I think we're good. We're good. Well, we'll get started here with the next fireside discussion. My name is Derek Archila. I'm one of the senior biotech analysts here at Wells. Very pleased to have Rhythm Pharmaceuticals, and the CEO and Chairman, David Meeker, with us to have our discussion. So David, good to see you. Thank you, Derek. Good to be here. All right. Well, maybe, just to start us off, be good to just kind of get a state of the business and what you guys are doing, obviously, in Imcivree relaunch and in BBS and other things in terms of the clinical front. Maybe just level set us there, and then we can dig into some questions. Yeah, sounds good. So, BBS launch, as people who follow company know from our last earnings call, continues to go well. Increasingly bullish about that opportunity. We're learning more. It's evolving in the way you would hope a rare disease, meaningful rare disease opportunity would evolve. So as you said, we can dig into that, but I think that's been a really strong story and will continue to be one. Hypothalamic obesity phase III clinical trial is the second value driver for Rhythm, and people are following that closely. We updated, you know, our timing at the last call, moving up our expected timing for full enrollment to the end of the year. So again, we're, you know, feeling good about the level of interest and, you know, patients getting in. Those are still operational challenges, as always, running these trials and getting sites up, but the level of energy and enthusiasm around that's been really good. Got it. Well, maybe, expand on the Bardet-Biedl launch. I mean, obviously, last quarter looked very good. You know, I guess the question is, like, are you starting to see this inflection point? Like, is this, is this it, the trend is gonna continue to ramp up? Maybe you can just kind of talk to what you're seeing and, and why that may or may not be true. Yeah. Yeah. I, I, you know, discourage this. Many of you know, the concept that there'll be an inflection point. I just, I just think rare diseases in general tend not to inflect, you know, 'cause they're always, driven. You don't, as a rule, have a very large population of patients who, once the world becomes convinced that this is the right treatment, then they suddenly put a big bolus of patients on. I think, you know, the conviction that this is the right therapy for BBS is really growing. Certainly, internally, we have enormous confidence in this mechanism, and we're seeing the, the benefits, in the patients. The inflection, you know, again, this is that rare disease where you, you have to find the patient. Every patient has their own journey to getting reimbursed and getting on treatment. So, for better or worse, characterize it as slow and steady, and rare diseases you have for a very long time as a rule, but you tend not to inflect. Yeah. No, I don't think this is gonna inflect. So maybe in terms of your identification efforts for BBS, like, where are you right now in terms of where you think, or how many patients have been identified? And but also, you know, you kind of frame out for us kind of the overall Bardet-Biedl opportunity and how that's... Your thinking on that has evolved over time. Yeah. I mean, when, again, rare disease epidemiology tends to be poor just 'cause they're rare and there's not a lot of information. Once there's a therapy, there's more research, people get more interested, and the data tends to get better. We started out with a 1,500-2,500 estimate for the U.S. prevalence. We updated that to 4,000-5,000 based on triangulating using European data, you know, the CRIBBS registry, our own experience, and the like. So, you know, the confidence in that number is really high. Again, if anything, I would skew us to the five as opposed to the four. I mean, I just think that this opportunity is real and, you know, that's informed by being out in the field, and you can diagnose these people. We haven't updated numbers. That's not a number I find useful 'cause it's inherently a little bit soft and fuzzy. But what we have said about numbers and what I would encourage people to think about in terms of this opportunity is, you know, what's the probability you can get 1,000 patients on? We've got, you know, over 400, 425 scripts is what we reported at our last earnings call. What's the probability can get to 1,000 patients? I mean, that seems extremely high out of the 5,000, 20% penetrated. You know, if you've got a, you know, $250 million-$300 million, $250,000-$300,000, you know, net kind of opportunity per patient, you know, that's a $250 million-$300 million opportunity right there. Could you get to 2000? 