Great. Good afternoon, everyone. My name is Ted Tenthoff. I'm a senior biotech analyst at Piper Sandler. And before I begin, I'm required to point out certain disclosures regarding the relationship between our next presenting company, Monte Rosa, and Piper, which are listed at the back of the room and also at the registration desk. So Monte Rosa is developing its proprietary QuEEN platform to rationally design molecular glue degraders, or MGDs. The company is about to report or update some Phase 1 data on MRT-2359, targeting GSPT1 for metastatic colorectal and breast cancers. But beyond this, it has a rich INI pipeline of MGDs, including MRT-6160, which targets VAV1 and is partnered with Novartis. And what I think is emerging as my favorite, MRT-8102, targeting NEK7. Here with us from the company today is Dr. Markus Warmuth, CEO. Markus, always a pleasure.
Thank you. Thanks for having me.
One of my favorite biotech stories: great to see the stock moving. I still think there is a lot in the tank here, especially when you look at some of the competitors. I think [audio distortion] is actually going to report in an hour or so in this room. And I think it'll be a really nice compare-contrast between the two. But perhaps you can start off by describing the Phase 1 that you're preparing to report on MRT-2359. Maybe describe the target briefly, but what should we be expecting from that data set?
Yeah. Happy to. And so interesting target, GSPT1, actually a translation termination factor, so a protein that catalyzes the separation of mRNA from ribosomes in new protein. And we have found through internal efforts that this protein is extremely essential in the context of MYC-driven tumors, right? MYC-driven tumors, transcription factor that drives a lot of transcription first and then translation. Lots of preclinical work, translational work that we have done to eventually end up now in this prostate cancer and breast cancer expansion arms. You will probably hear, as I continue to talk, that we are particularly excited about the opportunity in prostate cancer. Almost a bit of a sweet spot when you look at all the data, preclinical data that we have accumulated.
And so from that expansion arm, which is actually a combination with enzalutamide, so it's MRT-2359 plus enzalutamide as an androgen receptor antagonist, we have somewhere between 20-30 patients enrolled. Obviously, not all of these patients will be through scans or sort of ever made it to be eligible for a scan. But that's roughly giving you an idea of what our plans were for enrollment for those. And I think this is particularly important for us to emphasize for those patients. We will have RECIST on every single patient. We didn't want to fall into the PSA overread trap. So all patients needed to have measurable disease, which means they have visceral disease, which also means from a prognosis point of view, not the best subset. But obviously, for us, the most meaningful subset of patients to get an idea whether that modality can shrink tumors.
We'll have fresh ctDNA data on every patient, CTC data. And so overall, a very meaningful data set at the end of the year to tell us where to go next with that asset.
Yeah. Great. Well, we're looking forward to that. Switching gears to the INI pipeline, I'm going to start with VAV1, molecular glue degrader, MRT-6160. Tell us about VAV1 as a T and B cell target.
Yeah. So super exciting target. Really fits very well. It's almost emblematic for what we're trying to do with our INI programs. A target that sits downstream of both the T and B cell receptor. Its expression overall actually is fairly restricted through immune cells, T/ B, and actually monocytes, myeloid cells in general. So it sits downstream of two different receptors and thereby then obviously influences multiple different signaling pathways, which we think is a better way to go versus just being very strictly downstream of one singular cytokine receptor cascade. Fascinating preclinical data where we control both in vitro and in vivo that were impacting the Th17 pathway. Really great efficacy data in multiple models that are driven by Th17 T cells that included a model in rheumatoid arthritis. We have a model in IBD. We've just recently published on Sjögren's syndrome too.
A lot of excitement around that modality and hopefully soon more clinical data being generated through our partnership here with Novartis.
Yeah. So walk us through the Phase 1 data that you've reported to date, and then maybe remind us of Novartis partnership?
