Merck KGaA (MRK) Earnings Call Transcript & Summary

Dear ladies and gentlemen, welcome to the Merck R&D Update Call. [Operator Instructions] 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; Joern-Peter Halle, Head of Research; as well as Andrew Paterson, Chief Marketing Officer. For the Q&A part of this call, we will also be joined by Andree Blaukat, Head of Research Oncology, Amy Kao, Head of Research Immunology; Jan Klatt, Head of Development Neurology & 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. Andrew, Joern-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 3, 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 5 focused assets with first-in-class potential that, in line with our strategy, have distinct uncorrelated risk. Moving to Slide 4. We see that all of our 5 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. Berzosertib enhances the efficacy of chemotherapy, especially top line inhibitors. We'll talk about it later. M1231, which is our first antibody drug conjugate. With this novel asset, we are using "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 wide applicability across multiple solid tumors that we hope many patients will benefit. Last, but not least, the new and the novel kid in 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 5 focus assets and beyond leverages and extends deep expertises, and we see expertises truly multidimensional. What do we mean with that? We have a strong disease insights and wealth of data to inform our development strategy, especially in head and neck from and Erbitux in 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, and 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. So 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. And 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 we look no further than the numerous followers that we have attracted. Importantly, there is a significant time element here. This is not 1 pack of 4. Evobrutinib is in the lead with a key neck-to-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 efforts 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 2 points here. Brain penetration is not just a binary attribute, which is stick is 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. And beyond that, the real issue is whether you impact resident immune cells in the CNS, mostly the microglia. So 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. And last but not least, our integrated safety profile, our 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 #7 and talk about the dosing. Now all covalent BTK inhibitors that I showed on the previous slide, including evobrutinib, have a rather short plasma half life of something like 2 hours. So 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. Now the light purple line in the middle of the left panel shows that once daily dosings result in suboptimal BTK occupancy. And this is what you can expect to see for once daily dosing of any BTK inhibitor with a short half-life. Now in the middle panel, you see that 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 experienced the greatest ARR reduction of 0.11 with evobrutinib. And 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 by far less impressive ARR. So the data clearly demonstrate that you need to sustain high 95% BTK occupancy during the entire dosing interval to achieve strong ARR and 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. And 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. And we did that. We enriched our model with the most accurate data. We took CSF, cerebrospinal fluid, of evobrutinib-treated patients. And here, you see that evobrutinib concentration in the CSF from patients in the Phase II compared to evobrutinib concentrations in the plasma form patients in the Phase II. Now at the first glance, you may think that the CSF and plasma levels are different. So based on our population PK modeling, we know that these CSF and plasma levels are sufficiently comparable. And without getting into too much fancy modeling technical stuff, we expect that the majority of patients treated with the Phase III doses of evobrutinib will have BTK occupancy in the CSF, which is higher than 95%. Next, I'll show you 2 data sets to demonstrate what it does in the brain. So let's move to Slide #9. The first data point is from our proprietary mouse model of leptomeningeal inflammation, LMI. LMI in 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. So in Slide #10, 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. 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 acute damage that we measured with the well-known gadolinium-enhancing lesions. Slowly expanding lesions or SELs; SELs, I refer to SELs for the transcript people, 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, and 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 on Slide 11. We are 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 enzyme elevation. ALT elevations were asymptomatic and reversible upon treatment discontinuation. They occurred mostly or exclusively actually, during the first 3, 4 months of therapy and needless to say, up until now, no case of Hy’s Law or liver failure attributed to the drug. Now broadening the lens a little bit, when you look at the safety data of other BTK inhibitors, you see quite a similar ALT pattern. So the likelihood of seeing these LFT elevations as a class effect in our eyes is not low. And by the way, we have already enrolled more than 2,000 patients into our MS Phase III program, and the trials are being monitored as of now without changes. So in Slide #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. And our large safety database, as I've said before, shows very good safety and tolerability so far. The Phase III studies, as we said a couple of months ago, are fully recruited, and we are 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 of 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. And by the way, IAPs also have been reported to have immunomodulating properties. Now xevinapant blocks those IAPs, actually key 3 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. So in this type of cancer, escape from apoptosis is something that needs to be tackled when a definitively sought chemo regimen is administered, and we want to avoid the emergence of resistant clones. Now we're 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 2 points here. The first one is to strengthen the internal consistency of the benefits seen across all endpoints, primary and secondaries. We do see it as a strong proof of concept and by no means is 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 the locally advanced squamous cell carcinoma of the head and neck is -- this setting is a curative setting. These patients do not have metastatic disease, they have large tumors that may be difficult, if not impossible, to remove by surgery. But with the right treatment approach, we can potentially save many lives in this setting. And looking at the hazard ratios for 3 years for PFS and OS really provides an idea of the transformational benefit that we hope to deliver with xevinapant over the existing standard of care. Next year, at ESMO 2022, we hope to share the 5 years OS data. So 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 oncologists. So this is quite complex. Now based on our Erbitux heritage, we know the setting very well. In fact, our market leadership position in head and neck cancer appear 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 2x2 metrics shows the 2 key criteria determining treatment, tumor resectability and the patient's fitness, particularly when it comes to treatment with cisplatinum. Now the trialings or the Phase III study in cis eligible patients with unresectable tumors is underway and recruiting patients globally in most 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 second Phase III study in the cis ineligible segment. And the reason for that is, as you can see here, 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 trialings, 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 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 in 2025. 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. And more importantly, we are finalizing our second Phase III trial design in cis ineligible patients and plan to initiate it in -- towards the end of the first half of 2022. Let's jump -- let's skip Slide 17 and jump to straight to Slide 18 and dive into DNA damage reversal. Merck has built 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. And 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 SEL cycle to progress without DNA repair. So fast replicating tumor cells accumulate DNA damage, which eventually results in tumor cell death. Now 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. So 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 preexisting 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 a combination with chemotherapy and specifically a TOP-1 inhibitor. TOP-1 inhibitors inflict this DNA damage, and berzosertib prevents the repair [indiscernible] berzosertib actually enhances or potentiates the efficacy of TOP-1 inhibitors such as topotecan. 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, Slide 19, and talk briefly about small cell lung cancer. So this is our most advanced indication for berzosertib refractory small cell lung cancer. And 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. The contribution of IO in this setting has been rather modest, only adding a few months to overall survival in first-line maintenance. And the key challenge in small cell lung cancer is that responses are rarely durable, either first line or in second line. So unfortunately, patients progress very rapidly even after achieving a response. In Slide 20, we will see that with the 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 swimmers plot. Responses have been very durable with 2/3 of patients who have durability of response, which was longer than 6 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. So with berzosertib, we have 2 ongoing studies: a randomized Phase II controlled study run by the NCI, berzo plus topo versus topo alone and our Merck-sponsored study, the DDRiver 250, which is a single arm berzo plus topo, which is ongoing very well. Let's move to Slide 21. Our development focus with berzo is to maximize actually its potential in refractory lung cancer. We did not miss the gray 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 Joern-Peter.

