Dear ladies and gentlemen, welcome to the Merck R&D update call. As a reminder, all participants will be in a listen-only mode. May I now hand you over to Constantin Fest, Head of Investor Relations, who will lead you through this conference. Please go ahead, sir.
Thank you, Alan. Dear ladies and gentlemen, a very warm welcome to this 2021 Merck R&D update call.
My name is Constantin Fest, and I'm Head of Investor Relations here at Merck.
I'm delighted also to have with me here today, Danny Bar-Zohar, Head of Development, Jörn-Peter Halle, Head of Research, as well as Andree Peterson, Chief Marketing Officer. For the Q&A part of this call, we will also be joined by André Blaukat, Head of Research Oncology, Amy Kao, Head of Research Immunology, Jan Klatt, Head of Development Neurology and Immunology, as well as Victoria Zazulina, Head of Development Oncology.
We will now guide you through the key slides of this presentation.
This will be then followed by a Q&A for you to ask all your questions. Having said that, I'd like to directly hand over to Danny to kick it off.
Over to you, Danny.
Thank you. Thank you so much, Constantin.
Thank you, all, and good afternoon or morning, evening, wherever you are. Andree, Jörn-Peter and I are very excited to be here with you today and share our excitement with you about Merck's pipeline.
Now let's switch to slide three, please. At the CMD in September, we told you that we are well-positioned for long-term growth with mid-single-digit sales growth up to 2025, driven by established portfolio and recently launched products. More than that, we also feel confident about growth beyond 2025, when we expect an increasing contribution from the pipeline. We also spoke about focused leadership.
Today, we will share how we build focused leadership positions in areas of deep expertise and pursuing five focused assets with first-in-class potential that, in line with our strategy, have distinct uncorrelated risk.
Moving to slide four, we see that all of our five focus assets have first-in-class potential, and they address major unmet needs. Evobrutinib for RMS, for example, it aims to address a significant unmet need in this disease, which is reducing progression, which is always there in multiple sclerosis, in between relapses, driven by chronic inflammation inside the central nervous system, on top of reducing acute inflammation that delivers best-in-class annualized relapse rate reductions.
Today, we show the first evidence from our Phase II program of evobrutinib impacting chronic inflammation, and we share the data that underpins our confidence in the best-in-class potential of evobrutinib and what is actually the basis for the strong ARR data observed so far. With xevinapant, we aim to deliver nothing short of transformational patient benefit in locally advanced cancer of the head and neck. In this setting, this is a curative setting, and we aim to maximize the chances for cure.
Third is berzosertib, which is our lead program in our DDR portfolio. It targets a very different patient population as compared to xevinapant, aiming to treat patients that unfortunately don't have many options left. Now, berzosertib enhances the efficacy of chemotherapy, especially topoisomerase I inhibitors. We'll talk about it later. M1231, which is our first antibody-drug conjugate.
With this novel asset, we are using quote-unquote triple innovation approach that allows targeted delivery of a potent next-generation antitubulin payload with reduced on-target and reduced off-target toxicity, given mainly the bispecificity of this ADC. Now, this approach is expected to have quite a wide applicability across multiple solid tumors that we hope many patients will benefit. \
Last but not least, the new and novel kid on the block, enpatoran, small molecule TLR7/8 inhibitor. Enpatoran inhibits a central mediator or actually a central node of lupus pathology to block downstream signaling of multiple lupus effector cells and cytokines. We will discuss our reasons to believe that it will deliver an improved risk-benefit balance versus the established therapies in systemic lupus, as well as in cutaneous lupus, for which there are no approved therapies. Let's move to slide 5.
Now, there is a critical point here to make. Approaching to develop these five focus assets and beyond leverages and extends deep expertises, and we see expertise as truly multidimensional. What do we mean with that?
We have a strong disease insight and wealth of data to inform our development strategy, especially in head and neck from Erbitux and MS from Rebif and Mavenclad, areas which where we also have a very strong KOL relationship. This also extends to lupus and non-small cell lung cancer, where we have significant clinical development experience. Experience, even operational and high-quality data are assets as themselves for us, and we use them all the time. We have built deep biological expertise in immunology and oncology.
We have strong platform capabilities, and I would say world-class collaborations as we really aim to work with the best, and you saw many examples of that. Let's start with evobrutinib in slide 6. Evobrutinib is a pioneering program seeking to address the major unmet need in MS, chronic inflammation inside the central nervous system that drives progression even in between relapses.
This is in addition to reducing acute focal inflammation, aiming to deliver the best-in-class ARR reductions. Now, to appreciate the extent of this potential breakthrough mechanism of action, I think that you should look no further than the numerous followers that we have attracted. Importantly, there is a significant time element here. This is not one pack of four. Evobrutinib is in the lead with the key neck-and-neck competitor being tolebrutinib, where fenebrutinib and remibrutinib are quite far behind.
Now, we never, ever underestimate the competition. We know that all of them claim to be best-in-class, but we made the so far fruitful effort to be first and took the time to come up with credible best-in-class arguments that are substantiated by meaningful data to patients. Strongest evidence for that is the best-in-class ARR of 0.11 at 48 weeks in our Phase II study.
Our strong efficacy is underpinned by very thorough dose finding and population PK modeling.
Now, you may think that it's a little bit boring, but today I will demonstrate to you that in order to maximize efficacy, it is important to maintain at least 95% BTK occupancy throughout the dosing interval, even at trough levels.
Also, we keep on hearing a lot about brain penetration, and I'd like to make two points here.
Brain penetration is not just a binary attribute which is ticked as positive if you find traces of your drug in the CSF or not. It needs to be meaningful, so also here, trough levels do matter. Beyond that, the real issue is whether you impact resident immune cells in the CNS, mostly the microglia.
This will explain my excitement when I will present our biomarker data from the Phase II program that for us and for top experts in the world suggest that evobrutinib is indeed doing what it is supposed to do inside the central nervous system of RMS patients.
Last but not least, our integrated safety profile or safety analysis from over 1,000 patients studied in Phase II shows that evobrutinib to date looks very safe and tolerated compound. Now, let's move to slide number 7 and talk about the dosing.
Now, all covalent BTK inhibitors that I showed on the previous slide, including ibrutinib, have a rather short plasma half-life of something like two hours. With these properties, due to the continuous BTK protein turnover, you need BID dosing, even with a covalent binding to BTK, for the majority of patients to achieve 95% BTK occupancy at trough.
