All right, welcome back to the 46th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team here at TD Cowen. Really pleased to have next session here with Monte Rosa Therapeutics, where we're gonna start off with Markus Warmuth. The CEO's gonna give a few remarks with prepared remarks with a couple slides, just kind of level setting everybody. Then we'll go into Q&A, which I'll lead, but certainly anybody from the audience. We do wanna make it interactive. If you do have your own questions, so raise hands, we'll try to involve you as well. For Q&A, we'll be joined by Filip Janku, the CMO, as well. With that, I'll hand it over to Markus to get us started.
Yes. That's great. Thanks, Marc, for the introduction. Yes, I thought it's probably helpful to bring a few slides for those who aren't quite as familiar with Monte Rosa. We're still a relatively young company. We're now seven years in, so at some point I've got to stop using that as my introduction. We do molecular glue degraders, so we take out proteins in cells to eventually make medicines. I'm hoping obviously that a concept that's like somewhat old by now, serendipitously discovered by other companies, can be turned into a real machine doing it over and over again. As an introduction, we do consider ourselves as a leader in targeted protein degradation.
My general counsel said, I can't say the leader in targeted protein degradation, but I think we're pretty close to that at the very least when it comes to molecular glue degraders. A few things to consider here. We have definitely delivered a lot of value in that space. Thee programs now in the clinic. All three programs have produced positive clinical data. For each of these programs, in the course of this year, we'll initiate at least one, but in some instances, multiple phase II trials. Quite remarkable, given that we basically built everything from scratch over the years in-house. Certainly a lot of cool stuff coming behind industry leading platform. Platform's called QuEEN.
Obviously, at a point where we're not ready to disclose what some of these additional targets are, but certainly in line with what we have done so far, undruggables, across multiple disease areas, including oncology, I&I, and cardiovascular. Very well positioned for execution as well. Strong balance sheet. Actually, through our collaborations where we have brought in over $300 million in collaboration revenue over the last year, but then of course also through our financing that we have done earlier this year. Really, as said, well positioned to execute on our portfolio. This is our portfolio. I'm not gonna go line by line here.
Just again to reiterate, we're obviously spread across multiple disease areas, advancing towards phase II initiations quickly now. I'm gonna start with the I&I part of our portfolio. In this space, we're very keen to go after proteins that are undruggable or where degrading them makes more sense than inhibiting. We do like to be in a space where we can take out proteins that impact multiple signaling pathways and/or cytokines at a time. A great example is VAV1, which I'm not gonna talk about much today, but that is a signaling protein downstream of both the T and B cell receptor. Obviously, the actual molecule here, MRT-6160 is partnered with Novartis.
The focus today will be on MRT-8102, our NEK7 degrader. This is a program where we have released some quite remarkable data earlier this year. Just for background, this puts us into the NLRP3 inflammasome, a pathway that has become quite popular. Raised quite some interest through the recent acquisition of Ventyx by Lilly, but certainly also through other players in the field. Our focus for the program for now is ASCVD, although we're obviously trying to expand that and really brought that slide to also exemplify how we many times think about targets but also indications.
You know, we were obviously looking as we worked in that space on NEK7, can we learn from pathway expression signatures from primary samples? Yes, we did. We were able to look across various different indications and found that ASCVD actually ranks second highest in that list of indications we looked at in regards to how active is the pathway. It's actually scoring higher than a genetic disease known CAPS, where NLRP3, the component or central component of that inflammasome is actually mutated. Also looking at human genetics, too. There's variants in NLRP3, and they tend to be highly associated with a variety of different cardiovascular conditions.
These SNPs, or genetic variants obviously are believed to be activating. Had put data out earlier this year. I'm going to start with this. It's sort of benchmarking our results versus some competitor molecules, be it small molecules or antibodies. What you typically do when you look into this pathway for ASCVD is you look at CRP and how much you can suppress CRP and also in how many patients you can now get from elevated to normal CRP levels. The left-hand side has percent reduction. We saw actually an 85% drop in CRP levels in a cohort of individuals that were obese and had elevated CRP levels.
