Dear ladies and gentlemen, welcome to Merck's R and D Update Call twenty twenty. May I now hand you over to Konstantin Vest, 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 and D update call. My name is Constantin Fest. I'm Head of Investor Relations here at Merck, And 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. And 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, Konstantin. 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 and D and commercial leadership joining us on this call today. I'm 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 Virgi, Head of the Global Innovative Medicine Franchises and President of EMD Sirono. Furthermore, I'm delighted to also introduce you to two senior leaders from our R and D organization, Peter Halle, Global Head of Research as well as Claude Edsbadson, 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. And following this, we will then be opening the floor to your questions. And with that, let me hand it to Rehan.
Thank you, Emily. And welcome all also from my side. So 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. And 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 where the Executive Board left off at the Capital Markets Day. So Stefan introduced you to the three main drivers of growth for the group for 2022 and beyond. And you can see that more than 80 of the growth is expected to come from these big three.
And of course, the healthcare pipeline is a big part of this growth. And as you know, the $2,000,000,000 by 2022 has been our ambition. We remain committed to that. We're very confident in that. And not only the $2,000,000,000 but we also believe that based on the progress in the pipeline beyond 2022, we will see even more contribution from the healthcare pipeline to the growth potential of the group.
Slide six, please. Also just from the from the capital markets day, it's just a reminder that from a health care perspective, despite the pandemic, health care 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. And also we've had some really important developments.
The approval of Bavencio June 30 and now filings accepted by other major jurisdictions and agencies. We've seen tepotinib approval in Japan, 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. So now let's get into the meat of the R and D update and let me hand over to Luciano.
Terrific, Rianne. Thanks and 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 and 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 and D review. It's been an interesting ambition for us and a journey to get to the point to create an R and D organization that could be a serial innovator within specialty medicine. That's the ambition.
And we will give you a little bit some point of validation related to where we are today. And then I hope you're going to hear more from Peter in particular but also from Claus 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 entities that are still active in the pipeline. So these are first in humans since 2014 that are still active in the pipeline.
We are also very proud of them making rapid choice on other enemies in the pipeline once they were tested in humans. The point here is the quality of these enemies, the fact that 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. And 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 publications that report to meetings but the quality has increased quite a bit. You see some of the examples of the various journals, peer reviewed journals where we published 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 one hundred 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 can see their way to accelerate and to support the availability of real major, major innovation for serious diseases within oncology in particular. I mentioned that we had in recent year four breakthrough designation with Tepotinib at Bavencio, SAGICATI designation and recently also the real time oncology review mechanism has been used by FDA for some of our programs. Finally, 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 Tetsmedco. And you're going to hear more from Claus about that. And finally, I certainly think that Rhianna has already illustrated our ambition that this novelty will contribute significantly to our revenue in the future.
And you see that we start to see that uptick of contribution already. And Rianne 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 see what give us a window in the future, a window in how the company is trying to create research and clinical operation that can be sustained for the future. And to do that I decided it's very important for you also to know our leadership talent.
And we created a position of head of research that Peter All has accepted to take. And 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. So 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 and also a warm welcome from my side. I'm really looking forward to our interactions discussions in the future. So Luciano shared with you how our R and D organization has gained momentum in recent years. And I would like to give you a 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. But our work doesn't stop there. Preclinical combination data, biomarker data, modeling simulation, all of that informs our clinical development colleagues. And they then closed 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. So 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 concept, 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. And so we kept these three tips in oncology with targeted therapies, immuno oncology and immunology. This continuity builds 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. But we 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 UK, the NCI in U. S, Karolinska in Sweden and the Weizmann Institute in Israel, but also with biotech companies such as Biomedics in Heidelberg. This leads to new biology areas such as phagocytosis in TIP immuno oncology, stress and plasticity in TIP oncology and others you see here on the slide.
And we have mature areas such as oncogenic signaling and immune complex signaling that have developed 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, Evobutinib, Brinciphus, 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 bars, high quality bars for the quality of the molecules and the differentiation by 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, NBEEs and ADCs, as well as development platforms such as safety pharmacology, DMPK, CMC, all part of the research organization. So despite this internal success, we don't have a non invented Tear syndrome.
And allow me a side note, this shouldn't come to as a surprise to you with my former roles in biotech and business development. And the external innovation team that Luciano just mentioned spans the whole chain from lifecycle management to discovery and is still part of my team. So 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 a rigorous portfolio and partnering decisions to maximize the value of our pipeline and portfolio. As you can see from this internal bucket at the left side, we have projects that we execute from A to 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, AppLinks are examples and also in license and 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 expertise for the specific areas, Iomtura, Ascinoron 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.
