Good afternoon, everybody, and thanks for joining us once again for the 6th Annual Oncology Innovation Summit. I'm Yaron Werber from the biotech team at TD Cowen. With us today really needs no introduction: Sanjiv Patel, President and CEO; Don Bergstrom, President of R&D; and Peter Rahmer, Chief Commercial Development Officer. Gentlemen, thanks for joining us. We appreciate it.
Thank you, Yaron. Thanks for making the time.
Absolutely. This is definitely a good time to catch up. Right in front of ASCO, there is a lot going on in the space, and obviously, we are expecting an update from you as well. For the audience, if you have any questions, feel free to email me directly, and I will be happy to read it for you. You can also chime in through the Wall Street webcasting in that little box, ask a question, and then it pops up here, and I can read it anonymously for you. Just to remind everybody, at San Antonio last year, you showed the updated 2608. That is your selective, alpha-selective PI3Kα inhibitor, 2608 with fulvestrant. This was, I believe, nine and a half months of follow-up. Efficacy was 9.2 months on PFS. Specifically, if you look at second liners, it was 11.4 months and a 39% ORR.
To give everybody a flavor, TRUQAP and fulvestrant historically, and that's the control in the Phase III, did five and a half. So it's five and a half against 9.2, with a 26% versus a 39% ORR. Piqray, as you know, is a little bit more toxic. Historically, did 5.6-8 months PFS and 24% ORR. The data was even more profound in the kinase mutant patients. There was 11.4 months PFS and 67% ORR. That's the historical data. We're going to get an update now at ASCO, and that's going to be more than 12 months of follow-up. The abstract really didn't have anything new relative to San Antonio. What should we expect at ASCO? It's a long, phrased question.
Yes, I mean, as you know, the expectation at ASCO is we show the same data set we showed at San Antonio with longer follow-up. I think we're committing to now over a year of follow-up. We hope to show exactly what we showed in San Antonio, which is, if you look at all the numbers that you kind of read through there, the hormone- receptor positive, HER2- negative breast cancer PI3K alpha mutated market is a large one. 40% of patients with hormone- receptor positive, HER2- negative have a PI3K alpha mutation. This is a very large patient segment. Unfortunately, all of the data that we've seen over the last few years, including all the abstracts that came out last week, continue to show that this is still a very poorly treated patient segment.
All of the data around the previous generation of non-selective PI3K inhibitors, this kind of new paradigm of oral SERD, the CDK4 retreatment, CAT6, does not matter what mechanism you are using, no one has really broken through this kind of five and a half months to seven and a half months' worth of PFS. The numbers you stated for RLY-2608 on PFS, approaching double digits, response rate now approaching 40%, and the CBR now approaching 70%, none of these numbers have ever been seen in any other mechanism.
Our hope at ASCO is to reiterate that we are truly changing the game for these patients and putting numbers on the board that no one's seen before, and to give people great confidence that as we enter the pivotal trial here with RLY-2608 in CDK4 experienced patients, we'd be able to be successful and give these patients a therapy that they've always deserved.
Is there a chance that the ORR will deepen, or we're just looking at the durability of the PFS?
I think, look, at this level, as we saw, we saw 39% response rate across all mutations. We saw 67% response rate in the kinase. I think that at the response rate level, we're kind of almost 2x and some for the kinase, almost 3x or 4x what we've seen in the standard of care. I think that's pretty much baked. I think what we're looking now is durability and consistency. As you see the median follow-up come out above a year, I think we're looking to give people comfort that this data is now stable and to give us comfort that we can run the pivotal trial with great confidence.
Can we start getting some survival data?
I think it's too early for survival data at the moment. I think the data update will still be focused on PFS as the focus.
Okay. In the Phase III, is it exclusively patients who are, we'll come back to that in a second, but I just want to reference it relative to the data we just read out. It's in patients who are going to be CDK4/6 experienced.
That's right. Yeah.
Are those typically, this is really going to be a second line population, or this could be a third line population? Because we just read the delta on both of those.
Yeah. Look, traditionally, as you know, this market is dynamic at the moment. Traditionally, CDK4/6s would be used in the first line metastatic setting. What we would traditionally be focused on would be the traditional second line metastatic setting. Now you're seeing that increasing use of CDK4 inhibitors in the adjuvant setting. Patients that have seen a CDK4/6 in the adjuvant setting are eligible for the ReDiscover II trial. That's why we see this actually to be a much bigger commercial opportunity than I think people are starting to see. It obviously takes the traditional second line and adds with it now a part of the traditional first line. I think if you go forward a few years, this will all be blurred into essentially two simple categories: CDK4/6 naive and CDK4/6 experienced.
