Okay, great. Good afternoon. I'm Eric Joseph, Senior Biotech Analyst with JP Morgan. Our next presenting company this afternoon is Relay Therapeutics. It's my pleasure to welcome and introduce CEO Sanjiv Patel to tell us a little bit about the company. There's a Q&A session after the presentation. Just raise your hand if you wanna ask a question, we'll get a mic to you. For those tuning in online, you can submit a question via the digital conference book. With that, Sanjiv.
Thank you. Thank you, Eric, for the introduction. Thank you, JP Morgan, as well for the invitation. We'll be making a series of forward-looking statements this afternoon, which are subject to the standard risks and uncertainties. The actual events may differ materially from the estimates and projections shown here.
For a comprehensive look at our disclosure schedules, please refer to our SEC filings. That's over, welcome, and thank you for braving the flood warning that we all got. It's not gonna be wet in here, so I think you will all be safe for the next 40 minutes. Those of you watching on the East Coast, good evening, and those of you who are outside the U.S., thank you.
Over the next 45 minutes, we'll talk about how we have got on on our journey of combining leading-edge experimental and computational techniques to make the discovery of medicines more efficient and effective. We set out a few years ago now in 2016 to validate our approach of using leading-edge structural techniques and combining it with computational approaches, and we wanted to do that as rapidly as possible, so we chose genetically validated targets in precision oncology.
Here we are now in 2023 with 3 programs wholly created by our platform in the clinic and the deepest pipeline in precision medicine behind it. We've gone a long way to validating our approach, and a couple of years ago, we've moved on now towards getting those medicines towards patients and scaling our approach across different therapeutic areas.
To remind you, our platform consists of a different set of integrated computational and experimental tools, capabilities, and it's all knitted together by multidisciplinary bilingual scientists. The more we do, we believe the better we get. We focus our effort and not on elucidating novel biology, but on working on validated targets and focusing on our platform on making medicines. We understand the protein very deeply and try and create new novel modulation hypotheses.
We identify hits and then rapidly take those hits to lead optimization and into the clinic. We focus on making medicines that are exquisitely selective and therefore more tolerable, and by definition, that allows us to inhibit the target much more deeply and create efficacy that patients are so sorely in need of. When I stood here three years ago, most of this was theoretical.
We were a preclinical private company with two named programs. Here we are, short three years later, for the first time back again, and we have a very deep pipeline of assets. What you can see here is one of the deepest research portfolios in precision medicine, and that helps us validate that our approach is productive in research.
Over the last three years, we've built a development capability that has executed as well as any other, and we've shown validating clinical data for our RLY-4008 program, and we're now starting to contemplate commercialization for the first of our assets.
We've expanded from being a precision oncology company now to expanding into genetic disease. We've gone from being a small molecule inhibitor-focused company to now creating degraders, and today we'll show you that we've extended that now into small molecule chaperones.
We have a pretty deep pipeline ahead of us, and so it's gonna be an exciting 2023 full of catalysts and milestones. Over the presentation, I'll take you through those. Let me start by taking you through the three clinical programs and franchises that we have. FGFR2 has all the hallmarks of being a cancer driver oncogene. It's altered in about 11,000-35,000 patients in the U.S. each year.
Unfortunately, traditional approaches to create medicines against FGFR2 have only resulted in non-selective inhibitors. Those non-selective inhibitors have a degree of off-target toxicity, namely hyperphosphatemia and diarrhea, and that leads to dose-limiting effects. We are unable to dose these patients to the level that will create efficacy that we hopefully will want.
The proof therapies have objective rates of response between 36% and 42%. Why is this? It's because traditional approaches to drug discovery lead to this, which is the FGFR2 protein that you see here looks exactly like the FGFR1 protein.
There's no real handle for selectivity. Using our platform, we synthesize the proteins, use leading-edge structural biology to understand the protein conformations and the dynamics, then use unprecedented computational power to create long time scale molecular dynamics simulations.
What you see is this, is the proteins look and behave differently. It gives our drug discovery teams the ability to create selectivity. We created a preclinical profile in RLY-4008 that did exactly that. We're happy to say that that is starting to translate into the clinical data.