40% penetrated on a 5000 number seems doable. You know, it might take some time, not projecting, you know, how long it takes to get there, but, but that's how I'm encouraging people, and we are continuing to find patients. I mean, it's, it's not like, you know, we often got asked, you know, you had your initial pools, it depleted, and you're gonna fall off a cliff. And the way, again, rare diseases work is that as you create awareness and more people start writing prescriptions, and the system begins to form around an opportunity like BBS, there's a virtuous circle where, you know, those elements help you find more patients. And so again, the more awareness, the more patients alike. And so that virtuous circle is beginning to happen, and you can see it. Now, every rare disease of this magnitude will always be rare, and you'll never be done trying to educate and create awareness 'cause most doctors won't think of BBS when they see them if they haven't seen one before. But you, you can create, you know, increasingly that critical mass that drives this phenomenon. What do you think is a fair, you know, penetration for an indication like Bardet-Biedl? Yeah, I use the Genzyme experience, you know, to inform this a little bit. I mean, one of the early diseases, Gaucher disease, I think when that was approved in 1991, Genzyme, you know, thought there was a few hundred patients in the U.S. I'm not following that closely now, but I think, you know, there's, you know, maybe approaching 8,000 patients who, you know, are on treatment, and the epidemiology continues to be pushed out. So- Hmm. The idea that you tend to underestimate is usually true. Occasionally, you get inflated numbers 'cause, you know, a company's trying to make some math work. But as a rule, the epidemiology tends to underestimate, and a lot of that happens. So Bardet-Biedl, just to put that in context. It's a syndrome, so it's described based on having multiple features, and those features, you're not born with all the features. They develop over time. And so if you're counting just full-blown BBS, by nature, you tend to underestimate that group of patients who, newly born, have only a small number and not diagnosed. So again, those are elements that, you know, we're beginning to see that happening and those discussions ongoing, so. In terms of the share, like, what do you think that—like, again, in Gaucher's, was it, like, 60% or, like, 20%? Like, again, it's probably a range for different rare diseases, but- It is. Are there good analogs for something like a Bardet-Biedl or type of syndromic, you know? No, I think my point about that was the share is hard- Yeah ... because the denominator keeps moving. Right. And so that's, that's why, I like to look at it where I described earlier, you know, could you get to 1,000? Yes. Could you get to 2,000? I think that's possible. You know, will that be 40% penetrated, or will the new denominator be 6,000 or 7,000, right? I mean, and so- Yeah ... that's the dynamic. But if I'm an investor, I'm really looking at, you know, what's the probability that this opportunity, that company can, you know, execute on 1,000-2,000 patients? I think that's not unreasonable. Got it. And maybe you could talk to the patient journey a little bit for Bardet-Biedl, and like, it was interesting, you know, in the last couple of quarters, I mean, we continue to see that kind of PCPs or primary care continue to be, you know, one of the more dominant prescribers, you know, of, in Imcivree, in Bardet-Biedl, versus kind of your pediatric endocrinologist. How do you kind of see that? You know, what does that mean early, and then how does that evolve, you know, over time as the launch continues to progress? Yeah, I mean, we've had quarter-over-quarter, with a growing number of physicians writing scripts. I think we reported over 250 different physicians have written scripts at the last call, but a quarter of those, were physicians we don't know, and many of those are in this primary care, pediatric, otherwise, area. So my the, the way that's happening, if you think about the Bardet-Biedl patient, their journey, like many diseases, rare diseases, is they may see five, six, seven physicians over a period of, you know, multiple years before they actually get a diagnosis. But once a diagnosis is made, there's no reason for that specialist to keep the patient. There's nothing to do historically. Yeah. So they get sent back to their primary care, maybe a pediatrician, maybe general practitioner, or whatever. And they're, that's where they are, somewhat disengaged, maybe from the healthcare system alike. And so what's reflected now in the numbers are those patients, I think, coming back, and many of it will be the patient who's plugged in on, you know, social networks and the like, sees there's a therapy, they go to their primary care physician, they say, "I know I have BBS, I'd like to give this a try." And, you