Eli Lilly and Company (LLY) Earnings Call Transcript & Summary

All right. Well, good evening, everybody. Thank you for joining us. I know it's probably been a long conference already, but we're very happy to host you here tonight at the -- in Chicago at the ADA Scientific Sessions. I'm Mike Czapar. I'm Senior Vice President of Investor Relations for Eli Lilly. Very happy to spend some time with you this evening. On Slide 3, we have the agenda. So we've got 3 speakers. We'll do some presentation, prepared remarks, followed by a question-and-answer panel. So to kick things off, Ken Custer, who is our President for Cardiometabolic Health, will give an introduction and give some backdrop on the cardiometabolic health strategy. We'll then hear from Dr. Jeff Emmick, who is our Senior Vice President for Cardiometabolic Health Product Development. He'll walk through some of our recently presented orforglipron data, ACHIEVE-1, as well as highlight some key events for the remainder of the year. And then to wrap us off, we'll hear from Dr. Ruth Gimeno, who is Group Vice President for Diabetes and Metabolic Research. And we'll then have a Q&A panel and hopefully finish timely at 8:00. So also for your reference on Slide 4. During this presentation, we anticipate making projections and forward-looking statements based on our current expectations. Our actual results could differ materially due to several factors, including those listed on Slide 4. Additional concerning factors that could cause actual results to differ materially are contained in our latest Form 10-K and subsequent filings with the SEC. The information we provide about our products and pipeline is for the benefit of the investment community, and it's not sufficient for prescribing decisions. With that out of the way, I'll turn the call over to Ken Custer to kick things off.

Thanks, Mike. It's my pleasure to be here kicking off our investor event at the 85th meeting of the ADA. For those of you whom I haven't met, my name is Ken Custer, and I've recently taken role as President of Cardiometabolic Health at Lilly. My colleague, Patrik Jonsson, is moving to lead Lilly International, and I look forward to working closely with him to have an enormous potential human health impact over the years to come. I began my career at Lilly 16 years ago, and I've worked in sales, marketing, R&D leadership, business development and general management, most recently serving as President of Lilly Canada. It's a privilege to be coming back here now to the business unit where I started my career to be a part of the next era, which we'll be talking about tonight. It's been exciting to see the science and clinical data presented at the meeting. In many ways, ADA is mirroring Lilly in that it's placing greater and greater emphasis on areas like obesity. We've been innovating in diabetes for over 100 years, and we remain committed to providing individuals with freedom to diabetes, but we're also working to address other areas of cardiometabolic health, including eliminating serious health issues caused by obesity and reducing cardiovascular deaths. Much of the conversation with our investment community over the recent years has been focused on incretins. In some ways, it can feel like it's -- we're an overnight success in this space. But it's important to remember, we've been working for many years in this area. In fact, we launched our first incretin medicine over 2 decades ago. Along the way, we've developed capabilities and expertise that have made us the leader we are today. And what we're very pleased with the impact we've had with Zepbound and Mounjaro, which launched really in the last 3 years, we're not satisfied. If we go to Slide 7, you can see the size of the problem we're trying to tackle. Right now in the United States, there are 8 million people currently being treated with incretin therapies. But if you project to the end of this decade, there are likely 170 million people that could benefit from incretin therapy due to various cardiometabolic diseases. That's just the U.S. picture. If we think about the total globe, by the end of the decade, you can envision 1.5 billion or so individuals living with overweight and obesity, 1 out of every 3 adults living with some cardiometabolic disease. Pick your statistic, whichever one you like, that's a lot of people. And it's unlikely we'll help them with a single molecule, even tirzepatide. That's why we're bringing forward the broadest pipeline in the industry of medicines that are really tailored to the needs and preferences of individual patients. We fully expect the obesity market will segment into several logical categories based on things like the patient's preferred route of administration, maybe less frequent dosing, tolerability, maybe a patient wants greater weight loss, different quality of weight loss. They want greater depth of glycemic control. Maybe they need additional metabolic benefits that our scientists can engineer into these molecules. Shown here is our current pipeline in cardiometabolic health. We flagged several molecules where we're sharing key updates at this year's ADA meeting. That includes orforglipron, our oral small molecule GLP-1 agonist; as well as eloralintide, our selective AML agonist; bimagrumab, our active and receptor pathway modulator; and finally, insulin efsitora alfa, our once-weekly insulin, where we're sharing Phase III data from 3 trials, which show that insulin efsitora provides comparable glycemic control to the best daily insulins -- daily basal insulins, while eliminating more than 300 injections a year for patients. As you look at the rest of our pipeline, you can see that incretins and incretin combinations remain our greatest area of focus. That's a reflection of the opportunity we see to positively impact human health. But the potential for incretins likely extends beyond cardiometabolic health. You can see in the lower right, we've highlighted some areas where Lilly has existing expertise and where we see opportunities based on observations from clinical data, real-world evidence and emerging biological insights that incretins could benefit patients in these categories. That includes areas like brain health, inflammation, pain and substance use disorder. These will become areas of focus for Lilly moving forward. Before I hand it over to Jeff, I just want to touch on orforglipron. Slide 9 shows a lot of the reasons why we believe that this could be an important medicine for the globe moving forward. Okay. There are many other exciting ideas that we continue to evaluate, and I fully expect that the trial footprint for orforglipron will continue to expand. It's important to note that orforglipron uses a separate manufacturing footprint than our injectable incretins. We've been investing at risk in manufacturing to support a global launch. And orforglipron, unlike our injectable incretins, does not require cold chain storage, which will simplify distribution, both in developing markets as well as developed markets. Last, as we think of the totality for orforglipron, we think this is a very attractive portfolio -- attractive profile. The idea of a once-daily pill with no restrictions on food and water that provides efficacy, safety and tolerability comparable with injectable GLP-1s, combined with Lilly's international reach and scale, we think this gives us the ability to impact human health at a scale that maybe no institution in recent memory potentially -- or has potentially done. So with that, I'm going to turn it over to Jeff Emmick for an update on our development work.

