Dear ladies and gentlemen, welcome to Merck's R&D Update Call 2020. 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, Abby. Dear ladies and gentlemen, a very, very warm welcome to this R&D update call. My name is Constantin Fest. I'm Head of Investor Relations here at Merck. It's great to have all of you here joining this call, which is also the third deep dive session of last week's Capital Markets Day. This is why I'd like to directly hand over to Amelie Schrader, Director, Investor Relations and Principal Healthcare Lead, to kick off this deep dive.
Thank you, Constantin. Dear ladies and gentlemen, a very warm welcome also from my side. I kindly ask you to please turn to page three of the slide deck for a brief introduction of the four representatives of our R&D and commercial leadership joining us on this call today. I am very pleased to welcome two members of our Healthcare Executive Committee, whom you know very well, Luciano Rossetti, Global Head of Research and Development, as well as Rehan Verjee, Head of the Global Innovative Medicine Franchises and President of EMD Serono. Furthermore, I am delighted to also introduce you to two senior leaders from our R&D organization, Joern-Peter Halle, Global Head of Research, as well as Klaus Edvardsen, Head of Oncology Development. Over the next half an hour, the team will be walking you through our key pipeline highlights, major achievements and upcoming milestones.
Following this, we will then be opening the floor to your questions. With that, let me hand it to Rehan.
Thank you, Amelie. Welcome all also from my side. On slide four, we have the agenda for today, and we're going to start with an overview of our research and early innovation, followed by a focus on select really promising clinical candidates. We're also going to include some updates on the launch momentum for BAVENCIO in the U.S., and also give you a sense of how the MAVENCLAD launch is continuing to progress. On slide five, I just want to link back to where the executive board left off at the Capital Markets Day. Stefan introduced you to the three main drivers of growth for the group for 2022 and beyond. You can see that more than 80% of the growth is expected to come from these big three. Of course, the healthcare pipeline is a big part of this growth.
As you know, the EUR 2 billion by 2022 has been our ambition. We remain committed to that. We're very confident in that. Not only the EUR 2 billion, but we also believe that based on the progress in the pipeline, beyond 2020, 2022, we will see even more contribution from the healthcare pipeline to the growth potential of the group. Slide six, please. Just from the Capital Markets Day. It's just a reminder that from a healthcare perspective, despite the pandemic, healthcare has some really strong underlying momentum. As you know, in H1, in the first half of the year, we posted good organic growth numbers, and so that showed some real resilience. Also, we've had some really important developments. The approval of BAVENCIO June 30th, and now filings accepted by other major jurisdictions and agencies.
We've seen tepotinib approval in Japan as the first selective and highly targeted MET inhibitor, and we continue to see real progress with MAVENCLAD while we're continuing to drive the pipeline forward. Now let's get into the meat of the R&D update and let me hand over to Luciano.
Terrific, Rehan. Thanks. I want to also send from my own personally, welcome to this conference. Many of you have been following our journey for a long time. I feel that slide seven will give you a little bit of a very quick summary of the journey before we get into the R&D review. It's been an interesting ambition for us and a journey to get to the point to create an R&D organization that could be a serial innovator within specialty medicine. That's the ambition. We will give you a little bit, some point of validation related to where we are today. I hope you're going to hear more from Peter in particular, but also from Klaus, about some of the evolving potential for sustainability of this success over the last few years. I start from the left side of the slides very quickly.
These are 10 new molecular entity that are still active in the pipeline. These are first-in-human since 2014 that are still active in the pipeline. We are also very proud of having making rapid choice on other NMEs in the pipeline once they were tested in humans. The point here is the quality of these NMEs, the fact they're testing first-in-class hypothesis and also the yield. The majority of the discovery output has really translated in the mechanisms that are currently tested in the clinic. I think that's an important point. They're trying to reduce the cost of failure. I move very rapidly. I think additional evidence of our progress is particular emphasis on the scientific leadership. We can see now that not only the number of scientific publication and report to meetings, but the quality has increased quite a bit.
You see some of the example of the various journals, peer-reviewed journals, where we publish some of our findings. I just want to remind everyone about the two New England Journal of Medicine reports on the VISION trial for tepotinib and on our JAVELIN Bladder 100 urothelial cancer very recently published in the New England, as I mentioned. Another way to look at our aspiration to go forward with, again, excellent quality of clinical development is the success in obtaining what FDA and other regulatory agency consider way to accelerate and to support the availability of the real major innovation for serious diseases within oncology in particular. I mentioned that we had, in recent year, four breakthrough designation with tepotinib and BAVENCIO, SAKIGAKE designation, and recently also the Real-Time Oncology Review mechanism has been used by FDA for some of our programs.
Validation also on the fact that we now have three major programs that are going into approvals, global approvals, six approvals within three different brands, MAVENCLAD, BAVENCIO, and TEPMETKO. You're going to hear more from Klaus about that. Finally, I certainly think that Rehan has already illustrated our ambition that this novelty will contribute significantly to our revenue in the future. You see that as we start to see that uptick of contribution already, Rehan will talk about this at the end, particularly in view of 2022. What we now want to focus on is the sustainability.
I know many of you have been asking for us to show you not only the success we had with these various programs in the clinic, but also give us a window in the future, a window in how the company is trying to create research and clinical operations that can be sustained for the future. To do that, I decided it's very important for you also to know our leadership talent. We created a position of head of research that Peter Halle has accepted to take. I just want to mention that Peter has been also, for a long time, the head of our immuno-oncology discovery and development operation early on, early development operations, as well as head of external innovation. He's been already an engine for this research success.
We cannot share with you details of many of the programs, but we have taken some samples to give you an idea of our thinking, how we want to innovate in the future. Thank you, Peter.
Yeah. Thanks, Luciano. Also a warm welcome from my side. I'm really looking forward to our interactions and discussions in the future. Luciano shared with you how our R&D organization has gained some momentum in recent years. I would like to give you better understanding about the drivers behind this success and why I'm so excited about the research team. If you look at slide nine, you see everything we do starts with the understanding of the disease biology. We run all steps of the discovery process, and identify then highly differentiated drug candidates. Our work doesn't stop there. Preclinical combination data, biomarker data, modeling simulation, all of that informs our clinical development colleagues. They then close the cycle by providing us in research with data and insights from clinical trials and real-world evidence to help us better understand the disease biology.
Let me explain to you which areas we have selected and we are focusing on slide 10. At the Capital Markets Day in 2014, we shared with you our Translational Innovation Platform concepts. We call those TIPs. Ever since, the three TIPs are fully empowered to drive the innovation strategy, and we apply a thorough peer review and establish scientific advisory boards. As you will see in a minute, this really paid off and boosted our productivity, we kept these three TIPs in oncology with targeted therapies, immuno-oncology, and immunology. This continuity built the deep expertise we need and helped us to double down on our success. What evolved, however, since 2014, is the collaboration between the TIPs. I will share with you an example later.
We now are not only evolving the organization, we are constantly reinventing ourselves, exploring new disease areas, biology areas, and partnerships with academic institutions such as the ICR in U.K., the NCI in U.S., Karolinska in Sweden, and the Weizmann Institute in Israel. Also with biotech companies such as BioMed X in Heidelberg. This leads to new biology areas such as phagocytosis and TIP immuno-oncology, stress and plasticity in TIP oncology, and others you see here on the slide. We have mature areas such as oncogenic signaling and immune complex signaling that have developed the drug candidates Luciano was already talking about. On slide 11, you see a full list of internally discovered products and development candidates such as BAVENCIO, eribulin, bintrafusp, tepotinib. You're very familiar with them.
As we continue on this successful path in research, so what we are doing, we really take conscious risk early on in the hit discovery phase, and then apply rigorous paths, high-quality paths for the quality of the molecules and the differentiation where the standard of care, and currently focus on eight projects in exploratory development. Some of them actually close to the nomination of a development candidate. All of this is supported by central discovery platforms for NCEs, NBEs, and ADCs, as well as development platforms such as safety pharmacology, DMPK, CMC, all part of the research organization. Despite this internal success, we don't have a non-inventive here syndrome. Allow me a side note, this shouldn't come as a surprise to you with my former roles in biotech and business development.
