Thanks, everyone, for continuing to join us on the Stifel Virtual Oncology, Oncology, excuse me, today event. Happy to kick off the public company firesides with Relay Therapeutics. We've got Sanjiv Patel, President and CEO, Don Bergstrom, President R&D. Thanks so much for joining us.
Thanks, Brad.
Maybe let's just kick off with an intro to Relay and the priorities for the company in 2025.
Excellent. Again, thanks for the invitation. Relay Therapeutics is a precision medicine company that's been around for almost a decade. All of the kind of work that we've done over that time has led us to 2025, which, as you know, is an unprecedented period that we're in. Over that time, we've been fortunate to build ourselves a fortress of a balance sheet of $780 million as we came into the year to enable what 2025 is for us, which is a year of execution. We're fortunate enough to have inside of our portfolio a very large near-term commercial opportunity in post-CDK4/6 pretreated metastatic breast cancer patients with the first PI3K mutant selective inhibitor. This year is all around the company sprinting towards starting that first pivotal trial for us in breast cancer. That's what we're focused on.
Hopefully, we'll be able to initiate that trial midway through the year. We're also continuing to do work around both triplets and potentially doublets of oral SERDs as we think about where else we can go with RLY-2608. Also, outside of breast cancer, we've just initiated a trial with RLY-2608 in PI3K alpha-driven vascular malformations. Behind that, we really consolidated down our portfolio. As we've said, these are unprecedented times that we live in, and having the balance sheet that we have is very precious. We've consolidated our research portfolio down into near-term assets that could get into the clinic NRAS-specific inhibitor and a Fabry's program, both of which we hope to try and get to IND imminently, and then a very small footprint now left in research.
That should give us plenty to do this year as we continue to execute on all these fronts.
Sanjiv, maybe just to double-click on that, because as you mentioned, you have several development options for RLY-2608. You do have a small portfolio behind that as well. How should investors think about your capital allocation priorities?
Yeah, I think we are laser-focused on making sure that with the cash that we have, we can generate meaningful catalysts for our stakeholders. The cash that we have will take us meaningfully beyond the top-line readout for the RLY-2608 pivotal trial in post-CDK4/6 pretreated patients. That is really the biggest catalyst that we could say that we could fund with the money that we have. Behind that, we will fund a more near-term catalyst, which is proof of concept in vascular malformations with RLY-2608. Behind that, even more near-term, we will be able to fund INDs in the NRAS and Fabry's program. There are kind of four big value drivers that are fully funded with the money that we have. Obviously, we will provide accurate time guidance on cash in the upcoming Q1.
Obviously, you can see from that time horizon that we have a very kind of long runway in front of us and then four clear catalysts. Behind that, we'll have a very kind of lean-focused effort against very hard-to-drug targets. I think we sit in a very nice position in the world that is around us where cash is king. I think we're very focused on it. You may have seen last week we made significant changes to our cost base to enable this. Over the last year, we've continued to kind of whittle down and focus our research portfolio. That kind of was finished up last week where we made some changes both to our team and to our programs to significantly reduce spend. We've kind of reduced research spend by almost 75% now from its peak last year.
I think we sit in a very strong position, but we do not take it for granted. Continuing to make accurate, timely cost choices is something that is always on our mind.
Maybe to drill into 2608, you presented data as a doublet with fulvestrant at the San Antonio Breast Cancer Symposium last December in 2024. What about that data set, and how would you describe it that increased your confidence in moving forward into the phase III this year?
Yeah, I mean, we've been working on this for many years now. As we started out, what we wanted to do was to create a mutant selective inhibitor of PI3K alpha. The hypothesis was if you could dial out some of these wild-type toxicities, hypoglycemia being number one, but diarrhea and rash following close behind, you could dose these patients at greater intensity and keep these patients on drug for longer. That should translate into better efficacy. That's what we've been working on for almost a decade now. We've seen that the current options for these patients' later lines are not great. Alpelisib has been launched, and it has, you know, in the real world, close to five and a half months' worth of PFS.
The toxicities, unfortunately, of high grades with hypoglycemia just do not allow these patients to stay on. Obviously, that has now been superseded by what is a very strong commercial launch from capivasertib and AstraZeneca's medicine, which has, again, a PFS of around five and a half months, but is in some ways perceived to be more tolerable. Although we have just seen the label change for capivasertib now also now highlight the hypoglycemia challenges that come with it. You know, that is the benchmark, five and a half months' worth of PFS and the kinds of rates of toxicity that we have seen, which are high grade three hypoglycemia, diarrhea, rash. What we were hoping to see is lower rates of grade three hypoglycemia, diarrhea, and rash and increased PFS significantly above the five and a half.