But 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's still significant risks as they are early development projects. So on Slide 13, let me start with M1231, our bispecific ADC.
As you know, ADCs reached the market and next generation approaches have created a lot of momentum and de making activity recently. But current technology still have limitations as listed here on the slide. Together with our partner Sutro, we have generated a bispecific EGFR MACH1 ADC that you see depicted in the cartoon and this ADC is addressing many of these limitations. It incorporates several advancements to standard ADCs, but 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.
And this higher internalization leads to much significantly more preclinical activity, sorry. The green bars on the right depicted relative to the standard mono specific 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 both targets, but on polarized cells and opposite side of those polarized cells, so the bispecific probably will not recognize these normal tissues. We published these data at this year's ASR and more ADCs are in our discovery pipeline. So stay tuned, we will report more about this.
On the next slide, Slide 14, another example for oncology, but that actually originated in TIP immunology. So an example for this great collaboration I was talking about between the TIPs. It is M3258, a highly selective LMP7 proteasome inhibitor. And in contrast to pan proteasome inhibitors, this one specifically blocks the immunoproteasome. And because the initial idea was to develop it in immunology, it has actually a favorable safety profile.
But in preclinical models, we saw the best activity in multiple myeloma models, data represented last year at the ACR in oral presentations and we are now in Phase 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. So let me share some internal not yet published data. Like abilumab and Bintrafusp, it comes from my 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 allow stimulation of CD226 or wire two twenty six, it also depletes high TIGIT expressing Tregs and other immune suppressive cells. And very important, it combines well with Brinchafer's alpha. This makes a lot of sense if you think about the mode of action, TGF beta is not only an important inhibitor of T cell activation, but it also blocks NK cells and trapping TGF beta via BINTRAFUS allows these NK cells in the tumor microenvironment to do their job via ADCC depleting these immunosuppressive cells. So we started a Phase one trial with this antibody in monotherapy, but the protocol already foresees combination with Bintrafusp.
And last but not least on Slide 16, let me come to M4344. You may wonder why I as 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.
And I would like to hand over to Claus, who will guide you through the oncology clinical development. Claus, 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, ventral phosphatipotinib 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 bladder 100 JAVELIN with a hazard ratio of point six nine, meaning a thirty one percent 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, these data has the potential to transforming the way we treat patients with advanced bladder cancer. Turning to updates given on Bavenshu at this year's ESMO, and I will focus on updates given on the JAVELIN bladder 100 trial. And as you see on the right side of the slide, there was presentations about subgroup 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 their potential abalumab could be a direct cell killing mechanism mediated by an AECC mechanism.
And then finally, some quality of life data showing that there were no negative effects 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 hypotheses beyond that monotherapy setting. And as an example, we can turn to combination with chemotherapy to initiate an enhanced immune reaction, and target fibrosis via the TGF beta pathway that would allow a bigger penetration addressing some of the known resistant mechanisms to checkpoint inhibitors.
We can also look further into the long program moving benzophosph alfa into earlier stages of disease, testing it against drelizumab in a stage three non small cell lung cancer nonresectable patient population. There are also attempts to explore the more direct role of adding a TTFB sequestering mechanism into the PD L1PD1 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. And finally, let me then mention combination with ventral phosphatase as the backbone. Peter did mention to you that we have initiated a dose escalation trial with our anti TIGIT, and there is a very clear aim starting combinations with a variety of solid tumor using as the backbone. You're 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 the PTL-one high patient population with a medium overall survival has not yet been reached, but showing that sixty seven percent of the patients are still alive in that trial after sixty sorry, thirty six months. Also showing data in biliary tract cancer in a Asian patient population after twenty eight months following in second line biliary tract cancer that continues to show durable, long lasting responses and long term overall survival with a near of twenty eight percent OS rate at two years. Please turn to slide number 22, turning to zepotinib.
We have been laying the foundation for that program with the ADDISION trial, showing an overall response rate of forty six percent with a median duration of response of eleven point one months in patients with exon protein skipping mutations in non small cell lung cancer. We have obtained an approval in Japan in March under the trade name of TEPmedco in all lines of the disease driven by that specific mutation. There is an expectation of a US 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 two that is testing MET amplification as a resistance mechanism for patients that are failing first line treatment with Tagrisso in an EGFR driven mutational 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 twenty five percent of the patients failing treatment based on that specific amplification. In situ is testing the resensitization by combining cibotinib with Tagrisso. And 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 teprotinib and Erbitux. And I want you to turn to slide number 23.