know, then Rhythm steps in, and we help that equation. But that's, that's a really healthy place, and, you know, I, I fully expect that the vast majority, not vast, maybe large majority of these patients are sitting in primary care. So the fact that we're able to get to those physician patients. Mm-hmm. Is a really, really healthy sign. Yes. I mean, is it... And is that being driven, you know, again, the patients find out about Imcivree, and then they go to their PCPs and talk about it, or the PCP is getting educated in some way? Well, in today's world, you know, this non-personal promotion. Yeah. I mean, you work all sides of the equation, but patients, of course, are, you know, informed and often highly motivated to see if there's anything to be done. But physicians, you can target physicians who, you know, might have, you know, an interest, might have practice. Certainly, the growing interest in obesity medicine, more and more physicians now are getting boarded in obesity medicine, and that's a natural specialty who. You know, part of what makes you a specialist is you know how to handle the common presentations, but you also really like the rare stuff, and the rare is often what makes it interesting. So, those are all elements that are out there, and, you know, we're tapping into that. Got you. Then also, you know, again, I think over 50% of the patients on Imcivree with BBS right now are adults. So again, is that a function of what you just described, these patients that are out there, kind of just sitting around and they didn't really have anything else, so they're finally kind of, that's kind of the early rush, maybe of patients coming in, and the adolescents and the younger kids will be later? Or maybe you can kind of share that dynamic. Yeah. Yeah, it's good. So a little more than 50% of the patients treated today are adults, so a little less are pediatric. Think about sort of the general distribution in the U.S., where about a quarter peds, three-quarter adults. BBS does not have a dramatically or significantly shortened lifespan, so you would expect the adult population of BBS patients to be not so different from the general population. However, they may well be more disengaged and sort of the silent majority, if you will. So the fact that we're getting that many adults on at this early in the launch is, again, great, really healthy. The CRIBBS registry, just remind people, that was our starting point, 600+ patients who were, you know, actively participating in this registry. 80%+ of those patients were pediatric. And again, the adults, and a lot of that's 'cause it's a complicated registry, and the families fill it out, and so when kids age out, you know, and they become adults, they may not stay engaged with the registry and the like. But long story short is, yes, adults are an important population, and we're getting them. Got you. And in terms of peds, like, is that... Are you seeing slower adoption for any specific reason, or is it just, again, what you just described, or is that kind of coming online a little bit slower, just given that, you know, maybe parents are a little bit more, you know- No, I would actually describe it as the converse, 'cause- Okay ... you know, again, just on ratios, you know, we're a little less than half who are peds. Right. Every patient, and this is a little what sometimes people don't fully appreciate, and it's sometimes can be hard to understand. You know, if you know you have a diagnosis and you know there's a treatment that could help you. Mm-hmm. Why would you take a year to get on therapy? The answer is: there's a thousand reasons, and yep, it just is. You know, just—whether it's the physician side or the patient or the family or, you know, who knows the different reasons why patients don't rush to get on treatment. You know, sometimes it just takes time. To answer specifically your question, there's no drag on the pediatric side at all. I guess, what do you see as the biggest driver of growth? Is it more finding new patients, putting them on therapy, or is it educating the docs to get existing patients that they know that are not on therapy on therapy? Like, what's kind of the- Both. -biggest driver? Yeah, both. I don't know, biggest. We have both pools. Yeah. You need the new patients coming in always, and- Sure ... as I said, that's the virtuous circle part of it, you just keep working. But yeah, there's physicians, and again, it's you know, sometimes it's the patient, you know, we're just not ready yet. It's a chronic therapy. It's a lifelong therapy. It's a daily injection. So, you know, they just may not be there yet. On the other hand, you know, it's physicians, in today's world, being a physician is tough. You know, schedules are full, busy, lots of other challenges to delivering