..for being here. Pleasure to have management team from Eli Lilly. There's a ton to go through, but, Dan, I'll turn it over to you on what's on top of your mind, and we'll jump right into it. Yeah. No, thanks for hosting us here. It's been a great meeting so far, and nice to have this opportunity to talk at a fireside. I guess, probably most people are excited about Lilly because of what we're doing in obesity and Alzheimer's disease. But just a reminder that we have a great business in immunology with a couple new products being planned to launch. And we're also doing great things in oncology with Verzenio as a huge product, and Jaypirca, which is in the early stages of launching across indications. So we're really a very diversified pharmaceutical company, even though I know we're going to spend a lot of time on the first two topics of obesity and Alzheimer's. Sure. Okay, so I know there's a ton to go through, and I'll intentionally keep the questions much more R&D-specific rather than more commercial in nature- Right. ... even though I had forgotten, but I recall last night that you do have some commercial responsibilities as well now. But maybe just so we're all on the same page, there's constantly this question that something's coming online in North Carolina, but we don't really know what exactly that is, and is it, like, modular or how that works? Maybe it speaks to a lack of understanding on how some of the manufacturing build-outs actually work, but... And I realize that's not what you work on on a day-to-day, but- That's fine. Yeah. What's the high level of... Is it, like, 500 stip end being made in Indy, and then North Carolina will do the same at some point? Yeah. Yeah, thanks for, thanks for that question. And of course, I think everyone's keenly interested in the capacity situation for our incretin business. You know, particularly here, you're highlighting the device assembly part of it, which is one component in the supply chain. Of course, there's API, there's sterile fill, there's device manufacturing. We haven't commented on, like, unit volumes per site, and so what we did say, though, was sort of a doubling of capacity potential with the North Carolina site coming on. Of course, you know, capacity is not exactly the same as supply, and we got to work into that to produce it. And that's just one stage of the process that we're talking about. Right. The North Carolina site is a large site that is coming up in stages, as you suggested. Over the course of the next couple of years, actually, it'll continue to improve in its capacity potential. Over the next couple of years? Yes. Okay. There's a sister site that's coming up, also in North Carolina, with a little bit of a longer time horizon, that will add another increment of capacity. You know, of course, we're excited that the demand for incretins and injectable incretins is so high, and we'll continue to invest purposely to improve the capacity to manufacture these. Got it. And, Dan, I don't, like I said, I don't understand how the staging of these manufacturing capacities actually plays out in practice, but is it reasonable to assume a third of whatever the total is could be online in the first half of 2024, for example, or it's hard to even quantify that? Yeah, I think it's hard to quantify. There's two ways that capacity improves over time from a given facility utilization. One is adding additional lines of operation over time, which can happen by fitting more in the existing footprint, also expanding facilities. Right. The other is within a line, we can optimize performance and get more unit volume out of it as we get more proficient at running it or things like that. So it's probably not accurate to sort of say what fraction of capacity comes up at a certain time. But as you understand it, it was the pens that was the bottleneck from a Lilly perspective, not the API? That's correct. That's the current bottleneck. Of course, I, I'm quite confident that, we can find bottlenecks anywhere in the supply chain for incretins, and whichever one we solve first, then the next one becomes equally important to solve. So we're working to increase capacity against all three aspects of manufacturing, which is API, the sterile fill, and the device manufacturing. Got it. Okay, so maybe let's go into maybe the first topic from a more R&D specific. Sure. I know there's a lot of focus on oral GLP- Yeah. Specifically as it relates to safety profile. Could you sort of characterize for us how you're thinking about liver safety? And also maybe even higher level, how are you thinking about overall risk on this program relative to some of the other GLPs that are coming forward? Okay, sure. Interesting framing to put it relative to other GLPs. But let me just start with the overall risk profile, and particularly focused on liver, since it's so much question. You know, one of the common ways that small molecules die in drug development is drug-induced liver injury, which is often difficult to predict. Maybe I could go stronger. It's impossible to predict from preclinical studies. It's not correlated with what we see in animals, and it manifests in humans as sort of sudden and severe liver injury. We haven't seen any of that with orforglipron, so we're really glad. We know, though, that a competitor saw that with their small molecule, GLP-1 agonist, and that's caused sort of increased scrutiny over the liver profile of the molecule. What did we see with our molecule Phase II? we had Phase II studies, one in obesity, one in Type 2 diabetes, published in New England Journal and JAMA respectively, and we detailed the liver safety findings in those two publications. First, at a group level, what we see is patients on drug actually have a decrease in liver enzymes, so that shows- Group level? At a group level, the average ALT/AST declines in a dose-related manner. That's probably related to driving fat out of the liver and improved liver health. And then there are a couple of patients noted that had excursions of liver enzymes above the normal range. That's not unexpected, particularly in a Type 2 diabetes population, where there's a very high level of comorbidity of NASH. And in all of our Type 2 diabetes trials, across