And just to highlight our expectations of the INSIGHT two program because we have fundamentally shown that teprotinib in a MET amplified setting is working. We have shown proof of concept by the INSIGHT one 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. And 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 versicertinib 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 hypotheses, among that, ARIDER1, ATR, and ATM mutations, and the plans of moving that program into PARP combinations to tackle moving the PARP field beyond BRCA mutated patients. On the DNA PK program, M3814 is progressing well in dose finding with chemoradiation in neoadjuvant rectal cancer. And when dose is established, the plan is to progress that into chemoradiation proof of concept study, clearly making us as a company a 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 gersosertinib.
First of all, on the right, in a randomized controlled 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. And finally, if you look on the left side of the slide, we have data in phase two 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, dapotinib. And by that, I would like to hand it back to Rhihan.
Thank you, Claus. So 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 US. So 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, you know, 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, you know, all of these conferences have been virtual. All of them reduced their fees. All of them saw far greater participation than normal. And basically, there was no fighting over who was going get the front row seat.
So I think in a way, this is potentially one of the net advantages of the context that we now find ourselves in. But now let's shift to how we're actually doing in terms of the actual introduction. So 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. And 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.
So 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? And the answer to that question is we're doing really well. When we look at our priority targets, so these are really some of the top decile physicians that have therefore this most significant volume of patients.
We've reached 70% of our targets basically within the first two and a half months. And 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. And so 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 Provencio has really demonstrated an inflection. So if you look at the eleven weeks sort of post approval versus the eleven weeks prior approval, you're looking at a 40% jump. And that continues to accelerate because if you just took a rolling four weeks view so the most recent four weeks versus basically the prior four weeks, you're at 50%. So 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?
So the breadth. And what we've seen basically is just a tremendous increase in the number of accounts that are starting to order Bavencio. And 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. And so 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.
And finally, when we look at penetration into the indicated segments, so these are patients that have received platinum therapy, patients who then have stable disease or better. These are the candidates for Bavencio maintenance. And what we see here is that basically since from July to mid August of the candidate patients, we estimate a penetration of about thirty percent into that segment. So what that means is that of all of those available patients that should be candidates for Coventry coming through in July, coming through in the August, we're getting about thirty percent of them. So it was about twenty seven percent in July, thirty four percent in August in that first half.
And this is really, really encouraging. Just a word on the data itself. You know, it's difficult to track, you know, this particular launch because of the unique context of a switch maintenance type approach. So 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. And this is going to be our primary means of really understanding treatment patterns and integration of Provencio as basically a maintenance agent following stable disease or better induction by platinum therapy.
So this is really positive. And to put the 30% also in context we of course look at benchmarks. And 30% penetration at this point into the target segment 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. And 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. So this is very positive. So now we'll move on to the neurology and immunology section. And 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.
So let me start now with evobrutinib. So I want to say a few things. There's a lot on the slide. We're not going to cover everything. But 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 three trials. And a big part of that is that we've 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. But 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. Two mechanisms that offer higher efficacy disease control that can be taken orally with the convenience of oral administration, only two. And 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's also important to recognize that in the field over the last decades there's 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 that could be one of the reasons why it's having such profound efficacy. But of course BTK is another way to get at that problem. And when you look then at the total market environment considered high efficacy agents, considered agents that are impacting the B cell compartment and considered the growth of the oral segment, it's just a no brainer to consider something like evobrutinib. So with that, let me hand over to Luciano.
Terrific, Rian. I will be going to Slide number 29 and very briefly. I know many of you have been following the evobrutinib story with us for a while so I don't want to reiterate too many points. But I want to make one point. This large Phase 2b 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 tyrosine kinase inhibition hypothesis in MS. This is really the most comprehensive data set. And even in our one hundred eight week follow-up we can confirm that we have efficacy on this primary endpoint for Phase three that is very comparable to CD20 and other very high activity. The other one is the safety database. We have now more than thirteen hundred actually patients in various trials that have been exposed for up to two years and plus actually.
And basically systemic adverse events are really minor and there is no sign signal for infection at the dose that we selected to go forward. Another very important point that I'm not going to reiterate in detail is that this compound SCNS penetration, but most important also by being an irreversible inhibitor is able to label and to block BTK in cells that traffic in and out of the CNS. That sets a huge upside potential in having an impact on many other phenomena so that BTK effect in 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 moderate simulation to really push forward with our analysis of the ideal doses.
