ELI LILLY & Co (LLY) June 6, 2026 Investor Update Transcript

Good evening, everybody. Thank you for joining us tonight at the 2026 ADA Lilly Investor Event. I'm Mike Zappar. I lead the Investor Relations Team. Tonight's format will be a short presentation where we'll go through some highlights of our recent updates on Lilly's cardiometabolic portfolio, followed by a short Q&A. I'm joined on stage by Ken Custer, who leads Lilly's cardiometabolic health president. We've got Thomas Seck, who is Senior Vice President for Product Development. and then Ruth Tomeno, who's the Group Vice President for Cardiomed Block Research. During tonight's presentation, we anticipate making forward-looking statements based on current expectations. Actual results could differ materially for various reasons. Please consult slide four for more information. With that, I will turn it over to Ken Custer.

So a busy day for us at Lilly, and we were very excited to share earlier one of our most anticipated readouts with the community. Okay, we're going to do this again with my mic on. So thanks, everyone, for joining us and spending some time with you at the end of what's been a busy day, both at ADA and for Lilly. We were so excited to share some critical data earlier today and look forward to discussing that tonight. I'm going to start with this slide, maybe just to provide some framing about what we're trying to accomplish at Lilly and really in concert with the entire health care community. And to put this scale into some frame of reference, right now in the United States, there are arguably 100 million or more people living with obesity and probably more with some cardiometabolic complication that could benefit from medicines like Anchor 10. And around the world, that number is probably 2 billion. And yet, in the United States, it's probably less than 1 in 10 people that could benefit from these medicines that are taking them. So when you put that all together, We're in the low single digits in terms of reaching people that we could help with the medicines that we make every day. We talked about this a little bit at last year's ADA update. And one of the really things we emphasize beyond the things that we do every day in terms of driving cultural change to recognize obesity as a chronic disease worthy of long-term treatment, beyond educating the primary community who's going to bear the burden of educating and treating patients with this large and prevalent condition, beyond investing in manufacturing, beyond driving reimbursement, is we need to bring forward more options for people living with these conditions because we know for a disease of this size, not everyone is going to be well-served by a single medicine. And so as we move to the next slide, we've made a lot of progress just since last year in building out the Lilly pipeline. Our goal is to bring forward the broadest set of solutions that are tailored to patients' individual needs and preferences, and we've done a lot in the last year. We'll start with terzepatide, or Manjaro and Zeppon on the left side, which have both achieved market-leading share and become standards of care in both obesity and diabetes around the world. Just since last ADA, we announced the results of the SURPASS CVOT study, and we expect to have those data in labels in the U.S. and around the world soon. We shared positive data on Surmount Maintain, asking important questions about how you can use alternative doses of ZepFound in maintenance therapy. And, of course, earlier last year, we shared data showing positive head-to-head superiority data versus 2.4 milligrams of Wegovi. Move on to Foundero, which, excitingly, in April, we got our U.S. marketing authorization, and shortly after that, authorization in UAE, we have seven positive Phase III registrational studies. We have six additional Phase III studies ongoing, and we've demonstrated head-to-head superiority versus multiple competitors in the field of type 2 diabetes, which we look forward to sharing at Monday's symposium. Reditrutide becomes what we anticipate to be our third medicine in the field of obesity. We were delighted to share the data just hours ago of the Transcend T2D1 and Triumph 1 studies. Thomas will recap those in a second, and we have multiple other indications underway. This medicine, we think, can really redefine what people can expect from an obesity treatment and move the goalpost on what powerful efficacy really means. And last but not least, aloralintide, which we only really introduced to the world last year at obesity week and quickly moved it into phase three. This is a medicine that we already have in five phase three studies ongoing. Later this year, we expect to share data on how allurelentide works in concert with terzepatide. And of course, we've already shown that this is a medicine that delivers incretin-like efficacy with more GI-like, excuse me, placebo-like GI tolerability. So all this together, I think, paints a picture of what a future of Lilly obesity and cardiometabolic health looks like, with multiple options tailored to individual patients. With that introduction, I want to take one moment to introduce the gentleman next to me. I think many of you got to know Dr. Jeff Emick over the course of many years. He had an illustrious clear at Lilly advancing multiple medicines ranging from Trulicity to Manjar and Zepan to approval. Cool. He retired last year, and I'm very delighted to introduce Dr. Thomas Seck as our new head of late-stage development in Lillity of Cardio and Metabolic Health. Thomas joins us as a 20-year veteran of the pharmaceutical industry, having played important roles across multiple leading pharma with roles in medical affairs, clinical development, and regulatory affairs. And Jeff has stepped away from Lillity, but our development engine is in very good hands with Thomas. So I'll turn it over to him to talk a little bit about Foundeo and Ratochutide.