The external innovation team that Luciano just mentioned spans the whole chain from lifecycle management to discovery, and is still part of my team. Let me talk about this in more detail on slide 12. On this slide, I want to give you a better understanding on how we make rigorous portfolio and partnering decisions to maximize the value of our pipeline and portfolio. You can see from this internal bucket at the left side, we have projects that we execute from A- Z internally, such as tepotinib, which we discovered in-house and brought to approval in Japan recently. We complement this internal discovery approach with co-discovery deals, Domain, Sutro, Ablynx are examples, and also in-license in focus areas such as the deal with Vertex in the area of DNA damage response.
This approach leads to such a rich pipeline and portfolio of development candidates that we cannot develop everything internally. We maximize the potential of our assets in co-development deals, GSK, Pfizer as examples, or spin-off assets into startup companies that have better internal expertise for the specific areas, iOnctura, Asceneuron are examples here. We also licensed back recently M9831 to Vertex for specific indications in gene editing. All of that to maximize the value of the portfolio according to the three lenses you see on the right-hand side. Let me switch gears. We promised you a closer look to the early portfolio, and in interest of time, let me focus on four assets. I'm particularly excited about them, but I also wanted to highlight that there is still significant risk as they are early development projects. On slide 13, let me start with M1231, our bispecific ADC.
As you know, ADCs, which the market and next-generation approaches, have created a lot of momentum and deal-making activity recently. Current technologies still have limitations, as listed here on the slide. Together with our partner, Sutro, we have generated a bispecific EGFR MUC1 ADC that you see depicted in the cartoon. This ADC is addressing many of these limitations. It incorporates several advancements to standard ADCs. Let me focus on one specific element, the bispecificity. As you can see from the red color on the pictures next to the cartoon, this antibody is much better internalized than standard ADCs. This higher internalization leads to much significantly more preclinical activity. Sorry. The green bars on the right depict this relative to the standard monospecific ADCs in blue that you can see on that chart.
In addition to this preclinical activity, we expect a better differentiation between cancer cells and normal tissue, as normal tissue sometimes express those targets, but on polarized cells and opposite side of those polarized cells. The bispecific probably will not recognize these normal tissues. We published this data at this year's AACR, and more ADCs are in our discovery pipeline, so stay tuned. We will report more about this. On the next slide 14, another example for oncology, but that actually originated in TIP immunology. An example for this great collaboration I was talking about between the TIPs. It is M3258, a highly selective LMP7 proteasome inhibitor. In contrast to pan-proteasome inhibitors, this one specifically blocks the immunoproteasome. Because the initial idea was to develop it in immunology, it has actually a favorable safety profile.
In preclinical models, we saw the best activity in multiple myeloma models, data we presented last year at the AACR in oral presentations. We are now in p hase I clinical trials and are so far very pleased with what we have seen. On the next slide, an asset that we haven't yet published, slide 15. It's our TIGIT antibody that Stefan Oschmann mentioned in the Q2 earnings call, and that created some excitement since then. Let me share some internal, not yet published data. Like avelumab and bintrafusp, it comes from our team in immuno-oncology. We consciously selected an IgG1 effector function competent antibody, and actually an antibody that has a rock solid preclinical profile. We demonstrated that its profound antitumor activity in preclinical models is driven by multiple mechanisms, not only inhibiting TIGIT and low stimulation of CD226 or [CD226]
It also depletes high TIGIT expressing T-regs and other immunosuppressive cells. Very important, it combines well with bintrafusp alfa. This makes a lot of sense if you think about the mode of action. TGF-β is not only an important inhibitor of T-cell activation, but it also blocks NK cells. Trapping TGF-β via bintrafusp allows these NK cells in the tumor microenvironment to do their job via ADCC depleting these immunosuppressive cells. We started a phase I trial with this antibody in monotherapy, but the protocol already foresees combination with bintrafusp. Last but not least, on slide 16, let me come to M4344. You may wonder why I, as the head of research of Merck, present this ATR inhibitor, which we in-licensed from Vertex.
The reason is that we don't stop research when we deliver development candidate, but continue to support our clinical teams. In this case, we run patient-derived xenograft models and could demonstrate that M4344 does not only have an interesting monotherapy activity, but that via combinations, we could broaden the response rate of PARP inhibitors independent of BRCA mutation status in individual patient-derived tumors. With this example for forward transformation, I really hope that I could convince you that we have an exciting pipeline and team in place. I would like to hand over to Klaus, who will guide you through the oncology clinical development. Klaus, over to you.
Thank you very much, Peter, and also a warm welcome from me. Turning to the development aspects of our pipeline, I will, on slide 18, share a few highlights on BAVENCIO , bintrafusp alfa, tepotinib, and our DNA damage response portfolio. Turn to slide 19, talking about BAVENCIO , and on the left side of the slide, showing the OS Kaplan-Meier curve of JAVELIN Bladder 100 with a hazard ratio of 0.69, meaning a 31% reduction in risk of death by adding avelumab to best supportive care in a maintenance setting.
This is so far the only IO data in bladder with a significant OS advantage, and therefore, certainly this data has the potential to transforming the way we treat patients with advanced bladder cancer. Turning to updates given on BAVENCIO at this year's ESMO, and I will focus on updates given on the JAVELIN Bladder 100 trial.
As you see on the right side of the slide, there was presentations about stock group analysis demonstrating an OS benefit irrespectively of the induction chemotherapy leading to a complete response, a partial response, or even stable disease. There were also data presented about associations between clinical outcome and exploratory biomarker, indicating that a potential predictor of OS is expression of some Fc gamma receptors variants that indicate that there potentially with avelumab could be a direct cell killing mechanism mediated by an ADCC mechanism. Then finally, some quality of life data, showing that there were no negative effect on standard patient-reported outcome measures, adding avelumab on top of best supportive care. Please turn to slide number 20. Moving into bintrafusp alfa.
This is a program that has been designed with multiple shots on goals beyond looking into a potential differentiation to checkpoint inhibitors in a PD-L1 high non-small cell lung cancer population as monotherapy. Actually testing multiple independent hypothesis beyond that monotherapy setting. As an example, we can turn to combination with chemotherapy to initiate and enhance immune reaction and target fibrosis via the TGF-β pathway that would allow a bigger penetration, addressing some of the known resistant mechanisms to checkpoint inhibitors. We can also look further into the lung program, moving bintrafusp alfa into earlier stages of disease, testing it against durvalumab in a stage three non-small cell lung cancer non-resectable patient population.
There are also attempts to explore the more direct role of adding a TGF-β sequestering mechanism into the PD-L1, PD-1 axis inhibition in HPV-driven disease that is primarily being tested out in cervical cancer and very likely also in head and neck cancer in the future. Finally, let me then mention combination with bintrafusp alfa as the backbone. Peter did mention to you that we have initiated a dose escalation trial with our anti-TIGIT. There is a very clear aim starting combinations with a variety of solid tumor using bintrafusp alfa as the backbone. You are also very familiar with our biliary tract cancer program with monotherapy in second line and against chemotherapy in the first line. Can you please turn to slide number 21. Let me give a few highlights of what was presented for bintrafusp alfa at ESMO.
There has been some long-term follow-up data presented showing that the three-year survival update confirms efficacy in second-line non-small cell lung cancer, especially in a PD-L1 high patient population with a median overall survival that has not yet been reached, but showing that 67% of the patients are still alive in that trial after 60 months, sorry, 36 months. Also showing data in a biliary tract cancer in an Asian patient population after 28 months following on in second line biliary tract cancer that continues to show durable, long-lasting responses and long-term overall survival with a near of 28% OS rate at two years.
Please turn to slide number 22, turning to tepotinib. We have been laying the foundation for that program with the VISION trial, showing an overall response rate of 46% with a median duration of response of 11.1 months in patients with exon 14 skipping mutations in non-small cell lung cancer. We have obtained an approval in Japan, in March, under the trade name of TEPMETKO, in all lines of the disease driven by that specific mutation. There is an expectation of a U.S. approval in the first quarter of next year. We are not stopping there with tepotinib. We want to tap into a disease setting where disease is driven by MET amplification. We have initiated a trial that is called INSIGHT 2, that is testing MET amplification as a resistance mechanism for patients that are failing first-line treatment with TAGRISSO in an EGFR-driven mutational non-small cell lung cancer population.
