Right. Thank you so much. Good morning. My name's Peter Lawson. I'm one of the biotech analysts at Barclays. Welcome to Barclays Global Healthcare Conference in Miami, and really pleased to have up on stage with me management from Relay. So we have Don Bergstrom, president of R&D, and also Megan Goulart, VP of IR and communications. I think first the first question for us, and we're always kind of forward-thinking and, you know, thinking about the data in 2Q, kind of what we should expect to see from the doublet, so your PI3K plus fulvestrant, in 2Q?
Yeah. First of all, thanks for having us here. And so for that, just taking a step back as a reminder, 2608 entered the clinic in early 2022, and then we started just escalation with a combination arm of 2608 and fulvestrant in the HR-positive, HER2-negative, PI3K-mutated patients, breast cancer patients, in about April 2022. And so we announced that we completed dose escalation the end of last year. And then we also initiated our first dose expansion cohort at 600 mg b.i.d. in July 2023. And so we also completed enrollment in that the end of last year. And so then we also initiated a second cohort of dose expansion at 600 mg.
So when we get into the second half of this year, we'll have—we expect about 17 patients from the dose escalation and then 20 patients from the first dose expansion arm, so nearly 40 patients, with at least six months of follow-up. Then we'll also have the additional 20 patients with some shorter duration follow-up, by the time we get into the second half of this year.
Gotcha. And, and so is that CBR24 that we should kind of be focused on, the durability? So that's really only that kind of 40 patients where we get to see the.
Yep. That we'll have that fairly robust. They'll have had a chance to be on at least 6 months, and that clinical benefit rate, which is stable disease at 24 weeks. We'll have a fairly robust measure of that. And then we'll also endeavor to do some analysis on, you know, a landmark PFS at 6 and potentially 9 months.
Gotcha. What, what's the bar for success there for CBR and these PFS?
Yeah. So when you look at the existing agents, the two approved agents are, alpelisib, which has a CBR of about 46%. And then you also have capivasertib and inavolisib, which they haven't reported CBR, but the PFS there in the post-CDK4/6 patients is 5.5 months. And in alpelisib, it's about 4-6 months in the real world. And so when we're looking at the bar for success, we're looking at about a 5.5-6 months PFS that we need to be and demonstrate, you know, meaningfully better PFS than that.
Gotcha. Okay. So we've got what, 600, 400 milligram cohorts. What's the balance between those two that we should be thinking about?
Yeah. So we opened the 400 milligram, in conjunction with adding an additional 20 patients at 600 milligrams. And this was primarily for satisfying prospectively anticipated pessimistic questions from FDA. They will be looking for the lowest dose that really optimizes clinical benefit. 400 milligrams, we feel, is biologically the lowest relevant dose for 2608. We think the 600 milligram dose is a more optimal dose, but we'll have the 400 milligram patients to serve as a comparator for the 600 milligram cohorts to be able to support this justification. And again, we've enrolled about 8-10 patients at 400 milligrams in dose escalation, and we've now initiated about another 20 patients on top of that.
Okay. And then, the safety profile has been pretty spectacular. And kind of where do you think that ends up? What's the most appropriate kind of goals that we should be set up for hyperglycemia?
Yeah. Well, I mean, I'll start overall with our goal on safety is to overall have a good safety profile that allows us to maintain dose intensity chronically over the course of treatment for these patients. That's ultimately been the challenge with many of the other agents. So alpelisib, for instance, the median patient in trials of alpelisib only stays on the drug for about 5.5 months before intolerability leads them to discontinue. And at least 25% of patients in trials have discontinued due to AEs. So the ability to maintain dose intensity in the disease where clinical benefit is determined by the duration of benefit is certainly compromised if you can't keep patients on drugs. So the first thing we'll be looking at is, can we maintain that overall safety profile?
