My name is Julianne, and I'll be your conference facilitator today for the Amgen Conference Call from the American Diabetes Association's 85th scientific session. All lines have been placed on mute to prevent any background noise. There will be a question-and-answer session at the conclusion of the last speaker's prepared remarks. In order to ensure that everyone has a chance to participate, we would like to request that you limit yourself to asking one question during the Q&A session. To ask a question, please press star, then the number one on your telephone keypad. To withdraw your question, please press star one again. I would now like to introduce Justin Claeys, Vice President of Investor Relations. Mr. Claeys, you may now begin. Thank you, Julia nne, and thank you, everyone, for joining us today. Jay Bradner will start by sharing prepared remarks, and then be joined by Susan Sweeney and Murdo Gordon for a question-and-answer session. This call is accompanied by an investor presentation that is available on the investor section of our website. Please note that we will be making forward-looking statements and that such statements are qualified by a forward-looking statement contained in the investor presentation. Jay, over to you. Good afternoon, and welcome, everyone, to today's call. Here at the ADA Annual Meeting in Chicago, I'm reminded that we find ourselves at an exciting time in the history of obesity research and development, most importantly for patients. Today, I'm pleased to share the compelling clinical progress on MariTide, our investigational therapy for obesity, diabetes, and obesity-related conditions. Obesity is a prevalent and serious chronic disease that requires new medicines which are not only efficacious in clinical study but also effective in widespread clinical practice. Medicines such as MariTide, that are built for long-term use, are highly active, tolerable, convenient, and less complicated. In November, we presented key results from the phase II chronic weight management study and initial insights from the phase I low-dose initiation study. Let me start by summarizing four key attributes of MariTide that are therefore now well known. First, MariTide is the first monthly or even less frequent therapy for obesity. As shared today at the ADA and simultaneously published in the New England Journal of Medicine, monthly MariTide showed approximately up to 20% average weight loss without a weight loss plateau at 52 weeks. Second, MariTide demonstrated rapid and sustained improvement in cardiometabolic parameters, including hemoglobin A1c, blood pressure, and C-reactive protein. Third, MariTide is well tolerated at target doses, and initiation of therapy benefits from dose escalation like other members of the GLP-1 agonist class of medicines. Fourth, beyond fewer injections for patients, MariTide's simple and infrequent dosing is more compatible with adherent long-term use than weekly injectables. Today, we are excited to share new information and new insights deriving from the MariTide program. We will share underlying data from all arms of part one of the phase II chronic weight management study that demonstrates consistent efficacy across all doses and monthly schedules, as well as strong efficacy even from every other month dosing. Further, we share new data from the phase I low-dose initiation study that shows how low initial doses and additional escalation steps improve tolerability without compromising efficacy. Finally, today, for the first time, we share the design of our two open phase III studies of chronic weight management in people living with obesity or overweight with and without type II diabetes. Okay, let's talk about the MariTide molecule and why it's so unique. MariTide is a first of its kind, peptide antibody conjugate that is both a GLP-1 receptor agonist and a GIP receptor antagonist. With its unique antibody backbone, MariTide's long half-life delivers powerful, durable weight loss with predictable exposure and a monthly dosing profile that supports long-term use and benefit. Inhibition of the GIP receptor has been validated now by experiments conducted in three research environments: at Amgen, by several prominent academic laboratories, and through genetic experiments conducted by Mother Nature herself, all of which converge on the same finding that GIP pathway inhibition accentuates weight loss. Turning now to the design of the phase II study. Provided on slide 6 for your reference is the study design for part one of our phase II study. To briefly remind you, this double-blind, placebo-controlled, randomized clinical trial measured the impact of MariTide on weight loss in adults living with obesity or overweight with and without type II diabetes. This study of 592 adult patients is comprehensive, with 11 arms that characterized 52-week weight loss from three target doses of MariTide: 140, 280, and 420 milligrams. Two arms featured dose escalation arising from a 70-milligram starting dose. Efficacy was measured using two standard methods in our field: the efficacy estimate and the treatment policy estimate. Both measured weight loss efficacy at 52 weeks, and both were clinically meaningful and statistically significant. Today's presentation will report data using the efficacy estimate, consistent with recent presentations in the field. For those who are interested, we provide a more detailed description of each in this slide presentation as a reference. Let's explore the 52-week phase II efficacy of MariTide in chronic weight management. In adult subjects with obesity or overweight without type II diabetes, across all active treatment arms, MariTide delivered progressive durable weight loss up to approximately 20% at 52 weeks, with no plateau, indicating the potential for additional benefit beyond 52 weeks. Notable here is the smooth, consistent downward trend in the weight loss curve, important for patient experience and unique compared to some weekly therapies. In addition, nearly all participants, up to 98%, achieved a clinically meaningful weight reduction of at least 5%, a benchmark associated with improved cardiometabolic health. Let me take you to the next slide where we break out the 420 mg arms. This slide exclusively focuses on the four arms assessing a 420 mg target dose. Here again, we observe robust and consistent weight loss across all arms. Now, you've heard us many times indicate that dose escalation does not compromise MariTide's weight loss efficacy. Here we show that a 420 mg dose given with and without prior dose escalation produces comparable weight loss at 52 weeks without a plateau. In fact, the best-performing 420 mg monthly treatment arm featured dose escalation. We are also excited to share today that 420 mg given every other month delivered comparable weight loss to monthly dosing, highlighting the potential for a less frequent administration schedule without sacrificing clinical benefit. These results reinforce the flexibility of MariTide's dosing strategy and its promise as