Hello and welcome. My name is Alex, and I'll be your conference facilitator today for the Amgen Analyst and Investor Conference Call from the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease Conference. 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 and the number one on your telephone keypad. To withdraw your question, please press star and the number two key. I would now like to introduce David Reese, Executive Vice President of Research and Development. Dr. Rees, you may now begin. Thanks, Alex, and good morning, everyone. Thanks for joining us for an update on the AMG 133 program in obesity and allied disorders. These are our review of data just presented at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease. Next slide, please. Here's our standard safe harbor disclaimer, and I should note that these slides are up on our website now for those who wish to follow along. Next slide, please. In terms of today's agenda, I will provide a brief introduction to our strategy in obesity and allied disorders, following which Narimon, the head of our Cardiometabolic Group in clinical development, global clinical development, will provide a focused review of the AMG 133 data just presented at the congress over this weekend, and then we should have plenty of time for questions and answers. Next slide, please. As you all know, obesity is one of the major public health challenges of the 21st century. It is a complex, very heterogeneous disease, with underlying complex biology. There is a strong genetic component that is rooted in evolutionary pathways, fixed into human evolution. This heterogeneity of the disease leads to diverse outcomes in different patient populations, cardiovascular disease, metabolic syndrome and diabetes, various respiratory disorders, mechanical complications, to name just a few. To tackle this disorder, we have taken an integrated structured approach at Amgen. Next slide, please. This approach first is focused on human genetics and our large capabilities in human data to understand patient populations, the heterogeneity of the disease on a biology level, and to understand how we may actually arrive at a precision medicine where we match treatments to the underlying drivers of individual patients with obesity. As always, we take a biology first, modality next approach, and anticipate over time both large molecules, small molecules, RNA-based therapeutics, and perhaps other approaches. We are developing a multi-asset portfolio with both incretin and non-incretin based approaches. Initially, we'll talk more about that as we get into 2023 and over the course of that year. All of this, again, is powered on insights derived from genetics and our human data capabilities. Finally, given the complexity of the disease and the multiplicity of potential targets, we believe multi-specific molecules, will be important, in the evolution of this field. A prime example of that is AMG 133, which really illustrates all of the principles that I've laid out on this slide. With that, I'd like to turn things over to Narimon, who will now go through a detailed review of the AMG 133 data just presented, and then we'll open things up for questions. Narimon. Thank you, Dave. If we may advance to the next slide, please. I'm pleased to share the highlights of the AMG 133 data recently presented at the WCIRDC Congress. Next slide, please. Recall that AMG 133 is an investigational therapy being evaluated as a treatment for obesity and obesity-related illnesses. Among its distinguishing characteristics is that it's an antibody-peptide conjugate. It has an antibody backbone that blocks the GIP receptor, and bound to this backbone are two GLP-1 peptides that stimulate or agonize the GLP-1 receptor. The molecule has been engineered to simultaneously inhibit one metabolic pathway, the GIP pathway, whilst stimulating the other, the GLP pathway. The rationale for this design is based on, one, the human genetic data that strongly suggests that reduced GIP receptor activity is associated with reduced body weight. And two, the existing body of knowledge and important clinical experience with GLP-1 agonists. Our preclinical experience suggested synergistic effects with this approach on weight loss, that led to the molecule being tested in phase 1. Next slide, please. This phase 1 study was designed as a randomized, double-blind, placebo-controlled trial with both single-dose cohorts as well as multiple dose cohorts. Patients that participated in the study were obese but did not have other medical conditions. The objectives of this trial were typical of phase 1 first in human studies. That is, they were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics, for example, weight reduction of AMG 133. Next slide, please. This is an illustration of the study schema with the single dose cohorts shown on the left. Each single dose cohort enrolled approximately eight patients, six of which would have been allocated to AMG 133 and two to placebo per cohort. Patients received a total of one subcutaneous administration in these separate cohorts. On the right, you see the multiple dose cohorts tested that similarly had subjects randomized to either AMG 133 or placebo. Patients enrolled in these cohorts received a total of 3 subcutaneous administrations, each 4 weeks apart, with the last administration just before day 60. As stated in the footnote here, for the multiple ascending dose cohorts, we have 3 other cohorts where the analysis is ongoing. 