Thanks, Ken. Great to see many familiar faces again. I know I've interacted with a lot of you a lot over the last several years. And I reflected today or actually this weekend. It's been another great weekend for us with several Phase III readouts. I think as some of you may know, I've been in this role now for, I think, 11 years with much of it working with my early phase colleague, Ruth Gimeno, and I've -- I'm fortunate to have had the opportunity to watch tirzepatide go into Phase II, into Phase III. We've had now like 4 or 5 years of major readouts at ADA, and now it's really rewarding to watch orforglipron, which when Ruth and I were involved in the business development deal with Chugai, was not even in a patient yet. It was preclinical. Watch it go through Phase II, presented at ADA a few years ago and now Phase III. And then efsitora alfa, which I won't talk a lot about tonight, but I hope some of you took note of the fixed dosing study QWINT-1 and the unique opportunity as we think about transitioning patients, not transitioning, but potentially having to add insulin to patients who are already on weekly incretins because it could make for a very easy transition. So I want to start by talking a bit more about our orforglipron development program. Hopefully, the slide advance will work. Okay. On Slide 11, you can see a summary of the program. I think all of you already know and Ken highlighted this. We have the ACHIEVE type 2 program which consists of 5 studies, and then the ATTAIN chronic weight management program which consists of 2 studies. I'm not sure if you know the entire global development program encompasses over 11,000 patients. So it's a huge program. And so we're just seeing a glimpse with ACHIEVE-1. A lot more to come through the remainder of this year and a little bit into next year. As we've announced previously, we anticipate starting submissions for chronic weight management later this year. And for type 2 diabetes in the first half of 2026. Before I get the question why diabetes after chronic weight management, I think many of you probably know that the diabetes development guidance requires 24 months of exposure versus 18 with chronic weight management. So it's really, we started the programs almost in parallel, but the trials are a bit longer. On the right side of the slide, I just wanted to point out that we also have ongoing orforglipron Phase III trials to address -- assess maintenance dosing, including maintenance dosing after injectables; obstructive sleep apnea, kind of following on our history with tirzepatide in that indication; and hypertension. Something we're also very excited about given the blood pressure reduction that's seen across the incretins. With respect to the ACHIEVE program, the 5 trials, as you know, assess patients across the type 2 diabetes journey. Starting with ACHIEVE-1, which was a monotherapy study, placebo-controlled where patients could only be on exercise and diet to ACHIEVE-1 -- ACHIEVE-5 which studies orforglipron in combination with insulin. I bring this up because it's important as we think about the baseline characteristics of the patients. They do vary across that continuum of ACHIEVE-1 to 5 with lowest baseline hemoglobin A1C values typically in the monotherapy studies, highest in our add-on to insulin studies. And one thing I would highlight that as we've done more and more work and analyze data, there seems to be a floor in hemoglobin A1C with respect to the GLP1-only mechanism. This was actually highlighted in the New England Journal paper yesterday. We're seeing that with GLP-1 only, you can maybe get to 6.4, 6.5. So yes, you might see greater reductions in some studies, but that's usually from a higher starting point. Very few studies do you see a mean ending hemoglobin A1c below 6.4, 6.5. We do see that with tirzepatide as we add the GIP component, which, obviously, adds a tremendous amount of insulin sensitivity. But I want to bring up that point because it's, I think, an important point as we think about what to expect in these studies. As shown yesterday, Slide 12 shows the primary outcome of ACHIEVE-1. On this slide, you'll see the plot of hemoglobin A1c over the 40-week study. Notably, all 3 doses showed significant reductions in A1c and significant reductions were seen as early as 4 weeks. So on the first titration dose, which is 1 milligram, see some dose response. We achieved a maximum reduction of 1.6%, which again gets down to about that 6.4, 6.5 ending A1C level that I mentioned because they were at a starting point of about 8 in this study. Also not terribly surprised, we didn't see much dose response or dose differentiation between the 12- and the 36-milligram dose. Actually, if you go back to SURPASS-1 with tirzepatide, we saw a very similar pattern with the 2 highest doses. So not a surprise in this monotherapy study. Also of note were the categoricals. Approximately 3/4 of the patients reached the A1C target of less than 7%, the ADA target, and 2/3 reached less than 6.5%. The next slide shows a summary of the weight reduction over the 40 weeks. The nearly 8% reduction we saw at the 36-milligram dose was again very consistent with our expectations. In this study, a monotherapy study early in the course of diabetes, somewhat lower body weight, 90 kilograms was the baseline body weight. And here, you actually do see a very nice consistent dose response across the 3 doses. And that, again, is actually similar to what we saw in SURPASS-1. So we saw more dose differentiation with weight in this population than we did with A1C. As you might expect from a 40-week study based on what we reported and others have reported, weight does not appear to be quite at plateau at 40 weeks. It may be getting close, but it looks like there's still some more to achieve. Why only 40 weeks? Because that's about the longest you can do a placebo-controlled trial in countries where you can even do it. These studies are getting extremely difficult to do. And in some countries, it's impossible. Slide 14 provides a summary of the tolerability and safety of orforglipron in the study. And as expected, the most common adverse events were gastrointestinal in nature, consisting of nausea, vomiting and diarrhea. I would submit to you that these are very much in the range of what have been observed for other incretin therapies, whether injectable or oral peptides. Most events were mild to moderate and resolved with continued dosing. I know there was a question at the end of the symposium yesterday. There is a figure in the supplement to the New England Journal manuscript that shows, and we've shown these previously, the pattern over time. I would also point out that less than 6% of patients at 36-milligram dose discontinued due to gastrointestinal adverse events, which is at the low end of what you would typically see in an incretin study. With regards to hepatic safety, I would like to first underscore that ACHIEVE-1 allowed inclusion of patients with transaminase value up to 5x the upper limit of normal. I think that Julio Rosenstock pointed that out yesterday. That's not because of a specific concern around this molecule. The FDA has actually been pushing to raise that across studies of many compounds. It allows inclusion of a more representative patient pool, particularly in disease states like type 2 diabetes and chronic weight management where we do expect to have some underlying MASH. So we're starting with a higher baseline cutoff. Notably, no patients with elevated -- well, first of all, no patients with elevated baseline transaminase value shifted to a higher category. That was the first piece I wanted to lead off with. That might not have been obvious in the New England Journal of Medicine paper. There were no cases that met Hy's Law in the study. And there were excursions to greater than 3x, but less than 5x the upper limit of normal. But the numbers and percentages were very balanced across the treatment groups. Of note, none of those patients were symptomatic. And every single one that was on orforglipron remained on drug and normalized or returned to near baseline while still on drug. So a really important point. I would also tell you that the percentages we're seeing here for 3x the upper limit of normal are actually very similar to what have been observed for other incretin programs. So not anything out of the ordinary. So in summary, there was no evidence of hepatotoxicity with ACHIEVE-1. And the overall safety profile, in our view, was very consistent with the GLP-1 receptor agonist class. I wanted to spend a few minutes kind of setting up ATTAIN-1 and our ATTAIN chronic weight management program, but specifically ATTAIN-1 since that will be our next study to top line. Slide 16 provides a brief overview of the ATTAIN-1 study, of course, patients without type 2 diabetes, but overweight or obese. Actually, the titration is identical to ACHIEVE-1. We started at 1 milligram, titrate every 4 weeks up to 36 milligrams. I will point out one key difference. In the ACHIEVE program, you may have noted that our lowest maintenance dose was 3 milligrams. Our lowest maintenance