This is shown in the dark pink line on the left panel. The light purple line in the middle of the left panel shows that once-daily dosings result in suboptimal BTK occupancy. This is what you can expect to see for once-daily dosing of any BTK inhibitor with a short half-life. In the middle panel, you see the patien.
The patients receiving 75 milligrams BID depicted in the dark pink in the left and middle panel, i.e., those achieving at least 95% BTK occupancy at trough. These patients experience the greatest ARR reduction of 0.11 with ibrutinib. You can also see that the patients dosed once daily in light purple in both panels, which achieved a lower BTK occupancy at trough, they achieved a by far less impressive ARR.
The data clearly demonstrate that you need to sustain high 95% BTK occupancy during the entire dosing interval to achieve strong ARR. According to our data, this requires BID dosing.
Now let's move to slide 8 and talk about another important battleground in MS, which is the brain itself, as so far we have talked about BTK occupancy in plasma. The principle is quite similar.
We want to ensure adequate BTK occupancy also in the central nervous system. We cannot measure BTK occupancy directly in the CNS, but we can model this with our population PK model because we have the data. We did that. We enriched our model with the most accurate data. We took CSF, cerebrospinal fluid, of ibrutinib-treated patients.
Here you see that ibrutinib concentration in the CSF from patients in Phase II compared to ibrutinib concentrations in the plasma from patients in Phase II. Now at a first glance, you may think that the CSF and plasma levels are different. Though based on our population PK modeling, we know that these CSF and plasma levels are sufficiently comparable.
Without getting into too much fancy modeling technical stuff, we expect that the majority of patients treated with Phase III doses of evobrutinib will have BTK occupancy in the CSF, which is higher than 95%.
Next, I'll show you two data sets that demonstrate what it does in the brain. Let's move to slide 9. The first data point is from our proprietary mouse model of leptomeningeal inflammation, LMI. LMI and MS has been linked to worse outcomes and faster progression due to greater demyelination in the cortex.
Our data shows that evobrutinib reduced established leptomeningeal inflammation detected by both MRI and histopathology. Now, I can get very excited about mouse data, but what happens in patients is by far more important.
In slide number 10, the next slide, we are really excited to show you the first clinical evidence of evobrutinib impacting lesions associated with chronic inflammation inside the brain of MS patients.
You know, new imaging techniques and biomarkers are being developed to overcome one of the challenges in MS, how to measure chronic inflammation inside the brain rather than the acute damage that we measured with the well-known gadolinium-enhancing lesions. Slowly expanding lesions or SELs are radially enlarging, smoldering lesions in the brain made visible on MRI.
They are chronically active demyelinating lesions driven mostly by sustained activity of those cells that I mentioned before, the microglia. SEL activity predicts long-term disability, and they are quite unanimously advocated as a strong biomarker for the biology of progression in multiple sclerosis.
It seems that approved RMS therapies have shown either little or modest or no impact on SELs. We are very excited to see a dose-dependent reduction of SEL volume at 48 weeks in our Phase II study. This study or the data from this study was only recently presented as an oral presentation at ECTRIMS in October and very well received. Last but not least, let's jump to safety in slide 11.
We're very confident about the safety profile of evobrutinib so far. I base this confidence on our large safety database that includes more than 1,000 patients studied in Phase II across several autoimmune indications. For example, infection risk, which is a primary concern for patients and for any neurologist treating MS patients, appears to be comparable to placebo.
Now, let me refer to the topic of liver enzymes elevation. ALT elevations were asymptomatic and reversible upon treatment discontinuation. They occurred mostly or exclusively actually during the first 3 or 4 months of therapy. Needless to say, up until now, no case of Hy's Law or liver failure attributed to the drug. Broadening the lens a little bit, when you look at the safety data of other BTK inhibitors, you see quite a similar ALT pattern. The likelihood of seeing these LFT elevations as a class effect in our eyes is not low. By the way, we have already enrolled more than 2,000 patients into our Phase III program, and the trials are being monitored as of now without changes.
In slide number 12, we'll summarize pioneering development program aiming to address major unmet need in RMS chronic inflammation that drives progression between relapses. Evobrutinib has a strong first-in-class and best-in-class potential. Our confidence in evobrutinib best-in-class potential is underpinned by our comprehensive Phase II data that showed ARR of 0.11 at 48 weeks.
It was achieved at a BTK occupancy of 95% at trough and this needs BID dosing. We consciously chose not to sacrifice efficacy for, I would say, a bit of extra convenience from QD dosing, and we believe that this is the right strategy. We also demonstrated evobrutinib reached relevant BTK occupancy in the central nervous system, and we have shown animal as well as clinical data suggesting that evobrutinib impacts progression inside the brain.
Our large safety database, as I've said before, shows very good safety and tolerability so far. Phase III studies, as we said a couple of months ago, are fully recruited, and we're looking forward to the readout in the fourth quarter of 2023. Now let's switch gears a little bit and move to slide 13. Resistance to apoptosis, totally different topic, is a very well-known or very well-established hallmark of cancer. Now this resistance to apoptosis is mediated by inhibitors of apoptosis proteins, IAPs.
By the way, IAPs also have been reported to have immunomodulating properties. Now xevinapant blocks those IAPs, actually key three of them, thereby sort of releasing the brake imposed by IAPs on the cancer cell death cascade.
Of note, squamous cell carcinoma of the head and neck is one of the cancers with the highest frequency of deregulation in genes encoding key constituents of the cell death pathway. In this type of cancer, escape from apoptosis is something that needs to be tackled when a definitive lethal chemo radio regimen is administered, and we want to avoid the emergence of resistant clones.
Now we are on slide 14. Many of you may be familiar with the strong xevinapant randomized controlled trial, the Phase II data published in The Lancet Oncology, and also presented in a variety of congresses, but I would like to highlight two points here. The first one is the strength and the internal consistency of the benefit seen across all endpoints, primary and secondaries.
We do see it as a strong proof of concept and by no means as an anecdotal finding. Yes, it was an RCT, so it was easy to compare, but we sort of kicked the tires here and looked whether the standard of care plus placebo arm behaved as in previous trials or in the real world, and overall, it did. The second one is a locally advanced squamous cell carcinoma of the head and neck.
You know, this setting is a curative setting. You know, these patients do not have metastatic disease. They have large tumors that may be difficult, if not impossible, to remove by surgery. With the right treatment approach, we can potentially save many lives in this setting.
Now looking at the hazard ratios for at three years for PFS and OS really provides an idea of the transformational benefit that we hope to deliver with savolagent over the existing standard of care. Now next year at ESMO 2022, we hope to share the five years OS data. I suggest to stay tuned to that. Now let's move to slide 15, a little bit of background on locally advanced squamous cell carcinoma of the head and neck.
