Rhythm Pharmaceuticals, Inc. (RYTM) Earnings Call Transcript & Summary

Great. Well, thank you, everybody, for coming. I'm Dave Connolly here at Rhythm Pharmaceuticals, and thanks for coming to our R&D event this morning. We issued a press release today that provides details on today's update on MC4R pathway programs, and it is available on our website. Our forward-looking statements disclosure slide here on Slide 2, please read them. And with that in mind, I'll remind you, this event contains remarks concerning future expectations, plans, prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly reports on file with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent dates, and we specifically disclaim any obligation to update such statements. As a brief overview of today's event, I'll briefly introduce each of today's speakers and run down our agenda. Dr. David Meeker is Rhythm's Chairman, CEO and President; Dr. Jennifer Miller, a Professor of Pediatric Endocrinology from the University of Florida; and then Amy Wood, Executive Director and Co-Founder of the Raymond A. Wood Foundation, a parent and patient-led rare disease patient advocacy organization dedicated to empowering survivors of craniopharyngioma and hypothalamic pituitary brain tumors. Each will discuss the landscape for hypothalamic obesity, followed by a Q&A, which will be moderated by David. And then we will hear from Dr. Dorit Koren, Medical Director and Clinical Development here at Rhythm Pharmaceuticals; and Patrick Sleiman, PhD, Director of Genetics and Translational Research and Development at Rhythm. Drs. Koren and Sleiman will discuss data and the genetics behind them from Rhythm's exploratory Phase II DAYBREAK trial. And then we'll also hear from Danica Grujic, PhD, Senior Director of Nonclinical Development here at Rhythm and Translational Research and Development. She will provide an introduction to RM-718, Rhythm's new MC4R agonist drug candidate, and Dr. Meeker will present top line data from our Phase III pediatric trial of setmelanotide. Then we'll conclude with a Q&A. For our sell-side analysts who cover Rhythm participating via the webcast, there will be a chat function through which you can submit questions, and we will read them aloud here. And then with that, I'll turn the call over to Dr. Meeker.

All right. Thank you, Dave, and thanks to all of you for showing up on a snowy morning and hello to all of you tuning in on the web. So Dave ran through the agenda for the morning. I'm going to provide a brief intro -- further intro into what you're going to hear today. So think back, Rhythm founded in 2008. First patient treated, I think, in the early teens. And when we treated that first POMC patient, it was like, wow, we kind of had no idea where it was going, but it was a pretty dramatic response in a world where obesity medicines don't usually have much effect. That was quite a bit pre-GLP-1s. But beyond that, we didn't know a lot. We didn't know how big this was going to be. We didn't know where else we might go in the pathway. We really didn't even know if there were going to be a lot of those patients, some POMC and leptin receptor Biallelics. I think we've learned -- there's probably a fair number out there. They're pretty hard to find. Those numbers are small, but that's where we started. And what you're going to hear today is that this has really opened up. And our understanding of the science is continuing to grow and the more we get that understanding, of course, more doors now open. A lot of it's about the genetics. It's very much focused around the pathways we'll talk about, but understanding the genetics of that pathway. And then we're going to go with 718, but not just 718, the pediatric program, commitment to life cycle management, expanding it and making sure that patients who need this drug not only get the drug, meaning all patients, all ages, but also get it in the best possible form, the most convenient form, the safest and most effective form. So again, continuing to work on life cycle management. It's been a good year for Rhythm, a good couple of years. I think we've talked on our other calls about the commercial execution, and that continues to go well. The hypothalamic obesity programs, which are an area of huge interest and focus for all of us, some no matter where you sit, and we understand that. Those trials continue to progress. And then today, we're going to talk about the rest of the development program here. We're not talking about M&A today. We'll come back at a later point in 2024 to talk more about that. But M&A taught us a lot. I mean that initial attempts to understand other genes, how do we do that, how we do well. We made some mistakes. We did some things well. So that's also been a learning process for us. Our favorite cartoon, I'm sure you're a favorite cartoon if you're not sick of seeing this already, but it's the anchor, it's just highlights again that we're all about the pathway, but -- in the beginning, it was the POMC neuron, I think increasingly, we're understanding that yes, the hypothalamus is a complex part of the brain. You've got multiple pathways. GLP-1s have continued to highlight, there's different sites of action and how do all these things interact, what's inhibiting, what's activating. And so our understanding of that, again, as you'll hear through some of the genetic work we're doing is growing. And all of that is translating into the downstream effects, which is patients who do have impaired signaling to the POMC pathway, as we know, have a deficit in alpha melanocyte-stimulating hormone. And again, this has been really one of the fundamental pieces we've just tried to reinforce with. We're not disrupting normal physiology with the pharmacologic intervention. We're replacing a deficit with a hormone. And setmelanotide is an analog of alpha melanocyte-stimulating hormone. What is deficient in the setting of POMC signaling impairment. So -- and the downstream part, the hyperphagia, again, I think I can use myself as an example. I mean i was just hungry. No, we all know what hunger means. And the reality is, no, I had no idea how complicated hunger is, and the idea of what we experience when we miss a meal and what individual who has an impaired pathway experiences when despite eating, they just cannot feel associated. They just continue to be preoccupied by food. And so not only our understanding of that trying to help the world understand that because all parts of the health care system are starting with that very fundamental -- and it's the doctors, I think, are the [ worst ] with all due respect to any doctors in the room, who in terms of really understanding the different aspects of that, what is it that's different about hyperphagia from just regular hunger. And then energy expenditure, yin yang of this whole thing, which is the sort of the dual curse here that these patients suffer from, not only are the MSA hungry, but their bodies slowing the metabolic rate because they think they're just no foods on board. Opportunities, again, the numbers on Bardet-Biedl is a very real opportunity. We're working that hypothalamic obesity. You'll hear more about. But larger number of patients. But again, the majority diagnosed, talking with Amy and maybe Amy will comment on this a little bit. They're probably under diagnosed. I mean, Jennifer -- Dr. Miller, I know is as well. And so I think, again, we're early in this whole process. And so a lot more to be learned there. Then the M&A genes, which do open up a much larger opportunity and kind of work in progress as we go through this. So what you'll hear today, again, Dr. Miller and Amy would begin. You've [ standlessly ] seen the graphics. I'm going to show you that graphic one more time because I like the graphics. But there, Dr. Miller is taking care of these patients, living with these patients. She was a lead investigator in our Phase II trial. She's an active investigator in our Phase III effort here. So an enormous experience, not only pre potential treatment, but also seeing the impact the treatment can have. And Amy, as Dave highlighted, living with her son affected by this and motivated to start the Raymond A. Wood Foundation and -- so not only having a personal experience, but also being a leader in the community, and hearing all of the other stories of families and patients who are struggling to deal with this. The exploratory Phase II Daybreak trial, again, well I think that's going to be really interesting as I told a couple of you. Press release is really hard to convey, a complex study like that and these preliminary results in a press release. So hopefully, you'll leave this meeting with a better understanding of what we saw there. I'm excited about it. I think there's something there. It's not going to be a simple straight shot, but I think we've got some ideas about the ways to think about paths forward here. 718, again, we've talked about, but you'll see why we're -- we feel really good about that. And then the Phase III pediatric trial will finish with that. It's -- we're confirming in a sense what we've demonstrated previously, but it's -- there's some really striking things about that trial. And one of it is just the severity of kids at such an early age. I mean it's almost unimaginable how affected you be so quickly. So a brief intro to our hypothalamic session, talked about the numbers. You're going to hear more from Dr. Miller about this whole disease. Like I said, I'm not going to leave without showing the graphic again, because I just think it's a good graphic and this hypothetical obesity world hasn't had the -- I wouldn't call it a luxury, but hasn't had the benefit of the therapy that could make a difference. So as you remember, we had the 16-week data with 18 patients. So this is on the trials. We had 18 patients, remember the disposition. We took it through. 14 patients went into the long-term extension. On our poster we -- all 14 are still in the trial. So we haven't lost anybody. We've had people bouncing it out a little bit, but they've come back. And coming back, it's very clear when you're off the drug, you regain your weight, when you go back on the drug, you lose it again. So Dr. Miller has one of those patients. So she can comment if she wants and she gets up. But then over 6 and 12 months, that -- those 12 patients continue to deepen. But not everybody -- and this is one of the things where trying to get off this concept that it's just endless reductions in BMI is the end game here because obviously, that's not the endgame. The endgame is to restore people to some level of normal functioning, whatever that BMI is for that patient. And so we have patients in this trial whose BMI is increasing after a very dramatic -- best example is a 6-year-old who's BMI is less than 50th percentile. It's increasing. It's no longer driving the mean BMI down. It's driving the mean BMI up, thank God. Because you would want that child to be gaining weight and doing it. And then as we know BMI in children is not a great metric. So we're looking at things like this BMI-Z, the obviously, you're seeing or deviations away from normal. So 2.5 as a starting point, very severe, decreasing to 1.5 to 12 months, anything over 0.2 is felt to be clinically meaningful. And then another metric that people are also very interested in is the percent of the 95th percentile. So what percentage above that 95th percentile are you, so 145% of the 95th and decreasing almost to 104%. So more and more, we'll be looking at can we get people back to normal, and normal may or may not be on a normal BMI growth curve, the BMI may be their prior that patient set point, where would they have lived if they had not developed this complication. And this is the individual. And as you can see, the red bars -- I'm sorry, -- the red bars are the 12 month. And essentially, everybody has had a further deepening or if they had a significant deepening, they've maintained that, and with the exception of one patient here who had a very good response and has had some regression back, but still maintains a significant change from baseline, the teenage are also continuing to grow. So with that, and this is our Phase III trial that you know is ongoing, 120. We're close to the end of getting all of our patients screened and ready to enroll. So 120 patients, randomized 2:1, and then that will be followed a 52-week trial followed by an open-label extension. So with that, I invite Dr. Miller up who Dave introduced already, but I've had the pleasure of getting to know Dr. Miller, and I will add only to the fact the professor of Medicine at the University of Florida, but one of the most passionate people. I've had the opportunity to get to know about what to do, and.