dose in the ATTAIN program is 6 milligrams. We did that based on Phase II data, where we believe the 6-milligram dose would provide more consistent weight reduction than the 3-milligram dose, but we were fairly confident that the 3-milligram dose would be highly effective in terms of A1C reduction, and I think ACHIEVE-1 shows us that. Like ACHIEVE-1, the 2 higher doses we are studying are 12 and 36 milligrams. On the right-hand side of the slide, I've provided key baseline characteristics for reference. I would submit to you these are actually very similar to our prior chronic weight management studies in patients without type 2 diabetes, specifically SURMOUNT-1 and SURMOUNT-5. SURMOUNT-5 particularly important because that was the head-to-head with semaglutide where on the treatment as demand of semaglutide produced about 13.7% weight reduction. So very typical of several of our prior studies, including SURMOUNT-1 or SURMOUNT-5. As we've previously stated and Ken really hit this nicely, our vision for orforglipron is will be an easy-to-use once-daily oral medicine without any food or water restrictions that can produce efficacy and tolerability in the range seen with the best injectable GLP-1. And I think ACHIEVE-1, we're very excited with those results. They seem consistent with our expectation. But I think it is important to remember, we have 6 more studies to read out and many thousand more patients worth of data to read out. So stay tuned. We look forward to the ATTAIN-1 results in Q3. I want to spend just a few minutes talking about retatrutide. We didn't have much data, obviously, at this meeting on retatrutide, but we are getting closer and closer to the Phase III data readouts for retatrutide. First of all, a reminder on this program. It's again a very broad development program for reta, which I think all of you now know is a GLP-1, GIP and glucagon triple agonist. We have 4 chronic weight management studies, and then we also have the TRANSCEND program, which are our 3 type 2 diabetes studies. I've highlighted this before, but we have this unique basket trial design that allows us within the context of the chronic weight management program to actually study obstructive sleep apnea and osteoarthritis. We've had the interactions with the FDA that would allow us to get indications for all of those simultaneously if the drug hits on the other endpoints. So pretty interesting program. And on the right side of the slide, you'll see a list of some additional ongoing trials as well as the anticipated time frame for submissions to begin. On Slide 19, I'm highlighting TRIUMPH-4 largely because that will be our first Phase III study of retatrutide with top line results, largely because it's our shortest Phase III study. I want to make note that TRIUMPH-4 is a study of patients with obesity and knee osteoarthritis where the primary end point is actually osteoarthritis pain and not weight reduction. Of note, we know that osteoarthritis patients can be older and actually tend to lose less weight with incretins as was observed in step 9 with semaglutide. I do this to kind of set the stage of what you might expect to see, so we don't expect to actually see the highest weight reduction levels in TRIUMPH-4 due to the length in the patient population, rather, you should look to TRIUMPH-1 for that. Having said this, we still have a very, very high bar for retatrutide. While we believe, and I think the data proves that tirzepatide is rapidly becoming a foundational therapy for chronic weight management, we know that some patients do not achieve their weight loss goals on even tirzepatide. And this is particularly true for those that might have very high starting BMI. And that's one of the reasons we actually enriched our TRIUMPH program for patients with a BMI greater than 35. So we're still studying patients with overweight, so BMI of 27 plus a comorbidity. But we did enrich the studies for patients with a BMI of 35. That could be the target, again, with the idea that tirzepatide is becoming a foundational therapy. We look forward to the readout from TRIUMPH-4 later this year. Now I want to wrap up with a few comments about SURPASS CVOT because I know that's on everyone's mind. We get a lot of questions. It comes up. And of course, there was the emulation study here this weekend. Again, this is our tirzepatide cardiovascular outcomes trial in patients with type 2 diabetes. As you know, we also have SURMOUNT-MMO ongoing in patients with obesity. Before I speak, I'm going to underscore, we have not seen data. I know they announced today the symposium at EASD. The fact that the symposium is announced does not mean we've seen data. We are still in the process of completing the study, but we're highly confident we will have the data before EASD. I thought it was important to point that out since there was so much excitement for those that were in the efsitora session when the head of the EASD announced the symposium, which I think they're posted anyway so you guys probably already knew that. Just a reminder on the design. It's a head-to-head cardiovascular outcome study comparing tirzepatide to dulaglutide. And it's actually the first ever head-to-head CVOT conducted in this space. I know some have questioned why we did the study to begin with. And I've seen some questions. What was the purpose of doing this study? It was actually a regulatory requirement when we started the tirzepatide type 2 program because that program was still done under the 2008 FDA guidance for cardiovascular evaluation of antidiabetic therapies, which required you to first discharge cardiovascular risk at a certain level at submission and then a post-marketing requirement to do an outcome study. However, with 2 classes of agents now in type 2 diabetes that have established cardiovascular benefit and indications, namely the SGLT2 inhibitors and the GLP-1 receptor agonist, we thought it was very challenging to do the typical placebo-controlled standard of care study because we couldn't allow GLP-1 in the study and keep it blinded. [ It can have drop in ] GLP-1 on top of tirzepatide. We had to allow SGLT2 inhibitors, but we know you often get differential drop-in as physicians try to treat to an A1C target. And with tirzepatide being so strong in terms of A1C reduction, we feared there could be differential drop-in of SGLT2 inhibitors on the dulaglutide arm versus the tirzepatide arm. And then in essence, you're doing an uncontrolled head-to-head study. So this was our way to avoid potentially doing an uncontrolled and unplanned head-to-head study. Keep it ethical. The ethics have to be considered here as well. But we were in a unique position with both dulaglutide and tirzepatide being in the same auto-injector that we could do a fully blinded CVOT with that device. And we hypothesize that the design would minimize this imbalance that was a potential concern and still provide for CV -- the potential for CV, protection in both arms of the study. So great for patients. And I think all of you know that dulaglutide has already demonstrated cardiovascular risk reduction, and this has been demonstrated both in the setting of primary prevention and secondary prevention in our REWIND trial. So dulaglutide is a great drug in terms of cardiovascular event reduction. Slide 22 provides more background on the statistical testing within the trial. We first designed SURPASS-CVOT to test non-inferiority of tirzepatide to dulaglutide. And based on our interactions with FDA, an upper bound of the 95% confidence interval of 1.05 was established as the non-inferiority margin that would translate into a cardiovascular indication for tirzepatide. So that's important. It's a tight non-inferiority boundary, but reasonable because you're proving essentially that you are no worse than the comparator. But we will also test for superiority of tirzepatide versus dulaglutide. And I know many of you have tried to estimate what the hazard ratio might be in that setting. Actually, I've read the notes. Some great modeling. I would say that for those I've seen, we agree with you. While just an estimate, a hazard ratio of approximately 0.9 or better should translate into superiority given the powering of the study. So several have come up with that exact number, and you're spot on with our approximation. But I want to put that into perspective. If this were a placebo-controlled standard-of-care trial, a hazard ratio of 0.9 against dulaglutide would potentially translate into at least a 20% relative risk reduction versus a putative placebo. And as we think about the studies that have been done in this space in type 2 diabetes, particularly those fully controlled for powered or for superiority, that would be one of the best hazard ratios we've seen. So it is a tough bar. And that's the reason we've stated on numerous occasions that non-inferiority would still be a great outcome. But stay tuned. We'll prepare for the top line data readout, which we still plan to occur in Q3. And with that, I'll now turn over to my early phase colleague, Ruth Gimeno, to talk a bit about our Phase I and Phase II assets. Ruth.

