AstraZeneca PLC (AZN) Earnings Call Transcript

Welcome, ladies and gentlemen, to AstraZeneca's Meet the Management event at the ASBMR Annual Meeting in Boston. Before I hand over to AstraZeneca, I'd 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 that 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 statements 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 raised hand feature to indicate you wish to ask a question. And remember to a mutual line when invited to speak. Now with that, I'll now hand you over to the company.

Thank you, operator. Good morning, good afternoon and good evening, everyone. I'm Marc Dunoyer, Chief Executive Officer at Alexion and Chief Strategy Officer at AstraZeneca. I would like to welcome you and thank you for joining us to hear about the efzimfotase alfa Phase III program in patients with the hypophosphatasia, or HPP, including the HICKORY data presented yesterday at the 2026 American Society for Bone and Mineral Research in Boston. 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 the agenda for today's call. We are delighted to be joined by Dr. Raja Padidela, Consultant Pediatric Endocrinologist and Metabolic Bone Diseases at Royal Manchester Children's Hospital, who will walk us through the Phase III HICKORY data presented at ASBMR. Next slide, please. Before we discuss the data, I want to remind everyone of AstraZeneca's broader ambition and the role our rare disease portfolio plays in delivering our ambition. I will also cover our strategy contributes not only to 2030, but well beyond. With this, next slide. This slide captures how we think about growth today: preparing for tomorrow and investing for the day after. Over the past 2 years, we have continued to deliver strong commercial performance and substantial pipeline progress, further strengthening our confidence in sustained growth for 2030 and beyond. Rare disease remains an important contributor to our outlook. We will drive growth through new launches such as Ultomiris in IgAN and Klygefa in GMG while advancing a pipeline of pioneering medicines, including efzimfotase alfa, which we will discuss in more detail today. In addition to the efzimfotase alfa data, we expect several high-value catalysts across our biopharmaceuticals and oncology therapy areas over the next 12 to 18 months, reinforcing the breadth of our pipeline and confidence in the durability of our long-term growth outlook. Next slide. We view rare disease as one of the health care greatest areas of unmet need, defined by delayed diagnosis, limited scientific understanding and the absence of approved therapies for most conditions. We believe these gaps require a pioneering approach to innovation, combining novel science, new modalities, advance diagnosis and close partnership with patients to develop transformative medicine where few or no treatment options exist. Next slide. Against this backdrop of significant unmet need, we focus our expertise across 5 disease areas where we believe we can make the greatest difference. Across each, we are pursuing medicines with the potential to be first or best-in-class or meaningfully change outcome for patients. Today, we are focusing on efzimfotase alfa, one of the leading assets within our bone and endocrine disorders portfolio. To provide some context, Gianluca will first introduce HPP, discuss the significant burden this disease places on patients, and provide an overview of the global Phase III program. Dr. Raja Padidela will then walk us through the HICKORY Phase III data presented at ASBMR and share is perspective on the potential implications for patients living with HPP. Next slide. And with this, over to you, Gianluca.