All right. So I'm going to just --. You heard a little bit about the hypothalamic obesity program. And so the hypothalamus and pituitary are sort of the master glands of our bodies, right? They sit in the middle of the brain, but they control everything, especially hypothalamus controls sleep, your sleep-wake cycle, your pain cycle, your heat-cold tolerance and all of your hormones from your pituitary, all of your endocrine hormones. And so tumors that disrupt the hypothalamic pituitary area or the pituitary stock, result in a myriad of complications for people who have had resection of these tumors, or even we're finding out now even with just proton beam radiation targeted at the tumors, you can still see profound injury to the hypothalamic pituitary region. And so this is complete pan hypopituitarism, so they need complete hormone replacement and a reduction in -- sorry, metabolic rate and also in about 50% of cases hypothalamic obesity that starts immediately after surgery. And so it's -- to sort of describe it to you, it's I'm going to show you a video in a minute, but these patients wake up in the PACU, and they believe that the nurses there are their waitress, and they immediately, as soon as they're awake, scissor set like a cheeseburger, french tries and milkshake. And then they go up to the ICU and the stacks and stacks of pancakes. And the thing is, is that we were talking earlier, Amy and I about whether or not people tell parents about this potential complication or talk about it. And I believe that they do, but in the midst of being a parent of a child with a brain tumor, all you hear is brain tumor, and that's it. You don't think about these other issues. And as a physician taking care of these patients, you're worried about all the endocrine complications that are happening postoperatively. They get central adrenal inefficiencies, so they have cortisol deficiency, which could kill them. They have diabetes insipidus, which is issues with sodium and water balance, which could kill them. So as physicians, we're not really attending to the fact of the appetite regulation and/or the weight gain, which can be quite remarkable, and I'll show you that on a graph in just a minute. There's -- that's the Rhythm slide that you all know. And the idea behind hypothalamic obesity being a target for setmelanotide is that the physical injury to the hypothalamus actually ends up resulting in blockage of the downstream signals, getting to the MC4 receptor. So therefore, it cannot activate out the MSH, which means there's no satiety. So we know with hypothalamic injury that you get a leptin resistance. And so Leptin, which is the Satiety hormone, cannot get through as well and buying to its receptors in the hypothalamus. Same thing happens with insulin. Insulin can't bind to its receptors as well, probably because of physical injury to the hypothalamus. And so when you can't bind these tidy receptors to start the activation of this pathway, then downstream, of course, you develop hyperphagia. So one of the biggest problems that we see in pediatrics is that craniopharyngiomas are really easy buy. This is the most common type of brain tumor that causes hypothalamic obesity in children. But often because these are children, they're often young children. And the symptoms are kind of nebulous, you get a headache, you bomb it, you gain or lose weight. They're often humongous by the time that they're diagnosed and disrupt a huge portion of the hypothalamic pituitary region. And so you know that when they're already physically that big, you're going to be in trouble in terms of how much hypothalamus and pituitary function you have left postoperatively or post radiation. All right. So this is my video to show you hypothalamic obesity and what it really is like. Maybe I have to hit it. [Presentation]

And it's constant and unrelenting. And when a kid is this age, there's no reasoning with a child who's hungry. And can you imagine as a parent, having to tell your child who is starving, no, you can't eat because you can't. The doctors say you already do that, and they're giving me grief about your weight. And so when you're restricting diet in a child who is hungry, it becomes even worse. And so -- and it really is nonstop kids get up at night to see food because they wake up and they're starving, they will steal food from other people, they'll eat garbage, they'll eat anything they can get their hands on, unfortunately, because they are so hungry. That's not what I meant to do, sorry. Okay. So as we talked about, you can see here a growth chart, i'm gonna show you a bunch of growth charts of a person who had his screen craniopharyngioma removed at age 8. And you can see that within the first month, there's no -- we're in the first month here, 20-pound weight gain in the first month in the hospital. So most of these kids are in the hospital for 2 to 6 weeks in general, managing all the endocrine issues, and this is the amount of weight gain. It's quite stunning. You never see this in any other condition this quickly. And you can see how quickly it continues to go up until it's above the -- way above the chart. And so we no longer can see how much it's going up. So there's multiple conditions that can lead to this. I speak mostly of premium craniopharyngioma because it's the most common, about 62%. But other -- children with other types of tumors are enrolled in the Phase II clinical trial, it gets with astrocytomas, hypothalamic hamartomas, these can all cause hyperphagia and decrease metabolism, so hypothalamic obesity. And so we include all of them. There are other causes as well as genetic causes, continual brain malformations that we see as endocrinologists, causing hypothalamic obesity that I think are a little bit more difficult to treat, especially genetics without pre rhythm, without the genetic testing that existed to help identify, now we can identify more of the genetic radiologies of these conditions. So this is the little boy I just showed you who is saying how hungry he was. And so here he is, tumor removal was at age 3, and you can see I put both weight and BMI chart on here, and you can see that, again, his weight went up 20 pounds in the first month. I mean, it was just insane and continue to go up. And here, he has BMI, same thing. Going up above. And so it's just -- it's unrelenting. And can you imagine, again, you're a 4-year-old doctors shame you for this as parents and they say, "Well, what are you doing? What are you feeding them? How are why? Clearly, the child is eating too much, but the metabolism sucks, afterwards because hypothalamic damage changes your metabolic rate And also they are starvingly hungry. So there is really, right now, no treatment algorithm for people with hypothalamic obesity. Most endocrinologists start with metformin. We know that children with hypothalamic obesity do have high insulin levels postprandially and metformin is an insulin sensitizer. So we feel like, okay, well, maybe we can prevent them from getting type 2 diabetes as a result of their obesity and these high insulin levels. So we put them on metformin and it does nothing, but it makes us feel better as doctors that we're trying something. And so almost everybody, I would say, with hypothalamic obesity has been tried on metformin at some point in time. And then after Vyvanse started approved for treatment of binge eating disorder, stimulants became more common for use in this condition. And so we try those as well. Those caused some initial weight loss, but then subsequently, the weight tends to stabilize on those medicines. And they have orlistat on here, which is almost never used, especially in the pediatric population because it causes you to excrete extra fat in your diet and your stool. So it makes you have oil stools and leaky farts. So not a good thing. So nobody likes that as a kid. So -- and so -- but like more than 25% of these individuals are on multiple medications to try to manage the symptoms of this condition because it's really hard. So obviously, the newest kid on the block, as Dave mentioned, is the GLP-1s and those -- the GLP-1s GIPs have been tried now for the past few years in people with hypothalamic obesity, and this is just a growth chart of one of my patients who was on -- started on at her highest started on Vyvanse Max dose. It did bring the weight down, as you can see, by about 20 pounds or so, and this is BMI actually, this is not a -- so this is the BMI curve because -- and children weight for height BMI line and weight for height matters. So it did bring our BMI down because of brought her weight down, but she's growing, developing individual. And so weight kind of stabilized at the 95th to 97th percentile. She's a 14-year-old girl, that's not good. Yes, I mean, when kids are heavy, kids are mean. And so she was really struggling, like we were pleased that she was back on the chart BMI-wise. She was not. Because she was still hungry all the time. She was really struggling to maintain that weight. She's going to the gym every day to work out, and she was restricting her diet and she still couldn't lose the weight that she wanted to lose. So we put her on a GLP-1.. The problem with GLP-1s is, as I mentioned, this is my thought, at least, is GLP-1s work in 2 ways, right? They work in the periphery to decrease gas delayed gastric emptying, so that you're supposed to feel full longer, and they work by hitting receptors in the hypothalamus to signal satiety. Well, if your hypothalamus is damaged by surgery, then those receptors are likely either not there because they've been damaged, or maybe just don't work as well because they've been damaged by the tumor. And so what we see with GLP-1s traditionally is this. You see about 20 pounds of weight loss maximum. And when you think about, I would say, most endocrinologists who have done this for a while, say that about 10% of people with HO respond to GLP-1. So it's a pretty low percentile. But what I maintain because I've been doing this a long time is that, that weight does not hold. It doesn't stick. They don't continue to lose weight on these medicines. And again, I believe it to be a problem with the receptors in the brain. The reason they lose weight, though, is very interesting. So delayed gastric emptying, they also -- remember, they don't feel full. So they will eat and eat and then they will throw up, because their stomach gets so stretched out by how much food they put in it and the longer you're delaying emptying, the more food you're putting in there, the more likely you are to throw up. So GLP-1s are very, very unfortunately miserable for this population because it results in a ton of nausea and vomiting, which we have a really hard time controlling even with things like ondansetron. And in general, most people, if they continue on it, it's only because they just want to maintain, but they're not happy about it because it's a miserable existence for most of them because they're growing up a lot. So this is just a case report. I'm going to show you a picture of this young lady in just a second. But she had a cranial resected at 8 years of age. She gained about a pound a week postoperatively, multiple treatment trials were tried, we used diet, exercising and famous metformin. We initiated Liraglutide at the time that was what was available and the newest one, and she lost about 20 pounds. She maintained her weight over about the next 12 months and then it began to increase over time. We changed her to Tirzepatide when it became available because it's stronger, GLP-1/GIP-1 and she had no additional weight loss on that. I didn't touch it. And so then she enrolled in the prior trial, which is the Phase II trial. So here is where the GLP-1 was initiated -- GLP-1 was initiated here. Tirzepatide initiated here, this one and when she was up at our highest, Rhythm came along with Phase II, and we enrolled her in the Phase II. And this is what happened. Straight line down. It's -- she hit a wall. So you can see here, this little area means that it's going out past age 20. And so she is now almost 21 years of age and she's been on this for closest January, it will be 2 years. And you can see here this is her weight, the better BMI has done the exact same thing. It's just come down, down, down, which you didn't see and you don't see with any of the other medicines that we've ever tried. So it's really quite remarkable. And here she is. I mean, when you look at her, she is -- she doesn't look all that heavy overall, but she is a teenage girl. This was extremely uncomfortable for her because she was teased and made fun of and whatever and was having to restrict or diet so much. Now she's in college, she's living in a dorm. She couldn't even drive before. Her parents wouldn't letter drive because of the food stuff. They were worried that she was going to go get food. And so they would drive her everywhere. But now she's living an independent life as an adult person, which is what an adult person should do. But these individuals with this condition could not do that without setmelanotide. And just one more because I love pictures, because I think pictures tell a thousand words. This is Travis he was a 20 -- I was with him when he got his astrocytoma resected. It was 9/11, I'll never forget it because we watched it happen together in the ICU while he was recovering. And he -- I followed him throughout his entire life, and he would come in and say, "Dr. I don't understand. I'm not eating that much. I don't have hyperphagia, but I'm gaining all this weight." And when the opportunity for 030 came along, I enrolled him, thinking I bet he does have hyperphagia, and he just doesn't know it or he's not admitting to it, but really it was his metabolism, honestly. And so remember that this condition, once you treat it, will slow metabolism down quite significantly. So even with really minimal changes to his diet, here he is last month. His BMI is down close to normal now. It's 32 from 52 when he started 1.5 years ago. He told me he was able to travel for the first time recently, because he could sit in a plane seat and he didn't have to have a seatbelt extender. He was, for the first time ever, able to sit in a regular plane seat and not have to have a seatbelt extender. I mean that -- I know it sounds silly, but it's huge quality of life things for these people that they don't travel because it's uncomfortable, and it's terrible to have to get 2 plane seats and have to have -- they say it's embarrassing. But to be able to live his life, he has a girlfriend, he's getting a master's degree right now, which he will finish this month. And he's working with Marcy to write a new hypothalamic obesity cookbook for people who are on setmelanotide. And so -- but anyway, that's just -- I love this picture because it's close to the same shirt and you can really see the difference. And I really think just look at the smile on his face. I mean that's -- as David mentioned, this is not just weight loss, right? Weight loss is great, but the other effects, these freeing effects that this drug has, it's life changing for these people. That's all I got.