Yeah. So Phase 1 was a fairly classical SAD/MAD safety PK/PD study, essentially single dose, multiple ascending dose study, more or less looking at can we degrade VAV1 efficiently and to a point where we think we need to, and we had set that level at 80% based on preclinical data. We then also looked through ex vivo stimulation whether that level of degradation really leads to functional pathway inhibition. And lastly, of course, you do this to establish safety. I'll start with safety. There was really nothing to worry about. On the cytokine release, again, very good-looking data with inhibition of release of IL-2, IL-17, and interferon- gamma. And we really liked the interferon- gamma readout because that allowed us to benchmark to some of the other assets in this space, in particular protagonist's IL-23 antagonists.
Clear to say we compare quite favorably where we basically wiped out interferon- gamma secretion across multiple dose levels.
Great.
And so our partnership with Novartis, obviously, we think this asset needs to be in the hands of a company that can explore it very broadly. And that is what we believe will happen starting soon. Obviously, the program now being with Novartis, it is a little harder to talk about specific timelines. But yeah, excited to see this in the clinic. We know this will be a broad development program. We have actually seen the clinical development plans with multiple indications launching at the same time, once the program kicks off.
Can you share any color on that, or is that something we should just wait and stay tuned? Because I know the plan is to do multiple Phase 2.
Yeah. I mean, not much I can share. Again, obviously, the plan is to go into multiple indications, launch those trials in parallel. The indications haven't been specified, but I've alluded to some of the preclinical work that we've done, right? Sjögren's syndrome, arthritis, IBD, and obviously, those would be really good indications to go into.
Yeah. That's perfect. Now, they must really like you guys because they came back for a second partnership. So tell us about the second deal and why they came back for more?
Yeah. I mean, honestly, it is one of the best partnerships I've been involved in. It's very interactive. It's not just sort of the more formal joint development committee. We're actually neighbors through our office in Switzerland, literally a five-minute walk between the two offices. So fairly easy for us to interact with Novartis across multiple levels. I meet with Richard Siegel quite frequently, who leads the INI group there. And sure enough, after we had signed VAV1, literally at the kickoff dinner for the program, we started to talk about, "Hey, is there anything else we can do?" It's a really cool deal, structured differently because it's earlier stage. But to keep it simple, Novartis has two options on programs from our preclinical INI portfolio. It's not a discovery deal where we would have to screen tens of targets. It's really around two programs we were particularly fascinated about.
Cool. And I know, again, very nice economics. I think $120 million upfront and upwards of $6 billion in milestones. So certainly very positive. So looking really at your wholly owned pipeline at this point, you started a Phase 1 study for MRT-8102. Maybe you can start off by describing NEK7's role in the NLRP3 inflammasome and why it's such a good target to degrade.
Yeah. So another exciting target. So now we're in the inflammation space. Also, those who follow the NLRP3 inflammasome story, turning more from inflammation into a cardiovascular story as we speak. But inflammation, obviously, is the key underlying mechanism here. NEK7, in that context, actually is a scaffolding protein that's absolutely essential to assemble a fully active inflammasome. And so when you take it out through degradation, not only do you inhibit the inflammasome, as a result, it never gets assembled, which obviously leads to fairly deep and long-lasting pathway modulation. And certainly, through this, in our view, provides an advantage over NLRP3 inhibitors that are just constantly on and off, inhibiting the activated inflammasome. And so interesting program, wholly owned to your point, so much better, easier to talk about. It's in a Phase 1 SAD/MAD study right now.
And then as an extension of this, we have a Part 3 or Part C that actually looks into inflammation in cardiovascular risk situations. We call it a CRP POC study. More recently, internally, I started to call it a mini ASCVD study because that's literally what we're looking for. And so in individuals that have an elevated risk for atherosclerosis and who have elevated CRP levels, can we actually lower those levels within the treatment period that we have here? And that's a four-week time period.
Markus said, "Kind of take a quarter step back." But you guys presented new preclinical data at AHA recently on these cardiovascular. Walk us through that and sort of where you really envision developing 8102 at this point?
