Roche Holding AG ($ROP)

My name is Henrik, and I'm the technical operator for today's call. Kindly note that the work now is being recorded. [Operator Instructions]. At this time, it's my pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.

Thanks a lot, Henrik. And could I have the first slide, please? So welcome to our fifth IR call in 2026, covering new Phase II results for enicepatide, previously known as CT388 and Petrelintide in obesity which just got presented at ADA in recent days. Today's call is scheduled for 90 minutes. We have planned for roughly 50 minutes for the presentation and then 40 minutes for Q&A. Let me quickly take you then through the agenda. Our first speaker today, as you can see, will be Morten Lammert, our Global Therapeutic Area Head Cardiovascular, Renal & Metabolism. Morten will provide a quick update on our overall obesity strategy before our second speaker, Manu Chakravarthy, Senior Vice President and Global Head of Product Development, Cardiovascular, Renal & Metabolism, will take us through the latest from the obesity pipeline, including an update on the study start of a Phase II multi-arm fixed-dose combination study called Synergy for Enicepatide and Petrelintide in obesity plus/minus type 2 diabetes. Our third speaker and, as you can see, will be Ildiko Lingvay, MD, MPH, MSCS and Professor of Medicine in Endocrinology and the lead investigator for CT88 study. Dr. Lingvay will take us through the Phase II anisapatide results in obesity. And finally, we'll have a presentation by Louis J. Aronne, MD, previous Director of the Obesity Society, Founder and Chair Emeritus of the American Board of Obesity Medicine and Professor of metabolic research Mr. Aronne is known to the broader scientific community for his foundational role as a pioneer who helped shift the medical perception of obesity from a just behavioral failure to a biological treatable chronic disease. He serves as a principal investigator and lead clinical trialist for key anti-obesity trials, including Petrelintide, and he will take us through the Phase II ZUPREME-1 Petrelintide results in obesity. Following these presentations, we will have our 40 minutes Q&A. And in addition to our 4 presenters, we will be joined for the Q&A by Louis André Villeneuve, our Lifecycle Leader for Enicepatide and by [ Maricel Zotska ] our lifecycle leader for Petrelintide. And with that, let me hand over to Martin to get her started. Morten, please.

Thank you, Bruno, and good morning from New Orleans. I'm Morten Lammert, I'm the Global TA Head for CVRM, and I thank you for joining us today. I will not take a lot of time, as I know, the true highlights of this call. is coming after my presentation. But I would like to take this opportunity to provide you with a high-level overview of our strategic group we are executing to become a leader in CRM. Obesity is the core focus within our SBM strategy, driving our ambition to deliver innovative and transformative solutions for patients. Our ambition is clear. We aim to become a leader in obesity. To achieve this, we are focusing on securing a strong market entry before year 2030 and differentiating our opportunities and offerings through the Rose unique capabilities. We have defined strategic pillars to deliver on this commitment. Firstly, we must deliver the near-term portfolio. We are focused on advancing our late-stage assets into Phase III at speed while preparing for launch of our diverse portfolio. Then we are expanding and differentiating. We will unlock the potential of combination therapies and iterate on validated motor actions. While over time, also developing novel treatments with transformative potential. And not only treatments need to be transformative. Also the care delivery needs transformation. We are thinking beyond the molecule, leveraging our diagnostic capabilities and ensuring we meet patients where they are in their individual journeys. Next slide, please. The global obese pandemic represents a monumental challenge to the individual, to the health care systems and to our societies. If prevention and treatment measures do not improve the global economic impact of obesity could reach USD 3.5 trillion by 2035. By that time, projection shows that more than half of the global population will be living with either overweight or obesity. Despite this health challenge. The treatment rate is still far below that of other chronic diseases. Data suggest that only 10% to 15% of all the eligible patients in the U.S. are currently treated with a branded anti-obesity medication. And treatment is also initiated too late at a point where the BMI is above 35%, and many of them have already established comorbidities with new and better treatments. We believe we can shift the curve and treat more people and treat them earlier. This would allow us to not only address severe obesity with obesity-related complications but also focus on health preservation and early disease in the early disease stages. Next slide, please. To successfully engage the patients earlier, we must go beyond one size fits all treatment paradigms. Our strategy is taking point of departure in the patient-centric insights shifting to tailored solutions that meet the needs for people with obesity. We have started how patient needs and decision drivers change as a function of their disease states and their journey. If we are zooming in on the far right column, we focus on patients with obesity Class II or Class III and often will states be complications. The treatment of choice deliver maximum efficacy and has demonstrated benefit on the relevant comorbidities. And to achieve this, patients are actually willing to accept some side effects entry of the treatment and discomfort that to get that more and higher potency. Left column, our people earlier in this journey. They know it would be healthy and good for them to lose out. but would most likely not consider themselves as living with a chronic disease. Majority of people in this group are looking for 10% to 15% weight loss that can be achieved in the most and the most convenient way. In other words, they make a trade-off between the efficacy, the convenience and in particular, tolerability relative to the first group. This is why we need patient-centric approaches that is critical to deliver a treatment solution matching the different patient needs. Our go-to-market strategy align with these changing needs from specialized care for the high-risk patients to primary care and direct-to-patient approaches for early intervention and for health preservation. Next slide, please. Lastly, we are entering the next era of obesity management and expect continued and significant market growth over the coming decade. In addition to pricing and accessibility, we see three main drivers of this continued market growth. If we start from the bottom, a continued inflow of AOM naive patients is driving the market expansion today and will continue to contribute to market growth over time. Experienced users will, over time, become a significant part of the future market. This is not the classical switch patients, but represent the cyclical nature of AOM treatment, and the market will require new solutions to reengage those patients who, for one or the other reasons decided to stop their chronic care. Treatment persistence will continue to improve with very low level from the very low level today. Education, disease understanding and improved treatments and maintenance strategies will increase adherence and the long-term use. This market will continue to be hyperdynamic and we believe our pipeline is very well positioned to offer the right treatments across a heterogeneous patient population from early intervention to late-stage comorbidity management. With this, I would like to hand over to Manu for a pipeline update. Thank you for your attention.

