Merck KGaA (NYSE:MRK) R&D Update Conference Call June 14, 2019 8:30 AM ET
Constantin Fest – Head-Investor Relations
Luciano Rossetti – Global Head-Research and Development
Rehan Verjee – President-EMD Serono and Global Head-Innovative Medicine Franchises
Joern-Peter Halle – Head-External Innovation and Head-TIP Immuno Oncology
Conference Call Participants
Wimal Kapadia – Bernstein
Joe Lockey – Morgan Stanley
Sachin Jain – Bank of America
Michael Leuchten – UBS
Richard Vosser – JPMorgan
Luisa Hector – Exane
Emily Field – Barclays
Simon Baker – Redburn
Falko Friedrichs – Deutsche Bank
Very warm welcome. Thank you, Cynthia. Warm welcome to this R&D Update Call 2019. My name is Constantin Fest, Head of Investor Relations. And I’m delighted to have with me here today Luciano Rossetti; as well as Rehan Verjee. Luciano our Global Head of Research and Development; Rehan, President of EMD Serono and Global Head of the Innovative Medicine Franchises, and also I’m very happy that supporting for the Q&A, we also have Joern-Peter Halle, Head of External Innovation and Head of TIP Immuno Oncology here with us. And in the next few minutes, we’d like to run you through the key slides of this presentation following that, take all of your questions.
Having said that, happy to hand over to Luciano, so start this call.
Thanks, Constantin. And welcome, everyone. Good morning, good afternoon, depending where you are. I will keep the interaction a little bit short, but certainly it’s been a busy 12 months for us in the R&D organization. A lot of things happened in this roughly 12 months since we had this update call. Major pipeline progress especially on Bavencio, the first line RCC on Slide 3, I’m starting. The Bintrafusp alfa, you are all familiar, it used to be the M7824 with the progress and finally we are starting now several potential registration or trials, and we will cover them.
Evobrutinib, you’ve seen also the 48-week data regarding annualized response rate and MRI, and we are going to go into this detail a little bit. And then the Tepotinib, I think we want to put this program into context. But we had the major data coming out of the two major trials, the VISION trial and the INSIGHT trial, and we will mention the design and the future start of the INSIGHT 2 trial as well.
Finally, regulatory success with Mavenclad, in addition to the European and 55 country overall that we achieved over the last several months. This year has been characterized by the approval in the U.S. Bavencio first line renal combination with rixinative and also we have filed in EMEA and also in Japan early this year.
Finally, we announced that we are fully implementing the alliance with GSK on Bintrafusp alfa. Finally, I want to mention briefly that the scientific leadership of our team has been clearly proven and validated by our participation to the scientific meeting, much higher number of presentation, oral presentation and also peer-reviewed scientific publication of high-caliber, not just the number but also high impact journals we think two recent publications in the New England Journal of Medicine.
Let me move now to the next slide. We’re going to follow the presentation clockwise on this slide, Slide 4. And we want, before we get into a review of some of the registration of trials that are going to be ongoing in 2019, I want to give you a flavor of the – an example of the early pipeline. You have the pipeline to your backup slides but I think it’s important that we mentioned before getting into later stage that the early pipeline is also moving very well. We have a lot of programs in the clinical stage that are moving into proof of principle with very successful bio market data and even in clinical proof of concept stage in the next few months so not included in this presentation.
We focus next Slide 5, into – let’s switch to Slide 6 actually into a brief update on the DDR portfolio, DNA damage and response portfolio. You know that this is an area of great interest, perhaps spearheaded by the success of the part inhibitors. It’s a first example of DNA damage response having great success in several tumor types. And we have a very well-balanced pipeline with the multiple clinical stage programs, indeed we will have six different molecule in the clinic in this space.
And they are proceeding in early development. We are aware of the opportunities of affecting multiple different tumors by leveraging the fact that tumors cells have a defective DDR mechanism and if you are able to affect one or more of this DDR protective mechanism, the tumor cell becomes very vulnerable to proceed into apoptosis. So we have ideal combination programs because of the availability of multiple molecule in the clinical setting. And we are making some adjustments to our own strategy for DDR.
So we move to Slide 7 now. And I want to illustrate very, very briefly the major changes. We are focusing as the first priority into the synthetic lethality concept. So the concept that if you have either a genetic defect in one specific DDR mechanism, affecting the additional mechanism with a very selective molecule, will have devastating effect of the tumor cells and therefore precipitating the tumor dead, tumor cell dead. This can be elicited in two ways could be elicited because you’ve selected a population based on this vulnerability like ATM deficiency, or because you are able to combine two different mechanisms in a combination setting, and that obviously is facilitated by having three different major mechanism ATR, ATM and DNA-PK available in our [indiscernible] in addition to potential combination we got inhibitor.
The second priority is now the immune activation. So the combination between DDR portfolio and our portfolio immune checkpoint. And what used to be our major priority will remain in place, but it’s a little bit deemphasized compared to the past. And that leads to the idea to leverage the ability to amplify the DNA damage induced by either chemotherapy or radiotherapy. DNA-PK will remain the most solidly in that corner like the number three priority, particularly in combination with radiotherapy or radio chemotherapy.
Let me now put in context in slide – first to Slide 8 and then to Slide 9. I would want to switch to Rehan to put into context not just the Tepotinib trial, but how the opportunity for c-Met inhibition to be larger than currently understood. Please, Rehan.
Thanks, Luciano. So hello, everybody. So just to start on Tepotinib. I think many of you will have seen, obviously, the very positive coverage and reception of the data for the class, really at this ASCO. So just as a little bit of reminder. Tepotinib is an in-house discovered, highly selective oral, that’s given once daily and very, very potently, obviously, blocks the MET TKI. So this, of course, opens up opportunities where MET-mediated signaling is really known to, let’s say, be a primary oncogenic driver or a primary driver of resistance, okay. So that’s the way to think about it.
Now a few key points. In the core indication, and you can see that’s basically in the charts, you see sort of MET amplification and MET exon-14, or MET slice operations are about 3% or 3.5%, basically, of non-small cell lung cancer patients. So this is obviously a primary population that we’re aiming to target in the context of the VISION trial, and Luciano will emphasize I think some of the key results from that’s in the following slides. So that’s one side of it.
I think the other side, which is really important to consider, is obviously the amplification of MET in the context of resistance in particular, in the context of resistance to the third generations EGFR TKIs. And so basically as you’re thinking about this, you’ve got a population really in the primary setting where you’ve got amplification and Exon 14 Skipping. And this, if you look across Europe, the U.S., China and Japan, it’s a population of around 10,000 to 11,000 patients, okay. And about 40% of those patients are basically in the U.S. and in Japan.
And then if you look at the context of MET amplification in the context of EGFR resistance, and this is in lung-only, you are looking again at a population of around 12,000 to 13,000 patients, but again, around 40% of those patients are really being in the U.S. and Japan. So what you started to develop a picture of is that you basically have a very targeted therapy that can address basically an unmet need in a population, which today doesn’t respond well to standard therapy or has developed resistance to very potent EGFR therapy. And that leads us, obviously, into the program that we’re developing in lung. So that’s the VISION study and the INSIGHT 2 study.
