Welcome, ladies and gentlemen, to AstraZeneca's Meet the Management event at the ERS Congress 2026 in Barcelona. Before I hand over to AstraZeneca, I would like to read the Safe Harbor statement. The company intends to utilize the Safe Harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements.
Please also carefully review the forward-looking statement disclaimer in the slide deck that accompanies this presentation and webinar. There will be an opportunity to ask questions after today's presentations. Please use the raise a hand feature to indicate you wish to ask a question, and remember to unmute your line when invited to speak. Now with that, I will now hand you over to the company.
Thank you so much, operator. Good morning, good afternoon, good evening, everyone. My name is Ruud Dobber. I am the Executive Vice President for the BioPharmaceuticals Business at AstraZeneca. I would welcome you and thank you for joining us to hear about the phase III OBERON and TITANIA data for tozorakimab in COPD, presented earlier today here at the 2026 European Respiratory Society Congress in Barcelona. As always, the materials presented today will be published on the AstraZeneca Investor Relations website following this presentation. Next slide, please. Here are our usual forward-looking statements, which I encourage you to read. Next slide, please. This is our agenda for today's call. We are delighted to be joined by Dr. Frank Sciurba, Professor of Pulmonary and Critical Care Medicine at the University of Pittsburgh, who will walk us through the exciting phase III OBERON and TITANIA data presented earlier today at the ERS.
Next slide, please. Before we go into the data, let's take a step back and look at the role of R&I in delivering our AstraZeneca ambition in 2030 and beyond. Next slide, please. Many of you will recall that our Investor Day in May 2024, we set out our $80 billion risk-adjusted total revenue ambition for 2030. Since then, we have delivered strong commercial execution and substantial pipeline progress, further strengthening our confidence in the growth trajectory through 2030 and beyond. Respiratory and Immunology is an important contributor to that growth. Alongside the rapidly growing existing brands in our inhaled and biologics portfolio, tozorakimab is one of the key new medicines we expect to launch this decade, and we look forward to discussing its potential with you today.
In addition to the tozorakimab data, we have a number of upcoming catalysts for high-value assets across biopharma, oncology, and rare disease, which reinforce the breadth and durability of our long-term growth outlook. Next slide, please. Turning specifically to our respiratory and immunology portfolio, we have key inhaled and biologic medicines across asthma and COPD. Five recently launched brands have all delivered double-digit growth so far in 2026. We expect further momentum from the recent launch of BREZTRI in asthma and from the expansion of TEZSPIRE and FASENRA in China and Japan. We also have ongoing lifecycle management programs for a number of these assets.
For example, we recently announced positive high-level results for the CROSSING phase III trial in eosinophilic esophagitis, where TEZSPIRE demonstrated clinically meaningful and statistically significant improvements across both co-primary and all key secondary endpoints, opening the door for TEZSPIRE to potentially improve the lives of patients with this disease. Our R&I portfolio also has five new NMEs in phase II that will drive future growth, including our inhaled TSLP in asthma and other assets being studied in COPD, rheumatoid arthritis, Crohn's disease, and idiopathic pulmonary fibrosis. Taken together, this rapidly evolving portfolio and pipeline will fuel future growth for the business to 2030 and beyond. With that, let me hand over to Sharon to talk about how we are positioned to address the needs across asthma and COPD. Next slide, please, and over to you, Sharon.
Thanks, Ruud. As shown here, our respiratory portfolio spans the full spectrum of asthma and COPD care, from primary care-led inhaled therapies through to specialty care-led biologics as patients' treatment needs evolve. In asthma, we already have a strong inhaled presence with SYMBICORT, AIRSUPRA, and recently approved in the U.S. and Japan, BREZTRI, which is the first and only triple therapy approved in asthma for patients 12 years of age and older. Today, as patients continue to progress, they can move to our approved biologics, FASENRA and TEZSPIRE. We also have sunakiment, our inhaled TSLP, which recently read out its phase II-B study. This is the first-ever inhaled biologic in asthma that is being explored to potentially reach a significant number of patients who today are uncontrolled on inhaled standard of care and don't have access to a biologic.
In COPD, we have the potential to extend our inhaled portfolio beyond BREZTRI and SYMBICORT with TQC3721, the inhaled PDE3/PDE4 inhibitor for which we announced a licensing agreement in July. Similar to asthma, we are developing multiple therapeutic options to address the high unmet need in COPD. Specifically, in addition to tozorakimab, we also have TEZSPIRE in phase III and our oral IRAK4 inhibitor, AZD6793, in phase II, one of the five NMEs that Ruud alluded to earlier. This is a respiratory portfolio purposefully built to meet patients, no matter their disease severity or whether they are being treated in a primary or a specialty care setting. Next slide, please. COPD remains one of the greatest areas of unmet need in respiratory disease. Nearly 40 million patients are on inhaled maintenance therapy.
Of those maintenance patients who are on optimized standard of care, meaning dual or triple therapy, half still experience exacerbations, and these exacerbations matter enormously. COPD is the third leading cause of death globally. One in two patients die within three and a half years of their first severe exacerbation. That is a worse survival rate than a heart attack. Beyond the human toll, the cost to global health systems from COPD is expected to reach $4 trillion by 2050, driven in part by the high costs of these severe lung attacks. Preventing exacerbations is therefore a critical goal in the treatment of COPD, both to improve patient outcomes and to reduce the burden on healthcare systems. With that, I will hand over to Dr. Sciurba, who will take you through the exciting phase III OBERON and TITANIA data for tozorakimab.