And thank you, Morten and a warm welcome on my behalf as well, and good morning, good afternoon. Good morning, certainly from New Orleans. So I'll take you through the pipeline update and give you a little bit more of the progress that you've made since our last time together. So if you go to the next slide, please. So over the course of the last 6 months, we've had significant progress across multiple fronts, and I'll walk you through some of those key developments through this slide. It's a little complex, but I'll walk you through this asset by asset. So the first important advance that we've made in the -- since the beginning of the year is to advance zilebeseran, which is our once every 6 angiotensinogen sRNA for uncontrolled hypertension in a cardiovascular outcome study that we call it's 11,000 person study and happy to report that we're making really substantive progress in recoding that study now, and we're making really good headway there. In terms of Enicepatide, which you'll hear a lot about from Professor Lingvay in a second. But again, very happy to report not only the presentation of the 103 study at this conference. But more importantly, the advancement of this program into Phase III. So into chronic weight management with 2 pivotal studies that we call ENITH1 and ENITH2, which is in people with and without type 2 diabetes and obesity and overweight. We also have a fairly comprehensive program on our next update in terms of how we're developing it for glycemic control for a cardiovascular outcome study. So really a comprehensive package to really position Enicepatide as a potential best-in-class dual GLP-1/GIP agonist. In terms of additional progress the pegozafermin, which we have now completed the full integration Bio. So the company was acquired in October of 2025. And since then, we've completed the integration. And again, happy to report very good forward progress here with the 2 pivotal studies, which we call enlightened fibrosis enlighten cirrhosis. So both progressing quite well. And then Petrelintide, which you'll also hear a lot about from Professor Aronne in a second. And we also presented data on the ZUPREME-1 study here in ADA. So that has yielded very exciting results for us. And those results, along with the Enicepatide data gave us a lot of confidence to then do a combination study that we call synergy which I'm going to give you a little bit more of a flavor in a couple of slides. So that's a combination study with Enicepatide and Petrelintide. So that is to be initiated in the second half of 2026. And we've also made the decision to advance Petrelintide monotherapy into Phase III in the second half of 2026. Then we have our oral synthetic molecule, which we call CT996, which is a GLP-1 receptor agonist. Again, we anticipated for broad indications, both in obesity as well as in type-2 diabetes. So we're in the midst of our Phase II program for both obesity and Type 2 diabetes. We're making good progress there. we anticipate that we will be making a Phase III go decision in second half of this year as well. And then we have our ongoing what we call the [ Jim Mendez ] study, which is the anti-myostatin plus incretin combination study, which is on track to be reading out its Phase II data also at the end of this year. Then we have our atmopetide. So we've made the difficult decision, which is entirely strategic, to not advance this program for type 1 diabetes into Phase III. So as you may recall, atmopetide is a once-daily dual GLP-1 GIP agonist that we had developed for type 1 diabetes at this conference at the ADA, we presented at a symposium the really good efficacy and safety data and the results certainly speak for itself, but it was a strategic decision not to advance it to Phase II just want to emphasize here that while we're making a decision on a molecule, it doesn't mean that we're not committed to diabetes for both type 2 and type 1. So we remain highly committed. And you can see from our portfolio, there's actually some very interesting choices that could potentially be made to really ask ourselves what's the best molecule, what's the best mechanisms that we can bring to bear to really help people with the diabetes both type 1 and type 2. And then, of course, we have a [indiscernible] for MESH and the RPI in an earlier stage of a program for cardiovascular disease. So if you go to the next slide then, please. I'll give you a little bit of the quick snapshot on 3 programs. Obviously, we won't have time to go through all of them in detail, but I want to highlight 3 programs, and then we go deeper into the data. So Enicepatide is our fully biased dual GLP-1 GIP receptor agonist, and I'll explain a little bit better what that really means in a second with the next slide and what does bias really bring. But on the right, just to emphasize a little bit further what I said in terms of where we are. So we've now completed the full Phase I program, Phase II program for obesity is completed. We're in the midst of almost nearly completing the type 2 diabetes study, which we call the 104 study results are expected in the second half of 2016 and then all of these 4 Phase III programs that are either started or soon to be started are all underway. So in terms of what is special about this molecule, we thought it might be best to explain it with a little bit more of an animation. So if you go to the next slide, please. This introduces the concept of signaling bias which is really the mechanism of [indiscernible], which provides this molecule [indiscernible]. [Presentation]

A critical role in metabolic control. After in hormones, GLP-1 and GIP are released and bind to the receptors on cells throughout the body, triggering the conversion of ATP into cyclic AMP see molecule that drives key metabolic functions, including insulin secretion and appetite regulation. However, this signal is naturally short-lived as binding of endogenous in lead to phosphorylation of the receptors, allowing for recruitment of beta-arrestin activated receptors leading to receptor desensitization and internalization. The an IP receptor agonist mechanism is being further evaluated for type 2 diabetes and chronic weight management. Enicepatide CT-388 is an investigational subcutaneous once-weekly fully signal biased dual-acting GLP-1, GIP agonist Enicepatide exhibits bias signaling at both GLP-1 and GIP receptors. Unlike endogenous hormones Enicepatide bias signaling selectivity, activate cyclic AMP pathways, while resulting in reduced beta-arrestin recruitment, in vitro results have shown that this bias leads to reduce to desensitization and internalization, which may support sustained cyclic AMP production and downstream effects. Designed with a dual agonist approach, Enicepatide is being evaluated as a potential treatment option for people with obesity, type 2 diabetes and/or related comorbidities. Of course, that signal by us, we've seen the benefits of it in preclinical models, several different studies, as you can see published here and the evidence continues to accumulate, and we have some early hints of our Phase II data that might support its benefits. And of course, Phase II will be the ultimate proof in the pudding, if you will, of how a signal bios molecule may eventually translate to better efficacy and potentially better tolerability. So now let's move to trilling, just as a quick high-level update here. Again, Dr. Aronne will speak a lot about the results, so I will not go there. But just suffice to say, in terms of its development program where we are -- so again, we've completed our Phase I. We've completed ZUPREME-1 Phase II and we're awaiting data from ZUPREME-2, which is the overrates type 2 population and that data is expected at the end of this year. And then as I mentioned in the pipeline update, we have best the monotherapy program, the Phase III and then excited now to present to you the kind of a study design overview for what the SYNERGY trial is going to look like. So if you go to the next slide, then please. So this might seem a little complicated, but I'll walk you through kind of the core principles of how the study is really designed. So we wanted to do a comprehensive Phase II program so where we can study both the mono components and the combo components all in 1 study. So that the end goal coming out of the Phase II is to be able to identify the ideal regimen of the best risk benefit ratio, if you will, of the best efficacy, best tolerability that then we can take into a streamlined Phase III design. So that we don't end up having to do monotherapy in Phase III, if possible. So you'll see in the bottom 3 ROS, arms 4, 5 and 6, really represent placebo, bitter monotherapy or Enicepatide monotherapy. And then the top 3 rows, #1, 2 and 3 are 3 different regimens, 3 different doses, combinations, if you will, of petrolincipicide combos that we are studying in a fairly comprehensive manner to identify, as I said, the best ideal combination that we can get to with tolerability and efficacy as the key centerpieces. So this is a 40-week study. This is going to be in people with obesity or overweight with at least one comorbidity. And this 1 is this 1 depicted is not in people with type 2 diabetes. And so the expectation is that emerging out of this trial, we will have identified the right dose for each and that we will take into a fixed dose combination into the Phase III study. This specific design is not a fixed-dose combination. It's a loose combination. So we are giving one injection of Petrelintide type 1 injection of Enicepatide separately. But once we identify what the right combinations, then we can make a fixed dose. So this is, again, slated to start in the second half of this year. Now my final update on the pipeline per se is on the next slide, which is our oral molecule, CT-996, if you go to that one, please. So you might recall, again, from a last update that we had, we were in the midst of our Phase I program, which is fairly comprehensive. It included people with and without diabetes. And so what you're seeing on the left there is just a quick refresher of the weight loss that we saw over 48 -- sorry, over 4 weeks, in people living with obesity, but no diabetes. And so we saw a weight loss of up to 7.3%. A part of that study also included people with diabetes, and I'm happy to report that, that has now been accepted to the EASD and we can present the type 2 diabetes cohort there. and that will have completed our full package for Phase I. And then we are in the midst of 2 Phase II studies, which are also very comprehensive programs to really do a proper full dose ranging across multiple doses both people living with obesity and obesity and diabetes. So that's what we call the -- the Phase II studies. And then ultimately, making a decision based on those data, whether it will take this forward into Phase III towards the end of this year. And then my final slide before I hand it off, is just to kind of recap kind of where we are. So you heard from Morten very nicely that there are many unmet needs. And there is a wide heterogeneity of people living with obesity and then we need to meet people where they are in their journey because obesity is a chronic disease, it's relapsing and it's heterogeneous. So our approach has been a holistic patient-centered approach really anchored on what are the core unmet needs that we're trying to really satisfy. So you heard about tolerability. You heard about the plateauing. You heard about the weight maintenance challenges. The co-morbidities -- 2 out of 3 people living with obesity have at least 1 comorbidity. If you lose too much too fast body weight, especially in the vulnerable population, elderly population, muscle loss is a significant concern. So that's an important issue. And then 1 out of 5 people do not respond to an Infigen. So having more mechanism of actions to treat such a heterogeneous disease as the must have. So those are our anchoring pillars. And so when we ask those questions of what can we do in our portfolio to satisfy those pillars, you can see every 1 of our assets that we have carefully and thoughtfully designed and brought together is there to address those unmet needs. Again, I'm not going to go through it all again, but just simply just provide this visual to say that the way we have constructed our portfolio is really anchored with patients as our North star and to ask ourselves, where are we going to make the biggest impact to help our patients. So those are the areas, and both in monotherapy and in combination therapies that we can bring our portfolio to bear. And then the final piece I will just emphasize are 2 other things. As Roche, one of the advantages that we have is also the benefit of multiple therapeutic areas. So not just CVRM, but we also have neuroscience, immunology, oncology, et cetera. And so we know that there are over 200 comorbidities of -- in people living with obesity. So we're also looking at what are our other assets within our other parts of our therapeutic areas that we can bring in combination at the right times. And then the final piece is, of course, the diagnostics and the therapeutics, both residing under the same umbrella, where I think we all can appreciate how important it is to not only diagnose monitor, but also prognosticate how patients are doing. And so having a diagnostic arm that works in tandem hand-in-hand with our therapeutics arm is another significant advantage that we see and that we want to bring to bear in its totality to really help patients. So with that, it's my true pleasure to hand it off now to Dr. Lingvay way to walk us through some of the core data pieces that we presented actually both today and we also had a late breaking poster yesterday. So, Dr. Lingvay.

