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 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, operator. Good morning, good afternoon, and good evening, everyone. I am 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 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 investors relation website following this presentation. Next slide, please. Here are our usual forward-looking statement, 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 Paediatric Endocrinologist in 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 two years, we have continued to deliver strong commercial performance and substantial pipeline progress, further strengthening our confidence in sustained growth through 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 - 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 healthcare's 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, advanced 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 five 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 his perspective on the potential implications for patients living with HPP. Next slide. With this, over to you, Gianluca.
Thank you, Marc. I'm Gianluca Pirozzi, the Head of Development, Rare Disease, and Safety at Alexion. HPP is a rare inherited lifelong disease caused by deficient alkaline phosphatase activity, affecting patients at all ages. The disease is heterogeneous and multisystemic, with a range of skeletal and functional manifestations significantly impacting quality of life. In its perinatal and infantile forms, HPP can be life-threatening and is often fatal before age two without treatment. In children, rickets, impaired growth, deformities, and fractures can affect development throughout life. Adult patients with HPP, their disease is generally milder, but it's far from benign. They may experience slow-healing fractures, tooth loss, chronic pain, muscle weakness, fatigue, and progressive disability, 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 from more than a decade of experience with Strensiq. Both medicines replace the deficient alkaline phosphatase enzyme, but efzimfotase alfa has four key differences to reduce treatment burden, improve tolerability, and support broader patient access. It has enhanced enzyme activity, allowing for a similar effect as 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 six days, supporting dosing once every two weeks rather than three to six times 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 that 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-onset disease and those without skeletal manifestation, using tailored endpoints 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. These 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 of Change score was +1.67 versus 0 with placebo, with a p- value of 0.0003. The Rickets Severity Score confirms significant improvement, showing substantial rickets healing within six 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 the safety switching between two 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 pediatric 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 Paediatric Endocrinologist in 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 data. You heard about the CHESTNUT study and MULBERRY data, and this would be data on HICKORY study. This study was performed in treatment-naive patient with hypophosphatasia. Patients were more than 12 years of age, so adolescent and adults were recruited for this study. This is a randomized, double-blind, placebo-controlled trial with randomization performed in 2 : 1 ratio. So two patients received efzimfotase alfa and one received placebo. Patient identification was based on documented confirmation of hypophosphatasia with ALPL genetic pathogenic variant, as well as looking at the plasma pyridoxal 5'-phosphate, 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. The primary endpoint for this study was to look at the Six-Minute Walk Test. The key secondary endpoints were to assess various functional and quality of life assessment in this patient group with hypophosphatasia. 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 received placebo. This is the results of the primary endpoint, which is the Six-Minute Walk Test. Efzimfotase alfa patients had numerically longer distance walked 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 Six-Minute Walk Test. 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 walked, 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 Functional 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 physical function in these groups of patients, those who were on efzimfotase alfa continued to show progress with the 30-second sit to stand and Lower Extremity Functional Scale, and this was clinically meaningful. And so was 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 on efzimfotase alfa showed steady progress and improvement in these scores. It was clinically meaningful with pain severity score, 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 FACIT-Fatigue score. We had pre-specified groups in this population. The pre-specification was based on the onset of their symptoms. Pediatric onset of hypophosphatasia was defined as onset of clinical signs and symptoms documented in the medical history before 18 years of age. In this group of patients, compared to adult onset, there was clinically meaningful improvement in Six-Minute Walk Test, 30-second sit to stand, Lower Extremity Functional Scale, and the pain severity score, of which the Six-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 Functional 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 Six-Minute Walk Test results. Overall, across three 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 two weeks because it is more potent. It has got a longer half-life, and patient achieved a median of 98.8% injection site reaction-free days while on treatment. The annualized rate of injection site reaction was five times 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 Six-Minute Walk Test. In the pediatric onset subgroup, Six-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 three studies, positive results in a broad hypophosphatasia population more than two 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 addressable patients across the top eight 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 restriction vary across markets. Informed by years of clinical experience with Strensiq and insight from real-world evidence, efzimfotase alfa was studied across a broader 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 discussed next, has the potential to expand patient reach beyond where Strensiq is today. Next slide. We believe the totality of evidence generated across the efzimfotase alfa phase III program supports its potential to expand the treatment opportunity in HPP, and we see four reasons for that.