Now, curative setting requires really a multidisciplinary approach involving surgeon, radiotherapy professionals and medical oncologist. This is quite complex. Now, based on our Erbitux heritage, we know this setting very well.
In fact, our market leadership position in head and neck cancer appeared to be a major factor in Debiopharm's decision to choose us as a partner for xevinapant, so we are very happy with that. Now, the treatment paradigm in locally advanced head and neck is complex. This two-by-two matrix shows the two key criteria determining treatment, tumor resectability and the patient's fitness, particularly when it comes to treatment with cisplatin.
Now, the TrilynX or Phase III study in cisplatin-eligible patients with unresectable tumors is underway and recruiting patients globally in more than 200 sites. It has probably, I would say, not escaped your attention that we have been taking our time to carefully define the optimal target population for our Phase III study in the cisplatin-ineligible segment.
The reason for that is, as you can see, the standard of care is very fragmented. There is no one single standard of care, and we want to ensure that the largest number of patients can benefit from xevinapant in the context of the lowest number of trials.
Now, let's jump to slide 16. Now, the TrilynX, as I said, is moving nicely where we are making the steps needed in order to operationally hand it over to us and be in the driver's seat. It's a multinational study that includes a significant proportion of patients from China and Japan. Both geographies have very high disease burden for head and neck cancer. Now, the earliest launch is 2025.
You know, obviously in such trials we have interim analysis and, based on accumulation of events, if there is something to tell you before that, so we will for sure do that. More importantly, we are finalizing our Phase III trial design in cisplatin-ineligible patients, and plan to initiate it towards the end of the first half of 2022. Let's jump. Let's skip slide 17 and jump straight to slide 18 and dive into DNA damage repair. Merck has built up deep expertise in DNA damage repair with, I think, research activity extending back more than 10 years. Now, the first generation, PARP field, was crowded, so we focused on what's next in DDR, which is pursuing multiple pathways.
It's becoming increasingly evident to us and also to others that the next frontier in the DDR field is ATR inhibition. Now, ATR inhibition allows the cell cycle to progress without DNA repair. Fast-replicating tumor cells accumulate DNA damage, which eventually results in tumor cell death. DNA damage repair is quite vital to the integrity of the genome and not just the genome, it's the overall function of the organism. Evolution has built up quite a bit of redundancy or alternative repair mechanisms to compensate for a defect or inhibition of a DNA damage pathway.
Therefore, as single agents, ATR inhibitors will work only in select patients with pre-existing DNA damage repair pathway alterations, while all other patients will eventually require combinations.
Now, berzosertib is the lead program in our DDR portfolio, and our development focus for the compound is combination with chemotherapy and specifically a topo I inhibitor. Topo I inhibitors inflict this DNA damage and berzosertib prevents the repair. That way, berzosertib actually enhances or potentiates the efficacy of topo I inhibitors such as topotecan. And I'm going to open parenthesis here.
There are tumors like small cell lung cancer, but also others that inherently, as a tumor type, are more dependent on DDR pathways and for sure there is no one tumor fits all here. Now let's switch to the next slide 19, and talk briefly about small cell lung cancer. This is our most advanced indication for berzosertib, refractory small cell lung cancer.
Refractory extensive stage small cell lung cancer is really one of the most aggressive tumors with few treatment options for patients. None of them are very effective. Now, the contribution of IO in this setting has been rather modest, only adding a few months to overall survival in first-line maintenance. The key challenge in small cell lung cancer is that responses are rarely durable, either first line or in second line.
Unfortunately, patients progress very rapidly even after achieving a response. In slide 20, we will see that with NCI, we have generated remarkable early data for the berzosertib topotecan combination in refractory small cell. We have seen a large number of responses in a small study, especially in platinum-resistant patients who tend to get very little benefit from single agent topotecan.
Now more importantly, I'd like to draw your attention, look at the swimmer plots. Responses have been very durable, with two-thirds of patients have durability of response, which was longer than six months. Now, this is especially remarkable as 20 out of 25 patients had platinum-resistant disease, and those patients typically progress within a few weeks on topotecan monotherapy.
With berzosertib, we have two ongoing studies, a randomized Phase II controlled study run by the NCI, berzosertib plus topotecan versus topotecan alone, and our Merck-sponsored study, the DDRiver 250, which is a single-arm berzosertib plus topotecan, which is ongoing very well. Let's move to slide 21. Our development focus with berzosertib is to maximize actually its potential in refractory lung cancer.
We did not miss the great data published in combination with Gemcitabine in ovarian cancer and are in advanced stages of embarking into a collaborative trial in ovarian cancer next year. Now, overall, we see potential for the combination of berzosertib with chemotherapy beyond this initial setting, and we'll be able to talk about it later, and I think that actually this is a perfect segue to hand it over to you and Jörn-Peter .
Yeah. Thanks, Danny, and also a warm welcome from my side. If you go to slide 22, you see the question, what's next in DDR? Danny nicely explained it already. It's ATR for monotherapy and PARP inhibition. Why do we need an oral compound for this while berzosertib is an IV compound? On the left side, left top side, you see actually berzosertib is really well-suited for the combination with IV chemotherapy. It's rather short-lived, and this allows you to precisely synchronize the chemotherapy and the ATR inhibition in this chemo ATR combination. Perfect fit here.
In immuno-oncology, you can combine with IV or oral, but if you go to synthetic lethality, and you see on the right-hand side two examples, either biomarker-driven tumors or combination with PARP inhibitors, you need a consistent and prolonged exposure, and this can only be done with an oral compound. We believe M1774 is here really ideal because it has a really reliable and excellent PK profile to achieve this consistent and prolonged exposure. Where are we with M1774? We are in the dose escalation and actually achieved already in the monotherapy the active dose.
We have a manageable mode-of-action-related safety profile. The PARP combination is ongoing, the dose escalation there, and we expect the dose finding soon.
Stay tuned. Actually, not only will we publish these results next year and then of course continue, but of course, overall in DDRI, we have an active discovery platform, and more to come there.
Let me switch gears to slide 24. Still oncology, but switching gears to antibody drug conjugates, ADCs. ADCs are pretty clear. The goal is to deliver a toxic payload via the antibody very specifically to the tumor. You probably know first generation ADCs have solid efficacy but have some limitations, actually outlined here on the slide, for example, safety, and others. There were recently actually quite encouraging data by competitors, second generation ADCs.