Thank you very much, Ken. Also a pleasure to be here. Welcome, everyone. Let's move, because I don't have much time, let's move right away to the Fondeo development program. As Ken mentioned, there are seven registration studies that have been completed. This is a very robust program with over 10,000 patients, so we are very confident in the profile that we have established around Fondeo. On the top, you see the Achieve program, which supports the type 2 diabetes indication. This is also a robust program where actually three out of five studies included an active comparator, and we will actually present two of them at the symposium on Monday that you hopefully will all attend, Achieve 2 versus dipacliflozin. I'm going to have one slide on Achieve 3 versus oral semaglutide, And then we also present a G5, which is in a more progressed patient population on insulin in comparison to placebo. On the bottom, you see the ATTAIN-1 and 2 studies. Those have been already completed and have supported the indication for weight management in the U.S., as Ken just mentioned. All over, things are on track for Fundeo. We already submitted, again, and have approval for the weight management indication in the U.S. We have internationally submitted type 2 and weight management in 45 countries so far. And we are in the process to complete the submission for type 2 diabetes the second quarter of this year. Additional trials you see as well can already elude to many of those. Those will inform the use of foundeo and further profile the compound for use by patients and physicians, but also provide new indications such as obstructive sleep apnea, hypertension, osteoarthritis pain, stress urinary incontinence, and then the cardiovascular indications as well with peripheral artery disease and our ATTAIN outcome studies, which again is a large study, to potentially provide evidence around the cardiovascular effect of foundeo. So going to the next slide, this is really just a summary. I'm not going to spend much time. These are the six studies that we have in type 2 diabetes patients, including the ACHIEVE studies as well as ATTAIN-2, which was conducted in patients with type 2 diabetes. And what you see here is a very robust and very consistent effect on HbA1c, which was a primary endpoint in the ACHIEVE program for all these ACHIEVE studies, in the range of 1.5 up to 2.2% for the highest dose of Fondeo. And you're looking at the baseline in these different studies, around 8%, and you can see when you subtract the 2.2 or 2%, you land at about 6% of HbA1c, which is really a testament to the ability of this medication to get patients to go, and actually even below the currently recommended targets. Going to the next slide, this is the one slide that I have around weight loss and Achieve 3. So this was an active comparator, large active comparator studies in 1,700 patients. We have robust results for HbA1c and for weight loss. What you see here is weight loss. We see reductions in this type 2 population of up to 9.2% with a higher dose of found ale. Again, you might be recalling that in type 2 diabetes patients, achieving weight loss is more challenging than in patients without type 2 diabetes. So this is a very competitive number. And if you look at the two doses of approved doses of oral semaglutide, you see weight loss up to 5.3%, which means that actually both doses of Fondeo were statistically significantly superior to the oral semaglutide doses. It's also important to note that we achieved superiority for HbA1c, again with both doses, the higher and the lower dose of Fondeo compared to both doses of oral semaglutide. It's also important to note, if you look at the, inspect that graph a little bit more carefully, you see that there's additional or superior or more weight loss with Fandeo compared to semaglutide or semaglutide even way early on. In the first three months, we already see a separation of these curves, and that is a time where the doses for semaglutide are actually identical to even the higher doses of Regovi that are approved for weight loss as compared to the doses approved for type 2 diabetes. Moving to the next slide, this is really just a high-level summary of what we saw in ATTAIN 1 and 2, focusing on the primary endpoint of body weight change from baseline. ATTAIN 1, a large study, over 3,000 patients without type 2 diabetes, we saw up to 12.4% weight loss compared to baseline. And in ATTAIN 2, again, a population with type 2 diabetes the weight loss was to 10.5 percent. Going to the next slide, this is maybe a different way of looking at efficacy, and it's based on studies that we published last week. We presented them also at ECHO in Istanbul. These are the Maintain studies. The left-hand panel shows you Maintain Maintain, and the middle panel as well, and the right-hand panel is from Surmount Maintain. And it addresses a critically important question for clinical management of patients with obesity, which is, once I achieve substantial weight loss with injectable therapies, can I potentially change to either an oral option, such as Poundeo, or can I switch to a lower dose of an injectable? What you see on the left-hand side panel, this is the switch from the initial therapy with Vigovi, injectable Vigovi. You see weight loss up to getting to 95 kilograms after Vigovi injectable, and then switching to Fundeo for another year results basically the same weight at the end of the study. So 95% of the weight loss is actually maintained with Fundeo. The middle panel, you see what happens if you switch from the maximum tolerated dose of SEP bound, which leads to a larger weight loss of to 90 kilograms at the end of that injectable phase then switching to foundeo brings you again to 95.9 kilograms at the end of the one year on foundeo preserving about 76 percent of the weight loss achieved with step bound and then on the right hand side this is actually injectable to injectable so if you go from maximal tolerated dose of ZepBound, then one year to ZepBound 5 milligrams, you again land on that number of about 95 kilograms. So I think overall, if you look at that across studies, across treatment arms, which has some limitations, it further supports the efficacy profile of Fundeo in terms of weight loss. Now, moving to a summary of the profile of Fundeo, and these are just a couple of bullets not doing fully justice to the number of data points we have assessed in this large program. Overall, 2.2% A1C reductions with a 17.2 milligram dose in achieve 3, 12.4% weight reduction in attain 1 with the highest dose and we saw, as I just tried to explain, the 95% maintenance of the weight loss achieved with Foundero after switching from maximal tolerated dose of injectable Vengovy. On the safety and tolerability side, the class tolerability and safety has been well established and the data for Fundeo are in line with what we see in the class. The most common adverse events are gastrointestinal and laser. They're mostly mild and moderate in severities. They're transient and typically do not lead to discontinuation. if you look at the all-encompassing treatment discontinuation numbers across all these studies, it's about 4% to 12% altogether. Again, this is the point where I would like to invite you to the symposium on Monday, where you see way more data than I was able to show you here. So now let's move to ritatutide, and I assume that many, if not all of you, have seen the symposium a few hours ago, and my job is now in five minutes to summarize what was summarized there in about, I guess, about one and a half hours. So looking at the Retire to Try development program, again, this is a very robust program. You saw the number of 22,000 patients included all together. This summarizes the weight loss program called TRIUMPH. You have seen the data for TRIUMPH-1. That was the first weight loss study that we have seen. and you have seen the first of the type 2 diabetes supporting pivotal studies with Transcent T2D1, which is a monotherapy study versus placebo. There's way more coming in terms of data, but also in submission. The submission remains on track for the second half of this year, and the type 2 diabetes indication will follow first half of 2027. Going to the type 2 diabetes study first called Transcent T2D1, and you see on the left-hand side the primary endpoint for this study, which is HbA1c, change from baseline compared to placebo. You see very meaningful reductions in HbA1c up to 2% with ritatotide. If you think about a relatively low baseline of 7.9%, That brings you to a very meaningful target on the mean for patients, and I can say that 80% of these patients achieve that relatively strict target of 6.5% or lower for HbA1c, and about 40% of patients basically achieve normal glycemia with an HbA1c of less than 5.7%. On the right-hand side, you see the remarkable body weight changes with vitatotide. Looking at the highest dose, it leads to 16.8% reduction in body weight after 40 weeks of treatment. Again, as you can see from the curves, the full efficacy has probably not been achieved. We are not in a plateau phase at that point. but really remarkable efficacy in terms of weight change in this type 2 diabetes population. All right, let's move to the TRIUMPH-1 study. A little bit more background here. This is a complex but highly innovative study design with TRIUMPH-1. We have a master protocol around weight management. That's 2,339 patients. But then we embedded, nested in this master protocol, two baskets. One is patients with knee, moderate or severe knee pain. That's 574 patients. Those we assessed with the primary endpoint around the WOMAC pain score. And on the right-hand side in the red, you see the second basket included here. That's obstructive sleep apnea patients. Here, the primary endpoint was the apnea, hypopnea index at week 80. And lastly, we have an extension in gray. This extension was intended for the first 500 patients who entered the study with a BMI over 35 and remained on treatment and the assigned treatment dose up to week 80. They were allowed to enter into a 24-week extension, and we obviously assessed body weight changes here as well. All these patients were switched to either retatudide 9 or 14 milligrams, 12 milligrams. I apologize. All right, the slide here is the slide that I think we spent a lot of time on in the symposium. I hope you see it here as well. This is the primary endpoint after 80 weeks. We see really sizable body weight changes of up to 28.3% with a retatutide 12 milligram dose. That brings us now really in a space that was actually reserved for bariatric surgery in terms of the weight loss we see here. And this is not only associated with body weight change, but we have remarkable changes in cardiometabolic markers, including systolic blood pressure, including non-HDL, including also 3-glyceride, 40% reduction there. It's even an LDL reduction, which I don't think we have seen before in an incuritin study of up to 20%. So quite substantial, not only body weight changes, but also improvements in cardiometabolic parameters. looking now at the extension as I said all patients were switched to the higher doses of ritatutide you see for placebo after these 24 weeks the placebo patients landed 19% dose reduction and 30.3% with the highest dose of ritatutide in the subset of patients that entered the extension that 30.3% actually translates to 85 pounds of weight loss in these patients. So quite remarkable. Next slide is something that also was emphasized in the symposium quite a bit because, you know, with this level of weight loss, now we have opportunity to look at achievement of targets in a slightly different way. On the left-hand side, you see a panel that looks at body mass index targets. A body mass index less than 30, meaning you no longer qualify for obesity. Two-thirds of patients on the redder 12 milligram dose achieved that target. And looking at a BMI less than 25, so actually not being classified as either overweight or obese, basically normal weight, one-third of patients on the highest dose achieved that very meaningful target. And looking at thresholds, there's way more that were pre-specified in the study. What we show here is only the 30% reduction, which is clearly in the range of bariatric surgery. Almost half achieved that level in the REDA 12 milligram dose, and 27% achieved a weight loss of 35% or more in this study. Now, maybe looking at the other end of the spectrum, the lowest dose of REDA, because I think the efficacy and the balance between efficacy and tolerability is also very favorable for this 4-milligram dose. This dose can be achieved after one titration step after four weeks on the 2-milligram dose, and we saw after 80 weeks a 19% decrease in weight. And actually, if you look at discontinuations due to adverse events, that was 4%, which is actually lower than what we saw in the placebo group. And you see the well-established treatment options here as well, how they stack up compared to a dose of 4 milligrams of vitatotide. Going now very quickly over the osteoarthritis of the knee and the obstructive sleep apnea results. This is the only slide on this topic. The Womack score, we saw very similar to what we saw in Triumph 4, a very meaningful reduction, 70% reduction in that pain score, which means many patients have either no pain or very mild pain. at the end of the study, so very relevant for patients. And on the right-hand side, you see the apopnea, hypopnea index in a very severe population, again, with sleep apnea. They had at baseline basically one apnea, hypopnea episode per minute, and the reduction that we see with the highest doses of retatotrile is about 60%, which is well within the range where you would say that's a clinically meaningful improvement. And then lastly, safety and tolerability that we observed in TRIUMPH-1. Overall, again, this is consistent with what we have learned from the Inquitin class. We see nausea, diarrhea, constipation, and vomiting. It's typically transient. It's typically during the abtetration phase and can be managed, and most patients actually remain on treatment. The discontinuation rate due to adverse events is 5% with placebo and with the highest dose of redder, it's 11%. We also saw in this study dysesthesia. This is not a completely new phenomenon. We saw that also with semaputide at high doses. And we saw an imbalance in urinary tract infections, certainly something that we will follow more closely once we generate more data out of our registration programs. And with that, I would hand it over to Ruth to talk a little bit more about alloralintide.

