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

Hello, and welcome to Relay Therapeutics Conference Call. [Operator Instructions]. I would now like to hand the conference over to Peter Rahmer. Sir, you may begin.

Thank you, operator, and good afternoon, everybody. Thanks for joining. We are excited to share these initial data for RLY-4008, now known as lirafugratinib in FGFR2-altered solid tumors with you. You can access the press release from today, the slides we are reviewing and a replay of this call by going to the Investor Relations section of our website. As a reminder, during this call, Relay Therapeutics will make certain statements that are considered forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 including expressed or implied statements regarding our strategy, business plans, objectives, the expected therapeutic and clinical benefits of our products, the potential of our platform and our product candidates and progress and timing and execution of our clinical trials. Such forward-looking statements are not guarantees of future performance, and therefore, you should not put undue reliance upon them. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. We refer you to our SEC filings available on the SEC website and on our website for a discussion of risk factors that could cause our actual results to differ materially from those discussed today. The forward-looking statements in this presentation speak only as of the original date of this presentation, and we undertake no obligation to update or revise any of these statements. Today on the call with me are Sanjiv Patel, our President and CEO; and Don Bergstrom, President of R&D. With that, I'll turn the call over to Sanjiv.

Thank you, Pete, and thank you for those of you joining the call this afternoon. We're excited today to be talking about RLY-4008. Our research team designed it using a combination of leading-edge experimental and computational approaches to overcome challenges that others could not overcome using traditional approaches. And we created the first highly selective FGFR2 inhibitor. In September of 2020, we dosed our first patient. And today, approximately 3 years later, we've enrolled more than 450 patients into our ReFocus study. And today, we announced that we fully enrolled our first pivotal cohort with more than 100 cholangiocarcinoma patients. This is a testament to the continued excellent execution of our clinical team. Moving to Slide 4. Our clinical experience has shown the exquisite selectivity of 4008 allows us to inhibit FGFR2 at very high levels. And as we've shown in the past, this translates into activity levels in cholangiocarcinoma FGFR2 fusion patients not previously achievable with the nonselective inhibitors. Today, we're thrilled to show this activity also translates across tumor types and alteration types and this opens up a much larger patient population that is currently underserved. Don will review the data in much more detail later. Moving to Slide 5. 4008 is 1 of 4 clinical assets that we've designed using our in-house tools using our Dynamo platform. Given the breadth of our clinical and preclinical pipeline and today's data showing the potential for 4008 to be in a much larger patient population, we have some choices to make as a company as we focus our team's execution capacity. For 4008, we have taken the decision to focus on the larger tumor agnostic opportunity as our first regulatory approval pathway and align the timing of accessing the cholangiocarcinoma opportunity to this. As you know, the IRA favors accessing larger opportunities initially versus the conventional approach of speed to market with smaller indications. This clearly pushes out our investment on commercial readiness. We've also continued to expand our PI3K alpha mutant selective efforts to target the very large breast cancer opportunity, with the goal of being able to treat larger patient population sooner in the life cycle of the PI3K assets. With this goal in mind, we are accelerating the exploration of triple combinations of CDK4/6. We plan to initiate the first RLY-2608 triplet this year. To enable all of this clinical execution, we'll pause our CDK2 program at IND. All of this will enable our team to focus on the highest value opportunities and significantly extends our cash runway by an additional year into the second half of 2026. All of these actions ensure we can generate meaningful clinical data on these key clinical programs and not be reliant on the capital market. Slide 6 clearly shows the broader tumor agnostic opportunity versus the cholangiocarcinoma one. There are more than 40,000 FGFR2 fusion patients globally each year. Over the next year, we will generate data from the fully enrolled cholangiocarcinoma pivotal cohort. And with the limited investment, we will also follow the tumor-agnostic signal and share further data in 2024 and the regulatory update on these cohorts as we determine the optimal path forward to help these patients. On Slide 7, you can see the PI3K mutant selective opportunity is also very large. PI3K is the most frequently mutated kinase in solid tumors and significantly larger than several multibillion-dollar franchises relating to alterations such as eGFR. It's also a very concentrated one with PI3K alpha mutation is prevalent in more than 150,000 hormone receptor-positive, HER2-negative breast cancer patients in the U.S. alone. The goal of this program is to enable PI3K alpha to be selectively inhibited to avoid the off-target toxicities that have unfortunately plagued the nonselective inhibitors. This will potentially allow us to serve patients in earlier and earlier lines and in combination with CDK4/6 inhibitors and also in combination with future targeted combination therapies. We believe our initial clinical disclosures have gone a long way towards showing 2608 is a potently inhibiting mutant selectively PI3K alpha while maintaining a very good tolerability profile. And we're excited to start the triplet trials of RLY-2608 with fulvestrant and CDK4/6 inhibitors later this year. On Slide 8, you can see we have a lot going on in the clinic with PI3K alpha franchise and look forward to a very data-rich next year, which will allow us to determine the next steps for these important programs. On Slide 9, you can see our broad portfolio of precision medicines. And in 2024, we'll be excited to unveil the next set of exciting programs. Moving to Slide 10. We have a team that has an execution culture that we've always been able to hit the challenging goals we've set for ourselves. We have the focus and capital to continue doing this, and we look forward to generating meaningful clinical data across a range of programs over the coming years. With this, I'll hand it over to Don to talk us through the data from today in more detail.