Thank you, Sharon. I am going to quickly present the data that I presented at the European Respiratory Society today on tozorakimab phase III studies, OBERON and TITANIA, in the prevention of exacerbations in patients with COPD. Next slide, please. Basically, what Sharon said is that COPD exacerbations are really important events in the life of patients. That first event does predict future ongoing decline and mortality. Repeated exacerbations result in accelerated lung function decline, is associated with some of the worst disruptive quality of life, and increase the cost through hospitalization and death. About 50% of patients remain at high risk despite current guideline-based therapy. Current approved biologics are limited to adults with inadequately controlled COPD and the hypereosinophilic phenotype. While that is often stated at 30%-40%, in my practice, it is not even that high. Next slide.
This unmet need really begets the need for more upstream mediators that impact on more downstream mechanisms than currently available biologics. IL-33 is a very interesting molecule that is released from epithelial cells following multiple stimuli, causing damage and death to those cells. It is released in its reduced form. That reduced form binds to the ST2 receptor on inflammatory cells and drive both directly and indirectly pathways of the recently hyped type 2 inflammation, but also the type 1 and type 17, which is the more common inflammatory pathways in COPD, which elicit neutrophils, a different inflammatory cell than eosinophils. That IL-33 can also be reduced or oxidized into the second form, and that second form binds to receptors EGFR and RAGE on epithelial cells, which drive mucus hypersecretion, another big problem in these patients, and epithelial remodeling, which results in more airway resistance and decline in lung function.
Both of these pathways really appear to be increasingly recognized and important in the downstream effects of IL-33. Next. Tozorakimab is a high-affinity monoclonal directed at IL-33, and first, its binding prevents then attachment to the ST2 receptor and impairs its downstream effects on the broad range of inflammation. It also prevents conversion of that reduced IL-33 to the oxidized form, and thus does not create the moieties that can bind to the EGFR and stimulate the mucus cell or the epithelial cell remodeling and mucus hypersecretion. The aim of this clinical trial that is the buzz today is to evaluate efficacy and safety of tozorakimab compared to placebo when added to standard of care, the care that is the maximum in actually most clinics in treating COPD and in those patients with a history of exacerbations. Next slide.
The design of this study was a very inclusive study, more inclusive than most of the other biologics in many ways. It included patients on optimized guideline-based therapy who continued to have exacerbations. It included current and former smokers, with the current smokers capped at 25%. The reason for that design was that a competitor found that there was some success in one of their phase II trials only in former smokers. That de-risked the product, but the company did not want to lose the possibility of a discovery in current smokers, and you will see those data. Post-bronchodilator FEV1s of less than 30% implies the worst stage of COPD, and recruitment went down to 20% predicted, so there were inclusion of GOLD 4 patients, which was not included in some of the competitors.
These patients were very symptomatic, and very importantly, eosinophils were not used in deciding who entered the clinical trial. The study design initially included two active arms of tozorakimab 300 mg subcutaneously every four weeks and every eight weeks versus placebo. The Q8 week was halted because of additional information before unblinding that suggested the pharmacodynamics may not be adequate. The analysis will be just based on the Q4 week versus placebo. The primary endpoint in this experiment, related to what I had told you about former and current smokers, was a subset of the overall recruited population and the effects in just former smokers as the primary endpoint of annualized rate of moderate to severe exacerbations.
The first secondary endpoint in a hierarchy was then annualized rate of moderate to severe exacerbations in the overall population of current and former smokers. The company felt confident that they would get it but did not want to put it as the primary, but they got it as the first secondary. We will show you some of the results of the other hierarchical secondaries down the line. Next slide, please. The overall population was well balanced between placebo and active arm. Interestingly, the blood eosinophil count included approximately 40% of people in that most unmet need group of less than 150 eosinophils, which is not covered by any of the other biologics. Overall there was a very severe population of that less than 30% predicted that represented about 20% of the patients. Next slide.
These are the big results, the primary results. Remembering the primary outcome was in former smokers, and that represented 29% reduction in exacerbation rate and 34% reduction in exacerbation rate in the OBERON and TITANIA studies, respectively, in former smokers. In the overall population of current and former smokers, the overall reduction was 30% and 29%. All of those were very statistically significant and clinically important. Next slide. These represent a graphic representation of the numbers I just showed you and shows their separation favoring tozorakimab early in the treatment, which continues through 52 weeks. What is important is to see that really this is balanced across both studies and in both populations that we analyzed. Next slide.
These are some of the secondary parameters, and we lost the hierarchy because the St. George's Respiratory Questionnaire, which is a quality of life with some symptom emphasis but really more general effects of the disease on quality of life, it did not reach statistical significance, even though there was a strong trend in one of the studies, less so in the other. FEV1, an objective measure of lung function, moved approximately 25 cc in both studies, statistically significant in OBERON and just missing statistical significance in TITANIA. Remembering this is a broad population of patients with high and low eosinophils. The E-RS score is a much more symptom-based score, less recognized, less familiar to the FDA, and SGRQ was put higher in the hierarchy with their preference, but E-RS did hit.
It was a symptom parameter that moved relatively strongly toward the minimal important difference, being statistically significant in both studies. It's really, if you saw the questions, it's a really pragmatic symptom questionnaire, cough, sputum, dyspnea type questions. Then the annualized rate of another important outcome, severe exacerbations, including ED visits or hospitalization in both trials in the overall population achieved statistical significance with a 36% and 33% reduction in the two separate clinical trials. Next slide. A pre-specified pool analysis, looking at the overall demographics and whether this was a consistent effect across all subgroups, showed that in fact, there was a consistent effect, and specifically former and current smokers, both had significance. The top row in this represents the effect in the overall study, and the green bar represents the 95% confidence interval, which most of the subgroups fell within. Next slide, please.
These represent a similar analysis in COPD specific parameters. Importantly, patients with both low and high lung function had significant improvement. Most important to clinicians and to increase the potential population of patients treated is that this was effective across all eosinophil levels, unique to any biologic right now in COPD. Next slide, please. Specifically, patients with the greatest unmet need with no therapeutic options at this time with respect to biologics had a 23% reduction in exacerbation rate. That's clinically important. It's along the lines of the overall effect of mepolizumab in a high eosinophil population.