2 of them were designed to assess potential dose escalation strategies and helped inform part of our planned phase 2 dose ranging trial. We also had 1 cohort designed to provide experience with digital tools that assess things like patient activity and eating behavior. As I mentioned, analyses of these cohorts is still ongoing. Next slide, please. Baseline characteristics of the patients are shown here. Notably, the BMI on average ranged from 32-34 in these cohorts, and the Hemoglobin A1Cs, as you'd expect for an obese but otherwise healthy population, were in a normal range. Next slide, please. Okay, here are the results from our single ascending dose cohorts with AMG 133. Shown here on the left is the mean percent body weight change observed the single ascending dose cohorts. Again, patients enrolled in these cohorts received only one administration of study drug. Dose dependent and durable reductions in weight were observed, as you can see, across the variety of doses administered and persisted for many weeks after the one administration. On the right, we show the pharmacokinetic data from these cohorts. The key takeaway here is that the molecules well behave with predictable dose dependent plasma concentrations and an extended half-life, which ranges from 14 to 25 days and is typical of molecules in an antibody-based type therapy. Next slide, please. All right, here we have the mean% body weight changes seen in the multiple ascending dose cohorts, where patients received a total of 3 subcutaneous dosing administrations each 4 weeks apart, with the last administration, as you can see in that red arrow, just before day 60. Again, in these cohorts, we see dose dependent and durable weight reduction. This ranged from approximately 7% weight reduction at day 85 for the 140 milligram cohort and up to approximately 14.5% reduction at day 85 for the 420 milligram cohort. Notably, no plateau effect was observed within the dosing period of 90 days, with effects persisting for several months after the last administration of drug. We continue to be encouraged by the mean percent changes in body weight, pace of weight reduction, and the duration of the weight reduction observed. Next slide, please. With regards to safety and tolerability in this study, we have not observed any notable safety concern, with most treatment emerging adverse events having been mild and transient, the majority of which were associated with the initial administration of drug. That is the first administration. The types of treatment emerging adverse events observed were generally GI related, consistent with the GLP-1 based therapies that have been approved. Next slide, please. To conclude, we've tested a novel approach that is to block the GIP receptor pathway while stimulating the GLP receptor pathway with AMG 133. The results of this phase 1 study suggest that extended dosing intervals, such as every 4 weeks, are viable for further testing. We remain encouraged by the weight reduction observed, the pace of the weight reduction, and the durability of the effect. The safety assessments have been supportive of further clinical testing in phase 2, which we are pursuing and plan to initiate in early 2023. This concludes this part of the session today, and I'll hand it back to you, Dave. Thanks, Narimon. Alex, why don't we go ahead and open up the Q&A session. Can you remind our attendees, how to ask a question? Thank you. If you'd like to ask a question, please press star followed by 1 on your telephone keypad. If for any reason you would like to remove that question, please press star followed by 2. Again, to ask a question, press star 1. Our first question for today comes from Umer Raffat from Evercore. Umer, you may proceed. Good morning, guys. Thanks for taking my question. Very interesting data set and maybe three quick ones if I may. First, If someone asked me what's the exact rate of nausea and vomiting, I don't know if I know that answer or maybe I missed it in the poster, but I don't recall seeing that anywhere. If you could just help us clarify that, number one, especially in the multi ascending dose. Second, have you, and I realize there's a lot of variability in small numbers, but have you been able to identify a Cmin which enables you to preserve the weight loss? That could be very relevant to your dosing plans. Finally, do you think, the more I look at this data, the more I wonder, do you think a quarterly dosing is possible on a maintenance basis once you're into the induction? Thank you. Great. Thanks, Umar. Good questions, all of them. I'll ask Narimon to comment on the rate of nausea and vomiting, as well as the, you know, the Cmin issue. I think that's important. In terms of potential quarterly dosing, yes, certainly one of the things we're thinking about is more extended dosing intervals in a maintenance setting, for example. Given the pharmacokinetics that we've observed and given the half-life antibody, like, half-life of the molecule, that opens up, I think, a lot of optionality, and we'll be exploring different dosing regimens in phase two to address that question. Narimon, do you wanna talk about the rate in particular in the MAD portion of the trial of some of the adverse events and the question around the Cmin? Sure thing. Thanks, Dave, thanks for the question. In fact, if I may refer to the poster table 2B on safety, we have the number of treatment emergent adverse events listed there, in general and qualitatively listed as mild, moderate, and severe. For those patients at the higher doses, 280, 420, I would say almost all of them in a mild range were nausea and vomiting, GI related. Now, with regards to the Cmin and concept for identifying what is minimally required to preserve weight loss, we certainly have preliminary information