molecules, we can see those kinds of excursions in liver enzymes. Importantly, the patients on drug, there were patients on placebo and drug, I think, in this program, who've experienced it, but the patients on drug returned to normal without cessation of therapy, which is usually not consistent with drug-induced liver injury. So when we saw the evidence, we felt pretty good. We actually felt quite comfortable, I should say, with the liver safety. Of course, when the competitor data came out showing a liver safety injury, we looked again, we came to the same Phase III program is going well. We have a lot of patients enrolled and continue to follow those patients over time with no signals here to be alarmed about. Of course, we monitor liver safety in all Phase III programs, and we're doing so in orforglipron, no different than the other programs. Dan, I guess one question that I can't answer for myself is- Yeah. When ALTs go above 10x for a patient in a trial, I'm not a clinician, but I would have thought I would pause whatever medicines they're on. I noticed in this specific instance on your oral GLP, they dosed right through it. Like, how does that play out practically? Yeah, different trials have different stopping rules for liver enzymes. Okay. Sometimes there's differences in time of when the investigator sees the labs or things like that. I honestly can't recall what the stopping rules were Phase II and whether they- Okay. The protocol asked them to stop or not. It. These were one-off, upticks, and they came right back down, or they kind of sustained for a little bit and slowly came down? How did that actually play out when they went up? I don't remember the time course. Like I said, it wasn't a particularly noteworthy liver profile. It just looked like background noise that we see in our trials a lot. Got it. Was it reported to you when it happened in Phase II? No. On a blinded basis? No. It wasn't. So you only found out afterwards, as in when Phase II was completely done on a safety basis? You're asking me personally, or you're asking the company? No, I'm actually saying on a blinded basis, don't you-- Wouldn't the, like, our rate of ALT above 5x is, like, five cases now on a pooled basis across trial. Wouldn't that information be getting reported? You're asking about the Phase III? Phase II, for that matter, but I guess less- Yeah, so Phase III, we do. Our safety team, of course, has access to the pooled data on a blinded basis. If they saw something, that would be a reason to show caution, but we're fine. Got it. Nothing like that's happening. I know there's been some confusion lately on the exact doses Phase II, you hit mid-teens at 45 milligrams, but also 35 milligram came about a point lower than that as well. My understanding is Phase III is not using 45 milligrams. It's got three doses below that. Can you just remind us of that? Yeah. Well, we've tried not to Phase III dosing, but I will acknowledge that Phase II, we saw probably a saturation of efficacy at the two highest doses. There wasn't much room between them at all. And so, I think that led to our determination of the right doses taken to Phase III. Got it. Is it usual, by the way—I was thinking back to, well, how often do I see three different doses for an active arm Phase III? it's somewhat unusual, but I don't know if it- Yeah ... necessarily changes the powering very much. No. They all work. Yeah. How do you think about that? Well, it's what we did for tirzepatide. Okay. So we're pretty excited about that profile because initially, when we designed the tirzepatide trial, there was a lot of uncertainty about tolerability and how much the tolerability would improve with titration. So that kinda led to having multiple doses. And then what we found when we launched tirzepatide is that patients enjoy the ability to actually manage their dose decisions with their doctor and find the right dose that gives them the efficacy. That's actually a positive in- Right ... commercial space, so I hope we can replicate that same kind of experience with orforglipron, which involves some manufacturing complexity because you're making more doses, but it gives patients the options to titrate up. So different than other therapeutic areas where you might try multiple doses because you're not sure which one will work, and you're gonna pick one to commercialize. I think the intent here would be to commercialize all of the doses- Got it. Got it ... if successful. Maybe not to harp on these doses too much, but Phase III dose selection, one of the things that stands out in some of the early data, both preclinical and in Phase I, is that oral bioavailability is perhaps not so high on this. So I was thinking back to tiny numbers, but 27 and 45 milligrams in Phase I having similar AUC, and three and 15 milligrams having similar Cmax, and then there's, like, a mouse paper talking about bioavailability being low. I guess I'm more asking that in the context of, sure, there's dose saturation from a efficacy- Yeah ... response perspective, but could that simply be a function of bioavailability playing out there? Yeah. Yeah, of course, we look at exposure related to response as well as dose related to response to pick our Phase III. but you raise a good point. I think it depends on what you're comparing it to. So if your yardstick is oral peptides, you would say it has excellent bioavailability, orders of magnitude better. On the other hand, if you're talking about, like, typical small molecule orals, I agree, bioavailability is quite a bit lower. But you know, compared to the alternatives here, which are either injectable peptides or oral peptides, up until now, I think this is a huge leap forward. Got it. My last one on this: I know there's a trial you're running versus insulin. It's ACHIEVE- 4 study. There were two things that stood out about it. The one, there's only one dose, not three dose levels, so I'm assuming it's the highest dose level. I could be wrong. The other one is, this was the only trial that you've posted online which has ALT and AST exclusion criteria spelled out on ClinT rials. I wonder if that ALT above 5x excluding criteria was implemented across Phase III program? I think that the liver enzyme