But I will say as well as that we are doing work at this stage as well to also continue to understand where potentially MET amplification, either in the primary setting or in the resistance setting, could play an important role in other tumors.
And so for example, if you consider where EGFR can also play a role in other tumors, the question is, does MET amplification play an important role in some of those settings, and could tepotinib potentially be an agent to also address resistance in that setting, okay?
So there’s actually, when you start to think about it, a big opportunity really for tepotinib to play an important role in the treatments of patients with non-small cell lung cancer but also growing body of evidence that suggest that there may be an opportunity even in a broader set of cancers where MET amplification could be either a primary driver or basically important in the resistance context. Luciano?
Thanks, Rehan. As you heard from Rehan, we believe that we have an outstandingly selective inhibitor of c-Met. We are having this to consider avelumab in validating prospectively the biomarket approach, particularly using liquid biopsy. And we claim now, as you see in Slide 10, to fully leverage this scientific achievement over the last 12 months or so in particular.
We started with the recent trial that prospectively addressed the recruitment of patients with METex14 mutation, both by liquid biopsy and tumor biopsy. The trial is fully enrolled for the METex14 combination – component, but is continued enroll into MET-amplified component. So we are going to file initially for the METex14 for both liquid biopsy selected into non-selected.
The other trial that started before this trial is the INSIGHT 1 trial that is in EGFR mutant fielding a first or second-generation TKI treatment and negative for the T790 mutation. In this INSIGHT 1 trial was 18 months follow up will be presented in meeting coming up in September. You will see very dramatic and positive data and I’ll summarize those briefly.
They led us to make a full commitment now to go in a registrational trial, they called INSIGHT 2 in which we will combine the Tepotinib with Osimertinib in EGFR mutant failing various TKI in first treatment. I also want to mention as Rehan already say, that we are considering or thought, the decision has not been made yet, a tumor agnostic approach to leveraging the fact that the amplification is relatively frequent in other tumors particularly colorectal cancer and that’s under consideration.
So the Tepotinib, both by marketing estimates and the quality of the molecule now in development will be leveraged by multiple potential factor development, that’s a novel strategic direction for us in R&D in recent time.
So let me go now to slide, the next slide that’s Slide 11 and very, very quickly give you a little bit of a flavor of several points regarding the VISION trial and this is the most updated data ASCO: Number one, the data now is extremely consistent, the various analysis we have done based on liquid biopsy, tumor biopsy, prospective recruitment and also investigator versus independent assessment are coming together very nicely.
Most striking data are obviously, the response rate, the consistency of this response rate across the line of therapy so far even though the numbers in first line are still small and this course is the most immature because started about eight months after the others. And most important, very clear sign of robust durability and also confirmed by the PFS data and you can see that despite the fact that the upper confidence interval has not been achieved yet, the data are very encouraging with durability over 12 months in every single small cohort and also with PFS around 10 months in our estimated the VISION trial.
So based on this and the use of LBx, so liquid biopsy prospectively, we are very confident that these could be a trial that will lead us to file sometime in the next several months in Japan and the U.S. initially. We also want to point out this was extremely well tolerated. The rate of discontinuation due to treatment was 4%, extremely low. And as you see also on the right side, as in many other driven mutation in non-small cell lung cancer, the response, the shrinking of the tumor was present in all line of therapy in visually more than 90% of the cases. The overall medium DOR was 14.7 months, if you take type cohorts together as presented recently at ASCO.
Let me move now briefly to Slide 12 and so why we are very excited about the start of the INSIGHT 2 trial that we already a positive in clinical trial. If you look on the left side, the INSIGHT 1 trial, there is now, I want to give you just a flavor of the comparisons that was made by the discussion of the last meeting, you’re going to see an update as I mentioned in September, but it’s pretty clear that we consistently see both in the Phase Ib and in our Phase II INSIGHT trial, roughly 67% to 68% objective response rate, if we have reached the patient population either by ICH, so immunocytochemistry or by genetic measurement by increased copy number above six in this case.
In addition that the primary endpoint was in the case progression free survival versus chemotherapy and you can see with the immunohistochemistry we had a doubling of the progression free survival eight versus four in the control. And by using what we plan to use prospectively that these genetic marker, a copy number is 21 months versus four months. So these are preliminary data, they are small where we having a randomized trial and that lead us to in situ that you see briefly on the right side of this slide.
For reason of time, I move now to a very quick conclusion on Tepotinib. We think that this is really the program now on c-Met that has the most comprehensive data across different important indication. The EGFR mutant that might be the largest. We have a very important data already presented, and we’re planning to move forward. The METex14 and the MET amplified as well as primary driver in a certain non-small cell lung cancer tumor.
The molecule exceptional durability and progression free survival demonstrated in this preliminary data to be confirmed when the data more mature, and we have been recruiting prospectively our patients for liquid biopsy in the VISION trial and plan to do so in the INSIGHT 2 trial.
Let me just now switch very briefly it an update on Bintrasfusp alfa, and we are on Slide number 15 now. I want to make the point, you know very well about these molecule, this is by a transitional fusion protein of PD-L1 and TGF-β. It’s the extracellular domain of TGF-β. Our two receptor that is able to block neutralize all the isoform of TGF-β1, TGF-β2 and TGF-β2 and even humans we’ve been able to demonstrate this neutralization. But the point I really want to make is to one is that because the PD-L1 is driving enrichment of the TGF-β trap into the tumor. We expect to have an enrichment over the neutralization TGF-β in the tumor in the presence of PD-L1 expression in either immune cells or tumor cells.
The second is that the effect of TGF-β are pleiotropic. You have effect that are directly emphasizing, and arming, augmenting the effect of PD-1 in increasing the immune responses versus the tumor shown on the left side of the mode of action. You have effect on the vascularization of the tumor, you have an effect on the EMT, the epithehlial-mesenchymal transition that are very important for metastasis but also for resistance to chemotherapy.
And finally you have anti fibrotic effect of blocking TGF-β that could be very important in combination with radiotherapy but they also might make the access of peels of lymphocytes into the tumor then facilitate it. So going from an immuno exclusion to an inflamed phenotyping the tumor. I don’t go into the remaining part of the slide, but I would like may be, Rehan, if you can briefly comment on the prospect regarding our recent alliance with GSK as well.
Thanks, Luciano. So it’s just to really underscore the point because I think both Luciano and I on occasion feel it underappreciated I think that the value of the – over the strategic value of the alliance and that is to say that this alliance and doing it in the way that we have has given us the opportunity to now really invest in parallel in the clinic in multiple parallel, let’s say mechanistic hypotheses, which are essentially non-correlated. So, if you look at the primary trial that we sort of started and spoke with you very early on, in the PD-L1 high, we’re sort of testing really there much more, let’s say the ability of the TGF-β compartments to really overcome some of the additional immunosuppressive properties of the TGF-β in the tumor micro environment.
