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

Welcome once again to the 46th Annual TD Cowen Healthcare Conference. I'm Yaron Werber from the TD Cowen Biotech team. It's a great pleasure to moderate the next fireside chat with Relay Therapeutics. With us today, we have Sanjiv Patel, President and CEO; to his left, we've got Peter Rahmer, Chief Corporate Development Officer; to his left, Don Bergstrom, President of R&D; and with us today, Jaena Han as well from our team. So I think we have a few slides to go through, and then we'll actually start the presentation thereafter in Q&A on vascular malformations, which is a new and important new area, and then we'll talk about breast cancer.

Excellent. Well, thank you, Yaron. Thank you to Cowen for the invitation. We're excited to talk about the exciting year ahead that we have. It's been set up because over the last few years, we've built the foundation. As you know, we've all lived through tumultuous times, and we made some very deliberate choices as a company to get through those so that we could focus all of our precious capital on advancing zovegalisib, which is our PI3K mutant selective molecule. And so to do that, we obviously focused our research organization. We staggered the entry of our preclinical programs that focused on NRAS and Fabry. And we out-licensed what was at the time, our most advanced clinical program, lirafugratinib. All of that extended our cash runway into 2029 and allowed us to focus our effort in 3 very large clinical areas, second-line hormone receptor positive HER2-negative breast cancer, first-line metastatic hormone receptor HER2-negative breast cancer and then PI3Kn-alpha-driven vascular anomalies. All of these are very large commercial opportunities. And our goal with the capital and resources we have over the coming years is to deliver these medicines to patients and make sure that we can meet these unmet needs. Over the coming year, we're going to share 3 different data sets that will hopefully derisk meaningfully, these 3 opportunities in the minds of our stakeholders, including our investors. And so let me go through those 3 disclosures that we hope to make. The first one will come in our second-line metastatic breast cancer area at ESMO TAT in Paris in a couple of weeks' time. Up to date, we've shared data from our 600-milligram BID fasted cohorts, which have shown a PFS over 10 months and response rate close to 40%. As you know, a couple of years ago, we did a food effect study, and we wanted to dose our pivotal trial using food. And so we selected an equivalent PK dose, 400 milligrams BID fed. And so the data from this disclosure will come from 57 patients who have had 400 milligrams BID fed as their dose. So the same dose that we'll use in our Phase III pivotal trial, ReDiscover-2. So the goal would be that it would show consistency with the data that we've already shown and meaningfully derisk our Phase III trial. On that note, we're kind of heads down executing. We're enrolling across the world, and we're very happy with how things are going. In our frontline approach, what we'll share this year is hopefully the design of our trial as we think about how to penetrate this very large market and the go-forward regimen that we hope to use. And then in the new area that we'll talk a lot about, I'm sure, today, around vascular anomalies, where there is an agent with accelerated approval where they have shown a 27% response rate in their accelerated approval. And then in the kind of failed confirmatory trial, they showed an 11% response rate at 12 or 14 or 16 weeks, I think 16 weeks. What we'll show is 20 patients' worth of data at the 12-week efficacy endpoint. And what we hope to show is meaningful differentiation from that. And hopefully, that will provide proof of concept for this mechanism. And then hopefully then, we'll be able to share next steps. So the goal of the year is to meaningfully derisk all 3 of these very large commercial opportunities and then for us to continue our journey towards getting these medicines to patients. So with that, maybe I'll turn it over to Q&A.

Yes. So I'll start us off. Clearly, vascular malformation and vascular anomalies are really coming into focus for you guys this year. Let's kind of zoom out a little bit. In Q1, you started your Phase II ReInspire study -- in Q1 of last year, you started your ReInspire study of zovegalisib in adults and children with vascular malformations. Could you provide an overview of kind of this indication as a whole and why vascular malformation should be amenable to treatment with a PI3K-alpha inhibitor?

Yes. Maybe I'll start and maybe, Pete, you could take it. But obviously, the condition is driven by PI3K-alpha mutations. And we've seen proof of concept with the nonselective PI3K-alpha inhibitor alpelisib and then the nonselective kinase inhibitor sirolimus in these patients. So we know that if you can inhibit this pathway, you do see responses. And so what we've been able to show in breast cancer is if you can [ mutantly ] selectively inhibit the pathway, try to reduce some of the off-target toxicities, you can achieve [ greater target ] coverage, and we see meaningfully increased PFS. We hope to see the same thing here in vascular anomalies to see meaningfully differentiated response rates. And so that's why we feel very confident that this is an area that we can be successful in.

