My name is Jason, and I'll be your conference facilitator today for Amgen's Analyst Investor Conference Call at the 2022 American Heart Association meeting. 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 speakers' 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 then the number one on your telephone keypad. To withdraw your question, please press star and then the number two. I would now like to introduce David Reese, Executive Vice President of Research and Development. Mr. Reese, you may now begin. Thanks, Jason, Good afternoon and good evening, everyone. Thanks for joining us today for an update on our general medicine portfolio, selected molecules in development. We have a lot of material to cover today, some interesting new data, So we'll move right into the program. On the next slide, you can see our standard safe harbor statement. On the following slide, you see the agenda for today's call. I'll provide a very brief introduction with some context setting. Then Professor Marc S. Sabatine, who's a Professor of Medicine at Harvard Medical School, Chair in Cardiovascular Medicine at the Brigham and Women's Hospital, and the chair of the TIMI Study Group, will review three sets of data, updates from the FOURIER study and the FOURIER open-label extension studies with Repatha. Then finally, our just published phase II-B study of olpasiran, which targets Lp(a) for atherosclerotic cardiovascular disease. Following Dr. Sabatine's remarks, Narimon Honarpour, who is the head of clinical development for cardiometabolic disease at Amgen, will provide a short update on the AMG 133 program, we know there is a lot of interest in that, make some concluding remarks. Then we'll move into a question and answer session. Next slide. On this slide, you see a depiction of contextually one way that we think about cardiovascular disease. Among the universe of individuals with high cardiovascular or metabolic risk, Many times those overlap, there are various drivers of cardiovascular disease, in particular, For today's discussion, atherosclerotic cardiovascular disease. Of course, LDL is the primary driver and should always be controlled. We'll provide updates, as I noted, on the Repatha program. In addition, beyond LDL, there are other drivers of residual risk. One of the primary drivers in the number of patients is lipoprotein(a), and that is targeted by olpasiran. As I think you'll agree, we've shown profound reductions in Lp(a) levels with olpasiran. Dr. Sabatine will provide a perspective on those data. One of the other drivers of cardiovascular disease and risk is obesity and its many downstream consequences. As most of you are aware, we have a molecule in phase I development. Full data will be presented in about a month for AMG 133, which is a molecule that antagonizes the GIPR receptor and agonizes GLP-1. Again, Narimon will provide a perspective on that molecule. With that introduction, let me turn things over to Professor Sabatine to review some of the data that were just presented within the last 48 hours here in Chicago. Professor Sabatine? David, for some reason, the room in Chicago, we can't seem to hear them, so they're checking into that right now to see exactly what's going on. Okay. If we can ask everyone online to be patient for just one moment. Yeah. Just stand by, everybody, please. Hey, Duran, are you still on the line? Yes, sir. Okay. For some reason, the folks in Chicago, we can't hear them who are in the conference room in Chicago, so we need to get them connected to ASAP. Yes, sir. Ladies and gentlemen, we have lost connection with the speaker line. Please stand by while we try to reconnect them. Hey, Jason, are you still on the line? Yes. Okay. Is this something on your end that we need to connect with the conference room in Chicago? It shouldn't be. Their audio should be fine. We are now back in the main call. All right. Okay, let's see if we can hear the conference room in Chicago. Hello? Yeah. Narimon, can you hear us? This is Narimon. Okay. Sorry. Go ahead. Yeah, we can hear you fine now. Yeah. Okay, Narimon. I think we can go ahead and begin. Narimon, can you still hear us or did we lose you again? I think they're dialing back in now. Let me go ahead and bring them in. We could hear them kind of momentarily, Jason, so I don't know what happened there. The team is back in now. Okay. Narimon, can you hear us? Yeah. This is Narimon. We can hear you loud and clear. All right. That's great. Okay. why don't you. Dr. Sabatine, why don't you go ahead and proceed? Thank you. Yeah. Great. Thanks, everyone. This is Marc Sabatine here. Happy to share the data. If we can have the next slide, please. Great. As I think many on this call will know, in the FOURIER trial, over 27,000 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo. We showed that evolocumab substantially reduced the risk of major adverse cardiovascular events. There was no observed effect on cardiovascular mortality. However, that has to be interpreted in the context of the relatively short median follow-up for the trial, which was only 2.2 years. I'll remind people on the call that the pivotal statin trials had a median follow-up of four to five years, and those trials demonstrated both a lag effect, and by that I mean that the clinical benefit grew over time, and that was particularly true for the effects on fatal events, where those event curves did not diverge, typically for about two years. Therefore, we weren't really well-positioned in the parent FOURIER trial to discern any effect on fatal outcomes. The trials also showed a legacy effect, and by that I mean that the clinical benefit persisted in extended follow-up even after the parent trial had ended. That was seen in trials regardless of whether patients, once they were done with the trial, didn't start on statin therapy or all started on statin therapy. The issue is that the LDL cholesterols converged. Still, there were differences between the two arms based on their original treatment. Therefore, very long-term data on the safety and the efficacy of LDL cholesterol lowering with PCSK9 inhibition are needed. Next slide, please. This just shows the study schema. I already commented on the patients who we enrolled in FOURIER. As I note here, the median follow-up was 2.2 years. As is noted here, a subset of patients, a little over 6,600, then