All right. It's a real pleasure to tell you a little bit about alloralintide. This is a very unique molecule. It's a selective amylin receptor agonist. And when we made this molecule, we chose to emphasize selectivity for the amylin-1 receptor as opposed to other molecules, which emphasize amylin-3 receptor selectivity. We built this molecule on an amylin peptide backbone, and we also dialed in selectivity against the calcitonin receptor. Our goal here was to make a once-weekly molecule, and if you look at the PK profile on the right, you can see that we easily achieved this goal. The next slide shows some highlights or key data from our Phase II monotherapy program in obesity. We published that data in Lancet last year. I want to draw your attention to the 3-milligram dose. At this dose, we see 12.4% weight loss within the range of what is seen with commonly used incretin options, but with placebo-like tolerability and no titration needed. Now, if you go to the higher dose, we see 16.4% weight loss in this study with no evidence of plateau. GI tolerability remained very favorable, and no new safety signals emerged. So looking at this data, it really suggests that alloralentite stands out among the amylin class as the most efficacious and most tolerable molecule to date. We have initiated a comprehensive global phase 3 development program for alloralentite. We currently have five studies in progress, including a study in obstructive sleep apnea, ENLIGHTEN3, a study in osteoarthritis knee pain, ENLIGHTEN-4, as well as a study where we add alloralentite onto incretin therapy to get additional weight loss. This is just the beginning. You'll see additional studies appear in the future. And overall, we anticipate that the alloralentite development program will become one of the largest clinical development programs in Lely's history. This is a molecule we are very excited about. We also look forward to the phase 2 data of alloralentite in combination with tersapatite. We expect to disclose that data in the second half of this year. And in general, just pulling it all together, right now we are very excited about this molecule. And we're very optimistic that this could become a very unique non-incretin option for patients with best-in-class efficacy, tolerability, but also simplicity. And with this, I'd like to hand it back to Ken.

