Corbus Pharmaceuticals Holdings, Inc. (CRBP) Earnings Call Transcript & Summary

Good morning, and welcome to the Corbus Pharmaceuticals conference call to discuss the Phase Ib top line results for CRB-913 in obesity. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Corbus website following the conclusion of the event. I'd now like to turn the call over to Yuval Cohen, Chief Executive Officer at Corbus Pharmaceuticals. Please go ahead, Yuval.

Good morning, Tara, and good morning to those of you who are listening in this morning. We appreciate you being here. I'd like to welcome Dr. Harold Bays, Professor Bays is a Board-certified in endocrinology and internal medicine. He is a member of numerous scientific and medical associations and fellowships. He's also the Medical Director of the Louisville Metabolic and Atherosclerosis Research Center, known as the Monroe Biomedical Research and a Clinical Associate Professor at the University of Louisville School of Medicine. He has served as an investigator in over 700 Phase I all the way to Phase IV clinical trials. He is the Chief Science Officer of the Obesity Medicine Association and the Editor in Chief of Obesity Pillars, the Journal of the Obesity Medical Association -- Medicine Association. And he has written and/or served as contributing author to -- for approximately 400 peer-reviewed scientific manuscripts and book chapters, a hundreds of abstracts and major scientific meetings. He is also the recipient of multiple scientific awards. So Dr. Bays, thank you for being here. Thank you for being part of our study. We really appreciate that. And with that, let's look at some data together. So I think at the overall overarching question around this project from its inception was can we design a safe and tolerable CB1 inverse agonist with competitive weight loss to incretin therapies. And obviously, there's a lot built in there. But fundamentally, the question was a question of essentially engineering. This is not a novel target. So those of you who have heard us talk about this over the last 3 years or so or are familiar with the literature will recognize that this GPCR, the cannabinoid type 1 receptor has been extensively characterized for the last -- nearly 30 years. We know an enormous amount about where it's found, what it does and its role in metabolism. The question has always been rather, can we engineer out the issues that were associated with that first generation of CB1 inverse agonists. 20 years ago, and Dr. Bays, and I will touch upon this a bit later. 20 years ago, this was a very high-profile mechanism of action for obesity and associated morbidities. Multiple big pharma were focused on this mechanism. But the focus was to target the CB1 inverse agonism, the action of it in the brain. These were highly brain penetrant CB1 inverse agonists. With the rise and subsequent fall of that class, a new effort came about and the idea was to try and exclude the action from the brain and rather focus it on those peripheral organs where CB1 is involved in metabolism. What is unique about our compound, CRB-913, is that it is an exceptionally peripherally restricted CB1 inverse agonist. So just to put that a little bit in proportion, we are at about 2% of the brain levels of the brain penetration of, for example, rimonabant, a member of that older generation of CB1 or compared to Monlunabant, a recently discontinued CB1 inverse agonist from Novo Nordisk, we are 15x less brain penetrant than that drug. And so what has been lacking to date in this field was a tool, was a compound that could truly be thought of as being peripherally restricted. A summary of what you're about to see here today. And so CANYON-1 is our Phase Ib study that explored the efficacy and safety, I should say, safety and efficacy of CRB-913. It enrolled 254 patients across 15 sites in the U.S. The trial represented a well-balanced representation of the population of obese patients or patients with obesity in the United States with an average BMI of 37 and of whom 71% were female. The efficacy that was achieved for our top dose, which was 60 milligrams of daily CRB-913 was an average of 5% at 2 weeks with no sign of plateauing. And all participants who had completed treatment at that top dose lost weight. And of course, equally important, the emerging safety and tolerability profile appears to be favorable with a favorable GI tolerability profile versus published data, especially on oral GLP-1s. And most importantly, a psychiatric AEs that are broadly in line with the GLP class and markedly, markedly different than the older generation or for that matter, Monlunabant of CB1 inverse agonist. This is a very simple schema of the study design. It is a perfectly ordinary initial proof-of-concept dose-range finding study in obesity with 3 doses as well as a Placebo and using a titration window of 2 weeks, which is fairly standard for these earlier-stage studies. This are our baseline demographics. And as you can imagine and as you've seen in so many other U.S.-based studies, the average patient that the study ended up with was female, typically middle age and weighing just over 100 kilos with a BMI of about first. We'll start with the efficacy because at the core of this question is, does it actually still work? Can you exclude the CB1 inverse agonist from the brain without compromising its efficacy? And the first signs of that were with Monlunabant, but we're delighted that a much more extreme or much more pronounced exclusion from the brain yielded the same time of efficacy or in line with what was seen with Monlunabant. First thing I'll point out to you is a very well-behaved placebo cohort. And then we have what appears to be a very satisfactory dose response with nice separation between the 3 doses explored. All 3 doses were statistically significant compared to placebo, as you can see. And we have a nice separation as the titration comes into effect between the doses. A reminder that very similarly to what you see with the GLP-1 titration scheme, initially, all the patients are on the lower dose. And then as time passes by, more and more patients are -- get to experience a higher dose of the