At San Antonio at the Breast Cancer Conference at the end of 2024, that's exactly what we were able to see. In a kind of robust data set of over 50 patients in terms of efficacy and a robust follow-up of over nine and a half months, we saw a PFS number of over nine months in all comers and in the second line only population over 11 months. We saw very low grade three hypoglycemia. I think two patients out of the kind of 60 patients that we showed, 60 plus, saw grade three hypoglycemia. Obviously, low rates of rash and, again, diarrhea was not an issue. I think we feel very confident that we built the asset and we've created the clinical outcome that we hoped we would and that now we're off to the races.
Obviously, we spoke with the FDA, aligned ourselves on trial design, and now the whole company is focused on giving these patients that sit with very poor treatment options of five and a half months of PFS something that realistically they need, which is better options.
As you mentioned, you unveiled the trial design publicly a few weeks ago. You ReDiscover-2 trial in the second line. Now, could you talk about some of the key design features of that study? We've gotten questions on the control arm, the size of the study, and the hierarchical endpoint structure that you've done.
Yeah, so we chose to go with capivasertib as the comparator because, as Sanjiv mentioned, it really is emerging as the commercial standard of care that's most broadly used in this patient population. Based on feedback we got from our investigators and KOLs, the feedback was pretty universal to choose capivasertib as a relevant comparator in this patient population. The patient population that will enroll will be 100% pretreated with a CDK4/6 inhibitor, and that includes patients who may have seen their CDK4/6 inhibitor in the adjuvant setting with increased usage of those agents in the adjuvant setting. While we anticipate our patient population will be majority second line patients, we do anticipate there could be some what would be considered front line patients as well who have seen adjuvant CDK4/6 inhibitor therapy.
We will use broad metabolic inclusion criteria in contrast to some of the recent trials that Roche has launched for their non-selective PI3K alpha inhibitor, inavolisib, that use very, very tightly controlled baseline metabolic criteria to limit enrollment to just the patients who are really the fittest patients. We'll use the same criteria that we've been using to date in the ReDiscover trial and allowing patients that generally reflect a Western patient population. And we'll enroll patients with all PI3K alpha mutations, so both in the kinase domain and the non-kinase domain. We'll exclude patients with existing PTEN or AKT mutations at baseline, given the hypothesis supported so far that these patients would be less likely to benefit from upstream inhibition of PI3K alpha. Now, with regard to the hierarchical design, it really allows us to do two things.
One is we know that there are competitors who are developing drugs that just target kinase domain patients. This will give us the ability to do a formal analysis of 2608 in patients with kinase domain mutations and to make label claims about the performance of 2608 in those patients. That would allow direct comparison to anybody who is running a pivotal trial in a drug that just targets that patient population. The other thing it allows us to do is we have seen in the ReDiscover trial to date superior performance of 2608 in the kinase domain patients manifested mostly through response rate, although there is a trend towards longer PFS in kinase patients as well.
While we anticipate, based on the data we've seen so far, to be able to show significantly better efficacy broadly across the entire patient population, both kinase and non-kinase, this does provide us some degree of insurance policy should there be overperformance of the capivasertib in the trial. It is important to us that this trial be positive. It's important to us that we be able to make the full set of claims that will support the differentiation of 2608. That's what led to the hierarchical design. With those considerations in play that led to our trial size of 540 patients, in terms of some other inclusion-exclusion criteria, we will allow patients to have seen up to one prior chemotherapy in the metastatic setting.
Generally, we will not allow multiple CDK4/6 inhibitors that will have inclusion criteria that generally will push us towards a largely second line patient population. We anticipate that with these design elements, we'll be roughly three years from when we open the trial to top-line data.
Now, on the mutation subgroups, you mentioned the phase Ib data. Why do you think there was such a large discordance between the ORR of those two subgroups where it wasn't as large for the PFS?
Yeah, I mean, I think we, you know, obviously need to run the definitive experiment in the ReDiscover-2 trial with better balanced patient populations on the larger end to really fully understand what the profile of 2608 is in the different patient populations. We did see some differences in the ReDiscover-1 trial in the baseline characteristics of kinase versus non-kinase patients. Our kinase patients were in or our non-kinase patients were more likely to be third line or later. They were more likely to have seen multiple prior CDK4/6 inhibitors. So they generally had baseline characteristics that would lead you to conclude that they'd be less likely to be able to achieve a PR. Now, as we've said, we're still seeing meaningful PFS benefit compared to what you'd expect for capivasertib in these patient populations.