Yes. 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? And Danny nicely explained it already. It's ATR for monotherapy and PARP inhibition. But why do we need an oral compound for this while berzosertib is an IV compound? So on the left top side, you see actually berzo is really, really well suited for the combination with IV chemotherapy. So it's rather short-lived, and this allows you to precisely synchronize the chemotherapy and the ATRi inhibition in this chemo ATR combination. So 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 2 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, and we believe M1774 is really ideal because it has a really reliable and excellent PK profile to achieve this consistent and prolonged exposure. So where are we with 1774? We are in the dose escalation and actually achieved already, in the monotherapy, the active dose, and we have a manageable mode of action-related safety profile. The PARP combination is ongoing, the dose escalation there, and we expect those findings soon. And stay tuned. Actually, not only we will 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. So let me switch gears to Slide 24, still oncology, but switching gears to antibody drug conjugates, ADCs. So ADCs, pretty clear -- the goal is to deliver a toxic payload via the antibody very specifically to the tumor. And you probably know, first-generation ADCs have solid efficacy, but have some limitations actually outlined here on the slide, for example, safety and others. So there were recently actually quite encouraging data by competitors, second-generation ADCs. But we still believe when we started our discovery activities in ADCs a few years ago and still believe today that there is tremendous room for improvement. Why is this? We believe that you need to optimize all 3 elements of an ADC simultaneously in parallel. So it's not sufficient to optimize 1 individual element. So the antibody, the linker or the payload, you have to really solve our puzzle like the Rubik's Cube that you see at the bottom, and we believe that for the first 2 ADCs we're bringing into the clinic or brought in the clinic, we have solved this. So the first one that entered the clinic in January is 1231, I come to this in a minute, a bispecific MUC1/EGFR ADC, and the second ADC become M9140 first in human studies are planned actually for early next year. So on Slide 25, let me dive a little bit deeper into 1231, our triple innovation ADC. So first of all, we have a bispecific ADC, actually, the first one in the industry that moved into the clinic, targeting MUC1/EGFR to increase the tumor selectivity and boost also the internalization. Number 2, we have a site-specific conjugation, which leads to a structural very homogeneous ADC with a consistent DAR, so drug antibody ratio, and we believe that's essentially for a good safety profile. And the third innovation is the next-generation tubulin payload (sic) [ anti-tubulin payload ] which is addressing not only multi-drug 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. So 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? And to answer this question, let me switch to Slide 26. Here, we compare 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 coexpression, and you actually can hopefully appreciate that a significant percentage of major tumors in the range of 60% to even up to 80% of these patients in these indications are expressing both targets on tumor cells. If we 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. But if you compare this actually, the majority of the tumors that express EGFR are also expressing MUC1. So actually, that's the reason why we have relative high percentages on the left-hand side with the co-expression. But 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 tissue. So the ratio between normal tissue and tumor depicted at the bottom of this slide is very high, too high for ADC. So 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 [indiscernible] HER2, which have a good ratio but especially to others like TROP2 and Nectin-4, which actually has a relative high ratio between normal tissue and tumor. So where are we with this program? Actually, we progressed significantly, which you can see on Slide 27. We are in dose escalation. It's progressing very well. We are close to an effective dose based on preclinical data. And if you reach the predictive therapeutic window, which we should reach in the near future, we will expand that study with 2 cohorts: one in third-line biomarker selected NSCLC patients and the other one in ESCC second line. So 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 Danny has already outlined in the later portfolio. Slide 29. Let me first describe the mode of action of a TLR7/8 inhibitor. So you probably know, TLR receptors are the receptors in the immune system, mainly in the innate immune system that are censoring 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 TLR7 and 8 and induce the innate immune system. So that's great. But actually in indications like lupus, there is an aberrant chronic activation of TLR7/8 by endogenous RNA that is released from dying cells. You have a chronic inflammation because of this. And 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, a very, very convincing data. So you can ask a question if this is such a great target. Why are not others pursuing this? And you should know that actually TLR7/8 was -- seemed to be undruggable, at least with small molecules. So some people tried this oligonucleotides and derivatives, but really, were not really successful. But we succeeded actually via phenotypic screen and with structural information from a collaborator to really identify and then optimize small molecules. And now we have a very potent and selective small molecule called enpatoran that is blocking TLR7/8 very efficiently. So 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. And then downstream, you have a variety of effector sales that are activated via this pathway, so dendritic cells, monocytes, neutrophils and B cells. So what you can now do to block the pathology of lupus is either you block all these effector cells that 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. Or you go to very specific modern treatments that deplete, for example, B cells. But 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. So 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. And 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. So again, we believe that this is a very, very nice way to address lupus with the central mediator. So is it just theory? No, we have actually 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 started. We see a very good safety profile. And with 200 milligram QD, you see the pharmacokinetic dynamic effects on the right side. Actually, here 2 examples showing that with this dose of 200 milligram QD, we blocked the induction of interferon alpha which would induce dendritic cells, and we can also block the induction of IL-6, which would stimulate macrophages. So 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 a study in COVID-19 patients, hospitalized patients with strong induction of inflammation. And what we saw actually is with various end points, a trend towards higher recovery rates, the analysis 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 2 cohorts: in cutaneous CLE, so the skin manifestation of lupus; and in SLE. We believe that we will -- could have proof of concept and then a submission earliest in CLE in '26 and 1 year later in SLE. So I think that's a very, very good example for how we approach R&D at Merck. Strong preclinical data, strong mechanism, strong science and a strong translational spirit. And with this, I'm handing over to Danny.