drug. Importantly, in a 12-week period, there is no sign of plateauing. And that, of course, is very satisfactory for us to see. The mean weight loss using an efficacy estimate that was seen in our top dose was 5%. Another very common way of looking at this would be a threshold analysis. In other words, how many patients lost x amount of weight at 12 weeks. A reminder, this is a short study. It's just 12 weeks. And we're delighted that it appears like so many other weight loss studies that you've seen recently from GLP-1s with the vast majority of patients losing a certain amount of weight. And then as we move those thresholds upwards, we start to see the real differences between the doses. There were high single-digit patient numbers who lost more than 7.5% of their weight in 12 weeks, which is, of course, very encouraging. And the highest weight loss seen in the study was in the 60-milligram cohort, and that was an individual that lost just north of 13%. Obviously, an outlier, but it's always nice to see that. This is a slide that, of course, has caveat. These are cross-trial comparisons. So we need to be careful and cautious as we approach it. But nevertheless, it gives us a certain amount of taste for the context of what does a 5% weight loss in 12 weeks look like compared to oral GLP-1s, which after all are the most relevant comparison in terms of efficacy for comparing a daily tablet to a daily tablet. And I think what we can say is what's emerging so far in this period of time is something that looks to be in line with an oral GLP-1. Of course, I'll reemphasize, this is not a GLP-1. It is not an incretin targeting drug. CB1 is not part of the incretin super family. It is a completely orthogonal, completely different target that does very different things. And so we found this to be very satisfactory and encouraging as we begin the journey with CRB-913 in terms of what could it eventually yield in terms of weight loss. Of course, the story is not about efficacy. It's really the safety that's so important. CB1 inverse agonism has been known to cause weight loss for decades. The question is, have we managed to engineer out some of the safety issues that plagued that first generation and for that matter, plagued Monlunabant. This is a slide where we focus on the worst possible adverse events that could happen. So severe TEAEs and serious TAEs and they're equivalent for TRAEs. And what was very satisfactory to see here is we had very few severe TEAEs, none of them was psychiatric or gastrointestinal, which was wonderful to see. We had very, very few serious TEAEs, treatment-emergent adverse events. But then when we look at the treatment-related adverse events, in other words, adverse events are adjudicated as being as a result of the treatment, the picture improves even further. We have the sum total of just one single severe TRAE in the 40-milligram dose, and that was a headache. And we had no serious TRAEs whatsoever in any of the cohorts. Lastly, looking at treatment discontinuations due to AEs. So due to any AEs, we had some ranging from 3.1% all the way to 13%. You'll notice that we have those in placebo as well. This is obviously a double-blind placebo-controlled study. And so patients don't know nor does the physician know if they're on active or placebo. And then if we dig further into the type of AEs that cause discontinuations, we see that we have some that are psychiatric in nature. Although remember, none of them was serious or severe. These were all mild or moderate. And we even have one such event, for example, in placebo. So this was a participant who judged themselves or judged to have a psychiatric adverse event that led to discontinuation while being on placebo. And we similarly have even fewer GI causes of discontinuation. The total rate of discontinuation for any reason, be it an AE or not, was on average about 20%, which is about standard for obesity studies these days. And of course, a similar number was seen for placebo as well. So let's dig a little bit deeper into this. If we focus on every single psychiatric AE that we had in the study, and a reminder, they are all either mild or moderate, none were severe or serious. The following picture emerges. Suicidality, there was no traces of suicidality. Much, much to our delight, we had just one case of depressive symptoms. It was moderate. And like all the psychiatric AEs here, that case was transient and resolved. It was a moderate case of depressive symptoms at the 60-milligram dose. We had low values for anxiety as did placebo. Our anxiety does not seem to be either dose dependent or particularly different than placebo. Similarly for insomnia, low values as are seen in placebo. And lastly, irritability. Irritability does seem to be a hallmark here. Our irritability was all mild. It was seen only with the drug, not on placebo. And one of the further analysis that we'd be so keen to do would be to understand how it relates to weight loss. Is this an effect of our drug? Or is this an effect of the weight loss that our drug triggers. All of these again were mild and every single one of these side effects was risk. But probably the most important way to look at our psychiatric adverse events is to contextualize what do they look like compared, for example, to the commercial injectable incretin analogs, because that will give us a feel to whether or not they fall outside of the ordinary. And what we see is our depression falls within the norm, as does anxiety, as does insomnia. Irritability presents an interesting challenge. It is not typically measured or reported with the injectable incretin analogs. So we need to understand better what is typically seen there. Again, whether this is an effect of our drug or whether this is an effect of the weight loss that we elicit. A reminder that in CANYON-1, we measure these effects every single visit. They are measured every 2 weeks. And there is a very heightened emphasis on testing for psychiatric adverse events at a very high frequency, something that's not always the case because it's not necessary with GLP-1 or the incretin mechanisms of action. Here's an example, though, of what CRB-913 does