But then if you move to something like the Stage III study, where you’re looking at this much earlier, where potentially the impact on things like angiogenesis, conversion to the EMT phenotype and obviously the antifibrotic properties given basically the combination with chemo and radio could be really important. You’re starting to see that we’re testing various different hypotheses and that potentially they’re not perfectly correlated.
I think for us this is really important because what it means is that, in the end TGF-β trap or Bintrafusp alpha may work in one setting and potentially not others or it may potentially of course work in all of them. But I think it was really important for us to be able to pursue in parallel, multiple parallel – multiple mechanistic hypotheses. So I think we’re off to a very good start and what we’re trying to – we’ll show, I think on the next slide you can see that the initial four studies all really are basically designed to test those different hypotheses.
Thank you, Rehan. I will move more rapidly because we have a lot to cover. And we are now on Slide number 16. I wanted to mention that four trials have already posted or either started or really shortly starting. Three of them are in non-small cell lung cancer, one is explorative in combination with chemotherapy, obviously, we have to do a safety vanguard. And the other three are potentially registrational, one is a very familiar to you is the 37 trial, that is in Stage IV cancer, PD-L1 high only and it’s head-to-head versus KEYTRUDA in that study. And then we have already announced also a Stage III unresectable radiochemotherapy combo head-to-head versus in CT and I’m going to have brief slide on that. And finally, the second line biliary tract cancer as the trial already started.
Let’s move now to Slide number 17, very quickly, why we are so excited about moving forward with the second line biliary tract cancer. The realities that there is no effective therapy in this population whatsoever, even recent data presented at ASCO have shown an overall survival that is less than seven month in very heavily and toxic treatment with chemotherapy. The competition in terms of immune checkpoint has shown the very best data, the richest data at 5.8% response rate, early data 13%, so the maximum response rate in the second line biliary tract, with the OS, the thesis that I mentioned in the range seven to six months.
Our early data, such as the response rate of 20%, in addition, we also have some late response. So progressional that then have shown very robust and prolonged responses later on. 20% objective response rate by independent investigator and is still progressing assessment overall survival of 13 months so far, but as I mentioned, the upper confident as well as to reach. Based on these, we decided to agree with regulatory agency to move forward into the next stage that could be a registrational in the 120 patients single arm trail with a similar approach 141 patients as you see there.
Let’s move very quickly on Slide 18. This is to give you a flavor of the design of the trial. I want to emphasize what Rehan just say, these tests an independent hypothesis, not only the very nice data we have in non-small lung cancer with special PD-L1 positive, very high response rate and very durable responses. But also the idea that we put them in the adjuvant setting having a positive effect in prevention of metastasis and also the synergy with the readiochemotherapy, very nicely demonstrated in preclinical studies and by others with the TGF-β block. So the trial that’s depicted on the right side is in a Stage III unresectable. They undergo radiochemotherapy plus Bintrafusp alfa or versus placebo. And then they are randomized in the current standard of care that is durable for maintenance or they Bintrafusp alfa for maintenance in the other arm.
Finally, we want to mention also the recent ACR update on a very striking data in HPV positive tumors, Slide number 19, where we have a number one response rate that are in the 30% range. But once more even more than in other settings, we see these phenomenonal late responses. So pseudo-progression followed by very dramatic profound responses that are very durable and that takes us to a total clinical response in the range of 35% to 40%. This include, obviously cervical cancer, head and neck cancer and many other rare cancer that are HPV associated and we plan to move forward with additional trials in this settings probably within this year or very early next year.
Let me now just switch gear briefly to our neurology franchise. And I would like to ask Rehan to introduce briefly why we think that they our BTK inhibitor, evobrutinib to be a very unique asset in the very crowded picture of MS therapies.
Thanks, Luciano. So we’re on Slide 21. So this is really going to be an update obviously on our Phase III plans really for evobrutinib. But before we get there, I think we just want to underscore a little bit around how we see, I think the relaxing in that field at this stage from an unmet need perspective. It’s often thought sometimes that there are many approved therapies obviously, which is fantastic for patients and that this means that there’s not so much stays anymore I think to bring forward, I think a new therapeutic.
I think if you do extensive research and if you really spend time in the community, I think you know that’s not necessarily the case. One of the first points of course to make is that many of the agents that are approved today belong to the same class, the same mechanism. And so therefore it can be very difficult actually for patients to cycle through, obviously from the same mechanism to the same mechanism. So that will immediately almost brings down the number of approved agents by about half.
And as you look at it today and you look at basically the patient experience and you look in the context of even clinical trials, even the highest most efficacious agent will – patients on that agent will experience breakthrough either by clinical radiological measures around 50% – in about 50% of cases. And of course, if you were to look more frequently with MRI and even more frequently with more powerful MRI, what you would continue to see is even perhaps even more disease activity. So the point is that while there are many approved agents and many effective agents and a lot of progress has been made, still there are not enough mechanisms and ultimately too many patients continue to experience ongoing inflammatory activity, detectable even in frequently and by relatively crude measures.
I think if you look forward and then you consider then what about the agents in development and in registration and late phase development of registration. What you do find again, is that again they are Me2 mechanisms, another entity 20 or another S1P1. So we believe firmly, based on the disease activity that continues to remain and based on the fact that there are not that many mechanisms available to treat MS patients today, that there still remains need, I think for new mechanisms. So that over the course – lifelong course of the disease patients can then ultimately potentially cycle through from one mechanism to another mechanism and the prospect of course, quietening down their disease.
I think the other point to make also as you’re the MS and relapsing MS is that there is only around five therapies that are really considered, let’s say higher efficacy. And of those only two are oral. So again, if you could bring forward a new mechanism that was higher efficacy that was oral, there’s a real opportunity, we believe basically for such an agent. I think it’s also important to mention today that none of the approved oral therapies have actually demonstrated a robust effect on progression versus an active control. So that is a bar that has not yet been crossed by any of the approved oral agents.
And finally, we continue to believe of course, that remains an opportunity to advance. I think on the benefit-to-risk. And that means, potentially, for example, improving, I think on the side effect profile and the lack of systemic side effects can often improve compliance and ultimately therefore, of course, on the efficacy aspect. And also if you had the prospect of potentially bringing forward an oral higher efficacy agent that did not significantly increased the risk of serious infections. That again, it could be a significant advantage obviously in the context of the MS treatment landscape.
So that of course then leads very clearly to the opportunity for evobrutinib. First and foremost, it is a novel mechanism and it actually addresses the potential immunopathology of MS in two distinct ways by addressing the innate compartment but also the adaptive compartment, so macrophages, particularly, and of course, the B cells. We have seen of course, and we’ll try to, we’ll touch on this in the 48-week data that we have very robust effect on both relapse and radiological measures of disease activity, that there were no systemic side effects. So there’s no GI disturbance, no flu-like symptoms. We did not see an elevation in infections, which is incredibly encouraging over the course of a year along the study.
