Susan Galbraith : As I mentioned in my prepared remarks. The actual time that you need to manufacture the Fasco is substantially shorter than for some other currently commercially available CAR T therapies. That’s 1 component of the turnaround time, obviously. So it’s 1 component also of the manufacturing cost I think it does help with scalability because the amount of time that you need to process each individual patient’s batch is also shorter within the manufacturing facility. So what that means is that you do get increased capacity for a given of the manufacturing building that you’ve created. So that’s important. But also, it means that you can be more predictable about the delivery. And because you are actually generating a smaller total number of the cells that have to be delivered to the patient the likelihood of success of each of those is higher. So all of these things, I think, contribute to the overall benefit that we see from the Fasco process.
Pascal Soriot : Thanks, Susan. Maybe we could take 1 online question, Tim Anderson of Wolfe Research. Tim, over to you.
Tim Anderson: Thank you, any headwinds to revenue growth for individual key brands in 2024 that you’d like to call out relative to where you see consensus. So in rare diseases, you’re facing some new competition? In oncology, you talked about in HER2, but what about Tagrisso or all Calquence in the U.S. seems to be stalling out, for example? And then second question on Dato. Any risk to approval in the U.S. in lung and non-squamous based on what you have today? To me, the regulatory precedent as it should be low risk, and you should get approved, but that’s not necessarily the consensus view. So what’s your confidence here? And what happens if OS misses and bond squamous remain supportive, but doesn’t formally hit?
Pascal Soriot : Thanks Tim. Proposed Marc, you cover and the general competitive environment. Dave, you could cover Calquence and Tagrisso. And Tagrisso maybe also talk about not only the headwinds but also the potential upside. And then Susan, you cover that, too?
Marc Dunoyer : So let me start with. So basically, the headwind that we can anticipate is the introduction of biosimilars in the PNH indication. Two competitors have started to gain approval in 2023. The impact on ’23 is still very limited, but obviously, this could increase over time. The way we counteract this headwind is by converting as fast as possible from SOLIRIS to Ultomiris and in the main indications both neurology indication as well as PH the conversion is very high. It’s in the magnitude of 80%. That’s the first thing. The — where we’re also sustaining the growth of the complement franchise is buying — expanding our regional presence. And we have augmented significantly in 2023. We still have more work to do in ’24.
We are increasing the number of approval and reimbursement for Soliris as well as for Ultomiris. And lastly, this is a long-term work that we have been doing to make this franchise sustainable, we are continuing to develop new indications. We have no that has been approved recently in Europe and Japan with very rapid uptake. We are soon to get the U.S. approval, but we will also continue with other indications, which are presently in Phase III. So not only on the C5. And then we have also — and if we want to but we have the nanobody bispecific 1720 givilimab that is well advanced in Phase III and should be coming to the market in very soon. So there is a future, a very bright future for the C5 franchise and the complement franchise overall.
David Fredrickson : Turning to oncology and Tim, on your question. So very directly on your first question, which is, are there any places where there’s headwinds relative to consensus? I commented in my prepared remarks on the only 1 that I would call out, but I think it’s important, which is that in Japan, in February, we had repricing on Imfinzi that I’m not sure is built into all of the models moving ahead, and we do anticipate because of some changes from weight-based to fixed dosing that we will see another in Japan Imfinzi price adjustment. With that said, on the specific question about Tagrisso I’m enthusiastic about where Tagrisso ends the year and where it comes into next year. As I mentioned, we’re seeing good underlying demand growth sequentially within the U.S. and within Europe.
And I think that is coming on the heels of ADAURA and FLAURA performing well. We’ve got an opportunity in China despite the competition that we’re seeing there to move out of this anticorruption shadow that I think has affected the ability to be able to really take advantage of a leadership position that we have, all doing the right thing, but just in terms of access in general to oncologists has been more limited. We’ve got FLAURA 2, which, knock on wood, we’ll see an approval on here sometime within the year, we’ve got Laura, which I think is a really important catalyst that will read out again here within the first half. So I look at the outset on this. And I think also on a competitive landscape basis, FLAURA 2 positions us pretty nicely.
