At this time, it's a pleasure to introduce you to Bruno Eschli, Head of Investor Relations. Bruno, the stage is yours.
Thanks a lot, Henrik. Could I have the first slide, please? Welcome to our fifth IR call in 2026, covering new phase II results for enicepatide, previously known as CT-388 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, 40 minutes for Q&A. Let me quickly take you through the agenda. Our first speaker today, as you can see, will be Morten Lammert, our Global Therapeutic Area Head, Cardiovascular, Renal, and 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, and 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, as you can see, will be Ildiko Lingvay, M.D., M.P.H., M.S.C.S., and Professor of Medicine in Endocrinology, and the lead investigator for the CT-388-103 study. Dr. Lingvay will take us through the phase II enicepatide results in obesity. Finally, we'll have a presentation by Louis J. Aronne, M.D., previous director of The Obesity Society, Founder and Chair Emeritus of the American Board of Obesity Medicine, and Professor of Metabolic Research.
Dr. 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. In addition to our four presenters, we will be joined for the Q&A by Luis Andre Villeneuve, our Life Cycle Leader for enicepatide, and by Marisel Salzgeber, our Life Cycle Leader for petrelintide. With that, let me hand over to Morten to get us started. Morten, please.
Thank you, Bruno. Good morning from New Orleans. I'm Morten Lammert. I'm the Global TA Head for CVRM. I thank you for joining us today. I will not take a lot of time, as I know the true highlight of this call is coming after my presentation. I would like to take this opportunity to provide you with a high-level overview of our strategic blueprint we are executing to become a leader in CVRM. Obesity is a core focus within our CVRM 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're focusing on securing a strong market entry before year 2030, differentiating our opportunities and offerings through the Roche 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. We are expanding and differentiating. We will unlock the potential of combination therapies and iterate on validated mode of actions, while over time, also developing novel treatments with transformative potential. 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 obesity pandemic represents a monumental challenge to the individual, to the healthcare systems, and to our societies. If prevention and treatment measures do not improve, the global economic impact of obesity could reach $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%-15% of all the eligible patients in the U.S. are currently treated with a branded anti-obesity medication. 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 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 studied 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 with established obesity-related complications. The treatment of choice delivers maximum efficacy and has demonstrated benefit on the relevant comorbidities. To achieve this, patients are actually willing to accept some side effects of the treatment and discomfort to get that more and higher potency. Left column are people earlier in the disease journey. They know it would be healthy and good for them to lose pounds, but would most likely not consider themselves as living with a chronic disease.
Majority of people in this group are looking for 10%-15% weight loss that can be achieved in the most gentle and 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 treatment solution matching the different patient needs. Our go-to-market strategy aligns 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. AOM-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 re-engage those patients who, for one or the other reasons, decided to stop their chronic care. Treatment persistence will continue to improve 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 hyper-dynamic, 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.
Thank you, Morten, and a warm welcome on my behalf as well. Good morning, good afternoon. Good morning certainly from New Orleans. I'll take you through the pipeline update and give you a little bit more of the progress that we've made since our last time together. If you go to the next slide, please. Over the course of the last six 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. The first important advance that we've made since the beginning of the year is to advance zilebesiran, which is our once every six month angiotensinogen siRNA for uncontrolled hypertension in a cardiovascular outcome study that'll be called ZENITH.
It's an 11,000-person study, and happy to report that we're making really substantive progress in recruiting 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 two 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, which you'll hear at 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, pegozafermin, which we have now completed the full integration with 89bio. The company was acquired in October 2025, and since then, we've completed the integration and again, happy to report very good forward progress here with the two pivotal studies, which we call ENLIGHTEN-Fibrosis and ENLIGHTEN-Cirrhosis, both progressing quite well. Petrelintide, which you'll also hear a lot about from Professor Aronne in a second, we also presented data on the ZUPREME-1 study here in ADA. That has yielded very exciting results for us. Those results, along with the enicepatide data, give 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. That's a combination study with enicepatide and petrelintide.
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. We have our oral synthetic molecule, which we call CT-996, which is a GLP-1 receptor agonist. Anticipated for broad indications both in obesity but as well as in type 2 diabetes. 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 second half of this year as well. We have our ongoing, what we call the GYMINDA 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. We have acmopatide.
We've made the difficult decision, which is entirely strategic, to not advance this program for type 1 diabetes into phase III. As you may recall, acmopatide 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 III. I just want to emphasize here that while we are making a decision on a molecule, it doesn't mean that we're not committed to diabetes for both type 2 and type 1.
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 diabetes, both type 1 and type 2. Then, of course, we have afimicabart for MASH, and then NLRP3 in an earlier stage of a program for cardiovascular disease. If you go to the next slide, please. I'll give you a little bit of the quick snapshots on three programs. Obviously, we won't have time to go through all of them in detail, but I want to highlight three programs, and then we go deeper into the data.
Enicepatide is our fully biased dual GLP-1/GIP receptor agonist. I'll explain a little bit better what that really means in a second with the next slide, and what does bias really bring. On the right, just to emphasize a little bit further what I said, in terms of where we are. 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 second half of 2026. All of these four phase III programs that are either started or soon to be started are all underway. 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.
If you go to the next slide, please. This introduces the concept of signaling bias, which is really the mechanism of action, which provides the selectivity.