Now, the components that go into maintaining that include three key AEs that have limited the ability to keep patients on alpelisib, and they are hyperglycemia, diarrhea, and rash. And there what we're really looking to do is not only keep the overall numbers of those AEs low, but especially for hyperglycemia, to completely eliminate or near completely eliminate grade 3 hyperglycemia, which is the tipping point where patients require management with insulin and where oncologists in practice grow uncomfortable managing those patients and either bring in an endocrinology consult or actually discontinue the patient from treatment.
Gotcha. Thank you. The 600-milligram cohort, that you increased that in size. Was any reason for that?
Yeah. So we had come to the end of the first 20 patients. We had fully enrolled them and didn't have any slots available. We are looking to use these data to drive our resource allocation decision for the next trials that we run. So we're looking to have as robust a database as we can on which to make that decision. So we decided to add an additional 20 patients, which again, overall, will bring us somewhere between likely 40-60 patients that we'll have to be able to evaluate to make this decision. The other small change that we made is if you think back to our August disclosure of the first 600 mg data, in those 17 patients, there was slight imbalance for patients who had non-helical, non-kinase mutations. So these are 90% of patients.
You would expect if you were just enrolling a representative population, you'd have about 90% helical and kinase, 10% other. We were running about 70/30. Again, for the purposes of thinking about these data in light of other data that have been disclosed in the class, alpelisib was essentially developed exclusively in kinase and helical patients. And in inavolisib, 95% of the patients in phase I-B were helical or kinase. To be able to ensure comparability between our data and some of the other data, in the additional 20 patients, we are limiting it to kinase and helical patients.
Gotcha. For as we think about those helical and the, oh, kinase and the helical patients and the non, which are easier to treat, respond, duration, etc.?
You know, I think consistent with our preclinical profile of 2608, we've seen relatively comparable activity of 2608 in patients with both helical and kinase domain, whether we look at CBR, in those initial 7 patients who are CBR evaluable, or whether we're looking at tumor measurements where the 5 patients were measurable at our August disclosure, 4 showed tumor reduction. Of those 4, 2 were kinase, 2 were helical, and the patient who had a confirmed PR was a helical patient. So I think we're seeing consistent benefit across, the various mutation classes. And I think this is consistent with what we've seen for some of the nonselective inhibitors like alpelisib, where, retrospective analysis of the SOLAR-1 trial looking at benefit of alpelisib in, kinase versus helical patients showed similar benefit across the two populations.
Gotcha. Okay. And will you want i mean, it sounds like you won't need to kind of balance the arms for kinases versus helicases.
No, we're not trying to balance between those. We're just trying to make sure that the overall number of kinase and helical patients are representative of what we'd expect, in a subsequent trial that we would run.
Gotcha. And then as you think about phase III, what would it look like? What would the control arm be? I know there's kind of such potential changes in the PI3Ks that are being used.
Yeah. So the first trial that we would be ready to start would be a fulvestrant doublet trial in the post-CDK4/6 setting. So these would be patients who would be second or third-line patients, largely reflective of the patients that we're currently enrolling, in the ReDiscover trial. So in that patient population, there are currently two regulatory standards of care. One is alpelisib plus fulvestrant, approved a few years ago now. And I think where we've really seen a plateau in the usage, in the clinic based on revenue numbers for that drug, we've also recently, in November, seen the approval of capivasertib, which is a multitargeted AKT inhibitor from AstraZeneca in combination with fulvestrant in this patient population. So those provide the benchmarks that Megan mentioned a few minutes ago.
We think a PFS of about 5.5-6 months. We anticipate that one potential pivotal approval path, and the path that would be the first available to us, would be a head-to-head trial against one of those regulatory comparators. We are hearing, as we talk to KOLs and investigators, growing enthusiasm for capivasertib and inavolisib at the cost of alpelisib. We've not yet seen any sales numbers for capivasertib to get quantitative confirmation of that qualitative feedback we're getting. I think if we see that play out, that could push us towards capivasertib as a potential comparator.