And of course, it has the added advantage of real rapid reversibility. So in the context of risk management, this can be incredibly important obviously for treating physician. Because something materialize, if you’re able to basically discontinue the drug and you know the basically the immune system will basically rebase line to where it was.
So our approach, and this is what Luciano will introduce, is to really make sure that we give this agent the greatest probability of being able to get into the clinic – into clinical practice. So we have chosen an approach that really enables us to maximize that probability of success while at the same time doing all of the necessary sub and ancillary studies in addition to the core study to make sure that we truly characterize the unique mechanism and the impacts that it could potentially have in the context of MS. And this is both in the CNS and obviously, the peripheral compartment. Luciano?
Thank you. I think where Slide 22, I can just mention one thing to emphasize. If you see on the left side, is a 12 weeks so extremely earlier, the very first MRI. You see the full effect on the primary endpoint of gadolinium positive lesions T1. That to me very, very striking and there is two highest dose really have a very rapid effect and that’s appreciated by tons of clinicians that just specializing in MS. And then you heard everything else from Rehan.
So let’s move to Slide 23. This is just to let you know that we officially can tell you now after also regulatory interactions that we are starting a Phase III trial for MS shortly. And we have agreed to detail to all the experimental design and you’re going to see them very soon in our clinicaltrials.gov. The bottom line today we speak that in Slide 23, we’re going to have parallel Phase III study conducted in a way that can get us to rapid registration with primary endpoint of annualized response rates. And also additional endpoint related to progression.
We have made a design that that will allow us, because it was a combined analysis to add the very robust assessment of progression that could leverage the double mechanism of evobrutinib both on the innate immunity and adaptive immunity, especially the effect of myeloid cells that might have effects that we have not seen the short term study yet, but they will be demonstrated in Phase III. So if we are going to be able to do this, we believe this is going to very differentiated and novel new track oral treatment for MS potentially with the demonstrated progression of benefit as well.
Let me move now very quickly to Bavencio. We are only going to touch briefly on Slide 25 to make the point to this is clearly been the covered very well that we add to the first interim analysis for our first line renal cell carcinoma trial with axitinib. The DNC alerted us that the data were very striking and they should be considered for a filing. The FDA agreed with that statement and we are filed very rapidly and we were approved in May. The point I want to make is the consistency of the data across these trial. It’s very striking. Particularly, if you look in the distribution based on prognostic factors like favorable, intermediate and poor, you can see the avelumab-axitinib combination add a very, very consistent effect across all different line, even though the favorable group was actually enriched in some of the other trials more than in this specific trial.
Also, the effect on PFS was very robust with the difference of six to five months depending on the PD-1 positive oral comer population. Finally, very good tolerability, basically no difference versus the control arm sunitinib and finally, the rate of this discontinuation only 4% due to side effects. So very interesting to see now all these goals, but it’s clear that it is very well received by all major experts in the field. This is my last data slide and then we’ll very quickly skip Slide 26. And I wanted to make my final summary points on the next slide. That is Slide 27.
I think we’ve been coming a long way as an R&D organization in the last few years and our goal was to take the great time that we were observing coming from the lab and translate that into registration in having drugs for this finally can make a tangible benefit to patients. And I can see now with the success on our regulatory path that starts to be able to evidence with Bavencio and with Mavenclad. But also with the 11 registrational trial that we’re going to have ongoing in 2019 and illustrated in the slide that we are on the right path to have consistent R&D productivity in the later stage of our clinical pipeline.
I can already tell you that we expect to have several potential clinical proof-of-concepts upcoming in the next year without going into detail related to immunology and also related to bintrafusp alfa. So based on that I wanted to open it up, we go to the next slide with the catalyst, but would like to just switch directly to Q&A. Thank you.
Thank you. First question please. Thank you.
Thank you. We’ll now begin our question-and-answer session. [Operator Instructions] One moment please. For the first question is coming from the line of Wimal Kapadia from Bernstein. Your line is open.
Okay, great. Thanks very much for taking my questions. Wimal Kapadia from Bernstein. So we’re going to start with tepotinib. So tepotinib seems to have a stronger first line overall arm and good data embayments. And your data looks better on duration, PFS and safety. I want to get your thoughts on what matters more for commercial potential. And just following on from that, I appreciate it. Tell your molecule, but why do you think the second line overall drop so much for capmatinib in the study.
The second question is just on the beta trap, you exactly given some commentary, which suggests the potential to fall early in some of the smaller indications. I guess I just want to get your thoughts, if that’s in a possibility, maybe HPV or an additional indication. And then the final point or final question is just on the BTK in MS. Is there are other competitors in the clinic in MS. So I guess you’ve now proven that it works. So how do you see differentiation in this market and do you think it could become very competitive longer term? Thank you very much.
Thank you. Maybe I’ll start briefly and then Rehan can address definitely the last question and also some of the first question tepotinib. I just want to point out that in my view, we should all be happy, that other players are coming into the field, because the most important thing that tends to happen is that patients need to be tested particularly with liquid biopsy for c-Met. We want to have the detection rate that is probably right now in the 10%, 15% go to 80%, 90% like each for EGFR. So adding some competitor in this major indication is good. One point I want to make is, it’s clear that tepotinib is the one that has shown a very, very durable activity with dramatic a PFS effect in all settings.
If you look at our INSIGHT data, we have a PFS effect that are truly remarkable and not matched by any data that I’m aware of even though in a randomized trial. And if you look at the VISION trial, average duration of responses, it’s 14.7 months that’s truly important. And so is the PFS, as I mentioned is not yet mature but it’s in the range of 10 months or higher. Regarding the small numbers that we have for first line, I wanted to caution everyone. We basically require a firm response. We have data that are really not mature yet for first-line because started later and the numbers in both – in all data sets are very, very small.
While the number in second-line and more already large numbers, all data set I’ve seen. And there you could see that durability, QD versus PID, liquid biopsy prospectively, PFS, that there are things that could potentially favor tepotinib. But I want to emphasize, I think that it’s very good at that different settings tepotinib will have some partnership because we have to make everyone aware how big actually the opportunity could be particularly, EGFR mutant and others. Maybe if Rehan, do you want to add something else, on the issue of the tepotinib and the market?
I think, you’ve made all the points and just to maybe emphasize, it’s really the duration of the response I think at this stage that we see is really, really promising. And we do see that the response rates are broadly, and I think the same ballpark, but duration really seems to be most important. And then we’re also, intrigued obviously, by the fact that we’ve been able to demonstrate the data EGFR setting and others have discontinued of course trial in that setting. So this is potentially indicating that there may be something genuinely differentiated. I think about the molecules.