On Calquence, no question that we’ve got a competitive environment, and we’ve got a direct competition. But I also like what our U.S. and European teams have been able to do in the face stack competition. I think that within that, we’ve got a leadership position within frontline CLL that we’ve been able to maintain I think if you take some of the month or the quarterly phasing out of the situation, we’ve seen really good, strong underlying demand growth on Calquence throughout the entirety of the year. I’m hopeful and optimistic that as co-pay within the U.S. is lowered. Pascal talked about this in his remarks, and we see affordability go from patients having to pay 5% of the catastrophic to 0, and therefore, a co-pay cap that is $2,000 that this is going to give patients the ability to be able to stay on and have greater adherence to continuous treatment to progression on BTK therapy.
So again, we have to see that play out. We have to see how that works through. But I think that these are elements that give me enthusiasm about the oncology portfolio and the opportunities in front of us.
Pascal Soriot : I think this co-pays, it should really not be underestimated because if you look at the U.S. system on the Medicare side, it is going to be a very, very good system. I mean, many countries have co-pays. I mean Australia has co-pay many countries of co-pays. And here in the United States, people, patients are going to be able to say, “I’m not going to pay more than $2,000 a year, regardless of how many drugs are received, regardless of how much they cost $2,000”. Now I might say $2,000 is a fair amount of money. But if you have a car insurance, house insurance, that’s going to cost you at least that and many people can afford this. And it’s a great level of reassurance in terms of taking your medicines and being adherent to them. And for us, it will mean a reduction of free goods, we have to give, which has been increasing substantially in the last few years as people — more and more people cannot afford to cover the co-pays.
Luisa Hector : Thank you. It’s Luisa Hector from Berenberg. Question on Dato…
Susan Galbraith : First of all, thanks for the question. We’re confident that Dato is going to be important medicine in the treatment of non-small cell lung cancer. Obviously, we’ve been having ongoing discussions with the regulatory authorities. TL-1 is a trial with a dual primary end point. Obviously, we met PFS as one of those primaries, but OS is going to be important in the second to third line setting. When you think historically other than checkpoint inhibitors no medicines have demonstrated OS benefit and tax currently remains the standard of care. I’ll remind you that in the non-squamous population, the data that we presented at ASCO, we showed that the hazard ratio in the non-squamous for OS was 0.77 with a confidence interval that only just overlapped on.
So it was 1.01 at the upper end. I think that shows that we’re not just seeing a progression-free survival benefit, but there’s a strong trend to OS within that patient population. So quite often as is normal as the OS events mature, we’ll often have an update of the OS during a period of review, and we’d anticipate that during the period of review for TLL1, we can update the OS.
Iskra Reic : Thank you. Luisa at Berenberg. I would like to ask Iskra Reic to comment on the Icosavax deal and just the attractions of the assets there and the opportunity to enter the RV market? And then also maybe to pillar from that slightly bigger picture question. But essentially a margin question, sorry. You’ve shown us the fabulous pipeline progress, the breadth and depth. We see the entry into new therapeutic areas, the modalities, vaccines, T cell therapies, et cetera. So it’s really bubbling. So really, it’s about how you can be so confident in some margin expansion midterm. How can that happen? Is there a point where selling costs, the infrastructure stabilizes? How do these fabulous products compete for R&D budget?
Is it about strict almost attrition, making sure absolutely the best projects are moving forward? So just any color on that so that you can give us confidence in the ability to raise margins given all the excitement within the pipeline? Thank you.
Ruud Dobber : Thanks, Luisa, the question for interest. So really strengthened vaccine and a costs lead asset is the combination RSV and PV vaccine that is Phase III ready. And that is important to us for 2 different perspective 1 side. This is a next-generation vaccine technology within the respiratory boxes because it’s a protein virus like particle vaccine and importance of that vaccine is that they have a potential to be better, more effective and more safe than a non-VLP vaccine. So basically, what you can expect to see from those vaccine is to have a higher efficacy and a longer durability of the fact and, at the same time, better safety profile. The second important aspect of this is that this is a combination of RSV and HMPV vaccine.
And although there are a number — you can argue there are a number of RSV vaccines for the other potation available in the market. There are no neither- preventative or therapeutic options for HMPV. And maybe that’s the virus that many of you even never heard about, but I can tell you that the RSV and HMPV are basically among leading causes of the severe respiratory infections. And if you look at the numbers of the hospitalization and infections are basically in the similar rate between HMPV, RSV and flu. And therefore, we feel we feel excited to use this vaccine on 1 side, accelerate and bring it to patients as soon as possible. On the other side, it’s a great strategic fit because it really builds experience in RS3 as well as build on our therapeutic leverage and serving the patients that are at risk of respiratory diseases.