a differentiated, patient-friendly treatment option. These data were in adults with obesity and overweight without type II diabetes. Now let's look at MariTide's efficacy in a historically tougher-to-treat population, those living with obesity with type II diabetes. Yet again, across all tested doses, MariTide delivered smooth, consistent reductions in body weight up to approximately 17% at 52 weeks with no evidence of plateau, suggesting the potential for further weight loss with longer treatment. While these are phase II data, to our knowledge, a 17% reduction in body weight is the most substantial weight loss observed in this population to date. Further, nearly 99% of participants derived a clinically meaningful weight loss of more than 5%, again, a key threshold associated with improved outcomes. Taken together, both cohorts demonstrate clinically meaningful, statistically significant, and competitive weight loss at 52 weeks. These patients facing obesity with type II diabetes are at much higher risk for cardiovascular disease. Let's look at the impact of MariTide on their cardiovascular risk factors. In adults living with obesity with type II diabetes, MariTide delivered robust glycemic control and broad cardiometabolic benefits, demonstrating therapeutic potential well beyond weight loss. We observed a rapid, deep, and sustained reduction in hemoglobin A1c across all dose arms. At the 420 mg monthly dose, MariTide achieved an impressive 2.2% point reduction from baseline. Notably, half of the participants receiving this dose were restored to normal glycemia, defined as a hemoglobin A1c below 5.7%, a powerful marker of disease control. Beyond glucose lowering, MariTide improved a range of key cardiovascular and inflammatory biomarkers. As shown in the table on the right, here we observed a clinically meaningful 11 millimeters of mercury reduction in systolic blood pressure, a 28% decrease in triglycerides, and a compelling 72% reduction in HSCRP, a validated marker of systemic inflammation. Together, these findings suggest MariTide could become the first monthly or less frequent therapy for type II diabetes, addressing multiple drivers of comorbid cardiovascular disease. A monthly therapy has been a longstanding goal in the field of diabetes drug development. A dedicated phase II study of MariTide in patients with type 2 diabetes with and without obesity is currently ongoing. Let us now look at MariTide's effect on cardiometabolic parameters in adults living with obesity or overweight without type II diabetes. Even in patients without diabetes, MariTide improved glycemic control and delivered comparably broad cardiometabolic benefits. Across all dose arms, MariTide led to a consistent reduction in hemoglobin A1c, with an average absolute decrease of 0.4 percentage points from baseline. Importantly, among participants who entered the study with prediabetes, 70% to over 95% across the various dose arms achieved normal glycemia, defined as a hemoglobin A1c below 5.7%. On the right, we see MariTide's impact on cardiometabolic risk factors. In pooled 420 mg dose arms, we observe an 11 millimeters of mercury reduction in systolic blood pressure, a 19% reduction in triglycerides, and a 53% reduction in C-reactive protein, again, a key marker of systemic inflammation. These statistically significant improvements in validated disease-driving biomarkers extend the potential impact of MariTide beyond weight loss, underscoring its potential to improve long-term cardiovascular health in a broad patient population. Having now discussed MariTide's impressive efficacy, let's turn to tolerability. MariTide is a safe medicine that has proven increasingly well tolerated through early clinical development. Across multiple studies, MariTide's overall safety has remained consistent with the GLP-1 class, offering a well-characterized and familiar profile. The most frequent adverse events have been gastrointestinal in nature and are predominantly mild and short-lived, occurring early in the initiation of therapy. At all target doses, monthly MariTide is very well tolerated, likely owing to durable and steady drug exposure conferred by the antibody backbone. We have taken steps to improve the patient experience with the initiation of MariTide using low-starting doses and stepwise dose escalation. In the phase II study, even modest one-step dose escalation substantially reduced GI events. Indeed, only 8% of patients on dose escalation arms discontinued treatment due to GI-related events. In the dedicated phase I low-dose initiation study, we observed that lower-starting doses with two-step dose escalation cut vomiting nearly in half, and zero patients on low-dose arms discontinued treatment for any adverse events. While tolerated at target doses, let's look at the underlying data. After initiation of therapy, MariTide is very well tolerated at target dose, as you see reflected here over 52 weeks of treatment. Here we share vomiting events for patients receiving 420 milligrams monthly or 420 milligrams every other month, both without dose escalation. Each bar represents the proportion of participants who experienced new vomiting events within the indicated week. Here, without antecedent dose escalation, vomiting events peaked immediately following the first injection and then decline rapidly thereafter. Very few new events occurred beyond the first week of treatment. Note, there are no spikes with subsequent 420-milligram injections monthly or even every other month. At target dose, MariTide is very well tolerated. In this next slide, added on the right, we share results from one-step dose escalation arms, which meaningfully reduced GI events using a 70-milligram starting dose. GI events on both dose escalation arms were primarily observed with initial dosing. They were primarily mild and short-lived in nature. Based on these phase II findings, highly encouraged by the excellent tolerability at target dose, we became interested to improve upon tolerability at initiation of therapy. In parallel, we conducted a dedicated phase I low-dose initiation study to explore two-step dose escalation using even lower initial doses. As shown in the schema on slide 15, 121 patients living with obesity or overweight, here without type II diabetes, were randomized to one of three dose escalation schedules, two of which used two-step dose escalation with lower initial doses of 21 or 35 milligrams. In November, we referenced preliminary data from this study. Today, we present complete data from the primary analysis at day 43. Day 43 is relevant because by that point, all patients have completed dose escalation and have received a first target dose, which in this case is 350 milligrams. In the two arms that feature lower initial doses, we saw markedly improved tolerability, in particular with respect to GI symptoms of nausea and vomiting. As before, these symptoms were predominantly mild and short-lived. As shown on the next slide, we collected daily patient-level symptom data to comprehensively