And I would only underscore the counters points. I think, having competition is only going to further drive, I think rapid adoption of testing and identification of these patients because as he said today, while net testing is basically on the guidelines in the U.S. in Japan, given the fact that there aren’t available therapies, patients don’t get ultimately tested for that. And so the yield today and net testing is more in the sort of 20% range. Whereas if we count had said for EGFR or ALK, it’s sort of been the 85% or even 60%. So I think we see that there’s a unique opportunity here really to build out from that class and potentially to really differentiate on the duration of the response and particularly in some of the novel indication such as EGFR.
Okay. Can I just very quickly go to Bintrafusp alfa? Clearly the biliary tract second-line is the potential right now the most fastest path registration we don’t commit to any specifics. There could be in the HPV field additional opportunities that you’re going to see fore coming, but no further mentioned there. One point I want to make is even the non-small cell lung cancer, there could be opportunity for a reasonable filing based on PFS, but I want to downplay a little bit expectation there. We may or may not be able to have the filing exclusively based on PFS. It has to be really a very robust difference in order to drive us into that direction. In that particular trial, I think, we will have probably to have some more data to supporting the PFS. That’s my reading of the 27 trial. But still that’s forecoming as well. Rehan, what about the evobrutinib if you want to touch based on the last comment?
So Wimal obviously, we’re – we understand obviously the MS, the MS landscape has evolved and will continue to evolve. Obviously, at the time points when we have the opportunity we hope to introduce evobrutinib into clinical practice. I would just come back to the fact that again despite I think what we anticipate to be the continued evolution, we still believe that given what’s in development today is basically need two mechanisms. Physicians are going to be place for yes with more choice, but not much differentiated choice. So if you’re looking to have a significant impact on the disease with the convenience of an oral therapy and ultimately not really predisposing patients with significant risk of infection, for example, with the option to potentially rapidly, deescalate from therapy, if you run into an issue.
Nothing that is in development today is really going to be able to address that. And so hence, we remain really confident, that the BTK profile that we have seen on evobrutinib profile that we have seen in Phase II bears out in Phase III. Then this is going to be an attractive option and a very relevant treatment option even in the midst of a relatively crowded landscape. I think one of the other points to really emphasize is of course the trial design is really powered, obviously, for the primary endpoint but for size so that we have a good probability obviously, of being able to demonstrate that we can have a robust effect on progression versus an active comparator. And of course that could be a real additional sort of upside and positive, given as we sort of mentioned that’s not actually been achieved before in the context of oral high efficacy therapy in the field of MS.
Great. Thank you very much. Appreciate it.
Next question comes from Joe Lockey from Morgan Stanley.
Thank you very much. Joe Lockey from Morgan Stanley. On the safety side of evobrutinib, what’s the liver tox mitigation strategies are you using in the Phase III trial? Will you be excluding patients with the prior hepatic conditions? And then will both trials be using beta interferon as the active competitor? And then, Luciano, on Tepotinib basket study, can you talk a little bit more about the tumors you would include? Do you view liquid biopsies as appropriate for patient selection in a treatment of agnostic setting? And then third quick one, if I can on beta trap alone [ph] 37. Can you comment on how it’s enrolling, and how many insurance are planned. Thank you.
Sure. Let me start with the evobrutinib. We can tell you today is that we have been confirming number one with the 48 weeks follow-up in the extension as well, that the incidence of these laboratory finding of high transaminases is restricted to the first 24 weeks. We really have seen that across the entire program and as you know we have a very large cohorts of patients in different trials, that this seems to be a very clear pattern. That allows us to monitor these lab findings more intensely in the first 24 weeks in limiting that to understand how we want to label that finally in the future.
So I think so far so good. We are only excluding some very specific condition that have been associated with potential vulnerability and more risk of having clinical consequences of this laboratory finding of increased LFTs, and among others could be hemochromatosis and others. So very limited excursions, very few patients, but I think it’s important to have those criteria included in the Phase III.
The second question was on the tepotinib in terms of its potential. And I mentioned this has not been agreed to basket trial. We think that in general, not just for the basket trial, but mostly also for the INSIGHT trial and even for VISION, having the liquid biopsy it’s an amazing and important benefit for the patient. In longer run, you can envision that the field will move to liquid biopsy with NGS with – next generation sequencing, we’d be able to detect several driver mutation in a single test and therefore having the ability, number one, to select a patient that have the clear- cut driver mutation, they might not even need a tissue biopsy. If the patients are elderly, this is an even more compounded advantage.
But when you think about the EGFR mutant setting or other tumor setting, in which you can also have assessment sequentially with a liquid biopsy or the status of this different genetic variant of the tumor, I do believe the future is definitely going to be a liquid biopsy rather than simply to more biopsy. Our objective obviously is to having to label both the projects to recruitment. No commitment yet as I mentioned on the tumor agnostic, but considering we have very consistent data across so many different trials, we have invested on the liquid biopsy technology, that’s a possibility that we will discuss at the Capital Markets Day.
Finally, I want to mention the enrollment. Let me tell you that so far very much on track, both in terms of size activation and the initial reading, we’re pretty early on the patient random mutation, really no issues at all at this point.
Great. Thank you.
Next question comes from Sachin Jain from Bank of America.
Hi, Sachin Jain here, thank you for taking my question. Just a couple of quick ones, please. First on evobrutinib of Phase III. Have you confirmed the dose you’re going with? I’m assuming it’s the higher dose given the duration in the AAN data. Secondly, Luciano, can you clarify your tepotinib filing comments? Just to make sure I understood what would be a timeline in a base case for filing and what would be a timeline for potential accelerated filing? And then finally on the TGF-β, could you just outline outside of the Phase III and the exploratory lung study timing of next potential data, should we expect anything through the back half of this year half of this year potentially as next, for example? Thank you very much.
Great. Thanks, Sachin. So let me start with the Phase III. The only thing I can tell you, it’s all just so your guess is correct in general. The great news for us is that we have no ambivalence and agreement also with regulatory agency that we can go forward with just one dose which is clearly declaring itself both on the benefits risk and obviously on the sustainability of the efficacy that is pretty striking. So just one dose is going to be included in a Phase III trial that allow us to give a lot more power also to the additional measurements that Rehan mentioned on the CDP on the progression assessment. We are very with overpower if you want on the annualize response rate, but we are really looking for a differentiated program. So single dose you will see more detail very, very soon. It’s going to be a highly effective dose. So your guess is correct.
The second one is, our view right now, base case, is that the first tepotinib filing, and remember there are several, the first METex14 is going to be some time next year. That’s really our best case. It’s unlikely that we can accelerate much more than that. What I can tell you, the trial for METex14 is fully enrolled for both cohorts, the liquid biopsy and the tumor biopsy prospectively and the requirement from the agency on the durability of response is that – we’ve actually found that is a good thing for us that they are very interested in their aspect is going to drive the specific timeline for the filing. Obviously, the presence of SAKIGAKE had some influence on our Japan strategy as well. So let’s say that we can just roughly say it’s going to be in 2020 and then we’ll update you if there’s any change.
