Sharon Barr: Yes. Thank you for the questions. So your first was, do we believe that this ECC5004 is competitive in weight loss? And yes, we do based on the Phase I data that we saw, it lines up very favorably with competitors in this class, which was very encouraging data. They gave us confidence in our ability to drive forward this molecule and see a differentiated target product profile in the clinic. You also asked about which of the combinations we are most excited about and that’s a little bit like asking you to choose a favorite child because we have such a broad portfolio that has the potential to combine with this molecule. That said, thinking about Farxiga and our ability to manage hypertension driven by obesity is a very appealing combination.
Thinking about our emerging oral PCSK9 was very encouraging data in Phase I. We see an opportunity to limit dyslipidemia while managing obesity in overweight patients. And also thinking about how we’re managing diabetes and the associated comorbidities gives us opportunities to also consider other mechanisms for managing heart failure and renal disease in combination with ECC5004. So we will be testing out this molecule both in preclinical and clinical studies moving forward and identifying the most favorable combinations for patients.
Ruud Dobber: So nothing to add. Are you also going to take the question about [Dato] [ph] or do I need to comment on that? So James, a good question. Of course, as always, time will tell and the data will tell which dose is the most effective one. But we truly believe that we have a drug which is effective. The 600 is now tested in the MIRANDA trial. Let me remind you that also the competition is testing different dosing regimens. And see it also a little bit as an insurance premium. We think that the 300 will be effective but of course, we try to push the effectiveness to the highest level. So hopefully, both doses will work. But time will tell when the data will [indiscernible].
Pascal Soriot: Maybe going back to the overall oral GLP-1 James, first of all, one of the two oral agents that maybe you have in mind is a twice a day agent this one will be once a day. And as Sharon explained earlier, we believe that the tolerability profile would be good. But the important thing to keep in mind is obesity by itself is one thing, but I think the more sustainable part of that market is really obesity, patients with complicating factors. People have cardiac metabolic risk factors. And so in that scenario, really combinations are critical. I mean, if you look at kidney disease, the Farxiga results are really exciting. They are great, but patients still see their kidney function decline over time. So we talk about combinations in cancer, but I also think that in many of those cardiovascular metabolic conditions, combination treatment will be the future.
So a combination for kidney disease, combination for the control of hypertension, possibly a combination for — well, actually a combination for the management of hyperlipidemia. So that’s where we believe that our pipeline is best positioned, it can play a role. So with that, maybe, Dave, do you want to or Susan, maybe cover the Dato question.
Susan Galbraith: Sure. So in the United States, we didn’t have to wait for bundling the 2 trials together. So we will file those two separately. In Europe, it’s better to bundle the two applications together. But I think is a good opportunity depending on the review time lines for the review to be completed during the course of next year.
Pascal Soriot: So the next one is Mattias Häggblom at Handelsbanken.
Mattias Häggblom: First with regard to the oral GLP-1, [Technical Difficulty] because I’m asking how long into 24 or perhaps even 25, depending on the duration of that trial, will the upside world have to wait before we can judge today’s comments around the different change in profile. And then secondly, [Technical Difficulty] China, where lung cancer patients [indiscernible], whereas for their preference of a monotherapy combination therapy survey which showed a close to 80% preference for the monotherapy regimen despite the combination was set in the service for a long time to recurrence. So I would be curious to hear if the company has [indiscernible] service based on other geographies. Again, trying to think of the 1 versus combination trials in these setting? Thanks so much.
Pascal Soriot: Thanks, Mattias. You were breaking up a little bit. The first question, did you get fully on Sharon, although voice maybe —
Sharon Barr: It sounds like it was around the timelines for the ECC5004 clinical studies. But maybe if you could repeat the question one more time?
Pascal Soriot: Can you repeat the question, the first one, actually, the second one was FLAURA2 China and 80% preference for monotherapy is it also in other geographies. But the first one, if you could repeat?
Mattias Häggblom: Sure. [Technical Difficulty] 2 trials in obesity, it’s reasonable to expect the market could judge today’s comments that you have a differentiated profile. We see Phase II trials in obesity short as 5 weeks up to 16 plus. So I’m just trying to frame the expectations for when we can get data of these patients, which we have yet to see.
Pascal Soriot: Okay. Thanks. So Dave, do you want to take the FLAURA2 question?
David Fredrickson: Yes, I’d be happy to. I’ve spoken to the discussions that we’ve had with physicians, both in the academic but also now, especially within the community setting. both WCLC and ESMO. And I think that what you see in the editorial is very consistent with what we are hearing across the globe. And I think that just maybe if I put into context within this, I mean, if you look at the U.S., you’ve got 70-plus percent of non-small cell lung cancer patients who are with advanced disease being treated in the community. And I think that within that community context, the benefit risk that I had spoken to before of efficacy, oral convenience, tolerability profile that’s really well understood and considered to be one that’s well able to be managed.
This is something that really does result in the monotherapy being I think really kind of the first port of call, that first real opportunity to look at. We do also know, and I think that this is something that comes through as well in the commentary that there are patients who can benefit from a more intensified approach to it. And within that context, I think that the editorial and others comment on that within this context, we expect FLAURA2, if approved, to be an option for certain patients that is going to be put on the table, but it’s going to be put on the table in the context of multiple criteria for making the decision, not just based upon a single efficacy end point.
Pascal Soriot: Sharon?
Sharon Barr: Sure. So your question regarding timelines for clinical development for ECC5004, obviously, front of mind for all of us. Thank you for the question. So as I mentioned earlier, we are in Phase I now, and we expect to have Phase I data in hand by the end of this year. And so we’ll be moving rapidly towards Phase II. We expect to initiate 2 Phase II studies, one in obesity and one in diabetes by the end of 2024. You are correct that these studies can vary in length, but we really want to be able to generate the outcome data that we think will add value to this program. So we are planning for studies that will span in the neighborhood of 18 months with interim analysis that will give us an early look at the data and will give us some confidence in our differentiation strategy.
Pascal Soriot: Next one is Mark Purcell at Morgan Stanley.
Mark Purcell: Two questions. The first one is on your bispecific T-cell engagers [indiscernible]. You talked in the press release around the potential to replace first-generation checkpoint inhibitors. So how should we think about the magnitude of benefit you expect to see versus KEYTRUDA, for example, in the EVOLVE [indiscernible] 2 trial. So what level of superiority are you seeking? And the second one, smart chemotherapy platform, your organic platform [indiscernible], we should get some data, I guess, for assets such as the B7-H4, maybe the EGFR SMA in 2024. So could you give an update in terms of when we should see these data? And when do you expect to potentially move into pivotal trials with these assets? Thank you very much.
