Good afternoon, everyone. Thank you so much for joining us. I'm Salveen Richter, a biotechnology analyst at Goldman Sachs, and really pleased to have with me Sanjiv Patel, President and CEO of Relay. Sanjiv, to start here, could we just level set here with an overview of the Dynamo platform and where you stand today with the optimization efforts that have played out and the acquisitions of technologies, as well as pipeline strategy and upcoming milestones that we should be looking at over the next 12 to 18 months?
First, thanks for the invitation. In terms of the Dynamo platform, I think kind of close to 10 years ago now, we were one of the first wave of companies that put together computational approaches with experimental techniques to try and make this drug discovery process a little more easier than it has been. For all intents and purposes, over the years, we've done a great job of this in that we've been very productive. We've had now several programs enter the clinic, all kind of wholly created using our approach. Given the capital markets that we're in at the moment, we made some tough choices over the course of the year to streamline our research portfolio down and focus on really kind of generating clinical data and value for our stakeholders.
In terms of the pipeline in front of us, our FGFR2 program, we outlicensed to Elevar, and hopefully they'll file an NDA imminently. Our PI3K alpha mutant selective program, RLY-2608, is about to start a pivotal phase three trial, which we're very excited about in a large patient population. Behind that, we have a vascular malformations program. Then behind that, we have two assets that are nearing IND. That's an NRAS selective program and a Fabry 's program. I think we have cash into 2029 now. I think we find ourselves in a very strong position with a meaningful runway ahead of us and significant clinical catalysts.
Starting with your PI3K alpha inhibitor, HER2 wave, could you walk us through the design features that position it well within this evolving HR positive, HER2 negative breast cancer paradigm? How is it different from competitors such as Lilly?
Yeah, so to start with, to level set, hormone receptor positive, HER2 negative breast cancer is a very large patient population. And 40% of these patients have a PI3K alpha mutation. And traditionally, they've been underserved. And all of the kind of emerging approaches have unfortunately led to, in the post-CDK4/6 world, to a PFS somewhere between five and seven months. And so we've seen a lot of promise around the oral SERDs, CAT6, CDK4/6 retreatment. But unfortunately, all of the data that we've seen over the last few years has still led us to this situation of PFS in the five to seven month range. And the challenge for PI3K inhibitors over the last few decades has been a lack of selectivity.
Unfortunately, the inhibitors are non-selective, and that leads to a range of toxicities, including hyperglycemia, diarrhea, rash, stomatitis, which means these patients can't stay on therapies. When we set out almost 10 years ago to create a selective inhibitor, we found a novel allosteric pocket and created an inhibitor that was mutant selective. The hope was it would dial out these toxicities, allow greater dose intensity, and that would translate into greater efficacy. That is exactly what we did. We entered the clinic as the first mutant selective inhibitor a few years ago. In terms of other mutant selective inhibitors, we know that Lilly has acquired STX478, which has a similar approach, at least kind of 12-24 months behind. There are a range of 1047R specific mutant selective inhibitors, which only target half of the population.
I think we find ourselves to be ahead and differentiated from the current standard of care.
Last week, you presented updated dose escalation and expansion data in combination with fulvestrant at ASCO. What did you see as the key findings with regard to the updates? How does it inform your view on the probability of success of the phase three study?
Yes, the data we showed at ASCO was a continuation of a longer follow-on there. It's a 12 and a half months worth of median follow-on from data that we had presented before at SABCS and in corporate updates. The key was we'd already shown back in December of last year numbers that the class has not seen before. We showed a PFS, a response rate, and AEs that were just better than anything we've seen in the class. The key thing for us was just, with a longer follow-up, could that data hold and be consistent? That's exactly what we saw at ASCO last week now. We showed in heavily pretreated patient population in the second line and the second line plus a PFS of over 10 months. In true second line patients, we showed a PFS of 11 months.
We showed a confirmed objective response rate across all PI3K alpha mutations of 39%. We showed in the subset of kinase domain mutations a response rate of 67%. These are numbers that are several fold greater than anything we've seen in the class before. I think also very encouragingly, we show a very clean safety profile, very low rates of grade three hyperglycemia, diarrhea, rash, stomatitis that have obviously plagued the non-selective inhibitors. I think what we were most excited about was the consistency of the data that held up with a much longer follow-up now over 12 and a half months. That gives us great confidence to now start and run the phase three.