That is based on the notion that MET amplification is one of the predominant drivers of resistance to TAGRISSO, with numbers as high as 25% of the patients failing treatment based on that specific amplification. INSIGHT 2 is testing the resensitization by combining tepotinib with TAGRISSO. Finally, we are also exploring what does MET amplification mean as a disease driver outside of non-small cell lung cancer, by doing an exploration in colorectal cancer with a backbone of ERBITUX, testing in a second-line advanced colorectal cancer, the combination of tepotinib and ERBITUX. I want you to turn to slide number 23. Just to highlight our expectations of the INSIGHT 2 program, because we have fundamentally shown that tepotinib in a MET amplified setting is working.
We have shown proof of concept by the INSIGHT 1 trial, showing a significant benefit of rescuing patients that fail IRESSA with a MET amplification using a combination of tepotinib and IRESSA, as indicated on the right of the slide. I want you to move to slide number 24, turning into our DNA damage response portfolio. We have previously discussed our strategy, so I'm not going to focus on the left part of the slide, but want to draw your attention to the right side of the slide. First of all, showing the breadth of our program, starting with ATR. We have positive clinical proof of concept data for berzosertib in ovarian cancer, as well as in small cell lung cancer, and I will come back to that in the subsequent slide. We have shown progress with our oral ATR program.
With the front-runner molecule M4344, we have defined a dose and are in the process of testing that specific oral ATR compound in specific single-arm expansion, testing out a number of mutational hypothesis. Among that, ARID1A, ATR, and ATM mutations, and the plans of moving that program into path combinations to tackle moving the path field beyond BRCA-mutated patients. On the DNA PK program, M3814 is progressing well in dose finding with chemoradiation in neo-adjuvant rectal cancer. When dose is established, the plan is to progress that into chemoradiation proof of concept study, clearly making us, as a company, very well-placed to deliver the first proof of concept industry-wide for a DNA PK inhibitor. Now I want you to turn to slide 25, and as I indicated, go into a little bit more detail on the positive proof of concept for berzosertib.
First of all, on the right, in a randomized control trial in ovarian cancer, in combination with gemcitabine against gemcitabine, we have shown a significant PFS benefit in all patients, but stronger benefit in the most platinum-resistant patients. Finally, if you look on the left side of the slide, we have data in phase II now in collaboration with NCI in small cell lung cancer. That unfortunately has not yet been published, and therefore I cannot share the actual data here, but I can clearly state that they are confirming the early signals that are shown on the left of this slide. Very well positioning us to start registration-driven trials in small cell lung cancer in combination with a chemotherapy agent, tepotinib. By that, I would like to hand it back to Rehan.
Thank you, Klaus. To close out this view in terms of the oncology section, we're going to touch a little bit on the performance of BAVENCIO now that it's been approved and introduced into clinical practice in the U.S. Let me start by really saying that the significance of this data set in frontline urothelial cancer is really underscored by the reception and the recognition that it has received in the community. From the ASCO presidential plenary to the FDA approval with broad label, the ESMO guideline inclusion, the NCCN evidence recognition, and an update to the guideline, and of course, the encore of data at ESMO with orals. All of this has really led to an incredible halo, some very good coverage in terms of education, which is really important as we basically try to rapidly change the standard of care.
I will say as well that the data dissemination has potentially been the one thing that has potentially benefited from the pandemic context that we're in, because as many of you know, all of these conferences have been virtual. All of them reduced their fees. All of them saw far greater participation than normal. Basically, there was no fighting over who was going to get the front row seats. I think in a way, this is potentially one of the net advantages of the context that we now find ourselves in. Now let's shift to how we're actually doing in terms of the actual introduction. The first real statement to make is that our efforts are working. We have leading share of voice amongst all of the players that today offer an immune therapy to patients with bladder cancer, whatever the setting that may be.
This means that basically, physicians are being more frequently contacted by us and have more frequent retention of the critical messages by us than they do for some of the other players. This means that despite the COVID context that we're in, we're actually able to reach and actually have an impact in terms of starting to move people's mental model towards adoption of BAVENCIO. We've seen very broad reach also, and obviously, in the context that we're in, this was going to be a concern. Can we still get to people, given that it's going to be virtual and people are overloaded with emails and requests for virtual sort of interaction? The answer to that question is we're doing really well.
When we look at our priority tech targets, so these are really some of the top SL physicians that have therefore, this most significant volume of patients. We've reached 70% of our targets basically within the first 2.5 Months. This is very consistent with basically benchmarks, leading benchmarks, that you might look at in a more standard context, not a pandemic context. Finally, also our virtual programming. We're getting really robust participation, really robust dialogue, and very positive feedback. Basically, there is a genuine thirst, I think, to understand the data and to understand how this needs to be integrated into their clinical practice regime. When we look at more concrete measures, I think, of performance, we share here basically that the unit growth of BAVENCIO has really demonstrated an inflection.
If you look at the 11 weeks sort of post-approval versus the 11 weeks prior approval, you're looking at a 40% jump, and that continues to accelerate, because if you just took a rolling four-week view to the most recent four weeks versus the prior four weeks, you're at 50%. The point is that this is a real inflection. Now, what's also important is that the units are going up and also that the base of prescribers is also increasing, right? The breadth. What we've seen basically is just a tremendous increase in the number of accounts that are starting to order BAVENCIO. As you know, BAVENCIO has been approved. It's been approved in MCC, it's been approved in RCC, it's been approved in second-line bladder.
To have a significant increase in the number of accounts starting to order is really, really positive, and this continues to accelerate. August better than July, September also looking really good. When we look at penetration into the indicated segments. These are patients that have received platinum therapy, patients who then have stable disease or better. These are the candidates for BAVENCIO maintenance. What we see here is that basically since from July to mid-August, of the candidate patients, we estimate a penetration of about 30% into that segment. What that means is that of all of those available patients that should be candidates for BAVENCIO coming through in July, coming through in the first half of August, we're getting about 30% of them.
It was about 27% in July, 34% in August in that first half, and this is really, really encouraging. Just a word on the data itself. It's difficult to track this particular launch because of the unique context of a switch maintenance type approach. What we have is a very customized view with a specific provider, where we actually do comprehensive chart reviews of a significant group of physicians on a monthly basis, and that's then accumulated on a quarterly basis. This is going to be our primary means of really understanding treatment patterns and integration of BAVENCIO as basically a maintenance agent following stable disease or better induction by platinum therapy. This is really positive. To put the 30% also in context, we of course look at benchmarks. 30% penetration at this point into the target segments is very positive.
We look in particular at one benchmark. We look at many, but one in particular, just to put on your mind, is the introduction of Imfinzi, basically as a maintenance therapy in stage three lung. That was obviously a very successful introduction, if you put the 30% here that we have in terms of the maintenance penetration into bladder cancer frontline versus that, you actually see that we are overachieving, I think, the level of penetration that they did at the comparable time period. This is very positive. Now we'll move on to the neurology and immunology section, Luciano and I will cover evobrutinib, the M5049, and also give you a sense of how we're progressing with MAVENCLAD from a data characterization perspective and also from a launch recovery perspective. Let me start now with evobrutinib. I want to say a few things.
There's a lot on the slide, we're not going to cover everything. I think that there is a reason why we have always been excited about this mechanism, and there is a reason why we were the first to clinic, and there is a reason why we were the first to push the button on significant phase III trials. A big part of that is that we have always maintained that there is a significant unmet need today in the field of MS, despite the tremendous progress that has been made over the last two decades. What's also important is that there is a significant continued momentum towards the use of higher efficacy agents in the treatment of MS.
When you think about higher efficacy agents, yes, there are quite a few that are now approved, but to be honest, there are only two mechanisms that offer higher efficacy disease control that can be taken orally with the convenience of oral administration. Only two. Therefore, there remains a need still for better disease treatments, more high-efficacy treatments, but also there is significant value in having oral higher efficacy treatments. It is also important to recognize that in the field over the last decade, there has been a growing understanding of the role of B cells in the immunopathology of MS. MAVENCLAD has a profound impact on the B cell compartment. We believe that could be one of the reasons why it is having such profound efficacy. Of course, BTK is another way to get at that problem.