inclusion exclusion criteria are the same for orforglipron as they were for tirzepatide, and as they are for retatrutide. I, I know the inconsistency in what we published on ClinicalTrials.gov is confusing. So sometimes it ends up on there, all of the inclusion, exclusion criteria, sometimes they're not included. But that I wouldn't read anything into that. That trial is not different than the rest of them in terms of the inclusion, exclusion criteria. Okay. Maybe the last one, on oral GLP for me- Yeah ... is, there's so much focus on this program now, Yeah, that's right. Maybe in part because there's so much generalist interest in Lilly, and they think of oral as the next thing after injectable. If that program did not exist tomorrow, all of a sudden, for example, do you think it changes overall the GLP strategy that you guys are on, and the commercial competitiveness? Yeah. I mean, of course, we want all of our programs to succeed, but I don't think Lilly's dependent on Phase III pipeline asset. I think part of the investor interest could be what you said related to general investors. But actually, I think the patient acceptability of a once a weekly injectable is quite high, actually, and we are seeing a lot of interest in primary care use. And on the other hand, I know there's a number of companies with oral incretin programs that are investable and biotech valuations, so that could actually drive a lot of investor interest that maybe they're rooting for their success or something. Got it. I think we're gonna be okay. I did say that that was the last one, but I did have one more last one. Okay, that's all right. I thought, I remember I was tracking when the first Phase III would come out for Lilly, and clinical trials used to imply January next year, and I think now it suggests April. I wouldn't think of oral GLP as something that would recruit slower, so- Yeah ... I'm not I'm not sure what happened there. Yeah, I'm not sure either. There's actually a computer program that populates ClinicalTrials.gov- Okay ... from our protocols and from our scheduling software at Lilly, and it- Okay ... changes the dates, but the- Must be ChatGPT. Yeah, maybe. I hope it's not AI powered, but the trial actually is enrolling faster than expected, so I can't really explain why the dates changed a little bit on ClinicalTrials.gov. Okay. All right. They're within an appropriate range of accuracy before and now, so. Excellent. Mike, did we miss- Just one question on, on, The fifth question on oral GLP? One question on toxicity. You guys conducted nine-month toxicology studies in non-human primates. The safety margin was very low, it was below one. Any reason why that was, or? He's talking about the no observed effect. Yeah, the no observed adverse effect level was three mg per kg in monkeys, but the exposure multiples for the 45 milligram dose were like- Yeah ... 0.77, 0.87. I actually don't recall the details of that, but I know in general, what we find with high-dose incretins in non-human primates is weight loss, and so often we have to stop the tox studies because of either weight loss or GI side effects. We know that weight loss is intended pharmacology, and GI side effects can be mitigated by dose titration. So often in the non-human primates, we can't get for any incretins, injectables or orals, we don't get multiples of NOELs because of the expected pharmacology. But in general, the non-human primates don't have diabetes or obesity, so it's not optimal for- I see ... studying these drugs. Okay, excellent. Maybe, let's talk about Triple G. Yeah. I don't know what the internal, Well, that is the internal name. Yeah. The external name is now retatrutide. Okay. Yeah. On Triple G, some of the cardiovascular observations on adverse events, they could potentially be on target because of the glucagon receptor expression in myocardium. How do you think about that and the overall safety profile on that program in particular? Yeah. I think most of the cardiovascular effects we see are probably GLP-1 mediated, but undoubtedly there's some glucagon pharmacology, and we know glucagon alone can cause some increases in heart rate and improvements in cardiac contractility. I think these are likely to be non-adverse to the drug, and they're within the range that is seen with other incretins. So, for example, one measure of heart rate excursions is 20 beats per minute, and, you know, how many patients got above 20 beats per minute increase in heart rates? That's a threshold that's commonly passed with incretins. So, for example, I think the semaglutide label has nearly a quarter of the patients having a 20 beat per minute excursion. I think we have fewer than that with retatrutide, but there are some patients who see increases in heart rate that attenuates over time, as it does with other incretins, including semaglutide and tirzepatide, where people have an initial increase in heart rate, and then as they stay on the drug, it comes back down. And we now know, I think, and the reason I mentioned semaglutide is, we know from the SELECT data that despite causing heart rate elevations in a fraction of patients, it results in an overall positive cardiovascular risk profile. So, that's not a particular concern for retatrutide. But, you know, like I said, for orforglipron, when a molecule Phase III, this is the time that you look for safety signals in a large population, and, you know, that's one of the many things that we look at with retatrutide. We also look at liver safety with retatrutide, just as we did for orforglipron. And we'll keep our eyes on all the safety issues. What about arrhythmia? Because I thought that was, or at least I recall now, arrhythmia, there was a prominent safety table call-out for that with the retatrutide. Yeah. I think that the arrhythmias we saw were related to the increased heart rate. Okay, okay. So they were tied to the heart rate. Okay. Yeah, I believe that's correct. Okay, excellent. Maybe the last one on this, I think there's early hints that there might be an interesting kidney clearance, eGFR increase potential here. Not just stabilization, but an eGFR increase. What would that look like? Could a 5-point eGFR improvement, something along those