from our phase 1 experience, we're gonna continue to follow the pharmacokinetics here in phase 2, I think we'll need to really investigate that further in the study to come. Thank you. Thanks, Narimon. It's a good question, Umar, and that's something we will be addressing directly in subsequent studies. All right, Alex, next question. Thank you. Our next question is from Matthew Harrison of Morgan Stanley. Matthew, your line is now open. Please proceed. Great. Good morning. Thanks for taking the question. I was hoping you could just talk a little bit more broadly on the dosing strategy you're thinking about for phase two. In particular, are you looking at potentially a higher dose to have greater weight loss, or are you considering some of these things around dosing frequency as more of a focus for phase two? Thank you. Yeah. Thanks, Matt. Obviously, a very important question. Narimon will comment in a minute here. What I would say broadly is we're designing a very robust phase 2 trial, with, you know, different doses, and schedules, really to preserve optionality as we come out of phase 2 for further development of the molecule. You know, this is something I feel very strongly about. This will be a, you know, a pretty hefty phase 2 trial. Narimon, maybe you wanna provide additional color on the dosing strategy we're taking. Thanks, Dave. I think you summarized it well. Matt, in summary, I would say we want to be able to explore both in the phase II. We want to look at the full range of the magnitude of dose, we want to understand as deeply as we can the appropriate intervals of that dosing. I will say, you know, what we've elected to pursue thus far because our phase II study hasn't been finalized. In other words, it's been submitted to regulatory authorities, but we haven't gotten the final go-ahead, is the details will be on ClinicalTrials.gov when we do have that final protocol ready to share. The experience will be bracketed by what we've seen and tested in our phase I study in terms of the magnitude of the dose. From a frequency perspective, we feel quite comfortable with every four week fixed interval dosing. We'll plan to assess that in the phase 2. We will be looking at longer intervals of dosing, meaning less frequent as well, and also we will include some dose escalation strategies into the phase 2 to really understand, you know, the optimal experience for patients and providers. Thank you. Thanks. Next question, Alex. Thank you, Matthew. Our next question comes from the line of Michael Yee from Jefferies. Michael, your line is now open. Good morning. Thanks for the update, and thanks for this call. We had a two-part question, but they're related. Based on the human genetics or at least animal, tox data, what can you say about long-term safety of GIP antagonism, and specifically as it relates to what you would predict with diabetes effects, since I know there's no diabetes patients here. Just comment on what you would expect for HbA1c and whether you'll even look at diabetes patients and/or go after that population. Thank you. Thanks. I'll take the second part, Narimon can summarize some of our human genetics work, which has been quite extensive here and potential long-term safety, in particular related to the GIP receptor. In phase 2, we do plan on studying both patients with type 2 diabetes as well as those who are normoglycemic. We'll get a look at both of those populations. Narimon, do you wanna comment on the genetics? Absolutely. Thank you for the question. We've worked closely with our colleagues at deCODE genetics in understanding this question. you know, in over 500 different disease phenotypes that are included in their analyses and the many, you know, the hundreds of thousands of patients, if not more, that they include in their databases. In looking at the variety of GIPR variants, there have been no particular safety signals or concerns that have come out of that analysis. We feel quite comfortable with our approach in terms of antagonizing the GIP receptor, and, you know, we'll continue to do the standard monitoring for safety in our clinical trials to come. Thank you. Thanks. Great. Next question, Alex. Thank you. Thank you, Michael. The next question comes from the line of Jay Olson from Oppenheimer. Jay, you may proceed. Oh, hey, congrats on these early results. Thank you for the update. Given the innovative design of this conjugate, could you talk about the relative contribution of the GIP or antibody and the GLP-1 peptides to the substantial weight loss that you're showing in this study? How are you thinking about the other assets in your obesity portfolio beyond 133 in terms of any other targets or modalities you may consider? Thank you. Yeah, thanks, Jay. You know, let me just address briefly the second part of your question, and then I'll ask Narimon to comment, in particular on our preclinical data regarding the relative contributions of the GIP receptor and GLP-1. You know, as I mentioned, we're taking an approach rooted in genetics and human data. We expect both incretin based and non-incretin based therapies or targets. We are interested in particular in molecules that have orthogonal mechanisms of action to currently available therapies or novel mechanisms of action that may be complementary to existing therapies. Over the course of 2023, as I noted, you know, we'll start talking about some of those approaches as we get ready to move forward. You know, it's a pretty comprehensive approach, but the foundation here, is really our human genetics and human data work. Narimon, you wanna talk about the relative contribution of these two signaling pathways? Thanks, Dave. I would say that in summary, there are contributions from both, but the real power from this approach comes from having both happen at the same time. From our preclinical data, there was a synergistic effect observed in having both simultaneous antagonism of the GIP receptor with stimulation or agonism of the GLP-1 receptor. We believe both components of the way this molecule had been designed are important in the effects that we're observing. Thank you. Next question, Alex. Thank you. Thank you, Jay. Our next question comes from Salveen Richter of Goldman Sachs. Your line is now open. You may proceed. Good morning. Thanks for taking my questions. 