Okay, I think we'll get started here. Welcome to the second day afternoon of the Wells Fargo Healthcare Conference. Right now, we have the pleasure of hosting Monte Rosa Therapeutics, and with us, we have Filip Janku, Chief Medical Officer. Filip, thank you for joining us today.
Thank you for having me.
Yeah, so maybe we can just start off with an overview of the company for people who are not too familiar with the story.
Mm-hmm.
and just the state of the business.
Yeah, so we are like a clinical-stage company based here in Boston. Still a relatively young company, but we specialize in the development of the molecular glue degraders and, specifically actually at designing them in a rational, target-centric way. From early days of the company, we decided that molecular glue degraders is where we wanna be, that we were not gonna focus on any other degradation approaches, such as PROTAC, because we believe that molecular glue degraders actually have quite a lot of advantages, and despite some conventional wisdom and prejudice, they can be actually developed and designed in a very to produce the very selective molecule-
Okay
... which otherwise are small molecules with good drug-like properties, which can be actually made oral.
Fantastic. So then maybe we can just dive right into, like, your lead asset, MRT-2359, the GSPT1 degrader. Maybe before getting to the clinical data that you've recently reported on, you can give us background on the preclinical data that you've seen that supports its development in clinic.
Yeah, so MRT-2359, which is a GSPT1, oral GSPT1 degrader, that actually has interesting history. It's a program, which goes actually to early days of our company. And what we identified early in the drug discovery that some GSPT1 degraders have actually differential toxic effects on the MYC-high cells, compared to non-MYC-driven cells. And obviously, at that point, there was not really like any literature behind it, so we had to do a lot of work to understand and uncover that mechanism of action, which we did preclinically. So I mean, preclinically, we actually, through the extensive cell line screen and the subsequent also in vivo work, we actually confirmed this differential effect in MYC-driven tumors, specifically with the high L-MYC and N-MYC expression, compared to tumors not expressing MYC.
We then actually took that from in vitro and cell line screen to large PDX study, essentially reproducing the same data, showing quite impressive waterfall plots for the biomarker-positive tumors versus the biomarker negative, and these were actually foundations for the subsequent clinical study. There were a couple firsts about this program as well. I mean, it's the MRT-2359 was actually the first molecular glue degrader, which was primarily designed to target non-hematological solid tumors, which is actually a relatively significant fact. Obviously, the IMiDs have been around for quite some time, but the IMiDs once they got resurrected, actually over 20 years ago, they went primarily to hematological malignancies, initially to myeloma, and then potentially expanded to lymphoma.
But as far as the primary development, 2359 is really the first molecule which went primarily to solid non-hematological tumors.
Got it. Got it. And then, what sort of safety and tolerability profile have you seen preclinically that speaks to your dose optimization that?
Mm-hmm
... you're doing now clinically, looking at the nine-to-five schedule, 21 to seven-day schedule, and then also allowing you to adjust from .5 mg up to .7 mg, and just to kind of discuss some of those, you know, challenges.
So one of the things which I think translated from preclinical stage to the clinical stage, which I think is probably important to highlight, and that's something which I've just mentioned briefly a few minutes ago, that 2359 has the differential effect on the MYC-high cells versus non-MYC-driven cells. And obviously, non-tumor cells, normal tissues, they are non-MYC-driven cells, so that would apply to them as well. So what we have shown and shared in previous disclosures that preclinically, we do see faster and deeper degradation in MYC-high cells. And what that actually means that you actually achieve the preferential degradation in these cells, which actually has the potentially sparing cells which are non-MYC-driven. And this is actually the important distinction.
It's not something which is universal to all GSPT1 degraders. So not all GSPT1 degraders are created equal because the differential effect on MYC high versus MYC low is actually somewhat dependent on the speed and depth of degradation. So you actually have to tune your molecule to achieve certain levels of degradation. Then paradoxically, if your degradation is too fast and too deep, you don't get the differential, and you get kind of a cytotoxic effect. And that probably also explains why not all GSPT1 degraders actually can be explored in this manner. Also, this gradient also gives you potential for like a good therapeutic index. So, and I actually think that's what translated in the clinic.