Although it's early in interim, what we've shown is we have a very selective molecule, and it has minimized almost completely the off-target effects of hyperphosphatemia and diarrhea. That's allowed us to dose much more than has been previously possible using the non-selective inhibitors, and we're able to dose at a sustained level well above 90% target inhibition.
That's led to efficacy that's not been seen before. At the ESMO meeting last year, we showed in 17 cholangiocarcinoma patients that we showed an interim early objective rate of response of 88%. Just to remind you, the approved therapies in this space have objective rate of responses of between 20% and 42%. This is a real step change in therapies for these patients. We've been able to, over the last few years, execute very effectively in the clinic.
This trial, the RLY-4008 ReFocus trial, commenced in the final months of 2020. Less than a year later, we were able to show clinical proof of mechanism by showing that we could avoid the off-target effects of hypophosphatemia and diarrhea.
We were able to engage with the agency and come forth with a dose that we wanted to use in our pivotal cohorts. Last year at the ESMO meeting, we showed interpretable early efficacy data of 88% objective rate of response. We were able to use that data set to engage with the agency and come forward with a path towards approval.
This year it's all about execution, and the milestones consist of two clear things, which is we commit to fully enrolling the pivotal cohort before the end of the year, and that should give you a sense of how we're thinking about getting this therapy to patients.
Secondly, the commercial opportunity here has been on people's minds. We commit to sharing the non-cholangiocarcinoma expansion cohort data to give you a sense of the size of the commercial opportunity that this medicine could have.
With that, it's all about execution and getting this medicine to patients as rapidly as possible. Finally, we'll start to think about how to commercialize and all the various strategic options that sit in front of us as we start to think about approval. I'll move on to our second franchise, which is breast cancer.
Hormone receptor-positive, HER2-negative breast cancer is a significant unmet medical need. It has been transformed over the last few years through the introduction of targeted therapies. In 2015, the first CDK4/6 was approved.
Even though these new therapies have come online, it still remains a significant unmet need for three reasons. Firstly, there are a limited amount of targeted therapies available to patients. Secondly, the toxicity profiles of these targeted therapies mean that they are very challenging to combine and create the durable efficacy that these patients require.
Finally, patients that have resistance to these targeted therapies, there are very few treatment options left to them other than salvage or chemotherapy. Our goal using the Dynamo platform is to create a set of selective medicines that can be well-tolerated together, can be combined, and can provide unprecedented efficacy for patients.
We do that through our cornerstone foundational set of assets against PI3Kα mutants, and we combine that with rational combination partners in CDK2, ERα degrader, and several other undisclosed programs. The goal here is to provide a new standard of care for these patients. I'll start by talking about our PI3Kα mutant selective franchise. This is a significant unmet need, with 30% of hormone receptor-positive, HER2-negative breast cancer patients having a PI3Kα mutation.
Unfortunately, traditional approaches to creating medicines for this target have led to non-selective inhibitors. These inhibitors are not selective at mutant versus wild type, and they're not selective against the various PI3K isoforms. Again, that leads to limited tolerability, with challenging effects of hyperglycemia, GI, rash, as well as fatigue.
All of this leads to limited ability to inhibit the target, and that in turn leads to limited efficacy in these patients. There's virtually no monotherapy activity seen in these non-selective inhibitors, and for the breast cancer patients that have these inhibitors in combination with fulvestrant, we're seeing around 19% objective rates of response.
We set out a few years ago to try and change the paradigm here. We synthesized what we believe to be the first full-length structures of mutant and wild type PI3Kα, and then created the first Cryo-EM images, and then created unprecedented molecular dynamics simulations. Actually, we found a novel modulation hypothesis. Actually, we found multiple ways to try and modulate this target outside of the active site.
We created a set of what we believe to be hypotheses for how to create mutant-selective PI3Kα molecules. RLY-2608 was the first of the preclinical molecules that we showcased. What you see in the preclinical profile on this slide is that it's selective. It avoids many of the off-target toxicities that the non-selective inhibitors have been plagued with. It allows us preclinically to dose well above the IC80, and it leads to efficacy in animal models. We were thrilled to bring this into the clinic in December of 2021, and the trial consists of two arms. First arm is in monotherapy in PI3Kα mutant altered patients, either in metastatic or locally unresectable tumors.
