AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

Good morning to those joining from the U.S. Good afternoon to those in the U.K. and Central Europe and good evening to those listening in Asia. Welcome, ladies and gentlemen, to the AZN Meet the Management Webinar, CVRM Weight Management for investors and analysts. Before I hand it 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 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 statements disclaimer in the slide deck that accompanies this presentation. [Operator Instructions] And with that, I will now hand you over to the company.

Welcome, everyone, to this our first AstraZeneca Meet the Management call on weight management and obesity. Next slide, please. This is our forward-looking statement, which I'd encourage you to take the time to read. Next slide, please. As you may know, we'd not normally hold a call -- an investor call to discuss Phase I data and preclinical data. However, we appreciate the high investor interest in this area and we wanted to make clear our weight management strategy, a differentiated strategy, which we believe AstraZeneca is uniquely positioned to deliver on. During this call, we will describe the clinical rationale behind this strategy, discuss the preclinical and Phase I data presented for our lead assets thus far and outline what has underpinned our confidence to accelerate these new potential medicines at pace with 3 Phase II studies already underway. We will have some time for questions at the end of the call. However, please do your questions focused on the area of weight management and obesity only and least limit the number of questions you ask to allow others a fair chance to participate in the Q&A. [Operator Instructions] With that, I will hand the call over to Sharon Barr, our Head of Biopharmaceuticals R&D. Sharon, over to you.

Thank you so much, Andy. So good morning, good afternoon, good evening, everyone. Hello from ObesityWeek at San Antonio. If we could move to the next slide, I think it would be helpful to start with the big picture. AstraZeneca has a bold ambition to deliver $80 billion in total revenue and 20 new medicines by 2030 and we have a solid plan to get there. As many of you may recall, we first presented this to you at our Investor Day back in May and we mapped out the programs and technologies in which we are investing that will drive growth today, tomorrow and the day after tomorrow, accelerating our growth beyond 2030. And I will highlight that our weight management portfolio, which we are presenting today is an important component of this growth. We anticipate several Phase III readouts in 2025. And as Pascal has previously mentioned, you won't have to wait until the end of the decade to see whether or not we're on track to achieve our 2030 ambition. Let's go to the next slide. where we turn to biopharma specifically. Across our cardiovascular, renal and medical portfolio, we have already launched Wainua in ATTR polyneuropathy and we have the potential to expand into the much larger ATTR cardiomyopathy population. We've also started 3 Phase III trials for our dapagliflozin combinations, and we'll have the first Phase III data for baxdrostat in hypertension next year. We'll soon have Phase II data for all PCSK9, as well as additional data across our weight management portfolio. And we are excited with the progress we've made thus far and I'm looking forward to progressing our portfolio with further updates to come. Let's go to the next slide. Today, I'm very pleased to announce that Dr. Mikhail Kosiborod, currently at St. Luke's Health System in Kansas City, will join us at AstraZeneca as the new Senior Vice President for late-stage cardiovascular, renal and metabolic diseases in January of next year. Mikhail, as you may know, is an internationally recognized expert in the field of cardiometabolic disease and has led and co-led numerous clinical trials, many of which have had a significant impact on treatment guidelines and clinical practice. His work has been critical to understanding the impact of SGLT2 inhibition and GLP-1 receptor agonism in improving cardiovascular outcomes and survival, representing some of the most important advances in clinical medicine in the last 2 decades. And with that, I'll let Mikhail introduce himself and invite him to give his view of the weight management landscape.

Well, thanks very much, Sharon, for your kind introduction. As Sharon mentioned, I am a cardiologist, currently at St. Luke's Health System in Kansas City and have been involved throughout my entire career in improving outcomes for people with cardiometabolic disease. We can go to the next slide. So we're here to talk about a very important issue in the space, which is the role of overweight and obesity in fueling the epidemic of cardiometabolic disease that we have been witnessing over the past 2 to 3 decades. So the critically important concept that I think we should highlight here is that overweight and obesity and its associated visceral [indiscernible] in many patients are not just comorbidities but can, in fact, be key drivers of many risk factors for cardiovascular, renal and metabolic complications, things like insulin resistance, hypertension, dyslipidaemia, inflammation and fluid retention that ultimately result in a multitude of downstream and organ damage and complications, including cardiovascular complications such as ASCVD, heart failure, atrial fibrillation, type 2 diabetes itself, chronic kidney and liver disease, sleep apnea and many others. It, therefore, should come as no surprise that many patients living with overweight and obesity, have at least one or more of those complications, nearly 40% of those living with overweight and more than 60% of those living with obesity. Now of course, these percentages that you see here are the proportions of patients that are diagnosed with these complications. And of course, many of these patients are not recognized or diagnosed. And so the real numbers are, in fact, likely to be much higher than what you see here. Therefore, the key in managing overweight and obesity should go well beyond weight loss and focus squarely on organ protection, that is prevention and treatment of this cardiovascular, renal and metabolic complications. It's a very big issue and it requires really bold and diverse solutions. So today, we already have incretin-based treatments that on the market and available in many countries around the world. These treatments have had demonstrated efficacy when it comes to clinically meaningful reduction in body weight and also emerging data on organ protection, including reduction in cardiovascular complications. But as we'll talk about shortly, the numbers of patients affected by overweight and obesity are staggeringly large and this will require many additional diverse solutions. So one of the solutions should be oral agents, including simple molecules that can democratize access to these therapies around the world, into various patient populations, offer ease and convenience of once-daily dosing and also allow for a fixed-dose combination with other organ protective therapies. And then, of course, we also need to go beyond incretin for a number of different reasons, partly because there is certainly emerging interest in this issue of weight loss quality that is fat specific weight loss while preserving lean body mass. It's a concept that is evolved and emerging scientifically and will continue to become -- to be important in further investigating. And also, we need to keep in mind that many patients do not tolerate incretin-based treatments long term and will require additional treatments and solutions that can improve tolerability and therefore, long-term sustainability of the treatment. Go to next slide, please. So let's talk about the numbers for a minute. Again, this is a huge problem that will require really bold and diverse solutions. As I mentioned earlier, the numbers are staggeringly large. Already in 2020, more than 2.5 billion people were estimated to live with overweight and obesity and that number will nearly double by the year of 2035, when more than half of global population is estimated to have these conditions. This is going to cost a lot of money. It's already costing a lot of money and that amount will more than double by the year of 2035, where the cost is going to be or at least estimated to be more than $4 trillion. So it's a huge problem and we need to have really diverse and bold solutions. And what's important to keep in mind is that even after weight management is adequately addressed, there will still be many patients around the world that will require treatments for cardiovascular, renal and metabolic complications that they already have in place including type 2 diabetes, heart failure, CKD, dyslipidaemia, atherosclerotic cardiovascular disease, chronic liver disease and so on. And one of the key reasons that I made a decision to join AstraZeneca R&D team is because of the depth and breadth of the pipeline that is being built to meet that challenge both for weight management and for the treatment of cardiovascular, renal and metabolic complications and for organ protection. And with that, I'm going to pass it back to you, Sharon.