entered into an open-label extension where all patients got evolocumab. Importantly there, the median follow-up was five years. Stitching the two together, the median follow-up was about seven and a half years, and some individuals went out to about eight and a half years of follow-up. Next slide, please. A couple of points to share for these open-label extension data. First, here I show the effects on LDL cholesterol. You can see on the left-hand part during the parent FOURIER trial, obviously the differences between the evolocumab and placebo arms. Once the placebo patients transitioned to evolocumab, you see the robust reduction in LDL cholesterol, again on the order of a 60%-65% reduction in LDL cholesterol. Down to an achieved level of around 30 milligrams per deciliter, really one of the very lowest levels of achieved cholesterol in any major cardiovascular outcomes trial. This slide also nicely shows the durable effect of evolocumab. Now, again, stitching together the two trials, you have about seven and a half to eight years of follow-up, which I think is the longest experience with any PCSK9 inhibitor. Next slide, please. Here, showing safety. Just to orient you, we're looking at a variety of different safety outcomes that have been examined in this field. The blue and the red bars show what the annualized incident rates were in the placebo phase of the FOURIER and evolocumab. The dark crimson third bar there then shows for the extension phase for patients who were then on evolocumab for seven to eight years. The message here is that there were no emerging safety concerns whatsoever. Next slide, please. Here's efficacy. Just to remind you again, this is just during the open-label extension phase. At this point, all patients are on evolocumab. You see in blue are the patients who were initially allocated to placebo, and in red, those who were allocated to evolocumab. You can see the earlier initiation of treatment with evolocumab then led to substantial reductions, not only in the primary endpoint. There was a 20% reduction in the key secondary endpoint of cardiovascular death, MI or stroke, and perhaps most importantly, significant reduction, 23% reduction in cardiovascular death now that we had sufficiently long follow-up. Next slide, please. The data I showed you were comparisons from OLE based on the initial allocation to placebo or evolocumab. A related question, though, is what is the optimal achieved LDL cholesterol with regard to cardiovascular and safety outcomes? Basically, what information can we glean in terms of when we write guidelines, what should we target for our patients? We explored the relationship between achieved LDL cholesterol, now agnostic to treatment arm, and the occurrence of long-term adverse cardiovascular and safety outcomes in the pooled FOURIER and FOURIER-OLE datasets. Next slide, please. Here you can see for both the primary endpoint on the left and the key secondary endpoint on the right, a continuous, really monotonic, essentially linear relationship between achieved LDL cholesterol and the risk of cardiovascular outcomes. The lower the achieved LDL cholesterol, the lower the risk. You can see that extends down. As you go from 70 to 60 to 50 to 40 to 30 to less than 20, the risk for cardiovascular events gets progressively lower. Importantly, there is no inflection point here. You can't get your LDL cholesterol too low in these individuals. Next slide. Now conversely, though, for safety outcomes, here we've binned patients into six different groups in the legend shown at the bottom there. There is no relationship between achieved LDL cholesterol and the risk of any of these eight safety outcomes that have been looked at, either in relation to statins or to low LDL cholesterol. We see no relationship whatsoever. That's reassuring. Next slide. For this part, I'll summarize that long-term use of evolocumab with a median follow-up of more than seven years appears both safe and well-tolerated. The earlier initiation of evolocumab is associated with continued accrual of cardiovascular benefit, including, importantly, cardiovascular mortality over the next several years. We observed a monotonic relationship between lower achieved LDL cholesterol levels down to very low levels, under 20 milligrams per deciliter and a lower risk of cardiovascular events up to 8.6 years of follow-up. These data are very timely because the most recent ACC Expert Consensus Decision Pathway on LDL cholesterol lowering now recognizes this principle. In that document, they state there appears to be no LDL cholesterol level below which benefit ceases. Again, reaffirming the notion that you can't, in these patients, get your LDL cholesterol level low enough. Next slide, please. Now I'll transition to data that we also presented here at the American Heart for reductions of lipoprotein with a small interfering RNA, and these are the results for OCEAN(a)-DOSE TIMI 67. Next slide, please. Thank you. Lp(a), just to orient people, is a low-density lipoprotein, but it's a special one in which apolipoprotein(a), a specific protein, is bound to this LDL particle. On the left, I show a histogram of Lp(a) levels in a population with atherosclerotic cardiovascular disease, and you can see the long right tail for that distribution. Just by way of a benchmark of an Lp(a) at or above 150 nanomol per liter, that's in about 20% of the population. On the right, I show the relationship between Lp(a) levels and the adjusted risk of atherosclerotic cardiovascular disease, adjusted for traditional risk factors. You can see here a continuous relationship between those, and that the higher the Lp(a), the higher the risk for cardiovascular disease. Not shown here, but there's also data from genetic studies, from Mendelian randomization studies also showing that relationship. The challenge is that up until recently, we didn't have therapies, dedicated therapies, that could robustly lower Lp(a) levels. Next slide, please. That brings us to the study scheme for OCEAN(a)-DOSE. In this study, we enrolled 281 patients between 18 and 80 years of age with known atherosclerotic disease and an Lp(a) level greater than 150 nanomol per liter. Patients were divided into one of 5 arms, 4 olpasiran arms and 1 placebo arm. For the olpasiran arms- They received either 10 or 75 or 225 milligrams every 12 weeks, and