We still believe, when we started our discovery activities in ADCs a few years ago and still believe today that there's tremendous room for improvement. Why is this? We believe that you need to optimize all three elements of an ADC simultaneously in parallel, so it's not sufficient to optimize one individual element, so the antibody, the linker or the payload. No, you have to really solve here a puzzle like the Rubik's Cube that you see at the bottom. We believe that for the first two ADCs we bringing into the clinic or brought into clinic, we have solved this.
So the first one that entered the clinic in January is M1231. I come to this in a minute. A bispecific MUC1 EGFR ADC, and the second ADC will come M9140.
First-in-human studies are planned actually for early next year. On slide 25, let me dive a little bit deeper into M1231, our triple innovation ADC. First of all, we have a bispecific ADC, actually the first one in the industry that moved into the clinic, targeting MUC1 and EGFR to increase the tumor selectivity and boost also the internalization.
Number two, we have a site-specific conjugation, which leads to a structurally very homogeneous ADC with a consistent DAR, drug antibody ratio, and we believe that's essential for a good safety profile. The third innovation is a next-generation tubulin payload, which is addressing not only multidrug resistance of tumor cells, but also due to its short half-life when released in the tumor, we limit systemic exposure and therefore further improve the safety profile.
Several of you have asked actually when we presented this innovation a year ago for the first time. Okay, I get the bispecific principle very good to target tumor very selectively, but what about the patient population? Aren't you not targeting a very small population by requiring both targets to be expressed on tumors? To answer this question, let me switch to slide 26.
Here we compared expression of different ADC targets that have been targeted in the industry. Let me first focus, of course, on the left-hand side. You see a boxed MUC1 EGFR co-expression, and you actually can hopefully appreciate that a significant percentage of major tumors in the range of 60%-80% of these patients in these indications are expressing both targets on tumor cells.
If you now switch all the way to the right, actually, if you compare this with EGFR expression, you of course see that in some tumors, the EGFR expression is higher. Obviously, these tumors are not expressing MUC1. If you compare this, actually, the majority of the tumors that express EGFR are also expressing MUC1. Actually, that's the reason why we have relatively high percentages on the left-hand side with the co-expression.
Of course, the major downside of EGFR is that it's not suitable for an ADC because the expression is not only high on the tumor, but also pretty high on normal tissues and widely expressed on normal tissues. The ratio between normal tissue and tumor depicted at the bottom of this slide is very high, too high for ADC.
With the bispecific approach, we only slightly reduce the patient population, but tremendously increase the tumor specificity and therefore have really here, we believe, great chances to have a much, much better therapeutic window, even compared to other classical ADC targets like HER2, c-Met, HER2, which have a good ratio, but especially to others like Trop-2 and Nectin-4, which actually have a relatively high ratio between normal tissue and tumor. Where are we with this program?
Actually, we progressed significantly, which you can see on slide 27. We are in dose escalation and it's progressing very well. We are close to an effective dose based on preclinical data.
If we reach the predicted therapeutic window, which we should reach in the near future, we will expand that study with two cohorts, one in third-line biomarker-selected NSCLC patients, and the other one in ESCC second-line. Good progress here on the ADC side. Let me now return to immunology and show you that we are continuing here to innovate beyond what Denny has already outlined in the later portfolio. Slide 29.
Let me first describe the mode of action of a TLR7/8 inhibitor. You probably know TLR receptors are the receptors in the immune system, mainly in the innate immune system, that are sensing pathogens and are alerting the immune system, so to speak, that something is invading the body.
Specifically for TLR7/8, the signal are viral single-stranded RNAs that trigger TLR seven and eight and induce the innate immune system. That's great. But actually in indications like lupus, there's an aberrant chronic activation of TLR7/8 by endogenous RNA that is released from dying cells. You have a chronic inflammation because of this.
Actually, there's very recent and very convincing genetic evidence that TLR7 is a critical driver of lupus pathology. You see here some statements and the literature are very, very convincing data. You can ask the question, if this is such a great target, why are not others pursuing this? You should know that actually, TLR7/8 was seemed to be undruggable, at least with small molecules. Some people tried this, oligonucleotides and derivatives, but really were not really successful.
We succeeded actually via phenotypic screen and with structural information from a collaborator to really identify and then optimize small molecules. Now we have a very potent and selective small molecule called enpatoran that is blocking TLR7/8 very efficiently. On slide 30, you can hopefully appreciate what such small molecule TLR7/8 antagonist could do in lupus.
Actually, let me focus on the slide or the cartoon at the bottom. First of all, on the left-hand side, you see what I already explained. You have multiple activators of TLR7/8, infections, but also in autoimmunity, the RNA complexes and extracellular single-stranded RNA. Then downstream, you have a variety of effector cells that are activated via this pathway. So dendritic cells, monocytes, neutrophils, and B cells.
What you can now do to block the pathology of lupus is either you block all these effector cells. That's what you do.
This you do with corticosteroids, but of course, then you have a lot of suppression of the immune system, and infections could be a side effect of this therapy. You go to very specific, more modern, treatments that deplete, for example, B cells. If you do this, first of all, you are not only missing out on many other effector cells, but you also of course impair the immune system, again, if you, for example, deplete B cells.
We believe we have a central mediator with TLR7/8, and we can address this with enpatoran on one side to have high efficacy and on the other side to avoid infection and keep the immune system intact. Let me give you an example.
If you think about COVID and the vaccinations here, preexisting immunity, either induced by vaccination or by infection, would be unaffected by the inhibition of TLR7/8. We believe that this is a very nice way to address lupus with this central mediator. Is this just theory? No. We have actual data to support this on slide 31. You can see that we have conducted a healthy volunteer trial.
In this trial and also in the COVID study, we see a very good safety profile and with 200 milligrams QD, you see the pharmacokinetic and pharmacodynamic effects on the right side. Actually, here are two examples showing that with this dose of 200 milligrams QD, we block the induction of interferon alpha , which would induce dendritic cells, and we can also block the induction of IL-6, which would stimulate macrophages. We are active here with this mechanism in the clinic. I mentioned that we also run a COVID trial, not only the healthy volunteer study.
Actually, when we presented this underlying principle and the data to FDA investigators, they agreed that we should run the study in COVID-19 patients, hospitalized patients with strong induction of inflammation.
What we saw actually is with various endpoints, a trend towards higher recovery rates. The analysis is ongoing, we didn't meet the primary endpoint, but the data package overall, the clinical data, but also the biomarker data here make us very, very confident to go into the next phase of development, which you see on slide 32.