All right. Thank you, Jeff. So in early phase, we're excited to share the first clinical results for eloralintide, which is our selective amylin receptor agonist. Now amylin has compelling biology, which makes it an attractive target for obesity. This hormone, which is co-secreted with insulin in response to food, has 2 key sets of actions. In the brain, it decreases food intake to lower body weight; and in the periphery, amylin slows gastric emptying and decreases glucagon secretion to improve glucose control. Now it turns out the amylin receptors are closely related to the calcitonin receptor. And as a consequence, many amylin receptor agonists, including cagrilintide, petrelintide and others, are actually dual amylin calcitonin receptor agonists. Now moving on to calcitonin. This is a hormone that's secreted by the thyroid to regulate blood calcium. It achieves this by decreasing bone resorption through direct effects on osteoclast activity and by decreasing calcium reabsorption in the kidney. Calcitonin also decreases food intake, but in addition, it activates aversive pathways, resulting in nausea and vomiting, which is a well-known side effect of administering calcitonin in men. Now preclinical studies have shown that the aversive effect of a dual amylin calcitonin receptor agonist are due to the actions on the calcitonin receptor, and consequently, we would expect a selective amylin receptor agonist to have an improved GI tolerability profile. Eloralintide is a molecule that was engineered for increased selectivity on amylin versus calcitonin receptors. It is an acylated molecule designed for once-weekly dosing. And in preclinical studies, we have seen an encouraging weight loss as well as a tolerability profile that's consistent with amylin -- selectivity for the amylin versus the calcitonin receptor. So in a 12-week multiple-ascending dose study in participants with overweight or obesity and without type 2 diabetes, eloralintide resulted in weight loss of up to 11.3%. The half-life of this molecule was long, as expected, 14 to 16 days, which enables weekly dosing. Eloralintide was well tolerated with an incidence of GI side effects of less than 10%. And note that these GI side effects were observed primarily at the higher dose levels. At dose level 2, for example, which was highly effective with weight loss close to 9%, we actually saw no incidences of nausea or vomiting. We have initiated, and it's also important to point out that in this study, we did not employ any dose titration. We have initiated a robust Phase II program that evaluates eloralintide alone or in combination with tirzepatide in individuals with obesity with or without type 2 diabetes. The first Phase II study will read out later this year, and we look forward to sharing the results with you as soon as feasible. Now bimagrumab represents a novel approach to the treatment of obesity. Bimagrumab is a monoclonal antibody that blocks signaling through activin type II receptors and then 2 important target organs to consider. In adipose tissue, bimagrumab blocks the activation, the action of activin E and GDF3, which increases lipid mobilization, decreases fat storage, resulting in increased fat mass. In muscle, bimagrumab blocks the action of activin E and myostatin, which results in muscle growth, increasing muscle mass. Tomorrow, we will share the results from the BELIEVE study, which is the first study to evaluate bimagrumab in individuals with obesity without type 2 diabetes. And this study evaluates bimagrumab alone or in combination with semaglutide. Bimagrumab was dosed IV once a quarter and semaglutide was dosed weekly. The BELIEVE study is just the first step. We have initiated additional Phase II trials, which investigate bimagrumab dosed subcu once a week, alone or in combination with tirzepatide, which is our intended route of administration and our intended combination partner. Now we have a robust portfolio of next-generation efforts in obesity, spending incretins, amylins and novel targets. Besides orforglipron and incretins, we are progressing a second small molecule GLP-1 receptor agonist in Phase II naperiglipron, previously known as GLP NPA II. We also just initiated a Phase II study for a new GGG tri agonist, which is designed for oral delivery. In amylins, we are exploring different selectivity profiles. We are obviously very excited about eloralintide, but we are also exploring dual amylin calcitonin receptor agonists together with our partner, KeyBiosciences, and they are currently progressing a molecule in Phase II in individuals with obesity and OA pain. Novel targets are an important part of our obesity strategy. Bimagrumab is one example, but we're exploring several additional mechanisms such as our PYY analog nisotirostide. As always, we set a high bar for safety and efficacy. And with novel targets in particular, we are looking for unique benefits beyond what can be achieved with incretins and amylins. Overall, we are very excited about our early phase portfolio and really look forward to updating you on the progress of these projects as they mature. And with this, I'd like to hand it back to Ken for closing remarks.