there was a fourth arm that also got 225 milligrams, but in this case, every 24 weeks rather than every 12 weeks. The primary endpoint was the% change in Lp(a) from baseline to week 36. Next slide, please. This just shows the baseline characteristics. For the sake of simplicity, we pooled the olpasiran arms. This is a population typical for atherosclerotic disease. The age is in the mid-60s. About a third were women. The majority had coronary disease, and roughly 10% had peripheral arterial disease, and about 20% also had cerebrovascular disease. You can see it was a well-treated population. Close to 90% were on statin therapy, about half were receiving ezetimibe, and about a quarter were receiving a PCSK9 inhibitor. By design, the Lp(a) level was high, and in this case, it was around 260 nanomoles per liter. Reflecting how well the population was treated, the median LDL cholesterol was just under 70 milligrams per deciliter. Next slide, please. This shows the changes in Lp(a) through follow-up, and I'll walk you through this graph. The top line in gray is what happened in the placebo arm, and basically the level stayed very similar, just a slight drift up, about 3%-4%. We can see in blue the olpasiran 10 mg every 12-week dose, where there was a roughly 60%-70% reduction in Lp(a) levels. When we get to the 75 and 225 mg doses every 12 weeks, now we're seeing reductions on the order of 90%-95%, and then greater than 95% for those two doses. In the yellow-orange color there, you'll see the olpasiran 225 every 24 weeks, where you can see that then by the end of that 24-week dosing interval, there's a slight drift back up in Lp(a) levels. Next slide, please. For the primary endpoint, which is the placebo-adjusted change, meaning we took the percent change seen in each olpasiran arm and subtracted from that the change seen in the placebo arm. You'll recall the placebo arm went up by a couple percentage points. Therefore, once one exceeded doses of 75 mg every 12 weeks, we achieved greater than 95% reduction in Lp(a) levels. Next slide. This slide here shows a waterfall plot. Now you're seeing the effects on each individual patient in each of these arms. What I'll underscore here is that for the doses of 75 mg or higher, there is a striking consistency in the effect. Really minimal inter-individual variability for the effects of the small interfering RNA. Next slide. For safety and tolerability, you can see here at the top the rates of adverse events. Overall, there were no differences. There were no differences in the rates of serious adverse events. I think that the metric that I find clinically most important is what were the rates of adverse events that led to discontinuation of study drug? Those were quite low, under 2% in all of the arms. For side effects that people have worried about in general for lipid lowering in the field, myalgias, liver-related adverse events, hyperglycemia, new onset diabetes, no dose response throughout. There were higher rates of injection site reactions and hypersensitivity reactions, but these need to be qualified. First, the injection site reactions were by and large mild, and the hypersensitivity is a function of MedDRA coding. It's not what clinicians, I think, would consider hypersensitivity. These were by and large injection site pain, but through how MedDRA coding worked, they sort of rolled up to that. These were not like an allergic reactions like a bee sting that you might think of for hypersensitivity. Again, these all resolved without any treatment, typically over 24-48 hours. I think a very reassuring safety profile. Next slide, please. In conclusion, Lp(a) we know is associated with atherosclerotic cardiovascular disease risk independent of traditional risk factors. Olpasiran is a small interfering RNA, and when dosed at 75 mg or higher every 12 weeks, really robustly reduces Lp(a) levels by more than 95% in patients with established atherosclerotic cardiovascular disease with really minimal inter-individual variability for this. Quite consistent effects. Olpasiran appears both safe and well-tolerated in this study, these findings then set the foundation for a phase III testing to begin later this year. Next slide. These results were just published in The New England Journal of Medicine you can go there to read more about this study. Next slide. This just sets the stage then for OCEAN(a)-Outcomes, as I alluded to. That will be the definitive outcomes trial with olpasiran, where again, we're enrolling patients with established ASCVD with an elevated level of Lp(a). They'll be randomized to olpasiran or placebo and then followed up. The primary endpoint is time to first coronary heart disease, death, MI or urgent revascularization. We estimate this study will start next month. I think that's the end of my part, so thank everyone for their attention. I'll turn it over to Narimon. Thank you, Dr. Sabatine. I'm pleased to share an update on one of Amgen's early pipeline programs, AMG 133, an investigational therapy being evaluated as a treatment for obesity and obesity-related illnesses. Next slide, please. Recall that AMG 133 is an antibody-peptide conjugate. It has an antibody backbone that blocks the GIP receptor. Bound to this backbone are two GLP-1 peptides that stimulate or agonize the GLP-1 receptor. It's a bi-functional molecule. The molecule has been engineered in this way on the basis of, one, human genetic data that our colleagues at deCODE contributed to, which strongly suggests reduced GIP receptor activity reduces body weight, and two, the existing body of knowledge and important clinical experience with GLP-1 agonists. Our preclinical data suggested synergistic effects with GIP receptor blockade and GLP-1 receptor agonism on weight loss and a number of other metabolic parameters that led us to advancing this molecule to phase I clinical testing. Next slide, please. As shared earlier in the year and shown here, the single-dose cohort data from phase I has supported the concept that these two mechanisms, blocking one receptor and agonizing the other, can meaningfully impact weight reduction. Next slide. We're pleased to share that we've made progress with the phase I study and have now completed both the single and multiple dose cohorts. Within each of the multiple dose cohorts, patients received a total of three subcutaneous