Thank you so much, JP. So let's move quickly to Slide 34. So 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. And today, as you heard, as we are focusing on the most important value drivers in our pipeline, our 5 focus assets here are highlighted. The list shown here is not exhaustive. 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 2 new 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 mutant patients with metamification non-small cell who have progressed on osimertinib. We expect 2023 to be a very busy year for us in terms of readouts, evobrutinib Phase III studies in RMS, berzosertib Phase II study in refractory small cell and up to 5 proof-of-concept readout that you can see here on the slide. And looking at Slide 36. From 2023 onwards, we are targeting at least actually 1 submission per year. Obviously, the visibility of the earlier assets, be it M1231 and enpatoran is slightly different, but this is the general team here. Our 5 focused 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 #37, in conclusion, we told you about how we center our pipeline around the 5 focus assets. We're building focused leadership positions in areas with deep expertise. We even further strengthened the pipeline. We started doing that 2022, we'll 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 second Phase III study for xevinapant and also the completion of recruitment for the TrilynX study, the readout of 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 3 of Merck. We have the science, the drive and most importantly, the people and the teams to drive that. So 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. And for a bit more than a year, I'm also responsible for immuno-oncology research. My team is based in Darmstadt, Boston, and Tel Aviv and have discovered several of the clinical candidates we are talking about today and have generated translation research data that guides clinical development. I'm looking forward to sharing more details of the cutting-edge research in our 6 focus areas: oncogenic signaling, DNA damage response, antibody drug conjugate, [indiscernible] biology, [indiscernible] biology and stress and tumor plasticity in future.