Yes. So among vascular anomalies, we have 3 kind of key subtypes. We have the PI3K-related overgrowth spectrum, lymphatic malformations and venous malformations as well as cerebral cavernous malformations. Are there differences between the subtypes and how sensitive they are to PI3K-alpha inhibition?

We don't think so. I mean, obviously, we have to run the experiment. It hasn't been a robust data set produced with the molecules that we have. And so we'll run the experiment. We think a priority, there is not.

And then how do you expect enrollment of between these kinds of subsets in your Phase II study?

Yes. In the ongoing Phase I/II study ReInspire and in the initial data disclosure, we imagine the bulk of the patients will be PROS patients. They tend to be the most severe patients. And because that's where you have alpelisib with accelerated approval, those patients are actively seeking treatment and are discussing systemic treatment options with their physicians. But over time, we think that we will be -- we will -- well, one, we'll have some lymphatic malformations and venous malformations in the study. And over time, the distribution will probably grow.

Right. And if we zoom out a bit, you say that PROS is the most kind of common. But in general, overall, what the prevalence of VM and what percent of that would be these PROS patients?

Yes. It's a good question. So at the highest level, there's about 170,000 PIK3CA-driven vascular anomaly patients in the United States on a prevalence basis. And then if you narrow down to the 3 subtypes that are most likely to be in our study over time, which is PROS, LMs and VMs, that's about 100,000 patients. 5,000 to 10,000 of them are PROS, 60,000 to 65,000 are lymphatic malformations and then about 20,000 to 25,000 in the venous malformations. And we think of that 100,000 of the cumulative -- those 3 subtypes, we think about 25,000 of them would seek chronic systemic therapy to treat their disease. So you can think of that to correlate with the severity spectrum of these patients. We believe that today, based off of the understanding the -- what's driving uptake of both alpelisib and PROS and then off-label and then sirolimus use, you're sitting at about 25% of those 3 populations seeking systemic treatment. The goal would be to present a therapeutic intervention option like zovega that could expand that patient population over time.

Great. And if we can just double-click on kind of standard of care. You've mentioned alpelisib and sirolimus. Kind of, what options do patients have? And what does the typical patient journey look like?

You want to take it, Don?

Yes. So as Pete mentioned, there's really a continuum of severity in these patients. So this is largely -- these are largely congenital disorders. Patients are born with them, frequently diagnosed in childhood. Patients with quite severe manifestations, so who have either large lesions or multi-tissue lesions. Those are the more severe cases. They tend to be picked up a little bit earlier. These are patients who were referred into these centers of excellence, multidisciplinary centers of excellence, of which there are roughly 30 or so in the U.S., usually children's hospitals. And they will undergo a number of either procedures. So they could have surgery, they can have sclerotherapy. So essentially, when you have toxins injected into the lesion, other types of interventional radiology procedures. But eventually, a large proportion of these more severely impacted patients will look for systemic therapy because the local therapies, whether it be surgery or sclerotherapy, both -- eventually, a multifocal disease, you can't control the disease anymore. And invariably, after either an excision or after sclerotherapy, the lesions will grow back, right? So these are patients frequently who will end up looking for systemic therapy. There are then patients with less severe disease who especially may present with skin disease. Frequently, it will be seen by dermatology. Frequently may go years with misdiagnosis, until eventually, they'll see somebody who will put the pieces together. And so really, the disease is quite heterogeneous in terms of the way it presents and quite heterogeneous in terms of the experience patients have through their diagnosis and treatment.

Right. And then can you remind us what you've disclosed so far on the trial design for Phase I/II ReInspire? Kind of in terms of target enrollment, primary endpoint, what doses you're evaluating, et cetera?