Good morning. I just want to thank my Rhythm colleagues for inviting me here today to share with you a little bit of the perspective of living with HO as a caregiver and for my son Alex. So just starting off with talking a little bit about Alex's journey. So Alex first-to-4 years old was very nerd -- was a neuro-typical child. We didn't know he had any health issues. He was leading a great 4-year-old life. He was full of energy, had lots of friends, was enjoying Pre-K. One Thursday morning, we woke up business as usual. But I noticed something was different about his left eye. It seemed to be drifting inwards. So he said that something is going on. But we have a history of lazy eye in my family. So I was like may just have a notice. So I made an appointment. Otherwise, he seem fine. I made an appointment with an eye doctor and sent him off to school. As the day progressed teacher contacted me and said, have you noticed the eye and I said yes, he has an eye doctor appointment. She said, he's walking unsteady, and I was like, that's odd. So I made an appointment in that afternoon with his pediatrician, brought him in and the pediatrician said to me, you need to take in the John's Hopkins ER and get an MRI. I think it's a brain tumor or brain cancer. That was the most have pivotal moment of our lives because that was where literally everything changed. So we got to John's Hopkins ER that night. They put them him in an MRI and they said, he has a mass in the middle of his brain, and we're going to have to operate immediately. So in the next 24 hours, Alex was in the OR. He came out. We sort of thought that he was going to be okay because they said it's a benign brain tumor. And you can kind of see in these pictures, this was this very week. We had gone to the strawberry patch. He was doing normal things that week. And then here we are towards the end of the week and 1 week later. So they told us it was acraniopharyngioma Dr. Miller touched on what acranio is. But they said, it's a benign tumor. So we sort of had the impression that we were going home in a couple of days, and he was going to be fine and how lucky were we? It's benign. Well, unfortunately, as the days progress, we quickly learned that he was facing a host of issues. And just -- I think Dr. Miller did a good job explaining acranio, but one of the things that I think we talk about from the foundation perspective is from a neurosurgery perspective, it is one of the most difficult brain tumors to treat because of its location in the brain. And Alex spent 4 weeks in the PACU and weeks after, the rehab hospital. And then the year after, we had multiple ER visits, med flights and emittances for seizure and hypothermia. And this is because benign is not fine. We say that all the time, but it's -- this tumor is almost mischaracterized because it's so -- it has so much impact on the brain. He developed pan hypopituitarism, so complete loss of endocrine function, a [ dead ] diabetes insipidus, so this is the brains in ability to manage the body's water balance, coupled with no thirst mechanism. So his hypothalamus was damaged in the way that he can't sense thirst to even be able to manage his body fluids. He had adrenal insufficiency, as Jennifer talked about, and growth hormone deficiency. But if a brain tumor and all that is not enough, we started to notice that he was beginning to gain weight immediately after surgery. He went into the hospital at 40 pounds and he left the hospital at 60 pounds. Alex didn't have much of an appetite prior to surgery. He was a picky eater, I was always struggling to get him to eat. After surgery, he tried to eat a napkin. And I was like, this is -- something is going on. It was later on, maybe about 2 or 3 months later where he received the formal diagnosis of hypothalamic obesity, but doing my research, I'm a researcher on these things, I had already seen that this could be an issue, and so started to kind of have these conversations with his doctor. And you can kind of see in these pictures how just the visual in the first year -- I mean he almost didn't look like who he looked like before. And that was tough to take as a parent. Because all of this was from a brain tumor, and when they told me he had a brain tumor, I thought that was the worst thing anyone could tell me and then here we are. So what is life like with hypothalamic obesity? So this is 8.5 years. He's 13 now. So we've been dealing with this for this long. And we have a lot of fears around him developing obesity-related conditions. So we already have this long list of conditions we're managing every day, two of which could be fatal. So we're constantly managing levels and assessing where he is to keep him safe. We then have fears that he could develop obesity-related issues on top of these, like sleep apnea, hypertension, diabetes and fatty liver disease. He -- a couple of years ago, suffered from aspiration pneumonia because he was eating so fast and so much at once, that food was getting into his lungs. He eats so fast and so much that at one time that we're constantly worried he's going to choke. He has a tree nut allergy. So that adds another layer to this because we have to watch it all times. Because Alex is very clever, and if we're at a social event and you've seen some lovely unsuspecting grandmother type, he goes right to that person and ask for food. And then you don't know, well does that brownie have nuts in it. So we're constantly watching him. He food seeks at night. Just the other night, I heard a noise at the garage door. He was up at 3 a.m. in the garage. We have food locked up in the garage, trying to get through the lock. So I sleep with one eye open always. And you can see we lock all of our food, our refrigerator. It's a constant stress on our family. We're socially isolated. It's the holidays. This is our least favorite time of the year because we're always worried about family gatherings and events. And it puts a lot of pressure on our -- not just our immediate family, but all of our family, because everyone worries about having the food out too long, what's on the table, where is Alex, if you're in an event he'll disappear with food in his pocket and hide in the bathroom. And he also has orthopedic issues. So immediately after when you start gaining the weight, you start having a lot of trouble with his legs and feet, and walking. So it's kind of one of these other side conditions like these patients face that isn't often addressed. But the thing that I should say is that we manage his care so closely and we manage his diet so closely. We lock everything up and we take painstaking efforts to keep him safe, but he is on the border line of overweight and obese. He's 94.6 percentile. And that takes daily effort. He doesn't go to school during meal time, he goes to school in the afternoon after lunch. And the other day, I get a call that he stole food out of another kids lunch box within -- on a shelf. So that's a lot to think about. So this is Alex at a party. He was watching this pie the whole time, and we were watching him to make sure he didn't get it. And I think that kind of shows you a little bit how he's preoccupied around food all the time. Imagine somebody -- I mean, you have kids and kids ask you a lot of questions, but this is Alex, Mom, it's 46 minutes to lunch. Mom, it's 11:20, lunch is at noon. Mom, it's 15 minutes to lunch. He is watching the clock every minute until its lunch time. So what if there was a treatment for HO? Have a slide, I'll go back to that. What if there is a treatment for HO, would Alex be able to think about other things? Like he -- his mind is so occupied by food and he's a smart kid, I feel like his learning would be better if he wasn't thinking about food all the time, just the things that he could do if that wasn't always what he was thinking about. Could eating meals being enjoyable family experience, because right now, when we eat together, we're trying to keep him from putting too much food in his mouth. And that is all we do during meals, Alex, take smaller bites, Alex, don't put too much food in your mouth. Will he be able to make friends? Because right now, he doesn't have friends. He's not able to make friends. He can't go over to someone's house because of the food situation. All he talks about is food. It's so all-consuming that there isn't space in his life for friends. And would you be able to have some independence? I mean what if in the future, he can possibly get a job because he wouldn't be inclined to steal food from his coworkers. So these are the things that I think are quite possible now that we have a potential treatment. And I want to go back to this, so the Raymond A. Wood Foundation, we published a caregiver burden study in August. And so we surveyed caregivers on the impact of disease around craniopharyngioma. And we found that in the survey, the data showed that about 88% of the patients had weight problems. And at hyperphagia or insatiable hunger with about 50% of those patients. So it's manifest in different ways. But 80% of caregivers are at risk of depression. And I can vouch for that. It's really challenging to manage this all the time and to deal with all of the social implications and the guilt. And so obviously, that is a mental load that we carry. And these are some of the quotes that we have had over the years from patient families. And I think it's important to kind of call out that the initial weight gain really quickly after surgery is that is scary because you don't know what's happening. And then you're on this 1 to 2 pound weight gain on average weekly after surgery. So you're watching this person literally double in size in front of you. And no matter what you do, all of your attempts to thwart that weight gain tend to not be successful. And it is really about fear isolation and helplessness. And a lot of our kids put themselves in harm's way or others to get to food. Siblings suffer a lot because of this condition. And just from an adult perspective, doubling in size after tumor surgery, without understanding what's happening to you is, that's a tough thing to manage. So with setmelanotide, where our patient community and myself as a caregiver are feeling very hopeful. This is a huge thing for us. And we are so glad that something is out there that can potentially help our kids and our family members and our loved ones in the future. Thank you.

Okay. I think everybody heard that. By the way, thank you. And of course, Dr. Miller said just about a lot of your creative trying to figure out how to help these patients. So Corinne.

I think on one of the slides that referenced like 59% of patients are on metformin or another kind of therapy for the obesity function like part of their HO, I guess why would patients not be on therapy? And do you expect there to be any change in terms of impulse to treat with the advent of IMCIVREE in this population?

Yes. I think that people will be much more prone to treat with this drug once it gets approved. And so -- but the reason people are not on metformin therapy, it doesn't work. So some parents will continue their kid on metformin just because they feel like they're doing something, but the great majority do stop it after a while because they realize that there's not doing much of anything. It's the same with stimulant. We see some people on stimulants for long periods of time, even though they're not actively losing weight on the stimulants or having good appetite control in the stimulants, but it makes the parents feel like they're doing something proactive. Is that a fair statement? Okay. So yes, so that's why. So those numbers are because people stop treatment.

Sorry. sorry. Whitney from Canaccord. So on the stimulants and also [ indi ], I think you mentioned just kind of spoke to the lack of durability of the weight loss or lack of continued weight loss. So actually, can you clarify, is it lack of durability of weight loss that's seen?

Correct.

And then what is the time course of that, I guess? And can you compare it?

Typically about a year.

A year. Okay. And so I guess, can you talk about your experience with setmelanotide, I guess, for the patients you've had beyond the year?

Yes. So so far, on the 2 patients -- or on the 2 patients we have 3 or on [ 030 ] that are still on setmelanotide, all of them have continued with excellent weight control. As Dr. Meeker mentioned, one of the kid that he mentioned that has had a regain in weight is because he's an adolescent young man who is also on testosterone and growth hormone. And his weight was so -- had gone so low on setmelanotide then I was like, we actually want them to stabilize and he did. But then when we had to add testosterone, of course, his appetite went back up, getting whatever, still very much better controlled, 1000% his parents would say, than predrug because he's not talking about food all the time. He's not asking about food all the time. He's not stealing food. But the weight itself, as Dave mentioned, is not necessarily that we offer these patients. It's quality of life. And so -- but regardless, except for him, everybody has continued down over the course of almost 2 years at this point.

Thanks for a very interesting presentation for both of you. Phil Nadeau from Cowen. I just wanted to dive a little bit more deeply into your last point in terms of BMI reduction, weight reduction versus hyperphagia. What really contributes to the improvement in quality of life for patients on setmelanotide? How much is it the reduction in hyperphagia versus the reduction in weight? And can you -- I'd love to hear from both of you, like what would be clinically meaningful? And then also in terms of the magnitude of reduction, what is clinically meaningful? Clearly, if you get a patient to normal in either of those categories, it's very meaningful. But how much of a reduction in hyperphagia and BMI would patients and caregivers appreciate?

