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Virtual investor event at EASD. My name is Henrik, and I'm the technical operator for today's call. Kindly note that the webinar is being recorded. I would like to inform you that all participants are in listen-only mode during the call. After the presentation, there will be a question and answer session. You're invited to send in questions for this throughout the entire session using the Q&A functionality of Zoom. In addition to that, you may also raise your virtual hand to address your questions verbally. For participants joining via phone, to raise your hand, use * nine on your phone's dial pad. When you then get selected to ask your questions, please follow the instructions from the phone and press star six to unmute yourself.
One last remark, if you would like to follow the presented slides on your end as well, please feel free to go to roche.com/investors to download the presentation. At this time, it's my pleasure to introduce you to Bruno Rietzschel, Head of Investor Relations. Bruno, stage is yours.
Thanks a lot, Henrik, and could I have the first slide, please? Welcome to our IR call, focusing on our emerging CBRM franchise and the first data presented at EASD for our weekly injectable biased dual GLP-1 GIP agonist, CT-388, and our daily oral biased GLP-1 agonist, CT-996. Let me quickly take you through today's agenda. As a speaker for today, we have with us Manu Chakravarthy, our Global Head of CBRM, Cardiovascular, Renal, Metabolism Product Development. Some of you might know him already, as he was the Chief Scientific and Medical Officer of Carmot Therapeutics, who was incremental to Carmot's broad and diverse development efforts in the obesity and diabetes space. Manu is also a member of Levi Garraway's leadership team and will head the product development for our newly formed therapeutic area, CBRM, in the future.
Today, Manu will first provide us an update on our obesity and diabetes assets from the emerging CBRM pipeline. Thereafter, he will take us through the CT-388 and the CT-996 early data sets presented at EASD in the recent days, and putting them a bit into a wider context. Finally, we have 45 minutes reserved for Q&A, as we expect that all of you will have a lot of questions. For the Q&A session, we will also be joined by Louis-André Villeneuve, our lifecycle leader for the obesity and diabetes assets. Can we have the next slide, please? On this slide, I just quickly wanted to provide an update on the remaining news flow for the year. A few updates here to Tiragolumab. I just want to confirm SKYSCRAPER-01 results for Q4. Inavolisib, everything on track for the launch.
PDUFA date is set for November twenty-seventh in hormone receptor-positive breast cancer. Prasinezumab, we expect the phase two PADOVA data in Q4. Risdiplam in SMA, the data, the readout just slipped into next year, early 2025. Trontinemab in Alzheimer's disease, we will provide a new data cut at CTAD. This is end of October, beginning of November, with an IR event focusing and summarizing the data. This will be, as mentioned before, more than 100 patients, the original dosing cohort, and then some patients from the extension cohorts. Gazyva in lupus nephritis, we expect the pivotal data in Q3. And then on the TL1A antibody, you will get an update here at the Pharma Day, September thirtieth, about new phase two starts and indications outside of IBD.
Vamikibart, our first anti-IL-6 in ophthalmology, we expect to see data in DME towards year-end. And then the CT-388 and CT-996, we will discuss today in more depth. And let me also point out here already that the phase 2 results for CT-868 in type one diabetes, which we originally expected for end of the year, have slipped over into 2025. Can I have the next slide, please? Yeah. Let me also quickly provide you an update on the upcoming IR events. On September thirtieth, we will again host our annual Pharma Day in London as a live event. The event will have two parts: a morning session with Thomas Schinecker, Teresa Graham, Levi Garraway, who will discuss group strategy, pharma strategy and progress we made on the R&D excellence side.
And then in the afternoon, we will have take you through the entire pipeline of our new four or five newly set up therapeutic areas. That's oncology, heme, neurology, ophthalmology, immunology, and CBRM. And during this event, you should have plenty of opportunity to meet and discuss with all our senior management, including Manu, who will be present as well. Next, on the first days of November, we will have the IR call focusing on the neurology franchise and the updated Trontinemab data presented at CTAD. And then finally, to finish the year, we plan now for a full Digitalization Day, which is now scheduled for November twenty-fifth. And with that, let me hand over to Manu for an update on the data and the franchise. Manu, please.
Thank you, Bruno, and good to be here. Next slide, please. So before we dive into the assets, it's worth taking a few slides to level set in terms of how at least at Roche we're thinking about building out the new CBRM franchise and how we really view obesity as part of that enterprise. So as many of you know and at this point in time, it's well accepted that obesity is in fact a core driver of many of the comorbidities that we're used to seeing, that were at one point independently sort of thought about, but now really anchored largely through the modification of adiposity or high body weight.
And you can see here that, obesity, you know, at this point in time, literally is associated or at least drives many of the comorbidities, including type two diabetes, MASH, even cirrhosis, heart failure, we've, you know, heard a lot about that, chronic kidney disease, of course, obstructive sleep apnea, osteoarthritis, and several others. And as we continue to emerge, with the learnings of incretins, you know, from this, EASD meeting, even neurodegeneration, you know, will eventually be on this list. So for this reason, if you go to the next slide, please. The market is, you know, responding to that, notion because of the fact that not only is obesity associated with so many comorbidities, the population, is also, experiencing a significant rise in the prevalence of obesity.
In fact, if you look at both obesity and overweight by the next decade or so, it's projected to be around 3 billion, which roughly is about half the world's population. So when you sort of look at it that way, it's really daunting. And so no surprise that obesity is one of the most dynamic segments, with an obesity market projected beyond 100 billion by 2030. So next slide, please. So for that reason, also, it is not surprising that a majority of the activity that we see in the marketplace today, and specifically across both large pharma and biotech and the general biotech sector, biopharma sector, is very active development of the obesity pipeline. Majority of this currently still is dominated by the incretins.
In fact, incretins have become the backbone of obesity treatment, and one of the key reasons why, Roche has entered into this space, with CT-388, CT-996, and CT-868 as the incretin backbone, upon which we will wanna build the franchise out further. And these gut hormones, which are shown on the right there, are prime targets to modulate, largely because they, you know, literally impact nearly every organ system in the body. They're centrally involved for glucose homeostasis, weight management, even addiction and behavior. So they really are at the core of everything that we're trying to do in terms of energy homeostasis, nutrient regulation, as well as understanding, you know, of some of the other end organ complications. Next slide, please.
So the current Roche clinical development pipeline in obesity and diabetes is shown here. These are largely focused on our clinical programs. We will not be discussing any of our research early pipelines today, but suffice to say, there is active work that's ongoing in the research side as well. Today, we'll talk a little bit more in detail about CT-388 and CT-996. So we'll come back to that. But just as a, you know, brief mention here, CT-868, which is also a dual GLP-1 GIP receptor agonist, but it's been designed specifically to be once daily, so that it's ideally best suited to be treated as a use, as a treatment for type one diabetes.
We believe that's a very important opportunity for Roche, because there's not many, I would say probably none at this point, that are formally approved as an adjunctive therapy for type 1 diabetes. Several incretins and SGLT2, et cetera, have been used off-label, but none have been actually approved on-label as a formal adjunctive therapy other than pramlintide, which was approved many, many years ago. So we're very excited about that. A little bit early in our pipeline is a long-acting PYY analog with an expected phase one entry date in twenty twenty-five. And then we have GYM329, which is our anti-latent myostatin antibody, which is planned for a potential combination study with one of our incretin backbones, again, you know, in the twenty twenty-five timeframe. Next slide, the next slide, please.
So just before we get into the specific data, it's worth spending a couple of minutes on how these molecules that were discovered at Carmot was actually thought about and designed. And you know, starting to lay out the potential for differentiation, not just, you know, from a clinical perspective, but really even on a molecular pharmacology perspective. When you think about native hormones that we just talked about, like GLP-1, GIP, all of these native hormones, which are all GPCR targeted molecules, they signal through what is called the G protein complex, which is the alpha, beta, and the gamma subunits.
And that G protein complex, when it gets recruited to the receptor, when the ligand binds to it, as you can see in the far left side of the graphic, it activates cAMP. As part of that signaling cascade is also another very important protein called beta-arrestin. And when beta-arrestin gets recruited to the incretin receptor, it's sort of thought about as an off signal, because when beta-arrestin binds, it actually helps to degrade the receptor, internalizes it, and shuts off the signal. So at Carmot, you know, when we first embarked on this, a few years ago, we asked a seemingly simple question, which was: What if we could actually turn off the off signal? Would that enhance the efficacy more?
Because now you don't have the protein that actually degrades the signal, removes the receptor from the membrane, and the signal stays on longer through cAMP. So because it signals through cAMP and not through beta-arrestin, we call them biased receptor modulators or biased signaling agonists. Now, of course, the big question is, you know, does this really matter? You know, you know, it's nice that you could do this, but, does it actually show any type of benefit in terms of its potential to increase efficacy? And in what way, you know, would that be really of use? So we have some preclinical data, because there we can really dissect this in a fairly detailed way. So if you go to the next slide, please.
We've, you know, done some of those studies in the clinic, in preclinically, and of course, you know, we need to do those experiments in the clinic to really, you know, build upon the story, so what you see here is examples of the beta-arrestin 2 activity on the top portion of this figure, just to show you how does this compare to either the native hormone, which is GLP-1, or another GLP-1 receptor agonist, liraglutide. I mean, we could have certainly used semaglutide here as well, and you get the similar results, and what you see on the GLP-1 receptor is, you have strong activity of beta-arrestin, as you would expect of an unbiased ligand like GLP-1 or liraglutide, and here we're using 868, but 388, you know, will also behave the same way.
You see that the blue line shows that there is a flat line on Beta-arrestin two activity, which is indicating that there is no Beta-arrestin signaling, both on the GLP-1 and on the GIP receptor. To the best of our knowledge, this is a, you know, truly a unique attribute of the Roche molecules at this point in time. On the lower panel of the graph, you can see the consequence of no Beta-arrestin. As I mentioned to you, Beta-arrestin is the molecule that internalizes the receptor and eliminates the signal. So you can see when we compare it to either liraglutide, native hormone, or in this case, we even compare it to tirzepatide, you can see the blue line which goes down, which indicates that there is very little to no internalization.
The black line and the gray line are the controls, because those are unbiased ligands. And so this tells you that in the native state there's a lot of internalization. Tirzepatide has a slow blunting of internalization, but you know, CT-868, CT-388 have you know, much more profound blunting of the internalization, which means that the signal is kept on in the on state longer. Now, on the GIP, you can see the same thing. Very significant, you know, reduction in internalization with the Carmot or the Roche molecules, tirzepatide, a little less.
So if you look on the right side, this is the, you know, the in vivo evidence that tells you that by keeping the receptor in the on state longer, you get more profound or more prolonged efficacy. So the graph that says blood glucose versus time, it tells you, you know, this is the data that shows that when you compare it to a native hormone or to liraglutide, which is in red, you see blood glucose goes up, and then it essentially, you know, comes back down a little bit, you know, in the setting of an OGTT, but remember, this was done 48 hours after the dose.
Okay, so the animals were dosed forty-eight hours later, we did an OGTT, and you can see the blood glucose is with liraglutide is the same as that of the vehicle. But with 859, which is essentially the mouse analog of 868, you can see profound and continued suppression, which tells you that it's, that's the case because you're keeping the receptor in the on state. On the weight loss, you just see the same thing. So when you actually dose, this is just with a single dose, and you give the dose, and then you follow what happens over a subsequent eighty hours or so. You can see that liraglutide, initially, over the first twenty-four hours, decreases the body weight, but it comes back up.