characterize the three arms. Lower initial doses of MariTide improved tolerability during the initiation of therapy. Shown here are the daily vomiting data for all 121 patients on study grouped by treatment assignment. Each row in these three boxes is an individual participant, and each day is accounted for by a square. Empty squares indicate days without any reported symptoms, and colored squares indicate a day where the symptom characterized as mild in green, moderate in yellow, severe in red. Note there's no red. The chart is organized left to right by dose escalation strategy, starting with group three on the left, which used the one-step dose escalation with a starting dose of 70 milligrams, akin to the phase II study. Then group two is shown with a two-step dose escalation using an initial dose of 35 milligrams. Finally, group one is displayed on the right, also with a two-step dose escalation featuring an even lower initial dose of 21 milligrams. Clear from these data is that dose escalation with lower initial doses improves MariTide's tolerability profile, as there are far fewer green squares with progressively lower initial doses. Group one emerges as the best-tolerated starting dose of 21 milligrams, with very few vomiting events that are mostly mild and short-lived, for example, a single event on a single day. Indeed, the vast majority of vomiting events are isolated incidents. Let's step back and reflect on the progressive learning journey we've taken to improve the GI tolerability of MariTide, particularly during the initiation of therapy. Here, in one figure, we bring together the path to improve GI tolerability. Graphed on the left are incident vomiting data from the phase II chronic weight management study, where MariTide was administered at fixed doses of 420, 280, and 140 milligrams without any dose escalation. As shown here, vomiting incidence was high across all groups, ranging from about 70% to nearly 90%. In the middle panel, we present the effect of a lower starting dose of 70 milligrams and one-step dose escalation, also studied in phase II, which meaningfully decreased GI symptoms and suggested that additional dose escalation could further improve tolerability. On the right, we present the most recent data from the phase I low-dose initiation study, which features even lower starting doses of 21 milligrams or 35 milligrams and two-step dose escalation, cutting incident vomiting by almost half to approximately 23-24%. Leading experts in our field link GI side effects of current GLP-1 agonist medicines to the abrupt changes in trough to peak blood concentrations after weekly injection. The stability of the antibody backbone of MariTide reduces the frequency of injection and produces steady, stable drug levels. For visual reference, we included the appendix pharmacokinetic data from the New England Journal of Medicine article that illustrates this. Taken together, the optimization of MariTide dosing has established excellent tolerability at target doses and a meaningful improvement in GI symptoms, nearly a threefold improvement with low initial doses and stepwise dose escalation. We next asked what the impact of lower initial dosing and two-step dose escalation would be on early weight loss efficacy. On this slide, we share today for the first time the weight loss data from the phase I low-dose initiation study. We observe strong initial weight loss with both two-step dose escalation regimens to a target dose of 350 milligrams. We see no obvious impact on effectiveness and weight loss efficacy with dose escalation, indicating that all doses employed are active doses of MariTide. Together, these results underscore a key insight: MariTide's tolerability can be improved through lower initial doses while maintaining meaningful and competitive weight reduction. Okay, zooming out, our MariTide dose escalation strategy has evolved through a disciplined, data-driven approach, culminating in a phase III dosing regimen designed to deliver an excellent patient experience and a competitive profile, delivering long-term adherence. This slide summarizes the learnings across the dose escalation journey and how these learnings directly informed our phase III approach. We've explored progressively lower starting doses, and patients have benefited from one-step and then two-step dose escalation. In phase III, we integrate and extend these findings with a 21 mg low-starting dose and now three-step dose escalation. We're confident in our phase III design and pleased to share it with you today. On this slide, we highlight the study design used in our two randomized, placebo-controlled phase III chronic weight management studies: one in adults with obesity or overweight without type II diabetes, and a second study in adults with obesity or overweight with type II diabetes. As shown, both studies include a 72-week treatment period, as patients on the phase II study were continuing to lose weight through to the end of the 52-week endpoint without plateau. Initiation of MariTide treatment features a three-step dose escalation over eight weeks from 21 mg to 35 mg to 70 mg before reaching their assigned target dose. Following dose escalation, participants receive one of three monthly target doses of 140, 210, or 350 mg. All three doses are expected to be efficacious, studied here comparatively to characterize a dose response anticipating patient needs. We selected monthly MariTide at 350 mg as the top target dose to deliver clinically meaningful and competitive efficacy, based upon the phase II results and pharmacologic modeling of both efficacy and exposure data collected to date. These two studies, initiated in March, are enrolling very well, with robust demand, indicative of significant interest in MariTide and continued widespread unmet need. We're continuing to advance the MariTide program on multiple fronts. Beyond chronic weight management, this year we are initiating three additional phase III studies to explore MariTide's potential in serious obesity-related conditions: atherosclerotic cardiovascular disease, heart failure, and obstructive sleep apnea. These studies reflect the broad potential of MariTide to impact not only obesity but also key cardiometabolic and respiratory comorbidities. Additionally, we have two ongoing studies, part two of our phase II chronic weight management study that explores an additional 52 weeks of MariTide and a dedicated phase II study in participants with type II diabetes. Together, this comprehensive clinical program will serve to further position MariTide as a broad standard of care for patients with obesity and related conditions. Let me close by summarizing why we believe MariTide has the potential to be an important medicine. MariTide is monthly, the most advanced obesity treatment in development with monthly or less frequent dosing. Efficacy is strong. With approximately 20% weight loss at 52 weeks without a plateau and with clinically meaningful improvement in cardiometabolic parameters, including