Any? Is the answer to your question, correct? Any reduction in these things is helpful and clinically meaningful to families. In terms of the quality of life, I think it's a combo of both weight and hyperphagia. I also have personally said to Rhythm for many, many years that I actually think setmelanotide does have an effect of reducing psychiatric issues like depression and anxiety. I see it. I mean we always worry about anything that works in the brain, possibly increasing your risk of depression and anxiety. And in this population, you see exactly the opposite. They become more active. They they're just happier, all the parents say it. The kids got a smile on their face all the time now. They have more energy. They're not taking a nap after school every day. So it's all of those things combined. And I'm sure that part of that is the weight, right? Because if you don't have the weight, the weight it's coming off your sleep at in it gets better, you sleep better during the night. You don't have the hyperphagia. You're not getting up at night to steal food. So you feel better. And so I think it's really a combination of different things. But I do honestly believe that there is some actual possible changes in sort of overall mental health in a very positive way.

Yes. And just to add to that, in our caregiver burden survey, we found that there was a really strong correlation with burden to hyperphagia. So while the weight was an issue for sure, there was even more of a correlation of burden to the hyperphagia. And I will say in the beginning and certainly still -- I mean, the weight is a big issue to us because we don't want any more medical conditions, and we certainly want to feel good. And I mean, the social stigma is still there. But for us, too, the hyperphagia is what really keeps us from going out or doing -- we -- many of us parents and some have this experience, our kids steal, so they can't be left unattended in stores. So the hyperphagia has a really high impact on quality of life. So while both are very important, we're working to collect more data around the impact of hyperphagia.

Well, and just to speak to that point, one of the things that every parent in the Phase II trial mentioned is they can go to a party now, and the kid doesn't look immediately at the food. They'll go to the pool with the other kids. It's not all consumed by where the food is and what the food is and when can I eat that food? And what can I eat out of that food that's okay for me kind of thing.

And that would be amazing.

That's life changing.

Michael Higgins, Ladenburg Thalmann. Just a follow-up from an earlier question for Dr. Miller on the patients that you're treating. Have you noticed hyperpigmentation in these patients? And how problematic is that? It seems like it haven't dropped off, but how big of an issue is that for you?

It's not an issue at all. So I've been doing studies with Rhythm since the beginning. I was part of the very first trial with setmelanotide, which was for Bardet-Biedl syndrome, and then part of the genetic obesity staff. And for those patients, the hyperpigmentation was a much more significant issue. For these patients, they don't care, like at all. Like they feel so much better that it's not an issue, like it just isn't. And so we see it, it's there. Everybody gets darker by -- and it used to be more -- I mean, in the genetic obesity population, specifically, African-Americans, Asians really hated it because they didn't want to be darker or have more dark spots or whatever. And in this trial, we have all races and nobody cares. Like they're not dropping because of that. That is not an issue at all. It's kind of remarkable. And I keep saying that to people like this is really interesting, like we've seen people drop off because of the side effect of the drug, but in this population, not at all.

Derek from Wells Fargo. Just 2 questions. First for Dr. Miller. I guess, is the patient journey that Amy talked about with her son, is that more typical just because of it's seen more in children? Or do you see adults also kind of with that weight gain? And how is their journey a little bit different maybe with undiagnosis? And then just kind of a question on kind of comorbidities. You kind of touched on this a little bit, but do the current treatments address any of like kind of again, some of the diabetes, maybe you're talking about metformin. I guess, the role of IMCIVREE and addressing that as well.

Good question. So the answer is craniopharyngioma most common in children, not in adults. I don't remember what the cutoff is, but it all kids. I am also a pediatric endocrinologists. But that being said, I mean, in our current Phase III trial with Rhythm, we have many adults and -- but they were all diagnosed as children. So I couldn't answer the question about if you were diagnosed as an adult because I just don't know the answer. Do you know or people?

I can kind of speak to that. So there's 2 forms of Cranio and papillary craniopharyngiom does affect older adults. So it's a little bit different from the childhood version. We have adults that -- I have one in particular, who, she was diagnosed with the tumor and treated and gained 100 pounds after treatment. And this is a woman that exercise, she ate right, so she didn't know what was happening to her. So she started working out really hard. I mean hours at the gym working out. And I was kind of watching her story. And it turned out that she was never told that this was a possibility from her tumor. So she thought it was her, something she was doing wrong that she was gaining all of this week. When she found out about hypothalamic obesity, she was so -- just -- it totally changed her perspective. And she's like, now I know that there's a reason for that. I find the adult population, they're sort of -- they're not as diagnosed as often, and that's probably just because the care is very different from pediatric patients, but it is a challenge for them. And so -- and many have had to not continue with their jobs, that kind of thing because there's hyperphagia and issues with that. So hopefully, that helps sheds light on those.

That's a good thing. I did not know that. pediatrics. And the answer is that IMCIVREE has reduced all of the comorbidities associated with the obesity. So we see people coming off diabetes meds, we see people coming off blood pressure meds, cholesterol meds. I mean it's quite remarkable to see the changes. The other thing, like I mentioned before, is we've seen people come off antidepressants on it, which is, right. I mean, it's because this is a really hard condition for these individuals to go through, and especially as they're becoming adults and with this condition because they have hypopituitarism, they also can't have children, right? They're infertile. And so add that burden as you get into your early 20s and 30s. And to everything else you're dealing with, and it is really hard. I would say a lot of these -- most of these patients are on an antidepressant at that age. And so to see them be able to come off and just live a happier life is really remarkable.

Dae Gon from Stifel. A couple of multipart questions, if I may. Dr. Miller. If we think about the biology of the signal malfunction that is affecting HO patients and setmelanotide is basically curtailing that or by passing that issue. I guess, to what extent would you expect some kind of a stabilization or a plateau effect in these patients since you would be maximizing that signal restoration? And related to that, once you restore that, how would you think about administering clip-ons or clip on GIPS since you could potentially amplify that? And I think the obesity week kind of talked about some of those potentials. And then second question is, if we go back to one of your commentaries earlier, how the endocrinologists don't necessarily see the weight loss as the primary goal, but rather the hormonal imbalance, what kind of education do you think needs to happen to make sure endocrinologists start thinking about weight loss as a sort of secondary or indirect output of hormonal restoration?

That was very many parts to that question. What was the first part of the question was?

Signal restoration.

Signal restoration, yes. So yes, I expect to see stabilization of that. And that is what we're starting to see over time is stabilization of the BMI and the weight. And so as Dr. Meeker mentioned earlier on, at some point, there becomes a set point, right? Where that's just where they are. That may be for that particular individual, it might be a BMI of 32. But certainly, he's healthier than when his BMI was 52, and he's happier and he's not eating as much and he's not hungry. So yes, there is going to be a stabilization for sure. I have no doubt of that. And then I don't know the answer to the question about adding the other med to this, whether or not that would augment anything or not. I'm really not sure. Because, again, my experience with the GLPs and GIPs are pre this drug, right? I mean so -- and just knowing what we saw naturally with those medicines. And I remember very distinctly about 2 years ago, someone said, these are miracles for these HO patients and I was like just wait. It's not forever. This, I think, is kind of a miracle. I mean to watch these patients continue to lose weight and then ultimately, like I said, to stabilize. So yes, I think there's going to be some that start out heavier that probably are going to end up heavier than we would maybe like them to be if we were as doctors you know, but that might be their set point. And it certainly be healthier even at that set point because it's lower than what they are without setmelanotide. And then the third question was yes, yes. Okay. So this is where Dr. Meeker has made me a fan, is when he said that this is hormonal replacement, no offense. I was always a fan. Yes, because I think that's what we have to emphasize to endocrinologists, right? Yes, is that this is not a weight-loss drug. This is hormone replacement for something that they are unable to make on their own. And to me, done deal. Would you?

Yes. I mean, when we were first presented with all of these neuropathies that we're dealing with, we were told everything is a replacement. But there are still things that aren't being replaced, obviously. I'm Alex's living endocrine system. And -- but this is clearly -- I mean, clearly, that pathway is disrupted and replacing that missing element. I mean, the possibilities of what that can do is huge and should be expected. And I think you were mentioning the diagnosis of HO. And I suspect, and this is just a hunch, and I kind of saw it with Alex, is the doctors are a bit afraid to diagnose it because they don't have something to prescribe for it. And anything that's possibly used off label right now takes a lot of management and trial and error, because there isn't data to support it. So we've tried a lot of different things that ended up not working because when it was just such an effort to try to find the right dose. And even then, it wasn't fully effective. So I think there's a little hesitancy like the elephant in the room kind of.

For sure.

Maybe that's a good place to end. And I think we've highlighted from the earliest point when we got involved here about how this rare disease differed in the sense that these patients because of the tumor and the surgery, very high rate of diagnosis. I think what we may be learning and as Amy and Dr. Miller said, a number of patients who are not giving -- been given a diagnosis may be higher than we think. And that's certainly true for most rare diseases. And if you've got a disease for which there is no therapy, as a physician, if you miss the diagnosis. So what? So it's really -- once there's a therapy and something to do, it doesn't matter what disease it is. It completely changes the overall paradigm. So I think -- it will be very interesting to see if setmelanotide continues to perform and it becomes an option for these patients. The whole diagnostic journey of these patients are on may also change significantly.

Definitely.

So we'll see where that goes. All right. Well, we'll end this part of the session. Thanks to both of you. Really great.

We talked about M&A, but I think this is just to remind us that the DAYBREAK, as we're going to move now and talk about DAYBREAK, we took a tentative step, if you will, down this pathway with these 4 genes that we're studying in our Phase III EMANATE study. But I'm not going to front run Dorit and Patrick here. I think the only thing that I -- as I get into the study, the one thing I just asked you to think about a little bit, if you think about clinical trial development, what is the most challenging aspect of clinical development, which is incredibly difficult? And I will argue it's heterogeneity. So if you want to run a perfect experiment, you look to identify a group of patients who look exactly the same, so that your drug intervention is the only variable. I have a bunch of patients that are all the same. One gets the drug and one doesn't, and so at the end of the day, I can be very confident that if I see a difference, it's probably due to the drug. So why do Phase II studies tend to have better results in Phase III studies? Because in Phase II, we can be really good at identifying that population, and then we go to our big Phase IIIs and suddenly have many more sites and it becomes much more challenging to try to enroll that population that got me my Phase II result. So then you go to a rare disease. And what's the challenge in a rare disease? It is overwhelmingly heterogeneity. Because by definition, it's rare. You don't have the luxury of saying, "I want a bunch of people who are 5 feet 5 and blue eyes and whatever, right? I mean you have to take whoever you can find. Why do we run trials where we enroll patients from the age of 4 to 65? Because we need the numbers. And the idea that a 4-year-old is going to respond the same as a 65-year-old is 0. But somehow, we need to interpret that data because that's what you're forced to do in a rare disease is to bring in all of these things. So you're going to see some data sets here in the DAYBREAK world, which are extremely small. And the journey that we're on and that Dorit and Patrick are going to help explain a bit how we're going to be thinking about this is how to understand these small data sets and begin to sort some of these variables, a lot of which are in the realm of the genetics, which is one gene doesn't the same as the next gene kind of thing. And so we'll walk you through that. But I think that's the headline here for the Phase II study, I think, really exciting from our standpoint in terms of potential here, but complex and complex for extremely understandable reason. So with that, I will introduce Dorit.