dosing administrations, each four weeks apart, with the last administration just before day 60. We continue to see encouraging data from the phase I study, specifically with multiple dosing. We've seen mean percent changes in body weight ranging from roughly 7% at the lower dose to 14.5% at the higher dose by day 85. No plateau on weight reduction was observed during the treatment period. We have not observed notable safety concerns, with most treatment emergent adverse events having been mild and transient. The pharmacokinetic data were dose proportional and demonstrated an extended half-life. What I'll say about the data on the whole is that we're encouraged. We're encouraged by the weight reduction, the pace of the weight reduction, and the durability of the effects seen in the phase I. We look forward to sharing these data in greater detail at the 20th WCIRDC Congress in December. In the meanwhile, we continue our plans to initiate a phase II study where the full attributes of this molecule can be elucidated. We intend to start that early next year. Next slide, please. Moving on to our conclusions. To conclude, we pursued a strategy of prosecuting genetically validated targets in our cardiovascular and metabolic pipeline, ranging from PCSK9 to Lp(a) for atherosclerotic cardiovascular disease, to GIP receptor for obesity. The results we've seen so far with this strategy are encouraging. The Repatha FOURIER-OLE findings outlined by Dr. Sabatine today are compelling evidence of the impact of early and significant LDL-cholesterol reduction and how this can impact cardiovascular events. The olpasiran phase II data show a rapid and sustained reduction in Lp(a). We're looking forward to initiating the phase III outcomes trial by the end of this year. Lastly, with AMG 133, a phase I program, we've demonstrated significant dose-dependent reductions in weight of up to 14.5% by day 85 with an every-four-week dosing regimen. We plan to initiate a phase II dose ranging study early next year to better understand the full potential of the molecule. This concludes this section of the presentation. I believe we'll be turning it back to Dave. Dave? Thank you, Narimon. Before that, thank you, Dr. Sabatine, for an excellent review. Jason, do you want to go ahead and review the process for asking questions with our listeners, then we'll go ahead and open it up to the Q&A session? If you would like to ask a question, please press star followed by one on your telephone keypad. If for any reason you'd like to remove that question, please press star followed by two. Again, to ask a question, press star one. Our first question is from Michael Yee with Jefferies. Your line is now open. Hey, guys. Thanks for the question. I appreciate the updates. I guess I'm going to go with the 133 question. David, thanks for the update there. Given the commentary, can you just maybe conclude where you see the strongest differentiation? Is it on efficacy? It appears that a negative 14% or dosing once monthly or the kinetics, or maybe just sort of summarize that and what you think is most important there. Thank you. Yeah, Mike, thanks for the question. Of course, we knew there would be a lot of interest here. I think potential points of differentiation here are really what you've articulated. Dosing interval, potential efficacy. We need to further test that in phase II, since the phase I trial only included up to three doses. We did not appear to see a plateau in dosing at the conclusion of three doses, and in fact, that weight loss was relatively sustained. We're continuing to follow most of those patients. Finally, the kinetics of weight loss, meaning the rapidity of weight loss we think is encouraging, and that's something that we will also be examining carefully in phase II. All of these are potentially important attributes, and we'll be generating more data in what will be a robust phase II study. Next question? Great. Thank you. Our next question comes from Matthew Harrison with Morgan Stanley. Your line is now open. Great. Good evening. Thanks for taking the question. I was wondering if you'd just comment maybe a little bit more broadly on phase II plans here for AMG 133. I guess, two parts to this question. The first one is, do you think the only path to registration here is a large outcome study or are there certain populations where maybe there could be a faster path to market? Secondly, maybe you could just comment on the dose range that was chosen in phase I and if there was any sort of upper bound related to potential safety concerns there, or think you may push the dose higher in phase II. Thanks. Yeah. Thanks, Matt. I'll ask Narimon to comment and provide a little bit more in terms of specifics on the phase II design. What I will say is that one of the things that we've really taken into account for phase II is preserving optionality. It'll be a relatively large study. It will include patients with diabetes or glucose intolerance and without that, and we'll look at a variety of doses and schedules to really then guide us for further development. I think it's probably too early to speculate on whether earlier registration could be achieved. That's something that we will, of course, take a look at, and as phase II proceeds, we'll provide guidance on our thinking on what that pathway may look like. Let me turn it over to Narimon to provide a little color on our phase II thinking. Thanks, Dave. We'll be pleased to share the details of our planned phase II study once finalized and available on clinicaltrials.gov. At a high level, it's planned to be a robust dose-ranging study of several hundred obese patients with longer follow-up than what we had in phase I. We'll be evaluating a range of doses as well as a variety of dosing schedules, including fixed doses with fixed interval dosing, as well as some dose escalation. We'll have both patients with and without diabetes included. In terms of what we'll be looking at, of course, weight reduction, as well as a number of other clinical parameters. Great. Thanks, Narimon. We will be sharing plans on that very soon. Again, we want to preserve optionality with this study, and we believe it's going to be quite a robust study design. All right. Next question, Jason. Our next question comes from Chris Schott with J.P. Morgan. Your line is now open. Great. Thanks so