When we went to the clinic, we've seen the full pharmacodynamic effect actually from the lowest dose level. And actually, for that matter, we've also actually seen clinical efficacy, while the safety was actually maintained at pretty excellent level, with mostly Grade 1 to a less extent, Grade 2, AEs, mostly gastrointestinal, as it can be seen in our disclosure from last year. So that's actually something which truly kind of materialized what we have anticipated based on the preclinical data. And because of that also, I mean, because, like, the saf ety was actually, like, a really excellent, I mean, it's there was and we had a data which preclinical toxicology data, which actually supported even up to more frequent dosing.
We actually decided to explore the 21 /7 dosing for three weeks on and one week off, which would be very similar to how all approved IMiDs are dosed. And the simple distinction from the five-nine schedule would be that simply you have the modulation of the GSPT1 for more prolonged period of time. So if the cycle is 20 days and the drug is given for 21 days, that in reality means that the GSPT1 is down-modulated for about three weeks and a half, because it takes several days for GSPT1 to come back once you stop dosing. While if you use the five-nine schedule, then you inherently have more pharmacodynamic play, more like a week on pharmacodynamic effect, followed by the week off, again, followed by the week on and followed by the week off.
Got it. Okay.
So that's kind of the important distinction. Otherwise, we were actually quite happy with the five-nine schedule, as I said, very well tolerated, showed already efficacy, but it need like, the conventional wisdom is that, more prolonged exposure is... Can be potentially of advantage.
Got it.
I think that was a good incentive to test that.
Wonderful. Then in terms of efficacy, so you're seeing efficacy at lower doses in 0.5 milligrams. So, what level of degradation are you getting then with GSPT1, and what level of degradation do you expect then to get with at the 7.75 milligrams? And, you know, how much additional efficacy, you know, would you hope to achieve-
Mm-hmm.
with that additional dose?
I'll go back to what I initially said, what I just said, that not all GSPT1 degraders are created equal, and the speed of degradation is actually the important factor, which are contributing for the differential effect on the tumor cells versus non-tumor cells. What appears to be a sweet spot for the level of degradation is somewhere between 60% and 70% with, based on the in vitro data. We have then tested the levels of degradation in our in vivo data, in our, like, PDX study, non-small cell, small cell, and neuroendocrine lung cancers. We actually found out that that was pretty much corresponding with the in vitro as well.
The degradation level was actually 60%, and that's what we have seen in the clinic as well, and that's actually what we shared with what we shared publicly in our prior disclosure. So when it comes to 21 /7, I don't necessarily anticipate, like, a different level of degradation because I think we are where we need to be from the lowest dose level of the five-nine. But what I would anticipate that that degradation would be maintained for the longer period of time, because simply there is more drug given continuously for during the study. It's not something which you can necessarily clinically measure, because obviously there's no way to do, like, a multiple serial biopsies.
You do biopsies at before dosing and on during the first cycle during the anticipated steady state. So I think I would anticipate that the degradation levels probably wouldn't differ that much, but the anticipation is that the degradation would be maintained for a prolonged period of time, just by the virtue that the drug is actually given continuously for the longer period of time.
Got it. Makes sense. Okay. Then, coming up on your recommended phase II announcement, phase II dosage announcement, you know, how distinguishing is this? How much of a catalyst is this? And... or should we expect to get more than just dosing, but also the dosing regimens, like 21/7 versus 5/9 ?
So the data disclosure, which we are guiding towards during this half of the year, so later on this year, should actually include the phase I study with corresponding safety, PK, PD data and efficacy data as well. I mean, obviously, like, in the study, the patients who are enrolled some time ago, they have like a more mature efficacy data versus patients who are perhaps enrolled towards the end of the study, but that's not really any different for anything else. So it's essentially the data package, which would summarize the phase I outcomes of the phase I, the recommended phase II dose, and the next steps.
Gotcha. And in terms of, like, patient size, what, how many patients should we expect to get data wise?