First, efzimfotase alfa offers a differentiated administration profile compared with Strensiq's weight-based dosing administered three to six times per week. Efzimfotase alfa is administered once every two weeks using a simple weight banded regimen. This results in approximately 12 times 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 one week, with 80% resolving before the patient next injection and four times 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. Finally, we believe efzimfotase alfa has the potential to expand patient reach globally. A broader clinical evidence base, coupled with lower volume, less frequent 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-$5 billion for efzimfotase alfa. Next slide, please. Today's discussion has highlighted the potential for efzimfotase alfa, as well as the strength 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 medicine, 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 these programs has generated phase III data and is either already approved in at least one 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-based medicine. Together, these programs reflect 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. The first person on the line is Luisa Hector at Berenberg. Luisa, can you ask your question?
Yes. Hi there. Thank you very much for the presentation. I guess my first question would just be on how you are thinking about any regulatory risk here, how the FDA will interpret this data, and 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? Just to frame it how we should think about this given the regulatory side. Thank you.
Thank you, Luisa, for this question. Gianluca, maybe you can help respond to Luisa.
With great pleasure. Luisa, thank you. Thank you for the question. First of all, I would like to say it is a little premature for us to speculate what the regulators will read in the data and how they will mention. We have filed in major geographies. We are currently under review, so I will not be able to speculate. But I can answer your question in terms of our interpretation of data set. First of all, the pediatric patient population, adult with pediatric onset, or adult have the same underlying disease. So mechanistically and genetically, there is no reason why there should be a difference in terms of response to treatment. Our medication is an enzyme replacement therapy addressing the underlying genetic condition, and therefore, we do believe that the data, the drug would be effective across the entire spectrum of the patient population.
Therefore, we design 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 use the endpoints of bone measurement, which has radiological endpoints, easy to measure, well-characterized, and they are 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. In the adult patient population, it is important to note this is the first time that we actually study adult patient, especially adult with adult onset.
There is 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 is where the unmet medical needs lies the most. Adult with adult patient have no available treatment and therapies. Obviously, we had to choose the endpoint to be able to do that, and we chose the Six-Minute Walk Test. The Six-Minute Walk Test is the only endpoint approved by regulators for the management and the measurement of the disease. That is why that endpoint was chosen. But it is very well known that the endpoint has 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.
When I focus on the Six-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 explanation 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 saw 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 two patient 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, and the adult onset group was older, mean age of 54.
They had more comorbidities, several number of patients above 64 year old and with assisting devices. All these confounding factor can be important for the assessment evaluation of Six-Minute Walk Test. Finally, the placebo arm started with 50 meters lower baseline. There was an imbalance, which also justified the finding on the Six-Minute Walk Test. That was a long answer to say that the endpoint chosen in the phase III justify the difference in the results. More, we do not think there is a justification based on the mechanism of the drug. But we look in 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 Six-Minute Walk Test data set and the lack of significance for the primary endpoint.
Thank you.
Okay. Thank you. Michael Jeffries, can you go with your question?
Yeah. Thank you, Marc. Gianluca, if you could just go back to what you said. I am just trying to understand. I get the difference in Six-Minute Walk in functional, but the adult population really only hit on fatigue. It did not hit really on pain either. Why does not that tell you that maybe the disease is different in adult versus pediatric onset? Going back to the regulatory question. I presume you had your pre-NDA meeting. You did get the FDA priority review given for patients above two 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 overreading a priority review in over two years? Thank you.
Yep. Okay, perfect. I will go back to the adult patient population. Just to clarify, when we say treatment effect in adult, we have to be careful by defining adult with pediatric onset, which includes also the other patient population, and adult with the adult onset. In the adult with pediatric onset, which is about 50% of the patient, 60 out of 124 were classified as pediatric onset. We do see a consistent treatment effect in the Six-Minute Walk Test with obviously nominal clinical significance because we missed the primary endpoint. We have to be very clear that all I am talking about is nominal significance. But it is also clinically meaningful and pretty much consistent across all the endpoint we measured in the adult patient population with pediatric onset.
Now, in the adult patient population with adult onset, we did not hit the endpoint on a Six-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 improvements in the Six-Minute Walk Test in the range of 200 meters, which is largely higher and uncommon in this HPP patient population. Remember, the number of patients in these studies are small. This is an ultra-rare condition, so we are talking about a total of 46 patients with adult with pediatric onset. You can imagine that two patients with a very high effect of placebo can skew the data set, that interpretation of the data. That is the main element to highlight. In addition to that, the presence of an imbalance at baseline is also important.