Thank you so much, Mikhail. Thank you for joining this conversation and we are really looking forward to you joining the organization in January of next year. So let's go to the next slide. We are at San Antonio ObesityWeek. And this week, we are presenting data across our 3 leading assets in this space. As we have highlighted previously, our weight management strategy is focused on 3 different populations and is designed to go beyond short-term weight loss target, delivering weight management, addressing cardiometabolic risk, offering organ protection and ultimately, better health outcomes. The 3 populations on which we are focused are first, patients living with obesity and additional comorbidities that require significant and durable weight loss while reducing their cardiorenal risk, both through incretin and non-incretin pathways, as well as unique combinations. The second population is people who are overweight, who need to lose a few pounds or kilos and have cardiorenal and/or cardiometabolic comorbidities that require moderate weight loss with organ protection through moderate doses of oral GLP-1 in combination therapies with our cardiorenal molecules like dapagliflozin or like our oral PCSK9, AZD0780. And the third population is patients with type 2 diabetes who are living with overweight or obesity, who may benefit from the cardiorenal benefits of GLP-1 receptor agonism that will help control A1C and manage weight loss with monotherapies and with oral combinations. Let's go to next slide. We have 3 high potential assets progressing into Phase IIb. Let's start with AZD5004. AZD5004 is our small molecule, orally available GLP-1 receptor agonist. Our ambition is to develop this molecule as an effective oral treatment for type 2 diabetes and obesity and also as a tool to manage weight in patients who need modest weight reduction as part of their overall management of cardiometabolic and cardiorenal risks. We have now elevated AZD5004 into Phase IIb development in both obesity and type 2 diabetes. Given that this is a true small molecule, our future plans include a number of fixed dose combinations across the fields of weight management, cardio renal protection and type 2 diabetes. AstraZeneca is uniquely well positioned to develop AZD5004 as both a monotherapy and as combinations with other molecules in our portfolio. The second asset that I want to highlight is AZD6234, that's our long-acting amylin peptide that has the potential to deliver improved tolerability and differentiated weight loss with lean mass bearing efficacy. AZD6234 also provides an option to patients that cannot tolerate or might not be eligible for GLP-1s. And we have now initiated a Phase IIb trial that is actively enrolling patients. And finally, let's turn to our combination of AZD6234, the long-acting amylin, with our GLP-1 glucagon dual agonist, AZD9550. This combination provides an opportunity to form a triple agonist that gives patients the best of both worlds, optimal weight loss with improved lean mass preservation and organ protection and we plan to initiate a Phase IIb trial here shortly within the coming 6 months. At our Investor Day earlier this year, we signaled the peak year revenue potential of more than $5 billion for our weight management franchise. So these assets represent significant opportunities to support that ambition. And with that, I'd like to hand over the presentation to my colleague, Elisabeth, Senior Vice President heading up the AZD5004 program to add more color.