Thank you, Marc. I'm Gianluca Pirozzi, the Development and Safety Head at Alexion. HPP Is a rare, inherited, lifelong disease caused by deficient alkaline phosphatase activity affecting patients in all ages. The disease is heterogeneous and multisystemic, with a range of skeletal and functional manifestation, significantly impacting quality of life. In its perinatal and infantile forms, HPP can be life-threatening and is often fatal before age 2 without treatment. In children, [indiscernible] impaired growth, deformities and fractures can affect development throughout life. Adult patients with HPP, in their disease, it's generally milder, but it's far from benign. They may experience slow-healing fractures, tooth loss, chronic pain, muscle witness, fatigue and progressive visibility, all of which can affect work, independence and daily activities. Next slide, please. Efzimfotase alfa is a great example of patient-centered innovation, a second-generation enzyme replacement therapy developed for more than a decade of experience with Strensiq. Both medicines replaced the deficient alkaline phosphatase enzyme, but efzimfotase alfa has 4 key differences to reduce treatment burden, improve tolerability and support broader patient access. It has enhanced enzyme activity, allowing for a similar effect to Strensiq, but a lower, simple-weight banded dosing regimen with a smaller injection volume. Its optimized Fc design reduces off-target interactions, while enhanced glycosylation extends the mean half-life to around 6 days, supporting dosing every -- once every 2 weeks rather than 3 to 6x per week as per Strensiq. Finally, an optimized manufacturing process improves production efficiency and reduces wastage, supporting broader global access. Next slide, please. The efzimfotase alfa development program was intentionally designed to capture all patients living with HPP. Recognizing the pain and fatigue are among the most prevalent symptoms experienced by patients, the program expanded beyond traditional skeletal endpoints to evaluate outcomes that directly affect daily functioning and quality of life. The Phase III program enrolled 196 patients across 22 countries, representing the largest clinical program in HPP to date. Importantly, it was the first to include patients with adult on the disease and those without skeletal manifestation, using tailored endpoint to generate data that reflects all patients living with HPP. The program includes treatment-naive children in MULBERRY, children transitioning from Strensiq in CHESTNUT and treatment-naive adolescents and adults in HICKORY. Next slide, please. The slides provide a recap of results from MULBERRY and CHESTNUT pediatric studies, which were presented at ICCBH in June. While today's discussion is focused on HICKORY data presented at ASBMR, it is important to consider these results within the context of the broader Phase III program. In MULBERRY, efzimfotase alfa demonstrated statistically significant and clinically meaningful improvement in bone. At week 25, the median radiographic global impression change score was plus 1.67 versus 0 with placebo, with a p-value of 0.0003. The rickets [indiscernible] confirms significant improvement, showing substantial ricket healing within 6 months, while placebo treated children showed no change. Importantly, MULBERRY also evaluated outcome beyond bone health alone, demonstrating improvements in physical function, motor proficiency and quality of life, providing evidence of the broad and clinically meaningful treatment effect. CHESTNUT investigated safety switching between 2 enzyme replacement therapies. Adverse events were comparable between children who switched to efzimfotase alfa and those who remained on Strensiq. Clinical benefits were maintained across bone health, physical functions and quality of life. Taken together, these studies provide important evidence supporting the potential of efzimfotase alfa across all periodic patients with HPP. With that context, I'll now hand it over to Dr. Raja Padidela, who will walk through the Hickory data presented yesterday.