not. And so we can juxtapose it compared to Novo Nordisk's recently discontinued CB1 inverse agonist Monlunabant. And a reminder that the drugs are, in many ways, very similar. Their main difference is the degree to which they penetrate the brain. CRB-913 is 15x less brain penetrant than Monlunabant. It is not a subtle difference. It is over an order of magnitude difference in brain penetration. And we found it very striking to see how that brain penetration difference translated into safety profile for psychiatric adverse events. It's not only this marked difference in the number or the degree of psychiatric adverse events, but the nature of them. None of our psychiatric adverse events was severe. That was not the case for Monlunabant. And all of our psychiatric adverse events, moderate as well as mild were resolved, again, not the case for Monlunabant. And so if we think of this as a hypothesis, of removing a CB1 inverse agonist from the brain and preserving not only its efficacy, but also very dramatically changing the adverse event profile for psychiatric adverse events, this is a very striking data set for us as scientists. Let's turn our attention now to a different set of safety measurements, gastrointestinal. We've known for 20 years since the days of the first CB1 inverse agonist that they tend to be milder in terms of their gastrointestinal adverse events. CB1 is not a particular gut GPCR and doesn't seem to have much effect on gastric motility. But we were really delighted to see these levels of vomiting, nausea, constipation and diarrhea. A reminder that they're always also found typically in placebo, often found in placebo, but we, of course, have more of them on the active trial. But it's the next slide that contextualizes that. So what we've done in this slide is compare them to the Oral GLP-1s, Oral semaglutide and then 2 cohorts of Orforglipron using 2 titration schemes. And this is where we see some very dramatic differences. We have markedly less vomiting. Our nausea rate has been cut by half. We have markedly less constipation. Our diarrhea seems to be either at the same or slightly higher levels. And as we start to experiment with longer titration periods, it will be interesting to explore. Again, a reminder that all of our GI adverse events were mild to moderate. We did not have any severe level of serious adverse events. Lastly, looking at discontinuations. And so here, what we've done is we try to find shorter studies for our, as it were, counterparts, the oral semaglutide and Orforglipron. And what we see is that treatment discontinuations for any reasons are ranges from about 17% to 26% for our case. We've also pointed out what the placebos are. I will remind everyone that in this study, as is typical in early-stage obesity studies, patients and physicians do not get the opportunity to dose down. In other words, if a patient is in a blinded fashion titrated to a high dose, they are unable to be titrated down to their previous dose. And that, of course, is one of the ways that you can reduce discontinuations. In terms of adverse events, it's a very different -- it's a range from -- in terms of our analog 6.9% all the way to 20% but notice the difference with Orforglipron with the titration schema. So again, as we move from a 2-week titration, which is a relatively short, aggressive one to a longer titration period, it stands to reason that our discontinuation rate will follow the same logic, which is to be reduced as patients have more time to adjust the dose. So what did we learn from this study? There are a number of important takeaway messages. We achieved up to an average of 5% placebo-adjusted weight loss in a period of just 12 weeks with no evidence of plateauing, which seems to be in a cross-study comparison, comparable to what we see with oral GLP-1s. Our psychiatric AE profile supports the benefit of peripheral restriction of CB1 therapy. And that, of course, is immensely satisfactory to see. That has been a 20-year voyage for this class. And of course, not surprisingly, although the extent of it is really gratifying, a favorable GI profile, certainly different in terms of some of the GI effects from the GLP-1 -- oral GLP-1 class. Our next steps, I'm delighted to let you know that we've been selected as a late-breaker for Obesity Week in about 2 months' time. So we look forward to being there in Washington, D.C. and presenting this data. We will engage FDA regarding the next clinical study, which we will name CANYON-2. That will be a Phase II, monotherapy study starting as quickly as we can next year. And last but not least, we'll evaluate the potential to combine CB1 inverse agonist in the form of CRB-913 with other therapies, orthogonal therapies from the incretin path. For example, obvious combination to consider to contemplate would be with oral GLP-1. Lastly, a slide that is familiar to all these -- all members of this audience. Just to remember what is at stake here. This is obesity is probably one of the greatest challenges to health care in the 21st century. There is an extraordinary number of people on the planet who are overweight and of those an extraordinary number of people who are obese with over 200 associated comorbidities. And a reminder to everyone that while the GLP class has been transformational for medicine and for these patients, there are a significant number of patients, more weight that is just provided by the GLP-1 class that could benefit from combination therapies. So with that, I'm going to turn it over to Professor Bays, and start with some questions before we open it up to our audience. So Professor Bays, thank you again for being here this morning. You were there at the start of the CB1 journey. We're talking about nearly 25 years ago. I think that a lot of our audiences don't remember it or they were not quite adults at the time. But I wonder if you -- having seen their initial rise and then fall of that class, if you could share some thoughts of what were the aspects back in the day that you and collectively found intriguing about the biology? What were some of the lessons that were learned? And how does our data sort of fit with all of that?