Yeah. I mean, there's plenty of opportunities. I mean, obviously, that being a cardiovascular meeting, we focused on that. There's really good data we have in monkeys, in CYNOs, where we show that after multiple days dosing, A, we obviously degrade NEK7 to a point where we think it becomes meaningful. But we then also inhibit the pathway, and we measure this through ex vivo stimulation and looking at induction of IL-1 beta or actually inhibition of that. There's other things we're currently doing. We finally developed a pericarditis model, and hopefully, we can soon put some mouse data out on that as well. Somewhat related, unrelated, we had actually done a gout model in rabbits, and that looked excellent too. So there's lots of opportunities.
It's an interesting program in a sense that, I'll say, for 2359, GSPT1 and 6160 VAV1, we've invented molecules, and then we needed to sort of establish where they can best be used. Obviously, the NLRP3 inflammasome, there's other companies with other modalities doing some work for us. Roche has a trial going in asthma, which we're hearing they seem to be excited about. Novartis has multiple programs in the pathway. IL-6 is obviously downstream of the pathway and through what Novo Nordisk was doing. And then Novartis's acquisition of Tourmaline Bio. There's some good information there as well. So we're not going to be short in regards to potential indications. But it's fair to say that cardiovascular, in particular, ASCVD is becoming more and more a focus of the company.
Very interesting. Now, you guys are also doing a preclinical CNS penetrant NEK7. Does that still make sense to go after diseases where the inflammasome is present in the CNS?
Yeah. I mean, there's certainly very strong data out there on the inflammasome, NLRP3 inflammasome in neurodegenerative diseases, Parkinson's disease, and Alzheimer's. One of the reasons why many companies in this space have started to look into CNS penetrant molecules was the idea that you can treat obesity with pathway agents, and that would require CNS penetration. We shall see if that actually holds up. I don't think the data is absolutely solid that CNS penetration is required for that. But in my eyes, no matter what, this pathway has so much potential that having a second molecule, regardless of whether you then use it for CNS or peripheral, always makes sense.
Yeah. That makes a lot of sense and very exciting. When do you think that one might go into the clinic?
I think the current guidance here is IND by the end of next year.
Great. Excellent. Again, just really impressed by the expansion of the pipeline over the last two years now. Now, you're also planning on filing INDs for molecular glue degraders against CDK2 and also cyclin E1, and these are oncology targets. Maybe just sort of share with us these targets and your interest level.
Yeah. So we're back in oncology now. Obviously, two highly validated targets in that space. It's actually a complex of CDK2, cyclin E1, and we're somewhat fortunate that we have molecular glue degraders for each side of that complex. Interestingly, when we tackle cyclin E1, we also co-degrade CDK2. It doesn't work the same way the other way around. Part of that is just the geometry of the ternary complexes that we're generating through each of these molecules. cyclin E1 is certainly super exciting from an indication landscape point of view. There's amplifications in multiple tumor types, including ovarian cancer. We do think that in that context, where cyclin E1 is highly amplified, going after cyclin E1 directly has an advantage over, let's say, inhibiting CDK2 as an example, simply because there are CDK2-independent functions of cyclin E1 as well.
We also think you can do this much more selectively than going after CDK2 with inhibitors. That said, our molecular glue degrader for CDK2 is also extremely selective, and we do think this molecule could have an interesting path in metastatic ER-positive breast cancer and certainly offer some safety advantages there, again, over CDK2 inhibitors. And so these are basically at development candidate stage and on track for potential IND filings next year as well.
Yeah. Very exciting. And again, just really demonstrating the breadth of targets. So I usually ask this question of Sharon and John, but since you're here today, you get to go into this. And I know you know this material extremely well too. One of the things that I've found very interesting about Monte Rosa, especially as we've dug deeper into the pipeline, is really just how you guys are using AI to design these molecular glue degraders. So how are your capabilities different from competitors? How are you really using that QuEEN platform to design these very elegant, very complex molecules?