2 for me here. What do you think the peak body percentage weight change would be if you were able to maintain the every 4-week dosing post the 60-day period? Secondly, apart from the potential benefit of less frequent dosing, you've spoken to differentiating by the population study, so looking at obesity associated with cardiac or metabolic disease, how do you study that in the phase 2? Yeah, thanks. Yeah, in terms of the potential peak reduction, you know, certainly at the higher dose there was no plateau observed. Obviously that's one of the key endpoints for the phase 2 trial, understanding just what that peak may be with prolonged dosing. You know, the durability that we're seeing also I think is quite important in this regard with a lack of relative rebound. One of the explanations for that may be a relative smoothing out of the peaks and troughs of exposure to the molecule that may occur with molecules that have require less frequent administration, for example, weekly. You know, Narimon, let me get you know, to comment, you know, on the second part in terms of additional indications. Obviously, as I mentioned earlier, Salveen, preserving optionality so that we may then attack, you know, tackle the specific indications going forward is one of the things we wanna see coming out of phase 2. Narimon. Thank you. Well, I want to just begin by saying that a phase 2 study in and of itself is not likely to be able to address all the questions with regards to a patient population as heterogeneous as obesity. It becomes very important to put that type of data in the context of broader data resources that we have available to us, like those that we work with decode genetics on. I would say the first point that would be useful to make is that we'll be looking at the phase 2 data in the context of broader datasets. The other piece that I think is important to consider is the depth of data that we'll be collecting in the phase 2. We won't just be looking at the anthropomorphic measures such as weight reduction, which are important, but also relatively high level with regards to understanding the mechanism of how AMG 133 works in particular. We'll have a variety of assessments, including deep phenotyping that we believe, and deep characterization that we believe will be important in getting biomarkers from these patients, et cetera. Again, putting it into the context of that larger patient population, data that we have access to. Thank you. Great. Thanks. Alex, next question. The next question comes from the line of Evan Seigerman from BMO Capital Markets. You may proceed. Hi, guys. Good morning, and thank you for the presentation of the data. A few from my perspective. I would love for you to talk about kind of the potential weight loss in terms of lean muscle versus adipose tissue. What are you seeing for AMG 133 so far? You know. Do you have any idea how fast too fast is it when it comes to weight loss? Any feedback from FDA kind of on this extended release approach? Thank you. Yeah. I, you know, I'll let Narimon address both of these questions. Obviously, the question about lean body weight versus changes in lean body weight versus changes in adipose mass are quite important. You know, phase 1, it, you know, is relatively small and hard to get a handle on that. You know, this is a very specific question going forward. You know, Narimon, if you can maybe tackle that as well as the second part of the question here. Sure thing. Thanks, Dave. At a high level, I think we could say what we expect are similar impacts as what one sees from the existing incretin class of medicines that have been put to market. You know, there are effects on both types of weight, lean and adiposity. In these patients in particular with high adiposity, high body mass index, you see a lot of the reduction happening in the reduction in fat mass. We haven't formally assessed that in our phase 1 data at this point. It is going to be limited given the small number of patients, so it'll be hard to be too definitive about what we observe. Importantly, we'll be looking at this question in the context of our phase 2 trial where we'll be making those assessments formally. There was a question that was asked with regards to have we received any feedback on whether there is such a thing as too fast a weight reduction. We haven't received that type of feedback. What I will say is, what we understand from our phase 1 study is that this pace of weight reduction that we observe seems to be well-tolerated and safe. We'll be continuing to monitor things in the context of our phase 2. Thank you. Great. Thanks. Alex, next question. Thank you. The next question comes from the line of Geoff Meacham from Bank of America. You may proceed. Hey, guys. Thanks so much for the question. Just had two quick ones. You guys, when you look at the weight rebound after the last administration, yeah, at the high and low dose, it looks like it did rebound and it