A few months later, in April of 2022, we started the combination trial in hormone receptor-positive, HER2-negative breast cancer patients in combination with fulvestrant. Our commitment this year is to share data from the clinical trials from both the monotherapy and the combination arm. The goal of that data will be aspirationally to show clinical proof of mechanism.
What we want to share with you this half year is PK, acute safety and tolerability, and PD. Ideally, what we want to show is that we can dose above the IC80 for PI3K mutants. We can see acute safety and tolerability profile that avoids hyperglycemia, rash, diarrhea, and fatigue to the extent that it has created tolerability challenges with the non-selective inhibitors.
That we can show PD assays to show that we're engaging the target, and obviously early antitumor activity. That should give us comfort that we've translated our preclinical profile into the clinic. PI3Kα is a significant medical challenge, we've continued to work on that over various mechanisms, both mutant selective and pan-mutant, as well as combining that with various combination partners to make sure that these patients have durable efficacy.
The first of those efforts after RLY-2608 to come into the clinic will be RLY-5836. This is a pan-mutant PI3Kα inhibitor, very similar profile to RLY-2608, but chemically distinct. The third of the efforts is a PI3Kα mutant selective effort, the first of the rational combination partners to enter the clinic will be a selective CDK2. This is a therapeutically relevant target because increased levels...
Increased activity levels of CDK2 are seen in CDK4/6-resistant patients. We were very pleased to rapidly create a CDK2 selective inhibitor going from initial molecules to lead series in just about a year. This will enter the clinic in the early part of 2024. Hormone receptor therapy has been the backbone of treatment in these patients, and there have been several novel approaches to creating the next generation of hormone receptor therapy.
We believe that heterobifunctional degraders have been one of the most high potential of these, and so we were very pleased to create, using our platform, degraders and going from these kind of trial-and-error empirical way that degraders have been created to date to using our platform to solve a complex three-body problem very rationally. We will nominate a development candidate in 2023.
All of this leads to a very deep pipeline of breast cancer assets that we hope will transform the treatment of hormone receptor HER2 negative patients. We look forward to sharing data for the first time this year. That leads us to the third of our clinical assets, RLY-1971.
This is our SHP2 asset that entered the clinic in 2020. We were thrilled to partner with Roche Genentech in 2020, this asset. We believe we have the potential to have a best-in-class SHP2 asset, and we believe that Roche Genentech has the potential to have the best-in-class KRAS G12C. We saw the first glimpse of Roche's data at the World Conference on Lung Cancer last year that starts to validate that. We're excited about the combination of RLY or RLY-1971 with Roche's KRAS G12C.
We're also excited about the partnership of having our SHP2 inhibitor potentially combined with Roche's deep pipeline of targeted therapeutics. The first of those additional trials started last summer with GDC-1971 being trialed in combination with Roche's PDL1 antibody. We look forward to Roche continuing to execute these trials, and as you know, we retain meaningful economics in our SHP2 inhibitor.
Finally, we have a very deep pipeline of preclinical assets. We have five unnamed on the pipeline and obviously others behind that. That splits across breast cancer, tumor-agnostic oncology assets, as well as genetic disease. As we've talked about, we've had small molecule inhibitors. We've also used the platform against creating degraders. Finally, for our genetic disease programs, we're sharing today that we've used the platform to create small molecule chaperones.
The platform consists of a group of capabilities split across leading-edge structural biology and experimental capabilities, as well as computational tools. We believe we have as deep as experience as exists in the industry in combining these two sets of tools together, and we have a team with a deep experience in doing that. The platform doesn't stand still and that we continue to augment it.
We were very pleased to add machine learning DNA-encoded library screen, so an acquisition that we made a couple of years ago, and we continue to invest in growing our automation and our automated chemical design approach, continues to make the design and synthesis of molecules much more efficient. With all of that said, we now have one of the deepest pipelines of precision medicine assets, that has ever been created, and we've done this incredibly rapidly.
Our research capability is about as productive as we'd ever hoped it could be. We've moved that now by building a very effective development organization, and we're on the cusp now of building a commercial capability. We've moved from oncology and now expanded into genetic disease.
We've gone from creating small molecule inhibitors to degraders to small molecule chaperones, and we now have a team that is as experienced as anyone in the industry of combining computational tools with leading-edge structural biology and deploying that platform against targets and bringing that preclinical data and translating it into the clinic. Our research organization has now been in place for over six years. The research leaders have been in place over that time, and they get better each time they do a program. I think they're excited about tackling the hardest problems in drug discovery.