Yes. So we were able to leverage when we started the ReInspire trial. We're able to leverage the fact that we had treated at that point, about 200 to 300 solid tumor oncology patients with zovega. So consequently, we had a good idea of what the safety profile looked like as a function of dose. So as we started ReInspire, we didn't have to go through sequential dose escalation in the new patient population. We're able to open randomized dose optimization in patients 12 years and older, where we are randomizing patients across 3 different dose levels of zovega with the top dose level being 400 milligrams BID fed, which is our oncology recommended Phase III dose. And then we're looking at 2 doses below that, 300 milligrams BID and 100 milligrams BID. So these are all biologically active doses that sort of span the range of target coverage. And we'll have 45 patients who are randomized 1:1:1 across those 3 doses, so 15 total. We then, once we finish that part of the study, can move into cohort expansion. So in the same patient population, but now with what we learned from the dose randomization, we can move forward with either a single recommended Phase II dose or a couple of recommended Phase II doses. We'll continue enrolling in a single-arm fashion there with an ORR endpoint. We feel that there's still the potential opportunity, given the fact that there are no approved therapies for these patients, to have an accelerated approval path forward. And we'll obviously need to talk to health authorities, but it's possible that the data we generate in the single-arm cohort expansions could be used to support an accelerated approval application. At the same time, as I mentioned, this is a congenital disease. So everything I mentioned is for patients 12 and older. We have recently opened dose escalation in patients between 6 years old and 11 years old. That will be weight-based dosing. We will initially dose patients at a dose that we think should give us exposure comparable to what you see at the 100-milligram BID in the adolescent and adult patients. And then with time, we have the option of opening as well, a 2- to 5-year-old cohort.

Right. And so even though ORR is kind of the primary endpoint for potential accelerated approval, when you think about vascular anomalies as a whole, what do you think is the most clinically relevant thing? Are we looking just at ORR, at DOR, PFS? And then kind of what is the bar that you want to meet here? Do you want to just be better than [ Vijoys ] was in their pivotal trial? Do you want to be better than their failed confirmatory? What are you looking for here?

Yes. So the precedented regulatory endpoint here is ORR. So it's measured by volumetric MRI. And what the FDA has looked for a few different times here is these patients generally are scanned about every 12 weeks. And so they're looking for your confirmed objective response rate, so 20% reduction or greater by volumetric MRI in a confirmed response. And the bar in EPIK-P2 was to exclude 15% in the lower bound of the 97.5% confidence interval. So that is at least the currently defined regulatory hurdle. And I think our -- and like you said, the bookends of the best that Apellis has done to date is 17% in their failed confirmatory study, 27% in their accelerated approval study, which, to remind everyone, was retrospective chart review of 37 patients treated on compassionate use. So by no means, a traditional clinical study. And then in their failed confirmatory study, the response rate at the most comparable time point that we'll be able to show in our initial data, it was 11%. So ultimately, we want to show a profile that's an approvable drug. And it's clearly, we want to beat the 11%. And ultimately, over time, we want to make sure that we have a data set that could clear the regulatory hurdle.

Right. And then on the safety side, what kind of profile do you think would be acceptable given that kind of these vascular anomalies are benign?

I mean, I'll start, and then Don. I think you characterize -- we all characterize these types of lesions as noncancers or benign. But the symptom involvement and the burden of the disease on the patients is far from benign. And so the safety and tolerability will be extremely important because the goal is to treat these patients chronically, starting in childhood. So it will be a critical component of how we assess what dose to ultimately bring forward. But we're also going to make sure that we are choosing a dose that has the best risk-benefit profile to allow patients and physicians to make their best treatment decisions. As folks that are understand rare diseases, there's commonly a lot of decisions being made by physicians and patients on -- around dose. And like if you look at any of the old sirolimus studies, there's constant moving around of the dose being used in those patients. So we'll kind of put all those factors together. We definitely want a safe and tolerable drug that can be dosed chronically, but also one that offers the maximum benefit for patients over time.

So do you see a similar profile to kind of what you've seen in breast cancer with single-digit rates of Grade 3 hyperglycemia and stomatitis, do you think that's good enough for vascular anomalies?

I think it's really just going to come down to the risk-benefit profile, so like what kind of response rate you're going to get for that kind of tolerability profile. And the totality of the data will tell us what the best trade-off is going to be.

Makes sense. And then also, how might zovegalisib be differentiated from Palvella's QTORIN rapamycin, which is also in development for lymphatic malformations and venous malformations?

Yes. That whole team has done an amazing job of bringing forth another option for patients that have no options today. So we definitely applaud all their efforts and are rooting for them to get that drug registered and bring another option forward for patients. We don't think that these patient populations, the one that they're pursuing and the one that we are pursuing, are going to have that much overlap. And so their drug is obviously -- it's a topical, so it can only treat topical cutaneous lesions. And as their KOL has described it, it's called going after the microcystic lymphatic malformations. So those are lesions that are cutaneous and 2 centimeters or less. And so I think there's a lot of these patients. There's a lot of unmet medical need. We believe that the bulk of the patients that we'll be seeing are going to be either mixed or macro cystic presentation. And so yes, we don't think that the patient populations are going to overlap that much.