Whereas with 859 or eight six eight or 388, all the biased molecules, you see this continued and prolonged suppression in blood glucose and in body weight. So overall, this is the evidence that that we have that says biased signaling could be indeed a potential differentiator. Now, of course, I will be the first to say that this is preclinical data, but this gives us very, you know, strong encouragement to take all these molecules into the clinic, which we did, to then continue to see if this hypothesis continues to pan out. Next slide, please. So 388, quick snapshot. Again, we'll go through the data in a little bit more detailed way. It is a once weekly dual GLP-1, GIP, again, fully biased on both receptors.
So we'll share with you the emerging data from the 101 study. Parts of the data from the 101 were already presented last year at the ADA. At the EASD this year, we're just continuing to build upon the data sets that's coming out of that multi-part, multi-cohort study. As Bruno mentioned earlier, we've already initiated phase two with CT-388, you know, with our what we call the 103 study which is in overweight, obese subjects. And then we have a study that is planned to initiate later on in the Q4 2024 timeframe with overweight, obesity plus type two diabetes.
So those two will position us very well as we fine-tune the final dose that we wanna take to phase three, the titration regimen that we wanna take to phase three, and then, you know, we're doing everything that we can to accelerate the planning for phase three as well. On the right is just a schematic just to give you a flavor of the phase two design. And that tells you, you know, that, you know, we are actually studying a wide dose range, going from a very low dose to a very high dose, across, you know, multiple different steps of titration.
At this time, we're not going to be able to discuss in great detail what those exact doses are, but suffice to say, it's, you know, it's in a wide enough dose range that gives us, all the information that we would need, to go into a pivotal, program. The primary and the secondary endpoints are all exactly what you're used to seeing, which is the % change in body weight, and our key, secondary endpoint is, of course, going to be, various other measures of body weight changes, including body composition. Next slide, please. Nine nine six, again, we'll cover this data in more depth, but this is also a program, you know, that is planned for, acceleration as best as, we can. So you'll, you'll see the data from the,
The some portions of the 201 study, because that also is a multi-part, you know, multi-arm study. And the data that we, you know, showed at EASD is from the MAD portion in the non-type 2 patients. And we also have an arm that is in the type 2 patients, which is, you know, planned to initiate in the fourth quarter of 2024, with an expected data readout in 2025. And then from there, we would, of course, you know, plan to initiate the phase 2 study with 996 as well. In fact, the data that we already have on hand today gives us the confidence to go into phase 2.
These data on the CT-996 I'll cover when we cover the CT-996 in some more detail, so we can go to the next one. So CT-868, as I mentioned to you, a very exciting program. It has the potential to be the first in class, as I indicated earlier, because there are no on-label adjunctive therapies for people living with type one diabetes today. So we've done already a fairly extensive program for this, which includes a study, a mechanistic study, which we call the CT-868-003 study in type two patients, where we showed, in a weight-independent manner, the profound lowering of glucose and insulin, enhancement of insulin sensitivity that CT-868 can bring.
We also have a similar mechanistic study that's actually almost completed, which we call 868-005, to continue to build the story on in type one diabetes. We completed a formal POC study, which we call 868-002, in type two patients, and that has been reported already in previous conferences, including the Obesity Society. I'll highlight for you some of the data in a second, and then 868-004 is our ongoing phase two study, proof of concept study in type one patients, that is currently ongoing with the data expected in 2025, and that data will then, we anticipate, should set us up for potential pivotal study in the subsequent time.
Just to give you a flavor of CT-868, because we won't talk about this in the rest of this call. A very potent molecule, very robust in terms of its activity. And you can see here, when we dosed patients with type two diabetes, overweight and obese, over a 26-week interval, what you see is a profound reduction in A1C, which was our primary endpoint. Placebo-adjusted change was 2.3% reduction in A1C. If you quickly scan over to the right side, you can see the proportion of people that achieved various hemoglobin A1C categories. Remember, all these people were diabetic when they entered the study.
By the time they left the study in six months, more than 70% of people no longer had diabetes, as defined by the ADA criteria of 6.5% or less. That's, you know, essentially a profound impact that this drug could have even for people with type two. But, you know, since we have obviously CT-388, you know, for type two, we're gonna focus on that, and this will be positioned for type one. So very exciting result. We feel that, you know, the flexible and easy integration of the QD regimen into an, you know, insulin regimen that, you know, people with type one diabetes take.
Many type one patients still take multiple daily injections of insulin, so adding this on will help them lower their burden of insulin and to improve their glycemic control and, of course, to improve their body weight as well. And then the next slide, just to again give you a flavor very quickly of our earlier assets I indicated, GYM three twenty-nine, anti-myostatin, and the long-acting PYY analog. So these are positioned as either standalones or these MOAs can in fact be tailored as add-on therapies or combo therapies to address the various comorbidities or to actually address the various segments of obesity, which clearly there are many of. So we don't look at obesity as a one-size-fits-all.
In fact, there are many segments of obesity that having such a portfolio allows us the luxury, if you will, to mix and match and really make sure that we're really bringing the right therapy to the right patient at the right time. So when we think about incretin-based therapies, what we envision is potential future combinations, you know, to either preserve lean mass, which we can do with our GYM329. We're looking at, you know, agents and mechanisms that can continue to augment the decrease in energy intake, such as the PYY. We are looking at agents that can actually increase energy expenditure, so that other side of the caloric balance equation, not just the decrease in food intake, but also the increase in energy expenditure.
We're looking at other different hormonal modulations of glucose control and other MOAs. So very exciting time at Roche for this therapeutic space to take hold of and to really then burgeon in the years to come. The next slide, please. So quick summary, quick snapshot, and then, you know, let's... I think we've already covered a lot of this. So I think we can sort of transition now to the next slide, to provide a little bit more of just a high-level view of how we are actually setting up our portfolio to leverage the opportunities that are available in obesity, which there are plenty of.
So I think we all recognize, and certainly many of you, having covered this space for a long time, will appreciate that despite the many approved therapies, and we can anticipate more therapies to be approved, there still remains lots of unmet needs, and some of which are highlighted here. And of course, the one that's on top of everybody's mind is muscle preservation. Sure, that's obviously something that we are interested in as well. And that's something that, you know, the field is also trying to think hard about. But it's not just that. I think there are a few other things. So we are highly focused on the totality of the patient experience, the holistic view, and really asking the question, you know, what do, what do obese patients living with obesity really need?
So I think the key things are, as I indicated earlier, obesity impacts lots of comorbidities, so we have to provide solutions for that. We have to think about solutions that can improve the tolerability profile. How can we actually not just induce the weight loss, but how to actually maintain that weight loss? In my view, that would be the holy grail of obesity therapeutics, is weight maintenance. Not easy to do, because the more weight you lose, the more metabolic adaptation you have, the harder it is to keep that weight off. That's why people regain all their weight back. So how do you, you know, essentially hack into the metabolism to tell the body to actually continue to preserve that weight loss? It's very important to be able to do that. Of course, convenience, compliance is important.
And then one of the other advantages that Roche has is, of course, its integrated diagnostic and digital solutions. So we have that opportunity to bring those capabilities to bear on the therapeutic space, to really marry the drug, device, diagnostic and digital health components that can help us really think about all the components that that's really needed to provide this holistic patient solution or the patient experience. And of course, combinations and segmentations are always in the forefront of our minds, because we don't, as I said, to reiterate, obesity is not a one-size-fits-all area. It is, it is indeed segmented, and so we have an opportunity with our portfolio, and not just the internal ones, but also the ones that we're planning on building, how can we address these segments? Next slide, please.
Just a quick word on the manufacturing approach. Any questions on this, we'll be happy to take later. But we do recognize that with the type of scale and the access and the ambitions that I just outlined, we cannot achieve that without the, you know, being able to bring these medicines in a scale that is commensurate with the need. So Roche has a global manufacturing network. It has industry-leading technical development and scale-up capabilities. There are internal capabilities already for device as well. And so, the organization is geared up to be able to supply the needs that is required to address this level of scale for the peptides. Now, of course, you know, one of the advantages with CT996 is that it's an oral synthetic small molecule.
So it's not a peptide, like what folks are used to seeing, you know, like semaglutide or the tirzepatide or any of the other dual GLP-1/GIPs. All those peptides have been converted to an oral through a formulation approach. The, you know, CT-996 is a true small molecule, and so the COGS will be anticipated to be much more straightforward, much more simpler to make. And therefore, this will be easily supportable by the Roche manufacturing network. So, the overall, you know, takeaway here is that, the organization is gearing up with all of the necessary requirements to supply the medicines that we need, not only for clinical, but hopefully for the launch as well. Next slide, please.
So at this time, I'm gonna transition from the overall approach, and we can, you know, during the Q&A section, session, we'll be happy to answer or elaborate anything further. But I'm gonna now transition to, you know, more data-specific presentations to give you some key point takeaways, you know, from the EASD presentation that we just did. Next slide, please. So we'll start with CT-388, which is, as I mentioned to you, a once-weekly dual GLP-1/GIP agonist. So if you go to the next slide. So I think we can skip this because we have already alluded to the characteristics of this molecule. So CT-388-101 is our first in-human, multi-part, multi-cohort, randomized, double-blind, placebo-controlled study. It's phase one study.
It was designed with thirteen different cohorts in it so that we could maximize the information that we could get as in the earliest timeframe possible. So the overall study objective was really primarily to look at the safety tolerability of the molecule, PK properties of the molecule, and of course, you know, to look at, you know, what happens at least in a secondary or an exploratory way to weight loss trajectories in both single and multiple ascending dose settings from as little as I said, two weeks, four weeks, twenty-four weeks. So a wide range of doses, wide range of time points. In this presentation, I'm gonna specifically focus our attention to two cohorts.
One was a 12-week cohort, which was dosed up to 8 mg, and another one was up to 22 mg over 24 weeks. So next slide, please. Here is the design of those two specific cohorts. So again, 8 milligrams was designed to be what we call a simple single-step titration to that was designed to achieve the 8 milligrams in a single step. So you go five and then eight, and then you maintain the eight for nine weeks for a total of 12 weeks of duration. The other cohort, which we call the multiple-dose 22 milligram cohort, was designed to be a little bit more elaborate. So we started at five mg and escalated all the way to 22 mg in as little as eight weeks.
So we went from five to eight, twelve, seventeen, twenty-two. So very steep, relatively, brisk, up titrations and up dosing in a very short period of time. There was flexibility, of course, provided for each of those steps so that, you know, patients could take an extra week or two to get to their dose, and whatever dose that they got to on week twelve was the dose that they maintained for the subsequent twelve weeks. So this had a rapid up titration period and a maintenance period to it. If you go to the next slide. So many of you on the call well-versed with the incretin literature, so I don't have to tell you that when you titrate low and slow, it has been shown to improve tolerability.
We already knew that, obviously, you know, when we designed the study. So this was not some revelation, that we did not know about. The whole point of why we did what we did was to actually have a, what we call a fail fast approach early in development. We knew that this is a highly competitive space. We don't wanna be taking molecules that do not have the bars that we would need to have, which are very high. They need to be very competitive. And so, the best way to do that is to actually de-risk early. And the best way to understand that is to do a brisk up titration.