Good morning, everybody. It's a pleasure to be here today to present the top line Stage 1 BMI data from the DAYBREAK Study. Well, because I don't know if you've seen this slide yet today. I'm not going to belabor it too much. What you're seeing here is the integration of the hunger signals from the agouti-related peptide neurons, and the satiety signals from the POMC neurons, which interfaced the melanocortin-4 receptor neuron to control caloric intake, energy output and generally help with weight maintenance in adults or appropriate weight gain in children. You've already heard earlier about how this process can go [ awry ] and individuals with variants that either reduces satiety signal or increase the hunger signal, you can get this bounce to [ off-kilter ] as well. So you can see increased hunger hyperphagia, reduction in energy expenditure and early onset weight gain. You're already well aware of our work in individuals with biallelic mutations in PCSK1, POMC, leptin receptor gene and the genes causing Bardet-Biedl syndrome. And David has already mentioned Phase III EMANATE study, looking at the effects of setmelanotide in individuals with heterozygous mutations and the leptin receptor PCSK1 and POMC as well as individuals with variants in SRC1 and SH2B1. I'm not going to tell you anymore about that, more to come in the future. So moving on to the DAYBREAK study, how do we select these genes? So we use a validated ClinGen framework, which integrated a number of points that you see listed on the slide here, looking to select a group of genes, which were in the melanocortin-4 receptor pathway, which were linked with obesity and which we thought had a stronger, very strong probability of responding to setmelanotide. And they're going to see a bit today about whether or not we did a good job in selecting those deals. This is the cohort of 31 genes, which were initially selected for inclusion in the DAYBREAK study. Now as is common in Phase II studies, we ended up closing a few cohorts early, due to either lack of interesting signal or difficulty with recruitment. So in the end, we included 24 genes in the final study cohort and the ones who are craft are the ones that we closed early. On this slide, you see the design of the DAYBREAK study. Individuals meeting the criteria for enrollment. So eligible variants in one of the genes that I showed them on the last slide, the proper age range and having obesity were then enrolled in the study. And the open-label stage 1, where everybody got setmelanotide for 16 weeks, including 2 weeks of a dose ramp up. Those who completed Stage 1 were then analyzed to see if they meet the primary endpoint of weight loss. And those who had the method prespecified endpoint for weight loss, were then randomized into Stage 2 of treatment with setmelanotide versus placebo because this is a randomized, double-blind, placebo-controlled portion of the study. That is still ongoing. More to come on that in a few months. Today, I'm going to present the Stage 1 data, looking at our primary endpoint, which is what proportion of patients by gene cohort achieved a reduction in BMI of at least 5% from baseline. On this slide, you see the demographics of our study participants. There are 164 participants in our full analysis set, and as you can see, we had 109 adults, 55 children. And these participants were by design quite obese. So average BMI of 48.5 and the adult participants ranging from 40 to up to 74, and for the children, the average BMI-Z score was 2.6. And as David already mentioned earlier, normal BMI-Z score for children is between minus 2 and plus 2 standard deviations around the mean for age 10 [ sets ]. So you can see here our disposition slide. So as I mentioned, 164 participants enrolled in the study and received at least one dose of study drug. Of these, 52 participants discontinued prior to the end of Stage 1. 100 participants fully completed Stage 1 and an additional 12 discontinued, but had their end-of-study visit within a prespecified 2 weeks of the end of Stage 1. So were included in the week 16 completers analysis. Of those 100 patients who completed Stage 1 fully, 49 patients met the endpoint for a weight loss for inclusion into Stage 2 and then were randomized. We don't have time today for me to review the results of 24 gene cohorts. So we picked 6 of these, which had some interesting results to review. And what you can see in this slide is the proportion of patients with these various variants in either of these genes or gene families who responded to setmelanotide, ranging from 25% in individuals with 1 variant, 56% in individuals with PHIP variants. This box and whisker plot is a little complex. But what it's meant to show is the variability of the response along with the average response. So the average reduction in BMI in each of these genes are in cohorts, which was around 5% ranging from [ 4% to 6.5% ] reduction from baseline. So just ARNT on the y axis [ 17% ] BMI change in baseline, 0 being the baseline. And then you've got a red line at the minus 5%. So a 5% reduction in BMI because, again, that was our primary endpoint. That said, as David mentioned earlier, there is a lot of heterogeneity here. Individuals do not necessarily have the same variants. And any given gene, there are multiple different variants, and Patrick will get into that more a little bit later, so I'm not going to steal his thunder. But because of that, it's actually really important to look at individual level data, because that tells a very interesting story. So for the next few slides, I'm going to break down each of these different genes or gene families and show you the results of the level of individuals on [indiscernible] plots. As you can see here, -- it's a similar orientation to what you saw before. On the Y axis, you see percent BMI change from baseline, with 0 being where they had started out. And each of these bars represents an individual. This is the, again, the red line at minus 5, because that's a 5% reduction in BMI from baseline, the primary endpoint for the DAYBREAK study. So for individuals with the SIM1 gene, you can see that 5 out of the 20 individuals who entered the study and the 16 individuals who completed Stage 1, met the primary endpoint for BMI reduction, with quite a bit of variability, right? So one individual actually gained weight, and a few individuals lost a substantial amount of weight. And there's some reason about to discuss that some more. Again, I'm going to let Patrick talk about the variants. Individuals with variants in MAGEL2 gene. And here, we had 10 patient starts, 7 patients complete. And you can see 3 patients met the primary endpoint of BMI reduction. TBX3, small cohort, an interesting signal. We had 5 entered the study, 3 completed Stage 1, of those 2, responded setmelanotide. The next couple of slides are a group of gene families as opposed to individual genes. They have homologous functions. So we looked at them together. You can see here on the bottom right of a lot of our population for [indiscernible]. So this is the [ lexon ] A group. And what you can see here is, again, substantial variability in the response. So 12 out of the 40 you've started. So [indiscernible] respond to setmelanotide, and then a few more almost there, not quite. But what you might notice is that the Y-axis here looks a little bit different, because we had one person lose 23.6% of BMI from reduction in baseline. So again, quite the individual level variable. This is the [indiscernible] [ 4 ] cohort again at the legend over here. And this cohort showed a more consistent response, I would say, albeit with, again, ongoing variability, but a high proportion of doses and especially those who completed Stage 1 responded to setmelanotide. I'm so sorry, can you not hear me in the back? I apologize. I apologize for that. I'll try to speak to the mic going forward. And finally, we move to the PHIP gene, which -- this was the gene which people showed the most consistent response to setmelanotide. 9 out of the 16 patients who entered the study and almost 70% of those who completed the study responded to setmelanotide. And that does make sense thinking about the biology. So PHIP influences a transcription of the POMC gene and variance in PHIP associated with obesity have reduction in transcription of POMC to reduce production of MSH, so it makes sense that setmelanotide would treat this pretty effectively. That's all I really have to say on the clinical results of the BMI loss, and I will now turn it over to Patrick to discuss the genetics behind the DAYBREAK. Thank you very much.