Fantastic. Thank you so much. Hello from New Orleans as well, and it's my honor to present the 103 study results. We can get the next slide. And that's on behalf of a number of coaters that have worked really hard on this study as well as all the study participants and the study staff that we're getting for these patients every day. These are my disclosures and these extensive collaborations with industry along with my first-hand experience with treating patients with metabolic conditions and extensive research experience have really informed the way I look at the field and the way I think about what's most needed in our field. Let's move on. So Enicepatide, as you've heard, it's a dual signal bias, both GLP and GIP reactor agonist. It's a once-weekly subcaneous injection and it's being developed for treatment of obesity, type 2 diabetes and weight-related comorbidities. You might remember that the Phase I trial, which was 24 weeks long, had very impactive results. The highest dose in that trial was 22 milligrams of anisepatite, and it produced reductions in weight of up to 18.9% in people without diabetes living with obesity. It's also its safety and tolerability. We're very reassuring, which means that this compound move into Phase I. And this is what we're hearing about to date. The Phase II study, which was intended to evaluate the efficacy, safety and dose response of any seaside in participants with overweight, obesity but without diabetes. Let's move on. All right. So this study was a double placebo-controlled multi-standard trial conducted exclusively in the U.S. It enrolled participants, adult participants between the ages of 18 and 75, and they must have a BMI over 27 with at least 1 weight-related comorbidity, or BMI over 30 and no diagnosis of diabetes. Participants that were eligible were randomized to 5 different doses of Enicepatide ranging from 4 to 24 or placebo, and the primary endpoint was reduction in weight at week 48. There were a number of secondary endpoints as well. The important one that I'm going to point out is the proportion of participants with normal glycemia among those who had prediabetes at baseline. Let's move on. This is a study design, and you will see that the lowest dose, the 4 milligrams did not have any titration steps. And then the higher the dose, the more titration stats as it should be. and the highest dose was reached after 4 titration -- 5 titration stats. Of note, which is important, and we're also looking at the results. is that participants had to come in weekly to the study sites to receive the medication. This obviously influences the practicalities of getting the medicine and participating in the study. And also in this study, there was flexibility on those titration, but to some degree, People were able to down-titrate or slow down the titration, if needed for safety but they must have been on a minimum of 4-milligram of study medication in order to stay on the medication. And also, there was that point at 27 weeks beyond which titration was not allowed. So whatever those they were able to titrate up to at that point, that's what they stayed on for the rest of the trial to capture that steady state effect of respective dosages. Let's move on. All right. So on the left, I'm showing you the baseline demographics, which are fairly typical for participants in obesity studies. Ages 49, predominantly female participants, BMI of 38% and an A1c that well in the normal range. but there were 50% of participants who had prediabetes at baseline. I also want to point out that there were a good representation of African Americans, which gives us confidence of the fact that the study results will be representative of a larger population that will be studied in Phase III and population specifically that we tend to use these medications in the United States. On the right, I'm showing you the disposition. And you will see that everybody received almost everybody received at least 1 study medication. And then you will see on the second line, the number of -- the percentage of participants who reached the full dose of the study medication. Remember by week 27, if they were not able to get to their assigned dose, they could not uptitrate after week 2. So in this context, happy to report that those on the 4-milligram dose achieved 99% of participants got to that dose. 8 milligrams, 97%. And then in the highest dose, 80% of participants were able to get to that 24-milligram dose. You will see the study completion that is quite good for the obesity studies. If you followed ADA this year, you would see that there have been struggles in the field with keeping participants in the study. You will see that 34% of participants in placebo stop the Medicaid, stop participating in the trial of the medication. And that's not unexpected for the field. People now have choices, and that if they see that they're not getting the responses that they're looking for, they no longer stay in the study. And also, this number is actually very good for the field as it stands currently among people who received any apatite anywhere between 14% and 31% stopped the study medication. I have to point out that I think this is a small study and the 12-milligram dose had an unusually high discontinuation rate, but it stands out, and I would -- we look at the totality of the data and see that in all the other arms, including the highest dose, the 24-milligram arm had only 19% discontinuations. And if you look on the last line, that's the most important one, how many people actually discontinue due to adverse events. And this is not just GI adverse events, any adverse events. And you see that the discontinuation rate because of adverse events, it's extremely low. Let's move on to the study results. This is the most important slide. So people treated with the highest dose, the 24 milligrams of Enicepatide reduced their weight down by 22.7% at the 48-week mark, that represents a placebo subtracted difference of 22.5%. And you would appreciate that, that line is quite steep, still going down. So it's anticipated that with ongoing care and ongoing treatment, people will probably lose quite a bit more than 22% of their value at -- on the right, I'm showing you the treatment estimate and with the highest dose of 24 milligrams, the placebo substructed weight decrease was 18.3%. I also want to point out that even the lowest dose, the 4 milligram, which was required, no titration, it's a one-stop shop achieved quite meaningful weight loss with a placebo -- I'm sorry, with 6.7% value weight loss by the end of the 48 weeks. Let's move on. So these are important secondary endpoints on the left is the categorical weight us data. And you will appreciate that the overwhelming majority achieved 5% value weight loss -- when you look all the way to the right-hand side, and it's probably unprecedented to see 30% weight loss category in these graphs. It's something that we just recently added to our graphs in various -- for various studies because not on the long ago, that was not even a number that we would dream of. but 26% of the people treated with the highest dose of Enicepatide achieved 30% body weight reduction. That's in the range of pediatric surgery, and that's quite impressive. Especially coupled with the on-treatment retention that we have seen in this -- on the right, I'm showing you the number, the percentage of people who achieved normal glycemia if they had prediabetes at baseline. So you will see at the bottom what number -- what the nominator we had for each of this group. Remember, about 50% of participants had prediabetes at baseline and up to 73% of people, just within 48 weeks, they reversed from prediabetes to a normal glycemic state. Let's move on. And these are the side effects and overall, pretty well tolerated for a GLP-1 receptor agonist. Participants who withdraw due to side effects I mentioned to you before, it's a pretty low number. But let's look at the participants with any GI adverse events. So that means either they had nausea, hocipation diarrhea or vomiting. And you see those numbers compared to placebo at 8 this range between 47% and 55% across the various Enicepatide treatment groups. Nausea was 19% in placebo and Enicepatide groups, it ranged from 33% to 46%. Constipation, around 25% across the various groups. Diarrhea around 15% with the highest percentage in the highest group and the vomiting was quite a good number. I know it's never good for anybody to have vomiting. But compared with other GLP-1s, especially GLP-1s that are able to achieve the amount of weight loss that we have seen in this study. These numbers are quite impressive. So with the lowest dose 8% and then the highest dose 21%. Most of these events were mark to moderate, very few, very few Grade 3 events. There were no Grade 4 and 5 events reported. Next, please. All right. So let's conclude. This was the first Phase III trial of Enicepatide, and it demonstrated clinically meaningful, very statistically significant pendent waste reductions of up to 22.7% at 48 weeks of treatment in the highest dose arm, the 24 milligrams the percentage of participants achieving 10% and 20% weight reductions was 87% and 47.8%, respectively. Among those with prediabetes, 73% had a reversal to normal glycemia. And then you -- I've shown you that fewer participants actually discontinued treatment in the active groups than in the placebo underscoring the favorable benefit risk profile. Thank you. And I will pass on back to the team.