Yeah. I mean, it's hard to tell how it compares to competitors because my competitors aren't showing me what they're doing. I started just saying, when we started six years ago, we didn't think we were going to be able to make absolutely selective degraders of proteins over and over again. If you look at our portfolio now, VAV1, NEK7, cyclin E1, CDK2, you name them, for every one of these, we have a monoselective degrader. Sure, in part, that was enabled by the AI platform. We realized very early on that for these interactions between a ligase and molecular glue and a new substrate, it's not necessarily important to have a particular design.
It was more sort of the surface interaction and developing AI to sort of scan surfaces, find matching surfaces, but also predict how surfaces change on binding of a molecular glue degrader and in a ternary complex, like having that in-house, and then the underlying experimental data that continuously improves our models just turned out to be absolutely key to get us to the level of productivity where we are now, and again, I believe our partnerships with Novartis are a great endorsement. They obviously had and still have their own internal efforts and believe they're still impressed enough by what we're doing to do those collaborations as well.
And what I love about it, and I apologize if I'm repeating myself, but we're really at this point now where this platform is just going parabolic in terms of output. And you're seeing it in terms of the compounds that are being taken into the clinic, the quality of the compounds, the quality of the partnerships. And that's really where the rubber hits the road in our business is producing new drugs. So it's exciting to see really how all this work over the last several years we've known each other is really now at this point of just incredible productivity. So hats off to you and the whole team for that because I've had a front row. I've been cheering from the stands, but it's really cool to see this happening right now. So last question for you. You guys have a very healthy cash position, $390 million.
I think you could get a couple hundred million more from partners over the next two years, specifically now, Novartis in particular. But what does this type of balance sheet enable Monte Rosa to accomplish? How long does that cash last? Where does it get you?
Yeah. And current cash guidance is through 2028, which means multiple additional value inflection points. It'll certainly enable us to go fairly aggressive with 8102 and its development. One of the great features of our Novartis deal around VAV1 is we don't have to pay for Phase 2 development. Also, we have a 30% P&L share for the U.S. So that's almost like additional milestone payments or revenues coming in. For those Phase 2, actually, we will get Phase 2 initiation milestones as well. And so I'd say from a cash runway position point of view, sure, you can argue there's never enough, but I think we're very well positioned to not just drive those now clinical assets through further inflection points, but to your point, really leverage that platform and create more innovation.
So we've got another two minutes. So I'll just pause to see if there's any questions from the audience. This is the one that I typically ask, but I think it's well-suited. Where do you see protein degradation, molecular glue in particular, but protein degradation, targeted protein degradation, and really Monte Rosa going over the next 10 years? How big of an opportunity is TPD for the company and really for the industry?
Yeah. I mean, I think for me, it's INI plus. Even internally, I many times compare us with the INI field, Alnylam, to mention one company specifically. Targeted protein degradation, despite [audio distortion] and the IMiDs, is still a relatively new field, and I think we're still learning where the technology is best applied. I do think that INI cardiovascular are good areas to go into. We know that ligase expression there, it doesn't even matter whether it's cereblon, which many companies use, or other ligases. Ligase expression seems to be fairly homogeneous as compared to tumors, for example, where different tumor types might have different levels of expression. And so I do think this could be a sweet spot for as long as we're going to be able to make super selective and safe molecules. But it does sound like that's working out really well in particular for us.
Yeah. And what about in neuro?
Definitely a good area. These molecules are small. Actually, our VAV1 degrader, molecular glue degrader, does go into the brain, does cross the blood-brain barrier. In fact, our earliest efficacy model was a mouse EAE model, right, to mimic multiple sclerosis. And so I definitely think it's possible. Our collaboration with Roche actually has neuroscience included. And so very excited about them. For us internally, of course, sure, let's do one disease area at a time. I've done oncology, INI, cardiovascular, kind of next, and then we can do neuroscience in a couple of years.
All right. Well, we'll hold you to that. Keep up the great work.
Thanks, Ted.
Really appreciate you being with us, Mike.
Thanks again. Thanks.
Super.
Thanks, everyone.