healthcare, so. Gotcha. And has that been something that you've seen, just like patients find out about the drug, and it's just time to getting into the office? And, you know, are they generally prescribing that first visit, or does it take multiple visits for them to, like, kind of come around to the idea of getting on therapy? Yeah, all of the above. Again, some it's like they're ready, and they go, and we step in and try to get it, you know, moving as quickly as possible. Others, it takes multiple conversations. It just, again, it's so patient by patient. Again, rare diseases, but it's just a patient-by-patient- Yeah -exercise. What about on reimbursement? Like, can you just kind of talk about kind of the payer aspect, and is there... are there any hurdles there for patients, or is it pretty, you know, accessible? No, I think I'm thrilled with how we're doing from reimbursement. I mean, you know, arguably from a simplistic standpoint, you know, we have a rare disease drug priced at a rare disease price point that treats obesity. So it wasn't automatic that we were going to be successful getting broad reimbursement. But as you know, we've done incredibly well on the commercial side. We're, you know, pretty much fully covered there, with the exception of these very small, you know, self-insured plans that don't cover rare diseases in general. On the Medicaid side, and there's a large Medicaid population here, about half, we've again done remarkably well. We have about 80% of the known Medicaid lives that we are covered. And so, you know, that additional or residual 20% is a mix between states where we just haven't had a patient in front of their Medicaid board yet, or they're just not moving, and we're not so optimistic in the near term. But you, you never give up on those, and and about 20%, you know,-ish, of the patients end up on our patient assistance program, but which is our free drug program. But once, once you go on that, again, you don't give up. Yeah. You know, patients can go on that for a while, and then their insurance status changes, or you get a breakthrough in that Medicaid state and, you know, you can move them back. So you just have to be prepared to stick with it. Again, patient by patient, do the work. Maybe last question, then I want to shift to the EU BBS. But, you know, in the U.S., I mean, have you seen, you know, fairly decent adoption or at least, you know, again, kind of at least maybe they'll start prescribing by the end of the year, like good education, they're kind of warming up at some of the major centers. Like, obviously, the Marshfield Clinic is one that always comes up. But like, any of these other centers of excellence, have we already seen, like, fairly good adoption, or do you think there's more kind of depth of prescribing that can kind of happen at these places? No, actually, I think the centers of excellence as they emerge are a bit of the tip of the iceberg. And the reason being is that, by definition, those centers have an interest, they know what they're looking for, and they're looking. And part of the reason, back to your earlier question of confidence in these numbers, is that if you look for BBS patients as a rule, you will find them. I mean, that's what I'm saying. It's the prevalent... They're there. And so expert centers who are looking, they're not going to exhaust the pool. I mean, they're going to be a continual, meaningful source of patients, I think, for... And then also, you know, referral patterns being what they are, as centers emerge as true experts, then, of course, they get, you know, a larger referral pattern- Sure to drive it. So. Understood. Yeah, maybe just talk about the EU opportunity in BBS, and I know you threw out some numbers earlier, but I guess, yeah, how do you view that, obviously from pricing perspective and all that other stuff, from a market opportunity standpoint? Yeah. Philosophically, again, from day one, we viewed this as, you know, healthcare's global, and we want to approach it globally. I think that's a critical part of being in a rare disease space. These are small communities that are globally connected. The KOL world network is, again, globally connected, so it's hard to carve up the world and do it in a really good way, one. Two, Europe is, again, ahead of the U.S., as a rule, in terms of rare diseases, just because they have centers of excellence, they have single-payer healthcare systems, so patients tend to get referred more easily to these centers of excellence. So the KOLs can do research, and they become true experts. So those are all elements which, you know, cause a place like Europe to be a much more favorable environment for rare disease. We think the overall prevalence is probably similar to the U.S., but more patients have been identified than we had in the U.S. as a starting point. We talked about 1,500 for a while there. That number's gone up, but we haven't updated it. Germany is the big, you know, the recent news for 2023, and we got approval and basically a second-half launch, so it's just now underway. You know, numbers in Germany are consistent with the U.S. We think there's, you know, over 1,000 patients from a prevalence standpoint. 