Thank you so much, Sharon. Can I have the first slide on the oral GLP-1? The next slide, please. I thought I'll start by sharing some preclinical data. So in a 9-month trial in nonhuman primates, we saw no adverse effects and we saw dose-dependent differences in body weight gain versus controls and that's what you see on the left-hand side here. We also did an intervenous glucose tolerance test, which confirms target engagement across the range of doses tested in the Phase I trial. You can here see the target engagement from 8 milligrams. The chart on the left-hand side shows doses equivalent to human doses up to 225 milligrams. Next slide. If we then move into the SAD and MAD trial that we are presenting data from here at ObesityWeek, starting with the SAD study, which was in healthy participants, there, we started doses from 1 milligram up to 300 milligrams in single doses. In the MAD trial, which was in patients with type 2 diabetes, we had 4 cohorts. Three of them were flat dosing that was 5 milligram, 10 milligram and 30 milligrams, so no titration. And then we had 1 cohort of patients that were titrated up to 50 milligram. The primary endpoint was safety and tolerability. We also looked at pharmacokinetics and we had exploratory PD end points, both related to glucose and body weight. I will remind you that was -- this was a controlled in patient setting, including a 14-hour fasting window and an 1,800 average daily caloric intake. Next slide, please. In both the SAD and the MAD studies, we saw flat PK profiles, which support the potential for improved tolerability and once-daily dose -- dosing. Next slide, please. We also did a food effect trial and we saw no significant food effects there. And the half-life at the 50 milligram was around 21 hours, both fed and fasting. So this supports once-daily dosing and the fact that this drug can be given both with and without food. Moving into the results then on the next slide. So this is from the SAD trial where doses 50 milligram or below were well tolerated in healthy volunteers. We saw no serious adverse events and we did see dose-dependent increases in GI side effects, which supports the target engagement of the GLP-1 receptor. Next slide, please. In the MAD trial, we saw a tolerability profile that is consistent with the GLP-1 class. We saw dose-dependent increases in GI side effects but we also saw that multiple doses were tolerated. The 5-, 10- and 30-milligram were without titration but also the 50-milligram dose showed a good tolerability. We didn't see any discontinuation due to nausea or vomiting. So based on this encouraging tolerability profile, we are including higher doses than the 50-milligram dose in the ongoing MAD study and also in the Phase IIb studies that are actively recruiting. Next slide, please. Looking at the exploratory PD data from the SAD trial, Here, we can confirm the target engagement of the GLP-1 receptor. We saw a reduction in glucose in healthy volunteers during the oral glucose tolerance test from doses of 4 milligrams and above, as you can see in this graph. This gives us confidence in the target engagement. Next slide, please. We saw reductions in glucose and body weight in the MAD type 2 trial at -- and this is the data from the 50-milligram cohort. When it comes to fasting glucose, we saw a reduction of 76.6 milligram per deciliter, for glucose area under the curve, following a mixed meal tolerance test, the reduction was 51.7%. And for body weight, we saw a reduction of 5.8%. I will remind you that this was in the cohort of patients with type 2 diabetes, where you usually see less of a body weight effect when it comes to GLP-1 treatment, 28 days, this was. Next slide, please. With the -- the reductions we saw in fasting glucose, glucose area under the curve, following the mixed meal tolerance test and body weight was dose dependent. And you could see the red line being the 50-milligram dose that I had on the previous slide. Based on the totality of the data that we see here, with the once-daily dosing, this being a true small molecule, the dose-dependent target engagement, the solid profile with a good tolerability of the top dose of 50 milligram, we are impressed by this profile and we are speeding ahead into the Phase IIb studies that are actually up and Running and Actively recruiting, as we speak. So if you go to the next slide, I will try to summarize what we have seen so far. We have a molecule here with a proven mechanism and potency. We have evidence of GLP-1 receptor target engagement. It's a potent drug. We have a flat PK profile, which will support better tolerability. It's a small molecule, which makes it possible for us to produce fixed-dose combinations. We have an encouraging safety profile at the broad range of doses, including the top 50-milligram dose that we have tested here. And we have a favorable route of administration. With the once-daily oral administration, since it's a true small molecule, we can create oral combinations and it can be taken with and without food. If we then move to the next slide, I will show you the designs of the Phase IIb studies that are actively recruiting as we speak. This is the Phase IIb study VISTA, which is in patients with obesity or overweight. The primary endpoint is looking at change in body weight from baseline over 26 weeks. We are also looking at the proportion of patients losing more than 5%. We will also follow up until 36 weeks. We also have a sister study. Next slide. In patients with type 2 diabetes, it's called SOLSTICE and it's designed to evaluate the effect on glycemic control. The primary endpoint here is change in HbA1c from baseline but we are, of course, also looking into change in body weight over that time. We are here exploring a broad range of doses. And based on the totality of the data from the VISTA study and the SOLSTICE study, we will make informed decisions on what doses to take forward to develop this compound in monotherapy for type 2 diabetes, for obesity and weight management but also explore the potential to develop fixed dose combinations with other compounds, which will take me to my next slide. We see a great opportunity for AZD5004, our oral GLP-1 receptor agonist to be codeveloped with other compounds that we have in our portfolio. I'm basing this on the fact that it is a true small molecule but also about the great portfolio that we have in our hands. I am, of course, thinking of dapagliflozin, Farxiga, our oral SGLT2 inhibitor. And the potential to further help patients with type 2 diabetes, chronic kidney disease and heart failure through this combination. But also with patients with dyslipidaemia and the opportunity to combine this molecule with our oral PCSK9, which is also a true small molecule. And with that, I hand it back to you, Sharon. No, I'm handing it over to Regina that will tell us more about the other molecules that we have in development. Over to you, Regina.

Thank you so much, Elisabeth. So let's move over and talk about AZD6234, which is our long-acting amylin peptide agonist. We are developing this molecule for healthy weight reduction in patients who are living with obesity or being overweight. So let's take the next slide, please. So in addition to inducing weight loss, it's known that amylin also has been shown in preclinical studies to have fat mass specific weight loss while sparing lean muscle mass. And we are presenting a poster at the ObesityWeek, where we have studied the effects of AZD6234 on fat and lean mass in the preclinical model of obesity. And as you can see here on the left, 15 days administration of AZD6234 led to significant and dose-dependent weight loss. And we could also confirm, as you can see on the right hand, that amylin drives fat mass specific weight loss while retaining lean mass. And this was different from the effect we saw with semaglutide, which did not have the same lean mass bearing effect in this preclinical model. So let's move to the next slide. So moving on to our Phase I single ascending dose study that we performed in healthy participants who were obese or overweight with the BMI greater than 27. So looking at the graph on the left, we could see a statistically significant reduction in body weight after a single dose at all doses tested already from the lowest dose of 0.3 milligram and with the most significant body weight reduction seen in the Japanese cohort where we tested 2.7 milligram. If you look on the right-hand side, tolerability, we could see good tolerability up to 2.7 milligram and we only saw severe vomiting at the highest single dose tested, 4.2 milligram. So these data, together with data from an ongoing MAD study has provided starting doses for the Phase IIb study, which is ongoing. So if we take the next slide, please. So with this encouraging Phase I data, we have initiated, as I mentioned, the Phase IIb trial in obesity. So if I summarize the data, in our SAD study, we saw good safety and tolerability and a PK profile supporting once-weekly dosing for this molecule. We were also encouraged to see significant changes in body weight already after a single dose. And we are excited about this non-incretin mechanism as a potential fat mass specific weight loss mechanism. If you go to next slide, please. So we have already initiated a Phase IIb trial, APRICUS, in patients who are obese or overweight and where the primary endpoint is a change in body weight from baseline to week 26, as well as the percent of patients achieving a 5% or more reduction in body weight at 26 weeks. We are studying 3 different doses and different titration schemes in this Phase IIb trial. So if we move to the next slide, we will continue with AZD9550. So AZD9550 is our GLP-1 glucagon dual peptide agonist. And this molecule has been designed to display optimal pharmacology for glucose control, weight loss and organ protection and it's a 5:1 ratio in potency for GLP-1 to glucagon. Next slide, please. So we have studied the pharmacology of this molecule in several preclinical studies. And on the left in this slide, you can see the significant reductions in body weight that we saw at various doses of AZD9550 in this preclinical obesity model. In our single ascending dose study with AZD9550, we could confirm dose linear PK and a half-life supporting once-weekly dosing, as you can see in the middle. We could also demonstrate good safety and tolerability with only the highest single dose of 1.2 milligram causing severe vomiting. You can take the next slide, please. So with the overlapping comorbidities that those patients who are living with obesity or being overweight have, we are progressing with a fixed dose combination with AZD6234, the long-acting amylin and AZD9550, the GLP-1 glucagon. And this triple -- this combination will enable us to target 3 complementary mechanisms for weight loss, amylin, GLP-1 and glucagon, with amylin potentially providing lean muscle sparing and GLP-1 and glucagon contributing to organ protection. We see the potential for these assets to address an unmet medical need with AZD6234 providing additional weight loss in obese individuals who need to lose more weight on a GLP-1 or another incretin, or for patients who cannot tolerate, were not eligible for an incretin therapy. With the fixed-dose combination, the triple mechanism amylin GLP-1 glucagon, we see could potentially replace incretin therapies and provide significant and healthy weight loss with lean muscle sparing and organ protection. So with that summary, I'm going to hand over back to you, Sharon.