Placebo patient, 50 meters lower baseline, which means they have a higher margin of improvement. What we see in Six-Minute Walk Test in interpretation for the adult with adult data is a confounding effect due to the use of the Six-Minute Walk Test and the underlying characteristic of these patients. I cannot deny that the important Six-Minute Walk Test obviously have results which do not reach significance 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 the 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—
Yes
—interpretation of the results from—
Priority review.
—the priority review. Yes. I can confirm that a priority review from the FDA was assigned to the totality of the dataset, so including pediatric and adult patient with pediatric onset and adult patient with adult onset.
Thank you.
Thank you, Michael, and thank you, Gianluca. The next question is for Peter Verdult at BNP. Peter, can you ask your question?
Yes. Thank you. I am Peter 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 hopefully you have spoken about the data with U.S. peers and colleagues, could you maybe just give us a little insight into the future? Should an approval come through, and let us 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, how is this going to change your prescribing habits when you think about initiating therapy in naive patients, as well as your willingness to switch patients from Strensiq onto efzimfotase alfa? Sorry, multi-part question, but all to Dr. Padidela.
Yeah, I'll try to answer. If I miss, then please do ask me if I missed any section. Strensiq works, no question about that. But we do have challenges with Strensiq, and one of the most important ones is the injection site reactions. 40% of our patients have to stop treatment with Strensiq because of injection site reactions. That is a huge number, and that is the group of patients where it is clinically beneficial, but the injection site reactions are so overwhelming that the patients decide, "Actually, I would like to stop the treatment." 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, Strensiq, but they do struggle with injection site reaction. I do worry that that does impact on the full effectiveness of the medication with Strensiq. 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 Strensiq 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 adult population, the adolescent adult, one of the major problems is injection site reaction. In younger children, it's the skeleton manifestation.
Sometimes the patients cope with the side effects and take it because the skeleton manifestation will significantly worsen. Whereas in adolescent adult population, it is the pain, the fatigue, the quality of life, which is significantly reduced. They 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. For my patients, with this medication, I would definitely switch over because I've got the safety and efficacy data, which is very encouraging, which is similar to Strensiq 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 if I actually can add on, Dr. Padidela, given that I've got the mic, so to speak. Your view on not hitting significance in the adult. Are you of the view that you're taking the totality into account, or how convincing or not is not hitting the primary endpoint?
Yeah. The primary endpoint was not met. Gianluca has mentioned various aspects which has led the outcome what it is. But when I look into the totality of the data, when I look into 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 is a lifelong disorder, and we are looking at just data on 49 weeks.
I am quite hopeful that this treatment would be beneficial for our patients. I do take the point that the Six-Minute Walk Test was not met, but there are various reasons for that, which Gianluca has already mentioned. There are two extreme values in the placebo group and older population with other comorbidities. I am 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 will benefit.
Very helpful. Thank you. Thank you for your time.
Thank you.
Thank you. Maybe I turn to the next question. Rajan Sharma from Goldman Sachs, would you like to ask your question?
Hi. Thanks for taking my questions. I've got one for the company and one for Dr. Padidela. Maybe, Doctor, if you could maybe just firstly talk about your current treatment for your adult HPP patients, given that Strensiq is technically, I guess, not approved in that setting. Then could you also just talk about how, if these patients are diagnosed and treated in adolescence or from a pediatric, how that sort of journey evolves over time?
For the company, 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 run, and it showed that there was no statistically significant benefit on Six-Minute Walk Test there as well. 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. Thank you.
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 five years of age. With treatment, 27% are mortality at five years of age. So it has changed that major manifestation of hypophosphatasia, that is, asfotase alfa has changed that. It hasn't been currently studied in this group of population less than two years of age. But the same group of population, when they go beyond two years of age, this medication has been studied with the switchover, 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 adolescent and adult, I do not look after patient beyond 20 years of age, but I do work in a center where I transition my patients to my adult colleagues. So in adolescence, 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 work very closely with my adult colleague in managing this patient, transitioning them into the adult service. The main issue at the moment, in U.K., 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 then they cannot take this medication. So for adult population with the pediatric onset, I remain satisfied. With regards to adult onset, I will let Gianluca discuss that with you.