And that's why we selected BID approach to really maximize the efficacy. So in terms of efficacy and safety database, this is very, very robust data. The most important update is that despite COVID-nineteen the trial is really doing very well. It's on track. And we still can get to the conclusion we projected now by the 2023 for this trial.
Let me move now very briefly to an exciting clinical development compound in the slide thirty first. And make very quickly a point that the Toll like receptor seven and eight inhibitor, it's a very unique program that really is trying to block the sensor for RNA in many immune cells. That's what TLR seven and eight is. And in that sense, there is a very strong similarity between our COVID-nineteen pathology driven by SARS CoV-two that is an RNA virus and the way this is sensed and trigger very robust immunopathology and immunohist cytokine responses that are probably a major, major driver of the COVID-nineteen 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.
So 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 to test these immunological diseases as explained briefly before. But the similarity between COVID-nineteen pneumonia and other diseases and 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 and TLR8 could play a very, very critical role.
So we decided to go forward with a randomized Phase II trial designed to test the hypothesis that the blocking TLR7 and TLR7 TLR8 with M5049 will have a beneficial effect in diminishing the consequences of the COVID-nineteen 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 Rian for some conclusive remarks.
Thanks, Luciano. So let me just touch on MAVENCLAD. So 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. And I think so the data sets that we presented there really support that. And what you see is a very profound effect and a very rapid effect within month one. And 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 further educating them, I think, on the profile. And in particular, think it's really reassuring to see that viral respiratory infections are really low percentage in terms of their occurrence. And 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. So 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, you know, if they are actually infected with SARS CoV-two and develop COVID-nineteen.
And so far I think we've been able to provide data, growing amounts of data that really suggest that at this stage there's nothing to worry about. Now this is really important because this is an area of, you know, 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. And so you know 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. And as a good example, there was a note sent out by Roche to all physicians in The United States saying that there may be an increased risk in particular of severe COVID complications if you are undergoing treatment with OCREVUS.
So 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. And here you see persistence rates over two years, basically above ninety percent. So now if we move towards what about the progress, when we talked about, you know, q two, you know, we told you very clearly that there had been an impact, you know, basically on 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 on to agents or start patients on agents if they weren't actually able to see them in person.
So 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. Now it's important to recognize that we're regaining momentum in the context of a higher efficacy dynamic market that is still depressed about twenty percent to thirty percent versus the pre COVID baseline. So the market is still depressed. Our momentum is returning. And 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.
And 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 that access. Access was a point that we continue to educate you on basically over the last twelve months. And 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 and we have not at all overpaid for that access.
So 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. And what we see here is new initiations have really started to rebound and potentially the leading markets in terms of the recovery is really Germany where they met 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.
And so 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. And 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. And then finally what's really important to us as well is that we finally cracked France.
So we received a positive recommendation from the Transparency Commission. And in H1 twenty twenty one, we will basically have our full commercial launch because we will have our price and access and everything. But basically the recommendation is positive and so you can look forward to that being a growth driver in 2021. So with that, we're going to trend over to the we're going to move over to the Q and A. But just a few words in summary now that you've heard from Peter, from Claus, 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 enemies with significant potential to differentiate that are now in the clinic and making progress. Since 2017, we 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 be able to deliver the 2,000,000,000 by 2022.
It's important also to us that you recognize that we're not just about the €2,000,000,000 We have growth momentum we think far beyond the €2,000,000,000 by 2022. And I hope that you see that that's underscored by the pipeline that Peter and Claus so elegantly spoke about. So 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 a question for our speakers, please press 1 on your telephone keypad now to enter the queue. Once your name has been announced, you may ask your question. If you you find your question is answered before it is your turn to speak, you can press 2 to cancel your question.
If you are using speaker equipment today, please lift the handset before making your selection. And 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, alemantinib data. I just wonder if you could tell us how you think tibotinib 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, you know, vague, depending on, rate of recruitment, etcetera. 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, and 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, you know, dynamic, opportunity, but 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. So just a little bit more update on your view of, of that, please. And then very finally, I wonder if we could ask Claus 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. Clearly you've moved from one oncology department to another.
It would be very interesting to hear your comparisons of what you're finding. Many thanks.
So, Klaus, can you go first on this virus oncology question? And then Yeah.
Absolutely. I'm happy to go first on the fifth question, Joe, 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 it's very obviously that Merck is having a very, 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.