Hi. Dr. Louis Aronne, and you've heard my introduction before I was involved in the development of this trial, ZUPREME-1, which was presented here at the ADA in New Orleans, where I am. Across the street, I can see the convention center across the street, I'm looking at it longingly because I haven't been there today for the first time in 5 days. I want to point out that in a different universe, Amylin analogs would be the primary drugs for the treatment of obesity. When Amylin -- the first Amylin analog, which was Petrelintide and Enicepatide, first GLP-1 were approved in 2005, almost simultaneously. We found in using them initially for weight loss that pramlintide and the Amylin action seemed a little bit better than the GLP-1s because it had fewer side effects. It was more tolerable, and produced very good weight loss. And we published several papers back then looking at the weight loss. But for reasons that I still can't understand, but I'm sure the industry does it was not developed for obesity at that point in time and was used for a very narrow indication, which was along with insulin in people with type 1 diabetes. But now we're beginning to see that there are Amylin analogs, May I have the next slide, please. And what I'm going to be presenting are the results of the Phase II trial of Petrelintide this new human analog. This study was led by Tim Garvey from the University of Alabama. I was on the steering committee for this trial and help to develop the treatment paradigm. Next slide, please. And these are Dr. Garvey's disclosures. Next slide. So you're well aware that obesity is a heterogeneous chronic disease and pharmacotherapy we're seeing makes a lot of sense despite many advances in the obesity medicines treatment persistence is the big issue. And it remains low for a number of reasons, including side effect profile. Petrelintide, which has a half-life of 10 days is being developed as a weekly injectable for long-term obesity pharmacotherapy, and the objective of this trial was to compare the efficacy, safety and tolerability and of various doses of Petrelintide versus placebo in people with obesity or overweight and with complications. Next slide, please. So here is the trial paradigm. It was a randomized, double-blind, placebo-controlled parallel arm to parallel group 10-arm trial, each dose arm had a Pleo arm, a matched placebo arm. The baseline characteristics, you should note that there are 485 subjects in total, age 47 years. Women comprised only 53% of this group and you saw that Dr. Lingvay presented about 68% women and in many trials of GLP-1s and even higher. This is important because what we have seen with the GLP-1s, and perhaps now with other trials of Amylin analogs, it's great weight loss in women. It's kind of the reverse of what we used to see with diet alone. And so this may have an impact on the results on the magnitude of the weight loss. The mean BMI was 37, body weight was 107 kilograms and subjects were not to have type 2 diabetes, although they could have prediabetes. The dosing was weekly and it escalated every 4 weeks as the subjects tolerated. The primary endpoints were the percentage change in body weight from baseline to week 28 and the secondary or exploratory endpoints included change in body weight at week 42, change in [ Wister ] conference at week 42, change in cardiovascular risk factors and treatment-emergent adverse events. So you can see 42 weeks, the titration went up to week 28, and then the dose remained stable, and then there was a following follow-up of 9 weeks. Next slide, please. Here is the efficacy as demand for the results. You see in the pooled placebo arm, 1.7% mean weight loss up to week 42. And the various doses, which you can ask the company about the apparently lowest dose 1, 8.7%, up to dose 5 was 10.2%. But dose 3 in the middle and pink was 10.7%. That seem to be the greatest efficacy. So placebo-subtracted weight loss of 9% to week 42, but the trend continues to be down. Next slide, please. If we look at cardiovascular risk factors, and this is a small selection of them, we see that Wister Conference, which is a very good summary of where the cardiovascular end points are going, ranged from 7.9 to 10.8 centimeters, very good reduction in water conference and proportional to the amount of weight that was lost. If we look at C-reactive protein, key measure of inflammation. It went from 17% up to a 41% reduction in the various doses and triglycerides similarly went from 12% to 21% reduction over the period of 42 weeks of treatment. Next slide, please. Now here is the most important slide for this trial. And that is pool Petrelintide versus placebo adverse events. And you can see that in the far left column, they're virtually identical. And this is -- I don't want to say unprecedented, but we have not seen so few adverse events in a treatment group compared to placebo, at least I haven't. And if we look at serious adverse events, you see that they are identical. This is really, really a striking finding so that while the magnitude of the way loss may not be what some people would want or that may just take longer, the safety profile here is quite remarkable, really remarkable. In the middle, we see the mild, moderate and severe side effects. And you see, again, parity and perhaps fewer severe side effects in the severe group. So there were fewer severe side effects in the treated group versus the pooled placebo group. And finally, in the right column, you see adverse events leading to discontinuation and virtually identical. So a very, very good side effect profile that I think if side effects are an issue for a patient, this would be what I would use. Next slide, please. Here, we look at selected GI adverse events. And most of them were mild. You could see that over 3 quarters or mild, and they were reported during dose escalation. That's typically what we see in our trials is as -- whenever the dose goes up, you may have an increase in the incidents of adverse events. So we see nausea 19.6% versus 6.2% in the placebo-treated group, diarrhea, exactly the same constipation, slightly greater in the treated group and vomiting lower, 6.2% versus 3%. So reduced incidence of vomiting in the petroleum tide group. So maybe it's a treatment for vomiting as well. Just kidding. Next slide, please. Here, we see the adverse events based on the preferred terms, and this is in those -- which were reported in greater than 5% of participants. You can see on the top line, the nausea numbers, which ranged -- so we see in the placebo group, 6.2% and in the petroleum tide group ranging from 12.3% to 28%. We see some fatigue, which we often see, again, clinically, I'm not sure how important that is. diarrhea, small increase injection site reactions, not many, but there and then constipation and then the usual side effect profiles that we see in our clinical trials. The one I'd like to point out at the bottom is vomiting. If you look at vomiting, you see that the numbers ranging from 3 -- from 0 in 2 of the doses to 8.5%. And this variability is undoubtedly because of the small size of this trial. But the point is that these are very, very low numbers and the pooled group, 3% versus 6.2% in the placebo group is very exciting to see because vomiting is extremely unpleasant in some cases and is the reason why people drop out of our studies. Next slide, please. So in summary, in this Phase II dose-finding trial, Petrelintide demonstrated statistically significant and clinically meaningful weight reduction across all dose cohorts at both week 28 and through week 42, and in a gender-balanced population. And again, I think that if you do the math, there should be significantly greater weight loss if women -- if there are more women and if women respond as they do in GLP-1 trials. The treatment was associated with improvement in cardiovascular risk factors. It was well tolerated with rates of GI adverse events and serious adverse events that were similar to placebo. And in conclusion, these findings support the potential of Petrelintide as an effective and well-tolerated obesity medicine with a distinct mechanism of action could be added to other compounds, for example, and these properties offer the opportunity to improve longer-term medication persistence because I think the reduced side effect profile is going to be very exciting. So thank you very much. And the Phase III studies are scheduled to initiate in the second half of 2026, and we eagerly await them. Thank you.

Thanks, Dr. Aronne. And with that, we will open the Q&A session. The first questions go to Graham Parry from Citi.

