Monte Rosa Therapeutics 3rd Annual Guggenheim Healthcare Innovation Conference

Yeah, sounds good. Yeah, thanks, Michael, for inviting us.

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 to 18 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.

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-1 beta, 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.

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.

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.

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.