800 or so, you know, may even be in a diagnosed category. And the Rhythm number, where the teams feel like they have some reasonable confidence that the patients are real, still alive, that they know where they are, was about 250. So, a really good starting point, again, one of the logical questions is, so is that going to inflect? And are you going to have 250 patients on by the end of the year? No. Yeah. It just takes time. And again, they, despite being better organized, there's a, I call it a somewhat of a relative conservatism in terms of how, you know, these patients are going on. So slow and steady is how we'll see the German launch. But that'll be the major contributor to the European story for the second half of this year. And then, you know, other countries will kick in largely in 2024. And then pricing, again, you know, you anchor off the U.S. price. What was really, again, gratifying is the different systems, you know, health technology assessments that you have to go through and the like, recognize this as a rare disease, recognize that this is a precision medicine specifically addressing the problem. And so, we have been successful in getting, call it a rare disease price. I don't like the terminology, but it is anchored off the U.S. price. It's discounted in every country. Those are—we don't share those discounts, but, you know, as I've said, it's between zero and 50, and it's not zero, and it's not 50. So somewhere in that range, but it's a meaningful contribution to the overall financial picture for Rhythm. Got it. And then in terms of like, again, the European sites, as you said, like, they're a little bit more organized, you know, around some of these rare genetic obesities. I mean, are most of them already... or have most of them either had experience through the trial or, you know, even with POMC, LEPR, PCSK1, like the other indications in treating those? Like, you know, are you kind of, or is it de novo, like these docs have never really used the drug? Like, you know, where, where are they on that spectrum? Yeah. No, our first trials, POMC and LEPR, again, which were very small, 10 and 11 patients each, but they were all Europe. Yeah. I mean, we only had, like, one patient in the U.S., and again, that was because... So the short answer is yes, they're experienced. They're very aware of the drug, and a number of these centers have used the drug previously. Again, they're also very connected. Again, they- Mm-hmm. Their information is shared much more easily in Europe, between KOLs and the like, than it is in the U.S. So it's very well set up. I think Europe is. It's as with many, but it's a market access challenge. You just have to work through, get your price- Yeah ... get market access, and then once you do, the healthcare system's prepared to deliver it. Gotcha. And then maybe you could talk about, you know, the recent news around in France, right? So France seems like they're not maybe as conservative as Germany. They seem a little bit more progressive here about the AP two early access for Imcivree in hypothalamic obesity. So an indication that you're currently running a phase III in. So, maybe just talk about that and how you think that could impact future sales. Yeah, that was a, that was a really important outcome, for many reasons. One, the patients in France will get earlier access to what I-- we believe will be a potentially transformative treatment for those patients. But, the AP one, this early access program, there's only been about 20, and there's AP one, AP two. AP one is just-- it's an access program before the EMEA has approved your drug. AP two is an early access program that is after the EMEA has approved your drug, but before you've agreed on a price in France. And so that's how you end up in one of the two buckets. So AP one, this was phase II data, obviously before, EMEA approval, and, they, they have approved it. The way the programs work is that they'll have one or two centers that will review the cases. So it's on a case-by-case basis. It's not that, you know, anybody in the country can just write a script. They refer their patients to be evaluated. So that's a bit of bureaucracy, and it puts a, you know, a natural break on how quickly some of this happens. But bottom -ine is, patients in France can access this drug now. Obviously, a lot of interest on the part of the physician, I think, patient community. So yeah, that'll