When you look then at the total market environment, consider high efficacy agents, consider agents that are impacting the B cell compartment, and consider the growth of the oral segment, it's just a no-brainer to consider something like evobrutinib. With that, let me hand over to Luciano.
Terrific, Rehan. I will be going to slide number 29, very briefly. I know many of you have been following the evobrutinib story with us for a while, I don't want to reiterate too many points. I want to make one point. This large phase II-B trial that we have completed in MS, with now very significant and conclusive information on annualized response rates, it's really the real proof of concept for the Bruton's tyrosine kinase inhibition hypothesis in MS. This is really the most comprehensive data set, even in our 108-week follow-up, we can confirm that we have efficacy on this primary endpoint for phase III that is very comparable to CD20 and other very high activity. The other one is the safety database.
We have now more than 1,300 actually, patients in various trials that have been exposed for up to two years and plus actually. Basically systemic adverse events are really minor, and there is no signal for infection at the dose that we have selected to go forward. Another very important point that I'm not going to reiterate in detail is that this compound has CNS penetration, but most important also, by being an irreversible inhibitor, is able to label and to block BTK in the cells that traffic in and out of the CNS. That sets a huge upside potential in having an impact on many other phenomena that are BTK affected in the CNS, including microglia, inflammation, and as I mentioned, trafficking within the CNS of cells. The final and critical point is that it's absolutely critical for this particular indication to have up to 95% BTK occupancy.
Because of that, we felt that we had to spend a lot of time to really create modeled simulation to really push forward with our analysis of the ideal doses, that's why we selected the BID approach to really maximize the efficacy. In terms of efficacy and safety database, this is very robust data. The most important update is that despite COVID-19, the trial is really doing very well. It's on track, and we still can get to the conclusion we projected now by the end of 2023 for this trial. Let me move now very briefly to an exciting clinical development compound in the slide 31st. Make very quickly a point that the Toll-like receptor 7 and 8 inhibitor is a very unique program that really is trying to block the sensor for RNA in many immune cells. That's what TLR7/ 8 is.
In that sense, there is a very strong similarity between our COVID-19 pathology driven by SARS-CoV-2, that is an RNA virus, and the way this is sensed and trigger very robust immunopathology and cytokine responses that are probably a major driver of the COVID-19 pneumonia and other inflammatory component of these very serious diseases. This is very similar to the sensing of RNA-based immunocomplexes and other signaling in autoimmunity, particularly in cutaneous and systemic lupus, but also other autoimmune indication, where blocking TLR7 and TLR8 will have a very strong potential to have a positive effect. I stop there. The phase I part of the trial is completed, and now we are, next slide 31, in the first of the phase II trials. We're planning obviously to test this in immunological diseases, as explained briefly before.
The similarity between COVID-19 pneumonia and other diseases in SLE and lupus, it's very striking in terms of the cytokines that are affected and in terms of mechanism triggering the cytokine, in where TLR7/ 8 could play a very, very critical role. We decided to go forward with a randomized phase II trial designed to test the hypothesis that blocking TLR7/ 8 with M5049 will have a beneficial effect in diminishing the consequences of the COVID-19 pneumonia in patients hospitalized for this disease. The trial is going on. We have several sites activated, and recruitment is picking up as we speak. I'll go now back to Rehan for some conclusive remarks.
Thanks, Luciano. Let me just touch on MAVENCLAD. There was a lot of data that was also at ECTRIMS that further characterized and I think substantiated the growing belief in the benefit risk profile of MAVENCLAD. I'll touch on a couple of the most important parts, that is one, that there was a study that basically showed how rapid the impact of MAVENCLAD is on the disease course. This is really important in the context of choosing higher efficacy agents, because if a patient comes in with a very hot MRI, has had a series of bad relapses, what you really want to choose is an agent that doesn't just work profoundly, but an agent that works rapidly and profoundly. I think so the data sets that we presented there really support that.
What you see is a very profound effect and a very rapid effect within month one. This adds to the body of evidence from the earlier clinical trials. From a post-approval safety perspective, we presented a very robust cut of data from 20,000 patients in the post-marketing setting. This is really reassuring to the community that we are doing this with this data because it's transparency and it's further educating them, I think, on the profile. In particular, I think it's really reassuring to see that viral respiratory infections are really low percentage in terms of their occurrence. There was also data cuts around malignancy, and the rates that we've seen so far in the post-marketing setting are below what has been indicated in the various different labels. Again, really reassuring to the community.
The other part, I think, of the data release, which was really important, is how do patients on MAVENCLAD actually do if they are actually infected with SARS-CoV-2 and develop COVID-19. So far, I think we've been able to provide data, growing amounts of data, that really suggests that at this stage, there's nothing to worry about. Now, this is really important because this is an area of decision-making where there's not a lot of evidence, but at the same time, it's become the primary driver for decision-making, particularly so in March, April, and May. It's reassuring that this is the case with MAVENCLAD, but it's important to recognize that that's not the case with every DMT for which there's accumulating evidence.
As a good example, there was a note sent out by Roche to all physicians in the U.S. saying that there may be an increased risk, in particular of severe COVID-based complications, if you are undergoing treatment with OCREVUS. This is reassuring, and I think the data will continue to inform. Finally, a piece of data from the NHS where the health system is really useful in being able to understand patient persistence. What it shows here is very much what we expect and what we've been telling you, which is that MAVENCLAD is very effective, very well-tolerated, and that if patients initiate a treatment course of MAVENCLAD, they tend to persist on MAVENCLAD over the term. Here you see persistence rates over two years, basically above 90%. Now if we move towards, what about the progress?
When we talked about Q2, we told you very clearly that there had been an impact basically on the prescriptions, purely really driven by COVID and the logistical issues that that presented because physicians were not seeing new patients, physicians were not seeing switch patients, and they certainly weren't going to switch patients onto agents or start patients on agents if they weren't actually able to see them in person. What we've actually seen now since basically the low point is a real recovery, progressive recovery, and our new prescriptions are really regaining momentum. It's important to recognize that we're regaining momentum in the context of a higher efficacy dynamic market that is still depressed about 20%- 30% versus the pre-COVID baseline. The market is still depressed. Our momentum is returning.
A big part of what is continuing to drive our momentum is the fact that despite the COVID pandemic, MAVENCLAD has continued to grow share. Grow share versus other higher efficacy agents and grow share versus other oral agents. You have here basically the share point increases from the pre-COVID period to the post-COVID most recent period. The other point to mention is also the access. Access was a point that we continued to educate you on basically over the last 12 months. I think we just want to draw a line in the sand here now and say that the access position for MAVENCLAD is great. It's very much on par now with basically what you'd expect for the established DMDs. We have not at all overpaid for that access. We're in a very good position from an access perspective.
If we turn our eye to the ex-U.S. performance as well, it was similarly impacted by COVID. What we see here is new initiations have really started to rebound. Potentially the leading market in terms of the recovery is really Germany, where they really did such a good job to control basically the pandemic, where you still have a lot of in-person physician engagement for the industry and also obviously then for patients. That's really taken off the most significantly, and the other markets have been following suit. What we've also seen is very good performance in terms of year two patients. Again, all of this really underscores the continued confidence in MAVENCLAD and the fact that MAVENCLAD will continue to be a really solid choice in this pandemic setting.
From a safety perspective, the continued data and the continued experience is really showing that MAVENCLAD's perception on safety, which was an overhang at the time of introduction, is improving. Finally, what's really important to us as well is that we finally cracked France. We received a positive recommendation from the Transparency Committee. In H1 2021, we will basically have our full commercial launch because we will have our price and access and everything. Basically, the recommendation is positive, you can look forward to that being a growth driver in 2021. With that, we're going to move over to the Q&A. Just a few words in summary, now that you've heard from Peter, from Klaus, from Luciano. We really have momentum.