Well first of all, thanks for the opportunity to be here today, and that was a very nice presentation. It's a very objective presentation. I really appreciated that. You're right. I was there in the day. Prior to the Rimonabant experience with Sanofi and such, there had been limited involvement of big pharma in obesity medication development. There have been some smaller companies and such, but again, not very many people were wanting to take the plunge into this space. There are a lot of reasons for that. There was a lot going on with diabetes and hypertension and lipids and these types of things. Plus there had been this just disastrous history of development of obesity drugs, where it just seemed everywhere we turned, problem, problem, problem, problem, problem. Okay. So finally, we have these new agents out there, cannabinoid receptor antagonist, the endocannabinoid system is ubiquitous. There was also the -- I like the word you said there, hypothesis. So the hypothesis was if you administered cannabinoids, people get hungry. You know what I'm talking about. People get hungry. And so the hypothesis was if you were to impair that, disrupt that, that instead of getting hungry, you would not be hungry. And so I guess what I really want to emphasize, my perception at the time was that the central nervous system was an essential component of the hypothesis, right? It was not a side effect. It was the intent, okay, that there would be effects on the brain that would reduce hunger and thus, there would be weight reduction. So that's how we went into it. And for those of you who don't know, one of the big things to come out of the whole rimonabant experience is, that's where we really started using the word cardiometabolic. Because that was going to be the big thing going forward. It's not just the weight of the patient, it's the health of the patient. And so we're looking into the cardiovascular disease risk factors and such. So again, entire development program, hypothesis, everything seemed to be going in a direction. We finally had big pharma engaged. And then there were other companies, Merck and other companies that had their own cannabinoid receptor antagonists and such. So we felt like we really had some traction. And then even though it got approved in Europe, it did not get approved by the FDA here in the United States because of depression, suicidality, these types of things. So that one development program really set us back. I'm talking about medical science. It set us back because there were so many people that were thinking about going into obesity that says, here we go again, just another problem. And so we went for over a decade until finally, we truly did get traction with some of the newer GLP-1 receptor agonists. So the question is now, how does this fit into the hypothesis? Well, I remember when they -- I don't know if it was you guys, but other people came to me and they said, look, we got this theory that instead of having effects on the brain, which now we know is maybe not the greatest thing, particularly with regard to depression and suicidality and these things. Given that the endocannabinoid system is just ubiquitous, which was the story, why don't we exploit that? Why don't we say we're going to take the brain out of the picture, and we're going to look at these effects upon peripheral tissues and see how that goes. And we look at preclinical data and it looked amazing. I must say I was a skeptic, I guess, because I've been burned with the previous efforts and such. And I was like, I don't know. I mean, sure, we'll do the trial. That's why you do the science. But -- and yes, it does look good. I'm not doubting the data, but wow, okay. So we do this CANYON-1 study and what was the hypothesis? The hypothesis was you have the brain and then you have not the brain. And we can go over what the other tissues are, but it was -- that's what it came down to, right? It's like brain effects, not brain effects. And we're going to take the brain out of the picture, and we're going to see if we can have efficacy and safety based upon the peripheral effects. And that's what I believe was the hypothesis of development program. And then sure enough, what do we find? We find, I think, some rather remarkable efficacy. And if you look at depression and such, I think even more remarkable effects on that aspects of safety. So at least for me, as you mentioned, I've been an investigator over 700 clinical trials spanning about 35, 40 years. And I can't say that I predicted this. As a matter of fact, I did not predict this. And it's always better to be surprised on the favorable side than be surprised on the not so favorable side. So overall, what I would say is this study, I think, realized the hypothesis of this sort of approach towards implementing therapeutics based upon cannabinoid receptors.