Thank you, Ruth. So to close, We have a broad development strategy building on our success with tirzepatide, which we anticipate will continue to be a foundational strategy. But looking ahead, we see the need for a next generation of medicines that better meet the needs of individual patients around the world. We welcome the segmentation of this market, and we feel like we're in a leading position in most, if not all, of logic or categories that we see emerging. Our industry-leading pipeline has been constructed through our internal expertise, but also through external innovation and decades of experience. This year, we anticipate several important data readouts that Jeff alluded to, and we plan to launch 2 new incretin therapies by the end of 2027, both orforglipron and retatrutide. We also have some key Phase II data readouts expected this year and next year, including for eloralintide. The overall opportunity here is large. We can have the opportunity to impact hundreds of millions of people, if not billions of people over the course of the years to come. And we feel we have a potential to drive a profound positive impact at the population health level. So to close, it's a very exciting time to be at Lilly and an investor in Lilly as we continue to advance this industry-leading pipeline of new medicines to treat cardiometabolic disease. So with that, I'll welcome Mike, Ruth and Jeff up to the stage, and we'll do some Q&A.

Excellent. Well, we'd like to get to as many questions as possible. If you can please raise your hand, we have microphones in the room, which will run around. Please identify yourself before you start. And usual rules do apply here, guys. One single-part question, please, so we can try to get through as many as possible. But also just been informed that there's a basketball game that kicked off. Work our way around. Trung?

Trung Huynh from UBS. So if you look at the ACHIEVE-1 weight loss curves, and Jeff, I think you touched upon this. Just towards the end of the study, near 36, 40 weeks, it does start slowing down and you're just plateauing. Obviously, we need to see a few more weeks to see if it does plateau. But is there a risk for the ATTAIN-1 study to see a similar plateauing around 40 weeks? Is there anything different between diabetes and obesity patients where you think that plateauing could happen or not happen or anything in the baseline populations between the 2 studies?

Great. Thanks, Trung. Jeff, do you want to take that?

Happy to take that. Thanks, Trung. So first of all, one of the things we know is that the greater the weight loss, the longer it takes to reach the plateau. We've seen that consistently with our tirzepatide studies, both SURPASS and SURMOUNT. It's kind of what you would want clinically. You don't want to rush weight loss. It's one of the reasons that our retatrutide studies are actually longer than our tirzepatide studies were because based on Phase II data and modeling, we expected them to take longer to reach the plateau, and we expected less weight loss in patients with diabetes. So it's not unexpected that you would reach that plateau at an earlier time point. So I don't use that at all as a read-through to ATTAIN-1. I think our -- as we've said, we still expect the efficacy of orforglipron, both in patients with type 2 diabetes and without type 2 diabetes in terms of weight reduction to be very comparable to the best injectable GLP-1.

Great. Thanks, Jeff. I think Courtney has the mic.

Courtney Breen from Bernstein. I just had a question and it kind of leads off where you finished the presentation about kind of the future of the fragmentation. Can you talk a little bit about how studies might have to evolve here? I'm thinking about perhaps switches or patients that have become refractory to sema or tirzepatide? Do you think you're going to have to do studies like that for retatrutide or some of these other high-efficacy agents in the future?

Great. Ken, do you want to start with some high-level strategy? And then Jeff, feel free to add.

Sure. I think it's a very pertinent question, one that's on our mind as we -- our own portfolio even grows more and more complex. We have to start to think about what things we'll evaluate in an RCT setting versus where we might generate evidence in a more efficient way. I alluded to the fact that in -- we're currently testing after the SURMOUNT-5 study, the idea of rerandomizing those patients on semaglutide and tirzepatide to orforglipron. That's one of the sort of clever things that we can do to start to generate that evidence. But it may be in the future, we need to start thinking about things more programmatic. We're leveraging real-world evidence to supplement the body of evidence that we can generate in RCTs because as you alluded to, the portfolio complexity just gets too high as you think about logical combinations thereof. There's very obvious questions about some of these things. Do you start them after you've maximally titrated on the first drug or do you combine them from the beginning? We're working through all of those things in the context of our portfolio.

Yes. I think you hit it, Ken. So switching to an oral drug, also, do you need the higher dose. So we also have to maintain concept. Do you need the higher dose throughout once you reach a plateau? Or can you back your dose up? And we're testing that with tirzepatide alone rather than switching. So I think as we have more therapies across the spectrum and we find therapies that can treat even those high, high baseline BMI patients, there will be various options. Some patients are very happy to remain on an injectable therapy once they've used it, gotten to where they need, but we still hear that some would prefer to switch to an oral if they could. Many of them are taking anti-hypertensives, lipidemia agents, et cetera, and just adding one more pill might still be easier than an injection once a week for some plus there's no cold chain. So you don't have the complexity when you go on vacation of having to store it, et cetera. So I think our goal is to provide that wide range of options, and we've got the portfolio to do that.

Great. Thanks, Ken and Jeff. I think Mohit has the mic. Go ahead, Mohit.