Right. In patients who are adjuvant CDK4/6, do they get retreated in front line?
They don't require retreatment in front line. If they've had disease progression within 12 months of completion of their adjuvant CDK4 regimen, they can come right onto our study without re-exposure to a CDK4/6 inhibitor.
As long as they, if they progress within the last six months, twelve months.
Yeah, within 12 months of completion of their adjuvant CDK4/6.
Okay. So it's spilling into even a front line study.
Yes. Yeah.
TRUQAP is not historically used in front line.
That's right. It has a traditional second line label, yeah.
It's going to be harder a little bit to enroll, given and try to put somebody on TRUQAP in true front line.
Yeah. Again, I think we're dealing with a patient population here that we're just getting experience as a field for what the performance is for a patient who receives a CDK4/6 inhibitor in the adjuvant setting. What is their performance in the front line metastatic setting? What benefit do you expect that they would see from retreatment with a CDK4/6 inhibitor? As we were designing the protocol, as we were seeking regulatory feedback and investigator feedback, we included this potential to be able to include patients who had seen their adjuvant CDK4/6 inhibitor with a randomization one-to-one between 2608 and Capivasertib. I think I can say generally there was good receptivity to it, given the uncertainties around how patients who have seen an adjuvant CDK4/6 inhibitor are going to benefit from their front line, from re-challenge of the front line CDK4/6.
Yeah. I guess the alternative is now that Roche's triplet is approved, is that etoveby, palbociclib, fulvestrant would be an alternative, right? And again, but no matter what, this looks like at least a second line study where in the kinase mutations, I mean, you're looking at a very long probably durability.
Yeah, I think you have it right, Yaron. We do anticipate the vast majority of the patients in this study will be traditional second line patients. There, as you kind of highlighted at the top, in our second line population, we're seeing an 11.4 month median PFS today across all mutations. The effect is even greater in the kinase.
Yeah. Great. The study is expected to start mid-year. You're excluding patients with PTEN or AKT mutations. I mean, obviously, that would be something TRUQAP would do. If you have that mutation, you go on TRUQAP. What percentage of patients, when you talk about the 40% that have PI3, are they typically exclusive, or do they coexist?
Yeah, they generally are exclusive of each other. PI3K mutations and AKT mutations are almost always mutually exclusive. AKT mutations are very rare anyway. PTEN mutations actually are dynamic. Recent publications have suggested that they are acquired with subsequent therapies. For example, you get into third line, fourth line patients. PTEN mutations can represent potentially 10%-20% of the population. Going into an earlier line population, like we anticipate with our ReDiscover II trial, it will be predominantly second line patients with some contribution of first line patients. We would anticipate that fewer than 10% of patients, probably closer to 5% of patients, would have both a PIK3CA mutation and a PTEN mutation. It is only a small proportion of that 40% number in the overall mutated population.
Got it. Okay, that's very useful. The primary specifically is going to be, the primary input in the Phase III is going to be hierarchical, initially in kinase mutations and then in all mutations, right? What percentage of patients have kinase versus helical mutations?
Pete, you want to take it?
Yeah, it's approximately 50/50. So about half the patients have kinase-domain mutations and the other half have non-kinase, vast majority helical. But it's roughly evenly spread.
Okay. It is hierarchical. You hit one, and then you will test the second one, they are coprimary.
Yeah, technically hierarchical, saying their tested sequence, you pass the first test, and then you can recycle alpha and use the full alpha for Span treatment.
Okay. So you use the full alpha. And based on the data, you can get approval in helical alone or in broad?
Yeah. Again, the way we'll do the analysis is we'll look at the kinase patients first. I think we wanted to make sure we had the ability to do a formal analysis of the kinase patients, given the very encouraging data we've seen to date with the 67% ORR and over 11 months PFS. We clearly wanted to be able to make labeled claims around that patient population. We set up the formal statistical analysis in that patient population. Of course, we have the formal statistical analysis in the overall population. I think the trial really is designed with the goal of getting the broad label across all PI3Kα mutated hormone- receptor positive, HER2- negative breast cancer.
It is designed in such a way that in a relatively statistically conservative manner, i.e., a relatively small number of patients, you can do the formal analysis in the kinase patients as well.
I think it becomes even more kind of commercially interesting in that we have kinase-only players out there, like Oncure and Loxo. We just want to make sure that as we come into the commercial back and forth, we have the ability to make very clear label claims against whatever data they will put up. Some of the numbers we're putting up here are going to be very hard to beat.
Yeah. Just remind us, how big is that ReDiscover II study going to be?
It is 540 patients. We randomize one-to-one for the RLY-2608 arm versus the Capivasertib.