be meaningful over time. I mean, for HO patients, I mean, obviously, they're known to the healthcare system, and again, what would be the deterrent for not using this drug? Uh. Under this program, is there any- Oh, under this, this program? Yeah, yeah. Like, is there any sort of like again, is it just as easy as like, oh, you know, it's approved, or, you know, you have access, or is there a lot of paperwork? Like, again, what would deter a doctor or patient from wanting to be on this? Awareness, one, I think- Okay ... that's probably the biggest. You know, so, you know, it's still rare and, you know, despite being much better than the U.S., as a rule, Europe, France specifically, is still rare, and there still, you know, will be areas where people just aren't aware, and so that's probably the biggest deterrent from patients getting quick access. Other than that, it's just bureaucracy. You know, they meet monthly. You know, they review five or six patients a month. I mean, it just takes time, and so for better or worse. But other than that, no, I think if you've seen the data, it's... I don't think anybody's thinking, "Oh, I'm not sure it's gonna work. Right. I mean, it seems like a big vote of confidence at this point in terms of- For the system to step up and say, "Based on 18 patients- Yeah - We're good to go. Yeah. That's a big vote of confidence. Interesting. Well, talking about HO, maybe just give us an update on where you guys are with the phase III trial. I know you said some in your prepared remarks, but, additional color there would be helpful. Yeah. So this is a 120- patient trial. We, as I said, we moved up our timing on enrollment there. The big variable was just how long it was going to take to get sites up and open, running. Europe and U.S., we have about, you know, equal number of sites on both sides, more heavily in the U.S. than in Europe, but importantly, Europe's got to come on. We'll have about 25 sites. What's different and why it's such a focus on the sites is virtually every site who we're going to be utilizing has a list of patients with HO. So it's not like, you know, "Yes, I'm willing to be a site, and then I'll go try to find some patients." They all have their lists. I think the patients', if they're eligible, why wouldn't they be eligible? So, for example, there's a weight criteria. You've got to have a BMI greater than 30, and hypothalamic obesity is one of those entities where you could be, and we have one of these children in our phase II trial, you know, a very skinny child who gets their tumor and suddenly they explode off their growth chart. And so they've gone from being, you know, the 25th percentile up to the 75th or 80th percentile. But to get into the trial, you have to be greater than the 95th percentile. Hmm. So they clearly have the problem. They've clearly had a dramatic change in their health, but they wouldn't qualify. So those are things that are frustrating for those patients, and we've already encountered some of those examples in our screening. But as a rule, everybody they're screening 'cause they know the entry criteria, we've had very few screen failures. Yeah, I was going to say, like, is that common? Again, is the screen failure rate, like, very high? It doesn't sound like it. No, the screen failure rate's low because the physicians know that. Yeah. So they're not screening patients who they already know won't do it. They're going to the list and saying, "Okay, I know this patient. They're going to be good." So that's why, again, very few surprises at the end of the day in terms of screen failures. So lots of confidence in the patient interest and the lists that are out there, and it's just execution. Yeah. We feel good about the end of the year, but still working it. What do you think that says about the commercial opportunity? Like just- Just it's confirmatory. You know, one of our board members, Stuart Arbuckle from Vertex, as you said, you know, trial enrollment's a good biomarker for future opportunities. I think that's, that's certainly true here. And the big difference between HO, as we've highlighted, it's just the number, 5,000-10,000 people in the U.S., similar numbers in Europe. The difference between that 5,000 and a BBS 5,000 number is that those 5,000 HO patients, they are diagnosed, and as a rule, they're engaged in the system. 