It will be a decent size data set. I think without getting into specifics, since these are not something we are updating in real time, but I mean, it's when we had the first disclosure about 11 months ago, which was reflecting of less than a year of the study enrollment. At that point, we shared publicly data on 21 patients across three dose levels, and the enthusiasm actually of our investigators has been pretty remarkable, so actually, enrollment was pretty robust, so it's probably even strengthened compared to already strong enrollment, which we demonstrated in previous disclosures, so it'll be a good data set.
Great. And then in terms of patient population, what tumor types should we expect, and will you, like, break out the data by tumor types? And within those tumor types, are there any that you expect potential accelerated approval pathways with?
So let's maybe go back to what tumor types we enroll. So it's not an all-comer study, but it's not a molecular enrollment-driven study either. So we actually, the way we deal with it, that we enroll selected tumor types, which we anticipate a high prevalence of, the MYC-driven tumors. And obviously, as a part of our biomarker biopsies effort, we do look at the biomarker status in the tumor tissues, which we obtain as a part of the study. So the tumor types, which are included, is non-small cell lung cancer, small cell lung cancer, high-grade neuroendocrine of any primary, and N- and L-MYC-amplified tumors. What the data which will be presented represent will roughly represent what the frequencies of these tumor types are in the population treated in the tertiary cancer centers.
Obviously, the non-small cell is more frequent than small cell. So I think all tumor types will be well represented. I mean, we've done reasonably well, even on the N-MYC-amplified, which is essentially we utilize the enrollment, utilize the clinical testing for N-MYC amplification, which is included in nearly all either CLIA-compliant or FDA-approved assays, which are used clinically. So I actually think that each of these entities will be reasonably represented. Obviously, the biomarker frequencies might differ a little bit, and since we don't pre-select based on that, but we essentially pick up the natural frequency of that. I mean, it might, it will now likely show that the biomarker representation into each tumor type is not always proportional.
Just to kind of put it a little bit into perspective, when we presented the data last year, we disclosed 21 patients. At the time, 15 actually had were evaluable for response, since it was the interim update. And of these 15, six were biomarker positive. So that's kind of like the frequency of the biomarker-positive patients, which give and take, we can potentially expect.
Got it.
Yeah.
Is that pretty, that prevalence, that pretty consistent across indications of non-small cell lung cancer, lung cancer, MYC, and
It does differ. I mean, we've done some of that. We invested quite a bit of effort into that when we were going into the study. So actually, it was part of some of our prior presentations. We actually worked with Tempus to try to figure out what is the frequency of N-MYC or potentially N-MYC and L-MYC expression. So in lung adenocarcinoma, actually, the N-MYC is not as frequent. It's like a high single digit, low double-digit number. But which, at the end of the day, kind of looking at the frequency of subtypes, of biomarker-driven subtypes in non-small cell lung cancer, is actually not a bad number, I would say.
I would argue that many of the other biomarkers which are now routinely used, or mutations which are routinely used, are less frequent. The small cell is a little bit different. The small cell has actually quite high prevalence of N-MYC, N-MYC and L-MYC.
Got it. And then, I guess, what sort of data profile would you be looking for to move 23 59 forward into advanced studies?
Mm-hmm.
either in multiple indications or any specific indications?
The study is actually designed that it allows up to five dose expansion cohorts, phase II expansion cohorts, which does not imply that we will do all five. But we will rather look at in which indications we have in the study and in the totality of the data, the most promising signal, and that's what we would plan to pursue and guide at the time of disclosure. Three cohorts are monotherapy cohorts in non-small cell lung cancer with the N-MYC high, in small cell lung cancer, and the third one is N-MYC and L-MYC-amplified tumors. Again, I'm not saying that all three will be done, but that's what the protocol allows.
The remaining two cohorts are based on actually pretty exciting in vivo data, which we also shared recently, showing the synergistic efficacy in c-MYC-driven tumors, such as hormone receptor-positive breast cancer in combination with hormone therapy fulvestrant and in castrate-resistant prostate cancer, including AR-V7 in combination with enzalutamide. These are two combination cohorts.
Okay. Wonderful. Can you elaborate on your current thinking then, on what the next steps could be for a potential phase II combo?