Okay. The next question is, you decided to use the 400 mg Fed dose, right, instead of the 600 mg Fasted dose, based on that Phase I, II, and based on that PK experience. Can you talk about that?
Yeah. As we kind of came into, I think, last year now, we started to think about all the various possibilities in front of us. As you know, we are running a monotherapy trial with RLY-2608 in vascular malformations. Obviously, that will predominantly be adolescents and then obviously even infants, as that obviously is a disease of childhood. We started to think about doing the fed versus fasted studies much earlier than maybe we traditionally would have done. Obviously, we started to get into discussions with Pfizer and combining with their Abemaciclib, which is also dosed fed. As we did the fed studies, we saw there was a food effect that allowed us then to investigate that over the course of the year.
What we saw was pretty clear equivalence between the 400 mg dose Fed and the 600 mg dose Fasted. We took all of this data, the totality of the data to the FDA. That is how we, in the end, settled on a 400 mg b.i.d. Fed dose, as we thought it would become much easier in the end, dosing both in vascular malformations and in combinations. That is how we got there. We see total equivalence between these two. We feel very confident that the transition will not cause any challenges.
Okay. What are the gating steps to now starting the Phase III?
I think the whole company is now just focused on exactly that. Obviously, we've been through lots of kind of processes over the last seven or eight years, from making the molecule all the way now to selecting a CRO, sourcing CAPI, opening sites, site initiation visits. I think there's nothing really now gating outside of our control now between site initiation and dosing a patient. This is all really now about execution.
In second line in that study, can patients have been on Alpelisib in the past in Alpelisib? So they're excluding.
Yeah, we're excluding prior PI3K pathway inhibitors.
Okay. Got it. Okay. It sounds like it's going to be more of the 12 months follow-up is really what we're going to see at ASCO. Nothing else that we should be looking for.
No. I mean, I think the one thing that people, I think, want to see is consistency of the data and the fact that it holds up over and is durable. As you know, the data we showed at San Antonio was already 2x the standard of care against Capivasertib. Then the kinase was almost three to four times. I think if we can hold that data up, I think that that would be a good thing to show.
Okay. Okay. Let's move to the triplet. That triplet started in Q4 of 2023. The data, you thought you'll have data year on 2024, and you decided to wait until the first half of this year, right, to have a more fulsome sort of data set. Or I think I'm not even sure if you said it was here, right? You said you'll just wait for a later time point.
Yeah.
There was also a dose-dose interaction that identified at some point with RIBO reducing the exposure to 2608 and not vice versa. I assume you've been dosing at the 600 b.i.d. with 2608, or how did you overcome that DDI?
If we go back in time, obviously, we started dosing with RIBO in 2024. Obviously, RIBO is kind of standard of care in the CDK4/6 field then because of its survival data. As you know, it is notoriously challenging to combine with. No one has really been able to kind of thread that needle. As you rightly point out, we saw a DDI. That DDI increased the exposure of, sorry, decreased.
Increased.
Increased. You're absolutely right. Yeah, I keep getting mixed. Increased the exposure of 2608. As we've talked about, we had this kind of Fed/Fasted dose exploration that was also going on last year. Obviously, we made the decision to dose Fed. That is really what's taking the totality of the time, just passing through that. At the same time, we then started dosing with Abemaciclib, Pfizer's CDK4/6. All of that data, I think we want to try and bring forward together slowly, deliberately. Once we have a full package of data, we'll be able to share it. At the moment, we're not guiding to when that is. We want to provide a kind of fulsome disclosure when we do so.
Okay. Is it possible for it to be this year, or it might actually spill into next year?
I think at the moment, we're just not guiding to it. I think we're just going deliberately through the steps. As you can see from the work we did in the doubler, we're very thorough around dose exploration and then obviously the Fed and the Fasted and providing a pretty robust set of data. We'll do the same in the triplet.
It sounds like you're also testing a different dose, though, right? We shouldn't be expecting 400 mg b.i.d.
I mean, we're still in the dose exploration part at the moment. Yes, with RIBO, we've definitely seen a DDI.
Okay. Okay. And you also, to your point, have a triplet with a tiramo.
Yes.
Where are you on the dose exploration there?
Yeah. We initiated the combination work with the triplet, largely in a patient population who's been experienced already to CDK4/6 inhibitors. I think we're very encouraged by the combinability of 2608 and Abemaciclib and encouraged by the progress of that combination, that triplet combination arm.
Is it possible to have data from that triplet before the RIBO triplet?
Again, it's all too early to tell at the moment. I think we just let us get through the exploration.
Who's running that triplet? Is it you or is it Pfizer?
Pete, you want to take that one?