Remind us why you see five and a half months for PFS as the competitor benchmark.
We're going head to head in the pivotal trial against Capivasertib, AstraZeneca's AKT inhibitor, which is becoming the standard of care. It has off to a great start in its sales trajectory. That has become the standard of care in the field because of its perceived better safety profile. Although in the real world, we're starting to see now that that may not be holding up. In their pivotal trial, CAPItello-291, the subgroup analysis of patients that had already been treated with a CDK4/6 inhibitor that were PI3K alpha pathway altered, the PFS in that group was five and a half months. That included PI3K alpha mutations, but also AKT and PTEN mutations. We know actually the AKT and PTEN mutations do actually better. The five and a half months may actually be an overestimate for true comparator line for us.
That's the benchmark. The numbers that we showed, obviously 11 months, there's a significant benefit for RLY-2608 versus CAPI. And so we're encouraged that we feel that we'll have a good chance of being successful.
For the phase three trial, could you speak to the population that you will evaluate and how you anticipate an initial label may look like?
Yes. So the population that we're going into is patients that have already been pretreated with a CDK4/6 inhibitor. Traditionally, that would be second line. Obviously, we're seeing greater use of the CDK4/6 inhibitors in the adjuvant setting. We might see earlier and earlier use of RLY-2608. Although given the kind of use has just begun in the Western countries, we imagine there will be only a small number of patients that are adjuvant treated in our trial. Obviously, we want the label to reflect this because as you go out into the future, we imagine much greater use of CDK4/6 inhibitors in the adjuvant setting. In terms of the kind of metabolic inclusion criteria, they're much more inclusive than some of the trials, such as the INAVO120 trial that led to the approval of inavolisib.
We're trying to offer this to as broad a range of patients as we possibly can. In summary, post-CDK4/6 patient population is what we'll try and include in this.
There has been some scrutiny around the need for statistically significant overall survival for oncology approvals. Just what gives you confidence here in your PFS primary endpoint for phase threes?
I mean, there's a long track record of PFS being the approvable endpoint. All of the agents that we've seen in this class over the last few years have had PFS as their approvable endpoint. We know that there has been some speculation around how the FDA will approach this. It's probably not for us to speculate. All we can say is that we had a very successful engagement with the FDA. We will use PFS as our endpoint, but we'll also reserve alpha for overall survival. We think we feel confident around the design of having both endpoints.
How are you thinking of the cadence that you will report additional data cuts from the phase two study?
I think we've just done exactly that, which is we reported data last September in a corporate update, then we showed data again from the same cut in December of last year at SABCS. I think we've just provided another update on the same data set back here at ASCO in June. I think we've done what we can. This last update was really focused on the medical community. As we're about to start a global phase three trial with a range of centers across the world, we want to make sure that this data is in the hands of medical professionals around the world. It's unlikely that we'll now update this data. At 12 and a half months, it's relatively now well baked, and we don't see it really changing too much more.
I think we'll probably provide no further guidance on if and when we'll update this data. I think what we may do in the future is provide a kind of full phase one two manuscript that describes it all. I think in terms of this data set, this is probably the last data set that we'll show and probably not guide to anything else.
Maybe speak to your strategy for potential frontline expansion through triplet combinations and when we might see that data.
Yeah, I think we're very excited about trying to provide RLY-2608 to patients along their kind of treatment journey. Obviously, this first pivotal trial that we'll run will be in post-CDK4/6 treated patients. As we start to think about how we can move this in earlier and earlier lines of therapy, it does make sense for us to explore a range of combinations. I think over the last year, we've been exploring a triplet combination with RLY-2608 plus fulvestrant plus ribociclib, which is the current standard of care, and then RLY-2608 plus Fulvestrant and then Pfizer's selective CDK4, atirmociclib. We're not guiding to when we'll show data. We'll wait until we have a kind of robust and interpretable data set.
This kind of dose exploration and combinability is the first step for us in terms of defining what the next regimen would look like as we think about going earlier.
Will you, I guess, when you look at these triplet combinations here, will you ultimately choose only one triplet combination to advance, either the CDK4 or the CDK4/6 inhibitor?