Great. Thank you so much, Dorit for your introduction, nicely summarizing the results of the Phase I trial, the Stage 1 of the trial. So as Dorit mentioned, there were 6 interesting signals from 6 genes. I don't necessarily have the time to go through all 6 today in depth. So what I'm going to present here is a secondary analysis, looking at some of the variants in 3 of the genes as an example. So we're going to look at -- I mean, you're familiar with this figure, but I'm going to look at TBX3 which is on the POMC side. It's actually a gene that's required for the differentiation of the POMC neurons. We'll also look at postsynaptic SIM1 and the MC4R neurons, again required for the differentiation of those genes. And then we'll look at one of the SEMA family gene SEMA3G which actually directs the projections, neuro projections from POMC to the MC4R. So it's an intermediary gene. So just to lay the sort of the groundwork for variants. We're talking about rare variants here, but collectively, rare variants are actually quite common. And you really get a view for that when you start to look at the hundreds of thousands of genomes and exome sequences and databases like the gnomAD. So for example, SEMA3G, that gene has 1,200 rare missenses reported in gnomAD. So that basically accounts for 50% of all of the coding basis, have a mutation in at least one individual. And clearly, not all of those are disease associated. So to help clinical labs really interpret these, the American College of Medical Genetics and Genomics, ACMG, developed an evidence framework to apply to rare variants. And that will lead to a categorization of the variants in 5 different categories. So they correspond to here on the right-hand side of this bell curve, to pathogenic variants. Those have a 99% probability that they're truly cause of all the disease. One step down from that are your likely pathogenics, those variants correspond to a 90% probability that they're causal of the disease. And mirrored on the left-hand side of the curve, you have benigns and likely benigns where we have, again, importantly, very good information that these variants are not cause of the disease. Now in between those 2, there's a very large fraction of variants where we simply don't have any evidence either way to classify them as benign or as pathogenic. And collectively, those are called variants of uncertain significance. Now what we do know from past studies is that looking at VUS variants, 20% of those are likely to be reclassified up towards pathogenic, and 80% of those are likely to be reclassified down towards benign. Now in terms of the trial, variants were included if they were VUS or above. So we're including a number of variants that we know are likely to be benign. But given the number of the VUS's and the fact that 20% of those are likely to be pathogenic, we had to include them in the trial. Okay. So a number of retrospective studies have now been carried out, and the largest of which was just recently reported at ASHG by [indiscernible], they're looking at 1.8 million variants now. So these are 1.8 million VUS variants, and they're seeing -- looking at the trajectory of how they've been reclassified. And again, a number of studies have been reported. But the important point is that they're all coalescing around that 80-20 split. So it's becoming fairly well established. And the sorts of data sources that they're using to reclassify those variants -- so it's a mixed bag. Some of it is new tools like prediction algorithms, supplies AI. There's a couple of newer AI tools that have just been released like AlphaMissense and primary AI 3D from aluminum. So this is just going to accelerate going forward. There's classical genetics approaches like testing family members. But by far and large, the most -- the largest fraction of data sources is new data. So looking at things like allele frequencies and databases like the gnomAD and functional data, whether they're in vitro assays, whether they're multiplex or not. And just a point on functional assays. The first 3 categories that I listed, they are largely passive to a company like Rhythm, as community generates data. But for functional data, that's an area where we can be proactive or we can generate data internally on our genes of interest. And the sorts of assays that I'm talking about here, they are in vitro assays, where you take a gene construct, you introduce a mutation, and you transfect those into cells and then carry out some sort of an assay comparing wild type to the [indiscernible] specific mutation carriers. So we're not looking really necessarily at animal models and in vivo systems here. But they're very useful for the classification of variants. So as an example, we did a comprehensive look at PCSK1, POMC and LEPR and published a paper on all missense variants in those 3 genes at the start of the year. And since then, our -- one of our partner labs -- so our clinical testing lab, PreventionGenetics has been able to reclassify 90 VUS variants in those 3 genes using our data. Okay. So let's get into one of our first examples. This is the SEMA3G. So this happened that since trial enrollment until data readout, 5 individuals with 4 unique variants were reclassified by PG from their starting classification as either a VUS or likely pathogenic, to likely benign. And 4 -- and these account for 4 of the 6 nonresponders. So the responders are in the top portion of the table with the response is actually in the third column, the black line delineates the 2, put arrows for the reclassified variants. And you can see that 4 of the 6 nonresponders that were actually shown to have likely benign variants. So overall, if you look at the starting ACMG classifications, your response rate is 57%. When you look at it using the reclassified VUS, when you look at the response rate, looking the reclassified variants, so we removed the likely benign variants, you increased the response rate to 78% with 7 of 9 responders. So our second example is SIM1. So this is one step back from ACMG classification. This is an example where Rhythm and there's a couple of other published studies have generated some in vitro data looking at SIM1 variants. SIM1 itself is a transcription factor. And so the in vitro assay, essentially, is assaying its ability to induce expression -- gene expression. So the in vitro assay, essentially you co-transfect SIM1 construct, be it wild-type or with specific mutations, with ARNT and HRE Luciferase into cell lines. You wait a couple of days. So the wild type SIM1 is able to initiate the luciferase, which releases light. So that gives us a baseline for the wild type. And then we can repeat that experiment with different mutations and see the level of light that's produced by the different mutants, and that gives us a gauge of how they're affecting the protein function. So at the time of the experiment that was carried out in-house, Rhythm had identified 213 different SIM1 missenses through its different sequencing programs. And the way this slide is laid out, there's a schematic of the gene in the center of the slide. Then each of the dots is one of the missenses. The missenses are arranged on the X-axis by position, and on the Y-axis by their percent activity compared to wild type. So all of the missenses that are plotted above the gene. Those all showed -- they retained over 70% activity. And so their class is wild type. They had no effect essentially on the protein. And the ones that are plotted below the gene figure, those all show the reduction in activity and were classed as either moderate or complete loss of function. So when we look at our completer analysis, and again, here I've included the percent BMI change from baseline in column 2 and then the results of the functional assays are included in the final 2 columns. So the second to last column shows any results from published studies and the final column is the result of the Rhythm assay. And where we had results for both, they were concordant in 100% of cases. So highlighted in the dark blue at the top of the table are the responders. And for those, you can see that we had 4 out of 5 variants assayed and 100% of those showed loss of function. And then for the nonresponders in the light blue, we had 9 of 11 variants assayed, and 56% of those showed wild-type activity. So we wouldn't expect us to have a deficit. So in a secondary analysis, if we exclude those wild-type variants on the SIM1 response rate, it increases from 31% to 45%. I also want to highlight one other observation here. So 2 of the 4 loss of function variants in the nonresponder group were actually the same missense, the 707 histidine. And in fact, we have 3 carriers of 707 histidine in this data set. One was a really good responder, one with moderate response and one with no response at all. And actually, we can explain this pattern in the very first paper that was reported by the [ Faruqi ] group. They actually called out this variants and showed that although it was moderately damaging, it is actually -- it expressed -- is variably penetrated. So it doesn't express in all no carriers. Our third example is TBX3. So here, we're one step behind again. So this is another of the -- this gene is also a transcription factor. But in this case, we don't have functional data. But what we do know is that the structure of the gene is highly informative. So missenses that have been reported, they all localized pretty much to the T-box domain. That's a very highly conserved region of the gene that's involved in the DNA binding. And if we look at our responders, both of those, and I've highlighted them on the slide by the red arrows, both of them, they localize inside of the T-box, inside of this domain. So we have one that's basically in the middle of the domain and one at the very first residue, and we would expect these to have a much more significant impact on the gene function than the 3 other missenses in the trial that were all outside of the T-box. Okay. So to sum up, if we -- in the secondary analysis, if we just take the ACMG reclassifications into account, we have a big impact on the SEMA3 family. So for the family of genes overall, that's SEMA3A through the G., the response rate increases by 11%, from 61% to 72%. As I presented earlier, if we look at SEMA3G alone, that gene had an increase of 20%. And then if we add in the functional data from the other 2 genes, that increases our response rate for the trial overall by 5%, up to 48.5%. So many of these genes, although -- many of these genes don't have good prevalence estimates in the literature. So we provided some here based off of our URO program. So these are projections from the URO program sequencing data. And just to note that although the PHIP and TBX3 are relatively modest numbers, these both have syndromic presentations, so they should be easier to identify these patients similarly to the BBS population. And so to sum up, even though we don't have huge numbers here, we're looking at small numbers. We're seeing a very clear correlation between the function of variants and their response rate. And so as we deepen our understanding of our candidate genes, we would hope to be better identifying our responders or responder population. So thank you for that.

Thanks, Patrick. So now we'll move on to our next-generation program.

Good morning, everyone. I have a great pleasure today to introduce a new selective MC4 agonist, next generation of setmelanotide RM-718. This molecule was built here in Rhythm, and it's designed to be more MC4 specific, with high potency. At the same time, we designed to eliminate activity towards MC1 receptor, and therefore, possibility to laminate hyperpigmentation effect seen with setmelanotide in patients. And also, we designed it to be patient-friendly as a weekly formulation for patients. All this extends the patent protection for around 10 years when we compare to setmelanotide up to 2041. It is important to say that 718 was built for fixed from the library of compounds, which were made out of the chemical space of setmelanotide. And same as setmelanotide, 718 is cyclic. Amino acid peptide but it's shorter for one amino acid. Setmelanotide is 8 [ octamer ] 8-amino acid peptide. As I said, it's designed to be very MC4 specific, that it's also MC1 sparing. And for patients, we give them as a once-weekly injection, which is sustained release formulation. Today, I don't have time to tell you all this preclinical development, which led us to hopefully Phase I study in the next year, early next year. But I thought I will show you some of the important studies, which are showing selectivity specificity and safety of 718. Initially, we tested the efficacy of 718 in the animal model where obesity would be induced in the diet. These are the [ rat BOE ] models. And we designed a final study of T groups, where the same dose of setmelanotide daily formulation was compared to the 718 daily formulation. The dose was 0.5 mg per kg. And as a vehicle control, we had a group of animals, which were all used in the study. As you can see clearly on the graph on the left-hand side, the body weight in the treated animals was reduced significantly from the vehicle control, and the maximum reduction was seen pretty much at the end of the 2-week study, and it was around 8% and 9% in Set group and 718 group, respectively. I want to point out that the reduction in body weight from control was seen pretty much from initiation of a therapy from day 2 of the study. On your -- on the right graph shown is a cumulative food intake in these animals. And you can see in both treatment groups in both Set and 718. The cumulative accumulation of food is lower versus placebo, around 20%. And again, this effect in food reduction was seen from day 2 of the study. Furthermore, we wanted to test present weekly formulation of 718 and compare with the weekly formulation use of setmelanotide these days in the clinical trial. And for that study, we used obese Zucker rat model, which is leptin-receptor deficient. And so these animals are actually developing obesity and have prediabetic stage. And one of the very important characteristic of these animals is that they have uncontrolled food intake. So they are hyperphagic, similar to our patients. So study was designed as a 3-week parallel study of 4 arms. Each group has 8 animals, and we compare the same doses of setmelanotide again and 718. The dose was 5 mg per kg, 2 placebo arm, which was our control group. We also, in this study, introduced 718 group, which was dosed with 10 mg per kg. So the higher dose. We wanted to see some dose effect in the study. And again, if you look at the left graph, body weight reduction was significant from placebo. It reached maximum at 3 weeks of treatment and was very similar between Set and 718 group, with around 13% and 14%, while in the group of animals dosed with the high dose of 718, we see some trend increase in body weight reduction around 16%. One thing I want to point here is if you look at the right graph on the right-hand side, the body weight gain was significantly reduced in those animals, while placebo group was gaining around 70 grams during 3-week period. Overall in all treatment arms, we see reduction in body weight between 20% and 30%. And you can see that this reduction was the highest within the first week and then animals maintained the weight. And that's why we see this very flat body weight change from placebo on the right-hand side graph. In the study, we also measured the concentration of 718 in both plasma and cerebrospinal fluid. And you see that based on the dose, we see the increase in concentration in both plasma and CSF, which was also reflected in body weight reduction, which was 30% in 5 mg per kg dose and 16% in 10 mg per dose. As I said to you, this animal have uncontrolled food intake, and they eat usually 35 -- around 35 gram per day as shown by placebo with a wide graph. And what is important in this study is that not only the food reduction was significantly reduced, but it was reduced to the levels in normal healthy animals. So I'm trying to address this that hyperphagia was reduced to the extent that animals were eating a healthy amount of food per day, which is very important. And accordingly, the water intake was normalized. We also look at the composition, fat composition in this animal, body fat composition was significantly reduced as well as insulin resistance. But one of very important studies, which was done very early on in the 718 development was to address cardiovascular safety. We know that one of the main features and why setmelanotide is successful as MC4 agonist is that it has also cardiovascular safety, which is very important characteristic. Previously developed compound all had some negative effect, especially to blood pressure and heart rate. So we did a study in monkeys, nonhuman primates, which is a species use to actually test MC4 agonist and be able to see if any negative cardiovascular events will happen. And I know graphs, and it's a busy slide. But if you look only at the graphs on the now upper right-hand side, you can see results with the observation with 718. In this study, where animals were infused for 3 days with the dose up to 5 milligram -- 1 and 5 milligrams during this 3-day period, we don't see in the actually 718 treated animals, any changes in systolic or diastolic blood pressure when compared to reference treatment animals, which were dosed with saline. So you should look at the purple triangle versus green or red line. This is opposite to Lilly compound, which was used in this clinical trial -- in this trial as a positive control. And you can see in both systolic and the diastolic graphs on the left-hand side, change from reference control, which is again shown by purple bar. Animals dosed with 1 mg per kg dose show increase in systolic, in diastolic blood pressure shown by those red lines. So for those who are interesting to see more about the detailed data, which changes the Lilly compound is shown on the table below in the right-hand corner. One thing I want to point here that animals dosed with 718, got the dose of 5 mg, the high dose was 5 mg per kg, around 5x higher than the dose of a Lilly compound. And you can see that the concentration was around 1,600 nanograms per ml, very high concentration comparing to 300-nanogram per ml, which was the concentration seen after 72 hours in animals treated with Lilly compound. So to confirm cardiovascular safety with the present formulation, we recently finished the study using 718 weekly formulation, with the doses up to 30 mg per kg. And again, we confirm this cardiovascular safety, which gives us a very nice safety margin of 30x from the planned dose in the Phase I clinical trial. And this brings me to our next step. So pretty much, we were able in the last year to generate very nice safety and efficacy package, which opened the path to do the clinical trial in next year, early in 2024. The study is designed as a 3-part Phase I study to evaluate safety, tolerability and PK of weekly formulation 718. Part A is a single dose-ascending study, where dose is between 30 to 50 mg will be tested in patients. These are the doses per day -- per week, sorry, and safety follow-up will be 10 to 14 days. After the interim analysis, patients, healthy obese patient will be enrolled in the MAD part of the study, which is multiple doses standing study between 3 to 40 milligrams, with safety follow-up, up to 28 days. And finally, a Part C study will be MAD type of study in patients in hypothalamic obesity, which is kind of signal-seeking study where doses between 10 and 40 milligram will be tested up to -- and safety follow-up will be 28 days. Study is designed to have open-label extension later on. So far, I demonstrated that 718 had similar or improved safety, tolerability and potential efficacy comparing to setmelanotide. In dose vials here, you can see that it shows and appears as a liquid light yellow solution, easy to be injected in patients. I told you that pretty much 718 is designed to be more selective MC4 agonist. In vivo safety result support no off-target cardiovascular effect, which is very important. And we also demonstrated in the toxicology study in 28-day toxicology studies, that we don't see any systemic toxicity, which is also important. No hyperpigmentation was observed in vivo and in vivo results in animal models are suggesting potential efficacy for body weight reduction, food reduction and especially hyperphagia reduction, which is one of the problem in our patients. And all together opens a path for treatment in hypothalamic obesity patient. Thank you.