much. Just staying on the 133 questions, can you just comment at all or elaborate on the HbA1c benefit you saw with the drug from the phase I? Maybe just more broadly, can you talk about how you'd expect this agent to perform on HbA1c, I guess, relative to Mounjaro, given the high overlap in the obesity and diabetes populations? Thanks so much. Yeah, again, I'll ask Narimon to comment in just a minute here. The phase I was not necessarily focused on patients with diabetes, I think we need a larger experience, and that's one of the things that we will be taking a look at specifically in cohorts in phase II, as I mentioned. It's also worth reminding all of us that weight loss itself can be an important part of control of type 2 diabetes. If one is able to achieve ultimately significant weight loss, such as 20% or more, that can restore, for example, peripheral insulin sensitivity and has a host of other metabolic effects. Narimon, do you want to comment a bit further on the hemoglobin A1c question regarding our phase I? Absolutely. Thanks, Dave. Preclinically, as you would expect, given the construction of the molecule, we did see effects on issues like insulin sensitivity, glycemic control, and others that you would expect to be favorable with human testing. As you pointed out, our phase I study excluded patients with an existing diabetes issue or other significant comorbidities. The patients were euglycemic when they came into the phase I, and we wouldn't expect to see significant differences on that basis. However, in phase II, we will be including patients with diabetes and metabolic syndrome, and we will expect to see those types of efficacy metrics best assessed there. Thanks. Great. Thanks. Next question, Jason. The next question comes from Salveen Richter with Goldman Sachs. Your line is now open. Good afternoon. Thanks for taking my question. Could you speak more to the tolerability and adverse event profile, and then help us understand what you'll be presenting in December at the Congress? Great. Thanks, Salveen. Yeah, I'll let Narimon speak briefly to tolerability. We don't want to give away the entire data set for next month to honor the embargo from that meeting. Narimon can provide a little color there on that and the adverse event profile and certainly will tell you what you can expect to see next month here in Los Angeles. Narimon? Thank you, Dave. Let me just begin by caveating our phase I experience is early phase experience. The types of cohorts and patient numbers that we look at in those cohorts are rather small. The totality of the phase I experience was around 70, 75 patients across many cohorts. I wanted to start off with that caveat. In terms of what we will be presenting in December, as Dave outlined, you'll see more detailed data from that phase I. What we can share today with regards to safety is that there were no significant or notable safety findings observed. In fact, most of the treatment emergent adverse events that were observed in the phase I study were mild and reversible. Now, in terms of the types of adverse events, the qualities of those adverse events that have been observed, I would say that they are typical of what you would see with the incretin class, with the most prevalent ones being related to GI effects. Thank you. Thanks, Narimon. Next question, Jason. Our next question comes from Jay Olson with Oppenheimer. Your line is now open. Oh, hey, thanks for the update, and thanks for taking the question. The New England Journal publication indicated that it's unclear how much of a reduction in Lp(a) concentration would be required to translate into a meaningful reduction in the risk of cardiovascular events. Can you just comment on what you see as the target for Lp(a) reduction and what role that may have played in your dose selection for phase III. Thank you. Yeah, great. Thank you, Jay. Thank you for asking an olpasiran question. I'm going to ask Dr. Sabatine to comment in a minute here. The one thing that I would point out, you recall that the average Lp(a) level was about 260 in the phase IIb study. A 90% reduction of that brings you to roughly 25 nanomoles. That is where many folks with so-called normal range Lp(a) live in. You're driving the Lp(a) into that normal range. Now, of course, we don't have the six or seven decades of history with Lp(a) that we had with LDL cholesterol. Part of our thinking was really to drive that into the normal to low normal range in as many patients as possible. Dr. Sabatine, would you like to comment on goals in terms of Lp(a) reduction? Yeah, sure. I'm happy to add, I obviously agree with what you said. I think the exact nature of the relationship between Lp(a) and cardiovascular risk remains to be fully defined. In some studies, it looked like that once you got down to a certain level, that if you were, as David said, in a sort of low range, that the risk was low. The exact threshold can vary. In part, it's also trying to gauge how much lowering, if it's like LDL cholesterol, how much lowering would translate into what% reduction. There have been a variety of genetic studies, and they've given a variety of estimates. I think that the good news for olpasiran is that it reduces Lp(a) so much that the effect should be quite robust. I think these first studies will actually give us the data like we have for statins and LDL cholesterol for that exact relationship. Otherwise, it's a bunch of extrapolation from genetic studies, but we should, in the outcomes trial, be positioned, given how potent this drug is, to see a robust reduction in clinical events. Great. Thank you. Next question, Jason. Our next question comes from Yaron Werber with Cowen. Your line is now open. Yaron, are you with us? Yes. Can you hear me? I can hear you. Hi. Now we do. Okay, great. Maybe a question for David and Narimon. Just on 133, is the data ITT that you're giving us, or is it on treatment? Then secondly, when you look at some of the other drugs, they're GPCR sort of partial agonists, and you're an antagonist. Can you give us a little bit of a sense, what are you seeing that the pharmacogenetic data between those two in the natural history? Thank you. Yeah, maybe I'll start with a perspective on the second part there and then ask Narimon to talk about some of the specifics and the ITT population in phase I. As Narimon noted, there