We really have strong momentum across the innovative medicines pipeline, and we think this is not one-off momentum, this is growing momentum. We have all of these entities with significant potential to differentiate that are now in the clinic and making progress. Since 2017, we've basically had three medicines approved across six indications across the major markets. We have growing contribution from new product revenue. We have increasing momentum around that, and we have real confidence that we're going to be able to deliver the EUR 2 billion by 2022. It's important also to us that you recognize that we're not just about the EUR 2 billion. We have growth momentum, we think, far beyond the EUR 2 billion by 2022, and I hope that you see that that's underscored by the pipeline that Peter and Klaus so elegantly spoke about.
With that, let me hand over to Abby, the moderator, so that we can get into your questions.
Thank you. We will now begin our question and answer session. If you have a question for our speakers, please press star one on your telephone keypad now to enter the queue. Once your name has been announced, you may ask your question. If you find your question is answered before it is your turn to speak, you can press star two to cancel your question. If you are using speaker equipment today, please lift the handset before making your selection. One moment, please, for our first question. Our first question comes from Jo Walton with Credit Suisse.
Thank you. Jo Walton here. I just have a few questions, please. At ESMO, we saw some excellent amivantamab data. I just wonder if you could tell us how you think tepotinib is going to fit in with that. On your COVID study at 2Q, you said that you were hoping to have some results by the end of the year. This slide here seems to be a little vaguer, depending on rate of recruitment, et cetera. I wonder if you could just flesh out a bit where you're doing that study, where your latest best guess of when you would have some data surrounding that. I have a question on your MS franchise. You talk about dynamic share. I wonder if you could just refresh us on what you think the proportion of the market is that is genuinely changing. We hear things about 30% change, dynamic opportunity.
Given that there are still an awful lot of people who are taking older interferons, it looks like it's a 30% that's the same 30% that changes every year rather than anything more addressable. Just a little bit more update on your view of that, please. Then, very finally, I wonder if we could ask Klaus to give his perceptions of the organization and the opportunities that he sees at Merck. He's a person that we used to see quite a lot of at Astra, and clearly you've moved from one oncology department to another, so it would be very interesting to hear your comparisons of what you're finding. Many thanks.
Klaus, can you go first on this various oncology question, and then Rehan?
Yeah. Absolutely. I'm happy to go first on the fifth question, Jo, because I must admit, I did not exactly hear your first question, but let me go on the comparison to one company to another. It's very obviously that Merck is having a very significant sustainable pipeline. I think that the whole aim as of today was to show that there has been a very clear transformation in the company, if I were viewing it from an external perspective, from building some very significant late-stage potential to significant approvals within these last number of eight months. As Peter very clearly spoke to today, there is, when I take Merck's size into consideration, an absolutely fantastic possibility from the early-stage pipeline that is in the forefront of science. I'm not saying that other companies that I have worked for are not in the forefront of science. Absolutely not.
There is an attraction for me in absolutely joining a company where there is that focus and vision, not being pushed by being considered a little brother, but actually being bold and ready to make some significant contributions, some bold risks. All in all, very impressed. I expect you would likely not have me to say anything different from what I was just saying, but I am actually in the company. I have been voting with my feet. What I saw when I was speculating joining Merck has absolutely been coming to fruition. That was the fifth one. The first one, I heard that you were saying you were seeing some excellent data. How does that fit with tepotinib? Sorry.
Sorry, no. It was the amivantamab data I was thinking of and whether that made any difference to your thoughts positioning your assets in multiple myeloma.
No, I don't think it does. I think it actually just substantiates what we are doing. I think it's very important to say that the Avastin data is a little bit of a different approach because it is actually adding on to see whether when in a treatment setting can get into a, first of all, higher efficacy and obviously also hopefully a longer duration of that efficacy. Whereas our positioning of the tepotinib program, if you speculate in non-small cell lung cancer, it's much more a positioning as a rescue medicine, if I can speak like that. That is by no means to say that's not a critically important element, because if you look at the number of patients that would be in need of a rescue medicine, irrespective of whether you have Avastin in the equation or not, is going to be significant in years to come.
If you look at the TAGRISSO FLAURA data with median PFS of around 24 months, it is about now that you would start to see patients in need of a rescue medicine. That's why we are putting such a significant effort into trying to understand whether the tepotinib combination would be the right thing to do there. As I hopefully showed you, we kind of have that proof of concept that tepotinib is a very clean, very safe molecule to use in that setting based on the INSIGHT 1 data. I hope that addresses what you were after.
Yeah. Klaus, that seemed very comprehensive. Let me just add on to the point around the MS dynamic share. I think let me make sure I've gotten this right, I think the question was really how big is that pool? Is it really going to continue to be a big pool? Therefore, is it a good source of business and can we count on that really for growth? I would say, the key point is that the dynamic opportunity continues to actually be significant and continues to actually be relatively stable. Traditionally, when you basically had new introductions, what you saw was a pretty big increase actually in the dynamic opportunity because it would drive a lot of switching.
What we've seen more recently is because there are so many drugs, that there are so many different mechanisms, that new introductions don't tend anymore to really drive up the dynamic opportunity, but what they do is basically sustain it. We've seen a pretty good stability, I think, in terms of the dynamic opportunity. What we are seeing, though, is continued increase, of course, in terms of the high efficacy share. When we say high efficacy, we're thinking the S1P, MAVENCLAD, the anti-CD20s, LEMTRADA, TYSABRI. We're seeing an increased share of the higher efficacies in terms of utilization in the dynamic segment. That's why we look importantly at how are we doing relative to other higher efficacy agents in terms of dynamic share accumulation.
I just want to complete the final question very quickly. The COVID-19 trial with the TLR7/8 inhibitor just starting. We are recruiting in several countries. Just recently activate Brazil, and we start to see good activity in Brazil and some U.S. sites. It's too early for me to speculate on how quickly we'll go. I just want to make one quick point. As you probably understood from the brief presentation, we believe that if the TLR7/8 is a sensor for RNA viruses and trigger these inflammatory responses, in particular cytokine storm, this is for us another opening for an additional venue for this novel first-in-class compound that goes beyond autoimmunity. Thank you for the question.
We will take our next question from Richard Vosser with JP Morgan.
Hi, thanks for taking my questions. Three, please. First question is on the differentiation of your TIGIT relative to the Roche and Merck TIGIT. Second question is on the MUC1 EGFR ADC. Could you remind us of the prevalence or the percentage of lung cancer that expressing MUC1? I think we had that in our minds for the vaccine a few years ago, what is that? Just maybe your thoughts on how this might look efficacy-wise, positioning-wise versus there's a couple of ADCs that are slightly ahead, the Trop-2 potentially, the CEACAM5. Just your thoughts on positioning here and how quickly you can move it to avoid having to do trials against another ADC rather than chemotherapy. Final question, just on MAVENCLAD.
If you could give us an idea of the proportion of patients that are naive to treatment at the moment versus those returning, and how that has developed through the COVID pandemic crisis. One aligned question, just if you could give us an idea of other launches beyond France that you might have through 2021 and 2022, and how big the French market is relative to Germany.
Thanks very much.
I'd like Peter to start, then we go to Rehan. Peter, please.
Yeah, let me take first the TIGIT questions. Rightly so, you asked the MSD and Roche question because we believe those two are the relevant competitors also with ADCC activity, which we believe is important in the field of TIGIT.
Let me say so much that we, as I mentioned, always profile wherever possible our molecules against competitors, and we feel very confident about the robustness in pre-clinical models, obviously. How this translates into clinical development, we just have to see. We started the clinical trial, but I think it's too early to speculate about the differentiation in the clinic, but we have good hypothesis based on pre-clinical data. Maybe let me take the first part of the question on the expression of MUC1 EGFR. Actually, of course, the answer, it depends on which level of expression you need for this bispecific antibody. Actually, that is relatively low in terms of receptor density on cells for both targets.
Therefore, we believe actually it's a significant part of non-small cell lung cancer, and of course, also other indications that express enough MUC1 and EGFR to trigger this internalization process that we believe is so important for the specific activity and selectivity of this bispecific ADC. Maybe on the second part of that question, comparing the chemo or ADC from the clinic, I would hand over to Klaus.