So the phase II combo would be, as I just said, I mean, one is enzalutamide and 2359 , and the other one is 2359 and fulvestrant. That's actually in the protocol.
Got it. And would you be looking at potential partnerships for registrational trials if you find any proof of concepts here?
It kind of depends on what exactly these next steps are. I mean, obviously, we constantly have discussions with our pharma partners, exploring if there are potentially mutually beneficial co-collaborations possibilities. I mean, it's without not necessarily implying one way or the other, they are certainly indications which can be developed well by us as well as in partnership. So let's say the path in molecularly defined non-small cell lung cancer, that path to indication or even accelerated approval is relatively well-established, and it's been established how many patients approximately you need, which is not that many, and what kind of efficacy you need to see. When it comes to maybe combinations in indications which would require a little bit less streamlined development, such as breast or to certain extent, the combination of prostate.
In that case, I mean, it can be done one way or the other, but the partnership might make sense as well.
Got it. Makes sense, and then maybe just one more question on MRT-2359. How feasible is it to test for MYC in clinical practice?
It is feasible. So what usually drives the development of any test is actually the availability of clinical therapies. I mean, we have been doing testing of these samples, not for the patient selection, but, I mean, we have been actually testing them using the qPCR. There are some other testing approaches which can be also actually looked at, including existing next-generation sequencing assays using the RNA-seq. But we use the qPCR in the trial. So what will be really the driver will be whether this one is actually the viable therapy, and I think the test will actually follow because that's what typically drives the development.
Got it. Okay. Then maybe switching to your VAV1 degrader, MRT-6160. Could you maybe just give a background on the molecule, its developmental path, and we can dig deeper into the data from there?
That's actually very exciting and novel target. It's a target which is very well validated at the preclinical level. I mean, VAV1 is a guanine nucleotide exchange factor, the major regulator of the signal transduction cascade from the TCR and BCR, so actually regulating the TCR and BCR activity. It's a target which is probably not very well known to clinicians in the autoimmunity space because it was deemed undruggable. Although, if you have discussions with, like, large pharmas, I mean, you would be probably quite challenged to find a large pharma which didn't at least attempt to identify the drug targeting that. But designing the guanine nucleotide exchange factors inhibitors is actually specifically for this one, is apparently hard. So the degrader is one of the potential related ways to go.
It's also because the degrader allows you to selectively degrade VAV1 while sparing VAV2 and VAV3. As I said, I mean, degrading VAV1 modulates the immune system on both T cells and B cells, which actually gives you kind of a broad potential spectrum of indications of autoimmune disorders, including the T cell-driven disorders as well as T cell and B cell-driven disorders.
Got it. So specifically calling out VAV, VAV2 and 3, are these potentially off-target tox-
Not for degrader.
Not for-
Not for degrader. I mean, it's, the degrader doesn't touch them at all.
Great.
Yeah.
What does the tox profile look like for MRT-6160 right now, and what sort of GLP tox studies were required to get into phase I healthy volunteers?
Obviously, the GLP studies, I mean, some of them are, some of the data we disclosed, we disclosed several months ago, and I mean, it's been part of the motivation behind that was some of the concerns about this, like, a very new target and very new way of targeting immune system. I mean, the tox data have been actually, like, incredibly clean. So the four-week GLP toxicity, which gets you to the clinic, to healthy volunteers, essentially raised no concerns whatsoever. I mean, we tested several doses which actually differed, like a sixty-fold, showing the VAV1 degradation, complete VAV1 degradation, while not actually achieving any notable toxicity.
I mean, the exposure at the levels which would kind of correspond to no adverse events level would be actually above, like, a 600 or even 1000 for odds of efficacy, predicted efficacy of exposures for human. So it's a molecule which actually appears to be very clean from the safety profile.
Got it. And then maybe you can walk us through the phase I trial design-
Mm-hmm.
healthy volunteers, its current status, and when we can expect to see some data from
So as we recently just communicated and announced, I mean, we had the IND clearance, followed quickly by the first participant dosed in the healthy volunteer study. So that's actually currently going on. It's a classical SAD/MAD, single-ascending and multiple-ascending dose study, which we guided that we will share the data from that study in Q1 of 2025 , of the next year. Obviously, in addition to safety and PK, we are also looking at multiple PD markers, which can help us to understand the molecule a little bit better.