Thanks, Ruth and Thomas, for the great recaps of the data we shared here and what's ahead for aloralintide. So we've now shared quite a bit over the last year on these four molecules, trisepatide, orthaglipron, retichutide, and aloralintide, and we think we are very well positioned to launch four or five obesity medicines by the end of this decade, as well as another incretin burn-epetide for some other interesting indications. Ultimately, again, our goal is to bring forward as many great options for patients and their healthcare providers to choose from, and we'll continue to invest in new ideas. We've talked about delivering greater weight loss and improved tolerability. We'll talk maybe a little later about how we might drive less injection frequency, next-generation oral, things we can do to engineer in new metabolic benefits or muscle benefits, how we might minimize or even completely eliminate tolerability, and how we can think about ultra-long acting options. More to come on those things in the future. In addition, with burn appetite, we are investing in entirely new areas, taking incretin biology into diseases like substance abuse disorders, psychiatry, and inflammation. Ultimately, we feel we're very well-positioned with our late-stage portfolio, as well as the deep early phase investments we're making to continue to innovate for years to come. We feel ultimately that Lilly is very well positioned for sustained leadership, not just in the overweight and obesity and diabetes categories, but in many related complications and comorbidities. We have a market-leading portfolio right now anchored by terzapatide in obesity and diabetes. We now have the first oral small molecule, GLP-1, with no food and water restrictions. And we're sharing here data on ratichutide, which really begins the conversation about delivering bariatric surgery-like levels of efficacy with a medicine. We also have a loralentide, as Ruth nicely recapped, which we think could sort of offer an option for patients either who can't tolerate a GLP-1-based mechanism or who aren't getting enough on their existing anchortin therapy. This is one of our largest phase three programs ever, and expect to see more to come on a lower lintide. And again, we are investing in the future with new mechanisms, with new technologies that could do things differently, and new indications. So ultimately, we think at Lilly, we have a significant opportunity to improve global population health, and I'm delighted to be a part of this journey with this team. So with that, I think we'll turn it over to Mike to moderate some Q&A. and I saw a few taking photos.