Thank you very much, Gianluca. I'm Raja Padidela, I'm a pediatric endocrine and metabolic bone disease consultant at Royal Manchester Children's Hospital. Good morning, good afternoon, good evening, wherever you are. I'm going to present to you HICKORY. You heard about the CHESTNUT study and MULBERRY data, and this would be data on HICKORY study. This study was performed in treatment-naive patients with hypophosphatasia. Patients were more than 12 years of age. So adolescents and adults were recruited for this study. This is a randomized double-blind placebo-controlled trial with randomization performed in 2:1 ratio. So 2 patients received efzimfotase alfa and 1 received placebo. Patient identification was based on documented confirmation of hypophosphatasia with ALPL genetic pathogenetic variant as well as looking at the plasma paradoxelphosphade, which is one of the substrates, which is elevated in hypophosphatasia. It was also a requirement that the alkaline phosphatase values were below the age and gender adjusted normal range. So the primary endpoint for this study was to look at the 6-minute walk test. The key secondary endpoints were to assess various functional and quality of life assessment in these patient group with hypophosphatasia. So this is the baseline characteristic. The demography was very similar in both the group of the patients receiving efzimfotase alfa and placebo. The patients were randomized and the numbers were 84 patients received efzimfotase alfa and 40 patients receive placebo. This is results of the primary endpoint, which is the 6-minute walk test. Efzimfotase alfa patients had numerically longer distance worked at 25 weeks, but this was not statistically significant from the placebo group. When you look into the open-label extension, efzimfotase alfa continued to show improvement in the distance walked in 6-minute walk test. So overall, over a period of 49 weeks, the increase in distance in this group of patients was 61.9 meters. The patients who were on placebo group were switched over to efzimfotase alfa at 25 weeks. And you can see that there has been an increase in the distance work, which was 43 meters from starting efzimfotase alfa. There were some dropouts, but this was not impacting on the power of the study, and the dropouts were not related to injection site reaction or any safety parameters. With regards to the key secondary endpoint, there was clinically meaningful improvement in the lower extremity function scale, the pain severity scores and the FACIT fatigue score, of which only the FACIT fatigue was statistically significant. Deep diving into other secondary endpoints, the pain score, there is a pain interference score, which looks into the pain which impacts on daily activities. And this was favorable and statistically significant in patients receiving efzimfotase alfa. Treatment satisfaction is important, and this was again statistically significant and favorable in patients receiving efzimfotase alfa compared to the placebo group. Continuing on the open-label extension, looking at the functional -- physical function in these groups of patients. Those who were on efzimfotase alfa continued to show progress with 30-second fit to stand and lower extremity function scale. And this was clinically meaningful. And so is the case in the placebo group, after switching over from placebo to efzimfotase alfa at 25 weeks, there was clinically meaningful improvement in these functional assessments. Similar results were found with the pain severity score and FACIT Fatigue Score. Those who were continuing with efzimfotase alfa showed steady progress and improvement in these scores. It was clinically meaningful with pain severity score. And such -- and similarly, the patients who switched over from placebo to efzimfotase alfa showed significant improvement in their pain score, which was clinically meaningful. And similarly, was the case with Facet fatigue score. We had prespecified groups in this population. The prespecification was based on the onset of their symptoms. So pediatric onset of hypophosphatasia was defined as onset of clinical science and symptoms documented in the medical history before 18 years of age. In this group of patients, compared to adult onset, there was a clinically meaningful improvement in 6-minute walk stairs, 30-second sit to stand, lower extremity function scale, and the pain severity score, of which the 6-minute walk test, 30-second sit to stand and pain severity score were statistically significant. In the adult group, clinically meaningful improvement in lower extremity function scale and FACIT fatigue was found. Only FACIT fatigue was statistically significant. We did have in the placebo group, in the adult onset, who had extreme values, which may have impacted in some of these assessments, especially with the 6-minute walk test results. Overall, across 3 Phase III programs, MULBERRY study, CHESTNUT study, HICKORY study, efzimfotase alfa had a favorable safety and tolerability profile, including in patients switching over from asfotase alfa in the CHESTNUT study. Efzimfotase alfa is administered once every 2 weeks because it is more potent, it's got a longer half-life. And patients achieved a median of 98.8% injection site reaction free days while on treatment. The annualized rate of injection site reaction was 5x lower with efzimfotase alfa than with asfotase alfa. To conclude from the HICKORY and the broader program, in the HICKORY overall population, clinical benefit was observed in physical function and pain and fatigue, despite not meeting the primary endpoint of 6-minute walk test. In the pediatric onset subgroup 6-minute walk test showed nominally significant clinically meaningful improvement together with measures of pain and physical function. Adult onset subgroup, fatigue showed nominally significant clinically meaningful improvement. In the open-label extension, there is continued improvement in physical function, pain and fatigue in patients receiving efzimfotase alfa. HICKORY results were consistent with clinical benefits observed in MULBERRY and CHESTNUT study. Overall, across all these 3 studies, positive results in a broad hypophosphatasia population more than 2 years of age with a favorable safety profile. Thank you very much.