Again, we're not guiding to exactly how and when we'll make this decision, but it does make sense that obviously, as we start to look forward to the next pivotal that we run, that we will choose one of these regimens. In terms of how we'll make that decision, it's really just going to be based on the data, the combinability, the AE profile. I think we have great confidence looking at the inavolisib triplet that they did with palbociclib, that this is a valid mechanism in earlier lines. Obviously, at ASCO last week, we saw overall survival data for that triplet to be positive, and there's great excitement around it. I think with RLY-2608's profile of having a very clean safety profile and obviously translating into efficacy, we think there is a position for it in earlier and earlier lines.
In terms of what's the ideal regimen, these patients are going to be on treatment for a significant amount of time. The tolerability of this triplet is going to be important. Obviously, the selectivity of RLY-2608 is very helpful to that. Obviously, there is this theory that the selective CDK4s will also be more tolerable than the current CDK4/6s, taking away some of the kind of cytopenias that you see with the CDK4/6s. We have to see the data play out. I think there is a real emphasis on the cleaner profile as possible as we start to stack these tolerabilities on each other.
What could the design of a potential frontline study look like in that context?
I think still we're just going to follow the data. I think on that one, it's probably too early to define exactly what that looks like. I think we are very focused on trying to make RLY-2608 available to as broad a patient population as is possible. We'll probably take that into account as we think about what the design will be.
What about tumor types outside of breast here?
Again, PI3K alpha mutations exist in a range of solid tumors. Obviously, we focused, and other developers have focused on hormone receptor positive, HER2 negative breast cancer, given it's such a large group of patients that are very well defined and identified. We know that other developers have started, like Roche, to look at triple negative breast cancer. Obviously, that could be an area of focus for us as well. Tumor types outside of breast cancer in general, colon, lung, I think all could benefit from this treatment, but probably not going to be a kind of short-term focus for us. I think given the focus on execution we have, it will remain focused on the pivotal trials that we'll run in hormone receptor positive, HER2 negative breast cancer.
You started clinical development in vascular malformations driven by PI3K alpha. This is clearly a group that's very heterogeneous. You have varied manifestations. How are you thinking about which indications to initially pursue and the path to proof of concept?
Vascular malformations is a kind of very large unmet need. There are about 300,000 patients in the U.S. that have this kind of umbrella condition named vascular malformations. Just over half of them, about 170,000, have a PI3K alpha mutation. There are about four different phenotypes that can be grouped. I think for us, the kind of two phenotypes that we'll focus on now are PROS initially, PI3K related overgrowth spectrum, and then a second much larger sector, lymphatic malformations. There are about 80,000 of those, and about 80% of them have PI3K alpha mutation. Still very significant numbers, but those are the two areas that we'll focus on. The PROS group is where Novartis's Alpelisib has the accelerated approval. That's where they're generating commercial sales at the moment.
Is an accelerated approval pathway here feasible in the context of these diseases?
I mean, over the years, our dealings with the FDA have always taught us never to speak on behalf of the FDA. All we can say is Alpelisib today only has an accelerated approval. Their recent confirmatory trial, EPIC-P2, unfortunately did not meet the endpoints. We do not believe that that will be converted anytime soon into a full approval. I think all we can do is go full speed ahead at generating proof of concept data and then check in with the FDA both at the start of the pivotal and at the submission of the NDA. Nothing today would say that the pathway of accelerated approval is off the table.
What about diagnosis of these patients? Are they currently being diagnosed and so you have this pool of patients you go into, or is there going to need to be a significant amount of identification and education on your side?
I mean, I think it's an evolving kind of nascent field. Unfortunately, the manifestation of these patients is very broad in terms of just the phenotype. Obviously, they present to their primary care physician, and from there, depending on the severity of their condition, they end in various different referral centers. There are only a small number of vascular malformation centers in the U.S. and in the major geographies across the world. I think, yes, there will be some education required. In terms of for a company like us to deal with commercialization, given the small number of centers that these patients do end up at, it is actually going to be quite manageable.
Given the large number of patients here, 300,000, we do think it is actually a very attractive place for a company for us to operate.
Touching on your out-licensed selective FGFR2 inhibitor, can you provide an update on how the development's progressing here with your partner?
Yes. As you may remember, we out-licensed this program, our FGFR2, liraflugratinib, to Elevar late last year. They've been a great partner to work with. They are fully focused on getting this in the patient's hands across the world as rapidly as possible. I think they've been publicly stating that they will file an IND hopefully late this year or early next year. They've been a great partner to work with. I think we'll continue to do everything we can to help them file that NDA.