You go to a higher starting dose, make more frequent step ups, you go to larger dose step ups so that you can actually get to that, what we call the NOAEL limits, the maximum dose that you can actually give, based on the tox studies in the shortest possible time. So this is, you know, one could argue, yes, it's a little bit artificial, but it's designed to be that way because we wanna get a rapid determination. Is there something unexpected in terms of safety, in terms of tolerability or efficacy? You know, are we going to see an early plateau? Are we not going to see the efficacy that you think you should be seeing? Or, you know, a safety signal that is not consistent with the class.
So those are things we would rather find out early and not take the risk forward. And our hypothesis was that if you could actually do that in such a setting, where you can actually get to a dose that's greater than twenty, which, by the way, you know, no incretin that I'm aware of has ever gotten to that point in that short period of time, then we have, you know, a significant amount of de-risking already done, and we can take our molecules confidently forward into phase two and phase three. So that was the background in which we operated to get to the data in the fastest way possible. So if you go to the next slide, this will give you a snapshot of the demographics so of the study that was conducted in those two cohorts.
The majority were in fact obese, which ranged between the BMI range between 35-38 or 39. A fairly good type range. By design, these were non-diabetic subjects. You can see from the A1C, the A1C was around 5.5%, which is essentially in the normal range. And then, the age is essentially what you typically see, you know, typically around the thirties or so. If you go to the next slide, it gives you a feel for the disposition of each of the cohorts. At eight milligrams, as we expected, you know, very benign, low dose, everybody pretty much completed the study according to plan. There were no adjustments in dose required.
Only one subject in the 8 milligram dose discontinued, largely because, you know, they had an unexpected pregnancy. They wanted to have an abortion, and so this was the patient choice. So obviously, we had to discontinue treatment. In the 22 milligram cohort, we had a total of 31 subjects enroll, seven into the placebo, 24 into the active group. And, you know, I have to say, I was actually pleasantly surprised to see that even though that we had artificially elevated the doses so high, 83% of people actually completed 24 weeks of treatment at that steep, very brisk titration. Four people, we actually discontinued, and they were all unrelated to the study drug.
One was withdrawal of consent, one was food poisoning, another one got pregnant, another one just, you know, was very non-compliant, didn't show up to the clinic. So all unrelated to the study drug. Majority actually completed the study at 22 milligrams, and five of them, so that's about 25% of the cohort, completed the study on 12 milligrams. So overall, when we actually look at it, you know, in the totality of what we did, this was very, again, further encouraging to us, that despite a steep titration, a majority actually tolerated this level of dosing really, really quite well. So if you go to the next slide, this kinda gives you a flavor of what the weight loss trajectories look like. So again, remember, the study was not designed to look for maximal efficacy.
In fact, efficacy was not even the critical endpoint here, but of course, you know, when you use a drug like this, which is highly potent, and a dual agonist, you're going to see this level of weight loss, so we see that right away, that whether you titrate slowly, you know, five and then just to eight, or you go very aggressively from five, eight, 12, 17, 22, in that 12-week period, the weight loss trajectory is pretty much more or less the same, you know, roughly around 10% to 12%, which further underscores that going slower doesn't sacrifice efficacy. In fact, one would argue that you probably should go slow so that you can truly maximize efficacy, because ultimately, you know, where people reach the plateau is dictated by the intrinsic property of the drug.
It's not about how fast you get there. So this is, again, you know, reassuring and tells us what the field has already taught us very many times, that going faster or going slower doesn't necessarily dictate the pace of efficacy. The other reassuring thing here was that, as I alluded to earlier, one of the unexpected things that we wanted to rule out was to see if we went to a high dose, do we see an unexpected loss of efficacy or an unexpected plateau that we wouldn't wanna see? In fact, there is no plateau. You know, the weight loss continues, you know, in a pretty, you know, linear fashion all the way, ultimately ending up right around 19% or so, at 24 weeks.
Majority of the people, if not all the people, achieved the regulatory endpoint of greater than 5% weight loss in 24 weeks, and 85% achieved more than 10%. 10% is, by the way, considered to be a very clinically meaningful threshold, and that's where you start to see disease modification. That's where you can really alter the trajectory of human health, because you can start to improve physical function, end organ function, cardiovascular health, kidney disease, et cetera. You know, to have 85% of people already get there in six months, that was actually pretty surprising, at least to me. This again underscores the significant potency of this mechanism.
So now let's go to the next slide, where we can talk a little bit more about the tolerability, which I'm sure is all on everybody's mind. And so I wanna help provide a little bit of context here, because there's unfortunately lots of conflation between the purpose of our study and how these are being compared to a phase 3 study or even to a marketed compound, which by definition, you know, that would not be a reasonable comparison. So just to walk through the results first, and then we'll contextualize. So overall, it was reassuring that despite this very brisk up titration, most AEs were mild or moderate in severity.
As I said before, at least, you know, to me, it was very reassuring that we did not see any study drug-related discontinuations. Remember that one of the ways of actually knowing whether a drug is tolerable or not is whether they actually wanna stay on it. And nausea, vomiting, of course, is there, but if people say, "Look, I don't wanna stay on this," that's actually more telling in many ways. So it was reassuring to see that very few, if actually none, were related to the study drug itself. So, we did see an AE leading to the discontinuation, and that was the pregnancy that I alluded to earlier. And of course, you know, when people get pregnant, we have to discontinue them, but that was not a study drug-related event.
So again, reassuring to see generally all AEs were mild or moderate, with very few severe events. And those severe events were largely because of a food poisoning, which I indicated to you. And then there were, you know, two cases of a transient increase in creatine kinase. And, you know, creatine kinase elevations can happen to anybody really, you know, if you're slightly dehydrated or you exercise a lot or you move around a lot, you know, you could see that. So this was a transient increase, came back right down, no changes in the, you know, dosing was done, again, related to, you know, noted as unrelated to the study drug. Next slide, please.
So now if we break it down by specific, you know, what we call preferred terms, and the preferred term, largely, not surprisingly, was GI-related. So most GI-related AEs are listed here, ranging from nausea all the way to abdominal pain. So these were the most common ones, and again, every one of these were largely consistent with what has already been seen. So nothing unexpected, nothing that we hadn't ever seen in the class before, nothing that stood out as "Oh, where is this coming from?" type of thing. Yes, so when you look at the results, the frequencies are higher when you actually escalate higher. Also, as expected, when you look at the eight-milligram cohort, we see rates, because remember, we started at a fairly high dose of five, and then we went to eight.
So you see the nausea, vomiting, diarrhea, constipation rates as listed there. And then when you compare it to the very rapidly up titrated period, you know, in the day one to week 12, all of those correspondingly are increased relative to a much slower, gentler rise. And then if you look at the far right side of the column, when the people that, you know, reached their quote-unquote, "maintenance," and they were maintained, you know, over the subsequent 12 weeks, majority again, at 22 milligrams, we see in many of them, those AEs tend to improve. For example, in nausea, it goes, you know, down from 75% to 33%... vomiting goes down from 75% to 33%. Nausea goes down from 83% to 54%, et cetera.
So you can see that the general pattern overall is no different than any other incretin therapy that has been studied at this stage in development. That's the critical point here to take away, is that at this stage in development, in phase 1, when you're rapidly titrating, we're seeing these events. And of course, you know, over the course of time, as we slowed the titrations down, and then you can start to get the hint already, as when we go to the maintenance period, we are not aggressively titrating anymore, we're starting to see easing, easing up of the, of those events. So just to illustrate this a little bit better, you know, graphically, so if you go to the next slide.
I've just, you know, we've just plotted it for vomiting, and we, you know, we've done the same for nausea and others as well, and we see the same pattern. But just for the sake of illustration, this is the typical pattern that you see when you go up really fast on the titration period. The overall nausea rates, you know, can, you know, peak up to 50% here, as you see, okay? But each of those peaks correspond to when the most rapid doses were actually administered. So when you go from 12 to 17, 17 to 22, you're seeing those bumps. When you're maintained at 22, you start to ease up on those frequencies, and ultimately, you get to a steady state. In fact, towards the end of dosing, there was barely any further increases.
If anything, sometimes it, you know, you even saw a little dip in the frequency. So overall, the pattern that we see here is, again, no different than what has actually been shown many, many times, with other, incretins, whether it's monos or duos or triples or any combination you can think of. So again, overall, our interpretation of all of this is that despite the brisk up titration here, we're not uncovering anything that's unexpected. Yes, the frequencies are what they are, and it's consistent with the up titration period, but, you know, in terms of actual events that we're seeing, there is nothing here that is unexpected, that is not seen in the class before. So next slide, please.
So to conclude, you know, this part of the, you know, data presentation for CT-388, you know, our takeaways here is that, overall very encouraging signals here, with robust 12% weight loss in week 12, 19% at week 24. And, what was really, really, quite reassuring for us, because this is exactly what the literature had taught us before, is that when you slow down the pace of titration, it does not meaningfully alter the weight loss trajectory. So we get a lot of, you know, questions about whether if you slow that titration down, yes, you might improve the tolerability, but will you compromise efficacy? And, you know, our data doesn't suggest that. The literature data actually doesn't suggest that. And you can see that here, right?
With eight milligrams, very simple titration, your first 12-week trajectory is almost the same. It's about 10% or so, compared to 12%. So 10, 12, right in that range. So over some period of time, as we give more time for the body to equilibrate, we anticipate that the titration will ultimately or the dose will ultimately dictate where we ultimately land up in the plateau. So we need to do the longer term studies to determine where the plateau actually occurs. And then, you know, of course, in terms of the safety tolerability, despite this, you know, rapid up titration, it was reassuring to see no unexpected signals. There were no treatment-related discontinuations.
We think that the tolerability profile will certainly improve over time, as has been demonstrated already by many other incretins. And then, quite reassuringly, our data actually supports testing higher doses. As I indicated to you earlier, at least to my awareness, there are not many other studies that have actually shown that you can even go up to these kinds of doses in as short a time as we have done. So all in all, these data certainly warrant for the clinical evaluation of three eight, and for that reason, we've already initiated phase two in July. And another addition, you know, phase two is going to be started in the fourth quarter. Phase three planning is underway. All right. So this is just to provide some actual data to what I just said.
This is a compilation. I'm sure that many of you have probably seen something like this in other formats. But if you actually take a look, and we've just selected some relevant ones, you know, so you have your AMG 133 compound, which is the GLP-1 GIP antagonist, and then you have tirzepatide, which is a GLP-1 GIP agonist, and then you've seen our data. So if you look at, you know, just the nausea rates, it ranges anywhere from, you know, 50% to 80%. When you look at the phase 1 data at the highest dose that tirzepatide looked at, nausea was at 50%. It goes down over time to the 20% to 30%. Same pattern with vomiting.
You see high rates of vomiting, in tirzepatide as much as 75% of people experienced vomiting, but it goes down over time. Same thing with diarrhea. It can be as high as 40%, and then over time, it improves. This has been done many times. The point here is that slower titration does improve tolerability. Slower titration does not impact efficacy. Okay. This was a poster. You can certainly download that as well. Let's switch gears to the oral module, another very exciting program for us. You go to the next two slides, please. Yeah. This one, I just wanna pause on this, again, not to mention about the whole, you know, obesity thing, but just to underscore one important fact, which is why is an oral required?