But as Peter very clearly spoke to today, there is, when I take Merck size into consideration, an absolutely fantastic possibility from the early stage pipeline that is in the forefront of science. And I'm not saying that other companies that I have worked for are not in the forefront of science. Absolutely not. But there is an attraction for me in in absolutely joining a company, where there is that focus, ambition, not being pushed by being considered a little brother, but actually being bold and and ready to make some significant contributions, some bold risks. So all in all, very impressed.
I I expect you would likely not me to say anything different from what I was just saying, but I am, actually in the company. I have been voting with my heat, and, what I saw when I was speculating joining Merck has absolutely been coming to fruition. That that that was the fifth one. The the first one, I heard that you were saying we were seeing some excellent data. How does that fit with tepotinib?
Sorry.
Sorry. No. It it was it was the amaventinib data I was thinking of and whether that made any difference to your, you know, your thoughts positioning your assets in multiple myeloma.
No. I I I I don't I don't think it does. I I I think it actually just substantiates, what what what 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 it it is actually adding on to see whether when in a treatment setting can get into, 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 lots more cell lung cancer, it's much more a positioning as a rescue medicine, if I can speak like that.
And that is by no means to say that that's not a critically important element because if you look at at the number of patients that would be in need of a rescue medicine, irrespectively of whether you have an antelipid in the equation or not, it's going to be significant in years to come. I mean, if you look at the Tagrissoflora data with medium PFS of around twenty four months, it is about now that you would start to see patients in need of a rescue medicine. And 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. And as I hopefully showed you, we 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 one data. Data.
I hope that addresses what you were after. Yeah.
Clive, that seemed very comprehensive. And let me just add on to the point around the MS dynamic share. So I think that let me make sure I've tried I've gotten this right. But I think the question was really, you know, how big is that pool? Is it really going to continue to be a big pool?
And therefore, is it good source of business and can we count on that really for growth? And I would say, you know, 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. But what we've seen more recently is because, you know, there are so many drugs, that there are so many different mechanisms that, you know, new introductions don't tend anymore to really drive up the dynamic opportunity but what they do is basically sustain it. So 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. So when we say high efficacy, we're thinking the S1Ps, Mavenclad, the anti CD20s, LENTRTA, TYSABRI. We're seeing an increased share of the higher efficacy, you know, in terms of utilization in the dynamic segment. So that's why, you know, 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-nineteen trial with TLR7eight 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. So it's too early for me to speculate on how quickly it will go.
I just want to make one quick point. As you probably understood from the brief presentation, we believe that if the TLR 78 is a sensor for RNA viruses and trigger these inflammatory responses and particularly 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 Wasser with JPMorgan.
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, but what is that? And then just you maybe your thoughts on how this might look, efficacy wise, positioning wise versus, there's a couple of ADCs that are slightly ahead, the the TROP two potentially, CEACAM five. So 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? And then final question just on, Mavenclad, and just your your your 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? And and one aligned question, just if you could give us an idea of other launches beyond France, that you might have through 2021 and '22 And how big the French market is relative to Germany?
Thanks very much.
I'd like Peter to start and then we go to Rianne. Peter, please.
Yes. Let me take first the TIGIT questions. Rightly so, you asked the MSP and Roche question because we believe those two are the relevant competitors also with ADCC activity, which we believe is important in 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 translate into clinical development, we just have to see.
We are in 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 preclinical data. And then 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. And actually, that is relatively low in terms of receptor density cells for both targets.
And therefore, we believe actually it's a significant part of non small cell lung cancer and of course also other indications that express enough MAG1 and EGFR to trigger this internalization process that we believe is so important for the specific activity and selectivity of this bispecific ADC. And maybe on the second part of that question comparing versus chemo or ADCs in the clinic, would hand over to Claus.
Yeah. Mean, very clearly, I I mean, you mentioned yourself, Richard, that that the main competition competitor landscape here is likely the C CAM. And and I think I mean, we we do not have any clinical data yet from from this program, but we kind of know what we are up against. And I think what we are up against is very clearly very efficacious ZCAM from from Sanofi, but only the ZCAM very high expressers that would actually narrow down that patient population pretty significant. So I I I think there are absolutely room to play there.
In in a in a chemo combination, I 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. But, I mean, as Peter alluded to, it's early. It's a very interesting new concept of a selectivity and uptake for EGFR derived in the wild type tumors that clinical data will drivers. But I clearly think that there is room based on what I have seen up to now, especially the CCAP.