Mohit Bansal from Wells Fargo, and congrats on all the progress, first of all. My question is regarding the persistence of diarrhea that was seen with orforglipron. So the question is, is this similar to the other incretins you have seen? Or the difference is because of the longer-dose titration? Or is there something inherent with this molecule that may be causing the persistent diarrhea?

Yes, I don't -- first...

Let me hand it off.

Thanks, Mohit. I don't think we necessarily saw it as persistent through the study. But I will also point out, and this wasn't obvious from the New England Journal paper, there were some significant geographic differences. And I know some have postulated could that be behind part of it. I think Julio was asked that question. He didn't necessarily get at it directly yesterday. We saw much higher rates of diarrhea in patients in India and China and extremely low rates in Japan and kind of midrange in the U.S. So -- and we saw very high rates in the placebo groups in China and India, probably representing difference in diet, those kinds of things. So I think it's very hard to compare a handful of percent differences in some of these GI adverse events between studies and between drugs when they're conducted in very different regions. And we'll have different representation across the other studies. We still think the profile looks very much. If I even look at those time course curves versus tirzepatide GI adverse events, they look very, very similar. And I go back to what I stated, less than 6% at the highest dose discontinued due to a GI adverse event. If it had been such a big problem, it would have expected higher rates of discontinuation.

Geoff, you've got the mic?

Geoff Meacham from Citi. I want to ask you on the ACHIEVE study, the screen-out rate was 300 patients. Can you talk a little bit about that? And maybe what that means for the commercial consequences, if any, I wasn't sure if there was something that you didn't allow that maybe would somehow narrow the opportunity looking in the future. I know you want to obviously enroll the cleanest and most profound study, but...

Yes. And I'm looking at my colleagues that probably know the data there in detail. There was nothing striking to me in terms of the screen failure rate in that study versus any other study. You get a lot of patients that come in, the investigators bring them in based on maybe some prior labs and then they fall outside the A1C range. They have exclusion criteria that aren't listed in the study. Certainly, studies are always more -- a bit more restrictive on some measures than real-world use. But I wouldn't say that, that screen failure rate is any different from any of our other studies, either you look back at SURPASS, SURMOUNT or studies we have coming. And sometimes they're even higher when you get into outcome studies because of needing to have the cardiovascular risk factors, certainly not the case here. Remember, they had to have been off of oral. And if they had taken oral medicines, it had to have been at least 90 days. Sometimes patients show up and then you discover they don't meet some of those criteria. So I don't know the details on it because really, it's not striking to me. It's pretty much what we've seen across all programs.

Alex.

Alex Hammond, Wolfe Research. How should we think about the orfo launch in obesity? Will it be a full launch of sampling in endocrinologists and primary care offices? And what learnings can you apply from the Zepbound launch?

Okay. Ken, do you want to give some maybe very limited commentary on how we're thinking about the orfo launch?

So orforglipron, we've already stated we do anticipate submitting that this year. So it will logically be the first launch, and I can assure you it will be a full launch.

Very good. And Terence has the mic.

Terence Flynn, Morgan Stanley. [indiscernible] two part question. [indiscernible] What can you tell us about the structure there of the orforglipron? And then on the oral GGG, I noticed you don't have an oral [indiscernible] Is that something also that you're working on [ behind one of the oral GLPs? ]

All right. Ruth, do you want to answer one of those questions?

[ Not very, but ] there's 2 major scaffolds that people are working off, and it's the other one, it's not the orfo scaffolds, so it's basically a structural diversification for us.

[indiscernible]

Yes, yes. It's -- and then in terms of -- what was the other question that I'm not supposed to answer?

The oral [indiscernible].

The oral. Yes. So I mean at this point in time, we're sort of interesting in moving to the next level of efficacy. As we design our triple G molecule at a lower dose, they actually [ chip ] agonist because the glucagon activity comes in at higher doses. So we think we'll actually be exploring both of them.

Great. Thanks, Ruth. Over here, James.

James Shin, Deutsche Bank. I just have one question for Ruth. Eloralintide slides shows basically design -- it is designed for once weekly. But is there anything to suggest for elora's half-life or PK/PD data is not immutable to monthly dosing?

So at this point in time, we're really focusing on the weekly dosing. We are not excluding that we'll study it for monthly dosing down the road, but we want to be focused on weekly for now.

Rajesh Kumar from HSBC. Just looking at the clinical trial plan for orfo, don't see an outcomes study there. So when we are thinking of the launch, and you did elaborate on that, thank you very much. That was very helpful to understand. How are you segmenting the market? Where do you see oral belong in the algorithm? Is it a part of first line, second line? Or is it -- and what is your strategic thought about how big oral should be in the entire pie for the treatment?

Jeff, do you want to talk a bit about the kind of clinical segmentation? And Ken, if you want to add anything commercially as well?

Yes. I'm looking, Jeff, the fact that you have the game up and you turned it around us doesn't mean we'll stay for extra time. So it's actually a little bit...

Distracted.

Distracted, yes. No. You're right. We haven't announced plans around the CVOT. I think you've heard us say this many times, we constantly evaluate other studies and indications we might evaluate. I will say it's getting harder and harder. Even in chronic weight management, you do worry about increasing drop-ins and placebo dropouts. But we continue to evaluate the options there. So no plans yet. If we plan one, we'll announce it. And Ken?

Sure. With respect to placement in the treatment continuum, maybe if we start with diabetes, we are very pleased with what we saw in ACHIEVE-1. And I think those data show that it works really well as early as in the monotherapy setting. And I would say thematically in terms of how we're developing this molecule, we are thinking about those earlier, bigger, broader ideas where, hopefully, you can keep patients from ever getting some of the complications and comorbidities that we're often talking about treating with later-line therapy. So that's thematically where we think we're going. More to come, though, on what other indications where we'll really emphasize placement in the market.

Great. I think we have one in the back here. Bryan.

Yes. Bryan Dollinger on behalf of Dave Risinger, Leerink Partners. So congrats on the orfo results. I guess, our question is regarding the liver profile. Could you comment on the blinded data you've observed in the 6 ongoing Phase III trials? Are you expecting that the liver safety will be similar to what you saw in ACHIEVE-1?