And finally the last one on bintrafusp alfa, I think that some of the HPV data emerging from our collaboration with NCI is probably forthcoming in the meaning that as you know, they recruit – they are recruiting in a basket trial between 90 and 120 patients. My understanding is they are doing well in their recruitment. That could be an additional trial. Don’t expect that we’re going to be able to provide a lot of data on the registrational trials. So there are some potential readouts, but they are going to be very carefully a firewall, because of the registrational nature of these trials.
Can I just clarify the last comment? When would the first interim analysis on any of the Phase IIIs be?
Not disclosed? So I cannot tell you anything.
Okay. Thank you.
Next question comes from Michael Leuchten from UBS.
Thank you. It’s Michael Leuchten from UBS. Few follow-up questions please. Number one, in terms of the filing strategy for evobrutinib, I thought you would need more than one Phase III trial in multiple sclerosis. So if you open trial program and not to support a filing or will it actually require additional Phase III trials? Question on INSIGHT 2, so you’re going into second line EGFR progressives, however, the Tagrisso is now first line. So I was wondering what you’re thinking is how to interpret the data given that the concept of care has moved on. And then on DDRs, it’s a slightly broader question. You’ve outlined your priorities and how to go after the earlier part of your pipe, but the mutations are fairly large, so how effectively are you going to fly that thinking to, how you’re going to move this into mid-stage clinical trials given the number of options that you have? Thank you.
Great. So let me start with the first question. That’s an easy one. As I mentioned in the slide, but also, we basically have two parallel Phase III trials. We will disclose also that some of the analysis are going to be able to be done across the two trials that are pretty much identical, but they are two parallel trials. So we are fully aligned with the regulatory agency on the registration requirements. And you are correct.
The second question is regarding the INSIGHT 2, so obviously we are, this is not going to be similar to INSIGHT 1. This is going to be going in any failure to patients that have EGFR mutation and there are three that we dose a little bit or other depending on the standard-of-care in different region EGFR-TKIs either T790 positive or negative ultimately, every EGFR molecule will fail. And we now know that between 15% and 20% of the patients, they fail, EGFR-TKI treatment in different way, not just T790 negative that we start in the INSIGHT 1 are going to be driven by a very robust increase in the copy number of c-Met or even other mutation in the next pathway. So that is the calculation we’re going to go after and the combination is going to be with osimertinib with rather than with the first or second generation EGFR.
Let me just go to the last question was – oh yes, sorry. On the DDR, I think that actually we believe that the synthetic lethality, considering the huge investment we’ve made over the year in understanding the potential biomarkers for DDR sensitivity, a lot of synthetic lethality work is done actually even in our own lab. It’s going to accelerate and facilitate the proof-of-concept for our ATR inhibitor and also for ATM inhibitor. So first, what we can go in genetic modified patient population. It’s not just limited to ATM deficiency, there are other potential homologous recombination defects that can be measured and we can prospectively then analyze the responses to the ATR monotherapy in that setting.
Second of all, because we have a very good ATM inhibitor moving into the clinic, we can look at the tolerability that the combination of ATM, ATR or other combination within DDR pathway can be assessed and to try to re-create the synthetic lethality. So I think that’s a new direction that we are taking more aggressive stand that could accelerate proof of concept for these molecules.
Next question comes from Richard Vosser from JPMorgan.
All right. Thanks for taking my questions. Richard Vosser from JPMorgan. So, just going back to evobrutinib, I’m just thinking about other trials. So maybe, first of all thoughts on doing trials in SPMS and PPMS and your thoughts there. Second question just on the choice of interferon beta for the comparator. We see the interferon class declining in terms of usage. So when the trial’s finish, there will potentially be limited use of that product. So what was the thought in using that as a comparator versus maybe Tecfidera or AUBAGIO. And then final question just on the INSIGHT 2 trial, may be more of the commercialization, I mean, Astra have a trial running with Tagrisso and savolitinib at about the same time and with probably the same sort of sizing. So just your thoughts in terms of whether you can overcome the bundling potential that Astra might have from that trial.
I think Rehan should take this question. Obviously, if we have any of molecular mechanism from evobrutinib suggesting effect on progression, your question is extremely important. So Rehan, can you comment on evo and also perhaps on the competition for the tepo in INSIGHT 2?
Sure. Thanks, Luciano. So just on the few questions on evo. So clearly, Richard, we’re very interested obviously in the concept of really having an impact on progression and that’s what we’ve sort of designed obviously, the Phase III to potentially be able to demonstrate. So, are we considering also potentially thinking about progressive phase studies? Yes. But I think we still feel that the best opportunity really for evobrutinib at this stage is to really progress I think on the core relapsing study. And, of course, if we continue to I think build on that core program with studies on progressive MS, we’ll, of course, let you know. But, of course, it’s a subject of real interest for us. I think in terms of the comparator, look, it’s – for us, it’s quite straightforward in the sense that if you look at the field of MS I think interferon beta-1a in particular has been used as an active comparator I think in the context of many different trials. The community knows how to interpret I think its effect and the community knows I think very well I think its side effect. So to have that as an established comparator, number one I think for the community is, is actually very informative. I think the second point is from our perspective and I’m sure you will appreciate this obviously is, it’s representing obviously the investor side. It makes a lot of sense to have interferon beta-1a as a comparator as well because we believe that this really truly maximizes the chance I think of superiority and ultimately therefore regulatory success.
So, it means that we’re really taking an approach, where the clinicians understand I think the comparator, they’ll understand how to value I think evobrutinib versus that comparator given the historic experience in other trials. And, of course, we give ourselves the opportunity to ensure that for the benefit of ourselves and the community that we ultimately get this agent into clinical practice, because we have a good probability of success to really basically reach superiority. So that’s kind of the frame. And I don’t think whether AVONEX is playing a strong role or not, I think in the future treatment of MS patients, it’s really a primary consideration in terms of establishing the benefit risk of evobrutinib at that point in time. So that’s that point. I think in terms of the Tagrisso question, if I could just ask you to repeat the question again and then I will address it.
Yes. I mean it was just trying to think about Astra running a trial very similar to the INSIGHT trial with savolitinib and at the same sort of timing. So given they have Tagrisso onboard, is that a commercial advantage for them? Is there anything that you – any concerns you have there?
So ultimately I think, at this stage, it’s something that we’ll watch, but it’s not a primary concern or a barrier to considering whether or not we basically move forward as we have, of course, with tepotinib in that setting. There are – there are a numerous reasons to believe that tepotinib may have a slightly better profile. One in particular I think is very consistent with what we presented at ASCO, where tepotinib with its exquisite selectivity and no doze limiting toxicity has really enabled us to establish a very reliable standard dose that we’re able to use really consistently across trials. And I think if you start to look across the various different c-Met inhibitors, you see that there’s no dose modification or very little dose modification, very little discontinuation with tepotinib while still having this profound effect and this really durable effect. That’s not the case for all the others. So I think what’s important first and foremost is to basically have the indication and ultimately hopefully, of course, the leading profile of that indication.