Thank you, Dr. Padidela, for taking us through the results. Can I see the next slide? HICKORY represents one component of the broader efzimfotase alfa development program and evidence package. I want to spend some time discussing the overall opportunity in HPP, how we think efzimfotase alfa is differentiated, and the role it could play in the future management of this disease. Next slide. As the only approved therapy in HPP, Strensiq has transformed disease awareness, diagnosis and patient care. However, as with many rare diseases, understanding the true epidemiology remains challenging. Published prevalence estimates vary widely across geographies and are typically derived from relatively small data sets that are extrapolated across broader populations. While prevalence estimates vary, available data suggest there are approximately 14,000 a addressable patient across the top 8 markets. 20% of these are pediatric cases, 60% are adult with pediatric onset disease, and 20% adults with adult onset disease, with approximately 43% of patients presenting with skeletal manifestations. Strensiq established the treatment paradigm for HPP. However, approved patient population, reimbursement criteria and access restrictions vary across markets. Informed by years of clinical experience with Strensiq and insight from real-world evidence, efzimfotase alfa was studied across a broad spectrum of HPP, including patients with adult onset disease and those without skeletal manifestations. We believe this broader evidence base, together with the differentiated profile [indiscernible] has the potential to expand patient reach beyond where Strensiq is today. Next slide. We believe the totality of evidence generated across efzimfotase alfa Phase III program supports its potential to expand the treatment opportunity in HPP. And we see 4 reasons for that. First, efzimfotase alfa offers a differentiated administration profile. Compared with Strensiq's weight-based dosing administered 3 to 6x per week, efzimfotase alfa is administered once every 2 weeks using a simple weight banded regimen. This results in approximately 12x fewer injections per year and significantly lower injection volumes, substantially reducing treatment burden and potentially lowering barriers to treatment initiation. Second, we believe the improved tolerability profile has the potential to support treatment continuity. Efzimfotase alfa was associated with a substantially lower injection site reaction with 361 days per year free from ISRs. When ISRs did occur, the majority resolved within 1 week, with 80% resolving before the patient next injection, and 4x fewer persisting beyond 28 days compared with Strensiq. Reducing treatment burden is important for both patients and physicians, helping support treatment persistence. Third, the program has demonstrated improvement across a broad range of disease manifestations. As discussed, HPP extends well beyond skeletal abnormalities and can have a meaningful impact on physical function, pain, fatigue and quality of life. The breadth of outcome observed across the Phase III program reinforces the potential for efzimfotase alfa to address the wider burden of disease experienced by patients. And finally, we believe efzimfotase alfa has the potential to expand patient reach globally. A broader clinical evidence base, coupled with lower volume, [indiscernible] dosing and enhanced manufacturing capabilities would help address some of the barriers that have limited patient access across geographies. Taken together, we believe efzimfotase alfa has the potential to become the preferred treatment option for patients with HPP. We expect growth to be driven by both the transition of patients currently receiving Strensiq and the expansion of the treated HPP populations. This underpins our peak year sales expectation of 3 billion to billion for efzimfotase alfa. Next slide, please. Today's discussion has highlighted the potential for efzimfotase alfa as well as the strengths of the innovation engine that sits behind our rare disease business. As we look beyond this program, our focus remains on evolving the portfolio, advancing the next generation of medicines, and building a pipeline capable of delivering sustainable growth well beyond 2030. Next slide. This slide highlights our near-term opportunities we have across rare disease. Each of this program has generated 3 Phase III data and is either already approved in at least 1 market, under regulatory review or approaching potential launch. Collectively, they represent a series of near and medium-term opportunities across multiple high-value, underserved rare diseases, including complement disorders, HPP and [ light chain ] amyloidosis. This gives us confidence in our ability to sustain growth from our existing portfolio as well as add new sources of revenue. Next slide. Finally, beyond these late-stage opportunities, this pipeline represents the next wave of innovation across rare disease. By combining deep scientific expertise with a diversified portfolio of modalities, we can pursue diseases that have historically been difficult to treat. This includes next-generation complement therapies, amyloid depleting antibodies, multifunctional fusion proteins, cell and gene therapies and oligonucleotide best medicine. Together, this program reflects our commitment to pioneering the next generation of rare disease medicine, creating a broad and diversified pipeline designed to deliver transformative outcome for patients and sustainable growth for AstraZeneca well beyond 2030. Next slide. And with this, let me open the line for the Q&A.