hemoglobin A1c, MariTide has the potential to transform the treatment of obesity, type II diabetes, and other obesity-related conditions. MariTide is safe and increasingly well tolerated with dose escalation. We've significantly improved GI tolerability without compromising weight loss efficacy. The phase III program is underway, well-informed by clinical data and now featuring three-step dose escalation to well-tolerated target doses. In sum, MariTide is positioned as a potentially transformative therapy, not only for achieving weight loss but for enabling sustainable, long-term health improvement for people living with obesity and related conditions. Thank you for your time and your interest in the MariTide program. We look forward to continuing to share our progress with you. Let's now turn to Q&A. Thank you, Jay. Julia nne. Can we have our first question, please? Thank you. If you would like to ask a question, please press star followed by one on your telephone keypad. If for any reason you would like to remove that question, please press star followed by one. Again, to ask a question, press star one. Our first question comes from Salveen Richter from Goldman Sachs. Please go ahead. Your line is open. Good afternoon. Thank you for taking my question. With regard to the phase III trial design here, could you speak to the confidence that you have enough information at this point to run this dose escalation portion to manage the vomiting and nausea? And I guess maybe to that point, you know, with the eight-week three-step dose escalation study, why not extend that period or add more doses to the intermediate aspect of that titration arm? Thank you. Salveen, thanks for the question and the interest in the phase III program. I'll ask Jay to comment on that. Yeah, thanks, Salveen. We're very confident in the design of the phase III study that starts low at 21 mg and progresses through three steps of dose escalation. MariTide is just different than weekly injectable peptides as a monoclonal antibody. Dose escalation is more smooth, more steady. As we just shared, the phase II and phase I studies perfectly instructed on the value of lower initial starting doses and additional steps of dose escalation. Two-step dose escalation had a meaningful improvement akin to a typical GLP-1 profile. As we showed on that heat map, low starting doses of 21 mg were just extremely well tolerated. Three-step dose escalation over eight weeks will deliver an even more competitive profile. Thank you, Jay. Thanks, Salveen. Julianne next question, please. Thank you, Salveen. Our next question comes from Courtney Breen from Bernstein. Please go ahead. Your line is open. Courtney? Courtney, we can't hear your question. You might be on mute. Okay. Juli nne, maybe the next question? Certainly, our next question comes from Michael Yee from Jefferies. Please go ahead. Your line is open. Hey, good afternoon, and thank you for the question. Two parts. One is, in your heat map, I believe that your data there is clearly showing that a two-step significantly reduces vomiting. And so my understanding is that three-step would significantly lower that even more. Can you confirm that understanding based on the heat map there that you show? And if they do that, wouldn't efficacy get better because you're staying on the drug? And therefore, in the upcoming data in November, you would expect efficacy to further improve beyond a year? Thanks, Michael. Jay, two parts of the question. Heat map and the two-step, would you expect improvement on the three-step? And does that lead to better efficacy given that people will be more adherent and will be able to continue on therapy? Yeah, I'm happy to speak to how we arrived at three-step dose escalation from the two two-step dose escalations in the phase 1 low-dose initiation study. From 21 mg, where we saw only 2.4% incident vomiting, there was an increase in vomiting stepping up to 70. I mean, it was small, but it was apparent. When we stepped from 35 to 70, that change was lower. And so it's quite sensible that proceeding from 21 through 35 to 70 can produce an even better patient experience, and we believe that we will significantly reduce incident nausea and vomiting. Can this read through to better efficacy on the drug? It's always hard to compare phase II and phase III data, though some of that's going on right now. We do believe that by improving the initiation of drug experience, this will lead to better persistence on the drug, better adherence on the drug, and that this great profile that we saw on the heat map with two-step dose escalation will only improve in phase III clinical investigation. Thank you, Jay. Thank you, Michael. Julia nne, next question, please. Thank you, Michael. Our next question comes from Yaron Werber from TD Cowen. Please go ahead. Your line is open. Yeah, thank you. I thought maybe also a quick two-part question. We just hosted an event, and one of the things they were talking about is whether patients, because the potency loses weight too quickly, it's important for them to have an option to fall back to another dose. Can you confirm in the study, if a patient's losing weight too fast, can they dose reduce and how that would work? Secondly, just confirm that all doses are going to be an autoinjector in the phase III. Thank you. All right. Thank you, Yaron. Jay, you want to address the first question? Susan, perhaps I can have you answer the question about the availability. Jay. Yeah, Yaron, thanks for the question. You know, it is a concern in the field that patients can lose weight too abruptly on these medicines. I made mention during the presentation, the shape of this efficacy curve has proven quite interesting and exciting to investigators that we've met with here at the ADA meeting in Chicago. This gradual, steady, consistent decline in weight is attractive from a clinical management standpoint. On this trial, should patients develop adverse events related to the medicine, there is built into the study a defined flexibility to adapt dosing along the way. Yeah, I think, as you said, Jay, the differentiation here should be very strong in our dose escalation and in the tolerability of the product at target dose in the chronic phase of management. While allowing for it, I think we'll see good tolerability. Susan, on the autoinjector? Correct. On the autoinjector, in the phase III trial, we are initiating the trial with prefilled syringes, but we'll be in the course of the trial having patients use a handheld single injection, single chamber, patient-friendly pen, which we expect to bring to market. Thank you. Thanks, Yaron. Julianne, next question, please. Thank you, Yaron. Our next question comes from Terence Flynn from Morgan Stanley. Please go ahead. Your line is open. Hi, thanks so much for taking the questions. Maybe two for me. The first one was the discussant raised a point about evaluating the minimally effective dose in the trial. Just wondering if you think you've adequately answered that question. The second