Gotcha. And that in no way changes the goalposts for you?
No. We think the goalposts are very similar for the two agents. Some differences in the AE profiles. Cap has some less hyperglycemia, more diarrhea, still has a 13% rate of discontinuation.
Gotcha. Okay. Thank you. And then in the pivotal dose, is that still to be determined, 400 or 600?
Well, I think, you know, it's our opinion that 600 milligrams is a potential optimal dose in this setting. Obviously, we'll have to have interactions with regulators both on a potential pivotal design as well as pivotal dose. So I can't conclude that that will be the pivotal dose until we're on the other side of those interactions.
Gotcha.
Now, you're not the only company pursuing this approach. You said any data or anything that's kind of changing the way you're thinking about driving this product ahead?
Megan, do you wanna take that?
Go ahead.
About the competitors we're gonna get. Scorpion.
Yeah.
Yeah. I think we've not heard guidance recently from either company. When Scorpion entered the clinic last year, they had guided to having data, this year. But they've also had some management change, recently. So we haven't heard that guidance confirmed.
Yeah. But otherwise, I don't think you know, at this point, for other competitors in the mutant-selective PI3K field, we've not seen any data. I think we are leveraging the fact that we were the first to enter in the clinic. And for the pan-mutant-selective approach, you know, we have roughly an 18- to 24-month head start. So we're leveraging that position to move aggressively with development of 2608.
Gotcha. Thank you. And then the Triplet data, in the second half, kind of I guess it's initially safety data.
Yep.
What should we expect to see in that?
So we only initiated dose escalation end of last year. So it's gonna be limited data this year. We're really focused on finding a dose, and then reporting the initial safety intolerability data. So this is also in the post-CDK4/6 patients. So we're not expecting to see much from an efficacy perspective there, in these patients that we're rechallenging with CDK4/6. Like I said, it'll be fairly limited, small numbers, small duration, really just dose finding at this point.
Gotcha. Okay. And then I guess I guess it's often asked just about Roche's Triplet data, which kinda gave you a window into what this could look like, you know?
Yeah. So obviously, those data that were disclosed in December at San Antonio Breast, I think were very exciting for us because they were very validating. There was some question leading up to that data disclosure about whether addition of PI3K inhibition to a CDK4/6-containing regimen would lead to additional benefit in patients who had not yet been previously treated with CDK4/6. I think what the Roche data showed within inavolisib is that unquestionably, yes, there is benefit of adding inavolisib on top of CDK4/6. Now, that was an experiment or a trial that was run in a very narrowly defined patient population. So the first key definition criteria for that trial was patients who are endocrine-resistant to their adjuvant endocrine therapy. So these were patients who progressed, either on endocrine therapy or rapidly after discontinuation of endocrine therapy.
It represents likely about 40% of frontline, metastatic hormone receptor-positive, HER2-negative patients. They then applied a second cut to the population based on baseline metabolic status. Given the hyperglycemia liability of inavolisib, they chose to go into very metabolically fit patients defined as a hemoglobin A1c less than 6 and a fasting plasma glucose less than 126. So those effectively exclude anybody with either well-managed diabetes or undiagnosed diabetes or prediabetes, which for CDC data would exclude roughly 50% of the U.S. adult population.
Gotcha. How does your entry criteria differ, you know? Do you have particular bars, around A1c?
We do. We do. So we allow patients with a baseline A1c up to 7, a baseline fasting plasma glucose of up to 140. So we are enrolling patients who are either have prediabetes or are at risk of hyperglycemia. It's similar to the inclusion criteria that inavolisib used in one of its phase 1B arms. It was arm D, fulvestrant combo, in their phase 1 experience where they used a hemoglobin A1c cutoff of 7. And in that patient population, the rate of grade 3 hyperglycemia was 22%, which is why they went with a more stringent criteria to get that rate down to 6%, in the phase III trial in more precisely defined patients.
Are you excluding any patients that would be in that post-CDK4/6?