Here you see what we are planning to start early next year. Phase II, combined proof of concept and dose-finding study with basket and adaptive design, so very innovative, in two cohorts, in cutaneous CLE, so the skin manifestation of lupus, and in SLE. We believe that we could have a proof of concept, and then submission earliest in CLE in 2026, and one year later in SLE.
I think that's a very, very good example for how we approach R&D at Merck. Strong preclinical data, strong mechanisms, strong science, and a strong translational spirit. With this, I am handing over to Danny.
Thank you so much, JP. Let's move quickly to slide 34. 2021 has been a very busy year for Merck R&D. We have been strengthening the pipeline, moving from programs with considerable correlated risk to pursuing distinct uncorrelated risk, and again, focusing on our key strength, be it tech modalities, disease areas, pathways, or all of the above. In 2022, we expect significant further progress, adding multiple assets or multiple studies to all at all stages of development. Today, as you heard, we as we are focusing on the most important value drivers in our pipeline, our five focus assets here are highlighted. The list shown here is not exhausted. Our pipeline is broader than that.
If you switch to slide 35, we see that 2022 is a year of new study initiations, where we will initiate two Phase III trials, up to 6 new proof of concept studies, and at least 2 new molecular entities starting first in human. You can expect the first readouts from our late-stage pipeline towards the year-end of 2022, when we hope to have the results for the tepotinib in second-line EGFR mutants patients with MET amplification non-small cell lung cancer who have progressed on osimertinib.
We expect 2023 to be a very busy year for us in terms of readouts. Phase III studies in RMS, berzosertib Phase II studies in refractory small cell lung cancer, and up to 5 proof of concept readouts that you can see here on the slide.
Looking at slide 36, from 2023 onwards, we are targeting at least actually one submission per year. Now, obviously, the visibility of the earlier assets, be it M1231 and enpatoran is slightly different, but this is the general theme here. Our five focus assets with first in class potential address significant unmet need, and they have blockbuster potential, perhaps with the exception of refractory small cell lung cancer, which is the initial indication of our DDR portfolio, but this is the overall picture. In slide number 37, in conclusion, we told you about how we center our pipeline around the five focus assets.
We're building focus leadership positions in areas with deep expertise. We even further strengthen the pipeline. We started doing that, 2022 will see substantial advancement of new study starts across our early and late-stage pipeline.
You can see here the key upcoming milestones, be it the initiation of the Phase III study for xevinapant, and also the completion of recruitment for the TrilynX study, the re-readout of tepotinib, the initiation of PoC studies and first-in-human studies.
Overall, we expect the pipeline to contribute significant growth from 2025, sustaining growth momentum from the big three of Merck.
We have the science, the drive, and most importantly, the people and the teams to drive that.
Thank you so much for listening to us. Before jumping to the Q&A session, I will hand it over to the other team members to present themselves.
Hi, good afternoon. My name is Andree Blaukat.
I joined Merck 19 years ago and have been in charge for targeted therapies in oncology since 2012. For a bit more than a year, I'm also responsible for neuro-oncology research.
My team is based in Darmstadt, Boston, and Tel Aviv and has discovered several of the clinical candidates we are talking about today and has generated translational research data that guides clinical development. I'm looking forward to sharing more details of the cutting-edge research in our six focus areas, oncogenic signaling, DNA damage response, antibody-drug conjugates, T and NK cell biology, myeloid cell biology, and stress and tumor plasticity in future.
Hi, today. My name is Amy Kao. I'm a rheumatologist with more than 20 years experience in lupus research, including more than 13 years in academia, conducted clinical trials, epidemiology and biomarker research, and seven years in clinical development in autoimmune diseases.
I joined Merck for about four years, one of five years, with both academic and also clinical development background. I now lead immunology research since July. My team discovered the clinical assets, as you heard from Danny and Peter, on evobrutinib and enpatoran, and also supports the development in neurology and immunology.
In immunology research, we leverage our expertise in the modulation of selective innate and adaptive autoimmune pathways while expanding into neuroprotection, tissue homeostasis, and repair for cutting-edge research, which we're quite excited about. Application of novel modalities such as ADC degrader. More to come. Let me pass it to Jan.
Hello, good day, everybody. My name is Jan Klatt, and I joined Merck recently coming from Novartis, where I've worked the last 16 years. I've joined Merck because of the ability to build up the N&I pipeline and to leverage both the history that we have here as a company and the available assets that Danny has described, as well as combining that with a fresh perspective on future opportunities.
In particular, the field of neuroimmunology is making tremendous progress scientifically that will hopefully translate into better or first treatment options for patients with tough diseases. Plus, having personally worked in the MS field for a long time in my former life, I'm very excited to have a chance working on a program which has really the potential to become the future standard of care for people living with MS.
Evobrutinib is well positioned to be first in class and best in class among the BTK inhibitors. Together with our team here in Darmstadt and the U.S., we'll do everything we can to advance that.
Good morning, good afternoon. My name is Victoria Zazulina, and I have joined Merck actually in October 2021. I'm the recent addition to the team, bringing more than 15 years of drug development experience in oncology.
My formative years have been spent with AstraZeneca in the global R&D, with Boehringer Ingelheim in the global R&D. I've also briefly touched Novartis in the earlier stages of my career. I have overseen the compounds in early Phase, in late Phase. I was also part of successful filing and registration in the non-small cell lung cancer field. I'm excited to bring all of this experience here and also learn, and together with the colleagues at Merck, continue shaping what seems to be a very exciting pipeline with many promises to come in the coming years. Thank you.
Thank you very much. Dear ladies and gentlemen, with this, we are now ready for the Q&A part of this call. I'd like to kindly ask you to limit yourselves to a maximum of two questions per person. This will allow more of you to ask questions in the first place. With this, Alan, I would kindly ask you for the first question, please.
Thank you, sir.
We'll now begin our question and answer session. If you have a question for our speakers, please dial star one on your telephone keypad to enter the queue. Once your name has been announced, you can ask a question. If you find your question is answered before it is your turn to speak, you can dial star two to cancel your question. Also, if you're using speaker equipment today, please lift the handset before making your selection.
Your first question comes from the line of Richard Vosser with JP Morgan.
Hi. Thanks for taking my questions. Two, please, on Ibudilast. First question is other companies have undertaken broader development of their BTKs within the MS field, looking at PPMS and other indications. Just your thoughts on why you have restricted development or so far to just RRMS.
Just a clarification, maybe more detail just on the liver enzymes, Danny. I think you mentioned that you thought they would be potential across all different types of BTKs from the competition. Just if you go through the reasoning in a bit more depth for us, that would be great. Thanks very much.