The slides aren't posted on our website, so I know it's kind of like muscle memory when you're at a medical meeting, but they're on there. Lilly Investor Relations. So, yeah, we'll do Q&A. For those that are in the room, please raise a hand. We've got a couple mics. Okay, I got some hands up already. If you could just please say your name, firm, and then please limit to one question. We'll try to get to as many as possible. So, all right, Jim. Looks like Mike, you're first.

Michael Yee from UBS. Maybe just a Foundeo question. I know we're at a scientific conference, but here we are with all these doctors and everyone. Can you talk a little bit about what you're seeing in the marketplace as it relates to Foundeo picking up, what you expect to look like? Is that an inflection as you begin to market, or is that steady growth? And how you're thinking about that versus where everyone else on Wall Street is looking at things.

Yeah, sure.

So we'll have Ken maybe make some high-level comments about the Foundeo uptake. but as you said Mike we're at a medical meeting we've got our scientists up here so the better better suited for the earnings call when you got other people but Ken you want to make some comments about the launch now to the the launch really excited about what we're seeing every day it's it's more and more people starting on this medicine and great feedback from customers definitely seeing strong use and the earlier in their obesity journey lower BMI population that's what we wanted to see to expand the population with this medicine. We haven't even begun to turn on the full promotional letters behind this medicine. Expect to hear more very soon on that. But again, very excited with what we're seeing here. And I think this will turn out to be a foundational sort of daily oral in the treatment of obesity and hopefully soon type 2 diabetes in the U.S.

Great.

Let's grab the mic.

Terrence?

Thanks. Terrence from Morgan Stanley. I had a two-part question. First, just on RETA, is CNPV a possibility here? Is that still a thing with the transition at the FDA? And then it's interesting to see the tolerability of the low-dose RETA 4-migs. Just wondering what's driving that versus high-dose terzepatide, because I don't think it's the glucagon. So maybe you could just elaborate on why you think you're seeing a tolerability profile that looks superior to high-dose terzepatide.

Maybe, Ken, you want to take the first one about the CMPRV, and then, Thomas, you can elaborate a bit on the 4-mig efficacy.

Yeah, sure. Sure. With respect to the CNPV, I don't want to speculate what the future process may look like. But if you go back to the first principles of the original CNPV program, this is clearly a medicine that addresses a key public health priority. This is a medicine that the U.S. will be a strong piece of the supply chain for. It's an innovative medicine with big effect sizes with the potential not just to address overweight obesity, but also some of the most debilitating things in society, including osteoarthritis, knee pain. So it certainly fits with those things, but we'll take it day by day and see what options might exist in order to accelerate the approval of this medicine for patients in America and abroad.

We got in the second question around the low dose, four milligram dose of ritatatide. By no means is this study sufficient to actually assess versus disepatide that requires a much different design and actually a larger data set. so I want to not just assume there's an assumed superiority that was not the intention it's also not the case that the 4 mg dose does not have any nausea, diarrhea, vomiting, it does occur it just does not lead to more discontinuation than we have seen with placebo so it's definitely in this study a well tolerated dose with a profile that is beneficial in terms of weight loss and the balance with tolerability but way more data need to be generated in order to actually change positioning of different treatment options. Chris?

Great. Chris Schott, J.P. Morgan. I just want to know Laura Lintide, just elaborating a little bit more on your views on the role amylin ultimately plays, and I guess as part of that, do you see some of these benefits we see with GLP-1s that go beyond maybe just weight loss also playing out with the amylins, or is that still in your mind something that still has to be addressed as we think about the profile as a whole. At the heart of the question is, with the tolerability, is this something that could displace GLP-1s for a lot of patients, or is this more of a kind of add-on or GLP-1 tolerant type of class? Thank you.

Let's let me have Bruce. Do you want to talk about the comparison of sort of AMLIN to GLP and what we know today and what we're going to learn more in the future about?

Yeah, maybe just in terms of benefits that are non- weight loss or that we are really taking a look at. we were actually really happy to see very strong HSCOP lowering, so anti-inflammatory effects of alloralentide. Obviously, the phase three development program will answer questions about sort of what happens in larger populations with outcomes. Personally, I think it could be a very attractive option for some people to even store that, not just as an add-on. I think we'll need more data on that molecule to see how it behaves. I think there's also a very interesting genetic study that came out recently that shows that some people just don't respond as well to incretins because of some genetic variants, and amylin might be a really nice option for them.