Before we go to Rianne, want to add Richard. There is an excitement about having the biospecific 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 MACH1 and EGFR within the tumor is going to that cutoff is going to determine prevalence. I think Peter explained that, but I wanted to clarify. So 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 would be done for that trial. But 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 Rian.
Sure. Thanks, Rian. So Richard, it's two questions really. One is sort of, you know, the split of patients in terms of where we're sourcing them from. So just as a reminder, The U.
S, basically all of the patients that are actually initiating MAIS and CLIMB, well, most of them, and anyway, 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 US, we see a pretty common pattern, which is that about thirty percent of the patients are sort of treatment naive, and about seventy percent 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, you know, 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. And it wasn't therefore driving sort of a push towards, you know, patients that are on treatment versus new diagnoses. So I hope that gives you some perspective. And as you think about the build of Mavenclad over time, you know, we're continuing to gain share.
We're continuing to build up new patients. But of course over time the importance of the returning patients also to the revenue build increases across all of the markets. But 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. Yes, so just to give you a sense, think the best thing to do at this stage is just to index France to Germany based on population and 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. But that should give you a good enough sense of the opportunity. And of course the rest is going be driven by the share that we managed to achieve there. And then 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. And in total, those markets do start to contribute meaningfully I think as we go forward.
And of course, the access dynamic in those markets can be different. Some of them come online later like Italy, like Spain. Some of them maybe coming online more in the time of France. So you can expect definitely some good contribution I think from outside of the major markets as well.
Thanks.
We will take our next question from Marietta Meimetz with PrimeAvenue.
Yes. Thank you very much. Few questions, please. The first is on Bavencio and bladder. 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? And 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 Joe'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 and J seem to be trying with their Mariposa trial, or do you think that that's really an overkill and the the preference would be to wait for a MET amplification to appear before a MET anti MET is given?
And, you know, what if you get the sense that it's it's 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 up front. And then 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 beta as opposed to other factors? Or 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 counters 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.
So we'll start with Rianne on the Obviously our indication for Bavencio is going to be in the patients that do not progress after initial chemotherapy. But yeah, let me
just add a point to that because as Luciano said, you know, our indication is distinct, meaning that you are going to be treated with platinum, have stable disease or better and then basically receive Bavencio. So in a way 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. Now 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. And actually what's really interesting coming out of that is the growing belief that there may be too much single agent IOUs basically in the front line. And as you know, you know, this is the initial approvals were based on single arm studies.
And we now have the benefits of additional data sets with single arm immunotherapy and combination immune therapy in the frontline setting. And, you know, this is leading people to really question, you know, whether or not PD L1 testing is really useful. And that's part of the indication for the single use monotherapy. And the other point is, you know, given the availability of avelumab following basically platinum induction and the significant improvement that that has on overall survival, the median fifty percent increase from platinum alone. The question is, you know, from all of the data sets now, why would you not be doing that in the vast majority of patients?
And why would you be using off label single arm immunotherapy when it has no advantage at this stage over platinum in terms of improving the median overall survival in randomized controlled trials? So 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 particularly in The U. S. For avelumab.
Now back to you.
Krausz, next question is for you on the table.
No. No. Absolutely. Thank thank you for for for for your question. I I I mean, let let me take it backwards.
I first of all, I would not find it necessarily a reasonable proposal not to have testing as to whether patient will have a disease that is driven by that amplification. Because, I I mean, reality is that if you look at at of 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. And there are variable assessments of what the actual prevalence of of the meta amplification mutation or aberration, I should say, is. I quoted up to twenty five percent after Tagrisso treatment.
There are other publications that are quoting higher and lower numbers, obviously. And and 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 approaches. 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 that that is a field that is absolutely under rapid involvement. I 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 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 twenty five percent as a resistant mechanism for failing Tagrisso treatment, if you look at an uptake in in countries where first line EGFR driven non small cell lung cancer is treated with about eighty five percent of the population with Tagrisso. And if the twenty five percent 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 drybulk disease is not fully established. I alluded to our explorations in 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 resistant mechanism it plays in colorectal cancer.
And that's part
of the exploration in our program.
Klaus, I think I'll take very briefly the Bintrafusp question. Think I thought it's a very, 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 has 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.
It looks like that the role of 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 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 the PD-one antibody driving the trap that is the extracellular domain of the receptor we are very dependent in non small cell lung cancer certainly from the targeting to PD L1.