This is pretty much in line with where you can get with, for example, IL-6 antibodies. This year is Novos' IL-6 antibody that's reading out actually later this year in an ASCVD trial. Definitely better results here for us compared to NLRP3 inhibitors. This year's the normalization data. 94% of individuals here going from elevated CRP levels to normal levels. There was literally only 1 individual that didn't normalize. Quite remarkable, benchmark setting data yet again. Again, keep in mind, this is comparing against three different doses for IL-6 antibodies, what's moving forward in the clinic for both of these assets. Right. Again, this is Novos'. This is Tourmaline's now Novartis'. It's moving forward in phase III.
It's very likely the middle dose. Actually, we know for Novartis, we're assuming it's the middle dose that's moving forward. This is the underlying data in more detail. I'm gonna go very quick. Again, this is the CRP normalization over time. This was actually a four-week dosing study that followed our SAD/MAD study. Very nice drops in CRP. That's the normalization data. We also looked at other inflammatory markers. As an example here, we brought fibrinogen, 31% reduction. This is pretty much also benchmark setting within the space for now. Really great safety. Obviously, with degraders, we believe because of the level of selectivity we can dial into these molecules, there will always be a safety edge.
It's good to see that that has now translated into a reality. There's no tox concern from the blinded safety data from our phase I. More recently, we've actually also obtained three months data from our Cyno tox study, which will enable dosing in phase II, longer dosing in phase II. Actually, literally no findings at all that were assigned to the test Article 8102, even where we were dosing in the range of 200-300-fold above what we believe the therapeutic dose is in humans. What we've done here is the data I showed you actually emerged from a phase 1 SAD/MAD and part three study.
Because of the results and trying to find a quick path into a phase II, we've decided to extend that part three to two more dose levels. Technically, this now becomes a phase IIa study. We're calling that study GFORCE-1. Obviously, one of these dose levels is the 40 mix that we had used in our initial data disclosure, two additional dose levels added here. Switching gears just very quickly to our lead oncology project. It's quite a jump I&I to oncology, again, one where we had to release some intriguing data actually late last year, and then an update just last week in the context of the ASCO GU meeting.
The target here is known as GSPT1, a protein that actually regulates translation termination. That's shown here. We believe that in the context of tumors like prostate cancer, where a lot of the disease is driven by transcription factors, including androgen receptor, but also MYC, this becomes very important. We actually also have a program on both cyclin E and CDK2, but I'm not gonna talk much about that today. But again, tells you a little bit sort of where we like to be undruggable targets or hard to drug targets within the oncology space in tumor types or pathways that are relatively well characterized at this point. This is the data that we had disclosed last year and then updated last week.
Intriguingly, in our clinical trial, we're seeing in the context of androgen receptor mutations a still 100% response rate. Five out of five patients in the trial that had a mutation in the androgen receptor showed a drop in PSA. That drop in PSA actually correlated to other clinical readouts. Actually, for all of them, we saw actual tumor shrinkage by RECIST. Two of these patients actually had RECIST PRs, the others not PRs. For these, I will say just yet, but given that these two are still on the trial and their PSA values have been improving, there's still an opportunity for those to convert into actual RECIST PRs.
Drops in ctDNA, actually also drops in the count of circulating tumor cells. Intriguing findings, obviously, small Ns. Because of then, we're now trying to go to the next step, a confirmatory trial in the same setting, metastatic castration-resistant prostate cancer with androgen receptor mutations, trying to see if we reconfirm that signal. I think from there, obviously, there's lots of opportunities to go to that we can discuss in the Q&A session. This really gives you an idea about our portfolio. As I said, a lot more to come. Certainly going to be a busy year.
As I said, not much to talk about today about VAV1, other than that, Novartis is planning to initiate a phase II program this year in multiple indications. For NEK7, I mentioned the expansion of our original phase I trial, now more a phase IIa trial called GFORCE-1. Their data will actually come in the H2 of the year, and around the same time, hopefully we'll start our phase IIb GFORCE-2 study. We also have a second-generation molecule we can talk about in the Q&A that's headed towards an IND submission this year, and then phase II initiation in the third quarter for the confirmatory trial for 2359. That trial is actually called MODIFIER-1. cyclin E, CDK2, I mentioned it.
Not enough time to give you any details, but another program where we're hoping to have an IND submission by the end of the year. With that, we can open it up to the Q&A session.
Okay. Give Marcus a second to get settled over here. This may be a little bit of a Filip question. Maybe just start off with just high level. You touched a little bit on your own data. There was a broad, you know, broader kind of wide-ranging number of data sets across the NLRP3 data set pathway in the last handful of months on CRP.