Yeah. Very clearly, you mentioned yourself, Richard, that the main competitor landscape here is likely the CEACAM5. I think, we do not have any clinical data yet from this program, but we kind of know what we are up against. I think what we are up against is very clearly a very efficacious CEACAM5 from Sanofi, but only the CEACAM5 very high expressers that would actually narrow down that patient population pretty significant. I think there are absolutely room to play there. In a chemo combination, I think the aim there is primarily to see whether you, first of all, in that setting, would be in a position to develop some new innovative ways of not having to use chemotherapy. As Peter alluded to, it's early.
It's a very interesting new concept of a selectivity and uptake for EGFR-driven wild type tumors that clinical data will drive us. I clearly think that there is room based on what I have seen up to now, especially the CEACAM5.
Before we go to Rehan, I want to add, Richard, there is an excitement about having the bispecific, in this case, driving potential better therapeutic index and much higher potency because of the selective internalization. The biomarker that you select and therefore the cutoff for both MUC1 and EGFR within the tumor, that cutoff is going to determine the prevalence. I think Peter explained that, but I wanted to clarify. The potential is very high. We did a lot of work pre-clinically to understand what was the ideal biomarker, but we're not going to reveal in detail how the selection will be done for that trial. It's an exciting, early, but very innovative approach to ADC to improve therapeutic index and increase potency in the selected population. Let's go back now to Rehan.
Sure. Thanks, Luciano. Richard, it's two questions really. One is sort of the split of patients in terms of where we're sourcing them from. Just as a reminder, in the U.S., basically all of the patients that are actually initiating MAVENCLAD, well, most of them, and anyway, all of the patients that are actually commercial patients, have received at least one prior treatment, and that is consistent with the label. If you go ex-U.S., we see a pretty common pattern, which is that about 30% of the patients are sort of treatment naive, and about 70% of the patients have previously received treatment. We haven't seen really any significant impact at the moment or change in that based on COVID.
All we basically saw was that there was just a general reduction in terms of new initiations, basically across the board, whether they were new patients or whether they were switch patients. It was basically the same because, again, it was fundamentally logistics. Being able to access the clinic, being able to be subjected to neurological exam, being able to be subjected to MRI. Those are the things that were really the barriers. It wasn't therefore driving sort of a push towards patients that are on treatment versus new diagnoses. I hope that gives you some perspective. If you think about the build of MAVENCLAD over time, we're continuing to gain share. We're continuing to build up new patients. Of course, over time, the importance of the returning patients also to the revenue build increases across all of the markets.
I would say that we're still very much in sort of the ramp-up growth phase, and the new patient acquisition is still a really important contributor to the revenue model. I think the other question was France. Yeah. Just to give you a sense, I think the best thing to do at this stage is just to index France to Germany based on population. Of course, there are fewer people in France than there are Germany. That's a better way to look at it right now, and maybe in the future, we can give you a little bit more precision. That should give you a good enough sense of the opportunity.
Of course, the rest is going to be driven by the share that we managed to achieve there. Beyond France, I don't think we comment on some of the specific opportunities, but I will say that we have made MAVENCLAD accessible, and it is approved in many markets. In total, those markets do start to contribute meaningfully, I think, as we go forward. Of course, the access dynamic in those markets can be different. Some of them come online later, like Italy, like Spain. Some of them may be coming online more in the time of France. You can expect definitely some good tail contribution, I think, from outside of the major markets as well.
Thanks.
We will take our next question from Marietta Miemietz with Primavenue Advisory Services .
Yes, thank you very much. Two questions, please. The first is on BAVENCIO and JAVELIN Bladder 100 . There were some suggestions at ESMO that patients who get IO in the frontline should still be getting IO in the maintenance setting. Is that actually something that you're hearing from the field? If so, would you expect patients to get switched to BAVENCIO in the maintenance setting or maybe even receiving BAVENCIO upfront to avoid switching later?
My second question is on tepotinib, and I just wanted to try another tack on Jo's question. I mean, MET amplification is obviously a very frequent resistance mechanism in NSCLC and maybe some other cancers. Do you think at a very high level that the community would be willing to give a MET inhibitor before MET amplification even appears, which is something that, for example, J&J seem to be trying with their MARIPOSA trial?
Do you think that that's really an overkill, and the preference would be to wait for MET amplification to appear before an anti-MET is given? If you get the sense that it's very much turning towards giving MET inhibitors in the frontline setting, would you then actually restructure your tepotinib program to make sure that it can be given upfront? My final question is on bintrafusp alfa and the biomarker program for the monotherapy. I was just wondering, can you give us a bit more of a flavor as to how you actually select patients that you think will really benefit from the monotherapy in the sense that the cancer is really driven by TGF-β as opposed to other factors?
Asked differently, given all the TIGITs are coming, do you realistically think that bintrafusp alfa as a monotherapy can be standard of care in some cancers ahead of TIGIT combinations? Or do you think that realistically you need the bintrafusp TIGIT combination to compete with other TIGIT combinations? Thank you very much.
We'll start with Rehan on the question regarding sequence. Obviously, our indication for BAVENCIO is going to be in the patient that do not progress after initial chemotherapy.
Let me just add a point to that, because as Luciano said, our indication is distinct. You are going to be treated with platinum, have stable disease or better, and then basically receive BAVENCIO. When you're thinking about the treatment, you've actually got this being a different segment of patients, meaning the segment of patients that weren't put initially on IO, but instead were actually put on a platinum-based regimen. One point that I do just want to underscore in terms of ESMO, because of course we've engaged with a lot of advisors post-ESMO to really digest the data. What's really interesting coming out of that is the growing belief that there may be too much single agent IO use basically in the frontline.
As you know, the initial approvals were based on single-arm studies, and we now have the benefit of additional data sets with single-arm immune therapy and combination immune therapy in the frontline setting. This is leading people to really question whether or not PD-L1 testing is really useful, and that's part of the indication for the single-use monotherapy. The other point is, given the availability of avelumab following basically platinum induction and the significant improvement that that has on overall survival, the median 50% increase from platinum alone. The question is, from all of the data sets now, why would you not be doing that in the vast majority of patients? Why would you be using off-label single-arm immune therapy when it has no advantage at this stage over platinum in terms of improving the median overall survival in randomized controlled trials?
I think what we may see is actually a progressive use of platinum, and of course, this could potentially increase the size of the opportunity potentially, particularly in the U.S., for avelumab. Now, back to you.
Yeah, I think. Klaus, next question is for you on the table.
No, absolutely. Thank you for your question. Let me take it backwards. First of all, I would not find it necessarily a reasonable proposal not to have testing as to whether a patient may have a disease that is driven by MET amplification. The reality is that if you look at MET amplification as a primary driver of disease, we are not talking about high patient numbers. I think where you start to see the big opportunity is, as I alluded to, in the resistance setting. There are variable assessments of what the actual prevalence of the MET amplification mutation, or aberration I should say, is. I called it up to 25% after TAGRISSO treatment. There are other publications that are quoting higher and lower numbers, obviously. That's not because there is necessarily a super contradiction about whether that is an important resistance mechanism or not.
I think it's more a matter of the biomarker approach, as do you do Next-Generation Sequencing to detect it, do you do FISH testing to test it? Do you do tumor biopsies, or do you do liquid biopsies to test it? That is a field that is absolutely under rapid evolvement. I would not recommend an approach where you would not have a very clear indicator that the disease is actually benefiting from having MET inhibition, based on even the highest expectations of what the numbers are. That's not to say that it's not small numbers, because clearly it is a significant proportion of patients that if you just stop at 25%, that's a resistant mechanism for failing TAGRISSO treatment.
If you look at an uptake in countries where first-line EGFR driven non-small cell lung cancer is treated with what, 85% of the population with TAGRISSO, and if the 25% of that patient population eventually is in need of a rescue mechanism, it's a significant proportion of patients. If you look outside of non-small cell lung cancer, it's fair to say that MET amplification as driver of disease is not fully established. I alluded to our explorations in colorectal cancer. There are estimates that as a primary driver of colorectal cancer, it could be single digit percentage. It is not yet fully understood what, as a resistance mechanism, it plays in colorectal cancer. That's part of the exploration in our program.