Thank you, Regina. And I feel like it now is a great time to point out that Regina and Elisabeth have such a strong track record of success here at AstraZeneca, having been responsible for building the portfolio that we have today and for bringing forward such important CVRM medicines like Farxiga and Crestor. This is the A team that we have focusing on our weight management portfolio. And together with the addition of Mikhail in January, I think we're really going to have a fantastic varsity team focusing on these important assets moving forward. Let's go to the next slide because I think now is an important time to really underscore the scale and complexity of the cardiovascular, renal and metabolic landscape. Mikhail mapped this out for us earlier today and it's worth noting that it is increasingly recognized that combination approaches aren't just desirable, they're essential. With at least 60% of people diagnosed with obesity or overweight living with at least 1 comorbidity, we know that we need to move away from treating these conditions individually and move towards treating them more holistically, removing from sick care to health care and driving for better health outcomes. We have strategically built a differentiated CVRM pipeline with capabilities across a range of modalities and pathways and we are going at pace to deliver the next phase of transformative medicines across cardiovascular, renal and metabolic disease designed to address the interconnectedness of CVRM disease. Let's go to the next slide. The data that we have shared today and that we are sharing at San Antonio ObesityWeek, across all 3 of our assets has given us the evidence and the confidence that we need to progress these assets at pace. We know that this is a huge unmet medical need and a significant market opportunity. Our growing pipeline of novel combinations and mechanisms is designed to address different aspects of obesity and overweight in the interconnected disease and we are so excited by this future potential. We're focusing on the underlying causes and mechanisms of obesity and overweight, with our growing pipeline of novel treatments and combinations with complementary mechanisms that aim to provide 3 things: durable weight loss benefit with monotherapies and combination approaches, weight management with cardiometabolic benefit and options for patients through combinations of oral medicines where we can target linked disease biology. As Elisabeth highlighted for you earlier, we have started 2 Phase IIb trials with AZD5004, 1 in type 2 diabetes and 1 in obesity or overweight with at least one comorbidity. We are excited by the strong target engagement that we've seen and the favorable safety and tolerability profile that we saw in Phase I. And we'd like to remind you again that our Phase I study was designed to show exactly that. It was not designed to look at body weight reduction, although we did see a clearly dose-dependent weight loss in our Phase I study. And we would also highlight that AZD5004 is a true small molecule. So it's suitable for combinations with other molecules that are already in our portfolio, such as dapagliflozin or such as our oral PCSK9. And as Regina told you, we've also started a Phase IIb trial with our long-acting amylin pipeline. We've seen promising, albeit early data showing that it has the potential in preclinical models to spare lean muscle mass and we expect that it can also be an alternative for patients who cannot tolerate GLP-1s. And finally, the combination of AZD6234 and AZD9550 provides patients the potential for the best of 2 worlds, optimal fat specific weight loss with improved lean mass preservation and organ protection and we plan to start a Phase IIb shortly. So I will leave you with the message that AstraZeneca is uniquely well positioned to be able to create the combinations that address the interconnectedness of cardiometabolic disease. And with that, we'll move to Q&A. [Operator Instructions]

Our first question is from James Gordon at JPMorgan.

James Gordon from JPMorgan. Two quick questions, please. One was the oral GLP-1. I didn't quite catch it but was this assessing that there was any liver tox because that was the grade one -- one of the grade events was? And so can you clarify how many cases of liver toxin and what grade it was or when I say liver tox, liver enzyme elevations. The other question was the long-acting amylin which looked interesting. And I know there's been quite a bit of excitement in some other long-acting amylins like [indiscernible]. I think is probably the most mature we've seen. And I think the pitch there was better tolerability than drugs like Wegovy or Zepbound with similar weight loss. But in terms of how you think 234 could be differentiated versus [ petri ], is the idea that could you hit calcitonin and that you could be even cleaner? Or is it some other aspect like body composition? How are you thinking it will be different because I think it binds a bit differently?

So James, thank you for the close read of the data and those insightful questions. So I'll start by addressing liver tox. I'll offer it up to Elisabeth to add any additional color and then I will hand it to Regina to talk about the differentiated profile for AZD6234. So with regards to live tox, were elevated liver enzymes seen in the Phase I study, there was 1 case of transiently elevated liver enzymes in a single patient who was treated at the 10-milligram dose. The elevated liver enzymes spontaneously resolved even as the patient was dose escalated. With these data in hand, we had no reason to hesitate and we are moving forward rapidly to Phase II. I'll pause here. Elisabeth, is there anything you'd like to add?

Nothing to add. We haven't seen anything in addition to that. And we are, of course, monitoring this closely as all compounds in the oral GLP-1 space are doing. So thank you, Sharon.

Great. And your second question, James, was about our long-acting amylin AZD6234, where we believe we have a very differentiated profile. And Regina speaks to this beautifully as the leader who's really piloted this program forward. So Regina?

Yes. Thank you for the question. So first of all, I just want to highlight that the amylin and the calcitonin receptors are closely related and it's been very challenging to develop molecules that are selective for amylin. So we have designed our amylin molecule 6234 to be selective for amylin, have a high selectivity versus the calcitonin receptor. And this builds on the biology of amylin, which is glucose control, regulating appetite, reducing weight and with potential for lean mass preservation, lean muscle mass preservation. We also know that the calcitonin -- the role of calcitonin is really on regulating calcium and phosphate levels. And there are several preclinical studies suggesting that calcitonin activation is linked to taste aversion which could potentially translate to GI tolerability issues in the clinic. So I would say that based on the data we have so far, the Phase I data, it's too early to speculate on comparisons in terms of tolerability and efficacy. And we will know more once we have the Phase IIb data coming out from various clinical trials, including our own.

