Good morning to this presentation, this fireside chat with Monte Rosa Therapeutics. My name is Michael Schmidt, senior biotech analyst with Guggenheim, and it is my great pleasure to welcome Markus Warmuth, the CEO of Monte Rosa. Markus, welcome. Thanks for joining us.
Yeah, sounds good. Yeah, thanks, Michael, for inviting us.
Monte Rosa has now three NEK7 phase II studies starting soon, and a partnered VAV1 program with Novartis as well, and a few oncology programs coming behind. For investors that are new to this story, how would you summarize where the company stands today on what defines the story of the next 12 -1 8 months?
Yeah, I mean, first of all, obviously, we feel really good about where we are. Still a young company, about seven years in now. Looking back seven years, I think there were quite many doubters around molecular glue degraders and whether you can take them into non-oncology diseases. Back then, what existed was Celgene's or BMS's lenalidomide and pomalidomide. I think where we are today with now actually two phase IIs for our MRT-6160 program partnered with Novartis, more coming on NEK7, MRT-8102, and then, of course, our portfolio in oncology, we are really optimistic for the next 12 -1 8 months. Obviously, some interesting readouts coming, in particular for our NEK7 program, MRT-8102 in gout. And then, as you pointed to, more studies starting over the next months as well.
This year was a very busy year for the NEK7 program. You had data for the GFORCE-1 study presented earlier this year. What did we learn about MRT-8102 based on GFORCE-1 study, and what gives you confidence in the NEK7 approach in general?
Yeah. I mean, GFORCE-1 was essentially, it was kind of performed in the background of cardiovascular disease or risk of developing it. But it is, of course, a short-term four-week PK/PD biomarker study. For those who aren't super familiar, NEK7 actually is a part of the NLRP3 inflammasome, right? So, we're testing how losing NEK7 breaks down that inflammasome and manages inflammation. We paid a lot of attention to the upstream components of that pathway, like what's close to the actual cells that have that inflammasome activated in themselves, essentially tissue macrophages. I would say the outcome of that trial is super encouraging. First of all, the drug's super safe, really nothing to be concerned about from an AE point of view.
But literally every single biomarker we looked at, and we looked at a lot of DAMPs, we looked at IL-1β , we looked at the further downstream ones like IL-6 and CRP, everything went down pretty much to normal physiological levels, which is essentially what we wanted to see after four weeks.
Okay. I'll come right back to that. But first, we obviously saw the Novo's ZEUS phase III trial readout earlier this year as well. It did not reduce cardiovascular events to the extent that was hoped for. How do you interpret their results, and why should inhibiting this pathway more upstream help?
How much time do I have? I mean, it's not easy, right? I'll try to summarize it quickly. I mean, we look at Novo's failure in the ZEUS trial as a combination of wrong target and suboptimal trial design in regards to the population that was chosen. I'll start with the latter. Obviously, that trial was heavily focused on patients with CKD. CKD on its own actually creates a lot of inflammation. At the end of the day, while these patients showed systemic inflammation as measured by IL-6 levels and CRP, it wasn't really clear where it's coming from and whether all of them or just a minor proportion of patients had ongoing inflamed atherosclerosis, because that's really obviously what you need to have to see the difference in cardiovascular outcome.
I think it didn't then help that Novo defined ASCVD a little bit more loosely than what you would typically do, right? They included stroke, they included peripheral artery disease. Now that we know the data, I think in particular PAD, and it wasn't the biggest subset of patients, but especially PAD looked very messy. All that said, we do still believe that IL-6 is just too far downstream in the pathway, right? It's a single point of interference, probably not so different from what we have now also seen with Lp(a), right? If you go after these single points of interference further downstream in sort of hyperlipidemia, inflammation of atherosclerotic plaques, your outcome will not be very convincing, and that's really why we like NEK7 as a target.
Is hs-CRP still a good surrogate marker in this space, or do you think other biomarkers are more important to pursue?