Thank you for that. And it's hard to sort of -- we're scientists at heart, and it's really hard for us to not get very excited because you're quite right, there is a hypothesis here, and that hypothesis has been around for 20 years. I think what's been missing was the tool, was the instrument. And we are delighted. We're absolutely delighted. So thank you for that.

Well, let me just say -- but I think in retrospect, I mean, we can say this now. I think there's perhaps a disconnect. You've heard cognitive dissonance where you're thinking two things at the same time that don't really go together. Back in the day, there was clearly an understanding that the endocannabinoid system was ubiquitous. We talked about that all the time. But I must say, I think as much as we said that, I think that there was a gravitation towards the belief that if there was going to be weight reduction, it had to be due to effect on the brain, right? And this other stuff is interesting as it is, that it's a ubiquitous endocannabinoid system is ubiquitous and it clearly has effects on other body tissues that could have favorable -- we kind of put that aside and we said, no, but it all comes down to the brain. It all comes down the brain. Well, as it turns out, obviously, we need to do confirmatory clinical trials and such. But at least for the data that were given, my goodness, this does seem to validate the scientific hypothesis that peripheral -- that the effects upon the endocannabinoid system in peripheral tissues does seem to have clinical application. And I think that's the biggest takeaway for me. It's great that you're not in the brain, and that's fabulous. But what I'm saying is I don't know too many -- I'll just speak for myself. I don't know that I really thought that the strictly and restrictively targeting the peripheral tissues with no effects on the brain was going to result in clinically meaningful weight reduction. I just -- I was skeptical.