one has to do with discontinuations beyond AEs. Recognize the rate of DCs due to AEs is fairly low, but it looked like the broader rate of discontinuations was high. Just wondering if you can give any more insight there, and then anything you can do to improve upon that in phase III. Thank you. Thanks, Terence. I think both of those, Jay, would be for you. Yes, in phase III clinical investigation, in particular for medicines beyond oncology, it's very important to establish dose response in clinical investigation. We feel very confident in the target doses that we've selected in 140, 210, and 350 mg. We learned in the study of patients with obesity or overweight with type II diabetes that doses above 280 mg would be required to see full efficacy and benefit. On a larger phase III clinical trial, in particular with a longer follow-up to 72 weeks, we are confident that these medicines will exhibit dose response behavior, and the pharmacologic and pharmacokinetic data strongly support a dose-dependent exposure to the medicine. This is something that we and the regulators firmly agree on. Great. The second part of that question, Jay, was discontinuation beyond the GIAs in the trial. Yeah, we expect the discontinuation rate to markedly improve as we enter phase III clinical investigation, both because of improved tolerability with three-step dose escalation arising from lower doses, as well as the phase III has more flexibility of dosing than we permitted in the phase II clinical trial. Thank you, Jay. Thank you, Terence. Julia nne, next question, please. Thank you, Terence. Our next question comes from Trung Huynh from UBS. Please go ahead. Your line is open. Hi, guys. Thanks for taking my question. I thought the discussant was quite critical of the data you presented. He brought up adverse profile of discontinuation rates, vomiting, and then even aspects of U.S.A.'s food design. What were your thoughts on his presentation? He's just wanted that picky. Okay, thank you. Jay, over to you for that, please. Yeah, thanks for the question. You know, from our standpoint, the session here at the ADA was brilliant. I so enjoyed the reflections from those investigators closest to this research. Here in Chicago, we've met with dozens of thought leaders who see MariTide as truly differentiated, offering simplicity and convenience that they haven't seen before in this field, and different than the thinly differentiated weekly injectables that are rising up. This medicine is going to help so many people. Thank you, Jay. Julia nne, next question, please. Thank you, Trung. Our next question comes from Evan Seigerman from BMO Capital Markets. Please go ahead. Your line is open. Hi, guys. Thank you so much for taking my question. You know, as we think about kind of the future of MariTide beyond induction therapy, would you ever consider a trial where you look at MariTide as a maintenance therapy for some of the commercially available GLP-1s? Kind of what could that look like? Thank you very much. Yeah, it's a question that we receive quite frequently, Evan. Thank you for your interest in that. Jay, perhaps you could comment, and then Susan, maybe you could add. Yeah, just like Murdo just said, we're getting this question about MariTide quite a bit, which we take as a sign of interest and expectation that people will want to be on this medicine. In order to fully characterize MariTide in the way that you asked, we first need to understand MariTide in a maintenance setting after some degree of weight loss. Indeed, we have an open maintenance study right now. Part two of the phase II clinical trial assesses an additional 52 weeks of MariTide therapy offered to patients on part one of the trial who achieved 15% or more body weight loss. From this study, we're going to have a chance to understand MariTide at lower doses for maintenance, at even quarterly schedules of 420 mg. This study will give us some guidance as to what maintenance might look like. That's maintenance after MariTide dosing. Your question also alludes to the possibility of switching to MariTide from other medicines. We're developing MariTide to be upfront therapy and maintenance therapy. In the fullness of time, it will be really important for us to provide guidance to prescribers and to patients how to safely transition off weekly injectable therapy onto a more convenient, simple, and sustained MariTide therapy. We'll have more to say about that in the near future. Jay, I've heard at this meeting, and this is really, I think, where you can comment, Susan, is there does appear to be an unmet need in the market where patients on weekly GLP-1s, not just for convenience reasons, but perhaps even tolerability reasons, may want to switch. So perhaps you could comment on that. Yeah, Murdo, to begin with, again, I think monthly MariTide is a great option for patients that are initiating therapy, but certainly, particularly as we see the part two of the phase II study, as Jay said, with the different maintenance arms for maintenance for patients. Because today, what we do know is that for the number of patients that are treated today, which 90% of patients in the market are not treated, the 10% that are 10% or less that are treated, about 50% of them go off therapy within one year. Exploring this both in the part two is going to be part of our plan, but we'll also be looking at other options. Thanks, Susan. And thanks for a very topical question there, Evan. Julia nne, next question, please. Thank you, Evan. Our next question comes from David Amsellem from Piper Sandler. Please go ahead. Your line is open. Thanks. I have a commercialization-related question here. You've got, in practice, most likely, it'll be multi-step dose escalation, and there'll be some degree of patient hand-holding. I guess my question here is, as you think about patients being managed through this journey, do you think that MariTide has the kind of profile that could gain significant traction among general practitioners, or do you think this will be a product that'll mostly be used by obesity specialists? In terms of that, how does this color or not color your thinking about the overall opportunity? Thank you. David, thanks for the question. Perhaps I can start and then ask Susan to speak specifically to MariTide. We have obviously been on a long journey in chronic cardiovascular care here at Amgen, ensuring that primary care physicians receive the education and experience that they need to be able to adequately treat their patients. We have done this with Repatha, and we continue to expand the prescribing of Repatha by primary care physicians. Roughly 50% of all Repatha prescriptions in the U.S. are generated by primary care doctors. It's absolutely our plan to make sure that we're educating both the specialists, the obesity specialists, the cardiologists, endocrinologists, and other specialties that focus on obesity, but also those important primary care physicians who have large numbers of patients who could benefit from MariTide. Susan, perhaps