I think, Jeff, I think you're next. We'll try to alternate sides of the room here, guys, so we'll try to get through.

Jeff Meacham, Citi.

A bit of a hot potato question. I'll give you my opinion.

I thought the discussant, I think, bigger is better, and I think that the comps were not really intellectually honest. but I wanted to ask you your response to some of the maybe lukewarm you know comments on the reddit data as of today I mean for the reddit discussing comments do you want to start can maybe we'll try to keep it short I'll start by by saying we're delighted by the the data from both transcend t2d1 and triumph one I think collectively show that this medicine is going to set a new standard in both the treatment of type 2 diabetes and obesity you know 17% weight loss in a 40-week diabetes monotherapy study, where very much the appropriate comparators here are sustain one and surpass one. And those are the only two appropriate comparisons, really, in this context. And it's setting a new standard for weight loss while delivering HP1C lowering of up to 2%, which is right in line with the very best incretensin weight loss. 28.3%, extending to 30.3% for patients staying on therapy. I think this moves the goalpost. as it relates to too much, I think that's actually something that's going to be addressed through dose selection. I am, it was probably the most exciting thing to me when I looked at these data for the first time just weeks ago, it was not just that we delivered 28.3% weight loss with a high dose with a 70% plus reduction in osteoarthritis knee pain and a 60% plus reduction in obstructive sleep apnea events, but that that four milligram dose with just a single dose step delivered 19% weight loss and a discontinuation relate that was less than the placebo arm. That tells me that this is a medicine that could fill multiple spaces in the obesity and complications progression. And so I appreciate different commentary and different views on the data. From my perspective, this is a medicine that's going to have the potential for broader use than probably even I thought, based on the data we've seen. Dave?

Thanks very much. Dave Reisinger from Larynx Partners. So I know that Dave Ricks has highlighted that Lily's going to focus much more on the consumer going forward. He talked about that in the last several months. But most of your development is for people with serious medical problems. And consumers include people like me with a BMI between 24 and 29. I won't disclose my BMI.

Or will we ask?

But I'm just curious about why Lilly isn't developing any drugs for the masses, for the overweight with a BMI of 24 to 29 globally. Maybe you could just talk, I guess specifically, the better question is, what are the regulatory hurdles to get an approval for a drug in that range for patients or people without comorbidities? Thank you.

Okay. A question about basically kind of consumer focus and what options we may have in the pipeline or kind of strategy. I mean, Thomas, do you want to maybe start and talk about what we are working on?

Yeah, I'm happy to allude to that. And I think you brought up the right point, which is the regulatory requirements. I mean, right now the requirement to be approved for as a weight loss intervention is to have either 27 and up with comorbidities or over 30. The space, however, is evolving quickly. And I do believe that agencies will at some point actually also move in their assessment. Clearly, you know, the visceral fat, you know, consideration of waist circumference, weight-to-height ratio. The Lancet Commission actually had now new guidelines where BMI actually might not be elevated, but where the waist-to-hip ratio, waist-to-height ratio is elevated. so that recognition of access and opacity in the visceral space as an unmet need, I think that's a growing recognition, and we hope that this is something that we can also work with regulators with on how to make steps forward.

And just a quick follow-up. That regulatory requirement, that's for the U.S., is that the same universally globally that you have to have a BMI 27 plus and comorbidities globally for approval?

Yeah, it is pretty similar across the world, especially in Europe and the U.S. There are some nuanced differences in Asia. There's a definition of obesity and overweight is different. There's typically lower BMI, where you see earlier competition of lower BMI. So there's a definition of different, and there's an opportunity for lower BMI. Thank you.

So Mohit earlier?

Thank you very much, and congrats on the data. Yeah, congrats on the Triumph. So the question is regarding the sub-studies you did, OSA and the new osteoarthritis. Do you think you can file on these sub-studies or you'll have to do bigger separate phase three trials to get these indications?

Okay, great. Yeah, Thomas, do you want to talk about the filing strategy?

Yeah, so that was what we talked about in Triumph 1, but that baskets, that will not be the only studies. We have actually Triumph 4 to complement these data, and we will do the same for OSA. So this is only part of the registration package, and we will have substantial evidence to support use in this population. Alex?

Alex Hammond, Wolf Research. So on Rotatrutide, how do you think about its profile in relation to direct-to-consumer? Do you think it's a good fit there, particularly that 4-milligram dose? And for initial uptake, do you think that will be driven by new patients or patient switches? Thank you.

Retta forming positioning, Ken, you want to talk about just sort of thoughts on the DTC and then also, you know, whatever uptake comments you think at this stage of the early game?