Yep, absolutely. And I will go back to your question. I think you mentioned the Strensiq data set, so I am happy to answer that and provide additional perspective on the adult data set. So first of all, the study you are 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 patient with a larger marginal improvement. In addition, in that study, actually, the doses of Strensiq were still under consideration, and we know that patients were underdosed in the study. So it is a very small data set in Strensiq, although we are very much aware of that.
As you know, we were aware of 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 Six-Minute Walk Test and explain what is the reason to believe in the data set for the adult patient population with pediatric onset as well as adult onset. I want to remind four elements why we believe the drug actually shows a treatment effect, which we are using also with regulators, of course. Number one, I go back to the responder analysis.
Which is a post hoc analysis but shows that 45% of the patient reach MCID versus 30% in patients on placebo. That is an odds ratio of 2.5 with a nominal p- value of 0.036. So the reason why we think responder analysis is very important because that is not confounded by extreme values. It only takes into account the true responders or much less confounders, and we clearly see a treatment effect by using this approach. The second one is the open-label extension. Dr. Padidela had already mentioned that, and I want to re-highlight that.
Over the course of the OLE, the treatment effect was from 35 meters, week 25, all the way to 61.9 meters at week 49, which is significant improvement over time. Also the placebos, which had additional gain of 43 meters within 24 weeks. So placebo also improved after switch. This additional open-label data in the Six-Minute Walk Test shows treatment effect. Then the subgroup. I mentioned previously, subgroups analysis in this data set was pre-specified, 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.
What we see in the subgroup is that in the pediatric-onset subgroup of 60 patients total, we see a Six-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 favored efzimfotase alfa, including fatigue, pain, which is also very relevant.
Now, in the adult patient population with adult onset, I mentioned all the reasons why we believe the Six-Minute Walk Test potentially failed, but I also would like to highlight an improvement in fatigue of seven 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 patient with adult onset. We believe we have reasonable argument to show treatment effect. And of course, we will discuss all of this with regulators.
Thank you, Gianluca. So, next question is for Steve Scala at Cowen. Steve?
Oh, thank you very much. Two questions, probably both for you, Marc. Can you speak to AstraZeneca's expected conversion of Strensiq to efzimfotase alfa, both in rate and time? For instance, do you expect 50% conversion in three years or some other target? Secondly, are peak sales of $3 billion-$5 billion achievable if the label is limited to pediatric onset hypophosphatasia?
Yep. Thank you, Steve, for these two questions. For the reason that Dr. Padidela has elaborated upon, we expect the conversion from Strensiq to efzimfotase alfa to be very rapid. He has, I think, clearly articulated the strong benefit and in terms of initiation, but also retention of patient. 40% of patient abandoning due to injection site reaction, I think should give you a good idea of the speed at which the conversion will take place.
To take on your second question, the range of peak year sales, which we have indicated between $3 billion-$5 billion, we are very confident that the sales will be within that range regardless of the breadth of the label. Obviously, if the label is more restrictive than we hope, it will be towards the $3 billion, and if it's the wider label, it will be closer to $5 billion. That's why we have provided, in May 2024, this range of $3 billion-$5 billion, which we happy to confirm today.
Thank you.
The next question is for Colin White at UBS.
Hi, Colin White from UBS here. Thank you for taking my questions. I just wanted to ask about the previous comments that you had said about efzimfotase alfa potentially expanding the patient population four to six times above what Strensiq had achieved. Given that the HICKORY study doesn't have a statistically significant benefit, I wondered if you could talk to your expectations of the expansion of the population. Also, given that the adult population is often misdiagnosed for something else, I was just wanting to confirm that those previous estimates didn't include the strong data in the adult population driving better diagnosis. Thank you.
Yes, I will talk about that. When we are comparing the size potential of efzimfotase alfa, we are comparing the number of patients to a baseline of 2022. We have said in the past that we would be between four and six times the number of patients of 2022. The numbers that we have confirmed in terms of revenues, $3 billion-$5 billion, are, I would say, consistent with this multiple four to six times the baseline of 2022. Now, why am I confident? As we have tried to explain to you today, I think the adoption will be easier for a patient to take a product every other week with very good tolerability.