Richard, Luciano, I just want to – if you look at Slide 12, you had some reasonable comparisons done by the discussions for the INSIGHT trial and I do think we compare pretty favorable. The other point Rehan made briefly I think is that they are including two doses of the c-Met inhibitor in their trial and I want to remind everyone that with tepotinib, not only it’s a q.d. drug, but we did a very sophisticated paired biopsy study to decide on the dose, in which we clearly analyzed that Cetro, the level of engagement of the target and, once again, this is a q.d. drug. So I think that we are very confident of the dose, we are very confident of the engagement throughout the 24 hours and the sustainability of the effect, not just based on the observation in the clinic, but also to this mechanistic study that we spent time doing before embarking into the VISION and INSIGHT trials, just a small point.
Perfect. Thank you very much.
Next question comes from Luisa Hector from Exane.
Hi, thanks for taking my questions. So on TGF-β, looking at the lung 005 study in the unresectable patients. I wonder how confident you are on safety whether you actually have any patient’s data on the combination of TGF-β with the chemo radiation. Because I believe, Astra chose not to combine, but to wait till that was complete before using any Imfinzi. And then maybe just to clarify on evobrutinib, so as I understand that there are three studies relevant to the first filing. And you’ve shown us the detail of the key study, but there’s also the two parallel studies. So just to confirm that those are placebo-controlled and relapsing remitting. And then perhaps just to confirm also the 96 weeks’ data that is required for the filing.
Yes. Let me first start with – your statement is right. We are going to have obviously in the trial vanguard that will reestablish the safety. I also know that the competitors have been going in a trial, in which immune checkpoints are now dozed also during the radio-chemotherapy. So, so far there have been not external evidence of any potential amplification of side effects of radio-chemotherapy. And further preclinical data and mechanistic data strongly suggest that bintrafusp alfa through the TGF-β inhibition could actually have a particularly important beneficial effect on the major side effect of radio-chemotherapy that is the induction of fibrosis, especially in lung. And that’s what we hope to see, not just advantage in terms of the response rate and mostly on PFS, but also potentially benefit on this particular aspect. We’re seeing our data very, very robust on this point, but they will have to be confirmed into the clinic. But your point is right. There is a vanguard incorporated into the design of that trial. So evobrutinib, I am sorry about the confusion, the 950 patients are distributed in two parallel Phase III trial. The Phase III trial are required for regulatory reasons, two separate Phase III, both are going to be against the same active control.
In addition, we claim to do some mechanistic study in parallel sometime during the development of these two Phase III trials to really demonstrate effect on progression and mechanistic data on the mechanics by which both mitotic cells and myeloid cells are inhibited and the reversibility – the rapid reversibility of this effect. So we have two Phase III trials in parallel both versus active control.
And the 26 weeks data, yes.
26 weeks is required, not only is required for regulatory approval, but I think it’s the best way to try to get an understanding of the effect on progression by EDSS or other measurement. Rehan, can you – you want to add something?
Yes, I just wanted to make sure that everybody understand. I think on Slide 23 where we have depicted the clinical design, that is the design of one of those Phase III studies and you can imagine that, that would be replicated. So that was only schematic, but, of course, we have two studies as depicted basically on Slide 23.
Yes. I’m wondering if, Peter, you want to elaborate on the bintrafusp alfa mechanism of action vis-a-vis radio-chemo on a preclinical as well.
Thanks Luciano. Definitely, as you know, in the Phase I trial we tested bintrafusp alfa as a monotherapy and while doing this we had an extensive program on preclinical data, not only internally, but with the NCI with other collaborators, also focusing on the radiotherapy combination and induction of fibrosis. So we went actually not only in oncology models, but also in lung fibrosis models and could really demonstrate that bintrafusp alfa is able in these preclinical models for lung fibrosis to prevent and fully restore lung function in these preclinical models.
So we are actually very confident that bintrafusp alfa or the potential that you’ve seen so far in monotherapy is actually only one part of the story. And then in combination with radiation and chemotherapy and other targeted agents that you will see other options for this molecule.
Next question comes from Emily Field from Barclays.
Hi, thanks. I was just wondering, on this call last year, you had a slide for a TGF-β sort of comparing the competitive landscape and I was just wondering if you could update us on if you’ve seen any major changes that you’ve maintained sort of the competitive advantage of your assets? Secondarily, how large is the patient population in second-line biliary tract cancer. And then lastly, when should we expect any updates on the programs for evobrutinib in SLE and RA? Thanks.
Why we do not start with Peter with the potential benefit and the competitive landscape that you see so far?
Yes. On bintrafusp alfa, actually, we believe, we are well, well ahead of the competition when it comes to bifunctional approach of course, we are intensively observing the competitive landscape in terms of small molecule receptor antagonists and antibodies and not only targeting TGF-β, but also other elements in the pathway. We are very confident based on our preclinical models that via this bifunctional mode of action that we bring the TGF-β blocking activity really to the tumor really there where the action is and should be. And if you think about what I’ve said earlier in terms of combinations, many of these combination partners, chemotherapy, radiation therapy are actually increasing PD-L1 expression in the tumor, which gives us really an option to further target it and rich bintrafusp alfa via the PD-L1 activity targeting this activity to the tumor, and we strongly believe based on preclinical data that this has an advantage relative to two separate molecules addressing those two pathways separately.
Yes. So Rehan, would you be able to take over the second-line biliary tract – the size of the…
Yes, absolutely, Luciano. So a few points for orientation. So I think if you’re looking U.S. only at this stage, I think it’s after you take out I think potentially the patients that could have, let’s say, a pre-study driver mutation, you’re looking at around 5,000 or so patients in the U.S. And then if you’re looking at Europe and Japan, you’d be adding potentially up to another 12,000 or so patients. And then of course, we continue to look and think about the opportunity obviously for all of our medications now in China, given obviously the evolving access environment there. And of course in China there would be up to 14,000 patients or so.
Yes. And Emily this is Luciano. Just wanted to clarify that we are clearly being explicit with our GSK alliance that we are planning to start soon also trial in first-line biliary tract cancer in combination with chemo, of course, based on the very interesting data showed to you briefly on second line.
Yes, thanks. And then just evobrutinib in SLE and RA?
Yes. So the trials are very close or fully enrolled today. We expect data to be available in the first quarter of 2020. It’s – as you probably have seen, the data of our Phase IIa data on rheumatoid arthritis seems to be confirmed by others. So I think we are very eager to see all this data coming up. The trials are going very, very well. I mentioned, as you know, we have more than 1,000 patients that in different Phase IIb trials at this point between MS, RA and SLE, so we’re going to get a lot of great information on these very exciting in selective molecule.
Thank you very much.
Next question comes from Chung Yun [ph] from Credit Suisse.