And our next question is from Sachin Jain at Bank of America.

Sachin Jain, here. Just a couple, please. On the oral efficacy data, it seems it's about 2.5% placebo-adjusted. So I just wanted to get a sense for 2 things. How much higher do you think it would have been in a pure obese population? Have you done some modeling work there? And then secondly, any sense of how much higher efficacy you can get with dosing? I know you're not disclosing the dosing but any sort of sense of multiples of dosing or increments of efficacy you're targeting, that would be very helpful. And then the second is a very broad question. Obviously, you've just started Phase II for all 3 assets. Any best guess at this stage on time lines for Phase II data and whether we should expect updates from Phase I prior to Phase II? And I'm thinking particularly for the oral on the higher dose cohorts.

Thank you, Sachin. So I will start with a broad overview and then Elisabeth, I'll ask you to add some more. So as you noted, we demonstrated that we saw a 5.8% body weight reduction reduced with placebo correction. And you asked whether or not we might expect to see something different in an obese population. As you've correctly noted, this was a highly controlled 4-week inpatient study run in type 2 diabetic patients. Also, as Elisabeth noted, in these patients, it was a 14-hour fasting period with an average calorie intake of only 1,800 calories. So with that in mind, we are pleased with the data that we have seen. Could we have expected to see something different in an obese population? It's impossible to speculate. It is worth noting that we tend to see across major studies, a more substantial reduction in weight loss in obese populations relative to type 2 diabetic patients. And I'll leave it there and ask Elisabeth to comment on additional expectations for our Phase II program.

Thank you, Sachin, for the question. I mean based on the data we see, we are rushing into Phase IIb and that's where we will get sort of the answers to the very important questions that you are asking. This was not designed to address questions on efficacy but on safety, tolerability and the PK profile. And based on that, we are confident. But to your point, patients, you usually see more of a weight loss in patients with obesity than in type 2 diabetes. So that's likely to happen. It was also 28 days and you are likely to see more over time. We are recruiting very fast but I can't give you any exact time lines on when we will get sort of the update from the MAD study that's going in parallel and the Phase IIb studies that will include doses higher than the 50 milligram that we saw here and that we found to be tolerable.

Can I perhaps take 1 follow-on then, just to get a sense on dosing. Sorry to just push on this. So how are you trying to triangulate the concept of having a single dose of fixed-dose combinations versus pursuing very high efficacy in your data suggesting you can titrate out the safety? Just any sense you can get then, asked the question slightly differently.

Do you want me to take that, Sharon?

Sure. That sounds great.

So as you can see from the data, Sachin, you saw target engagement from the 4-milligram dose and you saw good tolerability at the highest dose, 50 milligram that we tested. So we will test a broad range here and we will look for the optimal doses to meet 3 needs. One is for patients with type 2 diabetes, where we are looking at optimal effect on HbA1c but of course, also on body weight. We want to have the maximal tolerated dose for patients that have obesity. But then we are also looking for a dose where you might not need to have many steps or maybe not a step at all from a titration perspective, that would be good for combination with dapagliflozin, for example. And that's the reason why we are testing a broad range in Phase IIb to be able to find optimal doses for these 3 cohorts that Sharon described to you earlier.

And I'll just layer on that, Elisabeth. We are moving forward with both monotherapy and combination studies at pace and in parallel. We aren't waiting to fully understand the activity of the monotherapy before we move forward with the combinations. And our next question is from Simon Baker at Redburn.

Two, if I may, please. Firstly, on the triple. Can you currently or do you intend to co-formulate the glucagon GLP-1 and the long-acting amylin as a single solution? And then secondly, a slightly broader question. There's a lot of debate at the moment about how the injectables and orals fit together in the market. In some cases, it's driven by lower efficacy of orals being used in a maintenance setting. That doesn't appear to be relevant for 5004 given the magnitude of the effect we're seeing. So how do you see the interplay given you've got both of them between weekly injectables and daily orals?

All right. So first, let me start with your question about the triple combination, AZD6234 plus AZD9550. So this is the long-acting amylin combined with the GLP-1 glucagon, both as subcutaneous injectable molecules. You asked if we could co-formulate those. This is an area of active progress and we continue to explore a variety of different co-formulation approaches. It's early days yet. And I will pause here and allow Regina to add any additional color. And then I will ask my colleagues, Ruud and Mina to comment on how we view the market for injectables and orals.

So okay. So let me start with the formulation question. You are right, Sharon, we are working on the technical aspects in terms of co-formulating AZD6234 and AZD9550. And to tweak the properties in the right ways that they can thrive together in 1 formulation. That's our ambition. Having said that, the Phase IIb trial that we are planning to start in the next 6 months or so is going to be with individual components administered. So we are planning to work on the formulation to have it ready for when we start the Phase III trial.

Okay. Thank you so much, Regina. Simon, regarding your question, I firmly believe that in the future, both injectables and orals will get a clear space. Let's not forget and Mikhail did very well to show the enormous burden in the world, not only in the, let's say, the Western world but clearly also in the emerging markets. And we all know that especially in the emerging markets, oral drugs are doing very well and there's still a level of reluctance also in order to use injectables, linked to that. Of course, our pricing points probably will differ from the Western world from the emerging markets. So all in all, I think it's very important to keep that in mind that we don't have, let's say, the idea that orals will switch or will move away completely from injectables. But clearly, there's a huge opportunity here. And then secondly and we keep reinforcing that. I think the oral medication provides us at least the option in order to combine it with other products in our portfolio. Of course, Farxiga is already the cornerstone for cardiorenal diseases. But equally we're very excited about oral PCSK9. So the combinability of an oral medication, I think, will differentiate ourselves also easier versus injectables. Mina, is there anything I forgot?

No. The only small add would be, you saw from the portfolio we presented today, a mix of orals and injectables and combinations. At the end of the day, we think the type of patients and the science is evolving so much that our intent is to be able to address as many of the comorbidities as we can and address globally as broad a population as we can. And I think we've got a very strong portfolio to do that.

