Hi, everyone. Good afternoon. I'm Ellie Merle, one of the biotech analysts at Barclays. Very happy to have Monte Rosa here with us today at the Barclays 28th Annual Global Healthcare Conference here in Miami. Joining us from Monte Rosa is Filip Janku, the Chief Medical Officer. Filip, thank you so much for joining us today.
Thanks for having me.
You guys have a very exciting platform technology, one that I think deserves a lot more attention with molecular glues. Maybe before we jump into the specific programs, can you provide an overview of your platform technology and why this has potential to, say, reach previously undruggable targets and, you know, the advantages of, say, you know, molecular glues and compare that to heterobifunctional degraders?
I might start with that distinction because I think it's the important one. I mean, the molecular glue degraders is a modality which truly taps into drugging undruggable, right? Because, like, essentially, you don't really need any binding site. The molecular glue gets attached to the E3 ligase, to the cereblon, helps to reshape its surface. Then it actually allows for the protein-to-protein interaction with the disease-causing protein target which you would like to eliminate. And if you kind of compare it to heterobifunctional, which I think is a, like a quite smart modality as well, but the heterobifunctionals are essentially the compounds which have multiple components. They have a component which binds to the target. So in some way, you can actually see it as a small molecule, as a small molecule inhibitor.
It actually has a linker which links it to another part, which then engages the E3 ligase to the warhead, which engages the E3 ligase. It's kind of more about redrugging druggable rather than drugging undruggable. That's what we do.
Great. You have a handful of programs in development. Maybe can you start with an overview of some of the key highlights of your progress over 2025 and into the first quarter so far of the year?
Our pipeline is essentially kind of underlining what I just said, the focus on novel targets which are either undruggable or difficult to drug. I mean, which is kind of spread between I&I, which is kind of most of our portfolio. There's a little bit less in oncology. If I kind of go through our pipeline, our MRT-6160, which is VAV1 degrader, which has been licensed to Novartis, although we still have 30% of P&L shares in the United States. The next milestone is actually the initiation of the multiple phase II programs in the I&I indications. We have, and again, MRT-6160 is a VAV1 degrader.
It's the first and the only first-in-class degrader in that stage of clinical testing. We have a NEK7 degrader, MRT-8102. NEK7 is a protein which is an important and necessary part of NLRP3 inflammasome. If you actually deplete the cell of NEK7, you also eliminate or prevent the assembly of NLRP3 inflammasome. That program has been in the clinic as well since last year. We had a disclosure of some early phase pretty exciting data, including the proof of concept data, looking at the CRP modulation in the subjects with the high cardiovascular risk. That study has been expanded, focusing on that population, and we'll have an update in the second half of this year, which will include the data from that study.
The study is called GFORCE-1, which essentially is testing multiple dose levels and placebo in subjects in high cardiovascular risk defined by obesity and elevated CRP. We are also expecting actually rolling out the phase II study with MRT-8102 NEK7 degrader, which will be called GFORCE-2, and that essentially will be the next step to bring this asset to the phase III readiness after completion of the GFORCE-2.
Mm-hmm. That's exciting. Maybe talking about, you know, just the mechanism starting there. I mean, you mentioned hitting on kind of the NLRP3 with NEK7. Can you go into more detail specifically how NEK7 is able to access this pathway and then sort of what the NLRP3 and the IL-1 beta pathways mean in terms of inflammatory conditions?
NLRP3 inflammasome is actually the one of the ways how the pathologic inflammation can be initiated, and that's why it's actually a very attractive target for inflammatory diseases which are driven by the NLRP3 IL-1β signaling. I already mentioned that NEK7, it's a kinase, but actually its function in the NLRP3 inflammasome is allosteric. Degrading NEK7 prevents NLRP3 inflammasome from being assembled. That this is actually something which gives you long-lasting pharmacodynamic effect. It takes actually some time for NEK7 to come back. You really have a sustained effect from the pharmacodynamic and the clinical standpoint. That's actually also somewhat differentiating point from the NLRP3 inflammasomes.
I mean, if you actually look at our data, which we disclosed just a couple months ago, we have seen very profound effects on the CRP levels, which were essentially comparable to IL-6 antibodies. I think our CRP suppression at week four was 85%. It was actually achieved with the doses which were kind of in the medium spectrum of what we tested in the SAD/MAD. I mean, the doses which we tested in SAD were up to 400 mg. In MAD, we tested the doses up to 200 mg with no any significant adverse events observed, no dose dependency, no infection risk. The dose which we tested in the proof of concept study looking at the CRP was 40 mg.