We have retained high confidence that we'll be able to see broad activity across the patient population. I think we now need to go and run the proper experiment with larger and tighter inclusion criteria to ensure that kinase and non-kinase patients are more similar at baseline.
I think what you're hearing from us is that we believe that both subgroups, we believe, will be meaningfully better than the capivasertib. It could be that the kinase, it's just exceptional in its performance against it. We'll take it if that's the case that plays out in this trial.
Right.
Now, can you walk through the rationale behind switching to 400 mg BID fed as compared to the 600 mg BID fasted for the phase III dose? Because most of your phase one work was done in the 600 mg.
Yeah, I mean, as we went through the last year, obviously, we wanted to run a very comprehensive program. As we started to think about the future, there are a couple of options that got us thinking about doing a food effect study earlier than probably normal. First of all was the dosing in vascular malformations. As you know, that's going to be predominantly, hopefully, in the end state, children, adolescents. These patients are obviously diagnosed very early. We started thinking about potential combination partners that we would use 2608 with. Abemaciclib was obviously one of the first that we wanted to utilize. That is dosed fed. It started getting us thinking, which is obviously we should think about doing a food effect study earlier than normal. We did that early last year and saw a food effect.
We spent the rest of the year getting robust data to do a like-for-like comparison between fed versus fasted. That led us to the 400 mg fed BID dose. As we think about going into a pivotal trial, we want to make sure that ultimately this drug is as commercially successful as possible. Rather than rushing forwards with the 600 mg fasted dose, which we could absolutely have done, we're really thinking about maximizing the long-term NPV of RLY-2608. It makes sense for us to go forwards with a fed dose. We took to the FDA a very robust data package of obviously all of the data that we generated through dose escalation and expansion as we started this whole exercise, post-Project Optimus. We had a very robust package to justify the 600 mg fasted dose.
A second robust data set of fed dosing and showing the equivalence of 400 mg fed to 600 mg fasted was generated. We feel very confident that the right choice for us was to go forward with the 400 mg fed dose, allowing us maximum optionality to maximize the value of our medicine.
A few questions on future competition. I'd like to ask, what work have you done to understand the Scorpion molecule that is now at Lilly and how much more mutant pathway coverage it may or may not be achieving?
Yeah, maybe I'll take the first piece and then Donny can take the second piece. Obviously, we followed the molecule all the way through its journey. Obviously, the structure is now in the public domain so we can synthesize it. Obviously, they have shown data at San Antonio. I mean, I think what we can tell you is there are a couple of claims that we want to try and dispel. First one is around coverage. They showed a pretty detailed set of data in their San Antonio poster that showed they had a 30-fold coverage above the IC80. We've been able to make the molecule, synthesize it, test it in our own laboratories with our own molecules and alpelisib and abemaciclib as well.
There is no dose of STX-478 that we in our hands can see a greater coverage than RLY-2608 at the go-forward doses that we have. Just theoretically, a kind of 30-fold increase above the 30-fold excess exposure above the IC80 would lead to significant wild-type coverage. You would imagine that that would have significant off-target toxicities and this not be a desirable quality for the drug. We just can't make sense of that in our own hands. What we can see in our own hands is RLY-2608 has increased coverage versus STX. On the safety side, again, we've seen comparisons made using the San Antonio data sets that were presented.
Our nine and a half months' worth of follow-up in a robust number of patients in combination with fulvestrant, which is where the approved agents are, where you can make comparisons both with capivasertib, inavolisib, and alpelisib, where we show what is a very differentiated safety profile. The 1.9 months' worth of follow-up in a small number of patients in monotherapy. Obviously, there is a difference in some of the safety parameters. We saw the same. The closest data set we have is 2x that, four months' worth of follow-up, which we showed back in AACR in 2023. If you look at that data set, it looks similar in most metrics, actually better in some like hypoglycemia. I think we believe that on safety, it's still for STX-478 to prove out that it can be better than RLY-2608.
The two things that we didn't see were the DLT that they saw, or actually they saw multiple DLTs, myalgia, paresthesia. The LFT signals that they saw high grade in multiple patients. I do think there's a question mark where Lilly can obviously take the risk given the size and scope of the balance sheet that it has. If it gets it wrong, it's not really impactful to Lilly. If we get it wrong, it is impactful to us. Therefore, a clean safety profile was something that we were very keen to be able to see. On the final piece on the efficacy side, obviously, Scorpion spent a lot of time and money doing monotherapy dosing, which we decided very early on made no sense. There's no commercial market there.