Yep.
Just what do you think In taking those all in totality, what has the broader field proven already about NLRP3 and downstream NEK7, and what really needs to come from the later trials that you and the others are going to run next?
Yeah. I mean, I'm gonna go back to Novartis' IL-1β antibody canakinumab, which obviously had delivered proof of concept for ASCVD. They were certainly able to reduce the number of cardiovascular events, but it came with the downside of lethal infections. Sure, that's a little bit what you tend to be concerned about when you go into inflammation, and in particular, when you go after cytokines that have a broader role than just mediating inflammation in the NLRP3 inflammasome. There's other companies now going after cytokines, as mentioned, talking about the IL-6 agents between both Novo and Novartis. You could have similar concerns there, right? The phase II data looks relatively solid around the infection risk.
Sure, IL-6 as a cytokine is not just downstream of the NLRP3 inflammasome. As a matter of fact, in our Phase 1 program, IL-6 was one of the key cytokines we were reading out, so it's downstream of the Th2 and Th17 pathways in immunity as well. That automatically takes you into, okay, how can you do this more specifically? That would be going after the actual inflammasome complex, NLRP3 inflammasome. The way to do it, of course, is either inhibitors or what we do with NEK7 degradation. NEK7, obviously here, I didn't go into too much detail, is a scaffolding protein, right? Without NEK7, the inflammasome, the NLRP3 inflammasome doesn't even assemble.
We think, in a way, our data sort of documents that this is the superior way to go after it. As you saw, on the inhibitor side between the two example molecules we showed there, definitely superior impact on CRP. There is data now from another company that has an NLRP3 inhibitor that looks a bit equivalent to what we're seeing, which is really great, right, because it solidifies the importance of that upstream node, NLRP3 inflammasome, NLRP3 plus NEK7. They only saw it at the highest dose they have tested, right? Whereas we, at least in MAD, have seen it across pretty much every dose level we've tested from five milligrams to 100.
Obviously the expansion was only at 40, but sure, part of the GFORCE-1 expansion is to now go to lower doses potentially as well.
At the time of the data disclosure earlier this year, one, the safety data, as you mentioned-
Mm-hmm
...remained blinded. I think also a few patients in Part three, who were enrolled had not reached the four weeks follow-up yet. Just when should investors expect to see kind of the full phase I experience released?
Mm-hmm.
...often get some pushback from investor or some comments from investors about kind of the unblinded safety and why that was necessary. You wanna talk through that kind of-
Mm-hmm
...trial design element as well?
Yeah. I mean, couple of answers here in regards to sort of the different components of the trial. You know, SAD/MAD actually is unblinded separately from the Part Three, so basically what's now GFORCE-1, and there is an opportunity to rule that data out. It wasn't unblinded at the time of our data disclosure. You know, for us, this was like, let's get the CRP data out as soon as possible because it was so game-changing, where even in the blinded data, we obviously didn't see any issues. For Part Three or GFORCE-1, obviously, to maintain the integrity of that study because the placebo arm will be shared across the three dose levels, we won't be able to unblind it until now all these cohorts are fully enrolled.
Again, we wouldn't have disclosed our data, obviously, if there had been the slightest concern about toxicities. The data we have seen on the E so far is remarkably quiet. Most of all, not a hint for any increased risk of infections, which obviously is key to that thesis that I was describing vis-à-vis downstream cytokines.
Okay. Secondly, you touched on the for GFORCE-1, the three dose levels now, have you settled the doses or it sounds like maybe there's still a little bit of debate internally of exactly what?
No. I mean, it's been settled.
Okay. Yeah.
I mean, as a fact, we've started to enroll into those two additional cohorts, and that actually is going really well. That said, we haven't disclosed what the actual dose levels are. It's probably not hard to guess we're going to lower levels. Again, that's not because we have any tox concerns, right? This is more sure the lower we can go, the wider range we can create. Obviously, the more flexibility we have for future development and setting doses per indication.
Yep. Okay. Can you walk through the timeline since those are enrolling, the timeline to getting to data, and what beyond? Is there anything beyond kind of reconfirming CRP impacts that can be learned from this trial?
Do you wanna answer?