you could talk about what you've heard at this meeting in terms of the profile and how conducive it might be for primary care. Yeah, I do think that MariTide has, because of its unique profile, is going to be used by both specialists and primary care physicians. Specifically in primary care, the way that we've designed the phase III trial and how we think that MariTide works will have a very particular benefit to primary care physicians that have very busy offices, lots of patients that they're treating. We have an easier dose escalation process that's quite simple. And then after that, patients will be on monthly therapy, be able to get a prescription, be able to last for the remainder of that year, reset the prescription the following year, and be able to maintain their therapy. Thanks, Susan. Thanks for the question, David. Julianne, next question, please. Thank you, David. Our next question comes from Dave Risinger from Leerink Partners. Please go ahead. Your line is open. Thanks very much for hosting this session today. Considering how Slide 21 describes MariTide's second ongoing phase III study as a chronic weight management study in type II diabetes, does Amgen plan to seek an indication for weight loss in type II diabetic patients? Is that the planned indication, but not for the treatment of diabetes like tirzepatide is indicated for? Just to follow on, obviously, those are two different trials for two different indications, I believe. Is a single trial enough for approval in each of the indications you're seeking? Thanks very much. Thanks for the question, Dave. Jay, do you want to take that one? Yeah, no, thank you, Dave. For the chronic weight management indication, we need two separate studies. The FDA requires separately studying patients with obesity and overweight with diabetes and patients with obesity or overweight without diabetes. We intend to, and we are developing MariTide for patients with type II diabetes through a separate thread of clinical investigation. It is important that this is separate and that it begin with phase II because some patients with type II diabetes do not suffer from obesity or overweight. We need to characterize MariTide's activity and, importantly, safety in that cohort as well. Susan, maybe a reminder on the rest of the phase 3 program that we're also developing. Yeah, so that type II diabetes phase II trial is in progress right now, so we're moving that forward quickly. In addition to that, we're also initiating studies in cardiovascular disease with ASCVD, a heart failure study, as well as sleep apnea. Great. Thank you, Susan. Thank you, Jay. Thanks, Dave. Julia nne, next question, please. Thank you, Dave. Our next question comes from Umer Raffat from Evercore ISI. Please go ahead. Your line is open. Hi, guys. Thanks for taking my question. I have a rhetorical and a regular question, if I may. First, the rhetorical. I feel like Dr. Julio Rosenstock's on almost every company that I can think of on his disclosure slides, except Amgen. I was curious why that is. Secondly, on my more regular question, could you speak to any outliers in your low dose of the type II diabetes cohort where there was a 25% LDL elevation? Thank you very much. Thanks, Umer. We'll take the real question. Any comment on the outliers, potentially, Jay, in the type II diabetes study? If, Umer, you are referring to outliers in weight loss on the type II diabetes study, the chronic weight management study that had a cohort for type II diabetes patients. In these cascading plots, in that cohort, as with all cohorts, we see outliers with respect to weight loss. The performance by weight loss was quite consistent. Now, on the LDL side, the change in type II diabetes is also very consistent and really rarely, if ever, changed. Yeah, I know, Murdo. I would only add that if you want real LDL control, patients should be initiated with a PCSK9 like Repatha. Next question, please, Julianne. Thank you, Umer. Our next question comes from Chris Schott from JPMorgan. Please go ahead. Your line is open. Hi, this is Taylor Hanley on for Chris Schott. And thanks for taking our question. Just looking ahead, as we think about how the future obesity market could maybe fragment into different segments, Amgen clearly has a long-acting agent, but can you touch on how high of a priority it is for the company to build a portfolio of obesity assets and potentially play in these different market fragments? Thank you. Thank you, Taylor. Before we talk about the broader obesity portfolio, I would just remind you that we will have a large cardiovascular presence given Repatha and also our development program and our Lp(a) program with Olpasiran. Jay, perhaps you could comment on our obesity and metabolic portfolio. Yeah, thanks for the question and the interest. We've been in obesity research a long time. We didn't just show up in this meeting because it got hot and interesting. MariTide, you can tell from the sophistication of the molecule, is quite unique and belies an incredible amount of expertise that we enjoy in Amgen research. We have two clinical stage assets. Behind MariTide is AMG- 513, though we've not disclosed that mechanism of action as yet. It is progressing through phase I clinical investigation quite well and is an injectable therapy. Our preclinical portfolio is also strong, featuring both incretin as well as non-incretin mechanisms of action, injectable medicines, and some rising oral medicines. Please expect to see more from Amgen and our research portfolio in obesity. Thank you, Jay. We continue to build out that strategic cardiovascular and metabolic focus for the customer-facing organization, anticipating, of course, the Vesalius trial for Repatha in the second half of this year, where we will expand our primary care presence in the U.S. and around the world. Thank you, Taylor, for the question. Julianne, next question, please. Thank you, Taylor. Our next question comes from Matt Phipps from William Blair. Please go ahead. Your line is open. All right. Thanks for taking my questions. Since you want to go ahead and launch a cardiovascular outcome trial, I assume you'd only take one dose into that trial. Can you tell us which target dose you would? And then what influence do you think keeping patients in clinic for seven days after each treatment might have had on that phase one two-dose escalation study, just thinking about lower discontinuation rate, just maybe from patient compensation? Thank you. Yeah. So Matt, we're not providing details on cardiovascular outcomes trial design at this point. But Jay, perhaps you could comment on the phase one in clinic experience. Yeah. Matt, it's actually a pretty insightful question. In clinical investigation, we call that a potential ascertainment bias. We took the decision to be very thorough in our characterization of the side effects associated with MariTide so that we could, in a very short period of time, make really important decisions discriminating between doses. And then a higher event