The group that was greater than 150 cells per microliter had a 34% reduction, and the group that had greater than 300 cells per microliter had, for COPD, really a remarkable reduction of 43%, which on face value exceeded anything we've seen in COPD before with biologics, even in the high eosinophil space. Next slide, please. With regards to adverse events, overall, they were balanced between active and placebo arm, except with regards to site injection reactions, which is expected with biologics. MACE events, cardiovascular events were overall low, although there was a slight imbalance toward tozorakimab, and it was largely related to unexpectedly low rates in the placebo group. Next slide, please. So in summary, tozorakimab significantly reduced the annualized rate of moderate and severe exacerbations by up to 34%. In a pre-specified pool analysis, this effect was independent of eosinophil level, airflow obstruction level, and smoking status.
It was generally well-tolerated, these findings overall represent a first-in-class biologic with a true valuable therapeutic option now for patients in a broad population with a history of exacerbations despite guideline-based therapy. Next slide. That's all I got to say. Thank you.
Okay. Thank you, Dr. Sciurba, for taking us through the results. As you've just heard, tozorakimab was studied in the broadest COPD population of any biologic to date, enrolling patients across the full range of blood eosinophil levels and stages of lung function severity, in contrast to approved biologics, which have only been studied in narrower populations. What's especially exciting is the clinically meaningful reduction in exacerbations across eosinophil levels. We saw a 23% reduction in patients with baseline eos below 150, where no biologic is currently approved, a 34% reduction in patients with eos at or above 150, a 43% reduction in patients with eos at or above 300. This translates into highly clinically meaningful efficacy across the broad population, including reductions in exacerbations of up to 34% in former smokers and up to 30% in the all-comer population.
Given the strength of these data, we were pleased that the FDA has granted tozorakimab priority review with a PDUFA date in the first quarter of 2027. Next slide. This breadth of efficacy translates into what we believe is a large, differentiated opportunity to address the high unmet need in COPD. By 2030, we anticipate that there will be approximately 6 million people with COPD eligible for a biologic. Today, patients with eos levels below 150, 35% of that population, have no approved biologic at all, tozorakimab showed a 23% reduction in exacerbations. Patients with eos between 150 and 300, where tozorakimab demonstrated a 25% reduction in exacerbations, have only one biologic option. While there are currently two approved biologics for patients with eos greater than 300, we believe that the data from OBERON and TITANIA are highly differentiated in this subgroup of patients.
We also see potential beyond COPD. IL-33 is implicated in several respiratory diseases, trials with tozorakimab are already underway in severe lower respiratory tract disease and asthma. We are actively considering additional indications in which IL-33 may play an important role, such as bronchiectasis, chronic rhinosinusitis, and CTD-associated inflammatory interstitial lung disease. Our ambition is to build a leading respiratory franchise with tozorakimab. The broad and compelling efficacy demonstrated by tozorakimab is why we see this as a potential $5 billion-plus asset. With that, let's go to the next slide, I will turn it over to Pascal to discuss how tozorakimab fits into our broader growth ambitions.
Thank you, Sharon. Next slide, please. As you know, saw today and heard from Dr. Sciurba and Sharon and Ruud, tozorakimab is a very exciting product. It has delivered exceptional results across the broadest patient population ever studied with a biologic in COPD. Having received priority review with the PDUFA date in Q1 2027, we are, of course, working very hard to bring it to patients as quickly as possible. Given the strength of the data and the significant unmet need, we are confident in our guidance of peak sales exceeding $5 billion for this asset across indications. Importantly, however, tozorakimab is one of a number of promising medicines that we have in our pipeline. As you can see on this slide, we have 12 programs, each with a peak sales potential exceeding $5 billion, for which we anticipate pivotal data before 2030.
Together, they represent a meaningful contribution to our growth in the next decade and support us in our belief that we can continue growing post-2030 through the patent expiries that will affect us. We have already launched three of those important medicines, DATROWAY, ETCAMAH, and BAXFENDY, and there is more to come. In addition to this, we have also several programs with peak year sales between $3 billion and $5 billion that will also support our growth post-2030. Taken together, these products build a strong foundation as part of a diverse pipeline that we believe will more than offset future losses of exclusivity and drive sustainable long-term revenue growth beyond 2030. As we have said many times before, of course, our forecasts are all risk-adjusted, and account for some setbacks along the way. But so far, this is looking pretty good. If you look at the next slide, please.
A large pipeline continues to progress, and before I highlight some of the key readouts for next year, I want to briefly mention two especially significant catalysts from the past few days. First of all, on Friday, we were pleased to receive U.S. approval for ETCAMAH in the first-line setting for hormone receptor-positive patients with emergent ESR1 mutations. This marks the first FDA approval of a cancer therapy guided by the detection of a resistance mutation in circulating tumor DNA, and it validates an entirely new treatment paradigm of ctDNA- guided intervention before radiographic progression. ETCAMAH is the first oral SERD approved in the first-line setting, but it is also the first approved for use with all three globally approved CDK4/6 inhibitors. That sets us on the path to establishing a new endocrine backbone in hormone receptor-positive disease and driving growth both to 2030, but also beyond.
ETCAMAH SERENA-6 is clearly a blockbuster opportunity, which will of course partially be cannibalized by SERENA-4 if SERENA-4 is a positive study. But SERENA-6 will remain quite large, and even SERENA-4 turns out to be negative, which of course we all hope will not be the case. The second event is that earlier today, we announced highly positive results from the DeLLphi-305 trial evaluating IMFINZI plus tarlatamab in extensive-stage small cell lung cancer. DeLLphi-305 reinforces IMFINZI as the backbone immunotherapy across stage of small cell lung cancer, and we see this as an incremental blockbuster opportunity in addition to what we already achieved with CASPIAN, the CASPIAN indication. This blockbuster opportunity is additional to the current CASPIAN revenue, and it further supports our 2030 ambition.