Thanks, Sanjiv. Moving to Slide 11. As you've heard us say in the past, pan-FGFR inhibitors are not selective for FGFR2 and potently inhibit FGFR1, FGFR3 and sometimes FGFR4, resulting in toxicities related to inhibition of other FGFR family members, including hyperphosphatemia and diarrhea while achieving limited inhibition of oncogenic FGFR2 alterations. Consequently, there remains significant need for better therapeutic options for patients with FGFR2-altered tumors, including in late-line patients where the recommended therapies for NCCN guideline typically have less than a 15% overall response rate. Moving to Slide 12. Lirafugratinib has been evaluated in over 450 patients in the ReFocus study. The Part 1 dose escalation is now complete and 70 milligrams was selected as the recommended Phase II dose based on safety, PK/PD and antitumor activity. The Part II dose expansion is ongoing. Today's presentation at the triple meeting focused on the 3 expansion cohorts in the ReFocus trial for patients with FGFR2-altered tumors outside of cholangiocarcinoma. These include cohorts in FGFR2 fusions or rearrangements, FGFR2 amplifications and the FGFR2 mutation. On Slide 13, you can see that 124 participants with solid tumors were enrolled across FGFR2 alterations representing 18 noncholangiocarcinoma tumor types. Patients were heavily pretreated with most having 3 or more prior lines of systemic therapy. The safety population consists of all patients receiving at least 1 dose of lira. The efficacy population consists of 84 FGFR inhibitor-naive patients with at least one post-baseline imaging assessment. Moving to Slide 14. We show radiographic tumor regression and response per RECIST for patients with FGFR2 fusions or other rearrangements. Most patients had tumor regression and the majority had disease control per RECIST. And the overall response rate was 35% with responses observed across 5 distinct tumor types. Slide 15 shows the swimmers plot for patients with FGFR2 fusions or other rearrangements, where you can see most patients who responded have a duration of response in excess of 6 months. Slide 16 shows tumor regression and response for patients with focal amplification of FGFR2. Again, the majority of patients had tumor regression with 24% of patients achieving response per RECIST. Responses were most frequently observed in breast cancer, but were also seen in gastric cancer and colorectal cancer. The overall disease control rate was 62%. Slide 17 shows the swimmers plot for patients with focal amplification of FGFR2 with good duration of response, especially in patients who responded with breast cancer. On Slide 18, you can see tumor regression in response for the 10 hormone receptor-positive, HER2-negative breast cancer patients with any FGFR2 alteration enrolled in the ReFocus trial. These patients are very heavily pretreated with a median of 7 prior lines of therapy with all 10 patients having been treated with prior CDK4/6 inhibitor therapy. The overall response rate in these patients is 40% with 70% achieving disease control. Slide 19 shows the swimmers plot for the HR-positive, HER2-negative breast cancer patients demonstrating very encouraging durability of response with all 4 responders having response duration longer than 6 months. 3 of the 4 are ongoing with 1 ongoing longer than 1 year now, which is very significant in this heavily pretreated breast cancer population. Slide 20 highlights lira's activity in a heavily pretreated breast cancer patient with hormone receptor-positive, HER2-negative disease. The CT scans on the right show significant regression of multiple liver metastases. The patient remains in confirmed response that is ongoing at cycle 19. You can see the summary response table by FGFR2 alteration type on Slide 21. The overall response rate was the highest at 35% of patients in patients with FGFR2 fusions as shown in the second call. In amplification, the overall response rate was 24%, and we saw a 13% overall response rate in mutations across all solid tumors. Slide 22 shows the breadth of lirafugratinib efficacy in noncholangiocarcinoma solid tumors with FGFR2 fusions or amplification. The overall response rate across these 60 patients was 28%, with responses seen across 8 tumor types, including non-small cell lung cancer, ovarian cancer and pancreatic cancer in addition to the responses seen in breast cancer and gastric cancer. On Slide 23, we show NCCN recommended therapies for heavily pretreated patients across the indications where lira has shown promising clinical activity in the ReFocus trial. For these patients, late line standard of care is typically chemotherapy with response rates typically well less than 15%, highlighting the need for more effective targeted therapies for patients with FGFR2 alterations across a broad range of solid tumor types. As shown on Slide 24, safety data remains consistent with the previously reported profile of lira. With that, I will now hand it over to Pete to wrap up.