rate is actually very helpful to us from a decision-making standpoint. I suspect that using the MinVer reporting form as discussed today and asking patients every single day if they have nausea or vomiting led to a very sensitive surveillance and detection. We'll find out now that we're in phase three clinical investigation the true impact of these new dose escalation approaches. Thanks, Jay. Thank you, Matt. Julianne, next question, please. Thank you, Matt. Our next question comes from Courtney Breen from Bernstein. Please go ahead. Your line is open. Hi, everyone. I hope you can hear me now. We can hear you loud and clear. Thanks for getting back on, Courtney. Fantastic. I apologize for the issue before, and I also apologize if this question was asked due to my absence and getting back on. Just really quickly, as we think about the titration specifically, I think the differentiation to MariTide in many ways is the dose interval and the mechanism of action. It also feels like you're trying to differentiate on a relatively short titration for this product. Can you talk about why that is an important factor to you and why you haven't gone to a monthly sequence in this titration and perhaps extended it out over a longer period? I mean, we've seen a number of phase III that have extended that out to six months as well. I'd love to just hear those parameters and why you're really focused on that short titration period. Thanks, Courtney. That is a variation on a question that we have not yet had. I'll ask Jay to comment and provide that. No, thanks, Courtney. Thanks for recognizing that the dosing interval really is a major advance. We see how our companies are working to prepare their molecules for monthly dosing. Here we've shared today strong efficacy even with every other month dosing. You asked whether the eight-week dose escalation, which is shorter than in some cases the six-month period of dose escalation that some medicines in this class require, was selected based on differentiation. It really wasn't. It could be more simple and convenient for patients. We selected this particular sequence of doses and timing of doses based on the clinical experience of the phase II and phase I programs, as well as the different pharmacologic properties of an antibody. When you're given an injected peptide, you get a very high peak dose, and then it goes away. Then a very high peak dose, and it goes away. That sawtooth pattern, we believe, contributes to the inability to dose escalate more swiftly. When you give a dose of MariTide, as was shared today by our investigators in the ADA presentation, you see that this dose just hangs out with smooth exposure and that this affords us this eight-week path to dose escalation. Yeah. I think you were asking also about the monthly interval, Courtney. We are interested in continuing to explore less frequent options at target dose in our clinical program. That maintains a differentiation option for us and something that can help patients persist in adhering to medicine. Thank you, Courtney, for the question. Julianne. Thank you, Courtney. Our next question comes from James Shin from Deutsche Bank. Please go ahead. Your line is open. Thank you for the question. Two from me. Is 120 mg still on the table for any of the longer intervals? Number two, has immunogenicity been commenced for the antibody component of MariTide? Thank you. Thank you, James. Jay, do you want to take those two? Sure. Thanks, James. We see no immunogenicity challenge with MariTide, having now treated almost 700 patients. We are quite pleased with the performance of MariTide as a protein peptide antibody conjugate medicine, 420 mg, by our data and our pharma-cometric modeling, does not present itself to be required as a dose to deliver competitive and clinically meaningful efficacy. Rather, 350 mg is optimal for this medicine. I suppose, as you asked, 420 mg is always still on the table. We have a clinical experience with it. It was quite active and well tolerated. We are not carrying 420 mg into the phase III program for chronic weight management. Thanks, Jay. Thank you, James. Julianne, next question, please. Thank you, James. Our next question comes from Gary Nachman from Raymond James. Please go ahead. Your line is open. Hey, guys. This is Denis Reznik on for Gary Nachman. Thanks for taking the question. Can you just remind us as to what percentage of eligible patients rolled over into the MariTide phase two, part two? And then if you're seeing any blinded dropouts or any unexpected safety concerns there in the part two? Thank you. Yeah. So Jay, the part two of the phase II had a 15% weight loss eligibility. What percentage of patients rolled over? Yeah, 94% of patients rolled over from part one to part two, indicating that when we invited those in the achieved 15%, as you said, Murdo, 94% signed up to have a chance of getting another year of MariTide. Thank you. Thanks for the question. Julianne? Our next question comes from Mohit Bansal from Wells Fargo. Please go ahead. Your line is open. Hi. Thank you very much for taking my question. I think I just want to further build upon Courtney's question. Since you said that the drug hangs around for a while, why not dose titrate up every four weeks versus every two weeks in the beginning just to make it even more simple, given that it is a monthly drug? Wouldn't it introduce some additional complexity here? Thank you. Thanks for the question, Mohit. Similar question to Courtney's, Jay, four-week versus two-week interval in the dose escalation. Yes, thanks, Mohit. We surely thought about that. If that appeared to be required from the clinical data or the pharmacokinetic modeling, we would surely have undertaken this. These are active doses of the medicine. They wouldn't serve to delay the efficacy derived from MariTide. When we look at the incident, nausea and vomiting and other adverse events, I mean, there are very few of them. They're mild in nature. They tend to drop off after a couple of days after the medicine is given. The clinical experience and pharmacokinetic modeling strongly supports the mode of dose escalation that we've pursued. Yeah, I think it's important also, Mohit, to observe that in the two-step dose escalation employed in the phase I, we're already approaching the same kind of tolerability profile that semaglutide has been able to establish in the market. We feel quite good about the three-step dose escalation that we've taken into the phase III and the interval within it. Thank you for the question. Julianne. Thank you, Mohit. Our next question comes from Kripa Devarakonda from Truist Securities. Please go ahead. Your line is open. Hey, guys. Thank you so much for taking my question. Regarding the MariTide once every other month regimen, can you talk about the AE profile of patients who were treated with this regimen? Was there any difference between the reduction in AEs with each successive dose? I know you said your weekly data that you presented suggests that the first week after