Agree, Mina. So our next question is from Steve Scala at Cowen.

Two questions. First, apologies if I missed this but can you be specific on what doses are being studied in Phase IIb? And if you won't provide this detail, can you tell us if the 50 milligram is one of the higher doses or lower doses being studied in Phase IIb? And the second question is, do you see a role for monotherapy GLP-1 in the market down the road? And what portion -- if you do see that role, what portion of the market might be monotherapy?

Sure. So let me start and then I will ask Ruud to jump in. So you asked specifically about our Phase IIb doses. And as you correctly noted, we haven't shared them. And we are not ready to share those doses at this point. And then you asked a little more precisely, well, where does 50 mg sit in the overall scheme? And I will say this, in our Phase I study, 50 mg was the maximum dose tested in the multiple ascending dose portion of the study in type 2 diabetics. And in that cohort of patients, we saw a favorable tolerability safety profile. And the favorable tolerability profile led us to believe that we had the potential to further increase doses and we really want to be able to optimize the dose range for AZD5004 and fully maximize its potential. So we will be exploring a range of doses in the Phase IIb and we'll share those doses at a future medical conference when we're reading out the data. But I do appreciate the question. Your second question was about whether or not we see long-term utility for GLP-1 as a monotherapy. We do. We are developing AZD5004, both as a monotherapy and in combination because we understand that at least 60% of patients who are living with obesity and overweight, are dealing with at least one comorbidity. And the combinations are really giving us the possibility of more effectively treating the interrelated disease that is driving our current health care crisis. With regards to the proposed size of the market, I think that my colleague Ruud would be best posed to answer this.

Yes. So thank you so much. And a great question, Steve. We haven't disclosed that. But I think, once again, in the presentation of Mikhail, it's clear that, let's say, in the overweight patient population, there is a very substantial opportunity here. Many of those patients with BMI between, let's say, 26, 27, up to 30 are suffering from 1 or in many cases, 2 comorbidities. So in that sense, I think it's a very, very substantial population. And if you refer a little bit back to the success we are seeing with our dapagliflozin, Farxiga across renal and as well as cardiovascular disease, I think it gives you an indication of how big this market can be, assuming, of course, that the trials will be positive in the near future but it is a very substantial opportunity.

And thinking about not just the opportunities but the unmet medical need, I think it would be wonderful to hear from Mikhail, who's seeing these patients in his clinical practice daily. Maybe you could speak to your view on the use of monotherapies and combinations.

Well, thanks very much, Sharon. Yes, certainly, I would say, in my clinical experience, probably the best way I can summarize it is that we will have, hopefully, in a relatively near future, lots of different treatment options for lots of different types of patients. When you look at the numbers of people living with overweight and obesity, as I previously mentioned, it's a staggering numbers that's rapidly increasing. And so ultimately, it's a phenotype of the patient that will determine what kind of treatment we're going to be using in each individual situation. For example, somebody that has overweight and let's say, cardiovascular risk factors, risk factor for atherosclerotic cardiovascular disease or even established atherosclerotic cardiovascular disease, certainly using a monotherapy of GLP-1 receptor agonist would be a reasonable treatment option, perhaps with addressing other risk factors such as dyslipidaemia and hypotension. Whereas somebody who has heart failure and chronic kidney disease, either in isolation and combination, a fixed-dose combination with an SGLT2 inhibitor would be a great option. But if you're dealing with a patient that, say, has a BMI of 39 or 45, which is not all that uncommon, certainly not in the United States, there will be a need for a much more aggressive weight management than what we would expect with a monotherapy of GLP-1 agonist, whether injectable or oral. And that's where combination therapies with targeting various receptors, for example, the option that Regina talked about, which is GLP1-glucagon plus amylin, that would be an attractive potential treatment. And of course, also it will depend on where the patient is geographically and whether any or all of these treatments are actually available. So democratizing access is going to be absolutely critical as well. And the oral simple molecule certainly gives you that option.

Great. So we'll move to our next question and that's Rajan Sharma at Goldman Sachs.

Just on the amylin in the APRICUS trial, will you measure body composition and also bone density in that trial? And then ultimately, do you expect lean muscle preservation to allow for a label claim? And just kind of would be helpful to get some early thoughts on how you think the regulator may think about that. And then just a second on the amylin GLP-1 glucagon combination. What's the ultimate profile you're aiming for then in terms of kind of body weight reduction at 52 weeks, for example? And do you think there may be synergistic effects between 2 or 3 mechanisms at play there?

Great. Okay. So your first question about AZD6234, our long-acting amylin was about what we expect to see in the APRICUS trial. So I will, in one moment, hand that to my colleague, Regina, who is piloting that forward to speak more specifically about our plans for amylin in Phase IIb. And then your second question was a more speculative one, I think, about what sort of body weight we could expect to see with the triple combination. And to that, I will say it's early days. We have 1 molecule in Phase IIb and 1 shortly to enter Phase II. Our trials to date have been designed to show safety and tolerability and target engagement. And to that end, we are very excited about the profile that we see and it has encouraged us to move rapidly forward into the next phase of clinical development. It is too early for us to speculate on what we think could be the maximum weight loss that we could achieve with a triple active combination. But we think that the combination of both incretin and non-incretin pathways is very encouraging and allows us to really maximize on the potential of those pathways. So I'll pause here and Regina, maybe you could add some color to the APRICUS trial.

Yes. So thank you for the question. So in the APRICUS trial, as I mentioned, the primary endpoint is going to be percent change in body weight from baseline to 26 weeks. But as part of the clinical development program, we also have a mechanistic study where we will use MRI to look at fat versus lean mass specific wait class. So that's going to be an extremely important question to see -- to address, to see how our preclinical data translates into humans. And then as Sharon mentioned there, it's difficult to speculate, I think, on the triple mechanism but based again on preclinical data as well as on competitor trials, where there are several GLP-1 glucagon trials, for example. And also there are CagriSema, for example, GLP-1 amylin trials. So based on the data we see, both preclinically and clinically, we are anticipating a synergistic effect or additive effect on weight loss. But we still need the data, of course, to be certain about this specific combination.

And let's move on. The next question is Emily Field at Barclays.