It's relatively on the lower dose. If you put it into perspective with the NLRP3 inhibitors, you can actually see consistently that, if you look at the data which are out there, specifically looking at the CRP, that these NLRP3 inhibitors are typically dosed close to its maximum dose, at least for MAD.
Mm-hmm. Interesting. Yeah, can you maybe tell us a little bit more about the phase I study? You know, what was studied and just, you know, some other highlights from the data, especially as we head into additional data later this year.
in the phase I, we obviously did SAD/MAD. I mean, the important objective is safety, which I just commented on. I mean, there was not really any notable finding there. I mean, what we put out was still the blinded data, but even the blinded data actually looked fairly benign. the update on the unblinded data will be put out in the near future. We've obviously looked at the CRP, and both in SAD/MAD, we've seen quite interesting reductions in CRP as well in the SAD/MAD, even after the single dose. It's obviously a little bit harder because not everyone from healthy volunteers has elevated CRP.
Definitely the data got validated, and in the subsequent proof of concept CRP study, which we also put out the data from that 40 mg cohort a couple of months ago. A couple highlights from that. I mean, we've seen rapid reduction in CRP, up to 80%, on average after week one, which actually even deepened over time to 85%, by week four. I think this is an important distinction because also if you look at some other CRP studies, whether it's NLRP3 inhibitors or therapies targeting cytokines, you often actually see the rapid reduction in the CRP after one week. After week two, three, four, you can actually see almost a little bit of rebound. We didn't seem to have that. We actually seem to have, if anything, sustained to even deepened CRP response.
That was actually one of the main motivations why we decided to expand this initially relatively simple proof of concept study testing 40 mg versus placebo into the GFORCE-1, which essentially means adding two additional dose levels and the corresponding placebo. Because we actually felt a lot of the work which otherwise would fall into classical phase II, we can do in the phase I, in quite favorable timeline that we can at least have the full understanding of the relationship between the CRP effects and the dose.
Mm-hmm.
That will actually help us to be more nimble and faster in the phase II, which will be the GFORCE-2 study, which will be essentially the CRP study as well, but with longer administration.
Interesting. Can you elaborate on the design of the GFORCE-1 study and specifically what data we can look to seeing later this year?
Yeah. As I pointed out, I mean, it's a study which randomizes subjects with high cardiovascular risk. The high cardiovascular risk is defined by obesity and elevated CRP. These two components have to be met. These are technically people who are not acutely ill. I kind of don't want to call them healthy volunteers because they are arguably not healthy, but they are not subjects who are acutely ill. That's why I call them subjects or participants. They are treated for 20 days with either one of the three doses of MRT-8102 or placebo. I already mentioned that we put out data for 40 mg. We have
We are testing additional dose levels, and we are actually looking at the lower doses because one thing which I didn't mention from the SAD/MAD study, we've actually seen the NEK7 degradation, which was fairly comparable across all dose levels, ranging from like 5 mg to 200 mg or 400 mg respectively. That really suggests. That's not unusual for glues. I mean, we see it with our glues overall, that your pharmacodynamic index is actually, like, really broad. That's actually because of the mechanism of actions, how glues work. They have this catalytic mechanism of action. One molecule of drug can degrade thousands of molecule of your target protein.
You can actually get to the similar pharmacodynamic effect with the broad spectrum of doses. While the safety looks actually pretty spectacular, I mean, one of the advantages of if you can also actually test lower doses in the future programs would be that it would actually be definitely easier for the development if you have to manufacture a drug.
Mm-hmm. Interesting. Can you talk about the GFORCE-2 study in ASCVD? I mean, I guess first talk about the rationale for NEK7 here and why this is your first indication.
Yeah. Obviously, the CRP is a very strong surrogate for the cardiovascular outcomes. This is not necessarily new statement. This has been around for quite some time, but it's fair to say that the evidence over time has been strengthening and actually that's been also supported by what's happening in the medical scientific community, including the statement on CRP, which was issued by the American College of Cardiology and published in the fall of last year, which essentially shows that the CRP as a determinant of the cardiovascular risk and cardiovascular outcomes is really strong and probably scoring one of the highest, if not the highest, among the other factors determining the cardiovascular risk. The phase II GFORCE-2 is a CRP study, CRP study as well.