We have $1.1 billion on our balance sheet as of today. That leads us to the ability to execute very effectively against the milestones that we've laid out for the year. For our RLY-4008 program, our selective FGFR2, we commit to fully enrolling the pivotal cohort in the second half of 2023. We commit to disclosing non-cholangiocarcinoma cohort data from our expansion trials.
This is all about now executing to get this medicine to patients as rapidly as possible. On our breast cancer franchise, RLY-2608, which has been in the clinic now since December of 2021, we will show data in the clinic. Our hope is that we will show clinical proof of mechanism for this asset. The second of our pan-mutant PI3K inhibitors will go into the clinic in Q2.
We will nominate a development candidate for our ERα degrader, rational combination partner for our PI3K assets, as well as start our selective CDK2 in the clinic early in 2024. For our SHP2 assets, we'll continue to prosecute with Roche Genentech, the combination trials that are ongoing, and for our preclinical assets, we will continue to push those forward, both across degraders, small molecule chaperones, as well as inhibitors. With all of this said, the key thing is over the last four or five years, each year we put this slide up, and each year we've delivered against it. With that track record, I look forward to coming back over the course of the year and checking each one of these off.
If nothing else, this team is very execution-focused and is focused on making sure that we can get these, each of these goals checked off and get these medicines to patients. With that, I'm gonna invite Pete Rahmer, Corporate Development Officer, and Don Bergstrom, President of R&D, up. We will hand it back to Eric Joseph to take questions. Thank you.
Great. Thanks, Sanjiv. Oh, thank you. You guys come up. Where to start? I guess maybe just picking up on several data sets like forthcoming over the course of 2023, beginning with. Well, let's start with the updated, the full phase 1 dose escalation data anticipated in the first half of this year. By the looks of things, it'll include a good number of good additional number of non-FGFR2 fusion and also FGFR naive cholangiocarcinoma subjects at at least 70 milligrams. I guess, how should we be thinking of the balance of tumor types that are comprising the full escalation, you know, data set and sort of their treatment backgrounds, as, you know, level setting expectations for data?
Maybe I hand it over to you, Pete.
Yeah. Yeah, I think our expectation is we're not gonna learn too much more than we've already learned from the dose escalation data over the two data cuts we presented to date. As a reminder, that dose escalation data is largely in cholangiocarcinoma patients, and it's across 15 different dose levels and schedules. It doesn't include that many patients outside of cholangiocarcinoma. I think that number is still in the 10-15 range, again, it's across unoptimized doses. It's really just a box-checking exercise to bring that study to a close and give the investigators their due recognition for an amazingly executed study.
How should we be thinking about the depth of activity that can be achieved with 4008 in the non-FGFR2 fusion, non-cholangiocarcinoma cohorts that are being accrued? I guess, is there anything from pre-clinically, for instance, using patient-derived tumor models that suggest that would inform what the relative sensitivity is in those other tumor types to Relay 4008?
Don, you wanna take that one?
Yeah. I think we've generated a robust preclinical database across all of the major alteration types. Fusions, including obviously fusions in cholangiocarcinoma and beyond cholangiocarcinoma, focal amplifications of FGFR2, and then oncogenic activating mutations of FGFR2. I think based on these, we feel that all three are bona fide tumor drivers, and in the right tumor context could be highly responsive to RLY-4008. That being said, I think that right tumor context is going to be a key question that we're answering right now in the clinic. I think our belief based on the experience with other fusion oncogenes is that fusion oncogenes tend to be somewhat histology independent, so it doesn't really matter what the tumor type is. If a tumor is carrying a fusion oncogene, it tends to be driven by that oncogene and can be responsive.
When you get into mutations and amplifications, I think the experience in precision oncology is there can be more context dependence. For example, in certain diseases, you might have an FGFR2 oncogenic mutation that may coexist with activating mutations in other oncogenes as well. I think the question that we'll be answering right now in the clinic is, in that context, do you still see a response to 4008 monotherapy, or is the sensitivity blunted by the presence of a second oncogenic driver?