GLP-1 and GIP receptors are found in multiple organs and play a critical role in metabolic control. After eating, incretin hormones, GLP-1 and GIP, are released and bind to their receptors on cells throughout the body, triggering the conversion of ATP into cyclic AMP, a messenger molecule that drives key metabolic functions, including insulin secretion and appetite regulation. However, this signal is naturally short-lived, as binding of endogenous incretins lead to phosphorylation of the receptors, allowing for recruitment of beta-arrestin to the activated receptors, leading to receptor desensitization and internalization. The dual GLP-1 and GIP 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 biased signaling at both GLP-1 and GIP receptors. Unlike endogenous hormones, enicepatide's biased signaling selectivity activates cyclic AMP pathways while resulting in reduced beta-arrestin recruitment.
In vitro results have shown that this bias leads to reduced receptor desensitization and internalization, which may support sustained cyclic AMP production and downstream effects. Designed with a dual agonist approach, enicepatide is being further evaluated as a potential treatment option for people with obesity, type 2 diabetes, and/or related comorbidities.
That signal bias, we've seen the benefits of it in preclinical models, several different studies, as you can see published here, the evidence continues to accumulate, and we have some early hints of our phase II data that might support its benefits. Of course, phase III will be the ultimate proof in the pudding, if you will, of how a signal bias molecule may eventually translate to better efficacy and potentially better tolerability. Now let's move to petrelintide, just as a quick high-level update here. Again, Dr. Aronne will speak a lot about the results, we'll not go there. Just suffice to say, in terms of its development program, where we are. 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 overweight, obese, type 2 population.
That data is expected at the end of this year. As I mentioned in the pipeline update, we've advanced the monotherapy program to phase III, and excited now to present to you the study design overview for what the SYNERGY trial is going to look like. If you go to the next slide, then, please. This might seem a little complicated, but I'll walk you through the core principles of how the study is really designed.
We wanted to do a comprehensive phase II program, where we can study both the mono components and the combo components all in one study, 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 we can take into a streamlined phase III design that we don't end up having to do monotherapy in phase III if possible. You'll see in the bottom three rows, arms four, five, and six really represent placebo, petrelintide monotherapy, or enicepatide monotherapy.
The top three rows, number one, two and three , are three different regimens, three different doses, combinations, if you will, of petrelintide/enicepatide 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. This is a 40-week study. This is going to be in people with obesity or overweight with at least one comorbidity. This one depicted is not in people with type 2 diabetes. 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're giving one injection of petrelintide, one injection of enicepatide separately.
Once we identify what the right combination is, we can make a fixed dose. This is, again, slated to start in the second half of this year. 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. You might recall again from our last update that we had, we were in the midst of our phase I program, which was fairly comprehensive. It included people with and without diabetes. What you're seeing on the left there is just a quick refresher of the weight loss that we saw over 4 weeks in people living with obesity, but no diabetes. We saw a weight loss of up to 7.3%. A part of that study also included people with diabetes.
I'm happy to report that has now been accepted to the EASD, we can present the type 2 diabetes cohort there. That will have completed our full package for phase I. 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 in both people living with obesity and obesity and diabetes. That's what we call the 2 sort of the phase II studies. Ultimately making a decision based on those data, whether to take this forward into phase III towards the end of this year. My final slide before I hand it off is just to recap where we are. You heard from Morten very nicely that there are many unmet needs, and there is a wide heterogeneity of people living with obesity.
We need to meet people where they are in their journey, because obesity is a chronic disease. It's relapsing, and it's heterogeneous. 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. You heard about tolerability, you heard about the plateauing, you heard about the weight maintenance challenges, the comorbidities. Two out of three people living with obesity have at least one comorbidity. If you lose too much, too fast body weight, especially in the vulnerable population, elderly population, muscle loss is a significant concern. That's an important issue. One out of five people do not respond to an incretin. Having more mechanism of actions to treat such a heterogeneous disease is a must-have.
Those are our anchoring pillars. When we ask those questions of what can we do in our portfolio to satisfy those pillars, you can see every one of our assets that we have carefully and thoughtfully designed and brought together is there to address those unmet needs. Not going to go through it all again, but just simply to provide this visual to say that the way we have constructed our portfolio is really anchored with patients as our North Star. To ask ourselves where are we going to make the biggest impact to help our patients? Those are the areas, and it's both in monotherapy and in combination therapies that we can bring our portfolio to bear. The final piece I will just emphasize are two other things.
Roche, one of the advantages that we have is also the benefit of multiple therapeutic areas. Not just CVRM, but we also have neuroscience, immunology, oncology, et cetera. We know that there are over 200 comorbidities in people living with obesity. We are 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. 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.
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. With that, it is my true pleasure to hand it off now to Dr. Lingvay 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. Dr. Lingvay.
Fantastic. Thank you so much. Hello from New Orleans as well, and it is my honor to present the CT-388-103 study results. We can get the next slide. That is on behalf of a number of co-authors that have worked really hard on this study, as well as all the study participants and the study staff that were caring 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 is most needed in our field. Let us move on. There you go. Enicepatide, as you have heard, it is a dual signal bias, both GLP and GIP receptor agonist.