Klaus, I think I'll take very briefly the bintrafusp question. I thought it's a very good one. Let me start with the biomarkers that are a little bit more established with signals within the program. The one that are already delivering to us significant enrichment, it's been HPV so far, both in the cervical setting and the neck setting, and even in other tumors. This is a signal that we are further exploring, of course. Looks like that the role of TGF-β in the HPV tumors, it's somewhat validated by much higher response rate. The other one is in the triple-negative breast cancer. We have really found a very strong association between a specific marker within the TGF-β pathway and the responses in this setting, in triple-negative breast cancer. This has to be prospectively verified, and that trial is ongoing.
The third one is an obvious one because our construct as a PD-L1 antibody driving the trap, that is the extracellular domain of the TGF-β receptor 2. We are very dependent in non-small cell lung cancer, certainly from the targeting to PD-L1. We do see tumors with high PD-L1 being the one responding very robustly. You see even in the ESMO trial that we can get to, so far at 36 months, more than 67% of patients still alive in the high PD-L1, although the OS in the PD-L1 positive in general is very robust. In that setting, we don't see really differences in the negative PD-L1. We have been exploring many other biomarkers, particularly in the TGF-β, RNA-Seq and other, we don't have anything firmly proven to be helpful on the clinical side besides the one I mentioned.
I like your question on TIGIT. We see the non-small cell lung cancer signal still as very robust signal for us of TGF-β playing an additional role to PD-L1. We're very open-minded to leverage our excellent anti-TIGIT antibody with ADC activity similar to the leading one, to really understand whether we can create a chemo-free regimen for non-small cell lung cancer in that setting. In parallel, as you know, we're also testing bintrafusp with chemotherapy as a monotherapy in PD-L1 high. Finally, in the stage 3A, we're also testing the radiochemotherapy plus Bintra in PACIFIC-like trial. We're keeping our options open. I think your question about combination with TIGIT, whether that confirms you start from a higher baseline driven by TGF-β in terms of responses, this could add farther efficacy and then maybe compete with the chemo combo. Thank you.
[audio distortion] . Thank you very much.
We will take our next question from Michael Leuchten with UBS.
Yep. Thanks very much. Two questions on multiple sclerosis, please. Rehan, just interested in your chart that shows your trajectory or your projection for the MS market in 2024 with the B-cell depleting drugs and other high efficacy agents. If you're taking share with MAVENCLAD at the moment dynamically, that chart would suggest that the other high-efficacy agents are still holding on to a fairly big part of the market. Just your underlying assumptions around that 2024 bar chart, which I believe are your internal estimates. I'd be interested in that. Then probably for Luciano, one of your friendly competitors in the BTK space put a theory out that their BTK inhibitor potentially inhibits B-cell and myeloid cells activation in human blood, and puts the hypothesis out that there could be an impact on acute and chronic inflammation in MS. Just wondering how do you look at that?
They showed all the BTK inhibitors, and evobrutinib scores a bit lower on myeloid cell relative to the rest of the bunch. Thank you.
Rehan, start.
Yeah. Michael, in a way, most forecasts are generally you just got to accept that they're going to be within a range, especially when you're sort of getting out there. The way that we look at this is, and the way that I would look at this is just that net-net, we see basically that the higher efficacy segment is really tremendously going to increase between now and 2024. I think that's a really positive trend. I think that means that the dynamic share has to continue to increase significantly in order to drive that growth, which is definitely what we're seeing. That means, of course, then at the moment when one comes to introduce let's say a high efficacy agent like a BTK inhibitor, and evobrutinib specifically, I think there will be plenty of opportunity to basically recruit patients onto therapy.
That's kind of the way that we think about it. Then, of course, there's going to be some really good awareness, we think as well, which is something that needs to be factored in because you've now got three players, all of whom are basically putting forward different BTK inhibitors. You've now heard a lot more about what Sanofi knows, what they don't know, what Roche thinks, what they don't know, and you've seen a lot of data from ourselves and what we know. I think it's pretty clear now that these are different approaches, and we've all optimized in different ways. Our view is that our focus has always been to ensure that we get a BTK that goes forward that basically has leading efficacy.
I think with the selectivity that we have, with the dosing regimen that we have, and with the efficacy that we've shown in phase II, we're really confident that actually based on everything we have, that this actually has the prospect of being the leading one. Net-net, that's kind of the way that we're sort of seeing things, and the opportunity is really going to be pretty significant if we get this right. Maybe let me hand over to Luciano.
Thank you, Michael. Really good question. I'll start. Peter will add a little more details. Clearly, we have studied very, very extensively BTK inhibition in various type of myeloid cells. Actually, some of the best academic work has been done with evobrutinib. If you look not only at the traditional macrophage and to conversion and things like that, evobrutinib is very similar to any other BTK. There is one subgroup of myeloid cells, the basophil, in which the signal transduction is slightly different. It's different than other myeloid cells and certainly different than B cells. In that, the pocket by which evobrutinib is attacking the BTK has some influence in basophil's responses that are higher than in other in the in vitro setting.
When you go in the in vivo setting, we actually see that the most relevant myeloid cells are very, very robustly engaged by evobrutinib. This is more of an artifact on the basophil that probably don't play even a very significant role in the pathology. Peter, you probably even know the specific of the two signal pathway, the one the basophil is more involved in. If you have it, share with Michael.
Yeah. Actually I do. I wanted to mention here that actually both for MAVENCLAD and evobrutinib, we are really, as you mentioned, in detail analyze the mechanism in preclinical models, but also use reverse translation. Taking blood samples, analyzing them with single cell RNA, certain other tools, really to understand the mechanism to inform like you said, the clinical development strategy. Of course, from my perspective, equally important, we derive new ideas for new discovery projects from that deep understanding about how our drugs work and are already starting a new discovery project really leveraging the effect of evobrutinib on the myeloid compartment and on the other side, from MAVENCLAD on various subtypes of B and T cells. Again, I cannot go into the details, but it's really a great example for this reverse translation and informing clinical development strategy.
Thank you.
We will take our next question from Wimal Kapadia with Bernstein.
Great. Thank you very much for taking my questions. Wimal Kapadia from Bernstein. I was going to just ask a little bit more about the M5049 and specifically actually outside of COVID. When you look at the MOA, there's clearly plenty of activity, both agonists and antagonists in the clinic, but it seems like we've had limited success so far. I'm just curious, why has the preclinical success that we have seen not been translated into humans? Is there something specific to the target which makes it quite challenging? Is it now that we're only really truly understanding the TLR, the three-dimensional structure and the tolerability that comes with it? Just curious to hear your thoughts there. Secondly, in terms of indication, should we be thinking SLE and RA as a starting point?
Then just given your understanding of the target, have you ever considered an agonist approach for oncology, and is this something you are pursuing? Then my second question is just following on from Richard's question on TIGIT versus peers. It seems that the immunoglobulin backbone and the engagement with the Fc receptor seems to be one of the main differentiating factors across the TIGIT. Just curious to hear your thoughts specifically on these two components versus your peers. Thank you.
I guess I quickly start on M5049. We are aware of only perhaps one competitor at the same stage with the selective TLR7/8 inhibitor. Clearly, the mechanism is very well-suited, based on not only preclinical, but the little bit of biomarker data I can share with you, Wimal, for potential efficacy in SLE, particularly in cutaneous lupus, but also in some other indication in immunology. It's a little bit more of a gentle approach to suppressing immunity, much more targeted for the RNA sensing to TLR7/ 8, and the downstream pathways in interferon and NF-κB. Probably different doses of TLR7/8 could even distinguish between the various downstream pathways. I think the potential is very high. The preclinical data, just to be more generic, in this area of immunology are not very predictive, to be honest, of the clinical outcome. This is particularly true for lupus models.
Therefore, we have to wait for the trial. The only piece of really encouraging data, even in the phase I dose escalation, is that we can very easily monitor ex vivo IL-6 secretion in humans from circulating cells. We have a very nice dose response, really reflecting complete inhibition of TLR7 / 8-stimulated IL-6 secretion. We think we have a very good handle on dose focusing and at least the biological activity is there. When we go in these trials, both COVID-19 and beyond, I think we know at least we are engaging the target very robustly in humans, and we will test this novel hypothesis for the first time. Peter, anything to add on this? Most important, if you can take then some of the question related to the oncology and particularly TIGIT.