Great. I'll pass it on to Yaron to cover breast cancer.

Great. So as you mentioned, at TAF -- sorry, at TAT, we're going to see the data from the 400 mg BID, 57 patients. And if I recall correctly, previously, we've also seen sort of a 50s patient number at the 600 once a day, non-fed. The -- is the data going to be long enough to look at PFS?

Yes.

And the -- what about -- and I assume, on response rates as well?

Absolutely, yes. We should be both presenting both ORR and PFS.

And it sounds like there -- we can read between the lines that you're comfortable with the data and they're probably going to be fairly comparable.

Our goal is to show consistency between the 2 different cohorts. And I think we've been public to say that both cohorts we shared with the FDA are -- and that totality of the data was part of the granting of the Breakthrough Therapy Designation that we got in January.

In terms of maybe more data that we can expect this year, it sounds like you're saying this year, we'll get -- I imagine both the CDK4 combo with Atirmo and the CDK4/6 combo and the Phase III trial design. Is that sort of fair?

I think our goal is to share data specifically for the go-forward regimen. What more data we share at the time, we'll decide. Because obviously, it's going to be a lot of information to get over. We're going to need to share all the relevant benchmarks in the second line, the data of the regimen that we go forward, the frontline trial design, the next steps. So we just want to make sure that whenever we put out a disclosure, it is easy to digest. And so we'll see when we digest -- when we put it all together, we'll see what else we'll share, but we'll definitely share that.

Okay. As you think about what would make sense and would be innovative in frontline, I imagine there's an opportunity potentially to think more on the CDK4 axis as opposed to the CDK4/6. You could do a combination, I presume, with either one depending on tolerability and things like that. But would it make more sense to advance a CDK4 forward? And that could be actually a good -- in combination with the PI3, it sort of even derisks the CDK4 path to market depending on how their own data shakes out?

Look, I think the premise of a frontline regimen has been kind of -- the path has been blazed by the INAVO120 trial. It showed that if you add a PI3K inhibitor to a CDK4/6 and AI in the frontline, you add significant efficacy. The challenge in that regimen is the tolerability. And so the point you make is exactly the right one, which is this is about showing a tolerable profile. This isn't about proving the efficacy. That's already been proven. And so between the 3 triplets that we run, our goal is to try and figure out which is the one that is going to be tolerable for patients to take for 3-plus years. And the premise of having a CDK4 selected and a PI3K-alpha mutant selected together, the premise would be that would be the most tolerable. And so obviously, we have to let the experiment play out.

When you're thinking about a -- what would be the challenges to that kind of a regimen? I guess the one thing that comes to mind is the CDK4 head-to-head against CDK4/6 fails, how does that impact your ability then to get that regimen approved?

Yes. So I think, obviously, there's an ongoing trial of atirmociclib in the frontline, doublet versus doublet, the FourLight-3 trial. I think if we were to move forward with atirmociclib, we'd be looking at a slightly different hypothesis, right? The CDK on the efficacy side would not necessarily need to be superior to the existing CDK4/6 regimens for efficacy. We'd be looking at our triplet being superior. So the success of that approach does not necessarily hinge on the success of the FourLight-3 trial. Now there are questions about what the contribution of [ parts ] would be. We think that recent FDA guidance that came out last year for the development of these types of novel agents and looking at contribution of [ parts ] would be consistent with potentially using FourLight-3 data to support that. In a 1,000-patient trial, you would anticipate that you'd see on the order of about 200 patients who would be PIK3CA mutated that would receive atirmociclib that could potentially be used to support the contribution of [indiscernible]. But all of this, if we were to go that route, would require us to work through with the [ health authorities ].

Right. So you can potentially use the data that Pfizer is generating and get access to that data?

That would be consistent with recent guidance. Yes.

Any questions from the audience? Maybe an update to your ReDiscover-2 study going head-to-head against Truqap, both in combination with fulvestrant. Any sense how far along are you, enrollment-wise?