Because we get that question a lot, too. It's like, you know, "Don't you have an injectable? Isn't that enough?" Very excited about the injectable, of course. You saw the data already. But when you really think about the ambitions that we have as a company of really trying to reach the broadest scale and the impact that we can make, you know, by altering the trajectory of obesity, we need simpler, cost-effective solutions that can actually be applied with that scale. And the one way that you can do that is to actually, you know, use a truly synthetic small molecule that, as we talked about, will have COGS that can support that kind of that kind of campaign. But we don't wanna be sacrificing efficacy to get there, right?
So the efficacy that we set out to have, the bar, was to make sure that the efficacy was as good, if not better, than the current injectable mono-GLP-1 receptor agonist. So when we embarked on this discovery effort, you know, at Carmot. So next slide, please. We had those high bars. So before we get into the data, I wanna take literally one minute extra here to provide a little bit of context, because most people may not appreciate how difficult it is to actually make a truly synthetic small molecule GLP-1 receptor agonist. Because if it was easy, we would have done it ten years ago, okay? It's not that companies haven't tried, okay? People have tried and tried, and it's very hard.
The reason is because it's very hard to make, you know, sort of solve for two things: high potency, high selectivity, and to have high bioavailability at the same time. You can make a highly potent molecule, it may not be highly bioavailable orally, meaning that your PK may not support a once daily. And in our minds, if you really want to be competitive, you really want to be, you know, operating at scale, you have to have a once daily drug that is supported by the pharmacokinetic property, which is essentially the plasma half-life. So we had to solve for both things. We had to make a molecule that's highly potent and highly bioavailable, and that's what CT-996 is.
And in addition to that, the reason why most GLP-1 agonists today have failed is because it's very difficult to pass through the gauntlets of liver toxicity, right? So you need to have a molecule that has a very low DDI potential, has no reactive species that are formed, and one way to measure the reactive species is through an analyte called glutathione, which is the GSH adduct. Many molecules actually are GSH positive, and GSH positivity means that you might have a risk for liver toxicity. So we had to find a molecule that had all of those properties while having no GSH adduct formation, and CT-996 is one of those molecules.
And the final gauntlet, which is very hard to pass through, is to actually have a molecule that has a tox, you know, margin that is sufficiently large enough so that you're not, you know, compromised in the clinic to really test high doses early. Because you can always test low doses and convince yourself, oh, I don't have, you know, liver tox, but you'll ultimately find it, you know, when you go to phase two and phase three. So might as well find all these things out, and the way to do that is to go very high, very quickly, but you cannot do that if you don't have a tox margin. So we had to actually make sure that we had that too.
So when you really think about all those things, and to see that Nine Nine Six actually passed all of those bars, at least in my mind, you know, having done drug development for 20 years, this is not a trivial feat. So let's then look at the data that supports some of these contentions. So in terms of the potency, we obviously wanted to make sure that we're not compromising on this. So this molecule has sub-nanomolar potency on the human GLP-1 receptor. Okay, so you can see these molecules compared to the native hormone, very high potency here. We wanted this molecule to be biased. So you can see the, you know, the middle panel here, you know, doesn't have any beta-arrestin activity. In fact, it's 24 weaker on beta-arrestin compared to the native hormone.
Then this final on the top right, it shows you what I showed you with our peptides. Same thing, very low internalization compared to the native hormone. In fact, 204 weaker internalization, which means that we have a molecule that is, you know, essentially no beta-arrestin, keeps the receptor in the on state longer and perhaps that's one of the reasons why we see such high in vivo potency and efficacy. That's shown in the bottom panels there. You can see when monkeys are dosed with either 3, 10, or 30 mg per kg, you can see in as little as four weeks almost 12% of their body weight being lost.
Quite intriguingly to us, and this certainly needs to be repeated in humans, this loss of body weight appears to be preferentially fat mass loss. And you can see in the first red box over there that there's a very nice dose dependency to the fat mass, whereas the placebo actually had more fat accumulated, which is consistent because these are obese monkeys. And then if you look at the right box, you know, the second red box, much of that doesn't seem to be driven by the weight loss, it doesn't seem to be driven by the lean mass. So you can see the lean mass is more or less the same as the other placebo.
So this is, I'm not, I'm not claiming that this is somehow, you know, is preserving muscle mass, but it's certainly intriguing enough to us that this could be one more differentiating factor of this molecule that is worthy to pursue further with. Next slide, please. So again, this was a study 201, first-in-human, three-part, multi-cohort, phase 1, randomized, double-blind study, which had a SAD part, a MAD part, in obese non-diabetics and a MAD part with obese diabetics. The data that we presented at the EASD was from the part 2, the MAD part, with obesity without diabetes. Again, the overall study objective here is to really understand safety and tolerability. It's not designed for looking at efficacy. We don't even use the, in fact, the word efficacy.
It's more about the pharmacodynamic properties of this molecule, so if you go to the next slide, it shows you kind of the scheme, the schematic of what we did, so this was done in a single center in Australia, as you would do most phase 1 studies. Primary endpoint was safety tolerability, and you can see in this study, what we did was we actually enrolled about 25 people, randomized them into placebo or active in each cohort, and ultimately, when you broke the blind, what you end up with is roughly around, you know, 6 to 7 per cohort, ultimately landing with 4 different groups, so the first group was dosed at 10 milligrams for one week and escalated to 30, 60, and 90, each for one week, so we call that cohort one.
Cohort 2 was a much steeper titration. We started with 10, very quickly went to 30 in as little as four days, and then we boosted it to 2X right away, to 60 and to 90, and then 120. In cohort 3, we did the same thing for the first seven days, but then we slowed it down a little bit. You know, instead of going 2X, we went 1.6X, and then slowed it down a little bit more from 50 to 80 and then 80 to 120. The Cohort 3 was slightly slower than Cohort 2, but all in all, you know, fairly aggressive titration here as well, with the flexibility provided, so as to allow them to reach their target dose, you know, with an extra two to three or four days that they need.
So go to the next slide, please. As we've already elaborated this on the third date, I'm not gonna spend the same time here, but again, the key point here is to emphasize once more that the point of doing these studies is not to maximize efficacy, it is to really de-risk early. And because of all the baggages that oral GLP-1 agonists generally carry, it was incumbent upon us to make sure that we are taking a molecule that we're not going to be surprised with, that there are no unexpected safety signals or tolerability that we don't already anticipate from an incretin mechanism. So we needed to see that as quickly as possible, and the only way of doing that is to push the dose.
As I said before, we are, well, at least as far as I'm aware, we are one of the only few molecules that can afford to go to such a high dose in such a short time, because our toxic margins will cover that. If you go to the next slide. Demographics, again, very typical of a phase I study. You know, as I said, each of these cohorts are broken down into, you know, like, the three-to-one randomization, as I said. Six in placebo, six in cohorts I, II, and III. The weight was all in the obese category. BMI, you can see there, ranged from thirty-three to thirty-six. Hemoglobin A1C, normal range, by design.
But because they were all obese, you can also see that they were all insulin resistant, with a HOMA-IR of two or above. This is the population that you actually want to study. So next slide, please. And so this tells you, shows you, the disposition of the participants. Again, very reassuring to see that 92% of participants actually completed the study despite the titrations that we actually subjected them to. So again, Cohort I, there was one discontinuation, underlying schizophrenia, ultimately ended up having a psychotic episode in a domiciled setting. This patient should have not been enrolled, unfortunately, but, you know, they ended up doing so. So that was, you know, just a disqualification of the subject.
Cohort II, we had one subject discontinue, morbidly obese, 140 kilos, diagnosis of sleep apnea, still allowed into the study. Ended up with a spontaneous right bundle branch block, which usually happens with what is called right heart strain in the setting of sleep apnea, very commonly seen. As an abundance of caution, you know, the PI decided to discontinue that subject. Both of them were unrelated to the study drug. Other than those two people, everybody else went through the study, as I said, with a 92% completion rate, and amongst those that completed, Cohort III was actually the one that did pretty well overall, in terms of Cohort I and III. You know, they all were highly compliant. They followed the titration paths exactly as stipulated.
In Cohort III, all of them followed it, except for one participant, and they ultimately stayed at 50, then completed the study at 10. So that becomes important when we start to look at the data from both the tolerability as well as the safety, the efficacy side of things. So all in all, very encouraged by, you know, the number of people who actually continued the study, didn't discontinue the study because of a study drug-related issue. Again, as I said before, we anticipated some of that discontinuation, quite honestly, because of the very rapid and steep titration that we had subjected them to. The next slide, please. So here's the pharmacodynamic activity, which is weight loss over the four-week treatment period.
What you see right away is a very stable placebo response. This is the first thing, at least when I look at weight loss data, I always look at that to see, was this done, you know, in the right way? Is this consistent with what is available in the literature that I can anchor myself to? And the answer is yes. Roughly in this kind of study design, you see about a 1-1.5% reduction in the body weight. There isn't anything unusual, you know, here in the study center or anything that is giving us any pause. These are the kinds of unusual, unexpected things I was talking about earlier that we want to pick up and rule out.
Cohort I, which was dosed with a very slowly, you know, up to 90 milligrams, had a 2.3% weight loss change, and then the two highest dose cohorts, 120 milligrams fast, 120 milligrams slow, gave you a 5.8% and up to 7.3% weight loss. Now, you know, people would look at this and say, "Wow, this is, you know, in a very small number of people." Yes, it's from a small number of people, because that's how phase I studies are usually done. If you look at all phase I studies, you know, whether it's tirzepatide or anything else, they're all usually in the same numbers of people, you know, between 6 and 9 individuals per cohort, and then you look at the totality of the results.
What is really intriguing to us here is, how replicable this data actually is. Even if you don't believe the 7.3%, the fact that both doses ultimately kind of ended up in the same kind of range, you know, let's call it roughly around 6%, is in fact quite reassuring. You know, because how many times can you actually say that you can replicate within the same study with the same dose, a same result? Very few. So, so this is actually very good data in our minds because this tells us that in the same study. Two different cohorts, completely different people. We're seeing, good replication of the data. Somewhere between 5%-7% weight loss in a four-week period is very, strong evidence of, you know, robust pharmacodynamic activity.
Of course, we don't see the plateau, which we don't expect to see. That's another, you know, thing that we're looking for as the unexpected finding, if you will. And then you can see on the right is the actual graph, you know, summarizing day minus one, day one versus day twenty-nine. So all in all, very encouraging results, with a good, you know, solid replication of the efficacy profile or the pharmacodynamic activity profile. Next slide, please. Because they were all insulin resistant at baseline, we had an opportunity in this study to interrogate the question of potential improvements in insulin sensitivity, right? Because if this was a drug that could actually help improve insulin sensitivity, then, you know, it bodes really well for diabetes as well.
We of course know that it will, given that it's a validated mechanism, but it's always good to see the data in your own hands. You can see day minus one, which is in light blue, compared to the dark blue, which is post-treatment. When you compare before and after, even at the lowest doses, you're seeing fairly robust changes in glucose control or glucose lowering, I should say. What was, again, very encouraging here to see is the concomitant reductions in insulin, which tells you that when you have low insulin, low glucose, you're likely changing insulin sensitivity. Again, quite reassuring to see that in a relatively small, quick study. Next slide, please.