As a reminder, in small cell extended stage in the U.S., we only have today with CASPIAN 25% share of patients. This new study, this combination study, will enable us to dramatically grow IMFINZI in the small cell segment, we believe. Now, looking towards 2027, we have a number of important pipeline catalysts across the portfolio, including the first phase III readouts for six of the NMEs highlighted in the previous slide. Starting with biopharmaceuticals, we look forward to the first phase III data for laroprovstat, our oral PCSK9 inhibitor. This once-daily oral small molecule, which has no food effect and is combinable with other small molecules in our portfolio, has enormous potential, we believe. Laroprovstat delivered encouraging phase II results, and the first phase III readouts are expected in the first half of next year.
Despite the broad availability of and usage of high-intensity statins, most patients are not reaching their LDL-C goal. The need for continued innovation remains therefore critical to further reduce the worldwide burden of cardiovascular disease. In addition to this, PCSK9 inhibitors are very great products, but they are injectable, so an oral agent will enable us to go beyond the U.S. marketplace and, to some extent, Europe. A large population around the world cannot benefit from PCSK9 inhibitors because they are injectable and more expensive. We also expect the first phase III readouts from the dapagliflozin fixed-dose combinations with [bilastine and Renin] and zibotentan. These combinations bring together complementary mechanisms of action to address significant unmet needs in clearly defined patient populations, which today have very limited treatment options.
In oncology, while we anticipate the SERENA-4 data this year, more importantly, we await phase III CAMBRIA-1 data in the second half of next year. CAMBRIA-1 will be the first trial of ETCAMAH to read out in the sizable early breast cancer space. Here we are uniquely positioned with the broadest program of any oral SERD. Our trials cover patients at both early and late risk of recurrence and have the option to use ETCAMAH as a monotherapy in combination or post CDK4/6 inhibitor. We also expect the first phase III data for our PARP-1 selective inhibitor, saruparib, from the EvoPAR-Prostate01 trial. This trial looks to build on our established leadership in PARP inhibition with LYNPARZA and bring saruparib to the earlier hormone-sensitive prostate cancer setting across both patients with and without homologous recombination permutations.
Beyond these programs, we also expect more than 10 additional high-value readouts across the portfolio next year, underscoring both the breadth and the diversity of our pipeline. This catalyst-rich period clearly continues with a steady stream of important data expected over the coming months, and we look forward to updating you on our progress. Next slide, please. With that, I will hand back to Sharon to open the line for Q&A, and I apologize for my broken voice today. I hope you could follow me anyway. Thank you.
Okay, with that, I think it is time to open the lines to Q&A, and our first call is from Richard Vosser at JPM.
Thanks very much. One question from me, please, and it is for Dr. Sciurba. Just obviously very strong data across all patients with COPD. Just your thoughts on how you are going to use tozorakimab. Do you push this as a first-line biologic in COPD and abandon EOS testing? How are you thinking about switching patients that are potentially on Dupixent or the IL-5s given the stronger data, even in high EOS patients? Thanks very much.
Yeah. No, I appreciate the question, and I honestly I am not going to take probably the company party line on this. I think it is exclusive in probably less than 300. The competitor in the 150 to 300 space, if you look at the forest plots on those papers, doesn't have really much of a response in that space. When they just describe greater than 150, the real response is above 300. So, I will tell you that is the vast majority of COPD patients. I am not willing to give the above 300 space exclusively, because trials are not head-to-head. There are differences in inclusion, exclusion. Subtle differences can make a difference. They are certainly big players, and that absolute bottom- line in the absence of head-to-head is certainly compelling.
So no, I am not going to switch my patients doing well on Dupixent, but I am certainly not going to exclude considering tozorakimab as first-line in above 300, but probably not exclusively at this point in my practice. More data will come that could prove that in fact it deserves to be there.
Perfect. Thank you very much.
Okay, our next question is from Sarita Kapila at Morgan Stanley.
Thanks for taking my questions. Just on the launch, given that the trials showed efficacy across eosinophil groups, if the label comes without testing requirements, how much could this broaden and accelerate community adoption versus the existing COPD biologics? Ruud, you could indicate your level of comfort or launch readiness upside over consensus first-year sales of $265 million. Secondly, just a quick follow-up on the MACE and fatal adverse events imbalance. I know you mentioned there was unexpectedly low rates in the placebo group, but how should we think about this imbalance? Are there any potential knock-on label outcomes, so warning or monitoring requirements? Thank you.
Yeah, let me take the first question, Sarita, and thanks for that. First of all, let's also reiterate that the FDA has granted this priority review, so indeed we're aiming for a potential launch in the United States in the first quarter of 2027. Let's not forget that this is a highly skewed Part D population. If you look at the clinical trial, you see that the majority of the patients are over 65. Having said that, I truly believe that the data we have shown today are groundbreaking. So we will do everything in order to further increase the diagnosis rates. At the moment, the current biologics, as Frank said, are limited primarily to eosinophils above 300. There's a biopenetration of roughly 10%. So clearly, the number one priority is to further extend that biopenetration in a much larger patient population. So that's quite exciting.
Of course, we have quite a bit of experience in the biological space, primarily in the asthma space. I am not going to comment about, let us say, the first year of launch for the simple reason that we still need to. Oh, my. So sorry. There is an alarm here in Barcelona, so that is very unfortunate. I do not know what it is, but I will do my best. It is better now. I am not going to speculate about the first year of sales. First of all, we need to get over the finish line. We will be in active discussion with the payer anytime soon, and hopefully I can provide a little bit more color in the upcoming months.
[inaudible ] are having in Barcelona. Dr. Sciurba, if you could speak to Sarita's question about the MACE events in this study, I think that would be helpful.