lines, doable, or is there a certain minimum eGFR you have to be? I'm just trying to think about the CKD opportunity with this program. Yeah. Yeah, I actually think this has a very significant effect on the kidney, and maybe too soon to speculate on numbers. But actually, when I look at the totality of the data we have with retatrutide and compare it to, like, tirzepatide, there's a couple of places where you can put your finger on something that's likely to be glucagon-driven effect. I think the degree of weight loss, which looks likely that it'll be superior to tirzepatide, is glucagon driven. I think the profound decrease of liver fat to 90% is likely glucagon. And I think this kidney effect that is possibly a benefit for CKD is likely to be glucagon driven. So those are all things that need to be explored in additional clinical trials, for sure. Okay. Any questions on any of the topics so far? I wanna make sure everyone in the audience gets to ask as well. Okay, so maybe we'll keep going. I know GLP are the magic drugs right now, and they work everywhere. Is there an indication where you think they're higher risk than others? And conversely, what are the lower risk? And I'm talking beyond obesity, beyond diabetes now. Yeah. So, I don't know if there's much magic here, but, you know, clearly, abnormal metabolism and obesity are bad things, and, GLP-1s and, of course, particularly dual agonists like GLP-1, GIP, which is tirzepatide, seem to have a very important effect on improving metabolism, which could lead to benefits in a variety of diseases. So, of course, diabetes and obesity is where we're approved right now. In the next year, we're gonna have a readout in obstructive sleep apnea, in patients with obesity. I think there's a lot of potential there, but we don't have any data. We didn't do Phase II trial. Pharmacologic approaches here are untested, but we know that weight loss with bariatric surgery or with lifestyle modification can lead to improvements in obstructive sleep apnea, so I'm excited about that. We have a heart failure study that'll read out next year. I think, again, having seen competitors' data, we're pretty excited about the profound effect that this mechanism could potentially have there. And then, a NASH. We have a NASH Phase II, NASH study reading out next year, which, you know, I think could also be important based on the amounts of fat we drive out of the liver. So those are all pretty important indications that are tied to metabolism and weight loss that- Got it ... I think we could benefit in. I wanna spend more time on heart failure. Sure. Not right now, but on my own end- Okay ... down the road. But one thing that did stand out to me is much of the heart failure findings so far are not on a composite outcomes endpoint with the evidence to date, and it's more on measures that approximate those things. How do you think about cardiologists' interest in outcomes-based endpoints for heart failure, rather than some of the data we've seen so far? Yeah, I think they could both be important. The sema data we saw had improvements in the quality of life questionnaire. Right ... as well as, six-minute walk. But when you look at the outcomes, there were very few because it was a smaller, shorter trial. Right. I think we have a larger, longer trial. Maybe we'll get more patients driven to outcome and be able to demonstrate duplicates. And then if we want that, in your view? I don't know. Okay. Of course, it's always better to have outcomes than- Okay ... not to have it. So that, maybe that's an easy yes. Of course, it's great. There's so little advances for this population, though, that I think we should be pretty excited about what these ingredients can offer. Got it. And on NASH, the question that comes up is: liver fat reduction is clear, 70%. What about fibrosis improvement? Your expectations there, and any prior evidence that points us to fibrosis benefit. I don't know what the reversibility of fibrosis is with a metabolic agent. You know, when I think about the pathophysiology of NASH in simple idea, I think it starts with ectopic deposition of fat in the liver, which then leads, as it does in every organ, to inflammation, and then that inflammation leads to tissue destruction, which leads to fibrosis. So I would be confident, I am confident that we can reduce fat, and that can reduce inflammation. Probably, we should be able to see a reduction in progression of fibrosis. But in terms of regression or reversal of fibrosis, that feels like a higher bar to reach. Right. There's- But conversely, Dan, isn't it that if it's F4 patients, which you're not studying, then it's very hard to see them come back to F3? But F2- F3 is a spectrum that biopsy to biopsy for the same patient could go back and forth. As long as you're not getting much progression, you kind of end up with the fibrosis benefit, the way it's defined in the trial, while not necessarily getting... Yeah- … you were- You're raising a good point, Amar, which is that, you know, we kind of think of, you know, a quick glance, you'll say: "Oh, the biopsy is a gold standard. It tells you what's really happening to the patient." But actually, it's a tiny piece of tissue that's read sometimes in ways that can vary even from reader to reader. And when you take another biopsy from the same patient, you can get a different answer. And so if you've had lack of progression, that could look like reversion to the mean in a large enough study. I don't know if we have a large enough study to create that effect, but it's definitely possible. And for that very reason, even a reversal of fibrosis should be interpreted with caution in a trial like this. Well, I think Lilly has an important role, and we're making progress in advancing the field of NASH towards biomarkers. We don't love doing trials with liver biopsies, and I think the future will be non-invasive ways of monitoring liver function and NASH progression or regression if possible. Got it. As I was going through the SELECT data, which came out at AHA recently, we were trying to think about the North America, how that performed versus the overall trial. And we said, "Okay, let's go find CVOTs for other GLP studies." I know Mike made a nice