you give the dose is the worst. Is it possible to be a little bit more granular about the occurrence of these events? Thank you. Thanks for the question. Jay, t wo questions there. Each successive dose in the every other month. Then more detail on the weekly. I think that the heat map is probably the right reference on that one. Yeah. Thanks for the question. Look, the efficacy that we observed with every other month dosing is very exciting. We're studying every 12-week or quarterly dosing maintenance. When we collect these data, we'll sit back and think about alternate and more flexible dosing schedules. You asked about adverse events. Indeed, the adverse events and dropout rate on every other month dosing are higher than on other arms. The adverse events concentrate, however, to that first dose. In the every other month cohort, there was no dose escalation. I wouldn't take any learnings out of those comparisons. You also asked about successive doses. I found this very interesting that after eight weeks, two months after receiving a dose of MariTide at 420 mg, getting that second dose did not trigger patients to have a big spike in gastrointestinal adverse events, suggesting that this tolerization to the GLP-1 mechanism can last a really long time with a medicine like MariTide. I really do not have anything more granular than daily vomiting data like we showed today. But do please spend some time in the supplemental files from the New England Journal of Medicine paper where there are some additional insights. Thank you, Jay. Thanks for the question. Julianne next question, please. Thank you, Kripa. Our next question comes from Tim Anderson from Bank of America. Please go ahead. Your line is open. Hi. Thank you. I have kind of a three-part question on cardiovascular outcomes trial. By the time you guys launch, there will be several products entrenched in the market. Will you be required to do an active comparator trial for your cardiovascular outcomes study? That is the first question. Second question is the timeframe for completing such a study. And then last question is, will a cardiovascular outcomes trial be required for approval? Yeah. We had a question on the cardiovascular outcomes trial earlier. We are not at liberty to describe the protocol and trial design on that at this point. More to follow there. Thank you for the interest. It is clearly an important area that we intend to evaluate as an opportunity. Obviously, there is a lot of overlap with the rest of the portfolio that we have in cardiovascular. That is something that we will look into and we will get back to you. Thank you. Yeah. The only other thing to add to that, Murdo, is that for the chronic weight management, our first indication, that trial is not required for approval. Yeah. Thank you for that. Next question, please, Julianne. Thank you, Tim. Our next question comes from Jeff Meacham from Citi. Please go ahead. Your line is open. Hey, guys. This is Jeremy[guess] from Jeff Meacham. Thanks for taking the question. I just wanted to ask more along the lines of the titration that things have been leading to. The three target doses, 140, 210, 350, is there any reason why for the two higher target doses, you're not titrating through those lower ones? Hey, Jeremy. Sorry about the suggestion here. Hi. It's very hard to hear the question. Could you just restate it and maybe just try speaking right into the mic? That would help us out a lot. Thank you. Hi. Yeah. Can you hear me better now? Yeah. Perfect. Thank you. Great. Yeah. Sorry about that. My question is asking about the target dosing and dose titration. Any reason why you guys aren't going to titrate from 70 to 140 to 210 up to 350? It just seems like doing it that way might be a little bit better for efficacy and safety tolerability. Thanks. Yeah. I think the question is, from 70 to target dose, why are we not stepping through the other target doses to get to 350? Jay? Yeah. Thanks. Two reflections there. First is in the phase two, we had two dose escalation arms, as I showed a moment ago. One of them was a step-through approach after 70 mg. Actually, there was no benefit either at the moment of dosing of the step-through dose or in totality of adverse events when comparing the one-step dose to the step-through doses. Additionally, when you start to dissect the timing of symptoms from the phase one low-dose initiation study, once hitting a target dose of 70 mg, patients are pretty well tolerating MariTide therapy. Then receiving 350 mg is feasible. We are not stepping through on this trial because it does not appear to be required. Thanks, Jay. Thanks for the question, Jeremy. Last question, Julianne. Unfortunately, we are up on time here. Let's close out with another one. Thank you. Our last question comes from Luca Issi from RBC Capital Markets. Please go ahead. Your line is open. Thanks so much for taking my question and squeezing me. Maybe, Jay, one more if I can circle back on the dose. Obviously, we've seen very impressive reduction in weight loss here. When you look at the phase, the top dose there was obviously 420 mg. While in phase III, you're going to do 140, 210, 350 when you look obviously beyond escalation, which are obviously material 20 that you did in phase II. I guess the question is, what gives you confidence such dose will be both good enough to mitigate the toxicity and at the same time still retain the same impressive efficacy that you've seen in phase II? Any comment there? Much appreciated. Thanks so much. Luca, I believe your question is, with the dose selection in the phase III, do we feel we'll be able to hit the same target efficacy that we were able to establish in the phase II? I think you asked about tolerability as well. That's correct. Okay. Yeah. No, thanks for the question. Indeed, we have pivoted from a top dose of 420 mg from the phase II study to a top dose of 350 milligrams in phase three. This is not to mitigate toxicity. Any gastrointestinal adverse event improvement will derive from dose escalation. Actually, at target doses in the phase two study, all three target doses were very well tolerated at cruise altitude at the steady state of monthly dosing. 350 milligrams by the clinical data we've collected today and by our pharmacologic modeling will be adequate to deliver clinically meaningful, statistically significant, and competitive weight loss. Jay, Susan, thank you very much. Thank you, everyone, for taking the time on the call today. I believe Jay mentioned it already, but I would encourage you to take a look at the manuscript in the New England Journal of Medicine. It's an extremely well-written and clear paper with a very comprehensive supplement to that article where you can probably see even more detail on the questions that were raised today on the call. We look forward to telling you more about the Amgen portfolio as we move forward. Thank you again. This concludes our Amgen conference call from the American Diabetes Association 85th scientific session. You may now disconnect.