80%+ of the patients with HO require one or more pituitary hormonal replacements because not only are they injuring the hypothalamus when they get their tumor in the surgery, but they're often injuring the pituitary and, as a result, need, you know, additional medical care. So they're with specialists. They're not going back- Interesting. to primary care. Gotcha. That's our call point. Yeah. I mean, part of what's also skewing our numbers on the Peds and ENDO is we're a bit focused there. Yeah. It's natural, but, but for HO, yeah, we're focused there. Gotcha. And can you just remember, like, remind us, I mean, this, this trial is, like, very, like, well-powered. Just- Hmm Given that, like, you probably didn't need as many patients, but it was more the FDA wanting you to have a- Yeah safety database. But can you just kind of walk us through there, through that? Yeah, we're, you know, famously, ridiculously. So we're 99.5% powered. It's just the discussion with the FDA, we went in asking for a, much shorter trial and a much smaller trial. We ended up at a year 'cause that's the rule, 60 weeks, so- Yeah Two months of titration. But that was just the rule. And then the 120 patient was just a negotiation around getting a safety database that was large enough. So despite the fact that setmelanotide, Imcivree, is an approved drug with a pretty well-established safety profile for a rare disease drug, this is a new indication, and so anyway. So that's where we ended up. So the 120 patients is a safety issue, it's not a powering issue. Yeah. There's been questions about, well, what if you get a lot of dropouts? You know, patients figure out that they're, you know, gee, they're not on the drug 'cause they don't seem to be losing weight or whatever. Again, it's so overpowered. Yeah. That it's really... I don't think there's a lot of risk to this trial from that standpoint. I mean, would you think the dropout rate would be any different than some of the previous trials like? Only because of the duration. Now, BBS went out a year, but it didn't have the placebo. Right. The difference is we've got a placebo out a year. Right. And that, that's just tough. It's, you know, and for an injectable, it doesn't matter what disease, it's just, those are just tougher trials. Yeah. So. Interesting. Okay. And then just thinking about that market in HO, I mean, obviously, we always hear this, and we've been hearing this for a long time about, you know, what about SGLT2s? What about GLP-1s? Mm-hmm. What about now, you know, GIP/ GLP-1, what all these different, you know... So how do you think, or will those play a role in HO? Are they already, are they already there? And, you know, how does that impact you guys, you know, within Imcivree? Yeah. So, you know, there's sort of different answers, complementary answers to that question. So one is, you know, the rising tide lifts all boats. I mean, I think the GLPs specifically are just amazing drugs and, you know, the new focus on obesity has been, you know, tremendous, I think, for all, and it's helped this population as well, just, you know, people being more attentive to it, thinking about it, more willing to... You know, if you're trying to educate into that and say, "Yes, and now, you know, obesity, it's a disease, and you need to manage it, but it's not one disease, it's many diseases, and you should figure out which disease your patient has." So that's been a, I think, a helpful part of this whole thing. GLP-1s, I mean, the downside there potentially is there's so much noise and, you know, GLP-1s are a hammer, everything's a nail, and, you know, the assumption is that, "Well, that'll take care of it." So short answer on the, what's known, the early- generation, exenatide and, you know, liraglutide, more exenatide, have been studied, including one double-blind, randomized, controlled trial, and they had no effect. So clinically, it's a significant effect. Now, setmelanotide is obviously a, a much better drug, hasn't been formally studied. A handful of case reports suggest it can have some use. And I think the way to think about that is obesity is complex, and so you can have different reasons why you may be gaining weight, one of which may be your underlying hypothalamic obesity. But on top of that, you know, if you really like ice cream and you're just eating a ton of ice cream, then... So GLP-1s, in any given patient, for sure, will help that. They decrease cravings and the like. What they don't do, and I think what the data and what we're seeing and continues to emerge, is that this fundamental defect in the pathway that, you know, where in Imcivree, setmelanotide, if you think about it, that what's missing when that pathway is impaired is alpha melanocyte-stimulating hormone.... So it's, you, you have a hormonal deficit, and we're just replacing the hormone. And so, you know, that's a, a pretty simple, well-understood, you know, medical, concept, and, and people get that. So on the GLP-1s, they'll be used for sure 'cause they're out there. There's a lot of noise, and some patients will have effect. One of our experts said, yeah, she thinks that, you know, maybe about 20% of patients with HO may have an effect, and that the magnitude of that effect will be 10% or