The first one is kind of just on AZD5004. I mean I know you guys have been very consistent in describing this as a true small molecule. But I was just wondering if you could help us understand the structural difference between this molecule and orforglipron, which Lilly, obviously, describes as a large -- small molecule and just confirming that you will be able to manufacture this at scale if it were to reapproval. And then I had a follow question also on the tolerability shown on Slide 17. Were the 5- , 10- and 30-milligram dose arms not titrated at all? And then what was the up titration schedule for the 50-milligram dose? And then if you can, will you be using different titration schedules in the Phase IIb across doses?

Okay. Great. Thank you for the close attention to the data. So your first question was about the structure. And of course, we have not disclosed the structure and will not for quite some time. Your second question related to that was, are we confident that we can manufacture this molecule? So we have successfully simplified the synthetic route. We continue to work on optimizing the synthetic route and we are successfully manufacturing this molecule. AstraZeneca is proud have a robust and resilient supply chain and we are confident that we will be able to produce the right amount of 5004 at the right time so that we're ensuring that patients have access to the medicine. Your second question was about the tolerability profile and the degree of titration that was employed in our Phase I study. The best person to answer that question is Elisabeth Bjork.

Thank you, Sharon. So you are correct, Emily, that 3 of the cohorts in the MAD study were without titration. That's the 5-, 10- and 30-milligram cohort. In the 50-milligram cohort, the patient started with 10 milligram for 1 week, then another week on 25 milligram. And then the last 2 weeks, they were on 50 milligram. We have not disclosed what the dosing strategy is going to be in the Phase IIb studies but we are exploring a broad range of not only doses but also titration strategies, including flat dosing. Back to you, Sharon.

Okay. Great. Our next question is from Rajesh Kumar at HSBC.

Two, if I may. First, just on the supply side. You -- can you give us a sense of how complicated the manufacturing could be? Are we talking about a significant incremental CapEx requirement, or is it the kind of CapEx which can be absorbed within the normal AstraZeneca budget if you were to scale it up at a future point? The second question is, I might be being a bit naive here or probably not following you completely. But is the differentiation, the combination therapy where you finally combine it in HSM CKD with SGLT2 to get -- and then, if I look at the strategy you have and if I look at the strategy of the leading players in terms of what they're developing, they are going for comorbidities. They are going for many of the indications you highlighted. So -- if you could help us simplify how your strategy is different from, say, orforglipron or CagriSema, that would be very helpful.

Sure. So let me start with a very concrete question that you asked first about supply. You asked how complex is the manufacturing. And I started to address that in our previous question. So at the time of in-licensing, this molecule had a fairly complex synthetic route. Together with our collaborators at Eccogene, we've done quite a bit of work to simplify that synthetic route and we continue to further optimize that. We are confident in our supply chain. We have a top-notch team here that's working on this. And I will point out that our team routinely maximizes all of our internal capabilities as well as our external network. And proof is in 1 concrete example of Farxiga, where we are annually producing 8 billion to 10 billion tablets of Farxiga to ensure that we have a robust supply. You asked specifically if we would need CapEx to be able to support this? And yes, we expect that we will and we will invest at the right time. Your second question was about how our strategy looks different from everybody else's. So I will go back to brass tacks and say that at AstraZeneca, we believe that we are uniquely well positioned to be leaders in the management of interrelated cardiometabolic disease, both with monotherapies but more specifically with combinations with molecules that are already in our portfolio. And understand that we are moving beyond short-term weight loss targets, not thinking only of obese patients but also thinking about how we are helping people who are living with overweight, who need a modest dose of GLP-1, combined with other molecules in our portfolio where we think titration may not be needed or may be minimal. And so we think that we have a unique opportunity to differentiate our approach through our fixed dose combinations in both patients who need to lose just a few pounds or kilos to address both their weight and their comorbidities to the overweight population as well as the obese population. And in that regard, I think AstraZeneca is unique, both in terms of our approach and our internal portfolio, combined with our weight management assets. And I will pause there, Ruud. Is there anything you'd like to add?

You have articulated very well. And Rajesh, to be absolutely clear, we are targeting both segments. So the obese segment, which clearly requires titration and time will tell what will be the dose, how far, how high can you go. And that's, of course, part of the Phase II study. And equally, I think the uniqueness is also, once again, in the fixed-dose combinations, the combinability of a relatively easy oral GLP-1 with other molecules in our pipeline. And I think that makes the whole story a very strong story in order to capture the different segments of obese and overweight patients.

And let me just layer on in addition to everything that Ruud mentioned, it's important to note that the assets that we're presenting at ObesityWeek have the potential to be competitive as monotherapies and our combination control is, I think, a true potential advantage to our portfolio. Our next question is from Seamus Fernandez at Guggenheim.

So just my questions are, first, can you clarify with regard to any potential liver function SAEs? I know you mentioned one but we don't know the threshold that you were considering and if it occurred in the SAD or the MAD study. So hoping you could just help us understand the percentage of patients or the number of patients that were 3x the upper limit of normal, 5x or 10x. And if all of those cases resolved and actually were treated through in whatever cases. So just trying to get a bit more detail on the liver function abnormalities that we're seeing with the molecule across the SAD and MAD doses and if it's one, great. Just love to know the threshold that you're talking about for that SAE. And then the second question, I just wanted to... Great. And then the second question is actually on the amylin and GLP [indiscernible] potential combination. Hoping to just get a better understanding of -- if it's known that those 2 assets are combinable in the same formulation? Or will it require multiple injections or perhaps a novel formulation? And then just incremental to that, the safety profile, how you're thinking about or the importance of having a particular radio of GLP-1 to glucagon would also be helpful to just get your views on that, particularly as it relates to the treatment of diabetic patients with MASH or diabetic patients with obesity?