I w-we're.
With that exclusion criteria?
Yeah. We're excluding I mean, I would say our key exclusion criteria is we're excluding patients who have been treated previously with a PI3K inhibitor. But otherwise, our inclusion criteria are fairly representative of other trials that have been run in this population. So we require prior endocrine therapy. We require prior CDK4/6 therapy and up to one prior line of chemotherapy.
The one other place that the criteria differ is about a third of metastatic breast cancer patients have non-measurable disease. We're allowing both non-measurable and measurable disease, whereas their trial is measurable disease patients only.
Okay. And what do you wanna see for that kind of safety bar for that set of patients?
Yeah. Again, I mean, I think what we're looking to do is see high-dose intensity, the ability to maintain patients on their starting dose chronically. And to do that, we're looking to dial down the overall rate of hyperglycemia, dial out grade 3 hyperglycemia, dial down all-grade diarrhea as well as, hopefully, eliminate grade three diarrhea similar with rash, and then obviously not have any other safety signals that pop up that would compromise dose intensity.
Gotcha. Is there when you talk to physicians, what are the most important things to dial down? Is it the diarrhea, rash?
Yeah. I mean, I think the capivasertib and fulvestrant versus alpelisib narrative that we're hearing would suggest that with the dosing schedule that's used for capivasertib and fulvestrant, the overall rate of hyperglycemia is significantly lower than you see for alpelisib. And I think that makes management, it makes it more manageable, for treating physicians. So I think that is a benefit for physicians that pushes them towards capivasertib. Of course, it comes with the expense of diarrhea that shows up in the patient-reported outcomes for quality of life, for the phase III CAPItello trial that was run for capivasertib and fulvestrant. So it doesn't come without trade-offs. And you know, I think it does make it difficult for patients.
Gotcha. Thank you. And then as we think about other combination of the Triplets, you know, what's the next logical one? You're using, ribo.
Yeah. So the ongoing protocol, in the existing protocol that's open at sites has escalation with both ribociclib and palbociclib. We've initially initiated ribociclib. We also anticipate we will eventually initiate palbociclib as well to give us optionality there. And then, of course, the CDK landscape is not static. You know, I think we are very pragmatic, and open to considering, you know, potential other combinations of emerging agents either on the CDK axis or on the estrogen receptor axis. But obviously, with experimental agents, that would require us to have a clinical trial agreement with the sponsors developing other agents.
Gotcha. Don, is there any worry that you kind of pick the wrong combination partners? How do you kind of chase that evolving landscape?
Yeah. I mean, I think this is, you know, another case. We're in the post-CDK4/6 setting. The most recent approval we've seen has been capivasertib in November. That was still with a fulvestrant backbone. And I think in the combination setting, in the post-CDK4/6 setting, it's likely that, you know, for the foreseeable future where we would be starting a trial, I think fulvestrant would still be the relevant antiestrogen. Doesn't mean that in parallel, we might not generate evidence in combination with novel antiestrogens to anticipate a changing standard of care. Today, we anticipate a fulvestrant backbone would be the first registration path. I think when you get into the CDK4/6 setting, you know, we are seeing some settling in the market right now with a move towards ribo.
But obviously, you're going to have looming palbociclib, lots of exclusivity. You have other agents coming in that could have some uncertainty in that market. So obviously, we'll follow that closely as we make a decision on the design of an ultimate frontline trial.
Gotcha. Okay. And then maybe we could just touch upon the FGFR2 inhibitor, in CCA and kind of a broader set of tumors as well. Just how much data we should expect to see? I know you kind of paused that program for the broader group of patients to kinda catch up, just the rationale there and what we should see next in the second half.