Sure. Probably going to be as long as the orfo launch strategy question, but do you want to go ahead and take that one, Jeff?

Yes. And I'll answer it the same way. I mean, obviously, we look at blinded data, but we don't comment on what we see in the blinded data. We obviously have data monitoring committees who are looking at unblinded data for these trials largely for safety because we don't have any efficacy stopping rules. The studies continue. That's always a good sign. But I think Dan said this at the Q1 earnings call, we have 6 more studies to read out. So there's a lot of patient data to come, but we're very pleased with ACHIEVE-1, and we're pleased with where we are in the program.

Great. Thanks, Jeff. And Akash.

Akash, Jefferies. So you're trying 2 triples, the other one is eloralintide plus tirzepatide. When you think about the profile you're going for, should we be thinking not necessarily more weight loss, but perhaps healthier weight loss and more tolerable weight loss, but still similar weight loss to tirzepatide? And kind of as an add-on to that, I feel like with CagriSema, we were promised that amylin would induce healthier weight loss, but we actually saw incrementally worse muscle versus fat loss than what you've seen in tirzepatide. How much of that do you think is because they're hammering kind of both receptors versus maybe you need a more, I guess, nuanced approach where you're not hitting amylin as potently as they did with CagriSema?

Ruth?

So there's been a lot of discussion about amylin potentially resulting in less lean mass loss. I think all of that is based on preclinical data. And it's actually based on preclinical data in rats, which is a pretty complicated model to evaluate that. So CagriSema was the first time we looked at this in the clinic. What we know is that pretty much any weight loss, whether it's dietary weight loss, bariatric surgery, weight loss that is induced with incretins, and I guess now we've also seen weight loss induced with amylins, we actually do have some loss of lean mass. We're actually not concerned about that because we see from a functional perspective that there's really no functional deficits in individuals treated with, say, tirzepatide or some other weight-loss therapies. And maybe some of it is true because oftentimes, people with obesity, they have more muscle mass because they have more weight to carry around and some of it is normalizing that, some of it may be that you're actually losing the fat that's stored in the muscle. So there's more data to come. We will be looking at lean mass as well in our eloralintide trials, but I actually -- there's a lot of discussion on that, but it's all based on a small set of preclinical studies that I wouldn't put too much weight on. I think bimagrumab is a different story though.

Maybe I can add. With tirzepatide, we already have an agent that on its own can deliver the sort of weight loss that we shared earlier today, but with excellent tolerability, that's single molecule. I maybe want to just take the moment to state that I think the appropriate comparison between the data shared today and tirzepatide is SURMOUNT-2, not SURPASS-2. We've delivered that level of weight loss in the same setting. And so we have a foundational single molecule here now that we get to build on with an agent like -- or with a molecule like eloralintide with a little bit -- like we have a little more flexibility. We don't want to be pushing to get or eke everything out of it, but we can find the absolute right balance between tirzepatide and a molecule like eloralintide.

Great. Thank you. I think we had a mic in the middle.

[indiscernible] I'm here for Evan Seigerman from BMO Capital Markets. I was curious to your thoughts on the SURMOUNT-5 rapid responder analysis that Dr. Aronne presented yesterday. It seems to have both this substudy and Novo's REDEFINE that is becoming more clear that there's a clear separation of efficacy for certain patients based on their own biology. Given these differences that appear to be fairly dramatic in some patients, are you considering any changes to your own trial design or any further plans to further determine how those specific patients are rapid responders going forward?

Jeff, do you want to talk about the rapid responder analysis and any learnings that we can apply there?

Yes. I think, I mean, we're not completely surprised by those results. I think we've dug into our own studies over time, and you certainly see some of those patients, particularly in a flexible dosing study where we may have max tolerated, but you let patients decrease their doses, which you see us doing more of once we've defined the dose response relationship. I think we will have to take it into account, particularly as we get to drugs that have produced higher and higher degrees of weight loss. We aren't currently changing our studies, though, as a result of any of that. So our orforglipron studies are ongoing, our retatrutide studies are ongoing, and that's not driving -- that specific finding is not driving a change.

Okay. Thank you, Jeff. Jeff, on the front.

Jeff Holford, T. Rowe. I'm going to try and ask this so I don't get a very short answer. But with the orforglipron launch, it's clear that the attraction of this is going to lower all the points of friction. And one of the biggest points of friction is still cost. So I'm just trying to think about when you war game this out, to get the very broad access that you want from this, it means a lower price. How do you think about achieving that without cannibalizing the injectable franchise? I'm sure you'd love to cannibalize Wegovy and Ozempic, but you don't want to cannibalize your own products too much. So just give us some thoughts around how you achieve the very broad access that you want to get to without basically cannibalizing most of your injectable franchise?

Yes. I know a ton of interest in this topic. Ken, if you want to make a couple of high-level comments, but it's one that we're probably not going to get a satisfactory detailed answer on.

We're saying premature to speculate on exact price points here. I think of this, though, is like -- the big idea here is the long-range idea of how big of an impact you can have due to some of the things we described, positioning this earlier in the treatment continuum, sort of separate manufacturing network and a profile that we think is broadly attractive based on the data we've seen. I think people are also going to find that these medicines -- I think individual people, employers, healthcare systems around the world are also going to find that these medicines are going to save them money in health care expenditures. The people that aren't paying for obesity drugs now are still paying for obesity. They're just paying for obesity complications. And medicines like this, I think, are going to make a big difference there. We'll, over time, find ways to create access. That's the goal here. We understand that it's like one of the big inputs. But I won't speculate, like I said, on your exact question right now, but we're thinking big with this.

Great. Thank you, Ken. I think we have one on the right.

[indiscernible] I was wondering can you just give us a [ broader ] overview on [indiscernible] amylin and myosin in the [indiscernible] [ broader ] treatment paradigm along with the...

Great. [ I'll just repeat the question. ] How do you see amylin and myosin in the broader treatment paradigm? So do you want to start maybe mechanistically? And Jeff, did you want to talk to development?