Starting with the VAV1 degradation, but also looking at modulation of reflecting the effects on the TCR and BCR, whether looking at on CD69 on T cells and B cells, or looking at the relevant cytokines such as IL-2, IL-6, IL-17.
... Got it. And then in terms of starting dose, how close is that to the, like an expected therapeutic dosage? Essentially, how long do you expect it to take for you to get to a dosage where you'd find a therapeutic effect?
Mm-hmm. So I mean, we've done that modeling. I mean, it's a potent molecule, so, I mean, and there is kind of like a guidance which you have to do for your starting dose from the regulatory perspective. But I think we should get to relevant therapeutic doses pretty quickly-
Got it.
In the start.
Okay. And then in terms of indication selection, can you walk us through your thinking of that moving forward? And like, where is there data, you know, de-risking indicate VAV, VAV1 in indications in autoimmune?
There were quite a lot of thinking which went into this. Obviously, couple key factors were actually factored in when we were working on our clinical plan. One of them is that the VAV1, very well validated preclinical target, but we are the first one targeting it in the clinic. I think what we were kind of taking into account is where is the biology supportive, how we can actually show quickly proof of concept, and how we can show potentially proof of concept in more than one indication, potentially kind of generate the signal, which will actually inform the future development, as well as actually generate the value.
So from the preclinical package, we have actually pretty nice preclinical package, which includes several in vivo models, including T-cell transfer model of the colitis, collagen-induced arthritis model of arthritis and a EAE model of MS, and which were actually all positive. I mean, the VAV1 MRT-6160 in the low dose actually compared quite favorably to benchmark therapies, which included also the modern therapies, whether it was the TNF or in case of colitis, vedolizumab or S1P, S1PR. But so our proof of concept is actually expected to include several indications. The one of them is ulcerative colitis. I mean, a couple of reasons again, behind that.
I mean, it's obviously the biology is very supportive of that, including all the work which we did on T-cell transfer model and corresponding translational studies. But also it's a good indication in terms of the endpoints are also well defined and quite objective. And it's also the way we see these proof of concepts, we see them as studies which are relatively limited in terms of number of patients, which should actually enroll quickly and provide you this quick kind of a decision about a signal, which then will inform your subsequent phase IIb/III development. So you see from that standpoint, actually, it's checking all the boxes. We are also actually pretty excited about RA.
So that's actually planned as well as a proof of concept indication, as a proof of concept in the priority indication. We also actually included in our presentation some other potential indications, including neurological and the dermatological indications, as well as other rheumatological indications. But the plan is actually to have several of these proof-of-concept studies, which will actually generate quick signal readouts in multiple indications and inform the next steps of development, as well as actually create a potential additional value, mapping the space which this molecule can target.
Absolutely. Multiple large opportunities here. So, as you think about phase IIb/III trials in these large indications, in the magnitude and expense of these trials, are these trials you would expect to develop and pursue internally, or look for partnerships to help move forward in any sense?
Yeah, I think it's a great question, and it's a very, very relevant one. So I mean, the way we were actually trying to think about a proof of concept is to have like a representation of a little bit of everything. So in addition to have a disease mix, which represents the mechanism of action, meaning the T-cells versus T-cell and B-cell driven disorders, we also actually have a representation of the diseases which we potentially can carry on beyond the proof of concept. Obviously, there are also some which potentially would benefit from partnerships as well. So, I think, that's obviously something to be seen. It's a molecule which is certainly generating a lot of excitement, but I think both options are on the table, and it's indication dependent.
But I mean, taking them to the proof of concept, that's all indications which we are thinking about for the proof of concept or already kind of pursuing as a proof of concept, that they are fairly doable to get them to the proof of concept stage.
Got it. And then in these proof of concept stages, across these indications, do you expect, like, the same level of degradation will be efficacious across MS and arthritis, in ulcerative colitis? Or do you expect that you'll need to do dose optimization, to dial in, you know, an appropriate dose for each indication? And what would that look like?