slide around North America performance, and it looks like several other trials, I believe, including the Trulicity trial. North America did a little less than what the overall trial suggested. I guess what was the. Do you recall some of the FDA interactions around how North America population gets evaluated, or were they focused on the totality of the trial? I don't recall that being a review issue for Trulicity. I think with respect to sema, obviously, that feels like a Novo question. There could be a lot of reasons why different countries could perform differently. Probably, the first and most important one is that none of them are big enough to be powered for stat sig, and so the variability on a country-to-country basis is to be expected. Of course, the standard of care and what alternative treatments are available and used will always impact also the magnitude of benefit that you can have for a given drug, so that could be part of it as well. Okay, excellent. I'll spare the other question, which is more SELECT specific, which is not a Lilly question. Okay. We can talk about the early separation another time with a different company. All right. right. Yeah. But on the question on the trial you guys are running Yeah ... for past CVOT, semaglutide as a comparator. Sorry, did you guys consider using semaglutide as a comparator? Yeah, so we're running this trial as, which I think is a really bold idea, head-to-head against Trulicity, against dulaglutide. When we started this trial, Trulicity was the, the leading, GLP-1 in terms of, I think both TRX and NBRX. And importantly, and this is still true today, Trulicity is, is the GLP-1 that demonstrated benefit in a, a mixed combination of, mixed population of both primary and secondary cardiovascular, risk prevention. So we're excited to have the opportunity to compare to Trulicity as, as a gold standard for efficacy in this population. I, I think the, the study's designed around, non-inferiority, since Trulicity itself has a benefit against placebo. Right. I think it would be non-inferior to Trulicity that shows a benefit versus placebo, but I'm optimistic that maybe we could also hit superiority, which is clearly a secondary here. Having seen the benefits of weight loss, there's a pretty big difference in weight loss between Trulicity, which probably had very little or negligible weight loss in REWIND, versus what we expect to see with tirzepatide, which I think in trials of Type 2 diabetes patients showed about 14%-15% weight loss. Okay. But, but the critical thing, which is what I was gonna get at, in a sub-15,000 patient trial, the goal is non-inferiority because this is the first head-to-head versus the GLP- Yes - in a CVOT setting. That, that's the primary endpoint. Correct. Okay, makes sense. Mike, anything else on GLPs or anything from audience on GLPs? Yeah. Perhaps it's more of a commercial question, but how do you see maintenance therapy in the current class? Right now, it's not really being talked about or studied right now, but everyone assumes that- Yeah ... patients aren't gonna take, once they've lost the weight, patients aren't gonna take the drugs as frequently. Any thoughts there? Yeah, it's a good question, Mike. I'd definitely maybe caveat it by saying it's easier to predict scientific outcomes than it is to predict human behavior. So I'm not sure what people are gonna do. We wanna make sure they have options. One option that people have right now is they can change their dose with their doctor of their incretin. So, well, actually, tirzepatide has multiple doses that are approved, as we were discussing earlier, and I think patients enjoy having that control of their disease. In the future, I hope we can have other options for them too. Maybe some patients will prefer maintenance on an oral. I don't know. Maybe other patients will prefer to start their treatment with an oral, and if they don't get enough efficacy, switch to an injectable. We'll have to see. We haven't done any studies yet to test different maintenance regimens, but I look forward to exploring that area. I think it could be important for people to know what options they have once they reach their target weight. One thing we know that is not an option is coming off of the drug, and what we see is, for most patients, their weight gain returns if they come off the drug. So there's two components of that, Dan. One is you come off the drug, clearly, there's weight gain. Yes. I feel like we have not seen those randomized studies track long enough to see whether you go all the way to baseline, or do you go half the way to baseline. Do we have a sense for that? I think you're right that we don't have enough long-term data of people who withdraw from therapy, and becoming increasingly hard to do those studies because, well, we know treating obesity is important, and taking patients off of a drug that's working is a hard thing to do. Also- I, I don't know. My prediction is, if you look at the data with enough granularity, you'll find subgroups of patients who are better able to maintain at least part of their weight loss, and other patients who may revert back to baseline. I think the mean of the population, at least in the duration of studies we've examined, doesn't return to baseline, but surely some patients must. Got it. Have you guys, as we sort of, because there's multiple layers to this duration question- Yeah I'm sure there has been work done within Lilly just to understand Trulicity historic median duration, how that compares versus Mounjaro. And I do understand the Mounjaro question is a little more complex because it's loaded with confounders. Like, there were some payer changes, supply shortages, so you may not actually have a true duration number. But has that been a question that's been studied at depth internally on what is the actual realistic duration? Because that can clearly drive what type of future demand to expect based on the- Yeah. I don't think we have great ways of studying it internally, unfortunately. I agree with your comment, though, that looking back, you know, the last year of Mounjaro sales is not the way to do it, because we had patients on a $25 copay card, and then that went away, and then they