took, you know, maybe a few months, the middle dose there, it didn't. Was there something unusual on that cohort? Any sort of common themes with there? I know the question's been asked on A1c at baseline, can you talk a little bit about, you know, how you guys are thinking about that, as that trend as a, maybe, an indicator of, you know, your plans to move into a formal, you know, diabetes indication and maybe what are the steps there? Thank you. Thanks, Jeff. I'll take the second part of that question then ask, Narimon to talk about the kinetics of weight rebound. You know, as we mentioned, these patients in phase 1 were normoglycemic, by definition, per protocol entry criteria. One wouldn't expect a very big change, if any at all, in Hemoglobin A1c. Consequently, again, we're going to be enrolling type 2 diabetes patients in the phase 2 trial, you know, specifically, and we'll of course be tracking all of the metabolic parameters that are typically followed in that population in the clinical trial setting. Narimon, do you wanna talk about the question regarding weight rebound? Sure. I'll speak to what I believe the question was oriented towards the multiple ascending dose cohorts that were looked at. Specifically with regards to the middle dose, 280 milligrams, where it looks like there was steady maintenance of weight over the dosing interval. I'm sorry, post-dosing interval. There was nothing in particular about those patients in terms of their characteristics that would lead one to believe that they had some known reason why their weight stayed relatively flat. I think it is important to remain humble about phase 1 data, given the small number of patients. You know, you do expect to see some variability. It might be that the apparent differences that we're seeing here between the cohorts is just due to that, the small numbers and variability that you would expect, rather than it being driven by a particular, foundational element or driver. Thank you. Great. Thanks. Next question, Alex. Thank you. The next question comes from the line of Colin Bristow from UBS. You may proceed. Hey, good morning, congrats on the data and appreciate you guys hosting this. Could you give us a little more detail on these three cohorts which are ongoing and yet to be disclosed? Can you tell us what doses are being tested, and anything else that would be helpful? When should we expect any disclosure on these cohorts? 'Cause I'm curious, do you need to wait for them to reach completion in order for you to move to phase 2? Just a housekeeping one, really just within the data on the MAD cohorts, there were two patients who were replaced. Could you just qualify what was happening there? Thank you. Yeah, sure. I'll ask Narimon to address both of these, both in terms of some of the specifics on the ongoing cohorts, which is, you know, is not slowing us down, in terms of phase 2, Colin, I will say that. In addition to the ongoing cohorts, that speak to the specifics of the replacement patients. Narimon. Thank you. You're spot on the completion of these additional cohorts is not slowing us down and progressing towards phase 2. In terms of the details on what those cohorts were, in particular, for those in the dose escalation, we have 2 low dose administrations at 70 milligrams that are administered 1 week apart, and then we go to the highest dose at 420 milligrams within that cohort afterwards, for 2 subsequent administrations, each 4 weeks apart. For the second one, we have, again, this time, 4 low dose administrations, each 1 week apart at 70 milligrams, then hitting that target high dose at 420 milligrams, again, given for 2 doses approximately 4 weeks apart. These patients, we were looking primarily at the dose escalation strategies that could work, that might make the experience for patients a bit easier if it would attenuate or change any of the mild nausea and vomiting symptoms that they may have had. They aren't intended to examine things like the weight reduction that we would expect from these doses as we've qualified and characterized in the earlier multiple ascending dose cohorts that we have studied. We do have one cohort also open that is assessing the use of digital tools. Those patients have completed their experience, but the analysis of these is ongoing. In terms of digital tools, we're talking about things like wearables that assess actigraphy, sleep quality, that also record their dietary habits. This is very exploratory in its nature. As an innovative company, we're interested in understanding the utility of these tools and how we may apply them in our trial experiences. We thought that would be a good thing to try out as well. There was a question asked about patients that had been replaced in the 420 milligram cohort, and I wanna be sure to address that question. For the two patients that were replaced, they were replaced because they had withdrawn from the study early on, so within the first month. In order to understand the full characteristics of the drug at the high dose, we need to maintain our specified cohort size. With two subjects having stopped their participation in the study, rather early, we needed to replace them with two other subjects. That's the rationale there, and we don't expect that that would have impacted the overall assessments that we have at the 420 milligram cohort. Thank you. Thanks. I mentioned that that's a very standard approach to phase I studies of this sort. All right, Alex, next question. Thank you. Our next question comes from Mohit Bansal from Wells Fargo. You may proceed. Great. Thanks for taking my question and thank you very much for sharing