It is a once-weekly subcutaneous injection, and it is 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 impressive results. The highest dose in that trial was 22 mg of enicepatide, and it produced reductions in weight of up to 18.9% in people without diabetes living with obesity. Also, its safety and tolerability were very reassuring, which means that this compound moved into phase II. This is what we are hearing about today. It is the phase II study, which was intended to evaluate the efficacy, safety, and dose response of enicepatide in participants with overweight obesity, but without diabetes. Let us move on. There you go. All right. This study was a double-blind, placebo-controlled, multi-center trial conducted exclusively in the U.S.
It enrolled adult participants between the ages of 18 and 75. They must have a BMI over 27 with at least one weight-related comorbidity or BMI over 30, and no diagnosis of diabetes. Participants that were eligible were randomized to five different doses of enicepatide, ranging from four 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 pre-diabetes at baseline. Let's move on. This is a study design. You will see that the lowest dose, the 4 mg, did not have any titration steps. Then the higher the dose, the more titration steps, as it should be. The highest dose was reached after five titration steps
Of note, which is important when 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. Also in this study, there was flexibility on dose 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 mg of study medication in order to stay on the medication. Also there was that point at 27 weeks beyond which titration was not allowed. Whatever dose 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.
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's well in the normal range. There were 50% of participants who had pre-diabetes 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 the population specifically that we tend to use these medications in the United States. On the right, I'm showing you the disposition. You will see that everybody received, or most everybody received at least one study medication. Then you will see on the second line, 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 27. In this context, I'm happy to report that those on the 4 mg dose, 99% of participants got to that dose. 8 mg, 97%. Then in the highest dose, 80% of participants were able to get to that 24 mg dose. You will see there a 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 stopped participating in the trial and stopped the medication. That's not unexpected for the field.
People now have choices and if they see that they're not getting the responses that they're looking for, they no longer stay in the study. This number is actually very good for the field as it stands currently. Among people who received enicepatide, 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-mg dose had an unusually high discontinuation rate, but it stands out and I would look at the totality of the data and see that in all the other arms, including the highest dose, the 24-mg arm had only 19% discontinuations. If you look on the last line, that's the most important one, how many people actually discontinue due to adverse events? This is not just GI adverse events, any adverse events.
You see that the discontinuation rate because of adverse events, it's extremely low. Let's move on to the study results. There you go. This is the most important slide. People treated with the highest dose, the 24 mg of enicepatide, reduced their weight down by 22.7% at the 48-week mark. That represents a placebo-subtracted difference of 22.5%. 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 body weight. On the right, I'm showing you the treatment estimate, and with the highest dose, the 24 mg, the placebo-subtracted weight decrease was 18.3%.
I also want to point out that even the lowest dose, the 4 mg , which required no titration, it's a one-stop shop, achieved quite meaningful weight loss with 6.7% body weight loss by the end of the 48 weeks. Let's move on. These are important secondary endpoints. On the left are the categorical weight loss data, you will appreciate that the overwhelming majority achieved 5% body weight loss. When you look all the way to the right-hand side, it's probably unprecedented to see 30% weight loss category in these graphs. It's something that we just recently added to our graphs for various studies because not until long ago, that was not even a number that we would dream of. 26% of the people treated with the highest dose of enicepatide achieved 30% body weight reduction.
That's in the range of bariatric surgery and that's quite impressive, especially coupled with the on-treatment retention that we have seen in this group. On the right, I'm showing you the percentage of people who achieved normal glycemia if they had pre-diabetes at baseline. You will see at the bottom what denominator we had for each of these group. Remember, about 50% of participants had pre-diabetes at baseline, and up to 73% of people, just within 48 weeks, they reversed from pre-diabetes to a normal glycemic state. Let's move on. 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. Let's look at the participants with any GI adverse events. That means either they had nausea, constipation, diarrhea, or vomiting.
You see those numbers compared to placebo at 28%, these range between 47%-55% across the various enicepatide treatment groups. Nausea was 19% in placebo, and in enicepatide groups, it ranged from 33%-46%. Constipation, around 25% across the various groups. Diarrhea, around 15% with the highest percentage in the highest group. Vomiting was quite a good number. I know it's never good for anybody to have vomiting. 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. With the lowest dose, 8%, and then the highest dose, 21%. Most of these events were mild to moderate. Very few grade threee events. There were no grade four and five events reported. Next, please. All right, let's conclude.
This was the first phase II trial of enicepatide, and it demonstrated clinically meaningful, very statistically significant dose-dependent weight reductions of up to 22.7% at 48 weeks of treatment. In the highest dose arm, the 24 mg, the percentage of participants achieving 10% and 20% weight reductions was 87% and 47.8%, respectively. Among those with pre-diabetes, 73% had a reversal to normal glycemia. 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, I will pass on back to the team.
Hi. I'm 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 five days. I want to point out that in a different universe, amylin analogs would be the primary drugs for the treatment of obesity. When the first amylin analog, which was pramlintide, and exenatide, 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.
We published several papers back then looking at the weight loss. 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. Now we're beginning to see that there are amylin analogs. May I have the next slide, please? 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 helped to develop the treatment paradigm. Next slide, please. These are Dr. Garvey's disclosures. Next slide.
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 development of 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. The objective of this trial was to compare the efficacy, safety, and tolerability of various doses of petrelintide versus placebo in people with obesity or overweight and with complications. Next slide, please. 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 placebo arm, a matched placebo arm.