This is a very important slide, which is the slide that, you know, indicates to us exactly what we were trying to achieve, which is very hard to do, right? Which is to get to a plasma half-life that is truly once daily. You can see that, you know, when we dose, you know, whether it's 90 milligrams or 120 milligrams, the terminal half-life ranges somewhere between 17-22 hours. When we line up, you know, what's available out there, to the best of our knowledge, there's only one other truly oral small molecule that can achieve, you know, a PK profile with a half-life that can support a once daily. Cmax and AUC were generally dose proportional.
There was no food effect, which is another very, very important thing to check off the box with. Which means that you have the flexibility to dose this drug without regards to meals. Many other, you know, oral molecules get burdened with the inability to dose with or without a meal. So our data with our PK indicates that we may not have that problem. This is not excreted in the kidney, as you can see, with a very low fraction excretion in the urine over the twenty-four-hour period. Next slide, please. So then coming quickly to the safety and the tolerability side. So here, again, all the AEs that we saw were either mild or moderate. Majority were, in fact, mild. There were no severe events.
There was one serious AE, that was unrelated to the study drug, which I indicated to you, you know, was that psychotic episode that related to the discontinuation as well. But no study drug-related discontinuations were seen. Next slide, please. And so when we look at the overall AE profile, again, not surprisingly, the number one AE category, the preferred term, is gastrointestinal. And among the gastrointestinal AEs, what you see are the list provided here, ranging from nausea all the way to decreased appetite. So when you compare cohort one, which was slightly slower titration, you can see the vomiting rate is very low, you know, it's one out of six. Constipation, you know, two out of six.
The only one that was consistently present was nausea, so it was in five out of six subjects. Now, when you go to the cohort two, which is the steepest titration, all of those numbers, of course, all of those frequencies are higher, as you would expect. When you push the dose towards the NOAEL, you are going to see that, as rapidly as possible, you're gonna see those kind of events, yeah, accumulate. And again, in the same study, just as I told you about the efficacy, when you slow down the titration, you're not compromising the efficacy and you're improving the tolerability. So you're seeing generally, other than nausea, most of these other things going down. You know, the reflux disease goes down, vomiting, constipation, et cetera.
So this is already indicating to us within the same study, and certainly when we go to a longer-term, larger study, with a slower titration, we will likely improve the tolerability even more in line with what others have shown, and we would do that without compromising the efficacy. The next slide, please. This again further underscores what I've already said, so I won't belabor it, but just suffice to say that what was again reassuring for us when despite this very steep and rapid uptitration, all GI events, especially the four big ones, were all mild. The majority, or actually I would say, almost all of them, excepting for one per cohort. So just one subject per cohort had a moderate event. None of them actually had a severe event.
So again, very reassuring to be able to see that in this kind of setting because you're, you know, you expect many more moderate events, or at least a few severe events, and we don't see either of those two things. And quite reassuringly, as you approach the dosing towards the end of the week or end of the month, 22 and days 22 and 29, the frequency goes down even more. And the last slide on the data, and then we will take questions. So next slide, please. So in terms of the other findings, generally, otherwise pretty much unremarkable. You know, there was nothing here that we would not expect of the incretin class. So no other laboratory investigations, no signals of liver injury, as I told you earlier, that's very, very important to rule out.
There was one participant that had an isolated increase in lipase. So lipase is a pancreatic enzyme. It has nothing to do with the liver. It's just, you know, something that happens and seen oftentimes with incretins, and we can contextualize that in a second. Other than that, the laboratory findings were pretty much benign. ECG findings also pretty much unremarkable, except for that one isolated right bundle branch block. Mean change in systolic blood pressure was around six millimeters of mercury. The mean change in heart rate was about seven beats per minute. Again, very consistent with the incretin class.
Nothing here that is surprising to us, and you can see, just to put this in perspective, when you look at either the triple G, orforglipron or, you know, another oral GLP-1 agonist, GSBR-1290, all of them, you almost unanimously report increases in heart rate, and that can range from either three to four beats per minute to as much as 27 beats per minute. It registered, actually, had even cases of arrhythmia. So these are all things that are seen. It's there, but it's navigable. That's what other companies have done. That's what we would do as well. Same thing with the lipase. Almost universally seen. I mean, it's just a, you know, a natural consequence of GLP-1 activation.
So these are all things that we actually, as I said, are expecting to see because this is part of the incretin profile. So next, slide, please, and so in summary, I think, you know, we don't need to go through this in detail. I think I've summarized it as I've gone along. So let's, in the interest of time, because we wanna make sure that you have a lot of time for questions, I will pause here. Sorry to go over a little bit, but, you know, it was important to set the context so that you have, you know, all the information so that you can, you know, ask us the right questions, and I'm happy to clarify, anything further.
Yeah. Thanks a lot, Manu, for this recap of the data and also introducing our franchise. And with that, we start the Q&A, and the first question actually goes to Harry Sephton from UBS on AT.
Brilliant. Thank you very much, Bruno, and thank you, Manu, for the interesting presentation. So my first question is on the side effect profile for CT-388. So we've seen in the past, as you showed, that with faster titrations, you do see high rates of nausea and vomiting. But I think in your study, you could quite clearly see the rates of constipation and diarrhea did seem to be more prominent with CT-388 than we've seen with other studies, and that didn't necessarily improve at lower doses. Do you have an explanation for that? Or, you know, how manageable do you think that is?
So, it's hard to, you know, attribute too much weight to that, you know, just given the small sample sizes, and the other thing to also note is, you know, when we went back and asked, you know, is it really diarrhea or loose stools? Those two were very hard to separate. So sometimes loose stools get reported as diarrhea, and so in the phase two studies, we've now incorporated a more formal definition, you know, based on the WHO category of what diarrhea really means, so that, you know, people don't conflate, you know, loose stools with diarrhea. I think that could have been one of the reasons.
But again, you know, we have to be mindful of the fact that these are small studies with, you know, relatively small numbers, so one or two will skew, you know, either way. Because it's... You know, you see equal rates of diarrhea and constipation. It's a little hard to make sense out of that. Again, you know, so we have noted it and, you know, we will, of course, monitor that and see, you know, how that evolves over time. So it's hard to, you know, provide any more over-indexing on why we saw more diarrhea or constipation in this study versus others.
Brilliant. And maybe if I could just ask on nine nine six as well. So for the slower dose titration cohort, there did seem to be limited efficacy on weight loss. So albeit this being in a very small number of patients, given the commentary you said around trying to push the titration to the limit on the other cohorts, is the lack of efficacy in that lower titration cohort a potential issue, or have you seen anything that sort of better explains why it didn't work so well in that cohort?
So one of the things, so this is one thing that we are doing right now, is to get a much more quantitative understanding of what is called the PK/PD. So one thing that we are learning, you know, and this is probably going to be true for most GLP-1 receptor agonists, is that the exposure that you attain and the duration in which you keep that exposure matters a lot. So one of the things we learned about cohort one is that the exposure threshold was not quite attained, and you know in those that were attained was maintained for a very short duration of time.
Whereas consistently in cohorts two and three, we were able to attain, you know, the needed threshold, meaning the concentration that you need to achieve in the plasma, and maintain that for a substantively longer period of time, so that's why cohorts two and three are starting to you know, yield the type of pharmacodynamic activity that we anticipate, whereas cohort one did not achieve that exposure threshold. So that's what we have so far, but, you know, we will get to a lot more quantitative understanding as we continue to, you know, further analyze and dissect the data, and as we get more, you know, data from longer term studies, that's going to help refine that model as well. Harry, did we answer all the questions?
That's very helpful. Thank you. Absolutely. No, thank you.
Yeah. Then we move on. Next one is, Simon Baker from Redburn.
Thank you, Bruno. Thank you very much for hosting the call. That's been, it's been extremely useful. So just I suppose this question really applies to both 388 and nine nine six, but particularly 388. You're seeing in the study, but almost by design, very rapid, very significant weight loss. And we know that speed of weight loss, irrespective of the means by which one is losing weight, has an impact on the split between lean muscle loss and fat loss. Have you got any data for both studies on the mix there?
Is that something you're mindful of in terms of thinking of the dosing regimen in phase two and phase three, about getting to a certain weight loss, but not doing it kind of overnight, because of that mix between the two? The second question was on CT-996. You said there was elevated very small elevation in blood pressure. We've seen that with Danuglipron. And as far as I can tell, this is in the same chemical series as Danuglipron. But they also saw an impact on pulse. I just wondered if you'd seen that with CT-996. And then my final one, just quickly, you talked about manufacturing at the beginning for CT-388.
It looks like you're going down the Eli Lilly route of solid phase synthesis rather than the Novo route of doing it recombinantly, which I'm guessing has implications, positive implications for CapEx. If you could shed any light on how you're making this and what the relative investment requirements are for doing this by solid phase versus recombinant, that would be really helpful. Thank you.
So let me answer the first two. I'm gonna then hand it over to Louis-André for this third. Very quickly, on the nine nine six, we do see the increase in heart rate. I mentioned that, and sorry if I glanced over that really quickly. We see blood pressure drop on a mean average basis of around six millimeters of mercury. On a mean basis, we see an elevation in the heart rate of around seven beats per minute. So like you pointed out, yes, it's in very much in line with others in the class, so this is not an unexpected finding here. Your first question about the speed, really, you know, a great point. It's something that we have taken, you know, deeply into consideration in our design and thinking.
We agree, this rate of loss of body weight is too much. You know, to lose 2% a week is not required, and in fact, may lead ultimately to, you know, other things like, you know, lean mass loss, et cetera, that you alluded to as well. So precisely for that reason, we are, you know, taking on the path to slow down the titration, which you could do by, you know, a lower starting dose, smaller increments of the dose step ups, taking longer for each dose step up. So all of those things have been taken into account in the design of our phase 2 study that's, you know, that we're in the midst of. So we will collect that body composition data in those studies because it's of sufficient duration to make a meaningful interpretation of.
We anticipate that by slowing things down, we will have an overall improvement both in terms of the quality of the weight loss as well as in the tolerability profile. Louis-André, anything further to add on that? Or, and then please, you know, add to the manufacturing question.
Yes, thank you, Manu. So, we do recognize that there will be a requirement for a mix of in-house and external manufacturing for our assets. We don't comment on timing of investments, but what we can say is that the build requirement can be managed within our current existing CapEx, which is around CHF 3.5-4 billion annual. So this is all we can say at this point.
Maybe to add here from my side, I think we are looking into the different techniques available, what you mentioned, you know, for peptide synthesis or microbial expression, both possible. Mm-hmm.
Great. Thank you very much.
Okay. Then we take the next question, which the questions go to Peter Verdult from Citi.
Hi, Peter Verdult here from Citi. Apologies if there's any background noise. Just two questions, Manu. Thank you for your time. Portfolio strategy and timelines. I think a key takeaway from EASD this week was the, you know, rising excitement around amylin. We're gonna see data sets there. So just when you think about, you know, the Roche obesity portfolio going forward, do you have any amylin assets preclinically? Is this an area you'd like to get involved in? I mean, there are some assets probably available for partnership, just your level of enthusiasm around amylin and Roche strategy there. And then just on timelines, I think senior management at Roche has been in a couple of forums of late saying that, you know, launches for these, GIP, GLP-1 and oral GLP could be earlier than 2029.