So two questions for Dr. Lingvay. The 12-milligram group the CT3 had a very high a 14% dropout rate due to adverse events, it was double what we saw in 24 milligram. Just if you can isolate around what explained that? Was there any specific sort of AE that was causing the drop out there. And then secondly, a question for Roche. Are these the dose titration schedules that you'd be looking to use in A3 monotherapy? And then the last question is when you're talking about looking at fixed dose combinations for Phase III for the combination. Is that fixed dose in a single device. So unlike what we've seen with [ Cagri sema ], for example, where you have a dual chamber pen.

I guess I can kick it off with my question. And this is a Phase II trial with small numbers of participants. So you would imagine that any sort of occurrence of extra 1 or 2 events will influence the numbers quite significantly. And that's why I said that you need to look at the totality of the data across the cross the 5 treatment arms and look sort of at the trend across that the 12-milligram group was definitely a little bit odd. But the 14% dropout rate adverse event was not due to any specific adverse event with just a maturing of this and that. I also want to remind you that these participants had to be inside every single week to receive that injection and that does influence your willingness to stay in a trial when so many other external factors might influence your ability to come to the site on a weekly basis.

And I'll take the other questions on the FDC and the titration. So the FTC, so 1 of the advantages to Petrelintide is that it doesn't fibrillate. And therefore, it is compatible with other peptides. So we are able to take advantage of that property and therefore, provide that into 1 single cartridge. So it is not a dual chamber device. It's a single chamber device. Both will be in the same cartridge. Regarding titration, so this is an every 4-week titration. But as we learn from the field, both Dr. Aronne and Lingvay can add to this. We know that patients will require some degree of flexibility. And so in all of our trials, we have been very thoughtful in terms of providing such flexibility. So while it's every 4 weeks, there are provisions in the protocol that allows some flexibility to take some time to get to the next dose if they need to. There's a flexibility to downtitrate there's flexibility to stay on the same dose. And so there's multiple avenues provided to participants to get to their signed top dose. So flexibility is an important component of it, but the titration is on protocol is every 4 weeks.

Graham, that does answer all your questions? Do you have any follow-on questions?

So actually, one more. Just in terms of the combination, why would you be varying the elite days. I mean, it looks like if you just took dose 3, which looks like it's already optimized with no vomiting and then varied the CT 388 dose, that would be the sense way to, why do you need to vary the Petrol inside dose in the Phase II.

So we haven't disclosed all of the doses yet. So when we do that, you'll see the full dose ranging there. So we're going to take a full look at all of the factors and now that we have the full data set. But the goal here is really to try to find the optimal balance. As you can imagine, we want to maximize tolerability while also really maximizing efficacy. So I think it's a balance that we will look at.

Very good. Then we move on. Next question is go over to James Gordon from Barclays. James, please?

Hello. James Gordon for Barclays. The first one was on any as monotherapy. So is that you show superior weight loss versus second in obesity. And I heard the comments about -- and we had quite a of this at the conference about patients in the placebo arm now and not just going and getting them [indiscernible] therapies anyway, so it makes it harder to show a difference. So would you actually think about them putting an active comparator, so you can say you're better than something else and not have this issue orders just medicating with the GLP-1 anyway. And similarly, in terms of differentiation for Eddy, including as a Petrelintide combo. So I think Lilly you're already doing something similar in terms of doing GLP-1 GIP with their amylin, and they've already started the trial there. So the thinking on the differentiation there?

Okay. So I can take that. So regarding the head-to-head, again, we're in the middle of getting our clinical development plans all finalized. So as I mentioned to you, -- we have, of course, a comprehensive chronic red management program, but we also have a very comprehensive placemic control program. So in those studies, we anticipate that we will do head-to-head studies. We're fully aware that we're retaining patients in a placebo only arm is getting more and more challenging. And you already saw the hints of the data that Dr. Lingvay showed, 34% of people on placebo dropping out. So fully aware recognizing that as an issue, so head-to-head trials will be part of the package. We are also going to have long-term extensions as part of the package of keeping patients in trials as a way to provide incentive. So after they finish their mean what we call the primary intervention period, it will be invited to participate in a long-term extension. So that's part of our program as well. And then in terms of differentiation, I mean, great question, and we spend a lot of time, obviously, thinking about that every day. I think the way to think about it is on multiple fronts, right? So it cannot just be just can we get an extra 2% weight loss, and would that be a differentiator at the end of the day. So we have to think a little bit more broadly. So I mentioned already 2 of them. One is a package that includes head-to-head packages that include long-term extension a package that includes the flexibility of dosing so we're working on making the devices highly patient-friendly. So multi-dose pens, for example. And then ultimately, when we really think about overall differentiation, we have to also think about where -- what are the patient segments that we really want to go to. So one differentiation, and again, we'll await the 104 study with Enicepatide, which is a Phase II study in type 2 diabetes. We believe that the characteristics of the molecule plus the Phase I data that we have seen and all the vast body of everything that we have in the preclinical space has the potential that Enicepatide can have a differentiation on glycemic control. So again, the key message here is that we're trying to address the heterogeneic needs of patients, and then we have to figure out exactly where that unmet need will be best served by the characteristics of this molecule.

James, may I quickly double check. Was there an initial question from you about the superiority of weight loss seen versus test appetite we should comment on? Or was it just a comment?

Well, I guess the question is, do you think that you could be better because I think there was a comment before about how you don't plateau or if you [indiscernible].

How do we see the way weight loss..

It's mechanistically, and that's why we showed you the bio signaling, right? So what we know from the science -- and what we've seen very clearly and consistently and now actually supported by other independent investigators have also shown the importance of bias is that when you have that, you will have a chance for a deeper efficacy. Now the trajectory that Dr. Lingvay showed is very intensive, right? I mean you're seeing a very steep decline, 22.7% weight loss at 48 weeks, no evidence of plateau at all. So you could envision that if you take it to 60, 72 or even 80 weeks, you might get more. I mean -- but again, we have to do the study, right? So we're obviously excited about that profile. We have -- we see that as a potential way to differentiate, but we also see other ways of differentiating. So Yes, to answer your question, that is 1 of the levers where we see that could be a differentiation in terms of weight loss. But we also see differentiation in terms of A1c or other -- in other areas that I just mentioned.

Very good. Jim, have we answered all your questions?. Let me move on Next, please, Luisa Hector from Berenberg.

Thank you, Bruno. So I was wondering if you could tell us anything about the relative proportion of that versus mass loss, whether you've got some data when we might see it? And maybe just to follow up on that question on running the placebo-controlled trials. I see -- I hear you man, you've got your head-to-head, you're thinking about a long-term extension. But in the trials that have already started -- is there anything more you can do other than the long-term extension? Are you able to kind of check whether there's any unapproved use of GLPs happening along the way or anything you can work within that trial if it does happen?

Yes. So I'll start with the first two. I definitely might have to line to provide her perspectives in her own clinic about how she manages that. I mean we're fully aware that always going to be add-ins of GLP-1 and we have pre-specific endpoints to try to manage that. So regarding fat versus lean, I mean, of course, that's going to be a body composition analysis that we will have and we'll present some of that data at upcoming conferences. We don't have the data as yet right now, but yes, we have measured by composition, of course, in both our ZUPREME-1 study and the study -- what other things can we do on the placebo side. I mean we are going to do a thing that we possibly can to retain patients. And I mentioned a couple of key ways of doing this, right? I mean head-to-head trials, long-term extension. Great relationship with sites and investigators that we want to have to educate people that, look, this is a known phenomenon, but we have to be able to work with the right sites and the right investigators and the right patients. So I'm not diminishing that it's a challenge, but we do have methods in place that we feel that we can do that. And plus, we've had pretty specific analyses within our protocol to try to ensure that we have a way to look at both the truly GLP-1 naive population as well as those populations that may be using a GLP-1. And we recognize that there will be some diminishment of X just because you're adding it on to another GLP-1. So prespecifying it will be helpful and really get us a good understanding of what this effect will be. But Dr. Lingvay, if you have anything to add, please feel free.