So the first person on the line is Luisa Hector at Berenberg. Luisa, can you ask your question?

Yes. I guess my first question would just be on how you're thinking about any regulatory risk here, how the FDA will interpret this data, and whether -- I mean, is this a case of the different patient phenotypes, so age of onset being relevant here, would you expect the drug to have slightly different effects in the pediatric and the adult onset groups? Or is it a function of the endpoints not being quite right? So just to frame how we should think about this given the regulatory side.

Thank you, Luisa, for this question. Gianluca, maybe you can help respond to Luisa.

With great pleasure. Luisa, thank you for the question. So first of all, what I would like to say is, look, premature for us to speculate what the regulators will read in the data and how [indiscernible] We have filed [indiscernible] geographies we are currently under review. So I will not be able to speculate. But I can answer your question in terms of the -- our interpretation of data set. First of all, the pediatric patient population, adult with pediatric onset, adult, have the same underlying disease. So mechanistically, and genetically, there's no reason why there should be a difference in terms of response to treatment. Our medication is enzyme replacement therapy, addressing the underlying genetic condition. And therefore, we do believe that the data, the drug will be effective across the entire spectrum of the patient population. And therefore, we designed a broader program that includes all the spectrum of the disease. Having said that, we designed a study that had been tailored to be able to assess treatment effect by age group by measuring endpoints which are relevant of each specific age group. In the pediatric patient population, we used the endpoints of bone measurement, which has radiological endpoint, easy to measure, well-characterized and also objective in the measurement. In that data set, we saw exactly what we expected a very strong and clinically meaningful treatment effect of the drug, comparable to Strensiq, again, as expected, but with a much lower dose, much lower frequency of administration. So all the advantages that were mentioned during the review. Now in the adult patient population, it's important to note, this is the first time that we actually studied adult patients, especially adults with adult onset. There's very limited data sets on the adult with pediatric onset and we studied a broader patient population. So we purposely included a broader data set because that's what the unmet medical needs lie the most, adult with adult patients, no available treatment and therapies. Obviously, we had to choose the endpoint to be able to do that, and we chose the 6-minute walk test. The 6-minute walk test is the only endpoint approved by regulators for the management and the measurement of the disease. That's why that endpoint was chosen. But it's very well known that the endpoint at some limitation both in terms of variability and in terms of the fact that a patient can self-acquire knowledge during the course of the clinical study, which leads also to potential confounding evaluations. Now when I focus on the 6-minute walk test results, which I think, obviously, is the critical point here, indeed, we did not meet the primary endpoint. Nevertheless, there are quite important explanations that we can contribute, can explain these findings. First of all, the explanation resides on the fact that the adult patient population with adult onset, so higher-than-expected improvements in this endpoint, 28 meters against the 10 meters observed in the adult patient with pediatric onset. Several things contributed to that. Number one, a couple of patients in the adult patient population with adult onset on placebo had unusually large improvements, they are clinically uncommon for HPP. These 2 patients drove the clinical results in the placebo patient population justifying the results. In addition to that, as I mentioned, we enrolled a broad patient population. The adult onset group as older, mean age of 54, that more comorbidities, several number of patients above 64-year-old and with assisting devices. All this confounding factor can be important for the assessment evaluation of the 6-minute walk test. And then finally, the placebo arm started with 50 meters lower baseline, there was an imbalance, which justify the finding on the 6-minute walk test. It was a long answer to say that the endpoint chosen in the Phase III justified the difference in the results, more we don't think there's a justification based on the mechanism of the drug. But we look at the totality of the data of Phase III, we see a directionally positive effect across all the secondary endpoints. And we have a clear understanding of the reasons why we see the 6-minute walk test data set and the lack of significance for the primary endpoint.

Michael at Jefferies, can you go up with your question?