this data. Maybe, mechanistically, when you look at the data, and based on your preclinical models, what do you think... Do you think there could be any difference if with GIPR antagonism versus agonism in terms of durability of effect? We know with agonism, the weight reduction continues for at least a year. Should we expect similar results for longer duration, or is there, is there any reason to believe something different at this point? Thank you. Yeah. Mohit, you know, I'll tackle that. You know, all we can speak to our data, as you're well aware, again, we chose the antagonistic approach for the GIP receptor based on, you know, very powerful human genetic data that suggests that variants that associate with reduced signaling through that pathway are associated with lower weight. You know, I think the durability we're observing here is very encouraging. Obviously, you know, the durability will be really something we examine quite closely in the expanded experience in phase two. I'd say I'm quite optimistic on that front right now. Alex, next question. Super helpful. Thank you. Thank you. Our next question comes from the line of Michael Schmidt from Guggenheim Partners. You may proceed. Hi, guys. Good morning. Thanks for taking my question. Just another one on, you know, the potential safety of antagonizing GIPR. I guess, specifically in your preclinical models, have you looked at bone density? Is it something that, you know, you might be, you know, that you're confident in that there's no impact? The second question is, in your phase two study, you know, are you confident enough in the tolerability profile to look at exclusively the flat dosing, you know, schedule, or are you still planning to evaluate the step-up dosing in phase two as well? Thanks so much. Yeah. Thanks, Michael. you know, I can tackle both of those and then ask Niranjan to provide some color. Yeah, we will be looking at flat dosing approaches in phase 2, as well as dose escalation or titration scheme. Again, wanna preserve optionality there and really optimize both the clinical effects as well as the experience for patients. you know, in terms of the preclinical models and your question related to bone density, I believe this is rooted in a paper that's 7 or 8 years old that's, you know, that suggested that variants associated with the GIP receptor pathway could associate with a lower bone mineral density, specifically inhibition of that pathway. We have looked at a much larger number of individuals with our colleagues in Iceland. We find no such association on bone mineral density at all, a finding that we're actually quite confident in. Thus far, you know, that has not emerged as an issue in the program preclinically. We will be looking at this specifically in phase two to address the question, I can say with I think some confidence here that the genetics here are not pointing us towards any specific concern in terms of bone mineral density. Thanks. Next question, Alex. Thank you. Our next question comes from the line of David Risinger from SVB Securities. You may proceed. Yes, thanks very much. Just to follow up on that last question, and your response, what was the duration of treatment of non-human primates when you looked at BMD in non-human primates? Second, with respect to phase 2, I know that you haven't finalized planning. Tell us about the planned duration of treatment in phase 2. Thank you. Sure. you know, I'll ask Narimon to address this question. I don't remember off the top of my head, in the duration of therapy in the non-human, primate, study. Certainly, we can get that information to you. Narimon, if you know that off the top of your head, of course feel free to weigh in, if you wanna talk about duration of therapy in phase II. Thanks, Dave. I do not remember the duration of therapy for the non-human primate toxicology study. We certainly can follow up. Your responses before were spot on. There were not particular observations of concern from that study. The human genetic studies that we have looked at, which were extensive and managed by our Decode colleagues, showed no evidence of a bone signal. I think the important point also for me to add is that we did assess DEXA scans in our phase 1. Insofar as that data is concerned, we saw no notable signal for reduction in bone mineral density in the context of our phase 1, the same study that we're seeing these pharmacodynamic effects in assessing safety and tolerability. As you pointed out, we will be looking at this, out of an abundance of caution in our phase 2 trial. In terms of the duration of the study for phase 2, it will, as expected, be much longer than our phase 1 study and include patients that are obese. You've mentioned that they'll be inclusive of patients with diabetes as well, which is absolutely correct. We'll be targeting a duration of therapy for approximately one year. Thank you. Great. Thanks. Next question, Alex. Thank you. Our next question comes from the line of Chris Schott from JPMorgan Chase. You may proceed. Great. Thanks so much. Just a couple follow-ons on prior questions. I think you've mentioned a couple times in the call kind of a robust phase 2 program. Help us just a little bit on timelines about when we can think about data from that program and when you could make kind of a phase 3 decision. Is that something that's reasonable to think about in 2024? I'm just trying to get hands around when the next update we should think about here would be. My second one was just coming back to GI tolerability. I know the signals you're seeing here were highlighted as mild and kind of dissipating fairly quickly. Is