I just wanted to kick the tires with you, given you lead the program. Is that, is that really realistic? It feels a little bit optimistic to me. So just to an update on the timelines that you expect on these two assets. Thank you.
Okay, so regarding the amylin, so our view is that, you know, we are taking a holistic approach to the portfolio. We of course feel very confident about the, you know, the incretin backbone, right? I mean, that was the whole point of the Carmot acquisition in the first place. But it is the backbone, and we are fully mindful of the fact that it needs other combos. One of those combos is already in our portfolio, which is a PYY molecule that I just indicated. It doesn't mean that that's, you know, done and dusted, and we don't want anything more. We're actively looking at, you know, all opportunities, external or internal, to ensure that we have the most competitive build of the portfolio that we can.
And this is inclusive of amylin, other, you know, gut hormones, other things like energy expenditure modulators, et cetera. So it's, it's a, it's a comprehensive approach. Regarding the timeline, so at this point in time, you know, what we can share with you is that, you know, we're doing everything we can to accelerate these assets. As, you know, Louis-André already mentioned, you know, we're already looking into, you know, figuring out how we wanna do the manufacturing, with everything that, you know, at our disposal. We've already initiated the phase twos. Those are underway. We are planning on initiating phase two for nine nine six already in 2025. So things are in motion.
At this point in time, other than the acceleration of the phase III planning, I cannot provide you any more certainty or guidance in terms of when the launch will be, because there are many factors that will, you know, be involved there. But rest assured, though, it is being accelerated.
Thank you.
All questions answered, Peter?
Thank you, Bruno. Thank you.
Yep, okay. Then we move on. Next question goes to John Priestner, JP Morgan.
Hi, John Priestner, J.P. Morgan. Thank you very much for taking my question. So two on CT-388, please. So for the 22 mg dose, there was a serious adverse event of gastroenteritis or food poisoning. So can you kind of help us understand how that was diagnosed, and is there any extra color you can provide to give us confidence that that wasn't GLP-1 related, given-
Yeah.
the symptoms would presumably be very similar? And second one on CT-388. So you've spoken about the use of titration to optimize the GI side effects. Can you maybe help us understand just how much you think you can optimize those, and how much it can be reduced in terms of titration? I think you showed a very interesting slide on the rates, on the phase 1 rates, which is appetite, and I think it looks like the CT-388 22 mg dose has slightly higher rates of AEs. So maybe have you done any kind of computational modeling, or is there anything you've seen pre-clinically that gives you confidence in terms of being able to reduce those rates?
Sure. Regarding the gastroenteritis, the study in CT-388 was actually that part of the cohort was done in Mexico endemic for gastroenteritis, unfortunately. You know, it was very clear in this particular case, you know, the person actually had unfortunately some spoiled food the night before. Had a really violent reaction to that, as I'm sure many of us who have had food poisoning will experience, and essentially had to discontinue because it was you know so bad that they just couldn't even you know hold anything down. We just felt that it's just better to just you know have that person discontinue, feel better, and then not have to go through this.
So very clear diagnosis, and there was no concern at all by the investigator this was anything else but, you know, food poisoning event. Titration optimization. So that's the whole point of doing a phase 2 study, is to try to do a little bit of empirical data as much as we can glean from the literature. And I think I've tried to show that as in the slides, you know, using examples of tirzepatide as well as the Amgen molecule, because they're both GLP-1 GIP, it's just that one is an agonist and the other antagonist, but still of a quote unquote similar mechanism class anyway.
And in each of those cases, certainly with tirzepatide, because we have the most data on it and we can lean on that data, you see those rates improve. Now, we, you know, as we studied 22 milligrams, and, and we'll continue to explore these doses in phase 2, it doesn't mean that the phase 3 dose is going to be 22 milligrams, right? I mean, that's the other very important thing to take away from all of this, is that the one time we would have and the opportunity in drug development to really push the dose is in phase 1 and phase 2. So we and we, we anticipate and should see more AEs. So just because we see more AEs in phase 1 and phase 2, doesn't mean that automatically that translates to more AEs in phase 3.
Ultimately, what are doses in phase 3? We don't know yet, right? I mean, we're gonna. We have an idea of where it needs to be, but the final selection of that dose is going to happen after phase 2. So we have every confidence that the rates qualitatively will improve, and we've seen that, without exception, in anything that we've seen. I mean, I tried pretty hard to see if there was any exception in any of the molecules, and I couldn't find one. Whether you look at glucagon, whether you look at amylin, GIP, all the hormones, you know, do the exact same thing.
My answer would be that we feel quite reassured by the fact that even in this study, which was again, on purpose, designed to be, you know, artificially elevated and risk titration, when we go into the maintenance period, we're already starting to see some hints of the signal. I'm not saying that, you know, 50% is still great. It's just that, you know, we're looking at 80 versus 50, you know, 70 versus 30, et cetera. You know, directionally, it's moving in the right way. As we optimize the dose, the starting dose, going low and slow, I think that's an important principle. We feel very much as an expectation of 38%, that it would be improved. John, did we answer the questions?
Yeah, that's very clear. Thank you very much.
Then, next one goes to Emily Field from Barclays.
Hi, thanks for taking my questions. I'll just ask two. The first one is, and you know, at the beginning of the presentation, that was helpful, you know, talking about the hypothesis that the beta-arrestin impact could have a beneficial impact on efficacy. But actually, you know, one of the KOLs that we spoke to at EASD thought that that could perhaps be potentially contributing to some of the nausea seen in the early trials. So I was just wondering if you could comment on that. And then secondly, this is kind of a random one, but you know, I know Carmot was a California-based company, and then you know, the CT-996 study was at a center in Australia, CT-388 was Australia as well, really far from home.
And then, you know, you also mentioned that Mexico is endemic for gastroenteritis. So I guess I'm just kind of wondering, well, why would you then run a study there, you know, kind of knowing that? So I guess just sort of why run these studies so far away from home? Just... I know it's a random question, but thank you.
Sure. Happy to take the both of them. The AE profile with the biased agonist. So that remains a hypothesis, right? So actually, our hypothesis based on the literature and talking to, you know, KOLs specifically that have, you know, studied GIP in particular is that GIP actually provides the buffering effect, if you will, on the nausea, right? So if you look at the data from, you know, Matt Hayes at the University of Pennsylvania, he showed that, you know, by giving GIP, you actually dampen nausea. So that's one of the hypotheses as why a GIP agonist with a GLP-1 agonist, you know, would be a more suitable combination.
We've taken that hypothesis one step further and made the molecule biased, meaning you could potentially have even greater protection of the nausea because you have a GIP signaling now that is further potentiated, right? Because of the biased signaling, you're not internalizing the GIP, and in fact, have GIP stay on the membrane longer. So if anything, we hope that it will actually improve the nausea, and again, to be proven, for sure, but I would, I would submit that, in fact, it would be the opposite, that we would actually enhance the effects of GIP, whether it's on nausea or on glucose or on weight, whatever it is, we might potentiate the effect above and beyond, you know, a non-biased GIP. Regarding the geographies, you know, we operate globally, right?
I mean, you know, whether it's in Carmot or in Roche, certainly, and so when we do these phase 1 studies, again, what we're trying to do is, you know, stage the investments. There's no point in opening large INDs and, you know, opening up studies when you're not yet sure about the molecule. So going to a geography like Australia allows us, you know, the quick regulatory freedom, if you will, of getting the data that we need to make an informed decision of continuing investment or not, and by the way, all of these geographies are well established, you know, clinical sites. It's not like you're going off to some, you know, foreign land that you have no control over.
They're all, you know, audited sites, you know, by health authorities around the world, GCP controlled, and, you know, literally almost every pharmaceutical company that I'm aware of, including my previous ones, you know, operate in these geographies. So this is pretty much a, you know, par for the course, I would submit.
Emily, any follow on?
Thank you.
Okay. And the next one in the row is Louisa Hector from Berenberg. Louisa?
Thank you, Bruno. So a couple of questions. You're working on the oral GLP-1. Does that mean you're also working on oral GIP? And what could we expect there? And then in terms of... You know, it's very clear, you're accelerating, moving as fast as you can, but obviously, it's an evolving treatment landscape. So I'm just wondering what you're assuming around time of launch. For example, how many orals might be on the market? Like, what's your working assumption? And perhaps I could also ask, is there anything other than your phase 3 dose selection, which you would need before starting, outcomes trials, broader cardiovascular outcomes and, and so forth? Thank you.
Sure. I'll take the first one and three. I'll have Louis-André, you know, provide some perspectives on the acceleration piece, so regarding the early part of the portfolio, as I mentioned, we are actively working on all aspects of gut hormone biology, and that was the focus at Carmot. That remains the focus at Roche, so, you know, GIP, PYY, Amylin, you know, all of the gut hormones are within our purview right now of investigation and wanting to find the best combos that we possibly can.
I cannot speak to, you know, where they are in the pipeline right now since they're quite early, but suffice to say, that is all part of the portfolio strategy to really build the best combo, complementarities on the incretin backbone. Regarding the phase 3 dose selection, that is a, you know, a critical outcome of a phase 2. We fully anticipate that we will be well informed, based on the phase 2 studies, you know, that we have designed, which are quite extensive. These are relatively large studies, as you may have gathered from the ClinicalTrials.gov disclosures that we have, you know, roughly around four hundred people or so. So these are not small studies by any means, and we feel confident that that will yield us the dose.
We fully anticipate that will be the dose that will be that we will take into the outcome studies as well. There's no reason to think that that there will be any certain type of unexpected reason at this point in time. Now, of course, when we see the phase 2 results, I might come back and say we have a different, you know, data point there, but it'll be data driven for sure. Louis-André, want to speak about the acceleration component?
Yes, thank you. That's a great question. So, as Manu has mentioned earlier, it's very difficult to say, you know, when we're gonna be able to launch, but we are doing everything we can to accelerate. We are currently in phase 2 with the two assets, CT-868 and CT-388. And currently, you know, we are aiming at, you know, launching, you know, in the twenty twenty-nine plus timeframe. But at the moment, it's very difficult to say precisely when that will be.
Louisa, any follow-on questions?
Well, if I can, Bruno?
Mm-hmm. One.
What is the expectation of the marketplace at that time when you do launch? Would you expect other orals to be available? And on the oral GIP, so you're not saying that you've tried and it's too hard, just that that's further behind, and therefore very much these things are still in the mix. It's not that they've already proven to be too hard.
I'll have Louis-André clarify the first one, but yeah, to your point, yeah, these are all in our early research efforts. None of this can be said at this point, you know, that we've given up on it or we're not gonna pursue it, because literally it's too premature to say that, but it's actively being worked on. Maybe for the question around the overall, I think it's important to note, we believe the market will be really, really big if we think about the, you know, the billions of patients that, you know, that would be needing these therapies. We don't believe there is a market for one company, and we think that there is a market for multiple players.
We believe that by the time we launch, there will be other opportunities with other assets, oral and injectable. But we do believe that CT-996 and CT-388 are very well positioned to be differentiating and value adding for patients.