Yeah, I think so. Yes, other markers will be important. That said, it's still a great marker to look at systemic inflammation. It's great because, I mean, you can measure. It's an easy lab value to obtain. But we have to understand that while hs-CRP signals inflammation going down, if you interfere with inflammation at the wrong node, hs-CRP going down will not be meaningful, right? So it's a great biomarker. It's not causal. It's not a causal biomarker of ASCVD, and so you really have to understand the disease in order to interfere, but you can certainly still use it to guide your clinical trial.
What are the markers that you look for with the NEK7 program that should increase your confidence that it actually is doing what it's supposed to be doing?
Yeah, we've talked a lot in recent weeks ever since the ZEUS data came out on how we think about ASCVD, and how we fuse some of this additional information now to design our GFORCE-2 study. I've alluded to DAMPs, markers like calprotectin, HMGB1, obviously a lot harder to measure, not necessarily a standard lab value that you can easily get, but those are certainly more indicative of upstream inhibition of inflammation than hs-CRP. At the very least, you want to build that correlation in a study like GFORCE-2. I think what's becoming really evident in the last few months, if not a couple of years, is the power of imaging in ASCVD.
GFORCE-2 is now all designed to correlate inflammation based on imaging, FAI or FAI scores, with the inhibition of the pathway, again, using markers as far upstream as possible. Then possibly also human genetics, which again, I'm sure with the IL-6 receptor protective allele, that's not panning out. There's a lot of talk even on how much can human genetics guide our trials. Again, I think this really depends on understanding of what the genetics are and what the variants actually do short term versus long term, and whether they make for a good node of interference or not.
Maybe just to summarize then, what are you trying to achieve in the GFORCE-1 study, and what are some of the key outcomes you're assessing there?
Yeah, I think the ideal outcome here would be we identify a population that has elevated FAI scores as we start treatment. These elevated scores indicating local inflammation of an atherosclerotic plaque correlate with the biomarkers that I've pointed out, DAMPs, but also IL-1β, which we can now measure in plasma. And of course, hs-CRP downstream is sort of the easiest one to measure in a broader population. And of course, after six months, we want to see that FAI scores go down in plaques with treatment, and again, that correlating to the biomarkers I referred to.
Is it known what degree of reduction may correlate with positive outcomes?
Yeah, I mean, I think sure, that's still a little bit of an issue, right? Because there is some interesting FAI phase II studies, and clearly, there's an example of an antibody against oxidized LDL clearly reduces FAI scores, but we don't necessarily have the correlation to phase III yet. So, I would say that's still the gap that we have, that obviously, over the next few years, we see closing as more and more companies are starting to use FAI as at least a phase II sort of primary readout to predict whether you have an impact on local inflammation.
Okay. If GFORCE-1 is positive, would you undertake an outcome study on your own after that?
GFORCE-2, yes. It depends a little bit on the setting we are in and how scary the trial would be from a magnitude. We actually do think that with narrowing the patient population to patients with high-risk but modifiable disease, it doesn't have to be a 6,000-patient trial. We think it could be much smaller and also shorter. But really to be determined after phase II. Obviously, if we think it's something we can do ourselves, we will. If we feel this is something that has to be done with a partner, or in combination with something else, we'll certainly at least consider that.
Okay. Gout is another opportunity for this target that you're pursuing in the GEMINI-1 study. How well validated is gout as a condition to be treated with a NEK7 inhibitor, and how strong is that validation so far?
Yeah, I would say, I mean, of all the indications we're going after, it's probably the one with the most solid validation. I start with colchicine as a small molecule that hits the NLRP3 inflammasome. It's a different mechanism from NEK7, obviously. It's not a NEK7 degrader, but it does seem to disrupt the NLRP3 inflammasome. That obviously is standard of care with all its caveat, right? Not a pleasant AE profile with lots of GI side effects. Then there's actually multiple IL-1β antibodies, and so like one step further downstream. We obviously prefer to be upstream of IL-1β. I would say between the older data around canakinumab and now a couple of IL-1β follow-up molecules and studies in China, I would say the data there for flare prevention with blocking that pathway is extremely solid.
Talk a bit about the design of the GEMINI-1 study and what you're trying to show.
