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

Presenter at the BofA Annual Healthcare Conference in Las Vegas. My name is Jason Gerberry, I'm one of the biopharma analysts. Pleased to be introducing Relay Therapeutics. We're joined by Pete Rahmer, Chief Corporate Development Officer; and Don Bergstrom, President of R&D. So gentlemen, first, thanks for joining us.

Yes. Thanks, Jason, and thanks to the entire BofA team for having us.

So yes, I think -- I figure 2 relevant discussion points would be your PI3K and your FGFR2 programs, which are your most advanced programs. And for those of you less familiar with Relay, Relay works on validated targets in the precision oncology realm, looking to make better drugs than those that are, I guess, available to patients, oftentimes proving the therapeutic window for those medications. And so I thought it would be good to just start with the PI3K program just because of your more recent data update that you had at the AACR Medical Meeting. And maybe just -- if you can just talk a little bit about the data that you presented in breast cancer specifically with the combination arm, the good, the bad, and I guess, ultimately, the TBD, which is always the case with the first initial Phase I update.

Yes. Definitely. Maybe I'll start and then pass it over to Don. I think the one thing, just to be clear on, our goal with this program is to create an unequivocally differentiated medicine for patients with PI3K-alpha mutations as measured by the ultimate regulatory endpoint here, which is median PFS. And we believe that the initial data that we showed for RLY-2608 at AACR are the first step in being able to demonstrate the fact that we have a molecule that could potentially end up doing that. I think -- to remind folks, as we have been talking about for almost a year going into this initial disclosure, similar to our initial disclosure we made on RLY-4008, our FGFR2 inhibitor, the goal here is to demonstrate clinical proof of mechanism. And we had been defining that as being able to demonstrate that we could reach our target exposures, in this case, the target exposure that we defined was consistent coverage above the ICAD of the mutant form of the protein. Being able to do that at tolerable doses and so showing being able to demonstrate in a robust number of patients a safety profile that is in these initial data set differentiated from the nonselective inhibitors. And then being able to do that in the context of supportive pharmacodynamic data showing -- also showing that we are hitting the PI3K of a mutant form of the protein. And so I think the initial data that we showed checked all those boxes for us. We showed that we had multiple doses in both monotherapy in combination that achieved those target exposures above the ICAD. We're able to do that at a very favorable safety profile in this initial data set. The key toxicities that plague the nonselective inhibitors are hyperglycemia, rash, diarrhea, all with grade 3 rates that are certainly limiting the dose intensity of those agents. And we saw no grade 3 events for -- at those doses above the target exposure. So that was extremely encouraging to us. And then lastly, we were able to demonstrate that we were hitting the target through a number of measurements, our ex vivo PD assay that we created showing that we can inhibit phospho AKT at or above that 80% threshold. We showed ctDNA decreasing across the number of different doses. And then lastly, we showed antitumor activity. And I think where the -- there is probably a bit of a focus that resulted in kind of the stock price reaction was probably on the expectation of seeing a definitive response rate in the combination patients -- in breast cancer combination patients. And factually, we did not see a partial response in those combination patients. I think we gained confidence in the totality of the data. The key metric that we're focused on here again is, can we get confidence in being able to drive to a differentiated median progression-free survival to the existing agents? And I think that all the data that we've seen to date in the AACR presentation, start to give us confidence that we have the profile of the medicine that can accomplish that.

Yes. Yes. So you mentioned sort of the market's reaction to it. Clearly, from our perspective, you established safety and good target coverage out of the box with the combination arm. Were you at all surprised at all by the lack of responses? Or would you just chalk that up to small sample size and you need a little bit longer duration follow-up, ultimately?

I mean the latter, but I don't want to sound dismissive of the fact that we didn't see a partial response. Like you have to remember that if you were to go back and look at even the early combination Phase Ib studies with inavolisib and alpelisib, you're talking about these early response rates are somewhere in the high single digits to low teens. And when you look at the number of patients we had above the target exposure in combination, there are 7 of them in this initial data disclosure with measurable disease. And so that's a difference of one of those patients tripping over that 30% line. And that -- and when you break that down to the actual amount of tumor shrinkage, you're talking about the difference in millimeters of tumor shrinkage. So yes, we would -- I think we would have all felt more comfortable with this initial data disclosure, if there's a couple of those patients that tripped over that 30% line. I think we really have to keep in mind the disease context here. This is a disease setting where, one, response rate doesn't correlate that well with PFS. It's not an ultimate regulatory endpoint. And when you really look at some of the metrics that actually matter to being able to push towards -- or getting to a meaningfully differentiated PFS, one of the key things you keep hearing us talk about is dose intensity. And the reason why we do that is one of the most -- more robust assessments of why that matters in this patient population is when you look at the SOLAR-1 study, which was the approval study for alpelisib. They did a subset analysis of bi-dose intensity in that patient population. The label dose for alpelisib is 300 milligrams once daily. The median dose intensity able to be maintained in the SOLAR-1 study is 248 milligrams once daily. When they bifurcated that patient population and looked at the Kaplan-Meier PFS curves like those that were able to maintain dose intensity above 248. And those below, you saw the median PFS in the above patient population at 12.5 months. In the patient population below that 248, it was only 9.5 months -- 9.6 months. So again, we keep coming back to this concept of dose intensity. What makes people uncomfortable about that is that it takes time to define. We think we have a lot of the initial signs to point toward where we should be able to get there, but the more acute measurement that you can get in oncology studies is response rate, and the fact remains that we didn't see a partial response in the combination piece.