I guess what would be viewed as compelling activity in that, in those settings, those non-fusion, non-cholangiocarcinoma settings? I imagine, you know, the response is somewhat predicated on the performance of standard of care. Can you just kind of describe what that is and ultimately what would be compelling?
Maybe I'll give that one to you, Pete. You might talk about it.
Yeah. I think there's probably two different ways to answer that. One is in the expansion cohorts, these are largely late-line patients, and not really being enriched for any specific tumor type. Traditionally, in late-line cancer patients where there's not an existing standard of care, the regulatory hurdle placed on agents like that tends to be response rates in the neighborhood of 25%-30% with a median duration of response of around six months. As we evaluate these initial data sets, I would say that's the starting hurdle to understand the developable path forward.
As Don alluded to, as we see these data and understand where there may be an amplified signal, if it happens to be histology specific, as you allude to, Eric, it, you know, we can then start to assess existing standards of care and really understand what the clinical differentiation barometer might be.
I guess this, you know, the signs of optimism around, you know, could there be activity outside of the cholangiocarcinoma naive patients twofold. One is just the quality of the molecule that we've created and the depth of a target inhibition that we've been able to create, given the mechanisms avoiding the off target toxicities that have limited the non-selective inhibitors. The second thing is, obviously, the non-selective inhibitors have generated anecdotal data to show that they have generated a signal outside of cholangiocarcinoma. If you put the two together, there is some signs for optimism for why this data could show a signal outside of cholangiocarcinoma.
Okay. I guess concern or sorry, concern, is that the appropriate word? I guess there's been some concern about FDA's conservatism around the eligibility of accelerated approvals or the use of accelerated approval. Sorry, the use of single-arm studies to support accelerated approval in oncology. I guess is it your expectation that 4008 and the ReFocus trial, or at least the pivotal portion of the ReFocus trial will be eligible for registration on the basis of a single-arm design?
We had a robust end of phase I meeting with the FDA in which we discussed this very specific topic and came out of that meeting with general alignment on 70 mg once daily being a relevant recommended phase two dose and the size of a potential path cohort for a potential pivotal cohort, and that's the 100 patients in the FGFR2 fusion, FGFR1 naive cholangiocarcinoma patients. This always has a caveat of that's dependent upon the regulatory and standard of care context at the time in which that data is generated. We do believe that path is available to us as we look at the current landscape of accelerated approved agents and their timeline to potential full approval.
Okay. Any thoughts on what a confirmatory study design looks like?
I think it's gonna be a context-dependent conversation at that time. We've got some recent evidence of how the agency may be thinking about that, given that futibatinib received accelerated approval in October of last year, and the post-marketing requirement for them was a randomized study of just two doses of futibatinib against each other, as opposed to what we've seen with pemigatinib from Incyte running a frontline randomized controlled study as their confirmatory study. I think the agency has acknowledged that is a complicated requirement to put on for full approval.
Shifting topics to the PI3Kα program, 2608. Maybe just to come back to, well, Sanjiv sort of set expectations or set the stage a little bit in terms of the types of data that we might see later in the 1st half. Particularly on the point of pharmacodynamic activity, I'm just curious, you know, what types of assays, measures you are performing in order to define the PD relationship.
Yeah. We're really defining target coverage and the PK/PD relationship in a few different ways. Obviously, we have robust PK modeling and an understanding of what our target exposure is just looking at drug concentration in blood to be able to exceed the level that in preclinical models was consistently associated with greater than 80% inhibition of mutant PI3K and full antitumor activity.
Supporting that, we have a couple of different pharmacodynamic biomarkers that we're looking at. One is all of the patients we're enrolling on study do have PI3K mutations. Many of those patients at baseline have detectable PI3K mutations in circulating tumor DNA. We will be measuring, over the first cycle of therapy and then longitudinally, is RLY-2608 able to reduce the circulating tumor DNA, which would be indicative of being active against the PI3K mutant clone in the tumor. The other assay that we're focusing on is actually an ex vivo pharmacodynamic assay, that is robustly measuring serially the inhibition, in a reporter cell line, the inhibition of PI3K from patient plasma that is collected in the context of the study.
The final, pharmacodynamic biomarker that we'll look at, if you will, is CT scans, looking at early antitumor activity.