Well, the reason why we expanded that and why we are doing 3 dose levels is because we think that the study in this design, testing multiple doses can actually really be informative in terms of the relationship between the doses and the CRP effects. What we know that from 40 milligrams, which is actually already a relative dose, which is relatively on the lower side. I mean, just to remind everyone, we went up to 200 milligrams in MOD. The 40 milligrams does have actually profound impact on the CRP, which is maintained, right. Unlike if you look at some NLRP3 inhibitors, which show dramatic reduction in CRP levels after 1 week, but there is a little bit of bounce back in the weeks to come. We don't see that.
We actually go down by 80% at week one, then it goes even lower at week two, 85% at week three, which is maintained by week four. This is actually kind of very reassuring that this dosing can result in the durable reduction of CRP, and these additional two dose levels will actually figure it out what is our dose range, efficacy dose range, which then will inform the dose selection for the phase two, and hopefully will allow more rational phase two selection, in which we perhaps can maybe test fewer dose levels than our peers and competitors did.
Okay. In terms of those phase IIs, you know, obviously cardiovascular outcomes, you know, cardio inflammation is one place of significant interest. What else? You know, there's a lot of places in theory a NEK7 or anti-inflammatory could be brought, but where else is of interest?
Obviously, the ASCVD, I mean, that's already the ball is already rolling on that. I mean, we are going on that full steam ahead. As you pointed out, there are multiple other indications. I mean, some of them are something which we are considering really seriously and definitely some of the recent development in the company would allow to do that. I mean, from the flare indications, we actually do like flare prevention and gout. I mean, there is definitely potential to innovate because even with urate-lowering therapies, which seem to be seeing a lot of development, these therapies don't always, at least from the short to medium-term perspective, they essentially don't do much to flares.
If you kind of look at the data, if you start on KRYSTEXXA, after one month on KRYSTEXXA, you have more than half of the patients who actually experience another flare. That's kind of like a substantial problem. The flare reduction with the oral safe and therapy with [uncertain], some side effects actually would help, would provide a lot of innovation to the field. The other inflammatory conditions which are driven by NLRP3 based on the data which we have, I mean, one example would be HS. We also spoke about pericarditis. It's a little bit more narrow. It's a little bit more narrow indication, but certainly indication of interest. At the moment, there are no oral therapies. While the anti-IL-1 therapy, which is now approved, Rilonacept is actually quite successful.
I mean, it's still injection which has to be given weekly, which is perhaps not that appealing proposition from the long-term perspective.
Okay. Maybe Markus, a strategic question there. With that breadth of opportunity, you know, how do you approach prioritizing indications to develop internally, but then, you know, particularly things like cardiovascular outcomes, right? Like, you know, those often are beyond a small biotech to run themselves. You know, how do you think through partnering potentially and when to do it, particularly given that you can have indications that may be much more advanceable for yourself versus some others that maybe really need a partner?
I mean, you know, fair to say that as we pick additional indications beyond ASCVD, we want them to be indications where we feel we can self-develop. We do think gout and hidradenitis if we went there, fall into that bucket. All that said, for us, like pushing into that phase II in ASCVD still remains the top priority. There's lots of stuff we can learn from the trial that can inform some of the other development programs. There might be opportunities to sort of narrow the patient population to subgroups with higher frequency of events, which would allow us to do ASCVD on our own. Of course, you get to the finish line faster, but sure, the market would then be smaller.
As we do this, sure, I mean, we're gonna monitor what's gonna happen. We'll see what the interest from strategics is. One of the big advantages for us around MRT-2359 also is we kind of own the chemical space for now, right? There's opportunity for multiple molecules, not that additional one. I think long story short, fairly determined to sort of hang on to this program and try to self-develop it. We certainly acknowledge that at some point, ASCVD might become too big, and we have to think about some smart ways of partnering.
You sort of touched on it there, just having the molecular space and more molecules. Just what is the plan there? When's the right time to maybe start advancing some additional compounds into the clinic?
Yeah, I mean, as mentioned in my presentation, we have a second molecule now, that we're advancing through IND-enabling studies. You know, obviously, there's not a whole lot different about it from a, from a profile point of view, except it's a different chemotype. I think that'll help on diversification. At this point, there's nothing we feel we need to improve around 8102. Having that second molecule gives us a lot of strategic optionality around future pricing or, for what it's worth, strategic partnerships. There's other things we're thinking about in this space, other profiles, but a little bit too early to talk about those molecules.