have been three large GWAS studies that have examined the relationship between variants that affect signaling through the GPCR pathway. In general, those suggest that variants that are associated with reduced signaling through that pathway are associated with lower BMI and lower weight. In fact, major contributor to those studies was us with our team in Iceland. We've, in addition, done additional analyses that really convince us that antagonism of the receptor is the appropriate approach, given this wealth of genetic data. That's really what led us directly to the construction of this molecule. In addition, it's on an antibody backbone, which gives it a potential favorable pharmacokinetic profile and lead to the sort of dosing intervals that we've talked about. Narimon, you want to speak a little bit more about phase I in response to Yaron's question? Thank you, Dave. To be clear, the results that we are citing for effects are on-treatment results, Yaron. These are patients that we're taking on therapy. Most of the patients over the course of the phase I continued on therapy successfully. To perhaps put a double underscore on Dave's points, which are spot on, we have conviction in following human data, and the human genetic data have been quite convincing that it is reduced GIP receptor activity that is associated with reduced body weight, not more GIP receptor activity. We have designed this antibody to bind to and block the GIP receptor, and we believe that the effects that we are seeing are reflective of that. Now, that being said, there's obviously more opportunity to do mechanistic data preclinically to understand what happens with agonism and antagonism. What has been published in the literature and you can find is some papers that show that chronic agonism eventually leads to desensitization of the pathway and maybe functionally something similar to blockade. That work needs to continue. Thank you. Great. Thank you. Next question, Jason. Our next question comes from Umer Raffat with Evercore. Your line is now open. Hi, guys. This is Michael DiFiore in for Umer. Just two questions from me, both of them on AMG 133. Number one, I was wondering if you'd comment on how baseline body weight could affect drug exposure with this asset. We saw from the semaglutide data that the higher the baseline weight The less drug exposure, was wondering of how adding the GIPR mechanism may play into this dynamic, if at all. My second question is that given that weight loss didn't plateau, I realize it's early days with this asset, but was wondering if you could offer any commentary on how you're planning to strike the balance between convenience with less frequent dosing versus optimizing efficacy, perhaps by sticking with every 4 weeks. Thank you. Thanks, Mike. I'll ask Narimon, of course, to comment on both of these questions. One thing I would point out to start is that obviously exposure response analyses will be something that are important for us to take a look at in the phase II study as we've got a larger group of patients. One of the things, again, that I think is important about this molecule is that it does have an antibody backbone which gives it antibody-like pharmacokinetic behavior. I'll ask Narimon to comment on the issue of baseline body weight, and potential changes in exposure, and then the convenience issue. Regarding the latter, we will be, as Narimon noted, testing a variety of approaches, including fixed doses, as well as titration regimens in phase II to really preserve optionality for phase III designs. Narimon, you want to add some color? Thank you, Dave. Insofar as our phase I study is concerned, the baseline BMIs were approximately 32-34. Everyone that came into the phase I study needed to be an obese person. Insofar as our pharmacokinetic data are concerned, within the patients that we have looked at and within those ranges of weight, we have not observed notable differences across those patients in terms of their exposure. What we can also offer in terms of our dosing schedule is we feel quite comfortable with an every 4-week dosing regimen at a fixed dosing regimen. We don't think that we necessarily have to be pitting efficacy against dosing convenience with this particular asset. Thank you. Great. Thanks, Narimon. Of course, this field is relatively young. Over time, there will be a look at maintenance dosing and a variety of approaches. I think we've got a molecule that gives us quite a bit of flexibility right now. Jason, you want to go ahead to the next question? Our next question comes from Mohit Bansal with Wells Fargo. Your line's now open. Hey, thanks for taking my question and thanks for presenting this data. Again, one question on 133. Is there any reason to believe that an antibody approach versus a peptide approach could have some advantage on safety as well? The other part of the same question is that did you employ any kind of dose titration in this particular study? Thank you. All right. Thanks, Mohit. I'll ask Narimon to comment on the second part. All we can report so far regarding safety is what Narimon has discussed, and we're quite pleased with what we've seen so far. Obviously, those are data sets that will be fleshed out in phase II. Narimon, do you want to add any comments here? Thank you, Dave. I'll just say all of the data that we have shared today have come from multiple dose patients that were dosed in fixed dosing intervals with a fixed dose. None of those results have been reflective of patients that hadn't gone through a dose escalation or a dose titration. That's inclusive of the safety results that we've also commented on. We continue to apply our knowledge to testing a variety of different dosing schemes, including potential dose escalation schemes, which we'll also be looking at in phase II. We're keeping our options open, but we feel quite comfortable with our fixed dosing intervals at this point. Great. Thank you. Got it. Thank you. Go ahead, Jason. Our next question is from Evan Seigerman with BMO Capital Markets. Your line is now open. Hi there. This is Connor on for Evan. Thanks for taking our question. Just one question on olpasiran. Can you talk about your expectations for the cardiovascular outcomes data in the phase III trial, given the impressive Lp(a) reduction you've seen in phase II? On those expectations, what