Hi. Good day. 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 in biomarker research and 7 years in clinical development in autoimmune diseases. I joined Merck for about 4 years -- or 5 years, with both academic and also head of development background. I now lead immunology research since July. My team discovered the clinical asset, as you heard from Danny and Peter, on evobrutinib and enpatoran and also supports the development in neurology and immunology. In immunology research, we leveraged 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 and also application of novel modalities such as ADC, degrader, more to come. Let me pass it to Jan.

Good day, everybody. So my name is Jan Klatt, and I joined Merck recently coming from Novartis where I've worked for the last 16 years. And I 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 top diseases, plus having personally worked in the MS field for a long time in my former life. I'm very excited to have the 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 amongst the BTK inhibitors and 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. And 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. [Operator Instructions] With this, Alan, I would kindly ask you for the first question, please.

[Operator Instructions] Your first question comes from the line of Richard Vosser with JPMorgan.

Two please, on evobrutinib. 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 so far to just RMS? And then just a clarification, maybe more detail. Just on the liver enzymes, Danny, I think you mentioned that you thought there would be potential across all different types of BTKs from the competition. Just if you could go through the reasoning in a bit more depth for us, that would be great.

Thank you, Richard. I'll hand it over to Jan to tackle the first question.

Yes. Thank you for the question. So 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. And based on lots of scientific advance in this area, we now -- we are now basically looking into this in our Phase II data set. And for example, the SELs that Danny has described actually make us feel good about our ability to target progression overall. And coupled that with the fact that we know that evobrutinib has a strong impact on acute inflammation, as demonstrated in our Phase II study, makes them potentially ideal therapy for RMS patients, which still represent 85% of all MS patients. Now overall, maximizing patient benefit is very important to us. So 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. And 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 progress of MS because you can't run a proper PoC study there. But again, irrespective of the subgroups, the point is really progression is everywhere, and the effects on progression are of interest to us. And based on the emerging data, we do believe that evobrutinib has best-in-class potential.