Yeah
ADCC activity.
Maybe let me start with TLR and oncology, or why in the past people were focusing on actually agonists for oncology. It's also the difficulty to generate a very good TLR antagonist because what we have here is an antagonist. It's pretty easy to create an agonist based on the nucleic acid structure of the agonists. Again, it took us some time to develop a really good antagonist. Actually, the consideration for oncology, I'm long enough with this company to know that we had a program on a TLR9 agonist roughly 10 years ago, actually in clinical development with Idera Pharmaceuticals, was a partnership back then. The issue with TLR agonists, as we believe, is a systemic activation of the immune system rather than specific activation in the tumor. We are thinking along these lines.
Maybe to conclude on TLRs, we are, again, very confident about our molecule, the TLR antagonists, and are thinking about more selective agonists for oncology. The last question on differentiation of our TIGIT antibody. Again, what I've said, we have preclinical data, very robust, and compared to other competitor molecules, but allow me to wait for clinical data to confirm these preclinical observations. The thing I can definitely say today that in preclinical models, the combination with bintrafusp works especially well relative to other PD-1 or PD-L1 antibodies, because we believe that the ADCC activity that is needed for full TIGIT activation depends on NK cells, obviously, and that these NK cells in the tumor microenvironment are inhibited by TGF-β. Essentially, our differentiation hypothesis is around the specific combination of our TIGIT antibody with bintrafusp and the TGF-β blocking activity of bintrafusp.
Yeah, Wimal, Luciano here. Peter mentioned specifically the ADCC before. I just know that you know, but I want everyone to know that the majority, many of the TIGIT, anti-TIGIT antibodies that are in the clinic, with exception, frankly, of the two competitors you mentioned before and ours, they really do not have the ADCC activity. Peter mentioned very strongly that in our hands, the ability to deplete exhausted T cells, but also T regulatory cells and others, is really playing a big role in the efficacy of TIGIT. I think that distinction is important. There are not that many in the clinic with ADCC activity in addition to the synergy to TGF-β that Peter has mentioned very clearly. Thank you, Wimal.
Great. Thank you.
We will take our next question from Casey Conley with Goldman Sachs.
Hello, everyone. Thank you for taking my question. I have one on MS marketplace. As more and more patients start to use high-efficacy treatments, how do you think the number of patients who switch every year will change? Is it that the average duration that MS patients on a particular treatment goes up quite significantly and the dynamic market shrinks? Thank you.
Hi, Casey. Rehan here. I think there's a couple of different trends, honestly, that sort of move in parallel. You have to take into account that number one, higher efficacy agents are used to treat patients with more aggressive disease. Those patients still break through. That's not the same as treating patients with a low disease burden with a higher efficacy agent. I think that's one of the things to also keep in mind if you're thinking about how the market may evolve. I think the other thing is that generally speaking, what we've continued to see basically, as time moves on, is less and less tolerance for disease activity. If you go back in time to just when we had the ABCRs, you could have a few relapses and people would say, "Okay, well, it seems to have come down versus your historic baseline.
That's okay. You're probably doing okay. We'll keep you on therapy. Today, sometimes you develop a Gad lesion sort of nine months down the track on MRI, and they'll take you off even if there's no sort of clinical finding. Those factors also have to play, and you have to take into account higher efficacy agents are treating more difficult disease. The fact that generally speaking, as we go forward, we still anticipate that tolerance for disease activity will also basically continue to reduce, and therefore, there will still be a good amount of switching. Hence why having new mechanisms, I think, is really important because it can help people really achieve that goal of ultimately putting patients into a state of long-lasting remission where they have no detectable disease activity.
Thank you. Very helpful.
We will take our next question from David Evans with Kepler Cheuvreux.
Hi there. Thanks very much for taking my question. Really around bintrafusp. Well, on the several different components of the mechanism of action via TGF-β. Just wanting to get an update how you're thinking of the relative importance of the various components of TGF-β activity has changed over time. Maybe also to get just as a very general sense of, do you, in your minds, have numerous further studies, different settings waiting in the wings? Or have we seen maybe many of the settings that you're planning, at least for monotherapy by now? It sounded like you have quite major plans for future studies and combinations. What data points coming up would accelerate your program? I mean, the BTC study readout would the interim analyses in lung cancer have any impact?
Finally, on the safety side of bintrafusp profile, is it fair to say that you have gained more confidence on safety as partly feeding into the start of these various other new studies? Thanks very much.
I suggest to Peter, if you want to start with it first, and then Klaus and I are going to share the others.
Yeah, absolutely.
On the mechanism.
On the mechanism, we actually think about three mechanisms here, the direct anti-tumor activity, and of course, that depends on the status of the cancer cells. The more progressed the cancer cells are, the more likely it is that actually, TGF-β is activating their proliferation. TGF-β would block that proliferation as a direct anti-tumor effect. The second is prevention of metastases. We see this very clearly in preclinical models. The third one is the prevention of fibrosis, especially radiation-induced fibrosis. Again, all these three mechanisms contribute to the activity in preclinical models, and probably Klaus will talk about how we evaluate these mechanisms in clinical trials.
Yeah. Very good question. Klaus, just to give a little bit of a general view of the alliance from the beginning, the alliance with GSK, has taken an approach to be very targeted, very science and data-driven in the way we expand the program. I think anything you're seeing now with several new trials starting and the very prudent approach to the expansion is derived from that concept. That really is the frame here. I think the other point is that as Peter has described, different trials are trying to address very different mechanism of action, potential gain coming from TGF-β. The typical example is 005, in which we're trying to leverage some of the component related to fibrosis, with the radio chemotherapy combo in that setting, also to leverage the potential synergies with chemotherapy that has been also described for TGF-β.
I think I leave it there. Obviously, initially, we had to go in terms of testing the hypothesis with monotherapy to have much more pure signals. Now we are also thinking much more in where this pathway will add the most critical value in the standard of therapy in different settings. Therefore, we're changing a little bit toward trying to also explore combination therapy. Klaus, please. If you can make some examples, that would be very helpful. Thank you.
Absolutely. I think I alluded a little bit to it. It's very clear as Luciano is mentioning here, that to show a differentiation to traditional checkpoint inhibition in a monotherapy setting would obviously have been very clear. Let us also be acknowledging that by having a dual mechanism, it is of interest to look into potential modality that one way or the other can put the TGF-β pathway and TGF-β into play. Combinations with chemotherapy is one example of that. There are other examples, I think it is the way the program is being tailored is obviously that there will have to be shown a differentiation that you are adding a value by having a dual mechanism. There are readouts that are expected, I do not know whether we have communicated any of that. I'm too new to the company for that.
There will obviously be trigger point at that time where a real proof of concept, whether it is in that BTC indication, whether it's in a monotherapy indication in lung, will make us to expand into a combination program also. Clearly we have expectation that by having the dual mechanism that you would add a significant contribution above traditional checkpoint inhibition alone. It is also very clear that the checkpoint inhibition field is moving beyond monotherapy as well, and therefore we have to be ready also to see if there is a necessity to do combinations. You can speculate in VEGF inhibition, you can speculate in PARP inhibition, you can speculate in many things. I don't think that we have communicated any of that, because there's obviously clearly an element of an alliance that will have to align on that.
Very clearly the proof of concept, we will expand into a combination setting as I have alluded to, not only in lung but also in potentially head and neck cancer, with an aim there of also understanding what does HPV-driven disease mean, especially for the TGF-β component.
Thank you, Klaus. I just want to very quickly on the safety. Every combination trial that we are going on, especially the chemo combo trials in biliary tract and lung, they have a DSMB. They are checked on a regular basis. So far we are really no negative signal from those trials. They're small. So far we are encouraged that the combination are possible basically. Obviously there is always vanguard when we test this, and we will wait for the data for other combinations. Thank you, David.
All right. Thanks. Okay.
Thank you very much. That brings us to the end of today's R&D update call. Thank you very much everyone for your participation. We look forward to hearing you again at our next touch point at the Q3 earnings call on November 12th. Thank you.
Ladies and gentlemen, thank you for your attendance. The call has been concluded. You may now disconnect.