The baseline characteristics you should note were 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, it's 75% and even higher. This is important because what we have seen with the GLP-1s, and perhaps now with other trials of amylin analogs, is greater weight loss in women. It's kind of the reverse of what we used to see with diet alone. 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. Subjects were not to have type 2 diabetes, although they could have pre-diabetes. The dosing was weekly, and it escalated every four 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 waist circumference at week 42, change in cardiovascular risk factors, and treatment emergent adverse events. You can see 42 weeks, the titration went up to week 28, and then the dose remained stable, and then there was a follow-up of nine weeks. Next slide, please. Here is the efficacy estimand for the results. You see in the pooled placebo arm, 1.7% mean weight loss up to week 42. 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 in pink was 10.7%. That seemed to be the greatest efficacy.
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 waist circumference, which is a very good summary of where the cardiovascular endpoints are going, ranged from 7.9-10.8 cm. A very good reduction in waist circumference and proportional to the amount of weight that was lost. If we look at C-reactive protein, a key measure of inflammation, it went from a 17%-41% reduction in the various doses. Triglycerides similarly went from a 12%-21% reduction over the period of 42 weeks of treatment. Next slide, please. Here is the most important slide for this trial, and that is pooled petrelintide versus pooled placebo adverse events.
You can see that in the far left column, they are virtually identical. 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. If we look at serious adverse events, you see that they are identical. This is really, really a striking finding. While the magnitude of the weight loss may not be what some people would want, or it 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. You see again parity and perhaps fewer severe side effects in the severe group. There were fewer severe side effects in the treated group versus the pooled placebo group.
Finally, in the right column, you see adverse events leading to discontinuation and virtually identical. 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. Most of them were mild. You can see that over three-quarters were mild. They were reported during dose escalation. That is typically what we see in our trials is whenever the dose goes up, you may have an increase in the incidence of adverse events. We see nausea, 19.6% versus 6.2% in the placebo-treated group. Diarrhea, exactly the same. Constipation, slightly greater in the treated group. Vomiting lower, 6.2% versus 3%. Reduced incidence of vomiting in the petrelintide group. Maybe it is a treatment for vomiting as well. Just kidding.
Next slide, please. Here we see the adverse events based on the preferred terms. 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. We see in the placebo group 6.2%, in the petrelintide group ranging from 12.3%- 28%. We see some fatigue, which we often see. Again, clinically, I am not sure how important that is. Diarrhea, a small increase. Injection site reactions, not many, but there. Constipation. The usual side effect profiles that we see in our clinical trials. The one I would like to point out at the bottom is vomiting. If you look at vomiting, you see the numbers ranging from zero in two of the doses to 8.5%. This variability is undoubtedly because of the small size of this trial.
The point is that these are very, very low numbers. 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 a reason why people drop out of our studies. Next slide, please. 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 in a gender-balanced population. Again, I think that if you do the math, there should be significantly greater weight loss if there were 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.
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. 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. Thank you very much. Phase III studies are scheduled to initiate in the second half of 2026, and we eagerly await them. Thank you.
Thanks, Dr. Aronne. With that, we will open the Q&A session. The first questions go to Graham Parry from Citi. Graham, please.
Great. Thanks for taking the questions. First two questions for Dr. Lingvay. The 12 mg group in the CT-388 had a very high, 14% dropout rate due to adverse events. It was double what we saw in 24 mg. Is there any additional data around what explained that? Was there any specific sort of AE that was causing the dropout there? Then secondly, a question for Roche. Are these the dose titration schedules that you'd be looking to use in phase III monotherapy? 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? Unlike what we've seen with CagriSema, for example, where you have a dual-chamber pen. Thank you.
I guess I can kick it off with my question. This is a phase II trial with small numbers of participants. You would imagine that any sort of occurrence of extra one or two events will influence the numbers quite significantly. That's why I said that you need to look at the totality of the data across the five treatment arms and look sort of at the trend across them. The 12 mg group was definitely a little bit odd, but the 14% dropout rate due to adverse events was not due to any specific adverse event. It was just a smattering of this and that. I also want to remind you that these participants had to be at the site every single week to receive their injection.
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.
I'll take the other questions on the FDC and the titration. The FDC, one of the advantages of petrelintide is that it doesn't fibrillate. Therefore, it is compatible with other peptides. We are able to take advantage of that property and therefore provide that into one single cartridge. It is not a dual-chamber device. It's a single-chamber device. Both will be in the same cartridge. Regarding titration, this isn't every four-week titration, but as we learn from the field, and both Drs. Aronne and Lingvay can add to this, we know that patients will require some degree of flexibility. In all of our trials, we have been very thoughtful in terms of providing such flexibility.
While it's every four weeks, there are provisions in the protocol that allow some flexibility to take some time to get to the next dose if they need to. There's a flexibility to down titrate. There's a flexibility to stay on the same dose. There's multiple avenues provided to participants to get to their assigned top dose. Flexibility is an important component of it, but the titration is on protocol. It's every four weeks.
Graham, did this answer all your questions, or you have any follow-on questions?
Actually, one follow on. Just in terms of the combination, why would you be varying the petrelintide dose? It looks like when you just took dose three, which looks like it's already optimized with no vomiting, and then varied the CT-388 dose, that would be the sense way to it. Why do you need to vary the petrelintide dose in the phase III?
We haven't disclosed all of the doses yet. When we do that, you'll see the full dose ranging there. We're going to take a full look at all of the factors now that we have the full data set. 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. I think it's a balance that we will look at.
Thank you.