Thanks, Don. As you've heard from many of our peers, the IRA has flipped the script of the typical drug development approach of starting in small populations and expanding over time. Given this first approval now starts the [ 9-year clock ] price controls. As a result, we, along with other peers are now prioritizing pursuing the larger populations first. And so as Sanjiv mentioned, rather than continuing to pursue the CCA opportunity first, we are shifting our focus to align this with the larger tumor-agnostic opportunities that we've outlined today. Given the promising early data in these populations, we will continue enrolling the ongoing tumor-agnostic cohorts to enable us to collect more data. We expect to share initial potential regulatory development path and updated data next year. Our updated pipeline slide is reflected here on 26. It reflects the changes that we have talked to today. We continue to have a robust and deep pipeline, which is now more focused on pursuing the most significant opportunities and ensuring we have the capital to see those efforts through. And lastly, moving to Slide 27, echoing what Sanjiv started with, a key theme throughout the remainder of 2023 will be continued clinical execution, particularly with our lead clinical programs. For 2608, we plan to initiate the first triplet combination this year with the goal of moving into earlier lines of therapy, which is where we believe the true value of having a selective inhibitor like 2608 lies. The 5836 First-in-Human study continues ongoing, and we will make an additional PI3K alpha inhibitor clinical data disclosure in 2024. We have achieved our anticipated milestones of RLY-4008 in the second half of '23 of full enrollment of our pivotal cohort in the FGFR2 fusion-positive cholangiocarcinoma population and with today's exciting initial clinical data from the ongoing tumor agnostic cohorts. We have an execution-focused team, sufficient capital and a growing track record to continue advancing our key clinical programs, and we look forward to updating you on our progress as we go. With that, I'd now like to open the call to questions. Operator?

[Operator Instructions]. Our first question comes from the line of Salveen Richter with Goldman Sachs.

Congrats on the data here. Could you provide more detail on what is involved and the steps and time lines associated around a tumor agnostic label with regard to not only the FDA discussion, but how you'll design a [ trial with this? ]

Thanks for the question, Salveen. Maybe I'll hand that one over to Don.

Yes. So I think as Pete alluded to, I think the first thing we want to do is get some more patient experience and greater duration of follow-up with some additional enrollment to the ongoing ReFocus trial. I think we then need to have an FDA interaction to clarify with them what the anticipated path forward would be for a tumor-agnostic population. I think the question there will -- a question both of, what data is required as well as what the patient populations would look like in the distribution of solid -- of tumor types that the FDA would expect to see. And I think with that information, then we'll be able to provide more guidance for what the time line would be for a likely path forward for a filing in a tumor-agnostic indication.

Can I just follow up there? And do you think you'd be able to include more than one alteration? Or do you have any sense of what could be allowed here?

Pete, do you want to take that?

Yes. So it's really going to be a data-driven question in concert with the regulators as to what is possible here. So there's not much precedent for tumor-agnostic, alteration-agnostic even if you just combine, say, fusions and amplification. So we'll follow the data and have a constructive conversation with the agency as to the best path forward.

Our next question comes from the line of Brad Canino with Stifel.

Congrats on showing a triple. I want to ask as you're getting better durability in the fusion patients and even some durable stable diseases compared to the amplifications, do you have any data that correlates that differential in efficacy, maybe higher co-alteration in the [ amp ] patients. Just trying to see if you're seeing a difference in what's driving the tumor in those 2 different cohorts. And then a broader regulatory question, if that level of activity in [ amp ] around mid-20% ORR that you're seeing continues to be consistent at the later cuts. Do you anticipate that it could be sufficient to be included in that broader tumor-agnostic NDA package that you've now outlined.