Yeah, it's a fairly simple design, small study. I believe it's about 60 patients, two dose levels. Not placebo control for a simple reason. This is a study where we start with acute flare, so you start treatment with your first acute flare. The important readout though is flare prevention after that acute flare has been managed. There's enough historical data on how often these patients flare to be able to compare our outcome to that historic datum. So, a very efficient, quick trial design that will then set us up very nicely for phase III development.
What other any biomarkers that are important in this context in addition to the flare prevention, obviously?
Yeah, we'll be looking at much the same biomarkers as we did in GFORCE-1. As a matter of fact, when you look between say ASCVD, gout, and HS, the biomarker profile is extremely similar, right? Like massive elevation of DAMPs, elevation of IL-1β, and then of course everything that's downstream. As a matter of fact, there's lots of crosstalk between those diseases as well, right? Like patients with gout obviously have an increased risk for cardiac or cardiovascular events when they're prone to ASCVD. So we'll be looking much at the same biomarker profile because sure, that will continue to solidify our thinking about all the indications in the cardiometabolic space we're going after.
Okay. Just how would you frame the opportunity in gout, and how would a product like the MRT-8102 molecule be positioned relative to the IL-1β antibodies?
Yeah, it's the convenience of an oral drug, of course, versus the antibodies. Obviously, the ones I was referring to are currently being developed in China, so we'll see whether they will come to the United States. That said, a safe small molecule with no infection risk that can be taken on a daily basis with all the additional cardiovascular benefits that you might be deriving from it will certainly be superior. We really like the opportunity right now. Obviously, with this next wave of urate-lowering drugs, there's a lot of attention now being paid again to gout. These drugs won't take any markets away from us. As a matter of fact, they're kind of generating a market because any urate-lowering typically leads to more flares before it leads to fewer flares.
We really think about MRT-8102 as a next-generation anti-inflammatory drug that can be used to prevent flares across all lines of therapy in gout.
Okay. HS is another opportunity you're pursuing in a planned phase II study. I guess, what have we learned on IL-1 biology via the recent AbbVie data readout, and to what degree does that validate the opportunity in your view?
Yeah, I would say, sure, lutikizumab provided clear validation of the pathway. Obviously, there was a bit disappointment around the delta between treatment and placebo. I think here was a combination of treatment slightly underperforming vis-à-vis phase II, not untypical for HS as you go into a more global trial across multiple regions. Placebo overperformed. Again, that's something we have started to see again and again in HS, so it's something we're closely monitoring. As you know, Novartis will soon actually report their remibrutinib data in HS, so it'll be interesting to see if there's similar trends or whether they have found ways to better mitigate that overperforming placebo arm. But again, all in all, we continue to look at HS as a validated indication, great opportunity. There isn't really anything, small molecule that limits inflammation.
In a disease that is dominated by biologics at this point, we do think that there is great opportunities with the pending remibrutinib data, of course, to establish small molecules either as a single agent or later in combination with others.
Maybe talk about the GALAXY-1 study and what you are trying to show.
Yeah, it is a very typical HS trial design, obviously looking at improvement of lesions, HiSCR75 scores in that disease. Again, with all the caveats we talked about, like typically seeing some dilution of that efficacy signal from phase II into phase III, and again, something hopefully we can learn more about from the incoming phase III trials and how to better mitigate overperforming placebo arms.
Okay. So, that is starting early next year, I believe?
First half of next year, yeah.
First half, yeah. Okay, great. I just wanted to switch over to the VAV1 program.
Yep
It is partnered with Novartis. They have already started two large phase II studies. Maybe first, how should investors think about the overall opportunity for VAV1?
Yeah, we believe it is a huge, if not monumental opportunity, and we have done lots of work before we partnered the program around what diseases, what indications can be impacted. In our deck, we had at some point, I think it is still there, data on multiple sclerosis. We had data on rheumatoid arthritis. We had data on IBD. We had data on Sjögren's disease. You can really think of this as a well-tolerated, not immune suppressive therapy across many indications that are either driven by T cells or a combination of T and B cells with a bias towards Th17. That is kind of how we see it, and we are obviously very happy with how that development program is now going with two trials launched, but obviously, several more trials coming relatively near term.