Yes. So just happy to remind people that this is really not because we want to do studies against placebo. It's a regulatory requirement. And we would very much like not to do them against placebo, but not much of a choice in the matter here. Some of the glycemic studies can be done against active comparator in that space, but in the obesity space, really the placebo is the requirement that drives the design of these studies. That being said, I have to be a lot of people of Roche. It's one of the first companies that has these open-label extensions, which are truly meaningful. I'm hopeful that they will change how patients think about participation in the context of them thinking they might be on placebo. And it's not just a 6 months extension. It's a meaningful extension for everybody, and everybody can go to the maximum tolerated those. So I'm really, really thinking that this will be a game changer in the field of obesity when we're still required to use placebo. Of course, all the other measures that Manu mentioned, I think they're doing a great job at selecting the sites, right, educating the sites and the site staff and making sure that they're fully engaged with their patients, providing the dietary counseling, which is so essential for people to maintain that interest in the study and made good changes in the life that will help them and benefit them in the long run. And then making sure that they're staying through the end then and being great supporters of these patients so they can get to that open labor extension phase. Very good.

Then next question comes from Sarita Kapila from Morgan Stanley.

So Roche has previously talked to potentially dosing CT 388 above the 24 milligrams tested in Phase how much of a barrier is the 20% to 30% vomiting diarrhea to pushing the dose higher? And for any of the 3 combo regimens, do they include CT388 exposure above the 24 milligrams. And then just a quick follow-up on the no plateau comment for CT388, is it because the 24-milligram arm reach target dose late. So we noticed titration steps before reaching 24 milligrams. So how many weeks of actual exposure did the median patient received to 24 milligrams by week 48. Thank you.

Yes. So, good this one in my others as well as needed. So just the last question first. So it was 20 weeks because they finished the titration at week 8. And then going with a 48%, so they were at least able to take up to 20 weeks between 16 and 20 weeks. So you're right, it's -- could we have gotten more. This is why we feel very optimistic that we will, if they were to maintain at around 24 milligrams over a longer period of time. The other thing I'll try to remind people here is that, when we did very carefully the performance of people at the 24-milligram dose, the tolerability was actually really well tolerated. The challenge was from 12, 16, and then once they go to the 24, the background rates of nausea, vomiting constipation diarrhea generally tended to be very stable and certainly did not increase. So that gives us actually quite a bit of confidence to actually push the dose to higher doses. So I think this is a great opportunity to emphasize the other comment -- the other person made about how else can we differentiate, we can also differentiate by potentially going at a higher dose. And the reason why we are confident that we can go to higher doses is -- again, as I said, the current data set that we currently have, no plateau there, so it means that you can push to a higher dose, tolerability is actually quite good at 24. And then the final piece, how to ensure that we can get there, and this is still an evolution in terms of our final design elements. But one way is to just be more flexible, takes more time to get to the top dose. So I'll just remind people that it's not a race to the bottom to get to the lowest weight loss number in the shortest period of time. We want to be really mindful of taking people through that weight loss journey as comfortably as possible. And our properties of the molecule gives us confidence to say that we can do that safely. So more flexibility, slower titration great tolerability at 24 already that provides us confidence that we can go higher. And what the hire will be, we'll hopefully come back to you all once we have finalized that design to say what that dose is. But we fully anticipate that we will try to get to a higher dose than 24.

No, I think there was also the question whether the Phase II combo had already hired those included? Sarita, if I got your question right.

Yes, that was right.

So in the SYNERGY study, are we doing a higher dose?

Yes, exactly.

So this -- so the point of the synergy study is to try to maximize both in the current dose ranges that we have actually studied. We believe that with the current doses that we have had between a really nice dose ranging that Supreme One did a really nice dose ranging that the Study 103 did have plenty of doses there that we feel really confident to be able to say that we can mix and match the right dose combination to maximize the efficacy. And there, I'll just remind people that combination is really designed for people that are really needing that level of weight loss, right? So greater than 25% of weight loss, where maybe it's the high BMI category with type diabetes or other comorbidities, where getting to that degree of weight loss really will be helpful. But we also remind people that there are plenty of people who need only 10%, 15% of weight loss. And maybe there are other parts of our portfolio that can serve that like Petrelintide you heard from Dr. Aronne,right? So we have to really think about kind of where we want to use and where do we want to deploy these medicines. And given our portfolio, we're well positioned to do that.

And the next one, the queue is James Quigley from Goldman Sachs.

I've got two questions, please. Firstly, for Dr. Aronne and Dr. Lingvay. ADA, we saw lots of new data from different therapies and category [indiscernible] yesterday the rest side as well. So what are you thinking in terms of positioning for CT388 and Petrelintide. And I'm particularly interested in Dr. Aronne, your view on 388 and Dr. Lingvay your view on where Petrelintide sit. And second one is a sort of clarification as a reminder. So on the lack of dose response in ZUPREME-1, what were the reasons for that lack of those on is it also related to imbalance in gender between groups? Are there other factors that are at play there that you've noticed? And apologies if it was on the slide, but which doses going forward into Phase III for which dose levels going forward the next Phase III [indiscernible]. Thank you.

So I think that Enicepatide, the data is fantastic. It looks like it's at least as good as tirzepatide. I think you have to agree the weight loss hits the tirzepatide point of 22.5% weight loss plus/minus, and it's still going down. Is it going to abruptly plateau? I mean that doesn't usually happen. So it could be that the biased signaling is giving greater efficacy. We won't know until we treat people for a longer period of time, but it's at least theoretically possible, but also in looking at the weight loss curve -- it is -- I think it is definitely possible. That would be a big differentiator to have GIP GLP-1 that is more effective than tirzepatide. That's been kind of an invisible barrier, that people have been trying to break through. You see [indiscernible] hitting the same number and this is a triple agonist obviously goes past that, but this would be the first dual agonist that looks like it could go beyond that 22% to 23% weight loss in this type of trial. As far as the petroleum side, I personally think that, that could be 1 of the reasons we see the 10.7% maximum weight loss is that this is the lowest percent of women in a trial that I've seen for some time. So it is at least theoretically possible that, that will be a difference in that in the next trial. If you do the math, it should be 14% to 16% if the percent of women is what it is in other trials, around 75%. And also if the response is the same as it is with the GLP-1s. So we'll just have to see those.

And maybe also the same question then goes to Dr. Lingvay. I think the question was on how do you see petroleum positioned within the field currently?

Well, I thought Louis is going to take that, but I'm happy to say that because I'm a big fan of time. I think its safety profile is so compelling that it's going to be the for signed therapy for a lot of people, and especially in the primary care field, where they don't have the energy time or just multitasking ability to deal with all of the side effects and the multiple prescriptions on the multiple dose escalations. This is an ideal drug for primary cat patients and for really the way more than half of the population that needs and needs weight loss in the range of about 10% or so give while improving their cardiovascular risk. And we've seen a petrol does that very nicely. It improves -- plus sugar improves cardiovascular risk factors like blood pressure and lipids and therefore, it's really a nice general drug to deliver the type of weight loss that most people need. I'm also excited about the potential of exploring and using an Emily based therapy like Petrelintide in people that are older, that are more frail, that perhaps have more false fractures. Many of those people would benefit from weight loss, but currently, we're a little bit time about intervening with them. agents that we currently have because of the risk of muscle wasting and the risk of initial falls and fractures. If the data pans out as we hope it will -- that will be a huge population there in the 75-plus a range that would benefit from an intervention that is general that describes the potential of improved bone health and muscle health that will be such a welcome asset in that population.

