starting at a prevalent pool that large, it doesn't take a large percentage of those patients to seek chronic systemic therapy for it to be a very meaningful commercial opportunity for us. You know, we've done some market research suggesting that depending on what subset of vascular malformations you're in, anywhere from 10-40% of patients would seek systemic therapy for the disease.
Alpelisib's label speaks to what proportion of that?
They sit in a small subset of PIK3CA-related orbital spectrum patients. That's about 5,000-15,000 of that 170,000. That is one of the higher, it's one of the more severe subsets. And so, you know, that's where you get closer to about 40% of those patients seeking systemic therapy to control the disease. In lymphatic malformations, it's probably 20-30%. But there, there's about 80,000 of those patients. And the vast majority of them had PIK3CA-driven disease. And it is diagnosed clinically, not requiring a genetic test.
Okay. Maybe in the last minute here. In lieu of the, I guess, the strategic cost restructuring aspect of things, does that impede you at all to do kind of the earlier stage stuff, you know, as it pertains to Fabry or NRAS or any additional preclinical programs? Or, you know, are you still able to sort of move those forward? Depending upon external environment or just company catalyst, then you can kind of advance those forward at the right time?
Yeah. The current cash envelope contemplates taking Fabry's and NRAS at least to IND readiness and the ability to potentially bring one into early clinical studies. You're right. I think what we'll do is when we get to that IND stage, we'll do an assessment of where we are, the macro environment, and kind of make a business decision from there on those two programs. We are, the small focus research footprint we have left in the company is focused on one very high-value novel oncology target.
Yep. All right. Let's take a ride of time. Pete, thanks so much for joining us.