stopped. And there've been supply shortages for us, and I think also for our competitors. So it's a confusing scenario out there right now. But I do note that for Type 2 diabetes, which is where we've had Mounjaro up till now, for Type 2 diabetes, Trulicity had very good patient adherence and refill rates that were superior to the orals out there for Type 2 diabetes. And of course, Trulicity was treating something that was mostly invisible to patients, which was their A1C. Here, we're treating something that patients can feel and see, as well as giving them other kinds of health benefits. So they can feel the sense of hunger that often accompanies obesity, and with treatment on these drugs, that usually goes away. And people often report that the food noise has gone away, and that eating is a choice now. They say, "This must be how other people feel normally." I think that's a powerful motivator for people to stay on drug. We've also heard, this is anecdotal as well, that when they come off of drug, that returns, and even before the body weight comes back, they start to feel the hunger and the focus on food that they don't find favorable. And so that could be a motivation to stay on drug. So I think it's early days here in the class. My prediction is patient adherence will be high, and persistence will be long, because of the benefits that patients have with these medicines. Got it. I know lately there's been a big investor question around muscle issue. How big a deal is that realistically based on some of the feedback you hear from various sites that have been- Yeah ... working with you guys, commercial feedback? Yeah, actually, we haven't heard that it's an issue at all from sites or commercial feedback. Specifically, what you're referring to is the fact that patients lose some lean body mass along with their fat body mass, that probably they lose about- So that's how I lost my muscle by the way. Yeah. Yeah. Me, me too. So, probably it's a—it's about a 3:1 ratio of fat to lean mass loss. That, that's actually relatively consistent, whether we're talking about weight loss from pharmacologically induced weight loss, or bariatric surgery, or intensive lifestyle modification, that when the fat comes off, some lean mass comes off as well. That's probably a combination of metabolism, as well as utilization. So in other words, when people have more weight to carry around, their core muscles are stronger and exercise more. When they lose that, they're less needed. The question is: Does that have any functional consequences? Actually, what we've seen so far is functional benefits to weight loss. Again, whether it's intense lifestyle modification or bariatric surgery, or pharmacologic, there's actually functional improvements because their overall body composition has improved. They've lost more fat than lean mass, so therefore they generally feel like they can conduct activities better. Okay. However, there may be some patients, although we don't have evidence for who this is yet, that could benefit from both weight loss and maybe more muscle. And that was the thesis behind bimagrumab, and we're going to combine it with tirzepatide to see if we can drive weight loss, while at least preserving, if not increasing lean body mass. The challenge will be to show functional benefits from that, not just a difference on a DEXA scan, that show that that muscle mass really leads to even better function than the functional improvements we expect to see with tirzepatide alone. It's a long road- But wouldn't that be a very complex endpoint then? It is- Healthy individuals, knowing that Novartis' myositis trial was more tricky on that. Absolutely. I think regenerating functional muscle was proven not successful yet with this drug- Right ... or with others. Maybe maintaining functional muscle is easier. But I know a lot of, you know, investor interest and questions have been around: Well, is this correcting a liability of the incretin class? That would actually be easier to Phase III trial if it were the case, but that is not the case. Right. It's more about trying to add an additional benefit, which is gonna be harder to prove, but that's why we bought Versanis. We're ready to take that on. Got it. Dan, so one of the my impression of Lilly's R&D strategy, your R&D strategy over the last few years has been, there's been constantly this having iterations of various molecules on that validated target, oral, higher efficacy, different second target, et cetera, which has been very successful. One thing I've not seen enough of, or one thing I'm starting to see from other companies so far, is novel non-incretin orals going to the clinic. So Amgen has one, and Pfizer has one as well now. I guess, where's your head at on that, and is that something you're going down the direction of as well? Sure. I would say we're interested in all mechanisms for obesity. I think it's probably wrong to assume that just because the incretins are working for obesity, that this has sort of ended the drought, and now everything that we try will work for obesity. I think the bar is really high for anti-obesity medications, and we'll be selective about what kind of mechanisms we test. Probably the most important factor to consider is safety. The incretin classes set a high bar for safety, and I think there can be very little tolerance of safety concerns for anti-obesity medications. The second consideration is efficacy, and the incretin class has set an extremely high bar for efficacy. So, it's been you know, traditionally hard to make new mechanisms for weight loss. I expect that hasn't changed, but I know investor interest has changed. That's- Got it. That's great. Got it. We welcome more investment in this area. I wanna move past GLP in the last 10- minutes. Okay, excellent. But- Yeah. Since there's 18- seconds remaining- Okay, one more. I will ask you one follow-up. Yeah. Is there more intensified liver monitoring on your oral GLP Phase III? Yeah. I think there was some confusion around what you said on the call. No, it's. It's the standard- To my knowledge, it's the standard. Same as tirzepatide, same as retatrutide. Okay, got it. Okay, excellent. So let's move on past that. I know, for abemaciclib, there was