Yeah. So, I am going to just start with a perspective of death versus improved symptoms in this advanced population of patients. The mortality. Sorry, we are having these alarms blaring in our. Let me give you an example of endobronchial valves, which you may or may not know about. It is a different company. When I address patients often with the same level of symptoms and severity, and that is again another very precise population, they do not even care about the 5% risk of mortality for the chance to improve because they are really suffering. The other thing I want to tell you about is that most of the patients with COPD do not die of COPD. They die of cardiovascular events and comorbidity. Cardiovascular disease is disproportionately associated with COPD, independent of smoking, because of co-inflammatory mechanisms affecting endothelium. So, to see no events over a year was really surprising to me.
I will give it that perspective. The other thing to recognize is that colleagues who I very much respect reviewed the associations with product and did not find causal association. So they could not find any logical mechanistic link, and so that reassured me somewhat. Then the last thing, and I would urge you to pay attention too, because I am going to, is the extended data set, which will have a much broader safety profile. I am going to be looking for, and my understanding is that that is much more reassuring than what we are seeing in the one clinical trial here that seems to have a slight imbalance.
Thank you so much for your clinical perspective. I think that is hugely valuable. If I were just to reemphasize some of those points, I think it is fair to say that the MACE events on this study were rare. They occurred in a highly comorbid population. It is important to note that the events observed in the treatment arm were reviewed by an independent data committee and were not adjudicated to be related to study drug. Our overall data set, together with OBERON and TITANIA, I think will support what we have seen in this study, that tozorakimab is safe and well-tolerated. With that, let us move on to the next question from Sachin Jain, Bank of America.
Hi there. Thanks for taking my questions. I have got one follow-on to Sarita's, and then maybe since Pascal is on the call, I can ask a few bigger picture questions. The follow-on question is, just from both the AstraZeneca and physician perspective, what do you think the main barriers are to biologic penetration? Do you think the tozorakimab data is enough to change that? Just a follow-on, do you think it is EOS testing, or do you think there are other factors, cost, administration mechanism, and [Sarita] mentioned driving biologic penetration. Perhaps you could just give us some color on the factors that you think you can influence.
Pascal, just since you are on the call and it is the first call since the media M&A speculation, I guess the sort of pipeline midterm perspective is to partly address some of the questions that have been out there with investors. You very kindly given your confidence in growth through the post-2030 period, which I guess is the crux of investor debate, strength of pipeline versus patent cliff. I just wonder if I could push more, any quantification of what your base case is through that 2030 to 2033 period, and is that a sales or EBIT comment given what you lose as high margin? Just any commentary you can give us, updated on how you are thinking about large M&A. You did comment that M&A was not required for the 2030 targets on the 2Q call, but obviously, this is the first call since the media speculation.
Apologies for those last two questions, but I guess it is important. Thank you.
Okay, Sachin, let me take the first one. First of all, regarding the hurdles, the challenges, I think there are a few which we need to navigate, which is always normal with a new launch. First of all, what I've already mentioned is the diagnosis rates. The diagnosis rates, of course, in some countries, in well-developed countries, is high, but we also need to acknowledge that in large countries like China, there's still a lot of work we need to do in order to bring COPD higher on the agenda, and as a diagnosis. So that's one big area of, let's say, attention for our teams across the globe. The other one is what I've already mentioned, the biopenetration. At the moment, we clearly see primarily that biologics are used in a subset of COPD patients, roughly 30% of using the fields above 300.
I think the data today is clearly showing that we have a much broader population. We will discuss that, of course, with the regulator, but equally also with payers moving forward in order to secure a broad label, but also a broad, let's say, reimbursement for those patients. So I think those are more or less the two big-ticket items moving forward for the product. Last but not least, I think I dare to say that we have been highly successful in the asthma space, both with FASENRA and TEZSPIRE. So we are well equipped in order to detail on the level of the pulmonologist, and we will partly use our current field force for that as well moving forward. And time will tell then how fast we will get traction, especially with the Part D plans, which is always a little bit of a challenge.
But all in all, we feel comfortable that we have a very strong product in our hands, which we truly believe, I truly believe that it will set a new bar for any other competitor moving into this space of biologics and COPD. And we are very committed as a company in order to do a very good job here.
Pascal, to you for Sachin's additional questions in confidence post-2030.
Yeah, thank you, Sachin. It is a great question. We are absolutely confident in our post-2030 forecast and the fact that we can continue to grow post-2030 for the patent expiries. We believe that for two reasons. One is we already have a pipeline of products that are progressing very well. A few minutes ago, I mentioned 12 assets, 12 programs with a potential of about $5 billion each or more. A simple calculation tells you that in these 12 programs, we have a lot of potential revenue. Not everything is going to work. We keep repeating this to everybody. We do not expect everything to work. We wish everything to work. We pray for everything to work, but reality is we know not everything is going to work.
I have said it before, our average probability of success across our entire phase III pipeline is about 60%, so slightly less than the industry average. We have performed higher than the industry average, which is about 65%. We have been at about 75%-80% success rate over the last few years. So number one, we have a pipeline of a number of products that if they all worked, would deliver enormous sales, but they will not all work. That is number one. Number two, we have quite a number of technologies that will drive the future of medicines, we believe, and we started working on those in 2022 already as we were approaching the sort of 2023 goal. You will remember the famous $40 billion sales. We started looking at the next 10-year horizon. Of course, that included the patent expiry of products like TAGRISSO or IMFINZI.
We started working on those new technologies, cell CAR-T, PROTACs, radioligands, weight management, cardio metabolism. We worked on all of this, and we have invested, as you know, a lot, and we have made a lot of progress. A number of these technologies are now delivering products that are looking pretty exciting. AZD0120, which is not recognized very much these days, I can tell you is showing early data, but very exciting. Our cardio metabolism franchise is progressing very well. Our radioligands franchise is progressing well. Our ADC portfolio is progressing very well. So, what we have in our hands today in phase III plus the progress of these new technologies, these new platforms, give us confidence that we can grow past 2030 through the panel expiries. That does not mean we cannot create even more value for patients and for the company by adding BD deals.