Yeah. So just to clarify, we only paused commercialization preparation for cholangio. We're continuing. We announced, in October, that the pivotal trial or the pivotal arm for cholangio is fully enrolled. And so that's continuing. That itself wasn't paused. And then on the tumor-agnostic front, we disclosed initial data at the Triple Meeting in October, just promising but early. And so we continued enrolling some patients after that to get more data. And now, we're letting those data mature. And so we expect that we'll have enough data to take to regulators and have regulatory interactions in the second half of the year to help inform our path forward. And that's what we've guided to from a disclosure perspective, is providing an update on those data we use to inform those discussions as well as the outcome of those regulatory discussions in the second half.
Okay. Ha and sorry. How many patients would we see in that non-CCA population?
We designed it to have about 50 patients per arm.
Okay.
We haven't guided to how, how much we've enrolled beyond that, beyond what we announced at the Triple. But that was our numbers.
Gotcha. What's the mix of those patients that we should expect? Did you kind of, yeah, exclude patients or particular inclusion criteria?
Yeah. You know, I think, so the inclusion criteria, first of all, that the cohorts are arranged by molecular alteration, not tumor type. And we largely, after the Triple Meeting, continued enrolling the same mix of patients that we had going into the Triple Meeting with one exception in the amplified cohort. In our Triple Meeting disclosure, that cohort was overwhelmingly represented by gastric cancer patients. They were by far the largest tumor type that was enrolled in the amplifications. And as such, as we continued enrolling in the amplification, we did put a cap on the number of gastric cancer patients that could come on so we could get some representation of other tumor types as well.
Gotcha. Are there particular mutations you think would be more responsive in the larger data set?
Yeah. I think, you know, going into this, we anticipated that fusions and rearrangements would most likely be the most sensitive to FGFR2 inhibition. I think the initial data that we showed at the Triple Meeting was consistent with that, with a 35% response rate in the fusions, 24% in amplifications. But again, that was largely biased towards gastric. And then in the mutations, I think that that's where we're seeing probably the most heterogeneity of effect. We had a 13% response rate, some very good quality responses, especially in a couple of breast cancer patients. But I think the mutation population is the population where there's probably more work that needs to be done to understand either the impact on, on genotype, to sensitivity or on tumor type, for FGFR2 mutations being a driver in a particular tumor type.
Is there any risk as you add known gastric patients? Does that change the response rate, or?
No. I think, you know, we'll have to get the data and see. I think what we've seen with the gastric cancer patients, I think consistent with other experience in the space, is that in these late-line gastric cancer patients, it's a very, very aggressive disease. So consistent with that, I think what we saw in the gastric cancer patients is either patients where the responses were relatively shorter-lived than we saw in the other tumor types or where patients got, you know, an early scan response that didn't confirm. And I think, again, we need to understand, is that a factor of gastric cancer, or is that a factor of amplification?
Gotcha. What are the bars for success there, whether they're internally or from external data?
So in the tumor-agnostic populations generally, we're dealing with essentially last-line patients. These are patients who don't have any existing standard of care. The agents that would be out there that would be used for them, in the literature have response rates of between 0% and 15%. And this is a population where FDA precedence has been that having a response rate where you can exclude a 15% response rate from the lower bound of your 95% confidence interval has typically been a bar that's been accepted for a accelerated approval. Now, we need to vet that with the FDA.
There's also recent guidance about the distribution of tumor types and the homogeneity of effect across tumor types that obviously, as we look at our data and have discussions with FDA, we'll have to ensure that as we continue to build on this data set, should we build towards a tumor-agnostic approval, we're consistent with that guidance.
Gotcha. Don, what's the sentiment from the FDA around tumor-agnostic labels? Is it becoming more difficult, or?
I think they're becoming more precise in terms of defining what it means to have a tumor-agnostic label. And again, it's about really having confidence that the effect you're seeing of the drug is driven by the molecular alteration and not specific tumor type. Hence, the push to have representation of multiple tumor types and to have demonstration of clinical benefit across multiple tumor types.
Gotcha. Perfect. So thank you so much. Pleasure to speak, Don, as always.
Thank you, Peter.
Thank you.
Bravo.