Aradhana Sarin : Sure. So on the SG&A front, if you look at fourth quarter last year, which I think you mentioned is a concern in terms of the step-up. If you look at the last several years, the fourth quarter is always 1 of our largest quarter in terms of SG&A. That does not mean that’s the run rate sort of obviously going forward. And then when you look at 2023 and our updated guidance and some of these — some of the tax transactions and net tax changes that we were — we had in mind — and we manage the whole P&L. So we chose to invest in certain areas, including some of the launches that you heard about from Rod and so forth. So — that sort of explained the fourth quarter of 2023. I think on looking on 2024, we’ve obviously given guidance on top line and bottom line.
I’ve talked about some of the increase you’ll have in finance expenses. We’ve talked a little bit about the gross margin expectations. And so you can sort of consider that and see where the SG&A growth will be. We are obviously committed to operating leverage, and we do expect that given those puts and takes that the SG&A growth will be lower than the total revenue growth.
Pascal Soriot: Maybe I am just to add to this. I understand the question also the concern that you mentioned and connecting to James earlier questions. I think it’s important to keep in mind that we believe the product sales in our guidance, potash will grow strongly. I mean the guidance is low double digit to low teens, right? So that’s a range. And product sales will be in that range. So message is our top line revenue growth is not driven. I mean it’s not dependent on this one-off, as you said.
Ruud Dobber: Yes. So let me first phase, the opportunity in CKD market. There are more than 800 million patients around the world suffering from CKD. And despite the progress we have seen in the last few years, especially the SGLT2 class, including our on Farxiga, there’s still a huge unmet medical need. And hence, our let’s say, excitement also the products we have in development. Clearly, 1 is the combination of dapagliflozin placebo tenant. And of course, Sharon can talk about that as well makes us quite bullish about this opportunity. Now equally, Mark is developing a legion potential Egan molecule. This is a space where many companies have left the field, the kidney space, while we believe that there are huge opportunities based on our pipeline in order to really build a very strong pipeline. So I don’t know whether you want to talk a little bit about 1 of the combinations, Sharon.
Sharon Barr : So you asked us about the scope of our investment, and then I’ll also address your question about our space, our focus on metabolism. So to reframe what Ruud said, there are million people living with CKD and hypertension in the U.S. alone. So clearly, this is a very large market, and it speaks to the interrelatedness of cardio renal and cardiometabolic disease. So thinking about how we can address the different flavors of CKD with our portfolio — we are advancing the BaxtroDAPA combination. It’s in Phase III for CKD. We have Boston Renan combined with dapagliflozin, the miracle Phase II study in CKD with heart failure achieved high-level results at the end of last year. We really look forward to sharing those at an upcoming conference, and we are in the deck of Phase III planning at this point.
And then the combination of zibotentan, with dapagliflozin allows us to address CKD with high proteinuria, and we have initiated the ZENITH Phase III trial. So clearly, we’re heavily invested in this space, and we view this as an opportunity to manage the complexity of cardiorenal disease and to help people manage their overall health. With that in mind, we do think that our metabolism portfolio dovetails very nicely with these efforts to dive organ protection while managing health because we understand that these diseases are highly interconnected. So if we think that there are 64 million people with heart failure worldwide, 15 million alone in Europe in Europe alone. And we know that 50% of those patients have renal impairment and 42% have some interrelated metabolic disease.
It makes sense that we want to continue to expand our portfolio in the metabolism space. We have been, I think, very open about the acquisition and our interest in the 5004 program. Also this is not our only program. This is 1 piece of our overall focus on metabolic disease. Moving along at pace. We also have a long-acting amylin as well as a GLP-1 glucagon dual agonist. Speaking briefly to 5004, we are excited about this asset. We are encouraged to see it move forward into 2 Phase IIb trials this year.
Pascal Soriot : You want to say a few words about the manufacturing steps.
Susan Galbraith : Actually, I’ll say 2 things. The first is that 1 key focus for 5004 is being able to simplify our manufacturing process and come up with a simpler synthetic route. And together with our collaborators at Epogen, I think we’re making substantial progress on that front. The second thing that I will say continues to speak to the interconnectedness of disease, which is that 5004 as an orally bioavailable molecule is very well suited to potential combinations with other oral molecules in our portfolio. And so I would include in that list, Farxiga as well as our oral PCSK9 inhibitor. And so we look forward to sharing results of our Phase I trial, which only recently wrapped up. This was a highly controlled 4-week inpatient trial that was piloted by Ecogen. We achieved database lock at the end of December, and we look forward to sharing the data at an upcoming medical conference.
Pascal Soriot : Maybe 1 quick point is that every focuses on obesity, but there is this big segment of people are not abused their overweight. So they don’t need to lose 25% weight. They need to lose a bit of weight and they have metabolic disease sometimes with organ damage as well. And in that segment, which is extremely large and where the payers are more likely to pay managing the various dimensions of the metabolic syndrome with the PCSK9 with APA, with bacostat and being able to combine is going to be a substantial advantage if you have this portfolio that we have in.
Simon Baker: Simon Baker from Redfin Atlantic. Two for me, please. Firstly, on [indiscernible] and Safnelo. Now they’ve both been on the market for a while. I wonder if you could give us an update on the characteristics of the prescribers and patients so far for both drugs. Question on Gracell and FasTcar. If you could just give us an idea of how easily scalable that manufacturing technology is? And also, a bit more color on the comment that Gracell have made in the past that there was a substantial manufacturing cost advantage here, which sounds like it could be quite significant as you move into autoimmune areas. Any color on that would be much appreciated. Thank you.
Ruud Dobber : Yes. Let me first start with your question about Test. The product is doing very well, not only in the United States but also equally in the markets we have just launched. We have leading NBRx, new-to-brand market shares in countries like Spain and Germany. The patient population is a very interesting one. It’s primarily the patients who have, let’s say, a moderate or normal is in the full count but are allergic. So the low T2 patient population is highly dominant in what we see so far. But equally, we also know from our clinical studies that [indiscernible] is also very well established in the high ease in the fills in the United States. So the broad utility of the product and no need for a biomarker, no need for phenotyping, makes it a highly attractive choice for especially Alges and more and more pulmonologists as well.
So we have high expectations and together with our partner, I think it’s fair to say that the product is on its way to become a blockbuster anytime soon. So that’s one. Safanella is another very nice story. It’s the only interferon receptor antagonist as we all know, lupus is a disease with multiple manifestations and multiple organ manifestations. It’s particularly very impactful on skin disease, and we have seen very, very strong feedback from rheumatologists that patients primarily with skin manifestations are reacting very well on Safanella. Equally, only operating in the intra market as we speak. So we are doing for the last 1.5, 2 years, relatively large study for subcutaneous formulation. And I truly believe, hopefully next year, that study will read out, and we have a positive readout as we’ll provide another clear opportunity.
And as Sharon mentioned in her remarks, we are very keen to move Safanella also in multiple other indications in order to further grow the brand to also equally a blockbuster brands in the next few years.
Pascal Soriot: Thanks, Rudd. Do you want to comment on Gracell?