Very good. We move on. Next questions go to James Gordon from Barclays. James, please.
Hello. James Gordon from Barclays. Thanks for taking the questions. The first one was on enicepatide as a monotherapy. Is it though that you'd show superior weight loss versus semaglutide in obesity? We had quite a lot of this at the conference, about patients in the placebo arm now end up just going and getting themselves GLP-1 therapies anyway, so it makes it harder to show a difference. Would you actually think about then putting an active comparator so you can say you're better than something else and not have this issue, all the placebo patients just self-medicating with the GLP-1 anyway? Similarly, in terms of differentiation for enicepatide including as a petrelintide combo. I think Lilly are already doing something similar in terms of doing GLP-1 GIP with their amylin, and they've already started the trial there. The thinking on the differentiation there?
Okay. I can take that. Regarding the head-to-head, again, we're in the middle of getting our clinical development plans all finalized. As I mentioned to you, we have, of course, a comprehensive chronic weight management program, but we also have a very comprehensive glycemic control program. In those studies, we anticipate that we will do head-to-head studies. We're fully aware that 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. Fully aware, recognizing that as an issue. 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 an incentive.
After they finish their main, what we call the primary intervention period, they will be invited to participate in a long-term extension. That's part of our program as well. In terms of differentiation, 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? It cannot just be can we get an extra 2% weight loss, and would that be a differentiator at the end of the day? We have to think a little bit more broadly. I mentioned already two of them. One is a package that includes head-to-head, package that includes long-term extension, a package that includes the flexibility of dosing. We're working on making the devices highly patient-friendly, multi-dose pens, for example.
Ultimately, when we really think about overall differentiation, we have to also think about what are the patient segments that we really want to go to. One differentiation, and again, we'll await the 104 study with the 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 evidence that we have in the preclinical space, has the potential that enicepatide can have a differentiation on glycemic control. The key message here is that we're trying to address the heterogenic 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.
Thank you.
James, may I quickly double-check, was there an initial question from you about the superiority of weight loss seen versus tirzepatide we should comment on, or was this just a comment?
Well, I guess the question is do you think that you could be better? I think there was the comment before about how you don't plateau, or at least you hadn't plateaued in the assessment period.
Okay. How do we see the weight loss comparison so far?
Yeah. Mechanistically, that's why we showed you the bias signaling, right? What we know from the science and what we've seen very clearly and consistently, now actually supported by other independent investigators who 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 enticing, right? You're seeing a very steep decline, 22.7% weight loss at 48 weeks. No evidence of plateau at all. You could envision that if we take it to 60, 72, or even 80 weeks, you might get more. Again, we have to do the study, right? We're obviously excited about that profile. We see that as a potential way to differentiate. We also see other ways of differentiating.
Yeah, to answer your question, that is one of the levers where we see there could be a differentiation in terms of weight loss. We also see differentiation in terms of A1C or in other areas that I just mentioned.
Thank you.
Very good. James, we answered all your questions?
There's plenty more I could ask, but I'll let someone else have a go. Thank you.
Yep. We move on. Next please, Luisa Hector from Berenberg.
Thank you, Bruno. I was wondering if you could tell us anything about the relative proportion of fat versus
lean mass loss, whether you've got some data when we might see it. Maybe just to follow up on that question on the running the placebo-controlled trials. I hear you, Manu, you've got your head-to-head, you're thinking about a long-term extension. In the trials that have already started, Enith, is there anything more you can do other than the long-term extension? Are you able to check whether there's any unapproved use of GLPs happening along the way or anything you can work with in that trial if it does happen? Thank you.
I'll start with the first two. I would definitely invite Dr. Lingvay to provide her perspectives in her own clinic about how she manages that. We're fully aware that there's always going to be add-ins of GLP-1s, and we have pre-specified endpoints to try to manage that. Regarding fat versus lean, 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 that data as yet right now, but yes, we have measured body composition, of course, in both our ZUPREME-1 study and the CT-388-103 study. What other things can we do on the placebo side? We are going to do everything that we possibly can to retain patients, and I mentioned a couple of key ways of doing this, right?
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, we have to be able to work with the right sites and the right investigators and the right patients. I'm not diminishing that it's a challenge, we do have methods in place that we feel that we can do that. Plus, we've had pre-specified analyses within our protocols 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. We recognize that there will be some diminishment of efficacy just because you're adding it onto another GLP-1. Pre-specifying it will be helpful to really get us a good understanding of what this effect will be.
Dr. Lingvay, if you have anything to add, please feel free.
Just happy to remind people that this is really not because we want to do studies against placebo. It's a regulatory requirement, we would very much like not to do them against placebo, not much of a choice in the matter here. Some of the glycemic studies can be done against active comparator in that space. In the obesity space, really, the placebo is a requirement that drives the design of these studies. That being said, I have to be laudative 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. It's not just a six-month extension. It's a meaningful extension for everybody, and everybody can go to the maximum tolerated dose.
I'm 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 make the good changes in the life that will help them and benefit them in the long run. Making sure that they're staying through the end then and being great supporters of these patients so they can get to that open label extension phase.
Very good. Luisa?
Very clear. Thank you all. Thank you.
Next questions come from Sarita Kapila from Morgan Stanley. Sarita?