You also have these Fabry and NRAS programs that you laid out in an R&D day, but you're clearly, you put it on the sidelines for now based on your resource allocation strategy. Walk us through A, kind of your interest in these programs, but B, what you think will end up playing out in partnership, B, an opportunity for one or more of them.
Yeah, I mean, we are very excited about both these programs. The NRAS selective program, I know that the whole industry has been working on trying to provide an NRAS selective inhibitor, and we've been able to create one. Obviously, it's a scientific discovery. The utility of the NRAS inhibitors could be in a broad range of solid tumors, probably focusing initially on melanoma. We feel very good about the potential patient population for these. The same for Fabry. Galafold from Amicus has shown great promise over the years and obviously generating significant revenues. As many of you know, it only serves a part of the population, and it has a range of efficacy within that patient population.
If you could just get to a broader range of the mutations and make them more amenable, we think that we could benefit a broader range of these Fabry patients that are currently underserved or not served at all. I think we feel great about both programs. Now, obviously, we sit here in 2025 in a very tough capital environment. I think we have done the prudent thing here and taken what we have, which is a very extensive balance sheet. We have $710 million at the moment and make sure that we can generate as much value in the medium term as we can.
That is why you see us extend cash into 2029, which we believe will be well beyond the top line readout from the phase three we are about to start, allow us to generate proof of concept data for RLY-2608 in vascular malformations, allow us to generate the dose exploration work that we will do with triplets and define an earlier line pivotal trial for RLY-2608 in breast cancer. We will bring both of these programs that we have talked about here, the NRAS selective and the Fabry's program, to IND and then look for options. Those options could be that things are progressing much faster than we imagined in the programs that we have just talked about and allow us to bring them in the clinic ourselves, or as you rightly point out, look for partners. We are very excited about the programs that we have.
Obviously, we have this still research footprint that's focused on trying to solve some very hard problems.
How about your manufacturing footprint at this point, just as you look at these pivotal trials, your ability to then supply commercially?
Again, the great thing about all the molecules that we work on, small molecules, and so the manufacturing is something that we've thought a lot about. It's all entirely outsourced. We can flex up, and we've already started to think about the commercial supply for RLY-2608, think about launch later this decade now. There's not much of this decade left. We have to start thinking about it. It's a much clearer problem because it's a small molecule. I think we feel good about our ability to manufacture at scale.
How do you think about the field at this point, this motion-based design or the use of various AI, ML tools to create drugs? Just speak to how you stay at the forefront of what's playing out from a technological standpoint.
Yeah, I mean, those of you who followed us over the years, we're the biggest skeptics of this. That's because every day our scientists are kind of at the coal face working with thousands of different problems. We've always found over the years that you have to really find individual, discrete, granular problems and then use these approaches to make those problems just slightly easier than they were prior. There's no magic button here where you can push and suddenly it provides you with an inhibitor. For us, some of the kind of hype and hubris that has been around over the years has not unfortunately played out. We see this as a very complex task making a medicine. The problems that we face are slightly different in every time that we approach a program.
We stay ahead by just continuing to work on hard problems and see what works and what does not work. Over the years, we have worked on many new computational approaches that have kind of fallen by the wayside. I think over the last year or so, we have been able to hone that down onto the techniques and programs where we think it was going to have the highest impact. I think we have to hold ourselves accountable. These companies should only be judged on their output. Over the 10 years that we have been around, we have generated now many INDs, multiple clinical programs, and then multiple proof of concept data sets. Hopefully now we will be closing to filing an NDA for the liraflugratinib trial for RLY-2608. We think that is really the only measure.
Any company that's talking about data, like how much data they have and how many pre-clinical programs they've generated, we don't think that's the right measure. The right measure is how many drugs have you got approved.
As a last question here, what are you focused on from an execution standpoint in the near term? Is there anything you want to touch on with regard to strategy or the portfolio that we did not speak to?
No, I think we've kind of covered the portfolio pretty well. We've, as you rightly point out, been able to hone down our focus to very tangible clinical data that we want to generate over the coming years. In terms of execution, that's all we're focused on now, is standing up this pivotal trial, opening sites across the world for our Rediscover2 trial, generating awareness amongst the medical community, and then generating this data and then making sure we're ready to file an NDA and then commercialize. The entire company is entirely focused on that.
Great.
Excellent.
Over that, thank you so much.
Thank you. Thank you, Salveen, and thank you to Goldman.