Yeah, it's so, I mean, obviously, like, sometimes it's a little bit hard to guess before-
Sure
... before you get to humans. But I mean, the preclinically, it doesn't look like that there would be any massive like dose differences. But that being said, I mean, the dose exploration part of work will have to be done from the regulatory perspective anyway, at some point. So I mean, that will have to be done regardless as a part of the clinical research, probably at some point in the more like a phase IIb stage.
Got it. Okay.
That's kind of just as a general principle.
Sure. Okay. So, switching gears then to MRT-8102, your next NEK7 degrader. Can you walk us through the rationale of this degrader?
Mm-hmm.
-and, potential indications you would develop it with?
Yeah, so NEK7 interesting protein. It's actually a kinase, but the way it functions in activated NLRP3 inflammasome is actually through its scaffolding function. So that's kind of a nice example, which again goes with our philosophy, what targets we go after. So even though it's a kinase, actually drugging it with the kinase inhibitor probably wouldn't really lead to result in anything. That's also a differentiator from the NLRP3 inflammasome targeting drugs, that you essentially the target the inflammasome assembly. And the it's like program, which is super exciting in many ways, quite differentiated from VAV1 in the way how we look into that.
So, unlike VAV1, which is, clinically, at least in the clinic, a new biology, I mean, even though NEK7 degrader, it would be likely the first one. But I mean, it's, the NLRP3 IL-1 beta axis has been actually relatively well understood, and even in the IL-1 space, there are actually medications, approved. So I mean, in terms of like, how we approach it, how to get to the proof of concept, I think it gets a little bit easier because, I mean, you have certain paths, certain ways how you can actually, develop it and establish that. So the way actually we are, thinking about it, that from the, that there should be relatively, simple or straightforward path from the healthy volunteers, as SAD and MAD, to the proof of concept.
Got it. Okay. So I-
That proof of concept doesn't have to be in XY indications. It can probably be in one or two indications, since the biology is in which the biology is well understood, in which the NLRP3 IL-1 beta axis is known to be a driver.
Got it. Would obesity be on that list too?
Well, I think when it comes to—I mean, obviously, there has been a lot of, like, excitement over the last few months given the publication of some preclinical data, which I'm not gonna get into the detail, but I think in some way the jury is still out there. I think certainly we are paying attention to what's happening in the field, but we don't necessarily see this one as a path of development, as a path of the primary development. It's actually something which we would be probably well positioned to potentially expand if this one actually turns out to be a viable path.
Got it. Okay. So I think one of the strengths of glues in your developmental, your discovery platform is you can really explore multiple indications across several disciplines. You have pipelines in the neural space, immunology, autoimmune, and oncology. Can you walk us through your thinking and strategization for prioritizing in the different programs in allocating resources and funding?
Yeah, you have to, because, I mean, as you pointed out, we are a small company. There is only as much as we can do, while the potential is actually immense. And I actually think that's something which the company approaches quite smartly. I mean, obviously, in terms of what we are pursuing to the clinic now, as you can clearly see, looking at our pipeline, that includes oncology as well as I&I, quite substantial I&I efforts. But at the same time, I mean, we are very excited about our discovery partnership, which we have with Roche, which we have announced actually last year, and which, in addition to oncology, also includes the neuro space, which probably for us would be quite hard to get into on our own.
So, that's sort of actually how we potentially approach this and how we see that. I mean, obviously, we have to be strategic about what we do ourselves and for which we will leverage expertise of some of our partners.
Got it. And then maybe in the last minute here, can you walk us through your cash runway and what key catalysts, you know, you'd want investors to pay attention to in the next six to 12 months?
So I will start with the catalyst. Obviously, this half of the year, we expect the phase I GSPT1 MRT-2359 data, as we just pointed out. Then, Q1 2025, we expect the data from the healthy volunteers, MRT-6160, the molecular glue degrader. The cash runway is into the first half of 2027, and that includes what I just said, including the next several SAD, MAD, and proof of concept.
Got it. Okay, well-