I mean with amylin, it's another way to actually decrease food intake. We know that there's quite a bit of heterogeneity with the incretins. There's some people who respond very well, some people that don't respond as well. So we see amylin as another mechanism. There may be a subset of people for whom this is the appropriate medicine. I think the [ selective ] amylins, in particular, will see better tolerability, and that's going to be very attractive for a subset of people, particularly folks who cannot tolerate incretins as well. In terms of myostatin, and it's really just important to stress, we're actually not just looking at myostatin, we are looking at bimagrumab, which blocks a number of different ligands, including myostatin, but probably the more important ones are the ones in adipose tissue. So there, we have a unique mechanism. We don't think this is food intake driven. This is probably energy expenditure based on all the data we have to date. And again, this is really an orthogonal mechanism that allows us to reach patients in a different way. There are some initial data, but maybe we get better durability. Certainly, what would happen is normally if you decrease food intake, you also decrease energy expenditure. So the body tries to counteract that. If we eliminate that, I think we'll see probably better weight loss, healthier weight loss and weight loss that's less dependent on food intake. And then there is probably a subset of individuals for whom it's important to build muscle mass, older individuals, maybe they actually don't want to have as much weight loss. And for them, the balance is actually more important in people with heart failure. So I think there's a lot of individuals out there with obesity, and they have quite different needs. So we sort of view this as different mechanisms that could address different subpopulations. Jeff?

Can we restate what -- I didn't hear the development side of the question.

Just what type of role we see in amylin as well as myostatin and if there's any ways we're thinking of studying these in different ways. Ruth, I think, hit it pretty well, but if I there's...

I think Ruth hit it in her presentation. And on the amylin side, and I know I had a conversation with one or two of you before the meeting started. I mean what -- and the data that we showed, the Phase I data for eloralintide, I mean, we're very excited about the opportunity as a monotherapy. And many of the thought leaders are excited to have another option that is in the same ballpark as an incretin that might have a very different tolerability profile because they do still have patients that even with slow -- very slow titration, they cannot keep on incretin. So there's a great monotherapy opportunity. And then, as Ruth already alluded to, adding it to say, tirzepatide for those patients that need even greater weight loss. So it just provides even more optionality, much like retatrutide would. I think on bimagrumab, I'm not going to comment too much because I know the data is tomorrow. So I think once folks start to see some of the Phase II data -- and certainly, that's still only one study. We've got our study with tirzepatide later, but it's hard to talk about a development paradigm without having Phase II data in hand.

Very good. I think Seamus in the back.

Seamus Fernandez at Guggenheim. So my question is on SURPASS-CVOT, just we saw the emulation data or tried to fight our way into the room to see the emulation data. Can you maybe just put the emulation data into context relative to your own clinical trial design? Obviously, it implies a massive effect size I think on the work that we've done. If that effect size were hit, you would have stopped at an interim quite comfortably. At that level, 23% benefit over Trulicity would be staggering. So just trying to get a better understanding of how we should be thinking about that data? Or is the interim bar so high that maybe we shouldn't be quite that conservative?

Sure. And Jeff, do you want to maybe talk just about real-world studies versus randomized studies and some of the specifics of this particular one as well?

Yes. Thanks, Seamus. First of all, we don't comment at all on our interims and our interim stopping rules until the study is over. So I won't go there with that. First of all, let me start off by saying, obviously, we're happy to have seen the results from the emulation study. I think there is now 2 studies. There was also a study just versus GLP-1s not head-to-head dulaglutide in a real-world setting. So that's good to see. However, there's some significant limitations, and I know the authors have even pointed that out. There are some significant differences in the baseline characteristics, and we've -- our baseline characteristic paper is published. So I think you've seen those. And the other is that the median treatment or our median follow-up period was like 6 months. So it's very short relative to what we'll see with SURPASS-CVOT, which should be 3.5-plus years. So I think it's very hard to compare. Certainly, it's a nice way to start, but I don't know that you can read through a real-world evidence emulation study with those differences to a randomized controlled study like ours.

Great. Thank you, Jeff. Do we have other questions in the room? Go ahead in the middle.

This is Adam on behalf of Tim Anderson at Bank of America. For ATTAIN-1 and the other obesity trials with orforglipron, do you expect tolerability and safety to look any different than it did in ACHIEVE-1? Should we expect tolerability to generally be worse in obese patients versus diabetic patients?

Great. Thanks. Jeff, do you want to talk about expectations for ATTAIN-1 on safety tolerability?

Well, I don't have a crystal ball. So let me start there. I mean I think what -- our expectation is that we will see tolerability in the chronic weight management program that is similar to what's been seen for GLP-1s and chronic weight management. And there are sometimes some minor differences between type 2 diabetes and patients without type 2 diabetes who are overweight or obese, but that would be the best guidance I can provide. I can't give you any numbers until we actually see the data.

Great. Thank you. Jeff, is there one in the back. Yes, James, go ahead.

Just one follow-up on Dr. Rosenstock's advocating for the [indiscernible]?

Great. Maybe Ken, do you want to take that one and talk about the comments from the program?

Yes, I think you're alluding to Dr. Rosenstock's statement that an ideal combination would be like a first-line use of a drug like orforglipron with an SGLT2 inhibitor. Again, as I mentioned, we were very pleased with what we saw with ACHIEVE-1, which showed that using orforglipron early in the type 2 diabetes continuum delivered an agent. But even at the 3-milligram dose looked pretty compelling relative to other oral options that are available. Too early to say what settings we may choose to emphasize or potentially develop. But I think based on everything we said tonight, we see this as an early in disease treatment and are encouraged by leading experts like Dr. Rosenstock acknowledging that as well.

Excellent. Thank you, Ken. Any more hands in the room? No, it's been a long weekend already. So okay. Not seeing any. So with that, we'll go ahead and wrap. Well, I thank everybody for coming tonight. If you do have any follow-up questions, feel free to reach out to the Investor Relations team. And have a great rest of your night.

Thank you.