I agree with Dr. Lingvay completely. I also wanted to point out that if you look at the evolution of our field, as time goes on, people are going to be treated earlier and earlier. Right now, we're dealing with a lot of people with very high BMIs because they haven't had any treatment really available that was accessible to them. So there is a big need for extremely effective compounds. But over time, the right way to manage obesity is to treat people when they get to a BMI of 27 at the maximum 30 and they'll never get to these catastrophic weights. And at that when we think about it, if you had a BMI of 27, let's say, and you were treated with a medicine that had almost no side effects and you got down to 25% or 24%, that would be fabulous. That would be a really great outcome. So I think that is ultimately where we're going to be headed. And so a medicine like this is very well suited for that future.

I think there were two questions still open and think maybe Manu they go to you. On the lack of a dose response with petrol sort of plateauing and explanation, why this is? And then the second question, which dose to be taken in Phase III development.

Yes. So in terms of the doses to be taken for Phase II, we'll be able to get into a little bit more of the detail in a few weeks' time. We're not able to disclose that right now because we're still finalizing some of those protocols, and we need to get some regulatory feedback on the final design. So we're not able to share it for that reason. But based on the data that we have currently seen, we are confident of what those doses can be. Regarding the lack of dose response, I mean, this is still obviously in speculation territory, right? I mean I think one of the things we do know about Amylin as a class is that and like GLP-1s, which doesn't seem to have kind of essentially a plateau where you get to is largely limited by tolerability, not limited by efficacy here with ambulance, we are starting to see. There may be ultimately an efficacy plate as well. And so the study that was done, which is the right study to do, which is a full dose range, gave us that empirical information that gave us the actual clinical data that we needed to see in the 5 doses that we tested, where does the curve fall. So I think it's a mechanistic sort of difference. A lot of people are used to seeing [indiscernible], where you can keep pushing the dose. And as long as you're not tolerability limited, you will get more -- potentially more efficacy, but with Amylin as a different class a different mechanism, we're starting to see that there is, in fact, a plateau with the efficacy. But as I already mentioned, I mean, with all of the different caveats of this trial, 50% female maybe in retrospect, if it's 42 weeks, perhaps we should have gone a little bit longer, et cetera. We feel confident that the data that we have puts us in the right position to test this out in the right settings in Phase II. And obviously, in Phase III, we expect the population to kind of resort to the kind of the norm, if you will, where we'll see 65%, 70% of the population to be female. We obviously do a longer-term study. and then we'll really see how these deals as play out.

The next one in the queue is Richard Vosser from JPMorgan. Richard.

Sorry for the background noise. I've got one question just on flexibility. Manu, you mentioned flexibility and the importance and using it going forward. We've seen other companies have trouble with the right flexibility and the lead and that leading to lower weight loss than anticipated. So just wondering how you can guard against making sure that the flexibility doesn't impact efficacy too much. And also linked to that, just thinking about tolerability, the tolerability was pretty good with ENA but not maybe quite as good as appetite at the high dose. So just thinking about what else other than the flexibility you might be able to employ to further improve the tolerability there?

Sure. Okay. So if you're right. I mean, you have to have the right balance. If you have too much flexibility, you may not get to the top. If you have too much rigidity, you might have too much dropouts. And we've seen again, empirical evidence from 2 separate compounds showing exactly those 2 things. We have had a lot of learnings in the field -- and so we take those learnings seriously and try to provide that into this protocol where we try to achieve that sweet spot. Balance. I can't get into this every little detail, but there are very specific steps in the protocol, where we are allowing for certain flexibility, but not so much that they're not getting to their assigned top dose, whatever dose that they're assigned to. And again, I come back to what I said before, right sites, right investigators, and really trying to motivate the participants in a way that we can achieve this. So the benefit that we have is that we've learned a lot from the field. We try to incorporate those learnings will execute on the Phase III, and we feel confident that we'll get it at spot. Now the tolerability part, I mean, I know that a lot of people are comparing studies. But I just, again, caution people just look at the study for what it is, cross-se comparisons are a little bit challenging. Oftentimes, people compare a Phase I to a Phase III tolerability profile in Phase II to a Phase III, et cetera. This is a Phase II study. And we have to recognize that there are certain vagaries of the study, as Dr. Lingvay mentioned. They were coming in every week to get their injection, when you come to a clinic every week and you get asked how you're doing, do you have AEs kind of, in some ways, sort of prompting the question to some extent. So I think we have to be a little bit careful of not to try to make an app-to-app comparison with the Phase II and Phase III. But what I will say is that, as I said before, with the measures that we are putting in place, with the type of investigators that we have in our study and the learnings that we have, especially on the flexibility side, we will manage through the tolerability. And I think final piece I'll say I'll hand it over to Doug Lingvay. The data again speak for itself. Personally, I was actually very concerned about going to 24 milligrams. But I was reassured by the fact that in the Phase Ib, we were able to get there very fast titration, no safety signals. Yes, the tolerability was higher because you're forcing the titration. Then we slowed the titration down in Phase II to every 4 weeks, then we saw almost half to 2/3 less AEs compared to the Phase I. So which tells us that there's nothing here in the molecule that concerns us. We feel that with the learnings that we have, we can institute the measures to get to better tolerability. And I think the final proof is Phase II to Phase III and ultimately, a head-to-head comparison. So I would stay away from Phase II to Phase III comparison. But let me hand it to Dr. Lingvay.

Yes. So actually, I'm pretty passionate about these topics I wanted to speak up because there is a difference in priorities that it's emerging strongly between the regulators who are really looking to make sure that the medicines are developing are safe for everybody that might potentially use this medication investors like you guys, which are really just measuring these drugs against who gets to the bottom faster and harder and bigger. And then the patients and those who care for the patients who really want the right therapy for the right person. So we're designing this Phase III trials and Phase II trials with the regulatory requirements in mind, including people with a BMI of 27 and above. But then we're studying these drugs and pushing people to these highest dose drugs expecting 20%, 30%, 35% body weight loss. And the reality is most people, not only they don't need that, they should not get that, and we're hurting them by pushing them there. So yes, to marry all the interests here, we need flexibility in these studies. We need a lot of flexibility because if you don't get the flexibility, you are hurting people who are participating in the study who don't need that much weight loss, who might have side effect and there's no reason to push them up. If they're doing just fine on the lower dose and achieving the goals that they want. Again, if you would want to raise to the lowest, then we need to do studies that only enroll people with BMIs over 40 or people who truly need those amounts of weight loss that the investors are looking for in order to compare these studies against each other. So please don't measure development, drugs in development by their amount of weight loss. Look at how much of -- how safe these medications are and in the right patient, do they deliver what they need to deliver and make the people healthier. Lowest weight is not our goal. It's really not our wrong.

Yes, let's move on -- next one is Steve Scala from TD Cowen. Steve, please?

Two questions. Does Roche have a strategy for monthly dosing of -- and for Dr. Aronne and Lingvay, what percent of patients do you believe will be on a monthly product in 3 to 5 years? Is it a small minority? Is it the vast majority? Or is it somewhere between? And then secondly, on CT 996, you mentioned go no-go decision by the end of the year. What do you need to see to advance that molecule?

Well, as far as what percent of people will be on monthly. I think we still don't have enough data to really determine how tolerable it will be, how effective it will be. I think that there will be big demand for it. I think it's very appealing. It's very exciting to think that we could have that. Will it work? Will there side effect? Obviously, giving something weekly will produce a better side effect profile for the same amount of medication for the average drug. So making that transition, we still have to be certain that that's going to be okay. But I think it will I'm not sure if 3 to 5 years is going to be the time frame where there will be a massive uptake. But over time, I do think that for a chronic disease, this significant number of people may switch to monthly. And it's very appealing as a treatment paradigm, I think, for clinics too, like have the patient come in and give them a shot once a month. I mean that could be very good for a chronic problem like this.