And we do see tumors with high PD L1 being the one responding very robustly. And you see even in the ESMO trial that we can get to so far at thirty six months more than sixty seven percent 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, many other biomarkers particularly in the RNA six and other. But 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 TIGIT beta playing an additional role to PD L1. But 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 with chemotherapy as a monotherapy in PD L1 high. And finally in the stage 3A we're also testing the radio chemotherapy plus Bintra in PACIFIC like trial.
So we're keeping our options open. But I think your question about combination with TIGIT whether that confirms you start from a higher baseline driven by TIGIT beta in terms of responses that this could add farther efficacy and then maybe compete with the chemo combo. Thank you.
Thank you very much.
We will take our next question from Michael Lupin with UBS.
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. And then probably for Luciano, one of your friendly competitors in the BTK space put a theory up that their BTK inhibitor potentially inhibits B cell and myeloid cells activation in human blood and puts a hypothesis out that there could be an impact on acute and chronic inflammation in MS.
Just wondering how do you look at that because they showed all the BTK inhibitors and EVO scores a bit lower on myeloid cell relative to the rest of the bunch? Thank you.
Rianne, start.
Yes. So Michael, in a way most forecasts are generally you just got to accept that they're to be within a range, especially when you're sort of getting out there. But 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. So I think that's a really positive trend. And 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.
And 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. So that's kind of the way that we think about it. And then of course, you know, there's going to be some really good, you know, 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 know, 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.
And I think it's pretty clear now that these are different approaches and we've all optimized in different ways. And our view is that our focus has always been to ensure that we get a BTK that goes forward that basically has leading efficacy. And I think with the selectivity that we have, with the dosing regimen that we have, and with the efficacy that we showed 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. So 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 we get this right. And maybe let me hand over to Luciano to
answer Thank you, Michael. Really good question. And I'll start but then 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 basophils, in which the signal transduction is slightly different. It's different than other myeloid cells and certainly different than B cells. And in that the pocket by which evobrutinib is attacking the BTK has some influence in basophils 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 to myeloid cells are very, very robustly engaged by evobrutinib.
So this is more of an artifact on 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 that was also more involved in. If you have it, share with Michael.
Yes. Actually, do. But I wanted to mention here that actually both for Mavenclad and iverbutanib, we are really, as you mentioned, in detail analyze the mechanism in preclinical models, but also use reverse translation. So taking blood samples, analyzing them with single cell RNA set and other tools, really to understand the mechanism to inform, like you said, the clinical development strategy. But 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 ibrutinib on the myeloid compartment and on the other side from Mavenclad on various subtypes of BNT cells.
So again, 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. Thanks very much for taking my questions. Wimal Kapadia from Bernstein. Can I just ask a little bit more about the 5049 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 that we've had limited success so far. So I'm just curious, you know, why has the preclinical success that we have seen not been translated into humans? You know, is there something specific, to the target would make it quite challenging? And is it now that we're only truly understanding the TRL, the three-dimensional structure and the tolerability that comes with it? So just curious to hear your thoughts there.
And then secondly, in terms of indication, should we be thinking SLE and RA as a starting point? And then just given your understanding of the target, have you ever considered an agonist approach for oncology, and is this something you are pursuing? And then my second question is just following on from Richard's question on TIGIT versus peers. You know, 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. So just curious to hear your thoughts specifically on these two components versus your peers.
Thank you.
I guess I quickly start on 5,049. We are aware of only perhaps one competitor at the same stage with the selective TLR7eight inhibitor. Clearly the mechanism is very, very well suited based on not only preclinical but a little bit of biomarker data I can share with you 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 and TLR8 and the downstream pathways in interferon and NF kappa B. And probably different doses of TLR7, TLR8 could even distinguish between the various downstream pathways.
So 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-six secondretion in humans from circulating cells.
And we have a very, very nice dose response really reflecting complete inhibition of TLR7 and TLR8 stimulated IL-six secondretion. So we think we have a very good handle on those focusing and at least the biological activities there. So when we go in these both COVID-nineteen 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?
But most important if you can take then some of the questions related to the oncology and particularly TIGIT and
Maybe the ADCC 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 agonist. But again, it took us some time to develop a really, really good antagonist. And actually, the consideration for oncology, I'm long enough with this company to know that we had a program on a TLR9 agonist roughly ten years ago, actually in clinical development with Idera Pharmaceuticals was a partnership back then.