a trial due in prostate setting, which could have been sort of well beyond breast cancer. Is that, prostate trial CYCLONE- 2 still due late 2023? It's event-driven. I don't know if there's good visibility on that. Yeah, it's a... As you said, it's an event-driven trial, so we never know exactly when it'll finish. But I think late this year or early next year is the right target to think about for that trial. Pretty excited about that trial because we had a, you can think of this as an adaptive design, where there was Phase II part of the trial, which we didn't see the data from, but it had a high bar to adapt Phase III trial. so efficacy topped that bar, and then the trial expanded automatically to Phase III. so excited to know that at least in that first cohort of patients, who also comprised part of the final efficacy data set, they topped a high bar for efficacy. Right. I hope that holds up in the rest of the population, this will be a great drug. The previously disclosed data for abemaciclib in prostate, I'm not talking about the Phase II- Yeah ... that's passed the bar. Phase II. The prior data was only 7% response rate, but that's not unexpected because of CDK4/6 mechanism of, Yeah. But also PFS was about six months, 6.5 months. I guess, could you remind us, based on that alone, I wouldn't have said it as passed a high bar, but I know there was a randomized trial which passed a certain bar. Exactly. Can you remind us what the design was there? Sure. So, CYCLONE- 1, first of all, is this small trial, maybe it was a Phase I or Phase II- Right ... which enrolled pretty late-line patients with prostate cancer. So- Okay ... sick patients and tested monotherapy, which Verzenio works in breast cancer as monotherapy as well, but it's pretty small effect size. I think the main mechanism of the CDK4/6 inhibitors work is in combination with endocrine therapy. CYCLONE- 2 is in combination with endocrine therapy in prostate cancer. CYCLONE- 2 Phase III we're waiting for, started out as Phase II trial, and then based on a positive endpoint in Phase II portion of the trial, it adapted to become a Phase III. And that Phase II- Exactly ... was randomized? Yes. Okay, so that's critical. CYCLONE- 1 was monotherapy, CYCLONE- 2 was endocrine add-on, and it was randomized, and that's where you- Yeah. And I would imagine fewer lines of prior therapy, less severe population. Got it, got it. Got it, got it. Probably the endocrine therapy is the biggest contributor to efficacy, I would say. Got it. Okay, But we certainly wouldn't have Phase III based on CYCLONE- 1, in the absence of, right, CYCLONE- 2 sort of interim analysis. Got it. Maybe a program that's near to your heart, the Alzheimer's program. How are you thinking about a sort of donanemab set up into the launch next year? I realize Biogen is progressing with their launch right now, but there's a lot of commercial challenges they're encountering. Yeah. How are you thinking about sort of the market development? Is it not what you would have thought? Oh, I don't know. Of course, this is near to my heart because I've been working on it for a long time. All of our programs are near to my heart, but in Alzheimer's disease, having worked on it for a long time, I've noticed that there's a pretty slow adoption of new ideas and new technologies across the field. I think neurology as a practice is probably not seeing many advances in Alzheimer's disease. And so my expectation is it'll take a little while for practice patterns to change around diagnosis and treatment. And this is a complicated class of medicines to use, in many cases requiring a PET scan for diagnosis, which is a technology we developed and hope to see more uptake of now. And then, a drug that's delivered by infusion, in the case of our competitor, every two weeks, for donanemab, hopefully every four weeks, if it gets FDA approval, which we're expecting, early next year. So that, that's a new thing for neurologists. They don't give a lot of infusions. And then there's a side effect called ARIA, which requires MRIs to monitor, and that adds more complexity. So it's gonna take time. Most of the prescribers we talk to indicate a willingness to try these drugs, a belief in the efficacy, which is great news. I think that's huge progress, that they think the effect size here is real and meaningful benefit for patients. And their main focus now is on safety and going slow as they start patients, so they learn how to manage patients on these drugs. I think that's a healthy setup for long-term growth. But at the same time, I think that setup probably indicates a slower ramp than, for example, what we've seen with- Right ... obesity drugs or something like that. Dan, how are you thinking about the ARIA rate findings on remternetug, especially on some of the doses that are competitive? Yeah, it's still early to say. I think this is in kind of a dose-finding regimen, part Phase III that will then go into a focus on a single dose as the trial expands. I think our goal here is to, you know, continue to do our best to drive ARIA rates down, particularly symptomatic ARIA. That's what we're most concerned about- Yeah ... and particularly serious adverse event ARIA. The radiographic ARIA rates are probably a little bit harder to index on, and depend on a number of factors. Got it. In the last 4 minutes- Okay ... I wanted to touch up on your new job... Okay. Yeah. Immunology, and maybe a couple of questions there. One, how do you see the IL-23 class playing out in the IBD space? I always felt like the early data on UC was very competitive versus Entyvio. We know Entyvio is very sizable. You guys have obviously gotten a leadership position timing-wise on the IL-23 as well. How are you thinking about the broader IBD opportunity? Yeah. So, maybe I just start at a high level, which is, IBD is a pretty significant disease. There's probably about 1 million people with Crohn's in the US, and, less than that with UC, but still quite large. Biologic penetration still isn't where it needs to be, particularly in UC, and even for patients who get on biologics, many of them end up cycling across therapies because they don't get remission with the first biologic they try. So, that, that's a