Okay. Great. So let me start with your question about liver enzymes. And then I'm going to hand it over to my colleague, Regina, to add some detail around the triple combination with 6234 and 9550. So your question was about any evidence of liver toxicity in Phase I. So in our Phase I study, in the multiple ascending dose portion, there was one elevation of liver enzymes potentially attributable to drug. That was a patient who had transient liver enzyme elevation at the 10-milligram dose. The liver enzyme elevation spontaneously resolved even as the patient was dose escalated. With that, while I cannot share with you the exact numbers for the degree of liver enzyme elevations, I think the important story here is that there was nothing in the Phase I study that dissuaded us. Quite the opposite. We were encouraged to move forward rapidly into Phase IIb. The purpose of this study was to demonstrate safety, tolerability and target engagement and the evidence gives us all of the comfort we need to move forward to Phase II with 5004. Your second question was about the combinability of 6234 and 9550 as a co-formulated asset and also the additional implications for how we might use that in MASH and in obese patients. And with that, I will hand it to Regina, who is piloting this project.

Yes. So thank you for the question. So as I mentioned before, we are working on optimizing a co-formulation for 6234, 9550 to be able to have it in a single device at the time of Phase III start. The Phase IIb trial will be done with separate vials and syringe. And the Phase IIb trial, which we mentioned, we plan to start within about 6 months' time frame will be a dose-finding trial where we will look at the optimal combination of the concentration or the dose of amylin versus the dose of 9550. And with regards to the ratio between GLP-1 and glucagon, that ratio is fixed, is a fixed 5:1 ratio, 5x potency for GLP-1 versus glucagon because it's a dual active peptide. So it's a single peptide with activity on both, GLP-1 and glucagon. And we have substantial experience with this ratio from our cotadutide once-daily molecule and have performed studies such as continuous glucose monitoring to ensure that we have perfect glucose control, which, of course, is an issue if you go too high, for example, in glucagon. So we feel very confident with the right balance. And in relation to MASH, I can just mention that the primary focus now on that combination is for patients who are obese. But as we know that more than 70% of patients who are obese also have fatty liver disease or MASH, we see that this triple combination will have the ability to protect organs, including the liver and also help patients that live with MASH.

Okay. Great. And our next question is from Luisa Hector at Berenberg.

Sharon, I have a couple of questions, please. On the amylin monotherapy, you talked about use in incretin-intolerant patients. Does this mean you don't really see amylin mono as a first-line therapy in obesity? And then a bigger picture question, just thinking about the marketplace around the time that you anticipate your first launches. Can you comment on how many orals or how many injectables you think might be out there and essentially can AstraZeneca be within the first 3?

Okay. Thanks, Luisa, for those questions. So the first question you asked was about our messaging around AZD6234, the amylin agonist as monotherapy. We noted that this could be an option for patients who want an alternative mechanism or who, for whatever reason, are incretin intolerant. I don't think that, that message says that we don't view this as first-line therapy. The field is evolving and we understand that different tools may be best suited for different patients. We'll be able to offer patients the different opportunities that they need to best manage their weight and their interrelated comorbid disease. Your second question was, if I could broadly paraphrase, hey, it's going to be a competitive marketplace. There's a lot of molecules. And I will say that at this point, there are a lot of early players in the weight management space. We are excited about our capacity and our potential to move forward with the assets that we're presenting this week at ObesityWeek. This is AstraZeneca and we play to win. If we didn't think that we had a highly competitive molecule, we wouldn't be making the substantial investment that we need to progress these molecules forward into Phase IIb. You can see that we have moved forward quickly to advance both 5004 and 6234 into Phase II with 9550, quick to follow. That really speaks to our level of enthusiasm for this weight management portfolio and what we believe is our ability to be leaders with both monotherapy and combinations in this space. And we have one final question and that is from Richard Parkes at Exane.

I was hoping you might be able to help me with a couple of benchmarks. Obviously, it's the flat PK profile of the oral GLP-1 that it seems to be what you think would differentiate in terms of tolerability and the ability to reduce the titration schedule. So can you just help us to understand how it compares to other oral injectable drugs out there in terms of peak to trough? And what evidence there is that it's that peak to trough that correlates with the GI side effects with current drugs? And then secondly, on the long-acting amylin, can you help us by comparing its specificity for amylin versus calcitonin compared to other amylin targeting drugs in development. I'm thinking about cagrilintide given that it's likely to be the first to market.

Sure. So I'll step in with a brief overview and then ask some of my colleagues to comment. So with regards to a PK profile and how that relates to tolerability for 5004. In one moment, I'll ask Elisabeth to step in and comment on that. She's given it quite a bit of thought. And the second is the specificity for amylin over calcitonin. And I will note, as my colleague Regina did earlier, we specifically worked very hard to selectively design a molecule that would agonize amylin and not calcitonin. We think that's a very important feature in terms of the tolerability profile. So I will ask first Elisabeth to offer some color on PK and second, for Regina to speak further to our selectivity profile for amylin.

Thank you, Sharon. I'm not going to make any direct comparison on our PK profile and the others but it is true that we have a very flat PK profile and it is confirmed both in the SAD study and in the MAD trial. There is also substantial data supporting that the flat PK trial will translate into a better safety and tolerability profile. And I think the data that we have seen here today supports that thinking. But of course, this is early days. It's a Phase I trial and we will explore that further in the ongoing Phase IIb studies that we have up and running. Regina?

Yes. Thank you. Yes. So our amylin molecule has really been designed to be similar to the pramlintide, SYMLIN molecule but with a once-weekly dosing frequency. And the selectivity for amylin versus calcitonin is between 10 and 20-fold, depending on the assay you use. So since this is a lapidated peptide, it will vary a little bit with assay format. So 10- to 20-fold selective for amylin.

Okay. Thank you, Regina. So this wraps up our question-and-answer period today. And before we close the call, I'd just like to leave us with a few thoughts that I think summarize the data that we've explored today. The first is, I think that we are all aware. I mean the fact that we're on this call, that we're present here at ObesityWeek means that we are aware that the WHO has defined obesity as a public health emergency. By 2035, more than half of adults will be living obesity or overweight. And of those, 60% are dealing with comorbidities. AstraZeneca is uniquely well positioned to be leaders in the management of obesity and overweight treatment with our internal portfolio, allowing us to target the interrelated cardiovascular, renal and metabolic disease. And this week at San Antonio ObesityWeek, we have presented data on 3 molecules and a Phase I update for all 3. The Phase I data has provided us with the confidence and the evidence that we need to rapidly move forward into Phase II. So with that, I'll thank you for your attention and for joining the call and I'll bring this to a close.