your base case this drug's gonna require dose titration like we see with some of the existing agents? Is your base case that you think you can get there just with a, you know, kind of single, you know, kind of therapeutic dose from day 1? I just would appreciate, I know you'll have to wait for some more data, but just based on what you're seeing in the phase 1, are you kind of leaning one direction or the other? Thank you. Yeah, thanks. Thanks, Chris. You know, in terms of the timeline, you know, as phase 2 gets up and rolling next year, you know, I'll provide guidance in terms of expected data availability, but sometime in 2024, I think is a, you know, is a reasonable expectation. You know, we'll get more specific in that, on that in terms of once we see enrollment. In terms of GI tolerability, you know, I, you know, as I said, we wanna preserve optionality. I think it's quite possible that fixed dosing, you know, may be a regimen that goes forward or some form of dose titration. I don't know that I would heavily lean or be biased to one approach or another right now, and of course, that's something that we're going to prosecute quite carefully in phase two. Thank you. Next question, Alex. Thank you. Our next question comes from the line of Matt Phipps from William Blair. You may proceed. Good morning, thanks for taking my questions. In the poster, you break down the difference between the intact and total AMG 133, I guess, do you think there's any impact of this naked or maybe unconjugated AMG 133, given it does seem to have a longer half-life? Did you look at all or do you think that GIP antagonism has an impact on glucagon secretion? Yeah. Let me ask Narimon to tackle those questions. First is related to the, you know, the pharmacokinetics, you know, of both the, you know, the intact, and then, total. This is a reflection of the design of the molecule, itself, and then, in the GIP question. Narimon? Thank you. In terms of the pharmacokinetics and the intact and total molecules, just keep in mind that total is inclusive of intact. There is a lot of similarity there. In terms of the amount of circulating drug, a lot of it is going to be intact. The total is inclusive of the what I would call the naked antibody portion as well. Over time, the GLP-1 peptides can be clipped off, and they are relatively quickly metabolized as they are peptides. We don't expect those GLP-1 peptides to, once they are clipped, be contributing to the prolonged effects that we see with AMG-133. As we mentioned earlier, we believe both activities are important to the full complement of effects that we see because it was a synergistic effect that was observed with simultaneous GIP receptor antagonism and GLP-1 agonism in our preclinical models. There may be some mechanistic rationale for the GIP receptor antibody mediating some additional effect with the chronic dosing interval. Again, we believe most of this effect is coming from the intact molecule, and both mechanisms being important in the data that we observe with weight reduction. It's too early to give a view on the glucagon levels and frankly many of the other biomarker assessments from our phase 1 experience. It is a small cohort of patients that we have, so there's going to be some variability. This is a very good and important question. We'll continue to assess it in our phase two trial. Thank you. Great. Thank you. Next question. Thank you. Our next question comes from Yaron Werber from Cowen. Your line is open. You may proceed. Hi, it's Brendan on for Yaron. Congrats to the team on the data. Just a quick one from us, kind of building on some of the earlier questions. Obviously safety tolerability looks pretty solid so far, but is there really anything in particular we should watch for in terms of safety signals from either of the 2 mechanisms here that may be more of a concern as you move into some of these patient populations with other comorbidities? I know you addressed some of this in diabetes for the phase 2. Guess really just wondering, is there anything in particular you're watching for, maybe especially from GIPR, as you move into patients like with CVD, AFib, even COPD? I, and I guess in that same vein, assuming you'll continue to measure this moving forward, but do you have any reason to think that maybe the difference, in intact versus total AMG-133 might change at all across some of these, other comorbidities? Thanks. Yeah, you know, I can address the, you know, the second part here. You know, there's no a priori reason, you know, biochem-chemically around to think that intact versus total will vary in the different disease states. Obviously, that's something that we'll measure and compare between different cohorts, in particular, those with type 2 diabetes and those who are normoglycemic. Also, I would say that there's nothing that stands out now in terms of any sort of heightened safety concern related to specific populations. You know, obviously, we will break down safety across different cohorts, as we do in a standard fashion. Narimon, I don't know if there's anything you'd like to add to that. I don't have anything else to add to that. You summarized it well. Thank you. All right. Thanks. Great. Next question, Alex. Thank you. Our next question comes from Robyn Karnauskas from Truist Securities. You may proceed. Hey, good morning. This is Nicole on for Robyn. Actually, has gastric emptying been evaluated, and can you talk about any potential impact on brown versus white adipose tissue based on this mechanism? Thanks, Nicole. Yeah, let me ask, Narimon to address that question as to whether we evaluated it in the phase I