As you can see, over the last number of years, we have actually prioritized small- to mid-size deals. That has been our strategy. That is all I can say about this question, but I can really tell you we are very confident that we should be able to grow. Of course, we can be incredibly unlucky and everything can fail, but it is very, very unlikely.
Thank you.
Okay, and our next question is Steve Scala at Cowen.
Thank you so much. First for Dr. Sciurba, why do you think tozorakimab succeeded when other IL-33s failed? Do you think it is more likely to do with the molecule itself or unique study issues such as patients enrolled? Secondly, only 10% of the people were from the U.S.. Does that raise any issues, do you think, with the FDA discussions? Lastly, as a follow-up to the question you just answered, Pascal, should we conclude from your response that you do see very large M&A that makes sense for AstraZeneca? Thank you.
Okay. Frank, the first question is to you. Steve was asking why you think our tozorakimab trial succeeded where others may have been less successful.
Yeah. The company has described the reduced and the oxidative form and lack of conversion to the oxidative form, which directly affects the EGFR receptor and epithelial remodeling. I can tell you IL-33 is a very complex molecule, and those are probably two very important conformational states, the initial reduced state that binds to the inflammatory cell pathways, and then the oxidized state which results indirectly. It may be that simple. It may be that by blocking conversion to the oxidized state, it prevents that epithelial remodeling, which on top of the anti-inflammatory, puts it over the line. But what this molecule is, it actually has many different conformational states, and where that antibody binds very plausibly makes a difference in receptor affinities, whether it is EGFR, ST2, and how the molecule behaves.
There is every plausible reason why a monoclonal that interacts with a cytokine in a different way would have a different result, particularly with this cytokine. I think it is very likely that in fact, it is a biological effect. Overlaid on top of COVID with different times, it could have resulted in some methodologic issues that made it hard with some of the weird results from some of the competitors. But the degree of separation and the results of this study versus the others makes it feel less likely that it is a non-biological effect and just a study design issue.
All right. If I could just layer on that.
Yeah.
You started off by talking about the differences between tozorakimab as a molecule, and I think I might add one more thing that we were discussing earlier today. We believe that tozorakimab is uniquely differentiated in its ability to bind IL-33, prevent its conversion from the reduced form to the oxidized form, and in doing so, to be able to inhibit signaling through both the ST2 arm and the RAGE/ EGFR arm. The reason that we highlight that is because it is the RAGE/ EGFR complex that ultimately drives epithelial remodeling and mucus production. There were some supportive data presented here at the ERS Congress, although not in Dr. Sciurba's presentation, but in a poster presentation elsewhere, in which we demonstrated that with tozorakimab treatment, there was a statistically significant reduction in mucus plugs.
This is a key feature of disease, and it is, in fact, the first data that has shown the effect of a therapy on reduction of mucus. We know that's really important for patients with COPD because mucus production drives exacerbations, and exacerbations drive mucus production in a vicious cycle. This is a clearly differentiated mechanism for tozorakimab, and we think that it may have contributed to the success that we have seen in both OBERON and TITANIA. You also commented, I think, on the strength in trial execution.
Yeah.
I'll leave that there. Steve, your next question was, do we think that the proportion of patients recruited in the U.S. will raise issues with the FDA? I will say that the percentage of patients that we recruited from the U.S. is consistent with many of our other studies, consistent with studies run by competitors for approved therapeutics. While we can never say for certain, we're going to go through the review process. We are not initially concerned about this in our ongoing submission. Then Pascal, the third question was to you regarding M&A.
Yeah. Thank you, Steve, for pushing me, because I could have been misunderstood. I didn't say that at all. I thought I was saying almost the opposite. I was saying our strategy has been to focus on small BD, as you could see over the last number of years, because we try to do deals early to build value along the way. The reason I didn't really totally exclude larger BD is that it makes sense. It depends what you call large. Again, our priority is small ones, but if we found something like Alexion or $10 billion- $20 billion that makes sense, we would certainly consider it. Not that those opportunities exist everywhere, as you know. But anything we thought we would see that would actually make sense for us strategically, financially, scientifically, we would consider. But typically, we would really look at much smaller deal.
But again, I don't know what you had in your mind by big, but something in the range of $20 billion-$30 billion, if it made sense, we would certainly consider. Again, those are extremely rare. The last one we did was Alexion almost six years ago now.
Thank you.
Okay. Thank you, Pascal. Our next question is from Michael Leuchten at Jefferies. Michael?
Thank you. If I could just please go back to the secondaries in OBERON and TITANIA. I am interested in why a very substantial and consistent reduction in exacerbations does not really lead to an improvement in St. George's scores. I guess that is for Dr. Sciurba. And then also, if the IL-33 OX hypothesis is true, why do we not see more of an impact on FEV1? I guess maybe the follow-up is too short. And then maybe for Sharon as a follow-up, where does that then take us as we think forward? Does that mean we need to think about bispecifics to push that hypothesis on remodeling, or is that just more trials with longer follow-up? Is it a different modality? Any thoughts on portfolio would be great. Thank you.
Okay. Frank, the first question was to you about the key secondaries and why we think that there was not a statistically significant readout for St. George's.
Yeah. Recalling the ERS, the respiratory symptoms did significantly improve across both studies and both populations. But to your question, in a population that is that severe, often it is harder to move the quality-of-life metrics. I think this population is more severe than another company that did move SGRQ, and that, I think, is at least part of the answer to that. I was reassured that the ERS moved considerably and that the symptoms improved in these patients. Because it can be harder to maintain a patient on biologics without symptom improvement, and we did see statistically significant and clinically important symptom improvement, but it was nominally significant because it followed the SGRQ and the hierarchy.