Thank you.
Okay, next one in the row is James Quigley from Goldman Sachs.
Hope you can hear me. James Quigley from Goldman Sachs. I've got two questions for you. So first of all, on the conclusion that the dose doesn't really, or the titration to the dose doesn't really impact the weight loss, is there any data on the dose intensity for both the eight milligram cohort and the 22 milligram cohort as you're titrating up? It doesn't really look like there was much difference until around about week seven or eight, which is when the curve started to separate. So is it really fair to conclude that titration doesn't impact the weight loss with CT388?
Is there any other preclinical data that you can talk to that gives you the confidence in terms of the weight loss, or that slowing the titration will impact the weight loss significantly, or at least the slope of the curve of the weight loss? And then secondly, you've spent a lot of time on the call trying to show how some of your assets and your data is similar to competitors. So I'm a little bit confused just in terms of where the differentiation is. When we saw the first press release for both assets, the speed of the weight loss was impressive, and that seemed to support the beta-arrestin hypothesis.
But if this is just, you know, if we're now saying that the phase one data was to see how high you can go with the dose, when we then go to the phase two, phase three, and the slope of the curve may be shallower, where is the differentiation, or where do you hope to see the differentiation? Is it in the combination approach? And if it is, does the speed of the development program or the backbone really matter if the combinations are going to be part of the differentiation? Thank you.
Yep. Okay. So, there's two points of evidence really that we can point to why the speed of titration really doesn't seem to impact the slope or the trajectory of the weight loss, right? So the first one is the, you know, the 8 milligram curve and the 22 milligram curve. And so you can sort of appreciate that, you know, there isn't much of a difference between 10% and 12%. But I think the stronger evidence is really in the CT-996 side of things, right? Because there, you know, we have what we call cohort two, the 120 milligrams, and cohort three is also 120 milligrams, but the rate at which cohort two got to 120 milligrams was steeper compared to cohort three.
And so overall trajectory, yes, I mean, there's some variability because these are small numbers, but overall pattern is not dramatically changing all that, all that much. And then, of course, you know, we can point to the larger data set. So if you look at the very early studies of semaglutide and the very early studies of tirzepatide, their, you know, trajectories in the, in those early studies, were generally, you know, similar, whether they went really fast or generally slowed it down. And so ultimately, for us, you know, the point that we're trying to make on the, on the similarities, if you will, is largely on the fact that it's the, the pattern of the tolerability that we're trying to see.
We're not, we're not trying to say that, you know, ours is 50% nausea, theirs is, you know, 20% or whatever it is. It's simply that the pattern of findings that we're seeing is consistent for this stage of development with other things that is out there. The differentiation will come in various forms. One of them, you know, can be the fact that over the period of time, you know, with the right titration and the right duration, with the right sample size, could we be able to see plateauing not happening at week 36, for example? You know, somewhere around week 36, if you look closely at the AMG 133 curves, that's when you start to see the break. You know, between week 36, week 40, it starts to sort of kind of start flattening, if you will.
Could we continue that even further? We will get a hint of that, you know, when we get to a longer term study, which is very hard to do in a short-term study. So that's something you've certainly pointed out, and we agree with that. The other thing could be the tolerability as well. So remember that this is, you know, from 24 people. It is what it is. You know, we are reporting the data as is. We need to collect more of it, and when we do the titration the right way, could we actually see better tolerability? That is a really important question that the phase two is actually designed to answer that.
And if we start to see that, that could be a differentiation, and we would link that back to the biased GIP that I alluded to in, you know, the previous question that was asked. Final piece is, yes, of course, combinations are going to be a component of that, and that doesn't preclude us from testing the backbone. You cannot do a combo study without actually demonstrating that your backbone does in fact provide that efficacy and the tolerability that you want, and you have to know what your dose of your backbone is going to be, right? I mean, we don't want to guess that. We want to be very empirically data-driven on that specific point.
So regardless of whether the combos will become part of our, later differentiation, which we are, certainly anticipate it would, we have to do this, monotherapy study, if you will, first. Hopefully, that provides a little bit more context, but happy to clarify.
And just to clarify on the curves, I mean, the CT-388 in the eight milligram and the 22 milligram, it. There's more a question of dose intensity. Because if you look at this step-up dosing, you hit eight milligrams fairly quickly for the eight milligram group. So in terms of the cumulative dose exposure, it looks pretty similar until week seven, which you know that makes sense in terms of why the curves are hugging. But if you had a similar step-up dose for the eight milligram as you did for the 22 milligram, surely that wouldn't happen.
So that's what I'm trying to sort of get my head around in terms of the conclusion that the titration doesn't really matter in terms of weight loss.
So what I was alluding to was the shape of the 22-milligram curve. One would have anticipated much more separation on week 12, right? Because we got to a, you know, an exposure with a high dose that should have made the curve much more. So the fact that you're increasing the speed of titration and you're still kind of getting the same level of, you know, the trajectory, tells us that probably, you know, the speed per se, may not really matter at the end of the day. The exposure of the drug might matter more. But the best example, as I said, about the titration differences is in cohorts two and three of the 996, because they're both at the same dose. The final target dose was 120.
The speed at which you got to the 120 was different. So, again, we would be the first ones to say small numbers, and, you know, we need to take this all with a grain of salt. But the data from the literature continues to support, you know, what I just said, and our phase 2 data will continue to, you know, provide more specific data on CT-388 itself.
Perfect. And Bruno, can I slip one more in, Bruno? Sorry. On the heart rate increases, sorry, I know we're out of time. I mean, you've shown that it's in the same range as semaglutide, retatrutide, and empagliflozin, but obviously the other GLP-1, and it was mentioned in your session at the EASD that it's two to four that we've seen with the other GLP-1. So in terms of the dose modifications and the dose titrations, how confident are you that you could potentially get into the two to four range, or is seven around about where you think to land based on what you saw with what we've seen with empagliflozin?
So first of all, I think the heart rate change, it to us, is again completely on target. You know, whether it's three beats per minute or seven beats per minute, it's very hard to separate that in a smaller study. And there are many confounding factors to why you see the heart rate change at all, right? So heart rate can be on target, of course, to the GLP-1 physiology, but it could also be, you know, maybe precipitated by a, you know, a more steep drop in blood pressure. We did see that, right? I mean, so we saw roughly around a mean of six to seven millimeters of mercury drop in blood pressure. And sometimes the compensation for that blood pressure is to increase your heart rate.
There may have been other confounding factors, which is very hard to tell, so I think, you know, again, this is a data point, note it down, but nothing here that is surprising to us. Longer term studies will ultimately lay out where we will land. You know, whether we land at two beats per minute or four beats per minute is hard to predict, but whatever it is going to be, what we do know from the literature is that the heart rate per se doesn't really impact the outcomes, so you have, you know, everything from dulaglutide, which is probably one of the highest heart rates there is, you know, seven to eight beats per minute, to retatrutide, which actually causes arrhythmias.
I think the consensus of the field, as best as I can understand it, is that you actually kind of look at the heart rate as part of the, you know, kind of the tolerability and the safety aspect of it, but it's not really something that is concerning enough that impacts your outcomes.
Perfect. Thank you very much.
Next question will go to Rajesh Kumar from HSBC.
Thanks for taking my question. Hi, Manu. You appreciate that you said these trials were designed to fail fast, if you had to fail. What are the chances that you look back when you're in phase three and said that, you know, this tolerability profile should have caused us to decide to fail at this stage? I.e., have you done a hindsight analysis of you're making a decision to move ahead? I know these are small sample sizes, and you've made a very fair point that comparing it with phase three trial data on adverse events and tolerability can lead to completely misleading, you know, judgments, and I get that. But I'm just asking that, how have you made that decision to move ahead to phase two after looking at the data?
Were there any scenario where you said, "Shall we kill this now?" And you decided not to. So what, what was the choice calculus around that? If you can elaborate, that would... We would really appreciate. Second question is on the we are looking at really small numbers and, you know, % calculation on six, seven patient. That's a stockbroker land. I'm sure that's not a scientist land. So, I, I'm not going to even go there, but, how do you think about the risk that, you know, if, when you go to phase two, or, you know, what, what are you doing in a patient recruitment criteria to ensure that motivated patients are coming into your phase two trials so that you don't see churn due to other reasons?
We have seen in obesity trials that patient churn can set programs back quite a lot. You've seen in the case of another asset, which I'm not going to name, but I'm sure you are aware of which one I'm talking about.
Great. So thank you for the first question. I really appreciate that, that you asked that. So there were very specific no-go criteria, as I alluded to in the introduction to the CT-996. It's incredibly hard to make a safe, oral GLP-1 agonist, right? So our kill criteria was that if we did not see a half-life that would support a once daily, meaning if we saw, like, a four- to six-hour half-life, I think, you know, we would have stopped it, because that's not gonna be competitive in our view. Just because we need this to be QD, you know, once daily and once daily by PK, was really, really important because that reflects that you have sufficient bioavailability to give you sufficient exposure, to give you sufficient efficacy. So that's...
If we saw that, we would have been done. We didn't see that. If we had seen in the preclinical settings, you know, positive signals of liver toxicity, I mentioned this glutathione metabolite. If we saw that positivity, we would have been done. We didn't see that. If we had seen that this was not a potent molecule with no in vivo activity, we would have been done. So it's not that we kind of hurtled down quickly to a phase 1 study and said, "Okay, let's see what happens." There were very careful, quantitative, thoughtful considerations to make sure that we're not taking even into phase 1. There's no point in exposing, you know, any human volunteers to a medicine that you think will have no shot at all.
So there is nothing there that we would have looked at that, you know, if any of those things were positive, we would have been done. Those are what we call intrinsic properties. Those are properties that you cannot will yourself and hope yourself will go away. So that's what we call the intrinsic property of the drug. So it's there or not there. The rest of it is all a function of how the study is designed. Nausea, vomiting, heart rate, all that is modulatable. Those are not things that we would say, "Oh, that's a no-go." Because we all know, everybody in this call knows, that that is all a complete function of how you titrate, what dose you go to, how much you stress the system, if you will. You know, think about that like a stress test.
That's what we did. We are obviously not gonna do that stress test in phase one... phase two, because we've already done that and, in my view, in flying colors. So now in phase two, the focus, you know, will be fine-tuning, you know, tweaking. We feel very good about the intrinsic property of the drug. As I said, you cannot change the will, you know, somehow the half-life is gonna get better. You cannot will that, the tox, you know, metabolite is going to go away. Those things are not gonna be the case.
So I think when you really think about it very objectively and what we actually have and what we had to go through and the gauntlet that we had to pass through, that is the reason why we're confident to go to phase two. It's not just based on six people. Now, of course, all studies in phase one use this paradigm. So what we have done is no different than any company that I've worked in has done, right? So very, very typical phase one program. You do your SAD study, you do your MAD study, and then you make a decision, okay, I'm gonna go to phase two. Phase two doesn't mean it's a pivotal study.
If we see something that's unusual in phase two, we still have an opportunity to say, "Okay, maybe, maybe we don't make that large investment to go to phase three." So that's why we go in, in phases, and these are staged investments by definition. So hopefully that provides, you know, greater clarity for that. Your second question was phase two to phase three?
No, in phase two, what is the recruitment criteria?
Oh, yeah.
Yeah.