The approved agent here at the time when we all started these trials was alpelisib in a combination with fulvestrant. We did a very small number of monotherapy dosing. We obviously have three breast cancer patients, so we saw one response. I'm sure if we were able to dose more patients at some time, we would see the 20%-25% response rate they saw. I don't think we can really tell much on the monotherapy. We didn't dose any endometrial patients. The patients outside of endometrial and breast, I think Scorpion showed a response rate of zero. We've shown, I think, outside of the two tumor types we've just mentioned, at least a response. I think on all three elements, we believe at best, on its best day, STX-478 is close to RLY-2608.
It still has a lot to prove on efficacy. We've seen no combination data. It still has a lot to prove on safety. Obviously, if this coverage is true, then we're going to see the safety deteriorate just given the fact that you're going to see a lot of wild-type toxicity. I think at best, it's probably several years behind. We understand why Lilly would make such an acquisition. What we are seeing is a robust data set, and we're off to the races now with a phase III pivotal trial.
Now, Roche's wild-type inhibitor, inavolisib, is also now on market for frontline, and they have a second line trial ongoing. What has been the real-world experience of that profile that you've learned from KOLs and investigators, and how much of a competitor do you see it as?
I mean, before they ran the pivotal trial, they ran a whole series of phase I. In the phase I, you see pretty aggressive toxicity challenges. The grade three hypoglycemia, rash, and diarrhea is exactly the same as you would expect to see in a non-selective PI3K alpha inhibitor. We have obviously seen the commercial ups and downs of alpelisib now, given that it is a very similar profile. They did a great job on the clinical development strategy to limit the patients in their phase III to metabolically very fit patients. It restricted down the hemoglobin A1c criteria as well as the fasting plasma glucose to exclude what we believe to be almost half of the patients if you look at a real-world population. You did see a relatively tolerable safety profile.
Now, when you bring that into the real world, as you know, the label was not restricted on hemoglobin A1c and fasting plasma glucose, even though the pivotal trial was. It was an unusual outcome. What we're seeing now in the real world is exactly what you'd expect to see, which is a pretty aggressive safety profile that includes hypoglycemia, diarrhea, and rash. A couple of weeks ago, we saw a Dear Dr. Letter go out warning about the risks of diabetic ketoacidosis. I think what we're seeing is patients being treated that have what we describe in the U.S. to be normal hemoglobin A1c distributions, and you're seeing the toxicities. That's why I think that all kind of summarizes back to what we don't believe this will be a huge commercial success in the first quarter. Sales, I think, bear that out.
I also think that really the question is, what problem are we trying to solve in the first line? With ribociclib and fulvestrant, you're getting a reasonable outcome. Even though INAVO120 was designed to get 15 months' worth of PFS, you can actually just get that in a doublet. I think physicians are voting with the data and saying, "Okay, what benefit is it actually giving me?" Actually, what I'm seeing is increased toxicity. That is why I think there's a position here for RLY-2608. Clearly, in the post-CDK4/6 treated patients, what we're now seeing is close to 11 months' worth of PFS in the second line. That is 2x what we're seeing with capivasertib.
That's a big market, which I think people are discounting as like, "Maybe we should go earlier." There is a large number of patients that could produce a blockbuster outcome here. We're seeing with capivasertib, it was already on track to be a billion-dollar drug. If you could just double the PFS, have a better safety profile, you're going to see a blockbuster. Earlier, you really need a safer drug. A safer drug sits in the safety profile of RLY-2608. I think we're setting ourselves up very nicely to produce a commercial success in RLY-2608.
Maybe to close, you gave the pitch for the doublet in second line, but you are running the triplets as well. How are those progressing, and how would you describe the strategy for those today?
I mean, today, all we're doing is trying to understand the safety and combine-ability of these assets. I still think that the breast cancer landscape is continually evolving as we're seeing data sets come out. I think all our goal this year is to establish combine-ability and then see where and how these combinations could be used. We're seeing oral SERD data coming out every conference. We're seeing CDK4/6, CDK4 data coming out every conference, KAT6. I do think we have to really understand where and how to use these potential novel, novel doublets or novel, novel, novel triplets. All we can do is generate the data and understand the landscape while sprinting towards being in the market in the post-CDK4/6 treated patients as rapidly as possible and generating what we hope to be a blockbuster drug.
Unfortunately, we're out of time. Sanjiv, Don, thanks so much for joining us as always. Really appreciate it.
Thanks very much, Brad. Thanks to Stifel again .