And any sense of how Novartis is prioritizing some of these opportunities? Then maybe talk also about the economics for Monte Rosa and how much value could be created for the company.
Yeah, I mean, I'm not here to speak for my friends in Novartis. My gut sense is, it has very high priority. Obviously, I&I is a key pillar in Novartis' growth plans, as you can tell from what they're doing with remibrutinib. I think with Cosentyx getting closer to loss of exclusivity, it would make a ton of sense to keep investing into MRT-6160, and that's what we're seeing for us. The economics there are working out really nicely. We've obviously collected two milestones, total of $87.5 million, so these phase II initiation milestones are really quite sizable. Keep in mind that we've maintained a 30% P&L split in the U.S. We're not paying a single dime for phase II development. We'll obviously have to pay some as we get into phase III. So, really great partnership for us. It's been a really great interaction.
As you know, we have an office in Basel in Switzerland, literally right across from Novartis' campus. So, even just to sort of touch base on a very regular basis, super easy for us.
Okay, super. Then, I guess, how does the oncology pipeline fit into the overall Monte Rosa strategy?
It still fits very well. We've hesitated to let go of oncology as a disease area. I do admit and acknowledge that on occasion that it complicates a bit our story sometimes when you look from the outside. That said, we really like the data so far for MRT-2359 in prostate cancer, right, where we've seen literally 100% PSA response rate. It's a small sample size, so I don't expect it to stay at 100, but it's quite remarkable. We have a duo of a CDK2 degrader and a cyclin E1 degrader coming. These are both molecular glue degraders, of course. We really like CDK2, especially at a time where many pharma companies have started to discontinue their CDK2 inhibitor programs, not for lack of efficacy, but more for toxicity.
We think that this approach, MGDs, is the way to finally make these approaches extremely selective, and because of that, safe. We have some early exploratory tox data that suggests that we're essentially getting in preclinical species windows that are quite similar to what we have seen in our I&I program. Very excited about that, and the same will actually be true for cyclin E1.
Maybe a few comments on MRT-2359, your GSPT1 program. Where are you right now in this phase II work that you're doing in prostate cancer, and then what comes next?
Yeah, phase II has been initiated. First patient has been dosed. Obviously, continuing to ramp up the trial. This is a combination of MRT-2359 with apalutamide. It's a small trial. We really just wanted to confirm that initial signal we had in the phase I expansion arm. I think from there's many opportunities. We really do like, actually, believe it or not, Halda or Genentech's datum with the RIPTAC because it's essentially the same hypothesis, right? BRD4 AR is targeting the androgen and MYC pathway at the same time. We're doing the same also with two separate molecules. I think we get a lot of guidance from how their data is panning out on where to go next. We have interesting data pre-clinically in combination with eplontersen. Seeing huge synergy in preclinical mouse models.
I would say once we have that MRT-2359 signal confirmed, there is lots of opportunity to expand into different combinations and into earlier lines as well.
What is the next data readout for the MRT-2359 program?
It will be at least an initial read on that MODeFIRe-1 phase II trial. As I said, it is set up as a 25-patient small trial. There is an interim readout after 10 patients, so stage 1, stage 2 design. Obviously, open label, so as data comes up and gets more robust, we will basically report that out.
I guess, what is a good outcome for the study?
I would say, PSA response, and again, I'm always trying to be cautious because it depends so much on the patient population you're recruiting, but somewhere between 50% and 100% would be a good outcome. Obviously, in that phase I expansion arm, we had, I think it was 60% patients with prior Pluvicto treatment. They all actually had measurable disease, so per se, a patient population with not such a great prognosis, and obviously, that always plays into sort of how you interpret PSA responses, and then of course, the CDK4/6 resist.
Okay, great. Well, thank you, Markus. Unfortunately, we have to wrap up here, but appreciate your time this morning.
Sounds great, yeah.
Very insightful. Thank you.
Great. Super. Thanks.