And as you mentioned, ORR and PFS haven't always correlated in this area with other medications that we've seen.

Correct. Yes. And again, you got to in mind, this is the 5% -- this is the patient population, where only 5% of the patients are diagnosed in the metastatic setting. The bulk of these patients are found very early on in their disease course. They're not -- in the HR-positive HER2-negative patient population, these aren't patients that you're typically finding with extremely bulky disease where the benefit of seeing response rate early on, it gives you the comfort that you're debulking very symptomatic disease. That's not the case here. These patients are -- they're being monitored largely through CT scans and not because they are generally feeling very symptomatic progression of the disease. And so therefore, that's why there's this concept, when you'd speak to the investigator community, which we've spent a lot of time with post these data, there's a very different perspective than what Wall Street is seeing -- how Wall Street is assessing these data. They are very encouraged by these early data and giving them confidence for the first time that they are -- they have the option of a truly mutant-selective PI3K-alpha inhibitor at their disposal.

Yes. And I guess we jump right into a very micro level topic.

Sure.

This is metastatic breast cancer, really where the opportunity is and why that's relevant, I think, for you guys is FGFR2 was very good data, but I guess the pushback is small, maybe smaller tumor opportunity, whereas the breast cancer opportunity for PI3K is viewed to be kind of one of the bigger, more attractive opportunities, which is why it gets a lot of investor focus. So maybe -- look, totally makes sense. We've got to kind of wait and see how the data mature ultimately and how the PFS profile looks. One thing that comes up a little bit is just the reliability of the ex vivo target coverage data that you've generated. This came up with the discussant in the Q&A at the AACR Medical Meeting. So with FGFR2 inhibitor, you were able to corroborate really good target coverage with clinical efficacy. And so do you use the same assays with 2608? And just kind of if you can speak to the reliability of these assays and predicting target coverage.

Yes. Yes. I think one of the challenges of developing a mutant-selective inhibitor is the only tissue that the true target of the drug is expressed in is tumor. So frequently, you will see people use a surrogate tissue, they'll look at peripheral blood on the nuclear cells or hair follicles or some other tissue that gives you confidence that in-tissue your drug is doing what you would hope it to do. And then ultimately, people look at tumor biopsies. But tumor biopsies, you tend to not get very many paired tumor biopsies. The assays that are used in measure biomarkers and tumor biopsies frequently are not quantitative. So it's hard to build a quantitative PK/PD model. So as we approach this, what we did is we said, we're obviously going to look at PK and relay that back to all of our preclinical PK data and PK/PD efficacy in preclinical models. We will look at an ex vivo assay that in and of itself as a single data point is not necessarily definitive for saying what's happening in the tumor. But in the context of all of the other data we're collecting, again, it's another corroborative data point where we can look for consistency of effect across the various measures we're looking at to get confidence in the dose. And then we look at ctDNA, which is now a more direct measure of the pharmacodynamic effect of 2608 in the tumor because what you can see is that you actually are having activity against this specific mutant clone that is expressing your PI3K mutation. Then you can look for clearance of that ctDNA data. And here is now where I think you see all of the data come together where you say we would project that at 400-milligram monotherapy or 600 milligram, 800 milligram combo, we should be at our efficacious threshold. That is cooperated by the ex vivo phospho AKT assay that's showing us about 80% inhibition of PI3K in that assay at those doses. And then when you go to the patients who are treated at those doses who have detectable circulating tumor DNA, we're seeing significant reductions or complete clearance of circulating tumor DNA, actually at a rate higher than what you're seeing in patients at the lower threshold. And now I think we're getting more experience with these doses for efficacy readouts. And here, it's looking not only at tumor shrinkage and the potential for response. We talked about response quite a bit, but you're also going to be looking at how long patients stay on therapy. How long patients stay in disease control with stable disease or better as their response. And that will translate into clinical benefit rates. The stable disease are better at 24 weeks. And all of these data, I think, will be taken together in aggregate as we select doses to take forward.

And just a follow-up on dose. I think you framed 600 milligram and 800 milligram as therapeutically active doses. Curious that's 80% target inhibition with these doses. And in the preclinical setting, have you looked at sort of antitumor activity when you pushed beyond IC80 to maybe IC90? And maybe it's a question -- are you leaving any efficacy on the table by not pushing to greater target inhibition?