Yeah, I think that is very helpful. Is it fair to say in your clinical experience that because this relatively severe patient population, with 20% being GOLD level 4, were already experiencing a significant impact on their quality of life, and therefore it was more difficult to show an improvement in the quality of life in these relatively infrequent questionnaires?
That is what I said, except you said more eloquently.
We are good together then.
Yeah.
Okay. Michael, you also asked about our go-forward plans and our thoughts about the heterogeneity of disease. I think what we've told you today is a story that we have a very exciting development program in tozorakimab, and in fact, an exciting portfolio in our respiratory therapeutic area. I think we've also made fairly clear in recent weeks that we have two powerful franchises in IL-33 and TSLP, supported by our recent news of the TEZSPIRE EoE successful CROSSING study. We continue to look at a range of platforms. While long-acting antibodies are an exciting area of focus and part of our area of focus, we know that efficacy trumps convenience. Efficacy has to be paramount.
We have kept that in mind as we build out our portfolio in the early stage, and we continue to explore all the modalities that we think could bring better therapeutics to a broader range of patients. Most notably, we are in the planning stages for a phase III following our successful phase II trial for sunakiment. That is the first ever inhaled biologic targeting TSLP, which we have designed to bring efficacy to a broader population earlier in the treatment pathway. We continue to explore oral therapeutics, as I mentioned earlier in the call. Our focus will always be on delivering the best possible efficacy, which brings me back to the story today of tozorakimab, and the fact that I think that we have a first-in-class and best-in-class molecule with the data that we demonstrated today in the broadest possible patient population.
Our next question is from Graham Parry at Citi.
Great. It's Graham Parry from Citi. Thanks. Just wanted to query on the current smokers. There was a trend benefit that wasn't statistically significant, just specifically in that subgroup, but of course, it was significant across the all-comers population. Just how confident are you that current smokers would be included in the label reimbursed? Then for Dr. Sciurba, how comfortable would he be using the product in the current smoker population? Then secondly, in the eosinophil high population, is there a patient pool that he feels he would choose Dupixent over tozorakimab? Going back to the original question that was asked earlier, does he see the need to test for eosinophils now and to determine which therapy would be best for a patient out of the two? Thank you.
All right. So why don't we take it this way. Ruud, can you address the potential label in current and former smokers? Then Frank, can we go to you for your clinical experience, both with smoking status and with EOS?
Yeah, of course, and thank you so much, Graham. I am not going to speculate about the label discussions, but I think the totality of data we are presenting, both in the primary endpoint as well as the first secondary, at least that gives me confidence that the FDA will grant us a broad label. But once again, label discussions or at least the review of the package will start in the coming months. So I do not want to speculate too much about that. But of course, our ongoing position is that we will get a broad label from the FDA. Then your second question about the need for eosinophil testing. That is a great question.
If you have a little bit of, let us say, the similarity with TEZSPIRE, which has also a very broad label in the asthma indication, I think it is fair to say that despite the fact that there is no need for a physician in order to test the eosinophil count for TEZSPIRE, most physicians want to know what is the eosinophil count. So although it will not be, I think, a requirement from a reimbursement perspective, I think that most physicians, at least in the Western world, will decide in order to test it, so that they have a little bit more confidence at least regarding the phenotype of the patients. But we clearly see it not as a hurdle because it is so well embedded now, both in asthma and more and more also in COPD, to do an eosinophil test.
Dr. Sciurba, can we give the rest of that question to you? How would you address smoking status in your practice based on your clinical experience? Then from there, would you use EOS status to assess suitability for tozorakimab, and how are you using EOS in your practice?
Sure. Yeah. I want to start out with one thing. Nobody ever questions the use of cardiac medications in ongoing smokers. Yet, it's just an instinctive common question that I have to get. Should I treat a patient who still continues to smoke, with regards to their COPD? The answer is, I always look for opportunities for smoking cessation and, to the extent that I'll leverage using biologics and be a bit paternalistic, yes, we do that. But we still treat these patients, and they still suffer, and they have an addiction, often, that they just can't overcome, and they feel guilty about it at this point, and they feel bad, and we still help them. Yes, I will treat smokers. As far as the statistical significance, not significance. Remember, the numbers were very small. It was not powered for ongoing smoking.
The mean fell within the 95% confidence interval of the overall population. It's just that the error bars were wider. If the numbers were larger and it followed the same pattern, those error bars will narrow, and it would be statistically significant. I think it worked in ongoing smokers. As far as eosinophils, my reputation in COPD is phenotyping and endotyping. It's like, do an exam, does wheezing matter? We want to know the full range of the patient that we're dealing with. Yes, I'll still want to check it, and I think I'll have other options above 300. I personally will, within the zero to 300 range, consider this product now probably first in that entire range for ongoing exacerbator patients on appropriate maintenance therapy. I really think it's going to own that territory.
Okay, and our next question is Colin White at UBS. Colin?
Hi. Colin White from UBS here. Thank you for taking my question. It's for Dr. Sciurba. Taking into consideration everything that's been said about the testing and the penetration rates and use of other biologics, what percentage of the eligible patients would you treat with tozorakimab if it gets approved and has a broad label, and it's available next year at the different eosinophil levels, less than 150, 150 to 300, and greater than 300?
What percentage of eligible patients would I treat with tozorakimab, who I am treating with biologics? Is that your question?
No.
I am sorry.
Of the patients that would be eligible for treatment in those different eosinophil levels, less than 150, 150 to 300, and greater than 300, what percentage of them do you expect that you will treat with tozorakimab?
Yes. Okay. Yes. Let me just tell you, my center is having trouble doing clinical trials because all my people are programmed to use biologics, which is not the case around the world. We are informed, we have been involved. We see the impact of these on our patients. Now we have the ability to extend that greater than 300, basically, is who we look for and treat to patients who continue to exacerbate below 300. Yes. I do not know how the health plans are going to react, but we are going to do our best to fight them. I am sure we will get good penetration because these drugs work. It would be 100% below 150. The vast majority between 150 and 300. Then we are going to play around with it in the greater than 300 relative to the other products.