We know that the retention, and this has been discussed several times today, we have mentioned the 40% of abandonment of some patients. Then the regional expansion. Today, Strensiq is available in quite a few countries, but certainly not to the whole global territory. So we expect to do a much better job with efzimfotase alfa. Lastly, we still do hope to gain the adult-onset. We are certainly convinced in the company that this is the same disease, and the product has demonstrated efficacy in the population of adult onset.
We take as evidence the great benefit on pain, the great benefit on fatigue, which are in fact the symptoms with which a patient consults their physician when they don't understand why they are so tired at the end of the day, or where they have a pain in their muscle and joints and so on. That's why they consult their physician. Therefore, these are very important symptoms for symptom relief for the adult onset. That is why we believe that the size of the population will be larger than Strensiq. There will be a better adoption. There will be a greater retention. Finally, the regional expansion that we have demonstrated on the complement products of Alexion, I think we can reproduce that for the treatment of hypophosphatasia.
Then I will go to the next question, Christopher Uhde at SEB.
Christopher Uhde at SEB. Thank you very much for taking my question. I guess a question for Dr. Padidela. What factors drive the range of RGI-C and RSS responses with efzimfotase alfa? Because the data appear inconsistent with the Gaussian distribution. Obviously no one worsened, which is in contrast to the untreated population or even with Strensiq. I can imagine two reasons for that, and one of them would argue that there is maybe a difference between some patient groups. What are your thoughts there?
With regards to the RGI-C score and the Rickets Severity Score, is that your question you are asking about, that you feel the improvement is not that prominent?
It is not a bell curve in either one, and especially the RSS has some relatively extreme outliers compared to where most patients sit.
Well, maybe I can pass this on to Gianluca.
I think this is, again, I want to go back to the data set, the number of patients within data set. We are talking about a total of 29 patients within the data set in this pediatric patient. We do expect a distribution which was not necessarily Gaussian in the effect. When you look at the individual patients, what I can say, we definitely do not comment about individual patient, but we saw an improvement for every single patient in the right direction. Where do they land in terms of the Gaussian really depends on where they started in terms of severity of the disease. But individual patient improvement was observed for all the patients included in the study, and that is pretty much consistent also on the improvement seen by Strensiq in a, I would say, comparable patient population.
We have not done a direct head-to-head comparison for Strensiq because obviously we could not do that. But we have looked at Strensiq data sets in comparable patients, and I can confirm that generally the treatment effect is quite similar to Strensiq, despite the fact that we provide obviously a much lower dose in terms of in general and much less frequency of injection, which provides all the advantages for injection site reaction we mentioned previously. In addition to that, we also look at the switch data in the bone with Strensiq. We see consistency of response over time with no difference in terms of response. Overall, we are pretty confident that the bone data set, it is comparable to Strensiq, and potentially in the future when we assess additional dosing regimens as well to further improve this.
Right. But I guess what I am asking is, are there any differences in patients that, say, that you can identify that could explain why some have a much greater benefit than others?
Well, it is again, a bit heterogeneous in this population when it comes to severity of skeletal manifestation. We haven't seen anyone deteriorating with regards to skeletal manifestation. In some patients where the skeleton manifestations are more prominent, it takes much longer for the skeleton to improve. We are seeing a positive trend both in the randomized period and in the open-label extension period.
That is true also for Strensiq, by the way.
Yeah.
The same observation is valuable for Strensiq.
Okay. Thank you.
Thank you. Next question is for Richard Vosser at JP Morgan.
Hi. Thanks for taking my questions. One please just on Strensiq itself at the moment. I thought I'd take the opportunity. The commercialization of Strensiq has gone very well in the last few years, and particularly this year. Maybe you could talk about the acceleration that has occurred and what you've been doing to drive that and how that might apply to the identification of extra patients for asfotase alfa as well. Then second question, just if the adult onset is not granted by the regulators, would you consider doing a further trial given the benefits that you've seen on other markers other than Six-Minute Walk Test. Is there any, do you think, flexibility with the regulators or anything you could do here given the long patent life? Thanks very much.
Yeah. Thank you. Richard, the first question, Strensiq doing very well. Yes. Strensiq has been doing very well consistently. I think a lot of it is caused by the transformative effect of this medicine. Another very important factor is the effort in regional expansion that we have put across the network, and we are now gaining reimbursement as well as approval around the world progressively. We intend to leverage that for the launching of efzimfotase alfa. Obviously, as we said, there would be two source of patients. The first one would be those who are going to convert from Strensiq, but there will be also a source of patient coming from naive patient who have not been treated with an enzyme therapy. So we take this as a confidence for the therapy.