Thank you, Richard. I'll hand it over to Jan to tackle the first question.
Yeah. Thank you for the question. Look, I mean, progression a little bit different here as it really starts affecting patients already very early in the disease. I mean, in essence, progression is everywhere in MS, and it definitely happens also in RMS between the relapses. Based on lots of scientific advance in this area, we are now basically looking into this in our Phase II data set. For example, the cells that Danny has described actually make us feel good about our ability to target progression overall.
Couple that with the fact that we know that ibudilast has a strong impact on acute inflammation, as demonstrated in our Phase II study, makes it potentially ideal therapy for RMS patients, which still represent 85% of all MS patients. Now overall, maximizing patient benefit is very important to us. When prioritizing our development activities, we're fully evaluating what we know, what we don't know, for a mindful allocation of R&D spend. One concept that's really important to us is to make data-driven decisions, which is why we did this very comprehensive program in RMS, but it's actually a paradigm that's hard to apply to primary progressive MS because you can't run a proper PoC study there.
Again, irrespective of the subgroups, the point is really progression is everywhere, and the effects on progression are of interest to us. Based on the emerging data, we do believe that Ibudilast has best-in-class potential.
Thanks, Jan. To your second question, Richard, without getting into mechanistic explanation, which there are, and these are hypothetical at this stage, just look at the data. Other BTK inhibitors that are in the mix for MS have been studied in still by far lower number of patients. However, when you look at liver enzymes elevation in hematological malignancies, and you can see it for one of them, if I'm not mistaken, you can see the same signal, right? So this makes us believe that you're going to see that also with others, not necessarily for the same magnitude, but give or take, it will be a play around the same class of small molecules.
Thanks very much.
All right, next question will be from Matthew Weston with Credit Suisse.
Thank you very much. 2 questions, if I can please. One, a big picture one, which is really to do with R&D spend, which is you've outlined obviously the strength of the pipeline, a number of new molecules moving into pivotal development.
I'm just trying to size what the anticipated R&D spend is likely to be, let's say 2022, 2023, 2024, relative to the last couple of years. Now, I know you probably don't want to comment on costs, so if you can't talk about money, can you at least talk about the number of patients you anticipate to be in late-stage clinical trials growing, staying stable or shrinking over that period relative to recent history?
Then a second specific question about ibrutinib and the cell data that you showed us.
Can I just understand whether you think this is an ibrutinib effect, whether this is a BTK class effect, and if you think specific to ibrutinib, why?
Let me start with the R part of the R&D spend. In the next years to come, we expect the research budget to be flat. Actually, that's the good news because we are constantly delivering the first-in-class opportunities that you have seen. We are very productive with this regard. Actually, if you look at our out-licensing deals, in addition to fueling our own in-house development pipeline, actually, we've created several assets that we out-licensed to pharma companies like Novartis spin-off companies and other biotech companies.
Again, we believe we are very, very productive on the research side, continue to do so in the future, and deliver first-in-class opportunities for Danny, but also in addition, opportunities for out-licensing with this. Danny?
Yes. Thanks. Thanks, JP. Matthew, thank you for the question.
Now, we have shown today that we expect to deliver, let's say, a series of submissions from 2023 onwards that should really contribute substantially to the top line growth from 2025. We will be, as we have been, up until today, very disciplined, highly disciplined, I would say, in our execution, as we said, I think at the capital markets day. Generally speaking, we are keeping ourselves pretty much on par with our peers in pharma.
We expect R&D expense growth at a very moderate level, I would say. I think that it would be very important to mention that it will be opportunity-driven.
This will provide us the flexibility that if we identify additional opportunities with significant potential and suitable risk profile, we'll be able to pursue that in, again, in a very disciplined way.
Now, you asked a question actually regarding the number of patients that we expect. This brings me to this concept that we haven't spoken about, but it's very close to our heart, which is R&D efficiency. Now, we are looking at our processes and at our usage of data and advanced analytics and also some aspects of our geographical footprint. I don't know if you noticed that we have recently opened an R&D hub in India.
We are trying to reduce as many others do, but we are having quite a nice success in reducing the cost base or let me put it this way, reducing the fat in some cases in order to make sure that the resources go directly to programs.
Now, when it comes to the number of patients in clinical trials, actually, we don't measure it like this. I cannot give you an answer right now whether it's going to be 1,000 plus or minus. For me in the 2021 and onwards clinical trial arena, the number, the overall number of patients is not necessarily a marker of success of our programs.
We wanna have actually clinical trials with smaller numbers of patients with much more focused populations in order to showcase efficacy much better, much faster. I don't know if it gives you the answer that you wanted, but, you know, this is the trend actually in R&D overall.
Thank you. Helpful.
Now.
I'll turn it to Jimmy.
Yeah. Now regarding the slowly expanding lesions, I will hand it over to Jan to refer to that.
Yeah, thank you, Denny. The SELs indeed are very interesting emerging that really gets to the heart of the disability progression that everybody is interested in. As we talked about earlier, it's really everywhere and caused by chronic inflammation. The SELs are really a new and innovative way of looking at that that can be acquired relatively simply by an MRI in a conventional T2 sequence.
We actually do expect that we will see more of the SEL data in the future. Now, to which degree they will eventually be correlated with clinical progression remains to be seen. There's a lot of emerging literature at the moment that really has the common point that SELs really are a biomarker of interest.
Now, in terms of what we have seen so far, as we have shown for ibrutinib in Phase II, we have actually seen a dose-dependent and placebo-controlled effect. For Sanofi, we have noticed that they have recently presented SEL data in the appendix of their Phase II study.
We couldn't really find any reference to placebo or to a clear dose response in the data, as they were presented, both of which we could show for ibrutinib. Ultimately it will remain to be seen in the Phase III trials, how this pans out, but we are actually very encouraged by the initial and emerging data from the SELs in the field overall.
I would like to bring just one sentence. I would like to bring you back to the basic premise here, which is BTK occupancy inside the brain and outside the brain. I think that we have the, I would say, the most robust data set to show that although, you know, we're talking about a variety of BTK inhibitors, but with our dose and dosing regimen, we achieve the highest BTK occupancy inside and outside the brain.
Thank you.
All right. Next question will come from Peter Verdult with Citi.
Thank you. Peter Verdult, Citi. Thank you for doing the session today. Two questions. M1231, your ADC. Forgive me if I missed it, but what is the payload you are using in this bispecific, and how unique do you believe it to be? Secondly, Danny, when we spoke in September, you mentioned interesting data for your Bavencio and TIGIT combination in frontline bladder. Just wanted to know where we are with that program and when the broader market might see that combination or data from that combination in that setting. Thank you.