Yes. Thanks, Jan. To your second question, Richard, without getting into a mechanistic explanation, which there are and these are hypothetical at this stage, is just look at the data, other BTK inhibitors that are in the mix for MS have been studied in still by far less lower number of patients. However, when you look at the liver enzyme's elevation in hematological malignancies, then you can see it for one of them, if I'm not mistaken, you can see the same signal, right? And 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.

Our next question will be from Matt Weston with Crédit Suisse.

Two 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, '22, '23, '24 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? And then a second specific question about evobrutinib and the SEL data that you showed us. Can I just understand whether you think this is an evobrutinib effect, whether this is a BTK class effect and if you think specific to evobrutinib, Why?

Yes, let me start with the R part of the R&D spend. So in the next years to come, we expect the research budget to be flat. Actually, that's good news because we are constantly delivering the first-in-class opportunities that you have seen. So 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. So 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, 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. And 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. But I think that it would be very important to mention that it will be opportunity driven. So 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 gaining a very disciplined way. Now you mentioned something about -- you asked the question, actually, regarding the number of patients that we expect. And 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 our usage of data in 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. So we are trying to reduce as many others do, but we are having quite a nice success in reducing the cost base and -- or let me put it this way, reducing the fact 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. And I cannot give you an answer right now whether it's going to be 1,000 plus or minus. But for me, in the 2021 and onwards clinical trial arena, the number or the overall number of patients is not necessarily a marker of success of our programs. We want to have actually clinical trials with smaller number of patients with much more focused populations in order to showcase efficacy much better, much faster. So I don't know if it gives you the answer that you wanted, but this is the trend actually in R&D overall. Now regarding the slowly expanding lesions, I will hand it over to Jan to refer to that.

Yes. Thank you, Danny. So the SELs indeed are very interesting emerging that really gets to the heart of the disability progression that everybody is interested in. And as we talked about earlier, it's really everywhere [Technical Difficulty] caused by chronic inflammation. And so the cells are really a new and innovative way of looking at that, that can be acquired relatively simply by an MRI in the conventional T2 sequence. So 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, it will remain to be seen. There's a lot of emerging literature at the moment that really has the common point that SELs really is a biomarker of interest. Now in terms of what we have seen so far, as you -- as we have shown for evobrutinib 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 evobrutinib. So ultimately, it will remain to be seen in the larger Phase III trials, how this pans out, but we are actually very encouraged by the initial and emerging data from the sales 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 we're talking about a variety of BTK inhibitors, but with our dose and dosing regimen, we achieved the highest BTK occupancy inside and outside the brain.

Next question will come from Peter Verdult with Citi.

Peter Verdult, Citi. 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? And then 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?

Yes, for the first question, I hand over to Andree.

Yes. So the payload we are using in this molecule is a tubulin inhibitor called hemiasterlin. And this is a next-generation tubulin inhibitor that has reduced potential for drug resistance. And also it's supposed to have a short systemic half-life. So 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.

Yes. And for the second question, I'll hand it over to Victoria.

Thank you, Danny. So to update you on the status of the anti-TIGIT program, we're actually progressing very well on track. We are delivering the data to define the recommended dose for expansions. And once we have that in hand, which is happening towards the end of this year, probably January next year, [Technical Difficulty] the combination of [Technical Difficulty] cancer. So that's exactly delivered on track and viewing the interest in [Technical Difficulty] maintenance, second with [Technical Difficulty] established, we're just trying to build up on the strength of the data.

Our next question will come from Wimal Kapadia with Bernstein.

Can I ask about enpatoran? So just looking at the mechanism, there's activity for both agonists and antagonists in the clinic. But we've had limited success so far. So 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 3-dimensional structure that we can really improve the tolerability? And 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, and is it being suggested the target is quite interesting from a combination perspective? Also any comments there would be quite interesting.