Thanks, Danica. So last section here, the pediatric results. So genetic diseases by definition, the person at birth as with most genetic diseases, if you could intervene earlier, that would make sense, i.e. potentially at birth and avoid a lot of the subsequent comorbidities. Challenging because, again, without good strong newborn screening, that tends not to happen, it's very difficult to get on that newborn screening list and a long set of criteria. So these patients, as you've heard, in all of the realms we work in, they are on this diagnostic journey. Honestly, if you will, I'm trying to get a diagnosis. But a number of them do get diagnosed early. And they get diagnosed early because it's so clear that something is wrong, presenting with this uncontrolled desire to eat and being overweight for age. And I think one of the questions that came up about the adults and the [indiscernible] thinking, the advantage of pediatrics is that the pediatrician is taught, focused on where they are relative to their growth chart, where as an adult, we're all sort of grouped in this world of you're just overweighed and again, diet and exercise. So -- but we don't get the same scrutiny we do as a child where people were much more concerned about if you move off of that growth chart. So where we are, I'll show you a little bit of our testing samples in terms of the frequency of a positive result in patients at a very young age, and we are moving forward. We filed our regulatory submission type 2 variation has been submitted to the EMA, sorry, and we'll be filing a U.S. FDA submission in first half '24. So with regard to the testing results, so here's POMC, leptin receptor results. Here's the Bardet-Biedl results. And this is by age. So between the ages of 0 and 2, let's just focus on the PPL line here first, about a 1% hit rate as compared to 0.05% to 0.1% as we go through the other ages. And the same is for BBS where we have a 1.65% for biallelic BBS positivity here as compared to about a 0.5% to 0.8% response in the other age groups. And the reason for that is we have many fewer samples, some submitted at this age group, again, because parents, physicians don't often recognize and I was thinking about it. But if they do, the history is much more reliable. And so the presentation that would drive somebody to doing genetic testing here significantly increases the probability that you're going to have a positive result for genetic -- these 2 genetic tests, but this observation extends across all of the genes that we're testing here. So it's just a much more reliable history, leading to a higher rate. So for the trial, we had a small trial, 12 patients enrolled, demographics are here. There were 7 in the POMC leptin receptor deficiency, group 5 in the BBS group. The -- again, the striking thing -- these are BMIs, right? So BMI, not great in children to fully assess, but already a BMI of 34 in these children ages 2 to 6, mean age, it's mean age up there. No, it's mean age was around 3. And for BBS, not as severe as this group, but severe with 23 and the better metric of that severity is for these POMC leptin-receptor patients, their standard deviation -- deviation score BMI-Z score was 10.7. And for BBS, which looks modest compared to this, but it was 4.2, which is, again, severe. So strikingly compromised already at a young age. And then here are the results. So as you probably saw in the press release, the primary endpoint was this 0.2% -- or sorry, 0.2 change in BMI-Z clinically significant, right? That's not going to make a big dent in a child who's BMI-Z score is 10 at baseline. So as you can see, over time, the BMI-Z scores trended down and the change in BMI here, the mean percent change from baseline, despite the fact that these kids are growing was minus 18%. So again, quite strong. But as always, waterfall plots, individual patient stories, I think, are where you really begin to understand the data. And so if you look at the POMC group here, which are these 3 patients were POMC biallelic patients. This is the decrease in their BMI-Z scores, Remember, they had an average of around 10. So a minus 7, a minus 5.5, a minus 4 plus and a minus -- sorry, that's the left up the patient there. So again, really striking reductions from very, very severe baselines over the course of a 1-year period. In the leptin receptor, we had this one patient who was again extremely severely affected. I'm forgetting exactly apologies what his baseline BMI-Z score but he was one of these in the 10 range. I think, frankly, what happened was he dropped out the trial at 7 weeks. You had to start the trial at a dose of 0.05. And given his weight, and I just don't think -- and you have to titrate up. I don't think we got to a high enough weight for them to be able to appreciate a difference and got discouraged and left the trial, was lost to follow up. The other patients, again, for the leptin receptor, which sometimes, I think, may be more challenging than POMC, but as you can see, these 2 patients, very, very strong results, very similar to what we saw here. This patient -- yes, sorry, that's the 4 patients, this patient more modest with minus 2. But still, 0.2 was our goal, minus 2 was the result of that patient. And then the BBS group here, ranging from in the minus 1 range up to a minus 3 range. And this one patient, which I'm going to show you a little more detail is the only -- these were the 2 nonresponders. So this patient was lost follow-up at 7 weeks. And then this patient who initially had a response would seem to be on a good trajectory and then lost it and I'll take you through what happened there, and you can see the mean results here and the difference for the 2 different cohorts. So this is the patient who did have a good response. So it started at a dose of 0.5, with a decrease of their BMI -- sorry, BMIs in red and BMI-Z score so the blue. Had a side effect, which is unrelated to the drug. Nevertheless, the dose was reduced to 0.25. I think the parents were anxious and the patient began to regain weight over the course of the balance of the trial, even though when they were seen for the follow-up and recognize that they had lost their trajectory and we're now regaining. They were dose increased to 0.5. But we had their PK data. And as you can see early on, I think they were taking the drug and we had measurable levels. And then we had this period. These are post-dose administration laid in the trial, but I think we had this long period of time where they just weren't getting drug. So again, there's a consistency to the results here, which has been pretty much true, certainly very true for HO, but obviously, like anything, if you don't take the drug, it doesn't work. But as a rule, if you are taking the drug, you should see some effect assuming, and I think this is a question we still know as we get in these different populations, understanding dosing and the right dose. So this was our standard dosing for our approved label with patients 6 and above is we started 1 basically and dose escalate to 3. In this world, because of the younger kids, we did start at 0.5 and dose escalated to 2. Now we'll be seeking a label that's on the next sorry, I may just finish on the hyperpigmentation -- I'm sorry, side effects, which had hyperpigmentation, which is a universal effect. It's 100% of the patients will have some darkening. For some, they find it bothersome or the physician scores it. So that's why you don't get 100% scoring on hyperpigmentation, but it's 100% of the patients. And then the others are the injection site and the nausea vomiting. So nausea, it's hard to measure in these kids, but for sure, they had nausea. The vomiting, again, was -- there was a couple of events that were a little later in the trial related to viral issues and the like, a little more complicated population to evaluate some of this stuff in. But no -- very well tolerated overall and very similar to what we had seen in the others. So our conclusions here were a very clinically meaningful reductions, as I've highlighted, similar safety profile. And what I was starting to say was that we'll be looking for a label of 0.5 to 2.5 for this group between the ages of 2 and 6. And then once they get to 6, of course, they can go after 3 as needed. There's -- of the 11 patients who are on therapy in the bridging program, 3 of them have passed a 6-year old, so they're now on commercial therapy. I think that is my last slide. So we'll now open up for a few minutes for Q&A.

So the first question came in online from Jeff Hung, analyst at Morgan Stanley. Just a quick question on the DAYBREAK trial. What were the main reasons for the discontinuations during the Stage 1 of the DAYBREAK trial?

Here we go. There are a variety of different reasons. The majority are what you would expect, nausea, vomiting, site injection issues, didn't want to take daily injections anymore. And there are a few who discontinued due to lack of perceived effect as well.

This was all comer trials. So back to the all-comers meaning you had out of the gene, but back to Patrick's explanation, there for sure are a significant number of patients that had variants that were probably wild-type or benign in that sense and so not benefiting. And what we've seen across with most therapies, right? If you are not seeing the benefit and certainly, if you're not seeing benefit and you have some early side effects, you're likely to move on. So I think I'm not surprised at the number of "discontinuations" we saw in this group, back to my heterogeneous comment, it's just a very mixed group and... Yes. Yes, Derek.

Derek from Wells. Just 2 quick questions. So first off, just a follow-up on the discontinuations. I mean do you think -- was that expected to see that rate of discontinuations from the trial? And then in terms of the weekly 718, obviously looking very good preclinically. I mean, is there still a decision to be made regarding weekly IMCIVREE versus 718, or have you kind of already decided?

Yes. So I'll take this -- were we surprised in the discontinuations? No, I didn't. The DAYBREAK study was a massive undertaking for a small company, but being a rare disease, we had this 30 genes back to just -- we didn't know. I think what we are really pleased about with DAYBREAK is the goal was to begin to sort that list of genes. And it really did a pretty good job. I mean if we got down to -- we'll see where we end up, these are preliminary, right? I'll highlight that again. But if we got down to 6 or so genes where we felt there's some interest and the work that Patrick and Dorit are doing to drill down into those 6, right? I mean next round, we would run it differently. Hopefully, we'd be able to enroll patients that take us to that higher response rate, in other words, by doing a better job on sorting the variants, and that already could make a big difference. So if we can do that, then I think these become quite interesting. So no, I wasn't surprised on that. And then the issue on what to do -- what is going to happen with the weekly. What we've said and that absolutely hasn't changed, which is our original setmelanotide weekly formulation is on pause. It will be a backup program. As long as this program looks good, it's clearly a better drug. It has other advantages, as you know. So yes, we're going to push ahead. And hopefully, what you took away from Danica's presentation is there's limitations to what you can learn in the preclinical space, but these are pretty robust. And so -- and because we're following the path of setmelanotide, I think we can read through to a certain extent that if it looks good year, then hopefully, they look good there.