Thanks, Brad. Maybe -- Don, maybe you can start and then I hand it back over to Pete to take the second half of that question.

Yes. So I think we have a robust translational medicine program in this RLY-4008 overall development program. And I think one of the things that still needs to be done is fully characterizing what the baseline mutational status of the patients look like and understanding if there are any baseline molecular correlates that show an association with either likelihood of response or durability of response. That being said, I think we are very encouraged that when we do look at the amplified patient population while on average, overall, I think, you're seeing fewer patients with greater than 6 months duration of response. We have seen some patients, especially in the breast cancer patients, where the duration of the response we're getting is really, really promising, including that vignette we showed where the patients now out in cycle 19 treatment remaining in response. So I think there will be further work that we'll do to try and understand what some of those molecular correlates are. I think we are encouraged both by the signal we're seeing is manifested by response rate. And then within both the fusions and the amplifications, the potential to get very good quality responses with long duration.

Pete, you take the second question about the regulation.

Yes. On the regulatory side, Brad, I mean it's a good question. Look, the one thing that the FDA made clear on the draft guidance last year around this topic is they -- in a tumor-agnostic context, they want to see a good diversity in tumor type represented and consistency of signal across tumor types. I think that will probably hold -- that concept of a hold even when you think about trying to pool alterations. I think the context will matter as the data mature, it will be -- again, it will be a data-driven decision in consultation with the FDA as to what the options of pass forwards are.

Our next question comes from the line of Dane Leone with Raymond James.

Could you just give us a sense of what your expectations would be for continued enrollment in these cohorts and then what the future weighting of gastric would be specifically? And how you think you and maybe the regulatory bodies would interpret a certain tumor histology that seems maybe out of line with what you're seeing across other histologies taken and weighting to the total outcome of the study.

Thanks, Dane. Again, Pete, do you want to take that one?

Yes. I think -- it's a good question, Dane. And I think it's one -- here, one of the things that we didn't do thus far in the tumor-agnostic portion of the ReFocus study is we were not proactively trying to enrich or control for any one specific tumor type. I do think going forward, we will -- we'll keep the gastric portion -- gastric cancer patients capped at the current number that we have in there as much as we can and try to get -- as you alluded to, more diversity of tumor types in that amplification population. Because you're right, I think we're going to need -- if you want to have a tumor agnostic conversation, especially in amplifications, we're going to need greater diversity of tumor types in that patient population. And we have -- we'll continue to enroll and build out these arms. We have more headroom in the -- in these cohorts, and we'll continue to do that and generate hopefully more and more diverse tumors, especially in the amplification setting. But obviously, in the fusions, we're very happy with the distribution of tumor types and the consistency of the signal we're seeing there.

Our next question is from the line of Yaron Werber with TD Cowen.

So a couple of things. Are you thinking that 30% and 6 months durability sort of still the magic numbers given -- you're talking about now multiple tumors -- multiple types of mutations. I mean I imagine the mutations themselves might be out. It's going to be amplifications and fusions. But the standard of care, obviously, in many of these is much lower than that. I'm just trying to figure out how much flexibility do you think the agency has? And then secondly, why terminate or why deprioritize right now or halt the CDK2 and ER degrader programs? Is it for cash reasons? Or is it just because of just the landscape outside? And then finally, there are so many other -- the way we look at it, your platform is now validated with both the first 2 drugs. I'm just talking about validation of the program in terms of able to hit the target selectively that you want to. Have you considered FGFR3, for example, for achondroplasia or other targets outside of oncology, where you can potentially find a lot of prominence.

Thanks, Yaron, for the 3 questions. Let's take them one at a time. The last one, I think, as you know, we have a deep pipeline, 10-plus preclinical programs. I think we're excited about revealing the next one of those programs next year. And so you're exactly right, like with -- that's our focus is on precision oncology, genetic disease targets that our platform can really targeted that others can't. So obviously, we're not going to name the future targets today, but maybe that takes us to the second question around why deprioritize and pause our CDK2 and our ER alpha programs. And I think it comes down to clinical execution. Our focus very much is on all of the things that we have in front of us. And one of the things that we've been very true to is executing well in the clinic. And we've learned from all of the great precision oncology companies that have come before us to know that's how important that is. And so the focus over the next year in the clinic is obviously following the cholangiocarcinoma pivotal cohort patients, continue to enroll these patients outside of cholangiocarcinoma across the various mutation types and alteration types. And then obviously, our 2608 and 5836 trials continue. And as we said today, we're obviously running both the doublet and obviously, before the end of the year, a triplet trial. So I think we remain very focused on making sure that we can execute optimally to generate that data as rapidly as possible. At the right time, we'll go back and assess whether it's the right time to bring those programs forward. And maybe on the final question around the standard of care in patients outside of cholangiocarcinoma that we show [indiscernible].