There are still greater needs around the world in many different geographies, and we hope to do a great job on it. Regarding the adult-onset, I think the question there is speculating again on what the regulators will say or not say, and what will we do if they say this or if we say that. So I don't want to speculate today. The purpose of our call today was to explain the data, and Dr. Padidela explained this very well. Gianluca provided some background on this. We are confident we will have a very good interaction with the regulators, but we'll take it from there, and if we need to do more work. Anyway, in the rare disease, it is very common to continue the development work or post-approval. So we will certainly do more work on efzimfotase alfa in the future.
With this, I would like to ask Graham Parry at Citi to ask his question. Graham, are you on mute? Graham at Citi?
Hi, can you hear me now?
Yes.
Great. Thanks. Thank you for the question. So, one for Dr. Padidela. In the event that regulators didn't give the drug an adult label, how likely would you be, do you think, to use it off-label in either the pediatric onset or adult onset setting? Do you think that would receive reimbursement, and perhaps how do you think your international peers would view that as well? Secondly, to what extent is Strensiq already used by you and your peers off-label in adults? Is that particularly patients who are in the pediatric diagnose and then move through into adulthood? Actually, one question for AstraZeneca, just slightly off topic, but I'd be interested if you talk to the positioning and differentiation you see for Ultomiris in IgA nephropathy, given you've had positive data there this year. Thank you.
I think there were two elements to your question. I think the second one was how frequently and to what extent we'll be using off-label treatment in adult-onset. I think it'll be difficult to answer this question in the sense that with rare diseases, with medications which are at a cost they are, we don't tend to use off-label medications. We are very strict with using it within the licensed indication. So I don't think we will be able to do that. We will be only able to use this if the regulatory authorities approve this. So that's for the off-label question you had. I've forgotten the first question you asked. If you don't mind repeating that for me, please.
So that was the extent to which Strensiq is already used off label. I think you partly answered that with the answer to the first question.
Absolutely. Again, we don't use off-label medications. We don't.
Thank you.
Regarding the question, Graham, on Ultomiris again, I think the purpose of our call today is to talk at great length on efzimfotase alfa. We will take note of your question and at the next potential interaction, we will provide some comments on the differentiating or profiling or positioning of Ultomiris in IgAN, if you agree.
I would like to ask Simon Baker from Rothschild to ask his question.
Thank you very much for doing the call. Two, if I may, please. Firstly, going back to the adult onset group. I was wondering if in a sense adult onset was a proxy for disease severity, and I just wondered if there was any difference in response based on time from diagnosis within that group. Secondly, a question probably for you, Marc. Could you give us an idea of the relative importance of the increased duration of therapy versus the breadth of the label in getting to the $3 billion - $5 billion peak sales indication? Thanks so much.
Okay, so maybe Gianluca, you can take the first part.
Yeah. We did analyze the data and the details, but we did not see a specific difference in time to response based on the adult subgroup. As I mentioned previously, this is a very fairly small patient population in the study confounded by the effect of two patients specifically. Generally, what I would say is that patients above a certain age, over 65, probably tended to respond a little bit less, because most of that is driven by the confounding effect in this patient population and the use of devices, which was one of the elements that potentially could have affected the treatment response. But those are the only two factors that could justify a difference response of treatment. So it is more the presence of confounders in older subjects, more than a true differential treatment response.
Thank you. To just talk about the duration of treatment, we have mentioned several times today this abandonment that, in the adult population in particular, the abandonment is estimated at 40% due to injection site reaction. As the disease itself is a chronic therapy, if you could eliminate the cause of abandonment due to the tolerability, this would have a very substantial impact on the average duration of treatment. Obviously, we do not have the data because the product is not yet launched, but we can simulate to a greater duration of therapy on efzimfotase alfa versus an adult patient receiving today Strensiq. I think the abandonment of 40% will be helping you model that extended DOT.
Thank you very much.
With this, last question from Simon. Thank you very much, Simon, and I would like to close the call. Thank you all for your interest in efzimfotase alfa, and I do hope that we will be able to bring this molecule to patient any day sooner. Thank you very much.