I guess there'll be an update both on both in breast cancer patients in combination and treated in combination with fulvestrant, but also as a monotherapy. I guess, is there kind of greater emphasis that I guess would we expect initial update to focus on, you know, one regimen versus the other or sort of a profile across both treatment regimens?
Yeah. I mean, the focus is gonna be on the totality of the data. The goal is to try and show clinical proof of mechanism. In both, obviously, we'll be able to see the various doses that have been used. The goal is to show that we can dose above the IC80. Goal is to show that we can in either arm.
Avoid some of the toxicities that have plagued the non-selective inhibitors. Obviously the PD should give people confidence that we are able to dose and engage the target to the level that we're gonna need to generate meaningful efficacy.
Can you talk a little bit about sort of the number of dosing cohorts that you moved through so far? I imagine, you know, probably getting updated on the safety profile in fairly real time. I guess how are things trending? Any, any observable, you know, dose-limiting toxicity so far?
Yeah. As you can imagine, we can't comment on specifics of what we're seeing in real time from the study. I think the way I would characterize it is the when we guided to initial data in the first half of this year, it was when we initiated dosing of the combination cohort with fulvestrant, and it was with an eye towards making sure that we would be able to get through meaningfully biologically and clinically relevant doses so that we could assess the data and present data that can be interpreted against the parameters that both Sanjiv and Don have outlined. I think we're confident that the data we'll have in hand by the time we present will do just that.
I think the oncogenic addiction, I guess, is the term that sort of applies of breast cancer to activating PI3K mutations is fairly well established. Can the same be said for other tumor histologies, with activated PI3 kinase mutations, do you anticipate perhaps the need for partner partnering inhibitors, I guess, to achieve responses or depth of response?
Yeah, it's a great question, Eric, and certainly the amount of clinical data establishing PI3K as a therapeutic target outside of breast cancer is not as extensive as what we have inside breast cancer. We have chosen a few different tumor types to focus on in our first in-human cohort expansions and monotherapy because they are tumors where we feel that the genomic data as well as our preclinical data and previous clinical experience would suggest that these could be tumor types where you might see single agent PI3K inhibitor activity, so that's clear cell ovarian cancer, head and neck cancer, and cervical cancer, plus a group of patients who will be patients with two mutations in PI3K. It's about 10% of the overall mutant population.
This would be across histologies, but that's a marker of tumors that are very, very strongly driven by PI3K signaling, and we'd expect could be highly sensitive to PI3K inhibition. Outside of those patient populations, I think we do see a lot of co-occurring mutations in other pathways. For example, in colorectal cancer, there is a meaningful population of PI3K mutant patients, but many of those patients are also carrying mutations in the RAS or RAF pathways, and those might be patient populations where to really be able to achieve maximal benefit for patients, there may be need to combine with other therapies.
I think this is a place where having the profile that we've been able to generate with RLY-2608 and RLY-5836 is beneficial because by focusing on selectivity, we're focusing on getting not only improved target coverage and tolerability, but improved combinability with other therapies as well. Traditionally it's been a challenge to combine agents that target both the PI3K pathway and MAP kinase pathway simultaneously. I think it's our belief that as we have the emergence of evermore targeted therapies, especially therapies like RLY-2608, that are specifically targeting mutated oncogenes, that now opens up the possibility for higher order combinations to go after some of these tumors where there are multiple oncogenic drivers.
Maybe just one last question on the CDK2 program. A lot of folks in this room will be familiar with the CDK4/6 inhibitors. CDK2 is active, I guess, an adjacent sort of in the regulation of the cell cycle. I guess where are the potential opportunities for differentiation, or differentiated uses of a CDK2 inhibitor versus a CDK4/6 inhibition?
I mean, as you said, Eric, the CDK family members are implicated in cell division, and CDK2 activity has been shown to be increased in patients that have become resistant to CDK4/6 inhibitors. That's probably the most logical, rational place for us to use it in combination with PI3Kα. The goal here is to try and create rational combination partners for our foundational set of assets, and to try and create the durability and deep set of responses that we are looking for, and that's why we want to create the CDK2 selective molecule and put it in the armamentarium for Relay Therapeutics.
Pause here for any questions from the floor. If not, well, I think we'll leave it there for time. Thank you very much to the Relay team. Thanks, everybody for joining us.
Thank you.