But we will definitely be using it over 300. And where I will be in a year from now, I am going to be open-minded, but it is definitely going to be used.
Thank you. Okay, conscious of time, we will take one more question before we wrap it up. The final question, Luisa Hector at Berenberg. Luisa?
Thank you, Sharon, and great to see the data. I wanted to follow up on your explanation around the mucus plug and that being a feature of disease. Would you say that these trials were essentially enriched for this? And is CAT score the measure we should look at here? I noticed that CAT score above 30 had a really incredible hazard ratio. If that is a thing we should be thinking about, just checking if that is still the majority. And Dr. Sciurba, do you always measure CAT scores in patients? And a very quick one, do you expect an advisory committee meeting on this with the FDA? Thank you.
Okay, so let me break down those multiple questions. Your first one was about the mucus plug data that was presented at this meeting that I alluded to earlier. What is interesting about those data is the mechanistic support for the hypothesis surrounding tozorakimab's differentiation. The fact that this molecule is able to inhibit signaling through both ST2 to dampen inflammation, and through RAGE/ EGFR to affect epithelial remodeling and mucus production. That is the important part of the story. Notably, this was the first study that ever tested the effect of a therapeutic on changes in mucus production. It is the first time that we have been able to demonstrate this, and we were able to demonstrate a statistically significant reduction in mucus plugs. This is valuable because it helps reinforce our understanding of the mechanism of tozorakimab and why it is differentiated.
That said, we do not think that CAT score here is the most important metric. I think what's really important in today's data set is that we were able to demonstrate an impact on the most important feature of disease, which is exacerbations. Exacerbations correlate with disease worsening, and we were pleased to be able to show the impact on both mucus production, which correlates with disease worsening, and exacerbations, which are clearly correlated with disease worsening. You asked about whether or not Dr. Sciurba sees the CAT score and uses that in his clinical practice. Would you like to respond, Frank?
Yeah. Using it in clinical practice and using it as the priority outcome measure in clinical trials is different things. It is a very quick assessment to make, and yes, actually, we do offer that to patients through the health portal before they come to see me and visit as a quick screen. The SGRQ is a longer questionnaire. Most patients, unless they are part of a clinical trial, don't have a lot of patience to do the entire SGRQ questionnaire. CAT really correlates closely to the SGRQ as an outcome measure. But it is probably less sensitive to respond. So I don't know that that would have been a good outcome measure, if that is what you are asking. It was used in this trial as a stratification measure. A CAT of 10 is not really that high. The average score in this population was over 20.
Most patients who have frequent exacerbations are going to have CAT scores over 10. So I don't know if I completely answered your question, but that.
Okay. Luisa, your last question was about a potential outcome. As we have signaled, we have submitted our file. We have been granted priority review, which really, I think, signals the interest in the community about bringing forward this molecule to patients as quickly as possible. I think it is very early to speculate what will happen during the review process. But today, we have demonstrated that we have a very compelling data set that has the potential to change the treatment paradigm for patients with COPD, and we look forward to the future conversations with the regulators. With that, I will wrap up the questions and hand this back to Pascal for his final remarks.
Thank you, Sharon, and thank you everybody for your great questions and your interest. Let me just say that tozorakimab is a good example of what we try to do at AstraZeneca. First of all, we start with great science. We believe differentiated science. Then we take a risk if we believe we can make a difference for patients. It is a good example of this because, as you probably remember, most of you thought this agent would not work. I want to recognize Caterina Brindicci, our Head of Respiratory R&D, who was a champion for this product for many years. We take a risk, and then we work with great clinicians like Frank who accept to work with us to try to make a difference. In that instance, it actually worked.
I think this agent will make a big difference to the treatment of COPD. That is really what we try to do across the board. If you go back to the slides that Ruud presented at the beginning, we are doing this across the portfolio, and our existing portfolio is developing very well. In many cases, better than we expected back in 2024 when we presented that chart the first time. TAGRISSO, we are building a franchise with two new deals and the data sets with savolitinib and the ZEGFROVY acquisition that will protect TAGRISSO, but also extend treatment duration and grow this product. IMFINZI is doing very well. We just announced new data, as I said a bit earlier, that will actually continue to fuel the growth of this product. Every product is on track.
ULTOMIRIS, which many years ago, many people saw the C5 franchise of Alexion was going to disappear. ULTOMIRIS is doing very well, and the HIGHGROUND data look extremely good. We had one setback with renin in ATTR cardiomyopathy. That is part of life. That is what we try to do, but that is one setback out of many successes. The key NMEs we presented back in May 2024. Many of these products, which were our dreams and hopes then, are becoming reality. ETCAMAH, DATROWAY, BAXFENDY. Now, of course, today we show tozorakimab. We are going to show data next year with laroprovstat, saruparib. We have now data with [amsimfortas, with gefulurimab. These products are progressing very well. Finally, the new technologies that I mentioned a bit earlier are also looking good. We have absolutely no reason to doubt that we can grow post 2030.
I must say, sometimes I find this question a little bit intriguing. Are you not confident about your post 2030? Because if you continue looking at acquiring new technologies or new products, do you doubt your confidence in your pipeline? No, we do not have any lack of confidence. Our role is to continue adding value for our patients and our shareholders, of course. We will continue doing this, as I said, mostly with small acquisitions, but if we found something a little bit bigger, $10 billion-$20 billion, why not? People should not think because we acquire products or technologies that we have no confidence. We have all confidence in our post 2030 period. With this, I want to thank you again and thank the team for the amazing job they are doing, and in particular have done for this agent, tozorakimab.
I want to thank Frank for his great collaboration throughout the program. Thank you.