I mean, I guess what Jarby's saying, why wouldn't we, you know, offer a medicine like Retta-Truta via the same channels that we're offering Vandeo and ZepBound, given what we're seeing from this profile not just at the four milligram dose where you have this medicine that with a single dose titration step is delivering weight loss in the sort of 20% range with excellent tolerability but even for patients who need to you know progress up in dose to meet their individual needs so I don't see any reason why Lilly wouldn't bring the full breadth of its portfolio to people living with overweight and obesity in a very consistent way and support them to start stop and even switch between these medicines you know I don't know if don't want to speculate too much in terms of ratio of like new start versus switch you know right now we're focused on obviously generating the body of evidence to establish retitutide and register retitutide i'm sure people will experiment away with it in different ways in the market and will likely start some more studies in order to demonstrate how you can move between these medicines in the future i think we've been not you know it's interesting to watch how the market uses things relative to how you anticipate but this feels like a medicine that could have pretty broad use, both earlier in disease and later in disease.

Let's do Courtney and then Jameis. I'll try to queue up a few so we can move through as many as we can here.

Hi there, Courtney Breen. I just wanted to ask a little bit about aloralentide. You kind of highlighted it in the slides and emphasized the perhaps more biased binding that you have with euramilin compared to others. I think some others are emphasizing calcitonin as being kind of beneficial from a bone perspective, but kind of perhaps shifting away from calcitonin as beneficial from a tolerability perspective. How do you think about the relative evidence that exists for benefits associated with the bias signaling, but also the trade-offs that you're making with this particular asset, and why did you think it was the right choice to go down this path, which seems to be quite different to the path that everyone else has chosen with their amylins.

I think the one thing we've learned in the amylin field that preclinical data only take you that far and you really need to evaluate these molecules in the clinic. One of the reasons we sort of focused more on amylin-1 receptor because we were driven by human biology. I think the data is now pretty clear that amylin-1 receptor is more important in humans whereas amylin-3 receptor is more important in mice. In terms of the different benefits, I think, again, we need to actually generate the clinical data. It's only so far we can translate from it, especially in the amylin field. It's actually, I think every molecule has surprised us as we look at competitor molecules as well, and this is why it's important to just generate the clinical evidence.

Seamus Hernandez at Guggenheim. So two questions. There was a big focus at the phase two presentation of the original retitutide data on the heart rate changes and meaningful heart rate increases. I was actually really shocked to see in the supplement of the Lancet paper that it's only two beats per minute change. So can you help us understand that meaningful change? Is it all titration that helped manage that? or are there just some differences in how this was measured just to help us understand that? And then just the second question, we have gotten questions around the success of the Wegovi pill launch. Is Lilly considering or continuing to work on potential oral peptide approaches?

Great. Thomas, you want to talk about kind of heart rate impact across the Phase III RETF studies And then, Ken, you can maybe talk about if there's any thoughts about other oral options.

So starting with the heart rate increase, you're right about the Transcend Type 2D1 study, very limited increase in heart rate. However, in Triumph 1, the increase is a little bit more pronounced. With the highest dose, we see up to six, seven heartbeat increases initially, mostly really related to the titration phase, which return close to baseline with maybe a difference of about two to two and a half beats per minute at the end of the study. So there is an increase that seems to be further pronounced in non-type 2 patients versus type 2 patients. Ken?

Sure. I think we continue to be encouraged by the growth of the oral GLP-1 category, which validates our belief that a lot of people were waiting for these medicines. We're still in very early innings here, and as we think about the first slide that I shared and the idea that there's hundreds of millions of people waiting for these medicines around the world, we continue to believe the only way to get there is with a sort of hyper-scalable solution, and that's what a small molecule, GLP-1, provides. Beyond that, the profile of Foundel, which delivers excellent weight loss, strong tolerability, but importantly, no food and water restrictions. As we get this medicine launched in the U.S., United States, and abroad, we think it will become a mainstay of obesity treatment, as well as the treatment of diabetes and other conditions. So we're full speed ahead with Foundayo. I mentioned earlier in a previous conversation, we leave no sort of square uncovered on the board. So we're also looking at next-generation oral medicines, both with small molecule platforms and other competing technologies. We'll let the best product win in that regard.

I'm going to go with Truong and then Michael.

Thanks very much. Trung Nguyen, RBC. So there were some numerical imbalances in UTIs and hypertension-related events in people receiving antihypertensive therapy. Just can you help us understand here the underlying drivers, and do you see anything that could potentially influence the treatment selection for this?

Okay, great. Thomas, do you want to talk about the UTI signals and anything else from the trial you flagged?

Yeah. Yeah, you saw the imbalances actually writing on the slide and in the symposium. So there is a slight increase for UTIs. What we understand is it's mostly in women. It is mild and moderate, mostly actually mild. Two-thirds of these cases are mild, and they do not really lead to discontinuation. Continued treatment is absolutely possible. Obviously, we are very interested to understand, you know, is that a signal that will also be confirmed in our remaining phase 3 studies, which is still a large proportion of patients. So we will look at that very carefully. In terms of the pathogenesis, there is no clear winner in terms of if it really is a true signal, what it would be. It is maybe important to note that if you look at bariatric surgery, there is an increase in urinary tract infection described. Even there, however, the pathophysiology for that observation is not entirely clear, and we don't really know whether that's related to it, because we see it at lower doses as well. We don't have exorbitant weight loss. So it's something that we will address moving forward. Michael?