experience. We have explored gastric emptying. The data is rather small and variable, so it's difficult to draw any conclusions. I think that's what we can say. There is obviously preclinical and data and, you know, what is expected from the general body of knowledge from the incretin class, and you do expect there to be some effect on gastric emptying. It would be too much for me to say that we have clinical evidence of that at this stage. There was a second question, I believe, on the contributions of weight reduction for brown and white adipose tissue changes. We haven't looked at that specifically. This is work, you know, that we can continue to explore, primarily in the context of our preclinical models. I think it's important to consider the context here for the addressable patient population, which will have a large excess of white adipose tissue. Certainly there's gonna be an expectation on reduction of white adipose tissue, but proportionality versus brown is something that we'll just have to explore in the future. Thank you. Great. Thanks. I think we have a couple questions left, Alex. Thank you. Our next question is from Trung Nguyen from Credit Suisse. Your line is open. You may proceed. Hi, guys. It's Trung Nguyen from Credit Suisse. Thanks for taking my questions. Two, if I may. There was an eight-kilogram difference in baseline weight of the 420 mg dose versus the lower doses. I was just wondering if tissue penetration is easier and efficacy tends to be better if you have a lower baseline weight versus a higher baseline weight. Does it work that way? And then just secondly, on the two replaced patients, and I might have missed it, but why did they withdraw from the study? Thanks very much. Great. you know, I'll ask Narimon to comment on both, you know, why the two replacement individuals withdrew from the study and then the question of tissue penetration. The short answer there is that we don't expect significant differences in tissue penetration distribution, based on baseline weight. I, you know, suspect biochemically that's probably not relevant. Narimon, let me have you go ahead and weigh in here as well. Thanks, Dave. I'll start with the two patients that were placed in the 420. They withdrew from the study relatively early. There was no clear reason why they chose to stop the study. There was no clear association with adverse events or anything of that nature. You know, to the best of our knowledge, they just decided they didn't wanna continue participating in a clinical trial. With regards to the question on the degree of adiposity of patients and baseline weight and effectiveness, I think the key points to keep in mind are, given the pharmacology of this drug, the target coverage that we have modeled with the doses we've selected. Remember, we do have SAD data, or single-dose data, at the higher doses and in patients with higher weight, and we saw observed weight reductions there. Our conclusion is that the effects that we are seeing are driven by the higher dose, and we're not seeing a particular sensitivity at this point in time with regards to differences in baseline body weight. We'll of course, learn more in the context of our phase 2, and I want to be humble in saying we can't exclude the possibility, but we certainly don't see any signals at this point in time. Thank you. Great. I think we have our final question here, Alex. Go ahead and tee it up. Thank you. Our next question comes from Colin Bristow from UBS. You may proceed. Hey, thanks for the second lap. Just want to quickly follow up on just the responses to my first question in that you've... These two discontinuations, then you're pursuing a dose titration strategy up to the high dose, well, the 420 milligram dose, which, for which all AEs were mild. I'm just curious, you know, was that born out of concern over adverse events? I'm just trying to understand this in light of the fact that you're talking about exploring higher doses in phase two. Thanks. Yeah. You know, I'll ask Narimon again to comment here, of course. You know, of course, in phase I, you know, the number of potential approaches here is very large. We wanted to get some experience with dose escalation. Chose a lower dose, and then going to the higher dose, to sort of bracket that experience. The, you know, the lower dose titration was really designed to see if you could even further optimize the tolerability of the agent, which appears to be quite good so far. Narimon, anything you wanna add to this? I think you've hit it spot on, Dave. You know, the issue, I think at the root of exploring any dose escalation strategy is if we can make the path easier for patients and more optimized. You know, from the safety year that we have shared and articulated, you know, patients do have mild complaints of GI tolerability at the higher and highest doses. If there's an opportunity to make the experience better for patients and not have those mild complaints, then why not explore that in the context of our phase one, which we did, and carry that over as a learning into our phase two study, which we are pursuing. Thank you. Great. Well, I really wanna thank Narimon here, you know, who, as you can see, knows the data inside and out. We're very excited to be moving into phase 2. I wanna thank everyone for joining. As always, our investor relations team will be standing by for additional questions. If you've got them, please feel free to send those in. Thank you. I'll provide guidance as we get into the first part of next year on phase 2 launch and then expected timelines and further development over time. Thanks, everyone, have a good day.