Yes. Gianluca, if you could just go back to what you said. I'm just trying to understand. I get the difference in 6-minute walk and functional, but the adult population really only hit on fatigue. It didn't hit really on pain either. So like why doesn't that tell you that maybe the disease is different in adult versus pediatric onset? And then going back to the regulatory question. So I presume you had your pre-NDA meeting, you did get the FDA priority review given for patients above 2 years of age. That does suggest that the U.S. regulator does look at this as a continuation of disease across age groups, or am I over reading [indiscernible] to review in over 2 years?

Okay. Perfect. So I'll go back to the adult patient population. Just to clarify, when we say treatment impacting adult, we have to be careful by defining adult with pediatric onset, which includes also the [indiscernible] in the patient population, and adults with the adult onset. In the adult with pediatric onset, which is about 50% of the patients, 60 out of 124 were classified at pediatric onset, we do see a consistent treatment effect in the 6-minute walk test with obviously nominal clinical significance because we missed the primary endpoint. So we have to be very clear that all I'm talking about is nominal significance. But it's also clinically meaningful and pretty much consistent across all the endpoints we measured in the pediatric patients -- in the adult patient population with pediatric onset. Now in the adult patient population with adult onset, we didn't hit the endpoint of 6-minute walk test. And the reasons are the ones that I previously explained. Let me repeat them again. A couple of patients within the adult onset placebo had a very highly unusual improvement in the 6-minute walk test, in the range of 200, which is largely higher an uncommon in the HPP patient population. Remember, the number of patients in these studies are small. It's an ultra-rare condition, so we are talking about a total of 46 patients with adult with pediatric onset. So you can imagine the 2 patients with a very high effect of placebo can skew the data set and interpretation of the data. That's the main element to highlight. In addition to that, the presence of an imbalance at baseline is also important. Placebo patients, 50 meters lower baseline, which means they have a higher margin of improvement. So what we see in 6-minute walk test in the interpretation of the adult with adult data is a confounding effect due to the use of the 6-minute walk test and the underlying characteristics of these patients. I cannot deny that the importance of 6-minute walk test, obviously, results, which did not reach significant or nominal significance. However, when you look at the rest of the data set, including fatigue and pain, which are the most relevant and the most prevalent also symptoms in this patient population, we see a nominal clinical effect and also a clinically meaningful effect in the adult patient population as well. There was an additional question, I believe, in terms of the interpretation of the results from the priority review. Yes. And I can confirm that the priority review from the FDA was assigned to the totality of the data set, so including pediatric and adult patients with pediatric onset and adult patients with adult onset.

The next question is for Peter Verdult at BNP. Peter, can you ask your question?

Peter Verdult here from BNP Paribas. Thanks to all the speakers for your time. Maybe can we go to Dr. Padidela, a little bit of crystal ball gazing. When you think about your views in the U.K. and whether you -- or hopefully you've spoken about the data with U.S. peers and colleagues, could you maybe just give us a little insight into the future. I mean should an approval come through. And let's assume best case scenario across both adult onset and pediatric onset. Could you just give us a sense, assuming that reimbursement and cost is not an issue here, how is this going to change your prescribing habits when you think about initiating therapy in naive patients as well as the switching and your willingness to switch patients from Strensiq onto efzimfotase alfa. Sorry, multipart question, but all to Dr. Padidela.