Yeah, we are running it. We receive Abemaciclib from Pfizer via a clinical trial supply agreement. That study is being conducted under our ReDiscover study, our first in the study.
Got it. Yeah. To go back to Rediscover, the original Rediscover I, are you doing any studies in sort of other tumors outside of breast?
Pete, you want to take that one?
Not at this time. That study is focused in breast cancer right now. You obviously have the ongoing follow-up of the doublet patients. We have the two triplet arms with ribociclib and Abemaciclib. We may do some other dose-finding, dose confirmation studies with potentially next-gen endocrine therapies or even the existing aromatase inhibitors as we think about the potential different permutation of frontline regimens as we think about development plans there.
Okay. Got it. Okay. Let's move to the PROS, the vascular malformation with PI3K-related overgrowth spectrum. The standard of care right now is essentially Piqray, right? I think it's called Vijoice, right? But it's essentially standard dose Piqray. What percentage of Piqray sales are in PROS? Can we back into the market size right now?
Pete.
Yeah. So just a few high-level things to unpack there. As you mentioned, we initiated a study of RLY-2608 in vascular malformations in Q1 of this year. Inside of vascular malformations, there's a couple of different subsets of disease. There's the PIK3CA-related overgrowth spectrum, PROS, that you referenced. There's also lymphatic malformation, venous malformation, and then another category, cerebral cavernous malformation. Our first-in-human study will be done predominantly in PROS and lymphatic malformations, although it is open for venous and cerebral cavernous. Within, for Alpelisib, they do have a label in PROS. There's about 170,000 patients with PIK3CA-driven vascular malformations in the US. About 5,000-15,000 of those are inside of PROS. Obviously, that PROS population is entirely characterized by PIK3CA mutations. Alpelisib, Novartis got an accelerated approval back in May of 2022 for PROS.
They used Alpelisib just under a different brand name, Vijoice, as you referenced. Within that, they do not break out the sales of Vijoice versus Piqray. You can monitor the sales quarter over quarter going into that approval and after that approval. You would probably back into an annual run rate somewhere in the neighborhood of $200 million-$300 million a year from the PROS label. The last key thing to point out is that they were asked, as you would imagine, to go run a confirmatory study. They did so. It was called EPIC P2. They recently announced that that trial failed. It leaves the regulatory path a bit uncertain for the ultimate fate of Vijoice in this setting.
Positively for us, it does mean that there is not an agent with full approval at this point in time in vascular malformations.
Pete, you said 55% or 170,000 for PI3K, or did you say 5-15%?
So it's 170,000 total patients that have PIK3CA mutated vascular malformation.
Yep.
5,000 to 15,000 of those are within the subpopulation of PROS patients.
Okay. 5–15% of the 170, that's what you mean, are PIK3 or specifically PI3K?
10% or 5–15,000.
Yeah.Piqra
Got it. There is no control in that study?
No. In the first part of the study, there is no control arm. There is a part three in the study that could be triggered that would have a randomized controlled part of the trial that could support full approval. That is not our focus today. Our focus today is really on dose optimization and signal generation.
Yeah. What would the control be at that point?
In the current world, it's still a placebo-controlled trial. There's no approved, there's no systemic agent with full approval for these patients. It would still be a placebo-controlled trial.
Yeah. Okay. Team, I know we're over. Maybe in terms of any other data that we should be looking for for this year?
No. The core data we're guiding to is upcoming here at ASCO. You started with this is really not only this year, but the next few years is a big execution endeavor and focus for us as a company through the Phase III, through vascular malformations, and through continuing to progress both FabRays and NRAS toxicity.
You finished, remind us your cash position as of the end of Q1 because that's going to take you into through 2028, I believe, right? Into 2029 now?
Yes. Into 2029. The cash position at the end of Q1 was $710 million.
Okay. And so.
Which fully funds the Phase III with plenty of cushion on the other side, along with the vascular malformations through proof of concept, some of these other additional breast cancer studies, and continuing to progress both FabRays and NRAS.
Okay. And those will be on a preclinical development, or would that include Phase I?
Through to IND. Yeah.
Through to IND. Yeah. Would you consider getting a partner at some point?
Absolutely. I mean, I think all options are on the table given the capital markets the way they are and the volatility in the world around us. I think any company that states that they wouldn't, it's probably not telling you the truth.
Yeah. I mean, would it be retaining US rights and partnering ex-US rights, or?
Look, I think the main priority of this company is to get RLY-2608 across the pivotal line to fund any future studies around it. So I think we'd consider all options.
Yeah. Great. Terrific, team. I know it's 4:00. Thanks so much for joining. We appreciate it. We'll see you at ASCO.
Thanks very much, Yaron. See you there.
Thank you.