And I think there were also like two questions to you, Manu. What do we do in terms of our pipeline in terms of developing a monthly solution? And then 996, What does the go, no-go, decision, depend upon?

Yes. So regarding the let dosing, right? So I think the way we look at it is, again, coming back to the patient needs. As I said before, in my opening, the way we've designed our portfolio is based on really addressing those kinds of heterogeneous needs. Some people, as I said, need oral. Some people need injectables, some people need our weekly, some people need up monthly or maybe even a quarterly. So at this point in time, we are very open to look at all of them and part of our strategy has been to sort of see what are the long-term I mean, long extension half-life technologies that we would want to really bring to bear. And whether it's the monthly or quarterly, et cetera, we can come back to refining that. But on a strategic level, I mean, I think that optionality is exactly in line with our strategy that Martin laid out, right? So we're never going to say it's an either/or situation because just humbled by the fact that obesity is so heterogeneous and their needs at different stages for the same person actually. So I think we have to be open minded about where those needs are. But it will always be guided by the same thing, which is if we were to bring a long-acting, is this going to significantly improve their quality of life above and beyond what they're already getting with their weekly or an oral? Is it really safe? Can we put somebody on for that long? And we really be really comfortable with the fact that the safety and the tolerability profile will be good. What are some of the comments that they may be using during the period of time. Because, again, remember, there's polypharmacy and people living with obesity because they have so many comorbidities. So there may be some advantages to having short-acting compounds, for certain people, very long-acting compound. So it's really not that simplistic when we kind of look at it in that way. Regarding 996, I mean, we'll obviously look at all of the things that we all look at when we made the decision for either Enicepatide or Petrelintide. It's going to be a same set of very rigorous set of assessments, safety, tolerability, weight loss, glycemic control cardiometabolic risk factor modification, the full gamut, right? Because what we're trying to do with 996 is to position it also for a broad set of indications, which includes obesity, glycemic control. So I think we have to look at the totality of the data. I can't get into specific numbers of what we need to see, obviously, but suffice to say, it's a rigorous assessment to really make sure that it meets the bar as the way that we define the bar. So you've heard from Teresa and Levi define what the bar is, and so it has to meet our bars to advance this forward into our Phase III pipeline.

Very good. Then we quickly go on. Next one is Simon Baker from Redburn. Simon.

Thanks for taking the question, Bruno, apologies again for the background noise here. Two if I may. Firstly, just a question on Petrelintide. There's been a lot of debate over the conference about the importance or otherwise of bias between the various -- of the 3 receptors and calcitonin. I just wonder if you could give us an idea of the relative affinity truant for those 4 receptors. And then a question for both Dr. Lingvay and Dr. Aronne. I'm picking up on what Dr. Lingvay was saying, there is a clear disconnect between the market demanding ever higher percentage weight loss and clinicians demanding ever lower GI side effects. And it looks like with Petrelintide, you may have a product that fits that profile of about 15% weight loss and very low AEs. So a question to both of you. What proportion of your patients would be adequately treated with a by drug with that profile.

So I can take the first one and hand it off to both Dr. Aronne and Lingvay. So as you know, from the data that's been presented already in the public domain, Petrelintide is what we call a DACRA.So it's Dual Amylin Calcitonin Receptor Agonist. It basically has receptor selectivity for both the Amylin 3 and the calcitonin receptor. So at this point in time, I think the data is still premature to know that Amylin 1 is superior to Amylin 3 or not. Yes, on the surface, it might look like there's more to be had with ML1, but again, as I said before, I would caution us to not come into that trap of trust study comparisons because Supreme One had baseline characteristics that were quite different. The demographics were different. Duration of therapy was different and so on and so forth. So I think the jury, at least, in my mind, right, my own personal mind, is that it's still out in terms of what is the perfect ratio to have. But I think what we do know from the field is that having some calcitonin can be beneficial largely because it has potential beneficial effects on bone because we use an calcitonin today in clinical practice to treat osteoporosis. We know from preclinical studies, but having some calcitonin actually can enhance insulin sensitivity. Now whether all those things will ultimately translate into the clinic with a DAR or not in terms of those outcomes. To be determined, but that's our plan, right? I mean we want to have a robust clinical development program where we can interrogate the bone body composition, et cetera, right? So we do believe that, that mechanism lends itself to that and that's what we're excited by. But I think to overindex on AML or AML 3 purely on a cross-study comparison on rate loss, my own personal opinion, a little premature. But you want to answer the second question?

I can jump there quick because I believe it's a little bit premature to make this forecast. As I alluded to earlier, I'm very excited about the amylin base. product and especially because in primary care for the vast majority of people with no comorbidities and with a moderate amount of weight loss targeted. This is a good option. Now as far as additional patient populations are going to depend on what sort of data is [indiscernible] to be able to deliver will it deliver the diode that it prevents fractures and falls and muscle wasting and all the other potential benefits that we're thinking with position this really favorably for an older population, for example. If that's the case, that's really a quite important segment population that would favorable position to receive Petrelintide or a similar role. There's also a big question of whether this theralite or similar agents will have cardiovascular protection on their own without mixing it with the GLP-1 agonist. If they do, I mean, that's really a game changer because now it can position it across very wide age range and risk range and pretty much everybody with a weight loss need that is below 15%. It's a potential candidate. So I think as an initial phase, it does have a significant potential, especially in primary care and sort of entry level treatment with first-line therapy for overweight and obesity. Over time, as data gathers and more information is available, it does have the potential for these additional market segments that are well that are presented.

I agree with Dr. Lingvay. I see older people would be a great one, primary care because of the side effect profile. I would also add people who aren't responding to the other compounds. So because of mechanisms, I imagine, we're seeing a minority, a small minority people, but a significant number who don't respond to GLP-1s or even the GLP-1/GIP combination. And I think that with an additional mechanism added, we may get extra weight loss in those people who are refractory. I mean think about it, if it's just 5% of the population, you're talking about millions of people who potentially could benefit from a drug in this class. So I think there's plenty of market for compounds in this category.

So we have one final person. Actually, it's Graham Parry from Citi coming back with a final question. And then I think we will close the Q&A session. Parry, the final question goes to you.

Actually just a quick follow-up. So on CT388, you were saying you would run head-to-head studies in glycocemic studies in touch diabetes, but I wasn't sure if you said you would or wouldn't run head-to-head in obesity.

Just to clarify, I mean, we are still fully winding out all the Phase II and the Phase III plan for the current weight management side. So we're not precluding the possibility that we might run it there. But for glycemic control because the standards of care are already pretty established in terms of what your background therapy is going to be there, it just is much more obvious. And there back to what Dr. Lingvay had mentioned for, the FDA is actually well aware of the fact that those background therapies for type 2 diabetes have to be studied, right? So that's the reason why those head-to-hand studies are a little bit more firmed up for glyco control. But for chronic red management, there's still some uncertainty around can we not have a placebo from what we have understood from the health authorities is that they want to understand the safety profile of these novel therapies on a "clean background. And so it's not that we want to constantly keep doing placebo-controlled studies. I mean, just to be really clear, it's -- we have to meet certain regulatory requirements. And so exactly how those evolve when they evolve, we will adapt to those. And at that point in time, we may foresee doing head-to-head even in chronic weight management. But it's a little bit more established in place any control, and that's why we have more firmed up land in there.

I think with that, we close the call. Let me thank again for all our presenters for their time and efforts exploring new treatments for obesity patients. Let me also thank the IR team members who worked on the slides and prepared this event. So I have to call out on public [indiscernible] New Year and also Melanie Wolf for event organization. I hope WNS was helpful and provided a timely update on our CVRM franchise. And if there are any remaining questions, then please do not hesitate and reach out to the Roche IR team. We are happy to further help and come back to you. And with that, we'll close the call, and goodbye.