Yes, I'll try to answer if I missed, then please do ask me if I missed any section. So asfotase alfa works, no question about that. But we do have challenges with asfotase alfa, and one of the most important of those is the injection site reactions. 40% of our patients have to stop treatment with asfotase alfa because of injection site reactions. And that is a huge number. And that is the group of patients where it is clinically beneficial, but the treatment site -- injection site reactions are so overwhelming that the patients decide, actually, I would like to stop the treatment. And I think that is one of the most important thing, which I have seen with efzimfotase alfa. In the pediatric population as well, when you look into it, my patients struggle, it is clinically effective, it helps in skeletal improvement, asfotase alfa, but they do struggle with injection site reaction and do worry that that does impact on the full effectiveness of the medication with asfotase alfa. But with efzimfotase alfa, the data in pediatric population is very encouraging. It heals rickets, it heals all the skeleton manifestation. It has got a similar safety profile to asfotase alfa in the patients who switched over. But what is most important is the injection site reaction. Significant reduction. In the trial data, in my patients who are taking part in the trial, it's been very helpful. With regards to the pediatric -- with regards to the adult population, the adolescents and adults, one of the major problem is injection site reaction. In younger children, there's skeletal manifestation. So sometimes the patients take it because they cope with the side effects and take it because the skeletal manifestation will significantly worsen. Whereas in adolescent and adult population, it is the pain, the fatigue, the quality of life, which is significantly reduced. Need this medication for improving that. They see the benefit. But unfortunately, they can't continue because 40% of them come out of it because of injection site reaction. So for my patients, with this medication, I will definitely switch over, because I've got the safety and efficacy data, which is very encouraging, which is similar to asfotase alfa with regards to efficacy. And it is much, much, much better when it comes to the safety, especially the injection site reaction. Have I missed any other elements of your question?

Maybe just a tricky add on [indiscernible] given that I've got the mic, so to speak. Your view on not hitting significance in the adult onset, are you of the view that you're taking [indiscernible] into account? Or how convinced or not is not hitting the primary endpoint?

Yes. I mean the primary endpoint was not met. And again, Luca has mentioned various aspects which has led to that -- the outcome, what it is. But when I look into the totality of the data, when I look into the improvement -- the clinically meaningful change in pain, fatigue, and open-label extension as well, the placebo group does very well, the treatment group continues to improve. It is a heterogeneous disorder, it's a lifelong disorder and we are looking at just data on 49 weeks. So I'm quite hopeful that this treatment would be beneficial for our patients. I do take the point that the 6-minute walk test wasn't met, but there are various reasons for that. which again Luca has already mentioned. There are 2 extreme values in the placebo group and various -- and older population with other comorbidities. But I'm quite positive that once the totality of the data is looked into by FDA and various other regulators in different parts of the world in this rare disorder, the approval should come through and the patients would benefit.

So maybe I'll turn to the next question. Rajan Sharma from Goldman Sachs. Would you like to ask your question?

I've got one for the company and one1 for Dr. Padidela. Maybe doctor, if you could maybe just firstly talk about your current treatment for your adult HPP patients given that Strensiq, technically, I guess, not approved in that setting? And then could you also just talk about how, if these patients are diagnosed and treated in adolescence or from pediatric, how that sort of journey evolves over time? And then for the company, I hear your commentary on kind of the outsized placebo responses or the extreme placebo responses. But I think there was also an open-label trial with Strensiq, which was running, it showed that there was no statistically significant benefit on 6-minute walk test there as well. So just wanted to understand your confidence in the mechanism in the adult population or whether there's something in the underlying biology that makes an enzyme replacement not necessarily the correct intervention?

So I'll start with all the patient group. The most severe ones are the ones who are born with serious skeletal neurological and respiratory manifestation. In this group of patient, treatment is life-saving. Without treatment, the mortality is very high. When you look into the natural history study, without treatment, 85% of patients don't survive beyond 5 years of age. And with treatment, 27% mortality at 5 years of age. So it has changed that major manifestation of hypophosphatasia, that is, asfotase alfa changed that. It hasn't been currently studied in this group of population less than 2 years of age. But the same group of population when they go beyond 2 years of age, this medication has been studied with the switch over. And we have found that it has got the same favorable safety profile with much reduced injection site reaction. And what we have also seen is that it continues the improvement which we have seen in the skeletal manifestation with asfotase alfa. So from the pediatric point of view, we do manage patients with skeletal manifestations with a more objective. But we do also have a pediatric population where pain and fatigue is the most prominent symptom. And in this group of population, we do give asfotase alfa, but the challenge is the side effects, which impacts on the quality of life and sometimes they are more significant than the disease itself. And this is where we feel that this will be beneficial. When it comes to the adolescents and adults, I don't look after patients beyond 20 years of age, but I do have -- I do work in a center where I transition my patients to my adult colleagues. So in adolescents, the main challenge is the injection site reaction. And I believe that with this treatment, there would be a significant reduction with that and then the compliance would be better and the tolerability to this medication would be better. With adult onset, and I have -- I worked very closely with my adult colleague in managing this patient, transitioning them into the adult service, the main issue, at the moment in the U.K., we manage -- we can only give Strensiq medication to pediatric onset patients. So that documentation is required. But once that documentation is available, they receive treatment, and it is clinically effective. But the injection site reaction is a major issue with 40% of the patient dropping out because they can't take this medication. So for adult population with pediatric onset, I remain satisfied. With regard to adult onset, I'll -- let's get Luca discuss that with you.