Yes. I mean your question there, Yaron was, is 30% ORR and roughly 6 months durability still a good rough benchmark? I think it is, as you alluded to is somewhat context dependent. I think that 30% number comes from -- you've seen the FDA referenced a number of times that in these patient populations for their -- there is no alternative therapy. They're generally looking for a data set that can exclude 15% in the lower bottom of the 95% confidence interval. If you have 75 to 100 patients that would at a 30% response rate that would do that. So I think that's where that comes from. It's probably an okay general benchmark, but I think it will always be somewhat context dependent based off of the patient population we are talking about.

And look, I guess, the final thing going back to the CDK2, ER alpha question, obviously we announced today the extension of our cash runway into the second half of 2026. Obviously, in the capital environment that we're in, we think that's a prudent thing to do to make sure that we can always keep independent of the capital markets and generate the data that we need to in both of these key programs, 4008 and 2608. Thank you.

Our next question comes from the line of Eric Joseph with JPMorgan.

And let me add my congrats on these data, guys. Just 2 quick questions from us. First, just thinking about next steps, could you clarify whether you think the data so far in focus would be eligible for a potential sort of registration-directed study? Or is it thinking there that you may to pursue a tumor-agnostic label start a different trial together? And then secondarily, just in thinking about the scope of the tumor agnostic label, how should we be thinking about it by sort of line of treatment, right? So far here, we're looking at a rather heavily pretreated patient population. There are IRA considerations as well. How should we think about the potential to kind of look at incorporating use in earlier lines of treatment with 4008?

Thanks, Eric, for the question. And Pete, do you want to take that one?

Yes. I think, Eric, in the context of the -- are these -- is this kind of designed in a way that could be registrational. And the answer there is similarly to the cholangiocarcinoma arm, yes, we can based off of the conversation and interaction with the FDA, we could align on expanding the end and converting these to a potentially registrational single-arm study in any one of these arms. And then to the other question on the diversity of tumor types, I think it's going to be important to continue to follow the data. And this probably -- like I said in previous comments, there's going to -- you're going to need a diversity of tumor represented most likely in these cancers.

The way I was asking, I was trying to get a line of treatment.

Line of treatment -- yes. I think if you continue to consider an accelerated approval path, that would likely be not too dissimilar to what we've seen in kind of the [ TRK, RET ], BRAF, MEK types of labels which are for lines, generally say, have exhausted all other standard of care and/or giving the physicians a little bit of discretion of no alternative treatment. And so I think that's generally the type of label in that context that we would anticipate. But again, there's -- we have to generate a bit more data here, have a conversation with the regulatory authorities before we can get too far down that road of speculation.

Our next question comes from the line of Peter Lawson with Barclays.

In breast cancer, you had 3 patients that responded that had complemental treatment therapy so kind of in Slide 19. Want -- if you kind of talk through that, why they had that? And it looks like one was for just a single treatment, if you can talk about the other 2 patients that will be great.

Thanks, Peter, for the question. As you know these patients were heavily pretreated and maybe Don, you can get into the actual detail.

Yes. So the ReFocus trial for the hormone receptor-positive population does allow an investigator discretion the continued use of antiestrogen therapy in combination with RLY-4008. Again, these patients were extraordinarily heavily pretreated. The patients to what you're referring have at least 6 lines of therapy, one as many as 11 lines of therapy. And as you point out, there's 1 patient who did just receive a single dose of fulvestrant and then was not treated with any additional fulvestrant while they're on therapy. The other 2 patients who received either an AI or other antiestrogen therapy were patients who were also had seen multiple prior lines and/or had an ESR1 mutation. I think it's unlikely that the depth of activity and the duration of activity that we're seeing here in this trial would be attributable to the antiestrogen, and I think what we're seeing really is the true effect of 4008 in these patients with FGFR2-driven tumors.

What gives you the confidence around the fact that, that complemental treatment doesn't just like the extensive lines of treatments that the patients have already had? Or just any other details around that will be great.