Yes. As Sanjiv hit at the top of his remarks, we're very happy with the progress being made thus far. We are open globally now and enrolling patients. We're not currently guiding to full enrollment or top line data. I think once we have all sites open globally and have a good handle on what the enrollment rate is with all sites open, we will probably endeavor to try to give some kind of target date to full enrollment. Not quite there yet, but very happy with how the trial is rolling out globally.

Okay. There's been a lot of questions over the years on the Scorpion compound, 478. And now that we've seen its profile a little bit more, can you maybe remind us of your relative efficacy in all mutations and in the kinase mutation and tolerability relative to 478?

Yes. I mean, I think, obviously, we've done this one to death over the years. The monotherapy data, I think, started out strong and then deteriorated. Obviously, we've never really focused on that. We don't see that as the focus. We saw immediately for us to focus on the doublet with fulvestrant, where we showed 39% response rate. I think their latest data update was in the 20s. And then in the triplet, I think they showed some very early data where, again, they were below what they saw in the doublet. So I think on the efficacy front, I think we put out a bar which no one has beaten yet and no one has really even come close to. I think on the tolerability profile, there's some questions on the compound. I'm sure that they'll work through them. But obviously, you still see a very short follow-up, significant Grade 3, Grade 4 liver function abnormalities. And so that -- really, the question to answer on that compound is what is the dose going to be, and then what's the tolerability profile going to be. And I think we look forward to seeing the long-term follow-up data where we can really do head-to-head comparisons and really come to a conclusion on what really is this compound.

In Phase III, they're still doing some dose finding in combination with CDK4/6s, right?

That's right, yes.

And what was the reason for that?

I mean, I think they obviously moved very, very fast as is their way. And this is their ability, the size of a company that Lilly can do. But I do think there is a significant question on what is the dose. And so I do think that's the fundamental is what's the tolerability profile going to look like and what's the balance between tolerability and efficacy. And as you know, these patients are going to be on the frontline on this regimen for 3-plus years. And as we've said right at the beginning of this, tolerability is what matters here, and that's critical. And so we'll spend time making sure that we've got the right frontline regimen, and I'm sure they'll do the same.

There's -- we've been getting questions from -- Celcuity's geda is expected to have the Phase III VIKTORIA-1 data. It sounds like it's going to be late this quarter or early next quarter. So they've shown 9.3 months as a triplet in the PIK3A wild-type, and now we're waiting for the PIK3A mutant data. Can you remind us what they've said in the past on their PFS? And -- we think it was a very small sample. And what do you think about that triple overall, just given the lack of convenience?

They -- so they've not shown any robust data from their Phase I/II study at that dose and regimen. I think they had a bullet in a presentation that said they had 11 patients that were CDK4/6 experienced treated at that dose and regimen, and they said that, that was a 19-month median PFS. That would obviously be a very compelling PFS if that held up in a randomized controlled Phase III trial. As you highlight, this is a 3-drug regimen where geda is administered 3 weeks on, 1 week off intravenously. And then it's combined with palbociclib, so CDK4/6 pretreatment. Then it's combined with endocrine therapy, fulvestrant. So...

And steroid [indiscernible].

And then there's prophylaxis steroids and prophylaxis antihistamines. So it's -- quickly accumulates to a 5-plus drug regimen. In the second-line setting, these metastatic patients are living very active lives, and it's going to be a very challenging regimen regardless of the PFS in true second-line patients. The mechanism of the molecule is a multi-targeted drug hitting multiple pathways. The safety profile from the VIKTORIA-1 study in the wild-type patients looks a lot like an mTOR inhibitor. And all we know is that we have a lot of data in mTOR inhibitor, in breast cancer that with everolimus -- and everolimus does worse in mutant patients than it does in wild-type patients. So at the end of the day, you need to see the experiment play out. But we don't believe in any outcome that it is truly a long-term competitive threat to our regimen in second-line patients.

Great. Any maybe final question from the audience? Well, maybe a final question for you. What about doing a PI3 and SERD combo?

Can you get it, Don?

Yes. I mean, I think it completely makes sense. And one of the things that we've been doing over the recent past is looking for the SERD space to settle out. I think we're starting to see that happen. Last piece we'll see fall -- or one of the last pieces we'll see fall coming up imminently is going to be the persevERA trial. But I think this is an avenue we definitely, I think, could go into in the future.

Yaron, you should have asked the question, should it be a combo with SERD.

Lasofoxifene is a good drug.

Well, terrific, everybody. Thank you so much for coming. We appreciate it.

Thank you.