Hi, thanks for taking my questions. Roche have previously talked to potentially dosing CT-388 above the 24 mg tested in phase II. How much of a barrier is the 20%-30% vomiting, diarrhea to pushing the dose higher? For any of the three combo regimens, do they include CT-388 exposure above the 24 mg ? Just a quick follow-up on the no plateau comment for CT-388. Is it because the 24-mg arm reached target dose late? We noticed there were six titration steps before reaching 24 mg. How many weeks of actual exposure did the median patient receive to 24 mg by week 48? Thank you.
Yeah. I'll start with this one, and invite others as well as needed. Just the last question first. It was 20 weeks because they finished their titration in week 28, and the endpoint was at 48, so they were at least able to take up to between 16 and 20 weeks. You're right. Could we have gotten more? This is why we feel very optimistic that we will, if they were to maintain it around 24 mg over a longer period of time. The other thing I'll try to remind people here is that when we actually looked at very carefully the performance of people at the 24-mg dose, the tolerability was actually really well tolerated.
The challenge was from 12, 16, and then once they got to the 24, the background rates of nausea, vomiting, constipation, diarrhea, generally tended to be very stable, and certainly did not increase. That gives us actually quite a bit of confidence to actually push the dose to higher doses. I think this is a great opportunity to emphasize the other comment that the other person made about how else can we differentiate, but we can also differentiate by potentially going at a higher dose. The reason why we are confident that we can go to a higher dose 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.
The final piece, how to ensure that we can get there, and this is still in evolution, in terms of our final design elements, but one way is to just be more flexible. Take some more time to get to the top dose. 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. Our properties of the molecule gives us confidence to say that we can do that safely. More flexibility, slower titration, great tolerability at 24 already that provides us confidence that we can go higher. What that higher will be, we'll hopefully come back to you all once we have finalized that design to say what that dose is.
We fully anticipate that we will try to get to a higher dose than 24 mg.
I think there was also the question.
I-
Whether the phase II combo had already a higher dose included. Sarita, have I got your question right?
Yeah, that was right. Thank you.
In the SYNERGY study, are we doing a higher dose?
Yeah.
Yeah, exactly.
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 ZUPREME-1 did, a really nice dose ranging that the CT-388-103 study did, we 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. There, I'll just remind people that that combination is really designed for people that are really needing that level of weight loss. Greater than 25% of weight loss, where maybe it is the high BMI category with type 2 diabetes or other comorbidities, where getting to that degree of weight loss really will be helpful.
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, as you heard from Dr. Aronne. We have to really think about where we want to use and where do we want to deploy these medicines. Given our portfolio, we're well positioned to do that.
Sarita, did we answer all your questions?
Yes, that was perfect. Thank you.
Next one in the queue is James Quigley from Goldman Sachs. James.
Great. Thanks, Bruno. Hopefully you can hear me. I've got two questions, please. Firstly for Dr. Aronne and Dr. Lingvay. At ADA, we saw lots of new data from different therapies, from CagriSema yesterday as well. What are you thinking in terms of positioning for CT-388 and petrelintide? Be particularly interested in, Dr. Aronne your view on 388, and Dr. Lingvay, your view on where petrelintide could sit. The second one is a sort of clarification/reminder. On the lack of dose response in ZUPREME-1, what were the reasons for that lack of dose response? Is it also related to imbalance in gender between groups? Are there other factors that are at play there that you've noticed?
Apologies if it was on the slides, which dose is going forward into phase III for which dose level is going forward for the next phase III for petrelintide? Thank you.
Would you like us to respond?
Yep. Dr. Aronne, you might want to start.
I think that in 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? That doesn't usually happen. 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. Also in looking at the weight loss curve, I think it is definitely possible. That would be a big differentiator to have a 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 CagriSema hitting the same number, and a triple agonist obviously goes past that.
This would be the first dual agonist that looks like it could go beyond that 22%-23% weight loss in this type of trial. As far as the petrelintide, I personally think that that could be one 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. 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%-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. We'll just have to see those.
Maybe also the same question then goes to Dr. Lingvay. I think the question was on how do you see petrelintide positioned within the field currently?
I thought Louis going to take that, I'm happy to take that because I'm a big fan of petrelintide. I think its safety profile is so compelling that it's going to be the first-line therapy for a lot of people, especially in the primary care field where they don't have the energy, time, or just multitasking ability to deal with all of these side effects and the multiple prescriptions and the multiple dose escalations. This is an ideal drug for primary care patients and for really the-Way more than half of the population that needs weight loss, and it needs weight loss in the range of about 10% or so, give or take, while improving their cardiovascular risk. We've seen that petrelintide does that very nicely.
It improves blood sugar, it improves cardiovascular risk factors like blood pressure and lipids and CRP, therefore, it's really a nice, gentle drug to deliver the type of weight loss that most people need. I'm also excited about the potential of exploring and using an amylin-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, currently, we're a little bit timid about intervening with the agents that we currently have because of the risk of muscle wasting and the risk of additional falls and fractures. If the data pans out as we hope it will, that will be a huge population there in the 75-plus age range that would benefit from an intervention that is gentle, that drives the potential of improved bone health and muscle health.
That would be such a welcomed 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. There's a big need for extremely effective compounds. Over time, the right way to manage obesity is to treat people when they get to a BMI of 27, or at the maximum 30, and they'll never get to these catastrophic weights. At that point, 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. 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. In fact, maybe Manu, they go to you. One, the lack of a dose response seen with petrelintide, so the plateauing. Any explanation why this is? The second question, which dose to be taken in phase III development?