Thank you. So I guess a quick follow-up on the variant discussion. So it sounds like if you were to move forward with any of those, you would look to further narrow the entry criteria based on the variants. Is that kind of how you're thinking there? And then second question is...

Yes, the answer to that was yes.

Okay. I'll ask one at a time.

Dorit perhaps is nodding.

And the second question is would -- as you think about setmelanotide versus 718, if you were to move forward there, would you still be thinking about setmelanotide? Or is there an option to just going to move over to 718 as you think about the next mutations?

Yes. No, the setmelanotide, because it's setmelanotide. I mean we know it works well. We also know it's not MC1 sparing. It has hyperpigmentation. So there's the patent half-life, which is more attractive here. I mean, so there's a number of issues where, again, as long as 718 moves forward, and we'll learn -- I think that question will be answered firmly in 2024 as we do this Phase I study. If it doesn't work, we'll pull setmelanotide off the shelf, and we'll work about.

This is Corinne Jenkins with Goldman Sachs. Maybe a couple. One of the things you highlighted there in the pediatric study was the evidence that's really accumulated that you have to stay on drug to continue getting benefit. I guess maybe looking at other hormone replacement therapies broadly in the space, how should we think about a reasonable expectation for duration of treatment, both in these genetic obesity indications as well as HO?

Yes. We've got a lot of endocrinologists, actually Dorit, why don't you take that?

Sure. I'll take that as a pediatric endocrinologist by training. I think in terms -- are you asking about hormonal replacement and hypothalamic obesity for panhypopituitarism? That's quite long.

Is that a good way to think about direction of -- what's a reasonable expectation for duration of treatment and maybe that's a good analog?

Okay. I think I see what you're saying. It's replacing a hormone that their body is not making, either they were never able to make it appropriately due to these genetic variants or they lost the ability to some degree in the setting of the craniopharyngiomas or other pituitary hypothalamic tumors. So I think -- if you think of it as like a vitamin replacement almost, you need it and your body is not making it, that might help set the expectation that it's really expected to be a lifelong therapy.

And then is there anything else that's required? Or can you talk to us about what else is required in order to actually get label expansion down to the 2-year-old patient population from here?

So this trial was agreed upon with both EMA and FDA. We filed early in Europe because actually, the expectations there were a little lower in terms of patient number. They just wanted one patient in each of these 3 different cohorts. So we're well above that. So we have filed on that. And with the FDA, we're just finishing the trial. But no, this is -- there's nothing about this package that would, I think, create any concerns and review. So we'll see. But I would expect it to be a straightforward label expansion.

Michael Higgins, Ladenburg Thalmann. I just want to follow up on DAYBREAK. We've been talking in the last several months about potential market size. What can you share on your work so far? Are there patient support organizations out there like you had such a home run there with BBS and [indiscernible]. Do you have anything like that here?

I mean I'll let Patrick comment a little bit on the numbers, and I can answer qualitatively.

Yes. So in terms of the patient organizations for a couple of the genes like PHIP, there are. It's a syndromic -- it's associated with a syndromic presentation, Chung-Jansen Syndrome. So MAGEL2 is associated with [indiscernible]. There's a patient organization around that. PHIP is associated with Chung-Jansen Syndrome. There's a patient sort of advocacy group around that. So for a few of them, there certainly are. And then there's a number of genes like the plexins and the semas were more similar to the monogenic presentations, but more similar to the PPLs that would rely on genetic testing to identify those.

I mean, with that characteristic -- I mean the lowest number just to finish, so 4,000 was on the PHIP. And these are, again, with every rare disease calculation, huge caveats as we know, and those numbers move all over the place as a rule. I think our URO testing gives us some pretty good insight into what the frequency of this gene is and the size of that population. But at 4,000 in syndromic, that's BBS. So is that interesting to us? Absolutely. If the effect is significant, you can do that. The others, there were a couple of others there in the sema world that are more like some of the EMANATE genes where you get up in the tens of thousands.

Phil Nadeau from Cowen. Just a couple of follow-up questions. First, on DAYBREAK, David, could you go into your thinking of how you're going to evaluate the Part 2 data to decide which gene types to take forward in a bit more detail? So it sounds like, piecing together your comments, patient population, response rate and depth of response are 3 key variables, how do you fit those together as you evaluate what to take forward versus what to deprioritize? And then second, on 718, you mentioned longer IP. Could you give us some sense of how long the composition of matter patent there could last?

Yes. Let me take that second one first. So the -- the composition of matter is out to 2041. So that is composition of matter. It's not the formulation. For the setmelanotide weekly formulation, that was a formulation patent -- is a formulation patent out of 2038. So the strength of the patent is obviously stronger by virtue of being a composition of matter. So how do we think about the Part 2 data? It's just -- it's more data. I mean, it's not that that's going to dramatically, I think, increase. There will be more data. So how it will be more data. So those patients that get randomized to stay on their current -- stay on setmelanotide, right? Don't get randomized placebo. We'll just have much longer data and see if they do continue to deepen, that will be a huge clue. This is only 14 weeks. So it's still a relatively short period of time and some of those patients had a dramatic response in a short period. Some are around 5, which could be still very interesting. So the deepening, in terms of those patients who stay on, but withdrawal, this -- it's going to be a little bit challenging because the numbers are so small, and we don't have enough in each cohort to have a strong placebo versus treated for that specific gene. So I think what we're going to be looking at there more is we're testing the trial design almost as much as we're testing individual genes. So we'll be able to look at patients in all of the treated versus all the placebo withdrawal and say did the trial design work? Because the FDA didn't love this trial design when we first proposed. So taking -- we're taking a second shot at it here in a sense. But that will be, I think, a really important part. And then third, which is not related to Part 2, but it's just the work that Patrick's doing and continuing. I mean, I think you saw -- I mean, you gave 3 examples. In some, it's like just how we learn more about the variant that allows to reclassify it. That TBX example he gave, which is -- that's just saying, look, this is where it's located in the gene. We know this is the important part of the gene. And suddenly, it begins to explain why you might have one or the other. The variable penetrants, right? So here, you have a gene where they were both in the responder and the nonresponder. How does that work? Maybe it's not important, but it's clearly documented that you have variable penetrants, you now have an explanation for this. So -- and then the last thing I'll say, whatever we take forward, the bar is high. I mean, we're not looking to take forward something that's just 5%. We need to have some level of conviction that for these patients, it's really moving the needle in a way that other possible therapies could for them.

Dae Gon from Stifel. Three questions. One on DAYBREAK, just following up on Phil's question, when we think about the variants that you will identify that will most likely benefit from the setmelanotide treatment, can you talk to us a little bit about your confidence level that if you were to pursue continue into Phase III and show positive benefit that it would include the entire gene rather than the label, kind of narrowing it down to here the particular, I guess, variants that are more likely to benefit versus those that are not. In terms of 718...

Let me take that question before you run your list there easier. So the label -- go back to our EMANATE trial. In our EMANATE trial, we've basically already done that. So for the POMC heterozygo group, we narrowed that group to suspected pathogenic, likely pathogenic and pathogenic. If you remember from Patrick's graph there. So we've enriched that population in theory for those patients who would be most likely to respond. The label will be exactly that. So we won't get a label that will be for all heads. Now my view is, I don't want to label for all heads. I mean that's where it becomes really challenging because you've got a drug out there where some patients responding, some aren't. The community loses confidence. They don't really know how to use it. I mean every drug, you're trying to get to that point where ideally, 100% of the patients meet the definition, you get the drug and respond. So yes, it will be the label that reflects our variant piece of it.

If I can just add to that. So in terms of diagnosis, if you think about this from the other side about how a clinical lab would diagnose with patients, they would do a base off of the pathogenicity of the variants, right? So when you think about it, we're basically including all of these patients based off of the URO data, which is a sequencing effort. But in future, lab will actually diagnose the patient with a variant, if it's VUS suspected pathogenic, pathogenic or likely pathogenic. So it will exactly match the label. So all of that information will feed into -- that's why I was talking about why it's important to actually have the information to reclassify a ACMG variants in first place, it's because that's how you're going to identify and diagnose your patients in the future and it will [indiscernible].

And then on 718, the comparison between 718 and the setmelanotide in 2 different mouse models, it seems to show the sort of, I guess, like a dip before it kind of picks back up towards the end. But you only showed one dose level for the setmelanotide. So I'm just wondering what's the maximal degree of benefit you can see with the daily setmelanotide? And -- because I guess, ultimately, you're testing, what, 10 to 40-milligram, tentatively, in the hypothalamic HO patients. So how much confidence do you guys have there? And then just to quickly tack on that. In the slide, you mentioned it's going to be an efficient development plan. Can you elaborate on that a little bit?

All good questions. Thank you. So the first study, which I show you where we compare daily set, the daily 718. It was one of those proof of the concept study, where a single dose was tested. And we pretty much show that with the same dose of 0.5 mg per kg, we see the same reduction around 9%. But what I show you subsequently, pretty much in my genetic obesity model, with the higher doses, you can see further reduction in body weight and food intake. And it's dose dependent. However, you have to remember, these are the animal models. The first animal model is pretty much model of general obesity. And usually, an MC4 agonist were the best in the obese genetic population, because we are restoring this MC4 pathway. So what was shown in the study in the Zucker rat model with a genetic model of obesity with leptin receptor deficiency, we show you with 718 that the higher dose had bigger effect in body weight reduction, and I will expect the same thing to see with setmelanotide. But again, you don't want to pretty much -- you want to give the dose which will reduce this hyperphagia, but still they need to have normal healthy food intake, very important for growing kids. That's the first question answered, I hope. And the second one, can you -- I'm not a clinician. So I think the design, which was pretty much now in plan, is to affect -- to address safety and PK and tolerability in obese healthy subject, and we are going slowly increasing the doses between 3 to 40 mgs, which give us -- and we have a nice safety margin. Remember, this is a weekly formulation, so based on these PK results from this study and changes in the body weight, hopefully in hypothalamic obesity patients would be able to then really learn what is the therapeutic dose. Maybe.

No, no, that's perfect. And I think the most efficient part of this is the hypothalamic obesity part of the model, which we didn't have for setmelanotide in the beginning. It's such a sensitive readout. The hope is that even in that small trial, Part C, we will be able to sort out the dose. I am less concerned that it won't work, and I think it will work. The question is, how quickly can we get to the dose -- that's what we're looking for. Excellent. Well, with that, we thank everybody for showing up, showing interest here and look forward to updating you further. Thanks all.