The issue with TLR agonist, as we believe, is a systemic activation of the immune system rather than specific activation in the tumor. So we are thinking along these lines. Maybe so to conclude on TLR, so we are again very confident about our molecule, TLR antagonists and are thinking about more selective agonists for oncology. And then the last question on differentiation of our TIGIT antibody. Again, what I've said, we have preclinical data, very robust compared to both those 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-one or PD-one antibodies because we believe that the ADCC activity that is needed for full TIGIT activation depends on NK cells, obviously, and then that these NK cells in the tumor microenvironment are inhibited by TGF beta. So essentially, our differentiation hypothesis is around combination of our TIGIT antibody with BINTRAFAST and the TGF beta blocking activity of BINTRAFAST.
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 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. And 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. So I think that distinction is important.
There are not as many in the clinic with ABCC activity in addition to the synergy to TIGIT beta that Peter has mentioned very clearly. Thank you, Wimal.
Great. Thank you.
We will take our next question from Casey Eriketla 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 there a risk that the average duration that MS patients on a particular treatment goes up quite significantly and the dynamic market shrinks?
Thank you.
Hi, Casey. So Rohan here. I think there's a couple of different trends honestly that sort of move in parallel. And you have to take into account that number one, you know, higher efficacy agents are used to treat patients with more aggressive disease. Those patients still break through.
So that's not the same as treating patients with a low disease burden with a higher efficacy agent. So 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, you know, as time moves on is, you know, less and less tolerance for disease activity. So 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. So those factors also have to play and you have to take into account hierarchy agents are treating more difficult disease.
And 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, ultimately putting patients into a state of long lasting remission where they have no detectable disease activity.
Thank you. Very helpful.
And we will take our next question from David Evans with Kepler Cheuvreux.
Hi there. Thanks very much for taking my questions. So really around Bintrafusp and just well, on several different components of the mechanism of action via TGF beta. Just wondering to get an update how you're thinking of the relative importance of the various components of TGF beta activity has has changed over time. Maybe also to get a, just just just a very general sense of, do you, in your minds, have numerous further studies, different settings waiting in the wings, or or have we seen, maybe many of the settings that you're planning at least for monotherapy by by now?
I mean, it sounded like you, have quite major plans for future studies and combinations. And and what what data points coming up would accelerate your program? I mean, the VTC study readout, with the interim analyses in lung cancer have any impact? And then finally, on on the safety side of Bintrafusp profile, is it is it fair to say that you're that you have gained more confidence on safety as partly feeding into the start of these various other new studies? Thanks very much.
So I suggest to Peter, if you want to start with it first, and then Claus and I are going to share the others.
Yeah, absolutely.
On the mechanism.
On the mechanism, so we actually think about three mechanisms here. The direct antitumor 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 beta is activation activating their proliferation. So, TGF beta would block that proliferation as a direct antitumor effect. The second is prevention of metastases.
We see this very clearly in preclinical models. And 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 Claus will talk about how we evaluate these mechanisms in clinical trials.
Yes, very good question. Claus, I'll 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'd expand the program. And 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's really the frame here. And 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 beta.
The typical example is five in which we're trying to leverage some of the components related to fibrosis with the radio chemotherapy combo in that setting and also to leverage the potential synergies with chemotherapy that has been also described for TGF beta. And I think I leave it there. But obviously, initially we had to go in terms of testing the hypothesis with monotherapy to have much more pure signals. Now we're also thinking much, much more in where this pathway will add the most critical value in the standard of therapy in different settings. And therefore we're changing a little bit towards trying to also explore combination therapy.
But 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. I mean, 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. But let us also be acknowledging by having a dual mechanism, it is of interest to look into potentially modality that one way or the other can put the TGF beta pathway and TGF beta into play. Combinations with chemotherapy is one example of that.
There are other examples, and I think it is the way the program has been tailored is obviously that that will have to be shown a differentiation that you are adding a value by having a dual mechanism. There are readouts that are expected, and I I do not know whether we have communicated any of that. I'm too new to the company for that. But there will obviously be trigger point at that time where a real proof of concept, whether it is in the BTC indication, whether it's in
a
monotherapy indication in lung, will make us to expand into a combination program also. Because clearly, we have expectation that by having the dual mechanism that you would add a significant contribution above traditional checkpoint inhibition alone. But 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. But 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 TCF data component.
Thank you, Claus. 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 DNC. They are checked on a regular basis. And so far we are really no negative signal from those trials.
They're small. But so far we are encouraged that the combination are possible basically. And 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 and D update call. Thank you very much everyone for your participation and we look forward to hearing you again at our next touch point at the Q3 earnings call on November 12. Thank you.
Ladies and gentlemen, thank you for your attendance. The call has been concluded. You may now disconnect.