Yes, absolutely. And I'll go back to your question. I think you mentioned the Strensiq data set. So I'm happy to answer that and provide additional perspective in the adult data set. So first of all, the study you're referring to was an old study, small in size, open label. There were a total of 19 patients and only 13 of them were adults. The control were much younger, more impaired patients with a larger marginal improvement. In addition, in that study actually, the dose of the Strensiq was still under consideration, and we know that patients were underdosed in the study. So it's a very small data set in Strensiq, although we are very much aware of that. As you know, we were aware that before starting the study, and we did not consider that to be relevant in the assessment of the treatment effect of the drug. But let me go back again to the 6-minute walk test and explain why we -- there's a reason to believe in the data set for the adult patient population with pediatric onset as well as adult onset. I want to remind 4 elements why we believe the drug is -- actually shows a treatment effect, which we're using also with regulators, of course. Number one, I go back to the responder analysis, which is a post hoc analysis, but shows 45% of the patients reached MCID versus 30% in patients on placebo. That's an odd ratio of 2.5 with a nominal P value of 0.036. So the reason why we think the responder analysis is very important, because that's not confounded by extreme values. It only takes into account the true responders or much less compounders, and we clearly see a treatment effect by using this approach. The second one is the open label extension. Dr. Padidela has already mentioned that, and I want to really highlight that. Over the course of the OLE, the treatment effect was from 35 with 25, all the way to 61.9 with 49, which is a significant improvement over time. And also the placebos [indiscernible] had additional gain of 43 meters within 24 weeks. So placebo also improved after switch. This additional open-label data and the 6-minute walk test shows treatment effect. Then the subgroup. I mentioned previously, subgroup analysis in this data set was prespecified and also there was a stratification factor on the subgroups. The strata were part of the primary analysis data set, so it's a meaningful subgroup. And the subgroup also is based obviously on Strensiq label. So that's the reason why it's meaningful. And what we've seen as a group is that in the pediatric onset subgroup of 60 patients total, we see a 6-minute walk test improvement of 35.6 meters with a nominal P value and above the MCID. We also see treatment effect in other endpoints, including sit-to-stand and pain, which really gives confidence of treatment effect in the adult patients with pediatric onset, patient population for which Strensiq is currently approved globally. And finally, every single key secondary endpoint favor efzimfotase alfa, including fatigue, pain, which is also very relevant. Now in the adult population with adult onset, I mentioned all the reasons why we believe the 6-minute walk test potentially failed, but I also would like to highlight an improvement in fatigue of 7 points, which is highly clinically meaningful, as well as in pain. So in summary, I would say, we feel very confident on the pediatric data. We feel very confident on the adult patient with pediatric onset. We feel confident also in adult patients with adult onset. We believe that we have a reasonable argument to show treatment effect. And of course, we will discuss all of this with regulators.

So next question is for Steve Scala at Cowen. Steve?

Two questions probably both for you, Marc. Can you speak to AstraZeneca's expected conversion of Strensiq to efzimfotase both in rate and time? So for instance, do you expect 50% conversion in 3 years or some other target? And secondly, are peak sales of $3 billion to $5 billion achievable if the label is limited to pediatric onset hypophosphatase?