pretty good situation, I think, for us to enter into with the first ever IL-23p19 in mirikizumab, approved for ulcerative colitis. You know, we don't have head-to-head data in this indication, but certainly the numeric efficacy numbers we saw were as good or better than any biologic in this disease state. So I think your assumption that IL-23s are gonna be important for UC and IBD more broadly is a good one. I expect mirikizumab to do very well in IBD, that there aren't really small drugs in this category, and a lot of growth possible given the number of people affected and the lower penetrance and the multiple lines of therapy that are offered. Did you think TL1A data was differentiated over the IL-23 data? I think it's hard to say, comparing Phase II- Phase II trial. They seem roughly on par. I think the interesting thing about that mechanism of action is the ability to select potentially a subpopulation that can respond better. So the- Right ... biomarker positive data is interesting if that's reproduced, and if the two companies that have those two assets decide to pursue that as their indication. I think on the all comers, probably not differentiated. Got it. Okay. On the DICE molecule, it looks like it's active at the 200 mg BID dose, but to really hit the target properly, at least on a patient-level scatter plot, 800 mg BID seemed to be the right dose, which made me wonder, is 800 mg BID the viable program, or should we really be thinking about the preclinical one entered Phase I- Yeah - more potent? 800 BID is a pretty high dose. We don't see a lot of drugs with that kind of dose. Right. Of course, it all depends on efficacy and, and safety, right? Otherwise, dose is just a, a number. The 200 mg dose looked like there was efficacy. I, I think it was a little bit hindered by a couple patients who had really low PASI scores at baseline, so there wasn't much opportunity for improvement, and maybe another patient who discontinued therapy. So there's, you know, if we focus on the patients who had reasonably high PASI scores at baseline and stayed on drug, there's, I think to my eyes, although small numbers, there's definite efficacy at 200. Okay. Is it gonna be enough to be competitive with biologics, which is a profile we want for an oral? I don't know yet. I think that's why we're doing Phase II. so we're excited to see Phase II for the lead compound, and then the next gen compound looks quite a bit more potent. So my expectation is we could see similar efficacy to the 800 BID- Got it ... but at much larger. So the deal is not exclusively on the backup molecules? We purchased the company. We have a great team there and a great platform. I expect there to be multiple molecules coming from- Got it ... the DICE group in San Francisco. They remain intact and growing, and we're helping them develop more small molecules for IL-17, as well as other targets in immunology. Got it. So speaking of M&A, I did wanna ask two last ones. One is on POINT. I heard yesterday, I wasn't keeping close track of this. I heard yesterday that POINT is trading above where the bid came in. Yeah. Can you... What, what can you say- Yeah ... about POINT overall and- It's an unusual situation, a little bit confusing to us. I think Wall Street may be misreading some of the signals that they're getting here. Of course, you know, POINT is a radiopharmaceutical company working on a lutetium PSMA drug, which we think has great potential. It's partnered with Lantheus, where a lot of the economics will go. But Novartis released their data from PSMAfore, and I think there was some excitement about POINT, which is gonna have an upcoming readout in SPLASH, thinking that the Novartis data created an opening for SPLASH to do even better. I'm not sure about that. But you haven't seen the SPLASH data? No, we've not seen the data yet. And my baseline expectation is that it, there's no reason to expect it to be different than Novartis data. I think overindexing on immature OS data is a bad idea, and I'm not sure it really matters either, actually, because the OS data that matter probably are gonna be subsequent cuts of the data when it's more mature. Our interest in POINT is a lot around the platform. Again, the ability to make multiple radiopharmaceuticals, I think, is an interesting area of medicine. I've personally been interested in radiopharmaceuticals for a few decades now, and I think the time is right to get into therapeutic radiopharmaceuticals. They have a manufacturing facility under construction, and I hope we can- Got it ... complete the acquisition, help them build it, get it inspected, and start launching products. Got it. Just as we wrap it up, Dan, your overall thoughts on biz dev in general are- Yeah. It's interesting that you're being a little more active now, but being very careful. There's no big dollar checks. How are you thinking about that overall? I think it's hard for any pharmaceutical company to generate value for investors if they're the high bidder in a auction of a de-risked asset. It's not to say we'll never be the winner of- That's most of the large pharma space. I know. But it really is converting, you know, balance sheet to cash flow, which, you know, could be in a value-destroying way. I would rather be the acquirer of underappreciated assets that, you know, are maybe not easily understood, and that, almost by definition, means we'll be taking a minority view if we're gonna win it. We're not taking the majority view and outbidding everyone else, that we see value where others don't, or we have a unique way of finding value because of our portfolio, because of the strengths that we can add. It also means we'll go a little bit earlier than most. We have a bias towards great teams of people, different than other companies. Some companies have a bias towards great assets, and then they dissolve the team and find cost synergies. Our play is find great teams and retain them and grow them and see what they can accomplish. So it's played out pretty well for us so far. Excellent. Joe, did we miss anything? Joe said, "Thumbs up," so I think- Great ... we're good to go. No, thanks for the great questions. Excellent. Great seeing you. Thanks for the discussion today. Absolutely.