In preclinical models, no. We could push to IC90, but we had already maxed out efficacy at IC80.

Got it. Okay. Maybe how comfortable are you guys with the 600 mg hitting IC80 across patients, given there were some data variability just judging by the [ air bars ] and the drug exposure and the PK data?

Yes. I mean, there's clearly, I think, fairly standard interpatient variability for an oral molecule that we're seeing with 2608. So when we're showing those PK curves there an average of [ air bars ]. There could be patients who are just at the threshold or slightly below it. I think the threshold is a useful tool, but it's not necessarily a line etched in concrete. And if you look at our patient where we did see a monotherapy-confirmed partial response, that individual patient's PK exposure was actually slightly below the 80% exposure threshold line. So it is a continuum here. And I think with the 600 milligram dose, we're confident that in the bulk of patients will be at or above the line.

Got it. Maybe thinking a little bit about sort of next steps here as you advance 2608, the dose expansion here in the second half. Maybe just the timeline between now and AACR and going forward and what you aim to achieve in the dose escalation portion, any metrics? I mean I would assume that the focus will be probably on still response rates, but also PFS with the next data update.

Yes. So maybe 2 parts. I mean Don can start with some of the characteristics we'll take into consideration as we choose the dose or doses to take into expansion, and then I'll come back and talk about the 2024 update.

Yes. So right now, we are continuing to enroll the 600 milligram and 800 milligram doses in combination in dose escalation. The protocol is flexible and allows us to enroll up to 12 or potentially even more patients and still be in dose escalation so that we can get more robust data there. We are also opening a 1,000 milligram BID cohort. We think that is probably excessive compared to where we want to be in terms of exposure. But we're doing it to be able to design the full dose range and to be able to set up productive end of Phase I interactions with FDA. So the parameters we'll be looking at as we choose a dose or doses to take forward into expansion cohorts is we'll be looking at our target coverage, we'll be looking at the PD end points, we'll be looking at the safety profile and I think, importantly, we'll be looking at the ability to maintain dose intensity. And then we'll be looking at the efficacy readouts that come in conjunction with it. And we'll look at the totality of the data to be able to support a dose to take forward into expansion cohorts, which is very similar to what we did at about this time last year in our RLY-4008 FGFR2 inhibitor program where we had a very productive end of Phase I interaction with FDA based on that robust Phase I data set.

Yes. And the next data update -- the nature of the guidance in 2024 is so we can then take some of those data that Don just mentioned and let that mature and be able to have a -- what we would anticipate to be an interpretable robust disclosure that starts to give us a sense of this concept of dose intensity at a larger end at those doses above the target exposures and start to get an idea of this -- of what the CBR could start to look like, albeit early and likely somewhat immature, to start -- to really inform that ultimate endpoint of a median PFS.

Yes. Got it. And maybe just talk about past discussions with FDA around Project Optimus and sort of given the agency's push regarding dose exploration, how this sort of strategy maybe melds into this dynamic? You hear a lot about this from your peers that it's sort of impacting how they're going about sort of clinical exploration.

Yes. I mean I think there's certainly more dose exploration in the Project Optimus era than there was before a few years ago when this regime came into place. And I think we have learned from our FGFR2 RLY-4008 experience with FDA where we went into that end of Phase I meeting. We had 115 patients worth of data across 14 different cohorts. We had robust profiling across multiple different end points. I think we had a database that really allowed us to defend the 70 milligram once daily dose that ultimately we took forward. FDA ultimately agreed for that to be the dose that we would use in our pivotal design. Now I think it's important to point out that it's not any one single data point the FDA is looking for. They're looking for data across multiple different parameters. And when we went and had a discussion around 4008 with FDA, response rate wasn't a driver of that dose defense, right? Because at that time, we actually had very few patients who are FGFR inhibitor naive who have been exposed to 4008. So we didn't even talk about response rate, right? It was all focused on PK/PD, safety end points. And I think consistent with that, with 2608, we're trying to build a similar type of robust data set where we're profiling multiple biologically and potentially clinically active doses across a number of different parameters to be able to hopefully have another productive interaction with the FDA. We've not had it yet, so I can't comment on what will happen. But I think based on the successful interaction we had last year in FGFR2, I think we're well positioned as we go forward with 2608.

I know it's a little early, but just maybe talk about do you feel like you've, in some respects, optimized the profile, right? You've said that getting greater target inhibition, you're not seeing much bang for your buck there. The reductions in off-target AEs looks pretty good. So there are some other pipeline programs, competitors, right, that are touted as more selective. So as you kind of just look at yourself versus the field and what we understand about the different profiles, the different molecules, Eli Lilly, Scorpion, maybe if you can just sort of offer a little bit of your perspective.