Yeah. In terms of the doses to be taken for phase III, we'll be able to get into a little bit more of that 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. We're not able to share it for that reason. Based on the data that we've currently seen, we are confident of what those doses can be. Regarding the lack of dose response, this is still obviously in speculation territory, right? I think one of the things we do know about amylins as a class is that unlike GLP-1s, which doesn't seem to have essentially a plateau where you get to, it's largely limited by tolerability. It's not limited by efficacy.
Here with amylins, we are starting to see there may be ultimately an efficacy plateau as well. 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 that actual clinical data that we needed to see on the five doses that we tested, where does the curve fall. I think it's a mechanistic sort of difference. A lot of people are used to seeing incretins where you can keep pushing the dose, and as long as you're not tolerability limited, you will get potentially more efficacy. With amylin as a different class, a different mechanism, we're starting to see that there is, in fact, a plateau with the efficacy.
As Dr. Aronne mentioned, 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 III. 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'll obviously do a longer-term study, and then we'll really see how these doses play out.
Mm-hmm. Very good. James, all answered?
All answered, yeah. I'll jump back in the queue, Bruno. Thank you.
Yeah. Next one in the queue is Richard Vosser from JP Morgan. Richard.
Hi, thanks for taking my question. Sorry for the background noise. I've got one question just on flexibility. Manu, you mentioned flexibility and the importance in using it going forward. That leading to lower weight loss than anticipated. Just wondering how you can guard against making sure that the flexibility doesn't impact efficacy too much. Also linked to that, just thinking about tolerability. The tolerability was pretty good with INNA-051, but not maybe quite as good as tirzepatide at the high dose. Just thinking about what else other than the flexibility you might be able to employ to further improve the tolerability there. Thanks very much.
Sure. Okay. You're right. You have to have the right balance. If you have too much flexibility, you may not get to the top dose. If you have too much rigidity, you might have too much dropouts. We've seen, again, empirical evidence from two separate compounds showing exactly those two things. We have had a lot of learnings in the field, we take those learnings seriously and try to provide that into this protocol where we try to achieve that sweet spot, that balance. I can't get into 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.
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. The benefit that we have is that we've learnt a lot from the field. We try to incorporate those learnings. We'll execute on the phase III, and we feel confident that we'll get to that sweet spot. The tolerability part, I know that a lot of people love comparing studies. I just, again, caution people, just look at the study for what it is. Cross-study comparisons are a little bit challenging. Oftentimes, people compare a phase I to a phase III tolerability profile, and phase II to a phase III, et cetera. This is a phase II study. We have to recognize that there are certain vagaries of this 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 are you doing? Do you have AEs?" In some ways you're sort of prompting the question to some extent. I think we have to be a little bit careful of not to try to make an apples-to-apples comparison with the phase II and phase III. 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. I think the final piece I will say, and I'll hand it over to Dr. Lingvay, is the data, again, speaks for itself.
Personally, I was actually really concerned about going to 24 mg. I was reassured by the fact that in the phase I-B, we were able to get there very fast titration, no safety signals. Yes, the tolerability was higher because you're forcing the titration. We slowed the titration down in phase II to every four weeks. We saw almost a half, two thirds less AEs compared to the phase I. 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. I think the final proof is phase III to phase III, and ultimately a head-to-head comparison. I would stay away from a phase II to phase III comparison. Let me hand it to Dr. Lingvay.
Actually, I'm pretty passionate about this topic, so 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 they're 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. We're designing these phase III trials and phase II trials with the regulatory requirements in mind, including people with a BMI of 27 and above. We're studying these drugs and pushing people to these highest dose drugs, expecting 20%, 30%, 35% body weight loss.
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. 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 that flexibility, you're hurting people who are participating in the study who don't need that much weight loss, who might have side effects, 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'd want the race 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.
Please don't measure drugs in development by their amount of weight loss. Look at 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 goal.
Very good. Richard?
Super helpful. Thank you very much.
Yep. Let's move on. Next one is Steve Scala from Cowen. Steve, please.
Thank you so much. Two questions. Does Roche have a strategy for monthly dosing of a GLP-1? For Dr. Aronne and Lingvay, what % of patients do you believe will be on a monthly product in three to five years? Is it a small minority? Is it the vast majority, or is it somewhere in between? 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? Thank you.
Manu, you want to start?
Dr. Aronne or Lingvay? Yeah. Please start on the monthly.
Well, as far as what percent of people will be on a monthly, I think we still don't have enough data to really determine how tolerable it'll be, how effective it'll 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? Obviously, giving something weekly will produce a better side effect profile for the same amount of medication for the average drug. Making that transition, we still have to be certain that that's going to be okay, but I think it will. I am not sure if three to five years is going to be the timeframe where there will be a massive uptake. Over time, I do think that for a chronic disease, a significant number of people may switch to monthly.
It's very appealing as a treatment paradigm, I think, for clinics, too. Have the patient come in and give them a shot once a month. That could be very good for a chronic problem like this.
I think there were also 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-
Yeah
No-go decision depend upon?
Regarding the monthly dosing, 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 injectable, some people need a weekly, some people need a monthly, or maybe even a quarterly. At this point in time, we're very open to looking at all of them, and part of our strategy has been to sort of see what are the long extension half-life technologies that we would want to really bring to bear. Whether it's monthly or quarterly, et cetera, we can come back to refining that. On a strategic level, I think that optionality is exactly in line with our strategy that Morten laid out.