And I think that's fair. I think, again, as you mentioned, sort of the trauma of that first generation relegated this to corners of academia in mice. And so we're delighted. So thank you for that. I guess my second question for you before we open it up is, okay, so we have preliminary data, of course. We have a drug that induces weight loss. It is not in the incretin pathway or superfamily. This is a completely separate GPCR. It's an oral daily drug. What do you, putting on your hat as a clinician, as a physician, -- how do you use a drug like that in a paradigm where obesity is exclusively dominated in a wonderful way by the incretin pathway at the moment? Who needs this? Who gets this? What do you do with this?

Okay. So here's where -- I mean, I guess this is a good thing where I might have a little bit of disagreement is that one of your first slides says, we want to develop something that was going to be competitive against GLP-1 receptor agonist. And I think that's fair. I mean we don't know. Like you mentioned, there's not been a plateau, which I think is probably one of the -- I mean, the big takeaway messages, I think, from the efficacy side -- efficacy standpoint. And yes, there are people that are intolerant to the GLP-1 receptor agonist, but GLP-1 receptor agonist, particularly injectables, massive amounts of data, substantial amount of weight reduction, got all kinds of outcomes data and everything. So I don't think it is necessary to be -- that this be competitive to GLP, particularly not the injectables. I don't think having a competitive weight reduction that's comparable to injectable GLP-1 receptor agonist is what's necessary for success of this drug or clinical utility of drug. I don't think that's necessary at all. Now I don't know how much weight reduction you're going to get if you go past 12 weeks because we haven't done studies, okay? But what I will say is I think that there's clearly a role for different obesity medications having, I would say, different but potentially complementary mechanisms of action. So now when you go back and you focus on the oral, okay? So let us focus on the oral GLP-1 receptor agonist, okay? Is it possible that the clinicians would say, I would really -- if possible, I would really like to have the ability through use of oral administration, to have comparable weight reduction as the injectables. And so if you were to extend what we've seen here, so yes, monotherapy may be useful for people intolerant to the GLP-1 receptor agonist, I get that, okay? But -- but I think what's also exciting to me is say, what happens if you were have this combined with an oral GLP-1 receptor agonist? Or how about this? How about an oral amylin analog? What we're coming to realize is the amylin analogs are at least way more effective than I thought they would be. And in addition, there's safety and tolerability profile is really good as well. So I think there's opportunities for combining with other oral therapeutics. And if that's true and you were to even just get additive effects, now I'm not saying you're going to get 25%, 30% weight reduction. But wonder if you were to get 15% weight reduction at such or 15%, 20% weight reduction. I think that's through a pill, through a combination therapeutic agent, I think that would be profound. I want to -- the caveat with all this is, you got to do the studies, you got to look at the efficacy, you got to look at the safety. But I can only go by the data that's presented to me. And what I see here is I'm not seeing the psychiatric side effects that we saw with the older agents, which fulfills the hypothesis or supports the hypothesis. And what I'm also seeing is you're seeing that weight reduction 5%, 12 weeks without evidence of a plateau. That's what I'm seeing. And what I'm also seeing is this is an entirely different mechanism of action compared to the incretin therapy. So historically, whether you look at diabetes or hypertension or dyslipidemia, we have routinely had combination therapy, often within fixed-dose combination therapeutics. So that just seems like a very understandable approach to be taking.

And a reminder to our audience, both Corbus and separately, Novo Nordisk published with our respective CB1 inverse agonist data in DIO mice that was co-administration of our respective CB1 inverse agonist with GLP-1 agonist peptides. And as you just said, Professor Bays, these two orthogonal mechanisms of action for both cases were very promising in their additivity because they just do such different things. And when you put them together, those two different things led to meaningfully greater weight loss than just each one of them on their own. So yes, that will be fascinating to explore and agreed wholeheartedly, I think that we look at this within the universe of an oral daily therapy and what is available and what could be available. So with that, I'm going to turn to our audience, and Tara, if you can open it up to our first questions.

Absolutely. Thank you, Yuval. Yes. So at this time, we'll be hosting a question-and-answer session with Dr. Bays and Yuval. So please hold for a brief moment while we poll for questions. So our first question comes from Paul Jeng at Guggenheim.