Thanks for the question. Mike Nedeljkovic, TD Cowan. I'm curious about the attain, maintain, and surmount maintain trials. What seems to be coming through is perhaps the stubbornness of the homeostatic weight set point, I know that's kind of a controversial topic in terms of the biology, but do you agree with that? And is Lilly pursuing any mechanisms that could address that biology?

Okay, thank you. Thomas, do you want to start? Ruth, do you have anything to add as well? Please feel free to jump in on sort of maintenance setting and kind of set point concept.

Yeah, I mean, the set point concept, I think, is proven, right? I mean, once you discontinue treatment, there is a return to baseline relatively quickly within 9, 12 months. and that is something that we have to deal with. I think what's really clear is this is a chronic disease that requires chronic treatment. And the question that we answered or asked ourselves in the maintained studies is what are the options in order to achieve that? Is it a switch to a different dose for an injectable or is it even an option that many patients might ask for? Can I switch to an all treatment option with Fondeo? And you saw the results that this is a really successful strategy, especially when you maintain 95% of the weight loss after switching to Fondeo from the Govi.

In terms of set point, obviously that falls in the category of new mechanisms. We are very keenly interested in understanding this more and seeing whether we could develop medicines, but it's not an easy problem.

Amy?

Awesome, thanks so much. Amy Lee, Jeffrey, is here for Akash Twari. In your Reddit trials, there was a meaningful amount of non-completers in the placebo arm, So I was just curious on, you know, what those patients were. And do you see it being more difficult to run global controlled large-scale trials going forward? And how do you think companies will change their method of running these trials going forward? And then maybe one on siRNA approaches. Are you seeing any targets that particularly excite you that could actually show standalone weight loss? Or are you seeing it more of a maintenance, you know, more of a maintenance setting?

Okay. Thomas, you want to talk a bit about placebo discontinuations and potential need for more head-to-head? And then, Ruth, if you want to talk about sRNA or any other targets of interest?

Yeah, I mean, it's an excellent point, and it came up in the symposium as well. Clearly, it's becoming more challenging to do these studies, especially with very potent treatment interventions, right? If you're on placebo, you notice that there's not a lot of weight loss potentially happening, so patients realize that and might choose in some instances to discontinue the study. And that's what we see. We see it more now than we probably saw it five years ago because now there's treatment options available even outside of clinical trials. So it is an increasing and challenging problem in placebo-controlled studies. We are engaging with many regulators, again, on this topic as well because they mandate to a certain extent a placebo control to assess benefit risk. I do believe there are opportunities to change that to some extent, right? I mean, similar to the world in diabetes, you could think about a rescue kind of mechanism that you implement on the placebo side, or you do active comparator studies where you have an intervention or comparator that is very well defined from an efficacy and safety profile. But definitely something that needs to emerge and evolve.

Yeah, and I think maybe from an SARNA perspective, there's obviously quite a few targets that everybody's excited about. Still, very early days, we have to see the translation, and so far we have only seen little snippets of it. In general, those are energy expenditure-based approaches. We wouldn't expect to see as much weight loss as you see with sort of appetite regulatory approaches. Whether the weight loss actually rises to the level where you have sort of meet the regulatory threshold for weight loss is one question. Right now, there's no established regulatory path for weight maintenance only. And I'd also caution there's some pretty exciting preclinical data on weight maintenance. Whether those translate in the clinic is something else we'll have to see. Early days.

I think Umar had one in the front. And we'll probably give you the last word, Umar. So make it a good one.

All right. So I'll go back to a question I think Seamus asked earlier around arrhythmias. So phase two was somewhere between 8% and 15%. Phase three is low single digit. So I just kept thinking to myself, what changed? Because efficacy replicated, arrhythmia did not replicate. And I noticed ECGs were done monthly in phase two, and they're done every two months in phase three, and there may even be more difference in protocol. Could you speak to how phase three evaluation was different and whether commercially arrhythmia rates could look different than what phase three shows as a result? Or is it all subclinical, maybe?

Yeah, Thomas, do you want to take the follow-up on arrhythmias and anything you flag between phase two, phase three, or just if phase two is more signal than?

Yeah, I mean, first of all, phase two is typically smaller studies, right? So you have more fluctuation potentially around the signal. What we did in phase two in terms of more monitoring, more ECG, is not unusual in a phase two study. But with Agreement of Health Authority, we changed that for phase three with a little bit less or more spacing in between these assessments. It's also important to note that the reports of arrhythmias, these are not necessarily ECG-driven reports. These are a patient that might report palpitations or tachycardia, and then that's reported as an AE. So it's not necessarily that you miss events if you do an ECG in a less frequent manner.

Great. Well, it's been a long day. We're going to have to leave it at that, guys. I know it's a little warm in this room, so thanks, everybody, for joining us tonight. And have a good rest of the day.