Yes, let me take this question. Yes, we have to really discriminate here between autoimmune diseases and oncology. So we have an antagonist, a small molecule antagonist. What you see in oncology are mainly nucleotide derivatives that are activating the TLR7/8 pathway or other TLR agonists. Actually, we had, several years ago, an active program in this area. But after some clinical data we generated, decided to close down that chapter. So we are right now not pursuing this internally. Of course, we can always think about combination with other partners, and we're actually pursuing those. So we have a Bavencio combination study ongoing with TLR7 -- sorry, TLR9 agonist. But anyway, that's oncology, completely different field. And 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. So again, we are focusing internally here on antagonists. And here, there were some activities in the past to create oligonucleotide derived antagonists of the pathway. Those approaches failed. I think I already mentioned this in the presentation, but why are people still pursuing this or pursue 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. And again, we have to ready to discriminate between the 2. Amy, do you want to complement the statement?

Yes, sure. Thank you. And I'll just add to what Peter mentioned here is that that's why we also have Phase Ib in cutaneous [indiscernible] lupus to try understand the fact of enpatoran in actual patients. Furthermore, we also have data from the Phase II COVID-19 patients for patient data, which we are looking into the biomarker information that give us further confidence for the planning for the upcoming Phase II. So therefore, we felt that we have the data package to support our upcoming Phase II study for enpatoran.

And next, we'll go to Sachin Jain with Bank of America.

Just 2 questions, please. One, back on evobrutinib in Slide 6 where you call out the differentiation. One of the points you referenced is a Phase III fees supported by a robust Phase II in your question, the tolebrutinib dose range. Wondering if you can just give a bit more detail on that. Any implications you believe from that? Do you believe the competitor asset is underdosed or overdosed? Or is this a simple observation on the robustness of your Phase II program? I just want to understand the implications of that call out. The second one is a follow-on on the ADC platform and how you think it differentiates. Wonder 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?

Okay. Sachin, thank you so much. I will split the questions. The first one, we'll go to Jan. The second one on the ADC will go to Andree, if it's okay?

[indiscernible] to evobrutinib and the dose finding. I mean, certainly, I mean, how tolebrutinib exactly have approached their dose, I mean that's probably a question that the Sanofi colleagues can answer more appropriately, right? I mean, basically, from our standpoint, we have taken a very comprehensive approach to the complex [Technical Difficulty] of dose finding here. And dose in this case, it's 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. And the relationship in these models is actually quite complex. So getting the dose right with an oral drug with covalent binding in short half-life, actually need quite a bit of sophisticated modeling, as the concentration effect relationship is not linear. And 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. So we're actually really confident in that we got the dose approach here right, and it will remain to be seen how other companies deal with this question here. But we think we have the right dose, and that's what we are using in Phase III.

About our ADC platform. When we started to invest into ADCs, we started initially with partnerships. But 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. One Peter mentioned already, bispecificity. This should increase the specificity for tumors, but also leads to an improved delivery of the payload. So we have shown that with this bispecific approach, you have an enhanced utilization of this antibody drug conjugated to cell and deliver more payload, more payload than as compared to a monospecific version. And then 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. So 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 plan to initiate a Phase I study 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.

All right. Next question will be from James Quigley with Morgan Stanley.

A couple from me. So on xevinapant in the -- and the trial design in the appendix, it mentioned only 17 weeks on treatment, so there's no maintenance dosing. You mentioned there's an ongoing impact on tumor sensitization. So could you talk us through what mechanism is there and then why you have decided not to do maintenance dosing? And then also, again, it's probably a little bit early to sort of ask about commercialization, but how would you think about commercializing a product like that where there's a big sort of back-end loaded benefit without any dosing of xevinapant. And then on the ADC M1231, to what extent is bystander toxicity sort of a key part of the mechanism? And how does this inform your decision-making when you when you think about tumors that have sort of lower expression of the potential targets?