Starting to run a little low on time, maybe real quickly on GSPT1. Maybe, Filip, you wanna walk through with the phase II that Markus, you know, discussed, the design, the expansion. What do you view as kind of the bars there? What, what does good data look like in an AR-mutated population...
Mm-hmm
when we see, you know, more up towards 20, 25 patients worth of data?
I mean, we so far, we enrolled five patients in the expansion cohort, which is about to conclude. In the expansion cohort of the early phase trial. There were five patients with AR mutations. They all had a PSA response, as Markus pointed out. I would say that this is small but good data. Essentially, these 25 patients will be about to confirm if this signal still stand. I think to be somewhat naive, probably to hope that we will maintain the 100% response rate. I think we know what has been observed with AR degraders or with Opevesostat, which kind of had a PSA response rate, kind of around 50% or a little bit below. At the moment, we seem to be comfortably far above that.
I mean, if we stay far above that, even though at 100%, I think that would be the outcome which would definitely warrant the further development and might potentially open up some quick path to label.
Okay. That's the PSA response rate. you know, of course, So far, you've been really focusing on making sure you get RECIST valuable patients.
Mm-hmm. Mm-hmm.
1, is that still the focus in the, in the larger expansion? Two, from a RECIST perspective-
Mm-hmm
... what is, what do you view as kinda the bar?
Yeah. When it comes to requiring the RECIST measurable disease, we're not gonna mandate it for the phase II confirmation because I think the main reason why we did it was that we wanted to be sure that whatever we see is actually associated with the tumor shrinkage before we actually make some consequential decisions about actually planning some additional study activities. I think the We've shown that, right? I mean, we had two PRs. The three patients who didn't have PR, they have some noticeable tumor shrinkage, and two of them are still on therapy. I think they still have a chance, at least they have a chance to see even more shrinkage down down the line.
At the same time, what you do, if you do that, I mean, you are selecting the population, which is definitely less favorable compared to others. I mean, you can actually look at some bispecific studies. They don't even allow patients with liver metastasis. I mean, we had a representation of liver metastasis, quite substantial representation of patients with liver metastasis, including actually one of the responders. I think the phase two will be more kind of a conventional. The efficacy is designed around the PSA response rate, so they will have to be PSA measurable plus or minus, plus or minus RECIST measurable. If I kind of look at that, the RECIST response rate lingers usually about 10%, 15% behind the PSA response rate, although it's not always that.
I mean, in Opevesostat, the difference was even bigger between the PSA response rate and the RECIST measurable response rate. What kind of matters as well is actually the durability, so it's essentially the rPFS. I mean, if we see rPFS in that group somewhere in 6-plus, 7-plus months, I think with the good PSA response rate, I think we would have a very good case.
Okay. We are really getting pressed on time now. Maybe quickly also just VAV1, Marcus touched on it extremely briefly, but, you know, why is that such an interesting target? You know, what should we expect next?
Yeah.
I think there's belief in some phase IIs. When might we see kind of the indication selection coming?
I mean, you know, really, as I pointed out, interest is high given it's downstream of both the T and B cell receptor. The role is probably more dominant in T cell receptor signaling. In particular, where you have sort of chronic overactivation of T cell receptor, which is autoimmune diseases. One of the intriguing findings around VAV1 is that in a mouse, when you knock out VAV1, you protect from all sorts of autoimmune diseases, but you have a maintained vaccines response, which quite honestly no one can explain, but it's a fact that's highly reproducible. Now think about an immune modulatory drug, let's say in rheumatoid arthritis, where you can deal with rheumatoid arthritis, but you have a perfectly normal vaccine response, right?
This is probably one of the most desirable profiles you can possibly have. Indications have been selected. Obviously, they haven't been disclosed. You know, we're, you know, quite well aligned here with our partner, Novartis. Sure, I mean, we live in a very competitive world, active in a very competitive space, and there's no need to inform our competitors on where exactly we want to go. I can say that sure the indications we've now selected or Novartis has selected are like an identical overlap to where we would have gone, except sure, we wouldn't have had the funds to do as many indications as we can now do in this partnership with Novartis.
Unfortunately, we have to cut it off there. Thanks a lot, Markus and Filip, for joining us, as well as everybody in the room or on the webcast.