I've said already that some of the work in terms of the understanding dose relationship and the CRP dose, CRP reduction relationship will be already hopefully understood from the GFORCE-1, but the GFORCE-2 is also about actually getting the experience with the longer administration, including accumulating longer safety data before you commit actually to fairly sizable phase III efforts. The one thing which is really good about NEK7 or in general about targeting NEK7 NLRP3 IL-1 pathway is that it's actually the only pathway in the inflammation space which has been already clinically prospectively validated. I mean, people often forget about the CANTOS study, which is relatively old and is sometimes seen as a failed effort.
Actually, in fact, CANTOS, which tested IL-1 beta antibody canakinumab in 10,000 patients to prevent major adverse cardiovascular events, was actually a positive study on efficacy. It met its primary endpoint, and the reason why it doesn't have a label was because the safety wasn't there. That canakinumab reduced CRP only by 59% at the dose, which was clinically relevant and which was meant to be approvable, hence under 50 mg. We obviously have a higher CRP reduction, and we also believe that we wouldn't have some of these safety liabilities which, let's say canakinumab had. One explanation behind it is also the biology.
I mean, essentially, if you block the cytokine, whether it's IL-1, IL-1β or IL-6s, you essentially wipe out the cytokine regardless what the source of that cytokine is, because not everything is necessarily coming through the NLRP3. There might be reasons why you actually induce some inflammatory response because of, let's say, the defense against the bacterial infection. If you actually degrade NEK7, you are specifically shutting down just that NLRP3 signaling, and you are not actually impacting any part of inflammation which might be important for, let's say, anti-infection defense.
Another potential differentiation is that if you hit cytokines, whether it's IL-1 or IL-6, you essentially you wipe out effector cytokine, but you might have no effect on some other inflammatory, pro-inflammatory event such as pyroptosis, which dumps a lot of pro-inflammatory substances out. That's actually one thing which again is differentiating. If you actually target NEK7, you also shut down the pyroptosis, which is actually principal event resulting in pro-inflammatory consequences.
That's really interesting. How should we think about the timelines for when we could see data from GFORCE-2?
We haven't guided for the GFORCE-2, but the GFORCE-1, the guidance is out there. We are hoping to put that out in the second half of this year, and that will include not only efficacy, corresponding cytokines and unblinded safety. The GFORCE-2 will start in the second half of this year. These studies historically, because this will not be the first phase II CRP effort, have been reasonably fast when it comes to enrollment and also the time to the endpoint. While the guidance is not out there, it's probably not that difficult to look at the corresponding CRP studies and see how long did they take.
I also believe that comparing us to some other efforts from our peers, whether it was with IL-6s or similar, I believe that we can be more nimble because a lot of that efficacy dose relationship we already understand from the GFORCE-1.
Interesting. It's exciting. Looking forward to seeing this data. How should we think about other indications where this could be successful?
Mm-hmm.
Where you think there's maybe, like, evidence of biological involvement?
Obviously ASCVD is a lot of population. I mean, the addressable population would be 10+ million in the U.S. I mean, obviously ASCVD is even far more prevalent than that, but it's not only it, right? I mean, the NLRP3 is involved in multiple events. I think we as a company are thinking about several potential indications, which includes the diseases which are very prevalent to diseases which are less prevalent from diseases which are quite prevalent. We have been quite intrigued by chronic gout or essentially looking at the prevention of the gout flares. We think that there is definitely a large opportunity to innovate, which hasn't really been addressed by the efforts which are currently ongoing.
There seems to be quite a momentum lately on the urate-lowering therapies and they definitely advance the care of these patients. The downside, which people don't often realize, that urate-lowering therapies, including KRYSTEXXA at least from the near or intermediate time perspective, they actually don't do really much to flares and even arguably might be associated with some increase in flares. If you look at actually when you initiate, and these are data from the randomized data from KRYSTEXXA, I mean, if you look at the pegloticase, KRYSTEXXA initiation, I mean, the one month after initiation, about half of the patient, more than half patients have flares. That's so the flare prevention, we see that there is a large potential of addressable populations.
There are other indications which appear to be heavily NLRP3 dependent. We haven't necessarily communicated any detailed plan, but like HS, this is definitely something which we are looking at as an exciting opportunity. There are some kind of like more niche indications such as, let's say, pericarditis, in which the targeting IL-1 axis have been shown to be very effective and very successful. There is definitely need for oral therapies, which at the moment are not available or at least not the modern therapies. That's something which is an opportunity as well. There are many others. Obviously, we have to be kind of thoughtful about what we decide to move forward.
We actually anticipate to update our guidance, what else is included with a little bit more detail in the future, in addition to CVD, in which we have already plans to phase II out.