Okay. I will start with the first question on xevinapant, I'll hand it over to Andrew. And then on the ADC, we'll give it back to Mr. ABC -- to Andree. So look, just to go back to the mechanism of action of xevinapant, xevinapant is pretty much an apoptosis sensitizer, yes? And the tumor cells are most susceptible to apoptosis during the phase of chemoradiotherapy regimen that is given at the very beginning. It's not a chronic treatment. It's 3 cycles. So during these 3 cycles, we need to give xevinapant hand-in-hand as compared to the Phase II study, where we gave 3 cycles alongside with the chemo radiotherapy regimen. In the trialing 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. And then you continue for sure, 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, 2 weeks and then 2 weeks, 2 weeks, actually 4 times 2 weeks. I'll hand it over to Andrew to talk about how this seems from a marketing perspective.

Thanks, Danny. Yes, to say we're excited about xevinapant, I think is probably an understatement. We believe there's a real opportunity to deliver innovation here to a group of patients with a very, very high unmet need. We see 5-year survival rates of less than 50% [Audio Gap] We have -- obviously, we've seen a really strong PoC in the Phase II [indiscernible] the risk of death in combination with chemotherapy and the ongoing Phase III, we'll look to replicate that. So overall, we see xevinapant has -- absolutely has blockbuster potential. It's -- we see it as being highly complementary to our ex U.S. leadership already in the head and neck cancer with Erbitux, especially in the recurrent metastatic populations. And we obviously see strong commercial synergies and development synergies with our capabilities in head and neck cancer. I'd just say it's early days to really think about the absolute indications around your question, and I'm sure we will come back to you 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. So even if you have assessed by immunochemistry or by mRNA expression profiling, high expression of the target, it doesn't mean that it's expressed in each and every cell. And this bystander effect or bystander killing actually helps to address tumor heterogeneity. And that's one parameter we optimize for our ADCs. So yes, M1231 has bystander activity. And Peter wanted to...

Yes. 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. And 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 [Technical Difficulty] the whole construct on the binding side, on the antibody side, on the linker, on the payload on the anticipated diseases. So as you heard from Andree also are selecting the payload very, very consciously between different tumor entities or envision tumor entities. So again, we approach -- likely approach small molecule drug development with the successful projects like tepotinib, evobrutinib and enpatoran. So again, that's how we are approaching ADCs.

All right. We have time for one more question. Last question will come from Simon Baker with Redburn.

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. So when you've won that race and entered 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? And then secondly, on xevinapant. If I look at the [indiscernible] molecules, which are probably the 2 next behind you, they've both gone for bivalent dimers, whereas you've come from a monomer approach. I wonder if you could just give us some thoughts on why you've done that? And also, it looks like the patent expiry before any extensions is April 2028, I wonder if you could just confirm that?

I think, Andrew, would you like to take this?

Yes, perfect. Thanks for the question, Simon. Yes, as Danny alluded to, we see evobrutinib really being able to impact chronic inflammation in the CNS that is linked to progression. And that happens early in the disease, and therefore, we really believe that evobrutinib is ideally suited to be in treatment-naive patients or very early on in the disease course to have that maximum benefit for patients. So I think the other area that I think is really important for evobrutinib is the fact that it is nondepleting in nature. And maybe I'll ask Jan to say a few more words about that as well. And 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. And we certainly have not seen any of that in the Phase II, and we'd hope that will pay out strongly in Phase III [indiscernible] Maybe, Jan, do you want to take it from there?

Yes, sure. Thank you, Andrew. I think that's another very important concept. Because if we think about the anti-CD20s nowadays that are long-lasting and it can obviously come with certain infection risk or reduced immunoglobulins. And the potential of an oral agent with the half-life that has basically the ability to switch B-cell functionality on and off, actually be very viable treatment options for patients coming off an anti-CD20 who have experienced some kind of infection or reductions in immunoglobin. [indiscernible] certainly our ideal target patient would be an early MS patient, but nevertheless, for those patients who actually have experienced other effects on anti-CD20 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. Yes. Thanks for the question. We are aware that other companies are pursuing different approaches. 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, and 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 base of the current clinical development program.

Thank you so much, Andree. And to your question regarding the patent expiration, we're talking about approximately 10 years from launch. So just to give you this number.

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.