We're never going to say it's an either/or situation because we just are humbled by the fact that obesity is so heterogeneous, and there are needs at different stages for the same person, actually. I think we have to be open-minded about where those needs are. It'll 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 a weekly or an oral? Is it really safe? Can we put somebody on for that long and be really comfortable with the fact that the safety and the tolerability profile will be good? What are some of the con meds that they may be using during that period of time?
Again, remember, there's polypharmacy in people living with obesity because they have so many comorbidities. There may be some advantages to having short-acting compounds, for certain people, very long-acting compounds. It's really not that simplistic when we look at it in that way. Regarding 996, 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. What we're trying to do with 996 is to position it also for a broad set of indications which includes obesity and glycemic control. 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. You've heard from Teresa and Levi define what that bar is, it has to meet our bars to advance this forward into our phase III pipeline.
Very good. We quickly go on. Next one is Simon Baker from Redburn. Simon?
Taking the question, Bruno. Apologies again for the background noise here. Two for me. Firstly, just a question on petrelintide itself. There's been a lot of debate over the conference about the importance or otherwise of bias between the various of the three amylin receptors and calcitonin. I just wonder if you could give us an idea of the relative affinity of petrelintide for those four receptors. A question for both Dr. Lingvay and Dr. Aronne, picking up on what Dr. Lingvay was saying. There is a clear disconnect between the market demanding ever higher % weight loss and clinicians demanding ever lower GI side effects. It looks like with petrelintide, you may have a product that fits that profile of about 15% weight loss and very low AEs.
A question to both of you, what proportion of your patients would be adequately treated by a drug with that profile? Thanks so much.
I can take the first one and hand it off to both Dr. Aronne and Lingvay. As you know from the data that's been presented already in the public domain, petrelintide is what we call a DACRA. It's a dual amylin calcitonin receptor agonist. It basically has receptor selectivity for both the amylin 3 and the calcitonin receptor. 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 amylin 1. Again, as I said before, I would caution us to not come into that trap of cross-study comparisons because ZUPREME-1 had baseline characteristics that were quite different. The demographics were different, duration of therapy was different, and so on and so forth.
I think the jury, at least in my mind, my own personal mind, is that it's still out in terms of what is the perfect ratio to have. 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 salmon calcitonin today in clinical practice to treat osteoporosis. We know from preclinical studies that having some calcitonin actually can enhance insulin sensitivity. Whether all those things will ultimately translate into the clinic with a DACRA or not in terms of those outcomes, yet to be determined, that's our plan. We want to have a robust clinical development program where we can interrogate the bone, body composition, et cetera. We do believe that that mechanism lends itself to that, and that's what we're excited by.
I think to over-index on amylin-1 or amylin-3 purely on a cross-study comparison on weight loss, at my own personal opinion, is a little premature. Dr. Lingvay, you want to answer the second question?
I can jump in real quick because I agree it's a little bit premature to make this forecast. As I alluded to earlier, I'm very excited about an amylin-based 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. As far as additional patient populations are going to depend on what sort of data is amylin going to be able to deliver. Will it deliver the type of data that it prevents fractures and falls and muscle wasting and all the other potential benefits that we're thinking would 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 be favorably positioned to receive petrelintide or a similar drug.
There's also a big question of whether this petrelintide or similar agents will have cardiovascular protection on their own without mixing it with a GLP-1 agonist. If they do, that's really a game changer because now it can position it across a 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. 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 represented.
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 are not responding to the other compounds. Because of mechanisms, I imagine, we are seeing a small minority of people, but a significant number, who do not respond to GLP-1s or even the GLP-1 GIP combination. I think that with an additional mechanism added, we may get extra weight loss in those people who are refractory. Think about it. If it is just 5% of the population, you are talking about millions of people who potentially could benefit from a drug in this class. I think there is plenty of market for compounds in this category.
Mm-hmm. Very good. We have one final person. Actually, it is Graham Parry from Citi coming back with a final question, then I think we will close the Q&A session. Parry, the final question goes to you. Graham, the final question goes to you. Sorry.
Great. Thanks. It is actually just a quick follow-up then. On CT-388, you were saying you would run head-to-head studies in glycemic studies in type 2 diabetes, but I was not sure if you said you would or would not run head-to-heads in obesity.
Just to clarify, we are still fully vetting out all of the Phase III and the Phase III-B plans for the chronic weight management side. We are not precluding the possibility that we might run it there. 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 is much more obvious. There, back to what Dr. Lingvay had mentioned before, the FDA is actually well aware of the fact that those background therapies for type 2 diabetes have to be studied. That is the reason why those head-to-head studies are a little bit more firmed up for glycemic control. For chronic weight management, there is 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 quote-unquote clean background. It's not that we want to constantly keep doing placebo control studies, just to be really clear. It's we have to meet certain regulatory requirements. 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. It's a little bit more established in glycemic control, and that's why we have more firmed up plans there.
Great. Thank you.
I think with that, we close the call. Let me thank again 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. I have to call out here Jan-Patrick Schratzhans and Julia Breuer, and also Melanie Wolf for event organization. I hope the event was helpful and provided a timely update on our CVRM franchise. 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. With that, we'll close the call. Goodbye