Yeah. So, so this is pretty standard sort of recruitment criteria. You're right, you know, we don't wanna go to sites, that will, you know, delay us. So site, you know, selection, recruitment, retention, these are all kind of bread and butter of our clinical operations folks. I have no question at all. We have the greatest confidence in our clinical operations colleagues. They've done this kind of studies, you know, hundreds, thousands of times. So this is not something that, that is even on my mind, but honestly... But, but yeah, point noted. Site selection is critical. That is all the kind of key considerations that our clinical people take into account.
Of course, you know, the speed of recruitment matters a lot, and that is one of the reasons why we cannot sort of foretell and give you specific guidance of when the phase two is going to read out. We can do that perhaps once we actually formally start the phase two study.
Yeah, and then the first question probably was slightly misunderstood. So the way I was going is building on James's question earlier. Basically, you want to fail a product if you're not going to make a commercial return, right? And, the scientific criteria is great, you have that, but the differentiation is not going to be the speed of weight loss. It's probably going to be a combination. You already have bimagrumab by Lilly, which is a myostatin, which is further up in development. You already have other myostatins which are ahead of the curve. You already have approved weight loss. Basically, the thing is, do you see enough differentiation here that it was a go-ahead rather than a go, no-go decision? So what are the commercial calculus there?
So thanks for allowing me to clarify further. So the basic calculus was that, in our view, there isn't that many oral agents, other than one that I can name, that is truly meeting the kind of bars that we just are talking about. Most are peptides that are converted to an oral. You are going to, you know, have the same issue with the COGS and all these other things that, you know, we have to deal with peptides about. We're talking about a truly synthetic small molecule, oral GLP one agonist. And in our assessment of the field at this point in time, and when using objective criteria, it's yes, it's scientific, but we have to be scientific about this. There isn't any that really meets all these bars, other than one.
So, you know, the market space that we're going to be launching into, as we've alluded to many times, you know, with about three billion people that could potentially be overweight or obese with many comorbidities. We think it's a moral obligation to bring these things forward. It's almost impossible not to bring them forward. It cannot be just one or two companies that is supplying the world's medicines for all these people. So differentiation, I understand where you're coming from, but we're also looking at it from a purely, you know, a patient service approach, right? I mean, there are so many people with so many of these needs, and you need small molecules that can provide those kinds of solutions.
So I'm not sure that I would submit to the fact that if you don't, you know, win on weight loss, you know, by X% or win on the nausea by, you know, Y%, then this is not differentiated. I think you have to look at the whole picture. You know, what is the patient experience? How do they get access to these medicines? What is the scale and reach in which these medicines can be delivered? What are some of the ways that they can actually maintain their weight? We actually view oral medicines as weight maintenance therapies as well. So it's not a simplistic one-size-fits-all, and it's very hard to box all these things into that. I know that people like to do that, so you can kind of do your models.
But you know, drug development is very complex and messy, and taking care of patients is even more complex and messy. So I think we have to look at the broader picture, you know. That's kind of what I would say. Yeah, thanks a lot for the question.
Thank you.
We'll move on. Next on the row is Emmanuel Papadakis from Deutsche Bank.
Thank you for taking the question. I'll keep it very short with the time. Apologies if I missed this. Phase 2, have you told us or can you tell us anything about the titration regimen and the maintenance dose? Are you stepping up to something above 20 mg over eight weeks, or is it materially different to that? What is the design across the five active arms? And then a quick one on the potential phase 3 program. Would you contemplate doing an active comparator, or are you firmly set on doing it versus placebo? Thank you.
So at this point in time, you know, we haven't given the details of what our doses are. You know, we will work those things out, and then we'll come back, you know, at the right time. But it is a wide dose range, starting, as I said, from a very low dose to a high dose, with various different kinds of titration steps. So we will have, you know, both dimensions of dose, speed, and the timing worked out. And this is true for both of our phase two studies, you know, one in diabetics and one in non-diabetics. In terms of the phase three, can you just remind me what the question was again?
Placebo or active comparator.
Oh, placebo and active. Yeah. So, I think both are under considerations right now, so we can't, you know, obviously cannot give you the detail. But, we envision a very robust phase three program. Right? So, you know, for all the things you guys have mentioned, you know, competitive landscape, et cetera, we are prepared, you know, to handle that competition, and so we need a package that will support that. So it has to be a robust study. So there will be more details that'll come once we actually have got the phase threes nailed down. But I think we can anticipate, placebo-controlled studies, active comparator studies, all of that will be in the considerations in the mix.
Thank you.
Then, next one is, Sachin Jain from Bank of America.
Hi there. My question is just two. On the CT-388 phase 2 that you're starting, you referenced interim data in 2025. Can you just comment on the duration of follow-up you're looking for that interim stage? And whether you would be willing to make a phase 3 decision on interim, or we have to wait for final data. The second question is just to clarify the differentiator. You were very clear in the prior answer, talking about CT-996 being a small molecule. I wonder if you could just provide the same framework on CT-388. Is there any aspect of this profile you think is differentiated beyond efficacy or GI tols, or are we looking for differentiated efficacy, GI? And then just a third quick one. On CT-388, you've given the vomiting rates by titration and maintenance phase.
In the maintenance phase, once you're sort of through titration, the vomiting is still at roughly 10%. I think for Wegovy and their pooled analysis, that's down as low as 2% to 3%. So what I'm trying to understand is whether slower titration can impact the vomiting rates in a maintenance phase. It seems intuitively it can't, so I'm just trying to make sure I understand that.
Sure. So let me start with the third question. I will hand over the first question to Louis-André. So in terms of the maintenance phase, it's very important to remember that we already started at a very high titration level, right? So you've already set the frequency and the prevalence... I'm sorry, the case rates, if you will, in motion already by the time, you know, the way we started it. And so, you know, the lowering, if you will, is not going to be that dramatic because you've, you know, started high, they stepped up high, and you maintained it high, right? And so it's just not an apples-to-apples comparison.
You can, as I said before, we cannot compare our phase three results in whatever shape or form to phase one results, whether it's an active, you know, titration phase or a maintenance phase, because both of those phases are in this sort of very artificial setting in some ways. So hope that helps clarify that piece. The second is, you said about the phase two design, is that correct? Did I catch that?
Yes, it's just duration of follow-up for the interim, so we can gauge-
... Louis-André, do you want to quickly comment on that one?
So yeah, so it's a great question. So we're currently evaluating an interim analysis in twenty twenty-five, but we don't have all the details right now about this. But this is something that we'll use internally to make a decision for phase three. This is not something we're gonna share. I think we're gonna wait until the final analysis of the phase two later in twenty twenty-six. So this will be presented, but the interim is more for internal decision making.
Sorry, what was your first question?
Just you'd commented on nine nine six being differentiated on, you know, being one of the only other small molecules. I was just trying to get a similar parameter on 388. So beyond-
Right.
Efficacy and nausea, where do you think this is differentiated or is it differentiated on efficacy and nausea?
So, based on a hypothesis, right, which we have kind of tested and proven in preclinical models, we do need to do that experiment in human studies. The phase two is going to be that experiment, essentially. That will give us you know, a view into what is that thought, that efficacy trajectory look like? What is that efficacy profile, a tolerability profile ultimately look like? We will be able to answer that question of true efficacy, tolerability, differentiation once we actually get the data in the right settings. At this point in time, you know, we can only point to the preclinical data and, you know, when we've done our comparisons, you know, against what we call the unbiased molecules, compared to the biased molecules.
The biased molecules tend to typically do better pretty consistently in all measures of efficacy. So glucose, weight loss, duration of maintenance of weight loss, et cetera. So that's the data that we currently have. I you know shared a little bit of that with you, but the human experiment, you know, is currently underway.
Can I take one follow-up? What's your target profile for CT-388 at 52 weeks? You know, other companies throw out weight loss and sort of GI profiles at 52 weeks. Do you have a target profile in mind?
Louis-André, you wanna comment on that one?
So we do have a very, very tentative, hypothetical, twenty to twenty-five weight loss at one year. But this is, of course, something we'll have to evaluate in phase two, and we expect a profile that will be well tolerated.
Just to build on that, you know, I would say based on the data that we currently have, I think we can say that, you know, 20%-25% is what the trajectory should do. But again, you know, we will need to do some modeling, you know, even after the interim analysis is done, where we can further refine, you know, where is it? You know, is it kind of north of 20, north of 25? You know, that's something that we will get little bit more handle on after we get some more data. But based on just purely current trajectories, it's in preliminary sort of, you know, analysis, it's that kind of range, essentially.
Thank you very much.
Okay. Then we have a final participant here for questions, Ben Jackson from Jefferies. Ben?
Perfect. Thank you. Keep them very short, just given the timing. A little bit earlier, thinking for you, the fail fast approach that you've used here, do you think you'll continue to use that approach for future assets? Or given the increasing interest in the early stage readouts, will that make you reconsider how far you push the boundaries in these early stages? And then, I guess separately, on the PYY asset that you've touched on very briefly today, is there anything there that you've seen in the preclinical studies or while designing the drug, that perhaps builds confidence in its potential?
I guess what I'm trying to look to do here is understand whether there's something you're bringing to clinic due to a novel tweak that's been made before, especially when we look across the many PYY molecules that so far have been discontinued by competitors, with many highlighting high rates of nausea, given the biological mechanism of the PYY compound. Thank you.
Yeah, great. Thanks for those two questions. So fail fast. So, you know, our approach in early development is generally, you wanna work on the things that have the highest impact. It's an opportunity cost for us, you know, to work on things that are not gonna yield the type of, you know, profiles that we want. And so, we could have always designed our studies to mimic, you know, what's there in the literature, or knowing that going slow and low would be better. But that's not gonna serve the purpose of what we are trying to do. We're trying to bring the most transformative, life-changing medicines to patients as quickly as possible. I have no interest in developing medicines that will not do that.
So, at least as far as development is concerned, you know, we want to be mindful of making sure that we're bringing things to patients that are really going to change their lives. We're not interested to just do something, just to, you know, make ourselves feel better for a little while, only to find out later that that doesn't really meet the bar. So, you know, to me, the fail fast is more of a philosophy. It's not what we're trying to do, just sort of just to do it, right? It's what we really owe our patients for. Second of all, PYY. So yes, it's been in, you know, almost a graveyard, right? I mean, you know, people have tried and tried and failed, largely because of the nausea. So we knew about that.
So when we embarked on the discovery effort of that molecule at Carmot, very mindful of that fact, and so I cannot get into the specific details, but suffice to say, the design attributes have accounted for, that is the Achilles heel that we have tried to solve for. So our preclinical data, which I cannot get into details with, you know, generally shows that there may be a differentiation. That, you know, there's a profile here that is unique and different than what is out there or what was out there. And of course, the proof of the pudding will be when we take that into the clinic, which we plan to do in twenty twenty-five.
Very clear. Thank you.
Okay. With that, I think we are at the end of today's call. I would like to thank again our speakers, Manu and Louis-André, for the preparation, and also from the IR team, Julia Breuer and Sabine Borngräber for preparation. You will have, I think, another opportunity to meet, Manu, end of the month in London, at our Pharma Day event, if you join. And with that, I'm wishing you, good evening and, nice weekend. Bye-bye.
Thanks.
Goodbye.