Thanks for providing this great and really interesting update today. I had a couple on safety. So first, understanding that the CANYON-1 study was conscious of the class history and had some key screen-out criteria based on psychiatric parameters. I'm just curious how you think about the generalizability of the safety data and how representative it is of the broader obesity population? And then the second part of the question is sort of what gives you confidence that the psychiatric AEs will not be cumulative or perhaps worsen with longer exposure to treatment?

I can certainly start on that. Thank you, Paul, for your question. We had a more stringent PHQ-9 screening criteria than you would normally find a normal threshold is, I believe, over 15, so that will be moderate. And our threshold was over 4. One of the things that we wanted to understand was did we create an out of the ordinarily non-depressed population of patients. And there's a very easy way to find that out. We looked at our screen failures for PHQ-9, and they're miniscule. I believe they're about 4%. And so just randomly selecting 254 adult Americans living with obesity in the study, we barely had anybody fails for PHQ-9. In terms of the length of the study, do we see -- could we see more as studies lengthen? One thing to think about is when do these happen? And so if we look at either the published data for the injectable GLP-1s just because there's so much more data there. If we look at the published data of the injectable GLP-1s or for that matter, the published data for Monlunabant, it's a very similar pattern. The pattern is a median time to onset pole, which is very short. So for the injectable incretins, it's 11 days on average. For Monlunabant, that was about 14 days. We look forward to sharing ours, but it's in the same ballpark. And that's not surprising. These things arise when you first encounter the mechanism of action. It's rare to have them happen later. Monlunabant had no events past, I believe, 8 or 10 weeks. And as you'll see with ours, it's a very similar effect. So longer studies, and of course, you can never predict entirely, but longer studies don't seem to offer a risk in terms of having effects happen later, simply because by that stage, the participant has been exposed to the mechanism. The last thing I'll say, Paul, is, again, titration, titration, titration. This was a very aggressive 2-week titration because the study was short, of course. As we go into longer studies, we will emulate what's been done routinely in GLP-1 studies, which are longer titrations that allow patients to catch up, as it were, with the mechanism of action before moving to a higher dose.

Great. Then perhaps a quick follow-up. So on the efficacy, can you speak to any impact you've observed or qualitatively perhaps on this call on metabolic parameters beyond weight, blood pressure, lipid levels, et cetera? And then as you think about the Phase II, how do you think about potentially exploring higher dose levels? I believe you went as high as 150 milligrams in the Phase I MAD cohort, and there's been some dose-dependent weight loss. So just curious how you think about the next steps.

So Dr. Bays will be there presenting the data at Obesity Week. There's a lot more data that we have as well as data that we're still waiting for. So we look forward to sharing all of that at Obesity Week. Maybe I'll turn that question -- the second question to Dr. Bays. It's a new mechanism -- this is where we are at 60 sort of baby steps. What are your thoughts?

You're making me short of breath. That's what I'm getting through. I'm like, here. So for those folks on the phone, you're all experienced people, look, I just got this data, right? And I'm still kind of coming to grips with it. And here, we have this wonderful -- I don't want to characterize things. Okay. Here we have this -- I think it's reasonably characterized this as favorable response. And now people want to go to higher doses. I'm like, oh my gosh, let's be happy with what we got. Look, I think that any decision as to going forward with higher doses needs to take into consideration as to why these doses were changed or chosen to start with, okay? And I guess maybe I'm too cautious. I'm a cautious guy or whatever. I just wouldn't want to -- let's say you do go to, say, 120 milligrams or whatever, okay? And now you do start to see some signals. I mean just -- I would just think it would just mess up everything, right? It would just mess them and people wouldn't say, well, it's because you went too high on the dose. They would just know that it existed. So I don't know. I think just -- again, I just recently saw this data. For me, as a cautious person and having the experience of the past, I think I would really like to know -- the first thing I would want to know is what happens when a person's on 60 milligrams for longer time. Now one thing you all you didn't really -- I don't think you mentioned this. Can you go back to the titration?