Hello. I have two quick ones if I can. First question on tepotinib, you touched upon the tolerability in some of the questioning. How do you think that compares to the Novartis compound? And then second on evobrutinib’s Phase III. How are your thoughts about the blinding of the trial given interferon, they carry flu-like symptoms, injection site reactions, and your product is simply an oral product? Thanks very much.
Yes, on the first one was on – yes. So the tolerability of tepotinib so far has been really remarkable. I mean the fact that we have frankly almost 3% only of any type of vomiting and a very low incidence even of nausea around teens. It’s remarkable. And whether that’s due to the exceptional selectivity of the molecule I don’t know. The discontinuation seems to be very consistent with the same assessment, 4%. And I think that I wanted to make sure that we don’t talk negatively about any competitor frankly. They are very selective molecules, the two that we’re considering. The first generation molecules that were considered were full of side effects, including frankly, some of the ones we use now clinically. But these are relatively selective molecules. And I’ll let you just look at their data frankly related to the discontinuation and/or GI side effects. But that’s what I can tell you for us, it really has been remarkable, the tolerability of this drug. And remember these are 74, 75 year old patients, very frail in – for some reason these MET ex-14 patients tend to be even older. So having such an incredible selective drug that gave them such a robust prolonged efficacy, in our view, it’s going to be really transformational for these 3% of the population.
I also want to emphasize, I don’t know if I mentioned that we are hoping to enrich this particular trial with the MET amplified population, there might be another 1.5% based on high copy number, of course, to select the patient. That’s ongoing in parallel. Going back, you’re right, in terms of the blinding, there will be some symptoms like – also we encountered the same problem with Tecfidera that could lead to getting the different therapy. We are very carefully blinding in terms of injection and everything else with placebo, but I think the symptom part is always an issue that you can deal with. There was any other question here?
Thank you. Thanks, Chung. Did I answer your questions?
Yes. That’s great. Thanks.
Next question comes from Simon Baker from Redburn.
Thank you for taking my questions. Three real quick ones, please. Firstly on our evobrutinib. You cited one of the advantages of being the rapid reversibility of inhibition on treatment discontinuation. That looks in somewhat stark contrast to Mavenclad. So I was just wondering how you think about the positioning of the two products particularly as there’s a growing trend towards more active agents used earlier?
Then moving onto DDR and the chart on Slide 7. I wonder if you could give us an idea of this – the current split between your trial activity in synthetic lethality, immune activation and induced DNA damage. At the moment, a brief look on ClinicalTrials.gov suggests it’s a little bit more skewed to induced DNA damage. And I’m wondering how quickly you will pivot towards synthetic lethality. And then finally, a quick BTK question, but not on evo. I saw that the Phase I study for M7583 in B-cell malignancies was due to report in May or due to complete in May, I wonder if you could give us an update on that one, please? Thanks so much.
Why did – I’ll start with the second question regarding DDR and also the last one and then we go to Rehan, for the evobrutinib. Thank you, Simon. So really you got it. The reason I wanted to present briefly DDR is that we still believe this is an amazing opportunity. Every time I go to advisory board with a very top expert of the field or the people, they broke through the – finally broke the code, in my view, regarding the PARP inhibitor. They are so excited about our pipeline and they drove really somewhat of a change in our approach. It’s definitely going to be very important to continue exploiting the ability of DDR inhibitor to amplify the DNA damage induced by radiotherapy or chemotherapy.
We think DNA-PK is uniquely well suited for that. But we also realize, to be honest with you Simon, that this kind of trial require long, long time, a lot of safety vanguard, because wherever you are amplifying, you are also potentially amplifying some of the side effects of radio-chemotherapy effects of radio-chemotherapy. And it’s so difficult to distinguish what’s really due to the amplification of the signal versus not. So I think it takes longer. We’re still going to continue this approach with an old molecule, but we are pivoting very, very rapidly, probably even within this year to the others two emphasis.
We are – you are going to see at least two trials with avelumab, already ongoing, one with ATRi and one with DNA-PK, from my understanding, by the end of this year. And then you’re – we’re really gearing up for synthetic lethality trial. There is a combination with a PARP inhibitor as well that has been done in – we announced the collaboration with another company with Clovis. And you’re going to hear more in terms of our planning around the synthetic lethality. So the pivoting is happening as we speak. You’re probably going to see the full-blown new pipeline portfolio of proof-of-concept studies emerging over the next 12 months.
And Rehan, can you address…
Yes, absolutely. Yes. So hi Simon, so in a sense, the answer to the question I think is partly in the question in that. Look the MS, the MS field obviously has made tremendous progress. Physicians now and patients now have a considerable number of choices, all of which basically have their respective puts and takes. And so the fact that evobrutinib is going to be a very different proposition than Mavenclad, we see as an advantage because it’s going to appeal obviously to a different group of patients and a different group of physicians.
Simon, I didn’t address your very brief question about our other BTK inhibitor. That work, the Phase Ib is pretty much completed. We have a very nice signal, a very good tolerability of this compound in blood tumors, so – as you would expect for the mechanism. But we have the richness of choices right now in the pipeline. There are many that we’re not talking about that actually have reached pretty convincing clinical proof of evidence or confidence that we cannot pursue because we want to prioritize what we described to you today. So we’re looking for an external partnership for that oncology. It’s probably our preferred path forward, the molecule looks good, the data looks very encouraging, but it’s not something we are pursuing aggressively in-house.
Great. Thank you.
Last question comes from Falko Friedrichs from DB.
Yes, hello. Falko Friedrichs from Deutsche Bank. Thanks for taking my question. I have one left. What – so on bintrafusp alfa, what magnitude of benefit over KEYTRUDA and Imfinzi? Are the two Phase II and III trials have power to show? And is there any safety run into assess pneumonitis risk in the unresectable lung cancer trial?
I have to say that I know, but I don’t know if we are disclosing that particular quantitative question. I can only tell you that we’re looking for highly clinically significant difference in a randomized trial. So that’s why you can judge yourself based on the initial sample size. If necessary, we can have also some other patient, but it’s clearly that we’re looking for clinically significant effect versus the – what we wanted to study was the most recent established standard of care rather than trying to have the big win on a standard of care that is not anymore viable. But we’re still looking for very robust effect in order to win in these trials. I don’t think we have quantified the difference. Thanks, Falko.
Thank you for all of your questions. And with this, I’d like to hand over to Luciano, for closing comments.
So I want to thank all of you. I realized that with all these different meetings that we meet at ASCO inform that you feel that the update become less richer information. But I wanted to clarify for you some of the more context regarding our decisions to move forward in very important final trial for evobrutinib, the scope of our tepotinib trust and what we think that can deliver for us, and invite you obviously to our CMD in September for more and more update. Finally, allow me to go back to some of the earliest slide and mention that we might start to get on your radar screen also for our pipeline I hope now that we are getting into the registrational phases. The pipeline is very well balanced in my view, starts to have really exciting product in the Phase I space, but also start moving reasonably well into potential registrational trial. And that’s the message I think of this update. Thank you for attention. Bye.
Thank you and good bye.