less. So I think at the end of the day, if anything, you know, you may see some combination use. Mm-hmm. As I said, there may be different reasons. Semaglutide and certainly liraglutide has been out there for a long time. The fact that there are so few reports, again, just tells you if they were the solution for this population, which is pretty desperate- Yeah they would have been overwhelmingly used, so. Got it. Maybe the last couple of minutes, can you touch on, you know, Dou got DAYBREAK data coming out? Mm-hmm ... you know, later this year? I guess maybe just tee that up in terms of, you know- Yeah - number of patients, what we could expect to see, and ultimately, what's the path forward after, you know, DAYBREAK for some of these cohorts? If, again, maybe they don't hit or something like that. Yeah, it's so DAYBREAK, I think, the way it's panning out. Again, it's we're halfway through. We have an open- label portion, and then if you were a responder, you go into a randomized, blinded withdrawal phase so that we don't have that information. But we'll report out on the open label part. I've talked about, you know, five-ish plus or minus genes that we'll probably speak more specifically about. Not all of them have responses and the like, but I'm pretty happy with DAYBREAK. I'll say that at this point, and that it's been a pretty efficient way to sort a long list. Mm-hmm of genes that touch this pathway and might, you know, might be of interest. So I think we've taken a big step forward in trying to sort that, one. Two, if you do see positive results, what are you going to do? We have a lot to do, just executing on our different pieces. HO, certainly, one of the most important. So the bar is going to be pretty high in terms of rushing into another trial. I think we'll sort the data. Mm-hmm. We'll wait until we get the results of the blinded portion to make final decisions on that. And one of the things we continue to do is to learn more about not just DAYBREAK genes, but these genes in general, in terms of you have your genetics, which are categorized based on existing information, but most genes will have a big pool of the variants which fall in this variant of unknown significance. And the more we can understand that pool and determine who has true loss-of-function related to their gene and where that variant might just be a benign and therefore not driving their, their obesity, then the more efficiently we can run these trials. So those have things are happening in parallel, and again, the DAYBREAK next steps will be a 2024 decision. Okay. We'll provide some insight this fall. Gotcha. And then just a question on, you know, kind of the long-acting or weekly- Yeah Imcivree. So you made, you know, kind of a shift in strategy a little bit. Maybe just kind of talk about, you know, kind of two options now, basically two shots on goal, and why, you know, you're kind of looking at it that way, versus kind of pushing forward with the weekly Imcivree today. Yeah. So you heard, I think, correctly, and most people heard the pretty good high level of enthusiasm for this 718 next- generation. One is it doesn't have the hyperpigmentation related to the MC1R agonism, which we do have with our current therapy. So that's obviously a plus. You know, we'll see. I don't think I'm very confident it's not less potent than our current semaglutide or the weekly formulation of that semaglutide. So assuming all things go well, it's a just a more attractive opportunity, I think, in that sense. From an IP standpoint, again, the semaglutide is the daily's out in 2032. The weekly version of semaglutide took us to 2038, and we're fully committed to getting there. But, 718 takes us to 2041. And so from a, again, just overall portfolio standpoint, from all multiple angles, this is just a flat-out better opportunity and I think puts us in a really good place, going forward. Maybe last question. I think you guys highlighted you looking at like an R&D event at some point. Maybe just talk, like, you know, obviously, this business is largely centered around Imcivree. Is this going to be more about that in kind of, you know, different types of indication expansion for Imcivree, or is it going to be looking at, you know, again, you have the CHI asset, or maybe something else that's coming from the pipeline? Yeah. No, it'll be largely, if not completely focused on the pathway in Imcivree. We'll have some information on the 718. Okay more color around that, but it'll be largely this. You know, the CHI is coming. Well, we didn't talk about that today. Yeah. That is the next opportunity in the portfolio. We probably won't spend much time on that, at this upcoming R&D. Got it. Okay, well, we'll leave it there. David, thanks so much. Thank you, Derek. All right. All right, good. Thank you.