might you need to see in the phase III trial to drive real world uptake? Yeah. I'll ask Dr. Sabatine to comment on what he'd like to see in phase III. This is an outcomes trial that I think as it rolls out, you'll see that it's consistent with other outcomes trials in the field, and it's designed to show a clinically relevant reduction in major cardiovascular events. Dr. Sabatine, let me ask you to comment on what you'd like to see here and what you think clinicians will need to see in order to use this sort of therapeutic. Yeah, no, I think it's a great question. I would say again, because olpasiran is so potent at lowering Lp(a) that given the population we're studying, based on the data we've seen in the genetic studies, I think there should be, I'll say, a robust reduction in clinical events. That would be one that as a clinician, if I saw, I then want to give this to my patients. The second part, I think then is in terms of the uptake, and I think Lp(a) is being increasingly recognized as an important risk factor. The sort of good news for it is that the levels tend to be fairly stable over time. With more and more professional societies recognizing this, and now with drugs coming down the pipe that can then make a meaningful impact on Lp(a) levels, I suspect more and more clinicians will start to be measuring Lp(a), and then obviously once the results come out, and if it goes along as I anticipate there'll be a robust reduction, then I think clinicians will very readily embrace checking this for their patients. Great. Thank you. Jason, next question. Our next question comes from Robyn Karnauskas with Truist Securities. Your line is now open. I think, Gary, I'll throw a curve ball and ask a Repatha question. On the further long-term extension study, maybe Dr. Sabatine, you can talk to this as well. Amgen has guided to much more growth for Repatha. Can you talk to us about how doctors use extension studies? Do you think that what will it take for more patients to get treated with the drug, both at the specialist level as well as the primary care level? Thanks. Great. Thanks, Robyn. Of course, I'll ask Professor Sabatine to comment in just one moment. To me, one of the clinical lessons from the extension study is that not only is lower is better, but earlier is better, in that those who started Repatha later never quite caught up in terms of event rates. To me, there's a lesson for the field there. Of course, let's have Dr. Sabatine comment on that and how you put this into clinical context. Happy to do so. It's a great question. I think the open label extension data have been very well received by clinicians for multiple reasons. I think one, when we initiate lipid-lowering therapy, we envision then it'll be lifelong for the patient. We were spoiled in the statin era for having trials that, as I noted, had a median follow-up of roughly half a decade. We find that duration of follow-up comfortable or comforting to us when we prescribe a drug long term. OLE then gives us that, and in fact, as I indicated, for some individuals, even out to 8 years. I think that's very reassuring and gives a long-term profile that now is at or even longer than we've seen for statins. Secondly, I think for the efficacy, as I noted, that it takes time to see the full benefit for LDL cholesterol lowering. I think OLE nicely illustrated that with more time, you see not only a reduction in MI and stroke, which we had showed earlier, but now a reduction in cardiovascular death. That's the sort of benefit that clinicians really sort of sit up and pay attention to. I think that's coupled with the most recent consensus statement in both the European guidelines, which embrace a lower target than we had in the U.S., so they target under 55 milligrams per deciliter for high-risk patients, and even for those with recurrent events to be more aggressive and be under 40. The most recent U.S. guidelines, again, embrace under 55, note that there's no lower limit. As there's increasing recognition for that, and we want to, for our patients, at least for secondary prevention, get their LDL cholesterol levels down, and we want to do that long term and as early as possible, as David indicated. In those cases, you're going to need a PCSK9 inhibitor to get there for your patients. Great. Thank you. Jason, next question. Our next question comes from Geoff Meacham with Bank of America. Your line is now open. Hey, guys. I have a question for you on AMG 133. When you look at tirzepatide, it had benefits beyond just weight loss and HbA1c. It was looking at lipid lowering and blood pressure lowering. I am just curious if you have any data for AMG 133 on those type of biomarkers, and then what you would be looking for beyond just weight loss in the phase II. Thank you. Yeah. Thanks, Geoff. I will take that question. Obviously we expect effects on a wide variety of potential metabolic parameters, and we are going to thoroughly study that in phase II. Based on what we have seen so far, it is encouraging. Remember that this is relatively short duration of therapy in phase I, and so we need longer-term data from phase II. I think we are quite encouraged by what we have seen so far, and we will very thoroughly profile patients from a metabolic standpoint in the phase II study. Jason, why don't we go on to the next question? Our next question comes from David Risinger with SVB Securities. Your line is now open. Yes. Thank you very much. Could you discuss to what degree as an antibody or having an antibody backbone, as you describe it, AMG 133 crosses the blood-brain barrier and impacts satiety? Thank you. Yeah, great. Thanks, David. I'll take that question. Because of this molecule, it's a large molecule built on an antibody backbone, as we've said, we would not expect it to cross the blood-brain barrier or achieve appreciable concentrations in the CNS. Most if not all of the effects that have been observed, we would expect be due to peripheral activity of the molecule. Thank you. Jason, why don't we go on to the next question? Our next question is from Colin Bristow with UBS. Your line is now open. Good evening, and thanks for hosting this. Really helpful. A couple more. On 133, were these figures on a background of diet and exercise, and what was the specific time point that the 14.5% weight loss was measured at? Just one on Repatha. I