Mm-hmm. Great. Well, exciting program. You recently had some data from your GSPT1 in metastatic castration-resistant prostate cancer and with AR mutations. What were some of your takeaways from that data?
Well, that's a program which we are actually very excited about. We just presented the update at ASCO GU on 26th of February. These were data from our expansion of our early phase, our first-in-human trial, which tested combination of MRT-2359 and enzalutamide in castration-resistant prostate cancer. It was a heavily pretreated population. We required RECIST-measurable disease, which in prostate cancer kind of biases you towards a more difficult population. We had 27% of patients with prior liver metastasis, and they were heavily pretreated, more than half had PLUVICTO, more than 80% chemotherapy, more than nearly 80% prior enzalutamide or similar. What we actually seen that in patients with AR mutations, we've actually so far have been seeing 100% PSA response rate.
Obviously, you have to be cautious. I mean, we only had five such patients, but definitely data which seem to be very intriguing. Out of these, five out of five PSA responses, we have seen two PSA 90 responses. One of the remaining PSA 50s actually pretty deep as well, and that's a patient who is still on. That's a number which might change as the time goes by. We've seen two RECIST responses. From those who didn't have RECIST but PR, who had stable disease, they all had a tumor shrinkage, and two of them are still on therapy. Again, it's something which is actually still evolving. Definitely like a clear signal there.
I think we have done quite a lot of work on the molecular front, looking at the analysis of the tumor samples obtained as a part of the study before and on treatment, as well as ctDNA and CTC. I think we have pretty solid biological understanding why these patients are responding. It seems to have something to do with tumors which are strongly dependent on the strong AR signaling. We are actually very excited about taking it forward to the so-called signal confirming study, which will be the next step. In the Q3 of this year, we are planning to roll out the phase II study, which will focus strictly on AR mutant castration-resistant prostate cancer.
It will be done unlike our phase I in the prostate cancer-specific centers with the prostate PIs, prostate experts. Essentially in this study, which will enroll up to 25 patients, we are actually hoping to confirm the signal which we have seen in the early phase study, which will then dictate the next steps of development. What is kind of cool about is that this AR mutant space is relatively untouched. There are some therapies which showed activity in AR mutant patients such as AR degraders or the CYP11A1 inhibitors, although many of these are actually kind of like in the portfolio of development or all of them are in portfolio of large pharma, and they are not necessarily pursuing that mutation population by itself in the precision medicine fashion.
We kind of actually feel that it's a space which we can occupy. Also one thing which is in our favor, I think, is that the prevalence of androgen receptor mutation seems to be increasing as there are more therapies now available for prostate cancer because hormone therapies increase the frequency. The chemotherapy actually even increases the frequency. There might be more than that. As I said, I think we see the AR mutations as surrogate for the high AR signaling. Arguably, down the line, if we see the signal confirming, you can think about some other applications such as the earlier lines. We also have activity in which is not limited by the prior therapies, including PLUVICTO .
In fact, four out of five responders with AR mutations had actually prior PLUVICTO. That also kind of suggests that there might be some other potential indications or combinations to look at beyond AR mutations. This is our first step to confirm the signal.
Mm-hmm. Interesting. Yeah. Exciting data. Turning to VAV1, what's the latest in terms of that program that you're developing with Novartis?
Yeah, so as I just pointed out, the program was licensed by Novartis. We still own 30% of P&L. We are really delighted about this collaboration as a part of the development committee, and there have been a pretty thoughtful plan which, unfortunately hasn't been made public yet. Novartis doesn't seem to plan for necessarily any imminent disclosure. Part of it is also to protect the intellectual property. However, the guidance which we have currently, which we currently maintain is that there are expected multiple phase II trials to be initiated in the autoimmunity, in multiple autoimmunity indications this year.
Mm-hmm. Great. Oh, I see we're over, but quickly, just what the major catalysts are you see coming from Monte Rosa over the next 1-2 years?
Yeah. I'll start with the GFORCE-1 because GFORCE-1 will have a data update in H2. I think that's probably pretty major catalyst. Otherwise, for our additional programs, I mean, obviously, I just mentioned 6160, MRT-6160, multiple starting studies. That kind of covers the I&I. When it comes to oncology, MRT-2359, initiation of the signal confirming study in AR-mutated castration-resistant prostate cancer. We also have a guidance for our CDK2 Cyclin E1 program, the IND.
Mm-hmm. Great. Well, exciting time. Appreciate you making the time today. thank you everyone for joining us.
Thank you so much. Thanks for having me.
Thank you.