Yeah. For the first question, I hand over to Andree.
Yeah, the payload we are using in this molecule is a tubulin inhibitor called Hemiasterlin. This is a next generation tubulin inhibitor that has reduced potential for drug resistance. It also is supposed to have a short systemic half-life. If it's by accident released systemically, it's quickly eliminated, and this should improve the safety profile. In terms of efficacy, it is at least as good as the well-established and well-known tubulin inhibitors.
Yeah. For the second question, I'll hand it over to Victoria.
Thank you, Denny. To update you on the status of the anti-TIGIT program, we're actually progressing very well on track. We're delivering the data to define the recommended dose for expansions. Once we have that in hand, which is happening towards the end of this year, early January next year, we are going to start the combination of avelumab with anti-TIGIT asset for urothelial cancer. That's exactly delivering on track and pursuing the interesting hypothesis in this first line maintenance setting where, as you know, avelumab is already established. We're just trying to build up on the strength of the data.
Thanks.
All right, next question will come from Wimal Kapadia with Bernstein.
Well, great. Thank you very much for taking my question. Thanks for hosting the session. Can I ask about enpatoran? Just looking at the mechanism, you know, there's activity for both agonist and antagonist in the clinic, but we've had limited success so far. Just curious, firstly, why do you think the preclinical success has not translated into humans? Is there something specific to the target which makes it quite challenging? Or is it now only that we are truly understanding the TLR three-dimensional structure that we can really improve the tolerability?
Then just tied to that, just given your understanding of the target, have you considered an agonist approach for oncology and is this something you are pursuing? It's been suggested the target is quite interesting from a combination perspective.
Also, any comments there would be quite interesting. Thank you.
Yeah, let me take this question. Yeah, we have to really discriminate here between autoimmune diseases and oncology. We have an antagonist, a small molecule antagonist. What you see in oncology are mainly nucleotide derivatives that are activating the TLR seven eight pathway of other TLR agonists. Actually, we had several years ago an active program in this area.
After some clinical data we generated, decided to close down that chapter. We are right now not pursuing this internally. Of course, we can always think about combination with other partners, and we are actually pursuing those. We have a Bavencio combination study ongoing with the TLR seven. Sorry, TLR nine agonist. Anyway, that's oncology, completely different field.
I would agree with you that so far the translation from preclinical to clinic was, how to say this? Not 100%, let's put it this way. Again, we are focusing internally here on antagonists, and there were some activities in the past to create oligonucleotide-derived antagonists of that pathway.
Those approaches failed. I think I already mentioned this in the presentation. Why are people still pursuing this or pursued this? Because it's very, very difficult to create a small molecule antagonist against TLR7/8. We succeeded here in this, and, to our knowledge, the only other company that succeeded in the small molecule antagonist approach was BMS. Again, we need to discriminate between the two.
Amy, do you want to complement that statement?
Yeah, sure. Thank you. As just to add to what Peter mentioned here is that that's why we also have phase I-B in the cutaneous and systemic lupus to truly understand the effect of enpatoran in actual patients. Furthermore, we also have data from the Phase II COVID-19 patients with patient data, which we are looking into the biomarker information that give us further confidence for the planning for the upcoming Phase II.
We felt that we have the data package to support our upcoming Phase II study for enpatoran.
Great. Thank you.
Next, we'll go to Sachin Jain with Bank of America.
Hi there. Thanks for the call. Just two questions, please.
One, back on evobrutinib in slide 6, where you call out the differentiation. One of the points you've referenced is Phase III for you supported by a robust Phase II. You question the tolebrutinib dose range. I was wondering if you could just give a bit more detail on that and the implications you believe from that. Do you believe the competitor asset is underdosed or overdosed, or is this just a simple observation on the robustness of your Phase II program? I just wanna understand the implications of that call-out.
The second one is a follow-on on the ADC platform, and how you think it differentiates.
Wondering if you could just give a bit more color on the M1231, third line lung proof of concept due next year in terms of size of study, timing, target profile, and I guess what you're looking for, in terms of specific aspects of differentiation versus other, third line lung data sets out there. Thank you.
Okay. Sachin, thank you so much. I will split the question. The first one will go to Jan. The second one on the ADC will go to Andree, if it's okay with you. Jan, go for it.
Sure. To evobrutinib and the dose finding. I mean, certainly, I mean, how tolebrutinib exactly have approached their dose finding, that's probably a question that the Sanofi colleagues can answer more properly here, right? I mean, basically from our standpoint, we have taken a very comprehensive approach to the complex topic of dose finding here.
Dose in this case is not that easy to determine, because as we heard earlier, it's not only about the concentration, it's also about BTK occupancy, which actually is dependent on protein turnover. The relationship in these models is actually quite complex. Getting the dose right with an oral drug with covalent binding and short half-life actually needs quite a bit of sophisticated modeling, as the concentration-effect relationship is not linear.
That was one of the reasons why we have conducted a large, clinical Phase II study and, which basically allows us to model this rich data set. We're actually really confident in that we got the dose approach here right. It will remain to be seen how other companies deal with this question, yeah. We think we have the right dose and, that's what we are using Phase III.
okay, about our ADC platform. When we started to invest into ADCs, we started initially with partnerships. In the meantime we have built internal capabilities and have developed our own platform. M1231 is the result of a partnership where we try to combine or optimize several parameters of ADCs.
1, Peter mentioned already, by specificity. This should increase the specificity for tumors, but also leads to an improved delivery of the payload. We have shown that with this bispecific approach you have an enhanced internalization of this antibody drug conjugate into cell and deliver more payload. More payload than as compared to a monospecific version.
We talked already about the specific payload that we are using and about the very homogeneous product, which was a problem with first generation ADCs. We have here a very homogeneous product with a controlled drug antibody ratio. In future, you will see molecules entering the clinic that are based on our internal platform. The first example is M9140, where we will plan to initiate phase I studies next year.
This is based on a completely different linker payload technology that we have developed ourselves. I can't share too many details, but it's a DNA-damaging payload, and therefore we see significant synergy potential with our DDR pipeline.
Thank you, Andree.
All right, next question will be from James Quigley with Morgan Stanley.
Hello, thank you for taking my questions. Only a couple left from me. On xevinapant in the trial design in the appendix, it mentions only 17 weeks on treatment, so there's no maintenance dosing.
You mentioned there's an ongoing impact on tumor sensitization. Could you talk us through what the mechanism is there, and then why you have decided not to do maintenance dosing? Also, again, it's probably a little bit early to talk about commercialization, but how do you think about commercializing a product like that where there's a big sort of backend loaded benefit without any dosing? That's on xevinapant. Then on the ADC, M1231.
To what extent is bystander toxicity sort of a key part of the mechanism? How does this inform your decision-making when you think about tumors that have sort of lower expression of the potential targets? Thank you.
Okay, I will start with the first question on xevinapant. I'll hand it over to Andree and then on the ADC, we'll give it back to our Mr. ADC to Andree. Look, you know, just to go back to the mechanism of action of xevinapant. Xevinapant is pretty much an apoptosis sensitizer. Yeah. The tumor cells are most susceptible to apoptosis during the phase of chemo-radiotherapy regimen that is giving at the very beginning. It's not a chronic treatment. It's three cycles. During these three cycles, we need to give xevinapant hand in hand as compared to the Phase II study, where we gave three cycles alongside with the chemo-radiotherapy regimen.
In the TrilynX study, we added a fourth cycle just to make sure that we do not lose efficacy for the remnants of the last cycle. We had some evidence that we could do that, but nothing more than that.
This is not a maintenance therapy. Then you continue for sure, you know, following up the patients for their potentially high impact on disease-free survival and of course, of overall survival. We are talking about cycles that each cycle is actually 14 days long. Two weeks and then two weeks, actually four times two weeks. I'll hand it over to Andree to talk about, you know, how does he see this from a marketing perspective.
Thanks, Danny. Yeah, to say we're excited about xevinapant, I think it is probably an understatement. We believe there's a real opportunity to deliver innovation here to a group of patients with a very high unmet need. We see five-year survival rates of less than 50%. Obviously, we've seen a really strong PoC in the Phase II and halves the risk of death in combination with chemotherapy and the Phase III. we'll look to replicate that. Overall, we see xevinapant absolutely has blockbuster potential. We see it as being highly complementary to our Erbitux leadership already in head and neck cancer with Erbitux, especially in the recurrent or metastatic populations.
We obviously see strong commercial synergies and development synergies with our capabilities in head and neck cancer. As you say, it's early days to really think about the absolute indications around your question, and I'm sure we will come back to in due course on that in a later call.
Let me address the bystander question, which is an excellent one, by the way. The bystander effect is very important for the activity of ADCs. This means that once tumor cells take up the ADC, the payload is released and kills the cell. Then this payload is again released into the tumor and can kill cells that don't express the target. Because it is very well known that there's a lot of heterogeneity in the tumor.
Even if you have, you know, assessed by immunohistochemistry or by mRNA expression profiling, high expression of the target, it doesn't mean that it's expressed in each and every cell. This bystander effect or bystander killing actually helps to address tumor heterogeneity. That's one parameter we optimize for our ADCs. Yes, M1231 has bystander activity.
Peter wanted to
Let me conclude here on the ADCs. I think it comes across that we really have gathered a lot of experience and experts actually internally, but also we hired external experts here.
We are really approaching ADCs like you would approach a small molecule optimization program. Not just combining a payload and an antibody and hope for the best, but we are really optimizing the whole construct on the binding side, on the antibody side, on the linker, on the payload, on the anticipated diseases, or as you heard from Andree, also are selecting the payload very consciously between different tumor entities, or envisioned tumor entities.
We approach this like we approach small molecule drug development with the successful projects like tepotinib, ibrutinib and then Patalan. That's how we are approaching ADCs. Thank you.
Thank you.
All right. We have time for one more question.
Thank you. Exactly. Thank you.
Last questions will come from Simon Baker with Redburn.
Great. Thanks for taking my questions and for the call. Two if I may please. Firstly on evobrutinib, as you said at the beginning, the BTK field is crowded, but you're at the front of it. When you've won that race and enter the RMS market, which itself is crowded, I wonder if you could give us an idea on what the typical or the ideal evobrutinib patient looks like.
Then secondly, on xevinapant. If I look at the Medivir and Ascentage molecules, which are probably the two next behind you, they've both gone for bivalent dimers, whereas you've gone for a monomer approach. I wonder if you could just give us some thoughts on why you've done that.
Also, it looks like the patent expiry before any extensions is April 2028. I wonder if you could just confirm that? Thanks so much.
Okay, Andree, would you like to take this?
Yeah, perfect. Thanks for the question, Simon. Yeah, as Danny alluded to, we see evobrutinib really being able to impact chronic inflammation in the CNS that is linked to progression. That happens early on in the disease.
Therefore, we really believe that evobrutinib is ideally suited to be used in treatment-naive patients or very early on in the disease course to have that maximum benefit for patients. I think the other area that I think is really important for evobrutinib is the fact that it is non-depleting in nature. Maybe I'll ask Jan to say a few more words about that as well.
I think that's really important when we're thinking around the efficacy agents that exist in the marketplace today have a significant impact in terms of infection risk. We certainly have not seen any of that in the Phase II and would hope that would play out strongly Phase III as well. Maybe Jan, do you wanna take it from there?
Yeah, sure. Thank you, Andree. I think that's another very important concept because if we think about the anti-CD20 agents nowadays that are long-lasting and B-cell depleting, it can obviously come with a certain infection risk or reduced immunoglobulins.
The potential of an oral agent with a short half-life that has basically the ability to switch B-cell functionality on and off could actually be a very viable treatment options for patients coming off an anti-CD20 who have experienced some kind of infection or reductions in immunoglobulins, yeah. As Andree said, certainly our ideal target patient would be an early MS patient. But nevertheless, for those patients who actually have experienced other effects on anti-CD20s, this will also come as a natural switch option.
Cool. Thank you. Thank you both. I'll hand it over to Andree to address the xevinapant question.
Okay. Yeah. Thanks for the question. We are aware that other companies are pursuing different approaches. You know, we in-licensed this molecule from Debiopharm. They were responsible for the discovery, and we have done a very careful due diligence, including repeating some of the mechanistic data internally. We are convinced about the strength of this molecule, though it is slightly different than some of the competitor molecules. We have seen very strong data in sensitizing to apoptotic stimuli, to radiotherapy, and also to chemotherapy, which was the basis of the current clinical development program.
Thank you so much, Andree. To your question regarding the patent expiration, we're talking about approximately 10 years from launch. Just to give you this number.
Great. Thanks so much.
Thank you very much for all your questions. This now concludes this R&D update call, and thank you for joining the Merck journey. Goodbye.
Ladies and gentlemen, thank you for your attendance. This call has been concluded. You may now disconnect.