see in phase III you've moved the inclusion criterion up to 200 nanomoles per liter for Lp(a), I think versus 150 in the phase II. Just curious why you made that change. Thank you. Good questions, Colin. I'll ask Dr. Sabatine in just a moment to comment on the second one, on olpasiran why we chose a 200 nanomole cut point. I'll ask Narimon to comment on the diet and exercise question and the timeframe. Recall that, as Narimon noted, the weight loss of up to 14.5% was by day 85 or so. Narimon, do you want to add any additional detail there? Thank you, Dave. You got it spot on. It was by day 85 in terms of the effect. Just very quickly, with regards to diet and exercise, there was no specific instruction given with regards to diet and exercise in this phase I study. Thank you. Great. Thanks. Dr. Sabatine, would you like to comment again on the olpasiran Lp(a) threshold level that we've chosen? Yeah, sure. No, it's a great question. I would say it's analogous to what was done with statins, right? If you'll recall for 4S, looking at patients with existing coronary disease and started with very high LDL cholesterol levels, and so it was 188 milligrams per deciliter. That helped then define the magnitude of benefit. I think in an analogous way here, we want to start with the group with a very high level that I think we would have a high degree of confidence that we'll see a very robust reduction. I think it's going to be quite robust, and then, if it looks as good as I hope it will look, that would then open the door to testing populations with lower levels of Lp(a), but you have to start someplace. We're starting those with high levels. Great. Thank you. Next question, Jason. Our next question comes from Dane Leone with Raymond James. Your line is now open. Hi. Thanks for taking the questions. Apologies for adding onto the most analyzed phase I two-slide dataset that we've had for a large cap biopharma company. Just getting investor questions in. Can you just clarify in terms of how you actually cut up the high and low dose within that chart that you have for the mean change for baseline and weight? Was there any cut point of what the doses were for high or low and the number of patients in each that kind of gives you confidence that there's real separation and not a lot of statistical noise in there? Yeah, sure. I'll ask Narimon to comment on that. What I think you're asking is in part, are we confident of a dose response? I would add, before Narimon speaks, that this is probably the most discussed, not yet presented phase I trial that we've had. In any event, Narimon, do you want to comment on the dose response question? Yeah, sure. Phase I data, typically, we're looking at precious few patients per cohort. In this case, there were eight, and we had multiple cohorts over the course of the phase I. The dosing we'll disclose at the presentation, but every cohort had a specific dose assigned to it. When we speak to low dose versus high dose, it speaks to the cohort that was at the low dose and the cohort that was at the high dose for comparison. Great. Thank you. Yeah. You'll see all of that in some detail, Dane, in about a month. All right. We've got, I think, a couple more questions in the queue. We'll go a few minutes over here if we have to, since we had a brief delay earlier. Jason, why don't you go ahead and tee up our next question? Our next question comes from Matt Phipps with William Blair. Your line is now open. Good evening. Thanks for including me. You mentioned the human genetic data was behind using a GIPR antagonist to go with the blocking antibody there. I was wondering how you felt about potential impact on bone turnover given GIPR expression on osteoblasts and osteoclasts, and some GIPR variants with missense mutations have been reported as they have lower bone mineral density. Yeah, thanks, Matthew. That's a question that we've looked at directly. I'll ask Narimon to comment on that. I would say right now we're quite reassured based on what we know. Narimon? Thank you, Dave. We're familiar with this work. We've taken note of these observations. Our colleagues at deCODE genetics that do these types of analysis very rigorously have looked at this type of question, and they have looked and have not found such an association with fracture risks or bone mineral density reductions. We feel quite confident about that observation, but we are also going to make sure that we're going to continue to monitor for things like bone mineral density. We have done that in phase I. We have not seen notable differences to date, but we'll continue the monitoring into phase II just in case we're missing anything. Thank you. Great. Thanks. I think we've got one more in the queue, Jason. Our last question comes from Carter Gould with Barclays. Your line is now open. Great. Good evening. Thanks for doing the call. This has been very helpful. I guess, just going back to the dual mechanism with 133. We've seen with other related mechanisms some sort of bounce back in terms of weight gain upon stopping therapy. Can you maybe just frame how you think the dual mechanism here might compare on a relative basis? I don't know if there's anything from your preclinical work or the patients who stopped therapy in the phase I that you could point to on that front. Thank you. Yeah, maybe I'll handle that, Carter. As Narimon mentioned, we saw good sustainability. The other thing to keep in mind, because this is built on an antibody backbone, you don't have a sort of rapid on/off with these pathways. That may help, in theory, prevent some of the rebound that you've been discussing. Obviously, this is something we'll take a look at in phase II, but we've been quite encouraged regarding that question based on the data that we've seen to date. All right. Well, I think that gets through all of the questions. Really want to thank all of you for joining us today. As always, the investor relations team will be standing by if you have additional questions. I'm sure we'll see many of you here in Los Angeles for the presentation of the AMG 133 phase I data in about a month. At meetings throughout the remainder of this year and on into the first part of next year also. Thanks everyone, and have a